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Chemoselective Zinc/HCl Reduction of Halogenated β-Nitrostyrenes: Synthesis of Halogenated Dopamine Analogues

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A detailed account regarding the synthesis of 2-and 5-halogenated dopamine is given. The key step is a chemoselective reduction of a nitrostyrene by Zn/HCl at 0 °C. These conditions represent a simple, low-cost alternative to reduction by water-sensitive hydride donors and two-step procedures. Under these conditions, aryl fluoride, chloride, and bromide groups are stable. However, iodine undergoes significant reductive dehalogenation. An objective of our research is to explore the capacity of preexisting biosynthetic pathways to transform analogues of dopamine (1i, X 1 = H, X 2 = H), a metabolic precursor to at least 2500 benzylisoquinoline alkaloids (BIA) produced by 20% of all flowering plants, 1 into novel alka-loids. We have chosen to prepare halogenated analogues of increasing size to potentially identify sterically restrictive bottlenecks in the active sites of biosynthetic enzymes. Halogens that are accepted by multistep biosynthetic pathways are demonstrated to effectively introduce a selective unnatural functional group into a natural product for postbiosynthetic reactions such as cross-coupling
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LETTER 2891
letter
Chemoselective Zinc/HCl Reduction of Halogenated β-Nitrostyrenes: Synthe-
sis of Halogenated Dopamine Analogues
Halogenated Dopamine Analogues
Justin J. Maresh,* Arthur A. Ralko, Tom E. Speltz, James L. Burke, Casey M. Murphy, Zachary Gaskell,
JoAnn K. Girel, Erin Terranova, Conrad Richtscheidt, Mark Krzeszowiec
DePaul University, Department of Chemistry, 1110 W. Belden Ave., Chicago, IL 60618, USA
Fax +1(773)3257421; E-mail: jmaresh@depaul.edu
Received: 13.06.2014; Accepted after revision: 22.09.2014
Abstract: A detailed account regarding the synthesis of 2- and
5-halogenated dopamine is given. The key step is a chemoselective
reduction of a nitrostyrene by Zn/HCl at 0 °C. These conditions rep-
resent a simple, low-cost alternative to reduction by water-sensitive
hydride donors and two-step procedures. Under these conditions,
aryl fluoride, chloride, and bromide groups are stable. However,
iodine undergoes significant reductive dehalogenation.
Key words: reduction, nitroalkene, zinc, dopamine, dehalogena-
tion
An objective of our research is to explore the capacity of
preexisting biosynthetic pathways to transform analogues
of dopamine (1i, X1=H, X
2= H), a metabolic precursor
to at least 2500 benzylisoquinoline alkaloids (BIA) pro-
duced by 20% of all flowering plants,1 into novel alka-
loids. We have chosen to prepare halogenated analogues
of increasing size to potentially identify sterically restric-
tive bottlenecks in the active sites of biosynthetic en-
zymes. Halogens that are accepted by multistep
biosynthetic pathways are demonstrated to effectively in-
troduce a selective unnatural functional group into a natu-
ral product for postbiosynthetic reactions such as cross-
coupling.2 For example, a brominated analogue of the
BIA berberine was prepared by total synthesis, and Suzuki
coupling was used to generate a library of compounds
with greater potency against multidrug resistant bacteria
than natural berberine.3 Potentially, brominated berberine
could be prepared by biosynthesis from brominated dopa-
mine.
Here we describe an account of our efforts to develop a
general synthetic strategy for the low-cost production of
2- and 5-hal ogena ted ana logu es o f do pam ine (1ah, Table
1). A previous report has described the synthesis of 5c and
5e via halogenation, sodium borohydride reduction of the
aldehyde, substitution of the alcohol for chlorine, substi-
tution with nitrile using cyanide ion, followed by borane
reduction.4 We sought to develop a shorter, low-cost, gen-
eral synthetic approach employing fewer steps for all 2-
and 5-halogenated dopamine analogues. An account of
optimization of each step is described. Gratifyingly, no
steps in our scheme require column chromatography and
most of the products are obtained in good yields (Table 1).
Thus, dopamine analogues produced by this process are
suitable for large-scale production.
In particular, we highlight the utility of using Zn/HCl to
chemoselectively reduce the alkene and nitro groups of
halogenated nitrostyrenes to primary amines with no side
products in good yield and without the simultaneous re-
duction of aryl chloride or bromide groups.
Vanillin and isovanillin were selected as common starting
compounds due to their low cost and well-established
conditions for selective monohalogenation in good yields
(see compounds 2cf and 2h in Table 1 and the Support-
ing Information).5 m-Fluoroanisole was easily converted
into 5-fluorovanillin (2b) following a known procedure.6
However, we found that the equivalent preparation of 2-
fluoroisovanillin (2a)6 in fact yields an inseparable 1:1
mixture of regioisomers with a melting point identical to
the reported melting point of supposedly pure 2-fluoroiso-
vanillin.7 As a result, we found it more economical to pre-
pare 2-fluorodopamine (1a) via an alternative scheme.8
We initially attempted to complete the synthesis of halo-
genated dopamine analogues 1ah without protection of
the phenol functionalities. However, the high aqueous sol-
ubility of the corresponding phenolic phenethylamines af-
ter reduction (vide infra) prevented their isolation from
the reaction mixture in good yield. Thus, phenols 2ah
were protected as methyl ethers 3bh by reaction with
methyl iodide in a two-phase system of CH2Cl2 and aque-
ous hydroxide with a quaternary ammonium phase-trans-
fer catalyst (Table 1).9 To reduce the cost of this
convenient procedure, we developed a variation to recov-
er the relatively expensive phase-transfer catalyst for re-
cycling (see the Supporting Information).
All nitrostyrenes 3cf were easily prepared by nitroaldol
condensation of the aromatic aldehydes with nitrometh-
ane with ammonium acetate catalyst and acetic acid.10,11
Although we did not ultimately use the nitrostyrene prod-
ucts of phenolic aldehydes 2bh (vide supra), we wish to
note that these compounds generate significant side prod-
ucts when heated with acetic acid. Two nitroaldol reaction
conditions that minimize side-product formation with
phenols, reflux without acetic acid and sonication at room
temperature,12 yielded 30–60% conversion (as monitored
by HPLC). We eventually achieved high-yield, large-
scale conversion of phenolic aldehydes by heating at 130–
150 °C in sealed high-pressure glassware without acetic
acid (see discussion and results in Supporting Informa-
SYNLETT 2014, 25, 2891–2894
Advanced online publication: 29.10.2014
0936-5214 143 7-20 96
DOI: 10.1055/s-0034-1379481; Art ID: st-2014-s0514-l
© Georg Thieme Verlag Stuttgart · New York
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2892 J. J. Maresh et al. LETTER
Synlett 2014, 25, 2891–2894 © Georg Thieme Verlag Stuttgart · New York
tion). This procedure appears to be generally useful for re-
action of low reactivity aldehydes with sensitive phenol
moieties.
Although the alkene and nitro groups of nitrostyrenes may
be reduced in separate steps, we sought a simple, high-
yield, low-cost reaction that would selectively reduce both
groups in a single step without reducing the Csp2–halogen
bond.
Hydride donors are commonly employed to reduce nitro-
styrenes and nitroalkene groups in general. By far, the
most commonly employed reagent is LiAlH4 in dry THF
or diethyl ether.13 However, it is often observed that this
reducing agent leads to partial or complete reduction of
aryl halides.14 To avoid this side reaction, a single equiv-
alent of Lewis or Brønsted acid may be added to generate
in situ aluminum hydride (AlH3), a more electrophilic re-
ducing agent.15 This approach has been used previously in
a synthesis of 2-chlorodopamine (1c).11 Similarly, boro-
hydride reducing agents avoid dehalogenation. Borane in
dry THF has been reported to reduce nitrostyrenes with
catalytic NaBH4 or when generated in situ from NaBH4
with BF3·OEt2.16 Additionally, LiBH4–TMSCl in dry
THF has also been reported to cleanly convert nitro-
styrenes into amines. We chose to avoid hydride-donating
reagents due to the costs associated with the reagents
themselves and necessity for rigorously dry reaction con-
ditions.
Catalytic hydrogenation with either 10% palladium17 or
platinum on carbon in the presence of HCl successfully
reduced fluorinated nitrostyrene 4b, but resulted in partial
or complete dehalogenation of all other halogens (4cf,
and 4h).7 Moreover, significant poisoning of the expen-
sive metal catalysts necessitated their use in high propor-
tions and precluded catalyst recycling.
Metal reductions have also been applied to the one-step
reduction of nitrovinyl groups. Conversion in poor to
moderate yield has been reported with Fe/HCl (63
72%),18 Sn/AcOH (59–60%),19 SmI
2/H2O/i-PrNH2 (22
60%),20 and Zn/AcOH (24%).21 Recently, Zn/HCl reduc-
tion was utilized in the preparation of phenylethylamines,
but scant experimental details and no yields were provid-
ed.22 Additionally, amalgamated zinc with mercuric chlo-
ride in HCl has been reported to afford excellent yields
(85–100%).23 Based on this latter precedent, we explored
zinc reduction for this transformation of compounds 4 into
5.
Table 1 General Synthetic Scheme
Entry R1R2X1X2Yield of 3 (%)fYield of 4 (%)fConv. to 5 (%)g,h Conv. to 1 (%)g,h
12a –– FH3ai4ai5ai1a >99 (90)d
22b Me H H F 3b 97 4b 98 5b >99 (83) 1b >99 (91)d
32c HMe ClH3c 92 4c 99 5c >99 (73) 1c >99 (88.2)e
42d Me H H Cl 3d 96 4d 92 5d >99 (87) 1d >99 (98.9)e
52e HMe BrH3e 96 4e 99 5e >99 (77) 1e >99 (94.8)e
62f Me H H Br 3f 93 4f 93 5f >99 (83) 1f >99 (90.8)e
72g HMe I H3g 90 4g 5g 1g >99 (99.5)e
82h Me H H I 3h 97 4h 83 5h 0j1h >99 (98)e
92i –– HH3i 4i 98 5i >99 (85)
a Phenol protection: MeI, tetrabutylammonium hydrogensulfate, and NaOH in CH2Cl2 and H2O for 4 h at 25 °C.
b Nitroaldol condensation: MeNO2 and NH4OAc in AcOH for 4 h at 90–100 °C.
c Reduction: Zn dust, HCl in MeOH for 4–6 h at 0 °C.
d Phenol deprotection method A: reflux in 37% HBr for 1 h.
e Phenol deprotection method B: BBr3 in CH2Cl2 from 0–23 °C.
f Isolated yield.
g Estimated from relative HPLC peak area at 225 nm for the product and starting material peaks just before quench.
h Isolated yield in parentheses.
i It was more economical to prepare compound 5a by the route of Ladd and Weinstock (1981).
j Dehalogenation was complete. Isolation of product was not attempted.
O
H
OH
HO
+H3N
X2
X1
MeO OMe MeO OMe
O2N
X1X2
MeO OMe
H2N
bc
d or e
X1X2
X1X2
25a
O
H
R1O OR2
X1X2
Br-
2ai3ai4ai5ai1ai
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LETTER Halogenated Dopamine Analogues 2893
© Georg Thieme Verlag Stuttgart · New York Synlett 2014, 25, 2891– 2894
Due to the lack of prior literature precedent, it was not
clear if zinc would afford a high yield of product without
the addition of mercury or if it would be compatible with
aryl halide moieties. When zinc dust, 37% HCl, and 4i
were stirred at room temperature in methanol, we ob-
served multiple products by HPLC. Side-product forma-
tion was reduced by slow alternating addition of all three
reagents with solid zinc in excess. Side-product form ation
was effectively eliminated when the temperature was
maintained at ≤0 °C. In general, the disappearance of ni-
trostyrene was relatively rapid. The characteristic yellow
color disappeared within 30 minutes of complete reactant
addition after which one major intermediate dominated
(Supporting Information, Figure S1 illustrates this inter-
mediate in 4f reduction). Reverse-phase HPLC indicated
that the polarity of this intermediate was similar to the fi-
nal product and was likely to be the hydroxylamine. Con-
version of this intermediate into phenethylamine 5i was
the slowest step of this multistep reduction reaction, re-
quiring three to four hours.
This multistep zinc reduction is somewhat sensitive to the
concentrations of reactants and intermediates. However,
we have found that this reaction is reliable when all re-
agents are added in slow alternating portions with ade-
quate cooling. Besides controlling the reaction
temperature, slow, continuous addition of zinc dust accel-
erated the disappearance of the nitrostyrenes and lower
polarity intermediates (as monitored by HPLC) indicating
that one or more critical steps require an unoxidized zinc
surface. The reaction is also sensitive to high HCl concen-
tration. Either short bursts of rapid HCl addition or inade-
quate stirring during HCl addition often led to the
significant accumulation of an uncharacterized side prod-
uct with an HPLC retention time similar to the nitro-
styrene (see Supporting Information, Figure S2).
Additionally, we found that substitution of HCl with gla-
cial acetic acid resulted in three major and numerous mi-
nor side products, suggesting that this acid should be
avoided.
Scheme 1 illustrates the expected stoichiometry for eight-
electron Zn/HCl reduction of a nitrostyrene. Due to the
additional loss of zinc and acid as volatile hydrogen gas,
we found it necessary to at least double the equivalents of
zinc and HCl.
Zinc is well-known as a selective reagent for the reductive
dehalogenation of aryl halides in both acidic and basic
conditions at or above 20 °C.24 The relative rates for deha-
logenation by zinc are reported as I > Br > Cl. According-
ly, at 10–15 °C, we observed <5% dechlorination for 4c
and 4d, nearly 50% debromination for 4e an d 4f, and com-
plete deiodination for 4h by HPLC . Howe ver, be low 4 °C,
aryl chloride and bromide moieties were stable under our
conditions (see Supporting Information, Figure S1). We
attempted to minimize the loss of the aryl iodide moiety
by further lowering the temperature. At –10 °C, dehaloge-
nation of iodine was still rapid enough that only dehaloge-
nated species were observed by HPLC after 90 minutes
(see Supporting Information, Figure S3). Moreover, this
temperature also failed to generate phenethylamine prod-
ucts. Instead, the major species was a dehalogenated re-
duction intermediate (see Supporting Information, Figure
S3). Thus, iodinated products 5g and 5h were not conve-
niently accessible by zinc reduction and were ultimately
prepared following an alternative scheme4 (see Support-
ing Information, Methods).
Although Zn/HCl reduction cleanly generated halogenat-
ed phenethylamines, care was required for product isola-
tion without subsequent decomposition. Even after
filtration to remove solid zinc, compounds 5cf were still
prone to decomposition if the soluble zinc salts were not
completely removed. When the reaction was made basic
by slow addition of base (either saturated aqueous NaOH
or NH4OH), extracted into organic solvent (either CH2Cl2,
CHCl3, or Et2O), and the residual water removed with dry-
ing agents (MgSO4, NaSO4, or K2CO3), significant
amounts of inorganic solids were still recovered after sol-
vent evaporation. The presence of these salts led to deha-
logenation and decomposition of 5cf within hours, even
when stored at –80 °C. Moreover, elution of these organic
extracts through either Celite, silica gel, or alumina lead to
rapid decomposition of 5cf into numerous unidentified
products and should be avoided. To minimize the ex-
traction of salts, we avoided the formation of an aqueous
phase by precipitating zinc hydroxide with saturated
methanolic NaOH and washed the product amines from
the zinc hydroxide solids with CHCl3. Stable phenethyl-
amine products were recovered from this organic extract
in good yields (Table 1).
After reduction to phenethylamines, electrophilic demeth-
ylation by BBr3 in dichloromethane at room temperature
produced the target halogenated dopamine analogues as
solids in good yield (Table 1).
In summary, we have described a short route to the syn-
thesis of a variety of halogenated analogues of dopamine
with relatively low-cost reagents and high-yield steps that
do not require column chromatography. The electronic
properties of low-cost vanillin and isovanillin direct halo-
genation to the 5- and 2-positions, respectively. High-
yield methylation facilitates purification of the reduced
amines by simple extraction and avoids costly chromato-
graphic purification.
After nitroaldol condensation, fluorinated, chlorinated,
and brominated nitrostyrenes were cleanly converted into
Scheme 1
45
MeO OMe
O2N
X1X2
MeO OMe
+H3N
X1X2
4 Zn
9 HClaq
4 ZnCl2 + 2 H2O
Cl
MeOH
+
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2894 J. J. Maresh et al. LETTER
Synlett 2014, 25, 2891–2894 © Georg Thieme Verlag Stuttgart · New York
phenethylamines by Zn/HCl reduction at 0 °C without re-
duction of the aryl halide bond. The stability of aryl bro-
mide moieties via kinetic control at temperatures below
0 °C may extend to other zinc reduction reactions. Single-
step zinc reduction of nitrostyrenes has rarely been used in
the literature and with variable results. The reaction is sig-
nificantly lower cost, simpler than common alternative re-
duction procedures, and generates no side products.
Losses during isolation are the only limit on the yield. It is
our experience that this reaction is sensitive to the reaction
conditions, but we have described a reliable procedure
that should be widely applicable to related compounds.
General Procedure for Zn/HCl Reduction of Nitrostyrenes
For every 1.0 mmol of nitrostyrene, 2 mL of MeOH, 800 mg of zinc
dust (12 mmol), and 2 mL of 37% HCl (24 mmol) were used.
MeOH was vigorously stirred in an ice bath maintained <0 °C
(ice/NaCl or freezer-chilled commercial antifreeze). HCl, zinc dust,
and nitrostyrene were slowly added over the course of 30 min in al-
ternating small portions taking care that the temperature did not rise
above 0 °C. For large-scale reactions (>25 mmol), HCl was added
continuously by syringe pump. The reaction is typically complete
4–6 h after the yellow color has disappeared. The reaction may stir
for as long as 16 h in a 4 °C refrigerator without significant forma-
tion of side products. Once complete, the excess solid zinc was re-
moved by filtration. The solution was made basic by dropwise
addition of sat. NaOH in MeOH, while maintaining the temperature
below 5 °C, until the pH was greater than 11 by pH paper. Next, 10
mL of CHCl3 was added (per mmol of reactant). Solid anhydrous
MgSO4 was added to dry the organic layer. The organic extract was
decanted. The paste was extracted and decanted two more times
with CHCl3 and filtered through filter paper. Solvent was removed
by evaporation in vacuo to yield phenethylamine as an amber oil. In
cases when an oil was not obtained, the product was dissolved in
minimal CHCl3 and the remaining inorganic salts were precipitated
by addition of Et2O. An oil was obtained after filtration and evapo-
ration.
Acknowledgment
We thank the National Science Foundation CCLI A&I program
(Grant No. DUE-0310624) for support in purchasing our Bruker
Avance 300 MHz NMR spectrometer and DePaul University’s Col-
lege Sciences & Health for funding and support of this work. The
authors would also like to acknowledge the helpful assistance of
Amber Alberts, Mark D. Aparece, Emily Frank, Realino B. Gurdeal
III, and Mark Piraino for replicating the procedures described.
Supporting Information for this article is available online
at http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.
Supporting InformationSupporting Information
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Accounts and
Rapid Communications in
6<1/(77 Synthetic Organic Chemistry SUPPORTING INFORMATION
Thieme
Supporting Information
for DOI: 10.1055/s-0034-1379481
© Georg Thieme Verlag KG Stuttgart · New York 2014
1
Supporting Material
Chemoselective Zinc/HCl Reduction of Halogenated ɴ-Nitrostyrenes: Synthesis of Halogenated
Dopamine Analogs
Justin J. Maresh*, Arthur A. Ralko, Tom E. Speltz, James L. Burke, Casey M. Murphy, Zack Gaskell, JoAnn
K. Girel, Erin Terranova, Conrad Richtscheidt, Mark Krzeszowiec.
Contents
Supporting Figures ........................................................................................................................................ 4
Figure S1 .................................................................................................................................................... 4
Figure S2. ................................................................................................................................................... 5
Figure S3. ................................................................................................................................................... 6
General information ..................................................................................................................................... 7
Estimation of purity of halogenated dopamine analogs .............................................................................. 8
Synthetic Procedures .................................................................................................................................... 9
Preparation of halogenated vanillin and isovanillin ................................................................................. 9
3-Methoxy-4-hydroxy-5-fluorobenzaldehyde ...................................................................................... 9
2-Chloro-isovanillin (2-chloro-3-hydroxy-4-methoxybenzaldehyde).................................................. 10
5-Chloro-vanillin (3-chloro-4-hydroxy-5-methoxybenzaldehyde) ...................................................... 10
2-Bromo-isovanillin (2-bromo-3-hydroxy-4-methoxybenzaldehyde) ................................................. 11
5-Bromo-vanillin (3-bromo-4-hydroxy-5-methoxybenzaldehyde) ..................................................... 11
5-Iodo-vanillin (3-Iodo-4-hydroxy-5-methoxybenzaldehyde) ............................................................ 12
General methylation procedure ............................................................................................................. 13
3-fluoro-4,5-dimethoxybenzaldehyde (3b) ......................................................................................... 13
2-Chloro-3,4-dimethoxybenzaldehyde (3c) ........................................................................................ 14
3-Chloro-4,5-dimethoxybenzaldehyde (3d) ........................................................................................ 14
2-Bromo-3,4-dimethoxybenzaldehyde (3e) ........................................................................................ 14
3-Bromo-4,5-dimethoxybenzaldehyde (3f) ........................................................................................ 15
2-Iodo-3,4-dimethoxybenzaldehyde (3g) ........................................................................................... 15
3-Iodo-4,5-dimethoxybenzaldehyde (3h) ........................................................................................... 15
Method A: General procedure for nitroaldol reaction. .......................................................................... 15
2
5-fluoro-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4b) ........................................................................ 16
2-chloro-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4c) ........................................................................ 16
5-chloro-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4d) ....................................................................... 16
2-bromo-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4e) ....................................................................... 17
5-bromo-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4f) ........................................................................ 17
5-Iodo-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4h) .......................................................................... 17
3,4-dimethoxy-1-(2-nitrovinyl)benzene (4i) ....................................................................................... 18
Method B: General nitroaldol reaction procedure with free phenols. ................................................... 18
Notes on nitroaldol condensation in the presence of phenol moieties. ................................................ 18
5-Fluoro-vanillin nitrostyrene (2-fluoro-6-methoxy-4-(2-nitrovinyl)phenol) (6a) .............................. 20
2-Chloro-isovanillin nitrostyrene (2-chloro-6-methoxy-3-(2-nitrovinyl)phenol) (6b) ......................... 20
5-chloro-vanillin-nitrostyrene (2-chloro-6-methoxy-4-(2-nitrovinyl)phenol) (6c) .............................. 20
2-bromo-isovanillin-nitrostyrene (2-bromo-6-methoxy-3-(2-nitrovinyl)phenol) (6c) ........................ 21
5-Bromo-vanillin nitrostyrene ((E)-2-bromo-6-methoxy-4-(2-nitrovinyl)phenol) (6d) ....................... 21
5-iodo-vanillin-nitrostyrene (2-iodo-6-methoxy-4-(2-nitrovinyl)phenol) (6f) .................................... 21
General procedure for Zn-HCl reduction of nitrostyrenes ..................................................................... 22
5-fluoro-3,4-dimethoxy-phenethylamine (5b) .................................................................................... 23
2-chloro-3,4-dimethoxy-phenethylamine (5c) ................................................................................... 23
5-chloro-3,4-dimethoxy-phenethylamine (5d) ................................................................................... 23
2-bromo-3,4-dimethoxy-phenethylamine (5e) ................................................................................... 23
5-bromo-3,4-dimethoxy-phenethylamine (5f) ................................................................................... 2 4
Catechol demethylation reactions .......................................................................................................... 24
Method A. General demethylation procedure by HBr reflux. ............................................................ 24
2-fluoro-dopamine-HBr (1a). .............................................................................................................. 24
5-fluoro-dopamine-HBr (1b). .............................................................................................................. 25
Method B: General demethylation procedure by BBr3....................................................................... 25
2-chloro-dopamine. ............................................................................................................................ 25
5-chloro-dopamine. ............................................................................................................................ 25
2-bromo-dopamine. ............................................................................................................. ............... 26
5-bromo-dopamine. ............................................................................................................. ............... 26
2-iodo-dopamine (1g) ......................................................................................................................... 26
5-iodo-dopamine (1h). ........................................................................................................................ 27
Preparation of 2-iodo-3,4-dimethoxy-phenethylamine (5g) .................................................................. 27
(2-iodo-3,4-dimethoxyphenyl)methanol. ........................................................................................... 27
(2-iodo-3,4-dimethoxyphenyl)chloromethane. .................................................................................. 27
3
(2-iodo-3,4-dimethoxyphenyl)acetonitrile. ........................................................................................ 28
2-iodo-3,4-dimethoxy-phenethylamine (5g) ...................................................................................... 28
Preparation of 5-iodo-3,4-dimethoxy-phenethylamine (5h) .................................................................. 28
(5-iodo-3,4-dimethoxyphenyl)methanol. ........................................................................................... 29
(5-iodo-3,4-dimethoxyphenyl)chloromethane ................................................................................... 29
(5-iodo-3,4-dimethoxyphenyl)acetonitrile. ........................................................................................ 29
5-iodo-3,4-dimethoxy-phenethylamine (5h). ..................................................................................... 30
Cited References ......................................................................................................................................... 31
4
Supporting Figures
Figure S1. Zn/HCl reduction of a halogenated nitrostyrene 4f proceeds cleanly to phenethylamine 5f as
monitored by HPLC-UV. Of the chlorinated and brominated nitrostyrene compounds 4c4f, the 5-
brominated compound 4f was the most prone to dehalogenation above 4 °C. However, below this
temperature, less than 1% reduction of the Csp2-Br bond was observed (compound 5i). The retention
time of 5i was assigned based on an authentic standard. HPLC conditions are described in the General
Information section of the Supporting Information.
5
Figure S2. Reverse-phase HPLC chromatograms illustrating typical side-products generated by Zn/HCl
reduction. Reaction conditions: 25 mmol (6 g) of nitrostyrene 4c, 20 g of zinc dust, and 50 mL of 37% HCl
at -5 to 0 °C. Solid reagents were added in alternating portions over one hour while HCl was added
continuously by syringe pump over the same period. (A) Five minutes after the initial addition of 4c and
zinc dust. (B) At 40 minutes, approximately one half of the solid reagents and HCl had been added. (C) At
60 minutes, a short burst of 1-2 mL of cold concentrated HCl was added after the last addition of solid
reagents. HPLC chromatography revealed that one major and several minor side products had formed
immediately after the HCl addition. (D) Once the reaction had completed, the side products persisted
and were present after extraction. (E) A separate reduction of 4c with full adherence to the procedure.
HPLC conditions are described in the General Information section of the Supporting Information.
6
Figure S3. At -10 °C, Zn/HCl reduction of iodinated nitrostyrene 4h proceeds with complete
dehalogenation as monitored by HPLC-UV. The rate of iodine reduction was relatively rapid. Neither
phenethylamine products 5h or 5i were observed. Instead, a dehalogenated intermediate of 5i, was the
exclusive product (retention time of 1.3 minutes). The retention times of 5h and 5i were assigned from
authentic standards. Reduction intermediates that we have been previously observed in Zn/HCl
reduction are indicated with an asterisk (*). HPLC conditions are described in the General Information
section of the Supporting Information.
7
General information
All reagents were purchased from commercial suppliers at the highest available purity and used without
further purification. Milli-Q water refers to water purified to resistivity of 18.2 Mɏcm (25 °C) using an
EMD Millipore Ultrapure Milli-Q reverse osmosis water purification system outfitted with ion exchange
and organic removal cartridge filters.
All reactions involving air- or water-sensitive reagents were performed using flame dried glassware
under an inert atmosphere of nitrogen using standard Schlenk line techniques.
Reactions were monitored using high pressure liquid chromatography (HPLC) on a Waters Acquity Ultra
Performance Liquid Chromatography instrument with a photodiode array detector. The solvent and
gradient conditions used for HPLC analysis were as follows: Acquity UPLC BEH C18 column (1.7 μm,
2.1x50 mm); 0.4 mL/min; 0-70% acetonitrile in 0.1 % TFA over 4.75 minutes, holding at 70% acetonitrile
for 0.25 minutes. Percent conversion of reactions by HPLC was estimated from the HPLC peak areas
measured at 225 nm.
All details of UV spectra are listed from most to least intense wavelength maximum.
Gas Chromatography Mass Spectroscopy (GC-MS) analysis of products was performed using a Hewlett
Packard HP6890 Gas Chromatography System with an Agilent Technologies 5975 inert mass selective
detector.
High resolution mass data (HRMS) were obtained on a Waters SYNAPT G1 High Definition Mass
Spectrometer using an ESI ionization source and
1H-, 19F-, 13C[1H]- NMR spectroscopy were performed using a Bruker Avance 300 MHz NMR spectrometer
at 300 MHz, 282, and 75 MHz respectively. All 1H-NMR chemical shifts were referenced to a
tetramethylsilane (TMS) internal standard set to 0.00 ppm. All 19F{1H}-NMR spectra were externally
referenced to a sample of ɲ,ɲ,ɲ-trifluorotoluene 0.05% in benzene-d6 (Isotec distributed by Aldrich) with
the 19F singlet set to -63.72 ppm. For 13C-NMR, the residual solvent peaks were used to reference the
spectra as follows: in methanol-d4 was referenced as 49.00 ppm and DMSO-d6 was referenced as 39.52
ppm. Processing and spectra handling was performed using Topspin 1.3 program suite (Bruker Biospin
GmbH, Rheinstetten, Germany).
8
Estimation of purity of halogenated dopamine analogs
To ensure accurate concentration estimates of halogenated dopamine analogs in subsequent enzyme
assays and for isolated yields, the purity of each compound was estimated by quantitative 1H-NMR as
follows.
Certified quantitative NMR grade maleic acid (Fluka cat no. 92816) was used as an internal reference.
The certified fractional purity was used as Pstd in the analysis below.
To optimize the relaxation delay, T1 relaxation time was measured using the inversion recovery
method,1 employing 16 different tau delays ranging from 0.01 to 30 sec, a repetition delay of 60 sec, 8
scans, 16K complex acquisition data points, 8K processing data points, and 1.0 Hz line broadening factor.
Peak areas were fit to a three-parameter non-linear equation2 using Origin 9.0 (OriginLab Corp.). At
approximately 0.3 M in DMSO-d6, the observed T1 relaxation times for protons in dopamine HCl were 0.9
– 1.1 sec for aromatic protons and 0.3 sec for methylene protons. The T1 relaxation for maleic acid in
DMSO-d6 was 2.4 sec. This value matched reported literature3.
Each sample was prepared using an exact mass of dopamine analog (20 – 30 mg) and maleic acid (5 – 10
mg). The masses were taken as the mean of triplicate measurements. The mixture was dissolved in
approximately 500 ʅL of DMSO-d6, mixed by vortex, sonicated, and transferred into an NMR tube for
analysis.
Following recommended guidelines for quantitative NMR analysis4, 1H-NMR spectra were collected with
a calibrated 90° pulse and 30 sec relaxation delay, 12.5 times the longest T1 (the maleic acid proton at
6.03 ppm).
The area of the signals in a 1H-NMR spectrum acquired under these conditions is directly proportional to
the number of protons present in the active volume of the sample4. Thus, the equation below is used to
calculate the fractional purity.
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The subscript std represents data from the maleic acid standard and the subscript x represents data
from the sample. The remaining terms are defined as follows: P is the fractional purity (mass/mass), n is
the number of degenerate protons in the selected signal (n = 2 for maleic acid protons at 6.03 ppm and
n = 1 for aromatic protons from the sample), MW is the molecular weight in g/mol, M is the recorded
mass added to the sample, and A is the peak area.
9
Synthetic Procedures
Preparation of halogenated vanillin and isovanillin
3-Methoxy-4-hydroxy-5-fluorobenzaldehyde
Following the procedure of Ladd and Weinstock,5 4.0 mL (9.4 mmol) of 2.36 M n-butyl lithium was
added dropwise over 1 hr to a solution of 1.28 g (10 mmol) fluoroanisole (1) in 10.0 mL dry THF kept
below -65 oC by a dry ice/acetone bath. The solution was stirred for 2 hrs at -78 oC under nitrogen. 1.17
g (11 mmol) of trimethoxyborane in 2.00 mL dry THF was added dropwise over 1 hr at -78 oC and the
solution was stirred for an additional 30 mins at -78 °C. The solution was warmed to 0 oC and 0.88 mL
(15 mmol) of glacial acetic acid was added followed by the dropwise addition of 1 mL (10 mmol) of 30%
H2O2. The solution was stirred overnight at 25 °C. The solution was diluted with H2O (10 mL) and
extracted with THF (2 X 10 mL). The combined ether extracts were washed with H2O (2 X 7 mL) and 10%
Mohrs salt (2 X 3 mL). The ether phase was dried with MgSO4 and evaporated under reduced pressure
to yield 1.16 g of (80%) 2-fluoro-6-methoxyphenol. Yields for successive repetitions: 174 mmol gave 15.5
g (63%); 261 mmol gave 29.7 g (80%). 1H NMR (300 MHz, CDCl3) ɷ 6.82 – 6.63 (m, 1H), 5.51 (s, 1H), 3.90
(s, 1H). 19F NMR (282 MHz, CDCl3) ɷ -137.61 ppm (m, 1F). EI-MS: m/z 142 (M+), 127.
Following the procedure of Clark and Miller,6 2-fluoro-6-methoxyphenol 13.0 g (91 mmol) was added to
a solution of 19.5 g (160 mmol) 40% dimethylamine and 11.7 mL (160 mmol) of 37% formaldehyde in 91
mL of absolute ethanol. The reaction mixture was heated at reflux for 2 hours, cooled to room
temperature, and concentrated under vacuum to a white solid. The solid was triturated with ether to
afford 17.25 g (95%) of N,N-dimethyl-3-hydroxy-4-methoxy-5-fluorobenzylamine as a white solid that
was used without purification in the following step. 1H NMR (300 MHz, CDCl3) ɷ 6.67 (t, J = 4.6 Hz, 1H),
3.90 (s, 1H), 3.32 (s, 1H), 2.23 (s, 3H). 19F NMR (282 MHz, CDCl3) ɷ -138.08 (dd, J = 11.1, 1.7 Hz).
Iodomethane (100 mL) was added to a solution of 20.0 g (100 mmol) N,N-Dimethyl-3-hydroxy-4-
methoxy-5-fluorobenzylamine in CHCl3 (900 mL). The mixture was stirred overnight at room
temperature. The solution was filtered to afford 32.7 g (95% yield) 1-(3-fluoro-4-hydroxy-5-
methoxyphenyl)-N,N,N-trimethylmethanaminium iodide as an off-white solid that was used in the
following step without purification. 1H NMR (300 MHz, DMSO) ɷ 9.78 (d, J = 1.8 Hz, 1H), 7.14 – 6.86 (m,
2H), 4.41 (d, J = 7.0 Hz, 2H), 3.85 (d, J = 2.7 Hz, 3H), 3.13 – 2.84 (m, 9H). 19F NMR (282 MHz, DMSO) ɷ -
135.24 (dd, J = 25.8, 10.4 Hz).
A solution of 25.4 g (74 mmol) 1-(3-fluoro-4-hydroxy-5-methoxyphenyl)-N,N,N-trimethyl-
methanaminium iodide was dissolved in acetic acid (65 mL) and H2O (65 mL) and heated to reflux.
Hexamethylenetetramine 40 g (285 mmol) was added to the refluxing solution in one portion. The
10
mixture was stirred at reflux for 2 hours at which time concentrated HCl (16.4 mL) was added. The
solution was stirred an additional 5 minutes, cooled, and extracted with ether (3 X 175 mL). The organic
layer was washed with H2O (2 X 175 mL), dried over MgSO4, and concentrated under vacuum to give
9.00 g (72% yield) of 3a as a white powder. 1H NMR (300 MHz, CDCl3) ɷ 9.75 (s, 1H), 7.35 (d, J = 10.3 Hz,
1H), 7.31 (s, 1H), 3.88 (s, 3H). 19F NMR (282 MHz, C6D6) ɷ -134.71 (d, J = 10.2 Hz).
2-Chloro-isovanillin (2-chloro-3-hydroxy-4-methoxybenzaldehyde). Neat sulfuryl chloride (14.85 g, 110
mmol, 1.1 eq.) was added dropwise over 5 minutes to a solution of isovanillin (15.00 g, 100 mmol, 1 eq)
in 120 mL of glacial acetic acid in an ice-water bath. After 2 hours of stirring with ice-water bath cooling,
the reaction was filtered, washed with cold acetic acid, and dried under vacuum to afford 14.16 g of
white solid. HPLC and 1H-NMR indicate indicated the presence of unreacted isovanillin. This solid was
dissolved in boiling ethanol and recrystallized to yield 11.91 g (80%) of fluffy white needles (mp = 200.0
– 209.9 °C). 1H-NMR indicated <1% isovanillin after one recrystallization. 1H NMR (300 MHz, CDCl3): ɷ
10.19 (s, 1H, CHO), 9.83 (d, J = 31.4 Hz, 1H, OH), 7.41 (d, J = 8.6 Hz, 1H, ArH), 7.12 (d, J = 8.6 Hz, 1H, ArH),
3.93 (s, 3H, OCH3); 1H-NMR (300 MHz, DMSO-d6): ɷ 10.19 (s, 1H, CHO), 9.89 (s, 1H, OH), 7.42 (d, J = 8.6
Hz, 1H, Ar-H), 7.12 (d, J = 8.6 Hz, 1H, Ar-H), ɷ 3.93 (s, 3H, OMe); EI-MS m/z: 187 (M+2), 185 (M+, 100%),
171, 157, 143, 129, 115, 107, 99, 79, 65, 51. UV-Vis: 215.3, 237.2, 283.8 nm.
5-Chloro-vanillin (3-chloro-4-hydroxy-5-methoxybenzaldehyde). Neat sulfuryl chloride (14.85 g, 8.89
mL, 110 mmol, 1.1 eq.) was added dropwise over a 5 minute period to a solution of 15.00 g (100 mmol,
1 eq. ) of vanillin (4-hydroxy-3-methoxybenzaldehyde) in 120 mL of glacial acetic acid in an ice water
bath (0– 2°C). After two hours of stirring with ice bath cooling, the reaction mixture was vacuum filtered,
rinsed with chilled glacial acetic acid and dried under vacuum to afford a clumpy white solid. HPLC and
1H-NMR indicate the presence of vanillin starting material. The solid was dissolved in hot ethanol,
recrystallized, vacuum filtered, rinsed with cold ethanol and dried under vacuum to yield to product as
12.59 g (85%) of a chunky, white, crystalline solid (mp =163.0–170.0 °C). Product was 98% pure by as
estimated by 1H-NMR. Minor contaminating species included ~1% each of vanillin and di-chloro-vanillin.
1H-NMR (300 MHz, DMSO-d6): ɷ 10.54 (s, 1H, OH), ɷ 9.79 (s, 1H, CHO), ɷ 7.60 (s, 1H, Ar-H), ɷ 7.40 (s, 1H,
Ar-H), ɷ 3.91 (s, 3H, OMe); EI-MS m/z: 187 (M+2), 185 (M+, 100%), 173, 171, 157, 143, 115, 107, 99, 79,
65, 51. UV-Vis: 237.2, 278.3, 302.3 nm.
11
2-Bromo-isovanillin (2-bromo-3-hydroxy-4-methoxybenzaldehyde). Liquid Br2 (36.85 g, 11.6 mL, 225
mmol, 1.5 equiv.) was added dropwise at a rate of 0.1 mL/min over a period of 2 hours, using a syringe
pump or addition funnel, to a three-neck flask, equipped with septum and overhead stirring assembly,
containing a solution of isovanillin, 3-hydroxy-4-methoxybenzaldehyde (22.8g, 150 mmol), in 75 mL of
CCl4 and 75 mL of CHCl3. The reaction mixture was allowed to stir overnight (approximately 12 hours) at
room temperature. The resulting reddish brown precipitate was vacuum filtered and rinsed with 50 mL
of a 1:1 solution of CCl4 and CHCl3. After removing solvent under reduced pressure, the precipitate was
dissolved in 300 mL of ethyl acetate (EtOAc) to give a bright yellow solution. This extract was washed
with 150 mL of brine, 50 mL of 10% w/v sodium thiosulfate, and twice more with brine (2 x 150 mL
portions).The organic phase was dried with MgSO4, vacuum-filtered, and solvent was removed by under
reduced pressure at room temperature. The recovered white solid was recrystallized in ethanol and
vacuum filtered to afford 22.11 g (60%) of a fine, grainy, white solid, 2-bromo-3-hydroxy-4-
methoxybenzaldehyde (mp = 204.5–210.4°C). 1H-NMR (300 MHz, DMSO-d6): ɷ 10.11 (s, 1H, CHO), ɷ
9.94 (s, 1H, OH), ɷ 7.42 (d, J =8.6 Hz, 1H, Ar-H), ɷ 7.15 (d, J = 8.6 Hz, 1H, Ar-H), ɷ 3.93 (s, 3H, OMe); EI-MS
m/z: 232 (M+2), 231(100%), 230 (M+), 229, 214, 201,189, 187, 173, 161,159, 150, 143, 131, 122, 107,
94, 79, 78, 77, 63, 51; UV-Vis: 215.3, 239.1, 297.4 nm.
5-Bromo-vanillin (3-bromo-4-hydroxy-5-methoxybenzaldehyde). Method 1, bromination with elemental
bromine: Vanillin, 3-methoxy-4-hydroxybenzaldehyde (22.8 g, 150 mmol), was dissolved in 75 mL of CCl4
and 75 mL of CHCl3 in a three-neck flask equipped with septum and overhead stirring assembly. Liquid
Br2 (36.77 g, 11.6 mL, 225 mmol, 1.5 equiv.) was added dropwise at a rate of 0.1mL/min over a period of
2 hours by either addition funnel or syringe pump. As a large amount of solid orange precipitate forms
during the course of the reaction, which slows or stops mixing, adequate stirring is important to
minimize over-bromination. The reaction mixture was allowed to stir overnight (approximately 12
hours) at room temperature. The resulting orange precipitate was vacuum-filtered and rinsed with 50
mL of a 1:1 solution of CCl4 and CHCl3. After removing solvent in vacuo, the precipitate was dissolved in
300 mL of ethyl acetate (EtOAc) to give a bright orange/yellow solution. This extract was washed with
150 mL of brine, 50 mL of 10% w/v sodium thiosulfate, and twice more with brine (2 x 150 mL portions).
The organic phase was dried with MgSO4, vacuum filtered, and solvent was removed under reduced
pressure in a room temperature bath. The recovered white solid was recrystallized in ethanol and
vacuum filtered to afford (27.72 g, 75%) of a fine, grainy, white solid, 3-bromo-4-hydroxy-5-
methoxybenzaldehyde (mp = 163.5–168.3°C).
12
Method 2, bromination with N-bromo-succinamide: Vanillin (30 g, 197 mmol) was dissolved in
acetonitrile (250 mL) in a 600-mL beaker with stirring by magnetic stirbar. N-bromo succinimide (35.1 g,
197 mmol) was added to the solution. Precipitate was apparent after 30 minutes. Stirring continued at
room temperature overnight. The reaction mixture was quenched with brine (10 mL) and stirred for 15
minutes. Ether (100 mL) was added to aid in transferring to a separatory funnel. The solid precipitate
was not transferred but was washed with ether. These extracts were also added to the separatory
funnel. The combined organic layers were washed twice with equal volumes of 10% w/v sodium
thiosulfate solution and thrice with equal volumes of brine, dried over MgSO4, and concentrated in
vacuo. The oil was recrystallized from ethanol to give the product as an off-white powder (24.5 g, 106
mmol, 54%).
1H-NMR (300 MHz, DMSO-d6): ɷ 10.75 (s, 1H, OH), 9.78 (s, 1H, CHO), 7.72 (s, 1H, Ar-H), 7.42 (s, 1H, Ar-
H), 3.91 (s, 3H, OMe); EI-MS m/z: 232 (M+2), 230 (M+, 100%), 217, 215, 203, 201, 189, 187, 161, 159,
143, 135, 107, 94, 79, 78, 77, 63, 51. UV-Vis: 236.6, 282.0, 299.2 nm.
5-Iodo-vanillin (3-Iodo-4-hydroxy-5-methoxybenzaldehyde). Vanillin (38.1 g, 250 mmol) and iodine
(25.4 g, 100 mmol) were added to a 1 L round bottom flask containing minimal EtOH. Iodic acid (8.8 g,
50 mmol) was dissolved in minimal amount of water (50 mL), and added to the flask containing the
vanillin-iodine mixture. The flask was placed in a water bath at a constant temperature of 35 °C and
stirred. The thick consistency of the reaction mixture requires overhead mechanical stirring. While
reacting, minimal amounts of EtOH and distilled H2O were occasionally used to wash solids down the
sides of the flask. After 1.5 hours, the reaction was judged to be complete by HPLC. The cream-colored
solid was washed in a Buchner funnel with 1.5 L of saturated sodium thiosulfate (NaS2O3) and 0.5 L of
deionized H2O. The remaining solid was recrystallized in EtOH yielding 42.2 g (97.7%) of light yellow
prism-shaped crystals. 1H NMR (300 MHz, CDCl3) ɷ 9.74 (s, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 1.7
Hz, 1H), 3.89 (s, 3H). EI-MS m/z: 278 (M+), 263, 249, 235, 221, 207, 189, 179, 165, 151, 135, 122, 107,
91, 79, 62, 51. UV-Vis: 228.7, 297.4 nm.
13
Methylation reactions
General methylation procedure. Following an adaptation of the procedure of McKillop et al.7, an
aqueous solution of 1.20 g of NaOH (30 mmol, 3.0 eq.) in 50 mL of deionized water was added to a
stirring solution of 2.31 g (10 mmol) of 2-bromo-isovanillin (2-bromo-3-hydroxy-4-methoxy-
benzaldehyde) in 50 mL of dichloromethane. Next, phase transfer catalyst was added, as 3.40 g of either
tetrabutylammonium hydrogen sulfate (TBAHS, 10.0 mmol, 1.0 eq.) or recycled catalyst (assuming that
the recovered catalyst is tetrabutylammonium hydroxide, 2.6 g is 10 mmol, 1.0 eq). Once dissolved, 17
g (120 mmol, 12 eq.) of methyl iodide was then added to the mixture and the reaction was allowed to
stir at room temperature. Reaction progress was monitored by HPLC. As monitored by HPLC, reaction
progress generally showed complete turnover to product with no side products by 3 hours, however the
solution was typically allowed to stir overnight for convenience. The reaction mixture was extracted with
3 x 50 mL portions of CH2Cl2. The combined organic extracts were washed with brine and deionized
water, dried over MgSO4, filtered, and concentrated by evaporation under reduced pressure to yield a
either a white or yellow solid. To remove catalyst, the solid was first ground to a fine powder with a
mortar and pestle. This solid was poured on top of a 2 – 3 cm layer of dry silica gel in a 3 – 4 cm (I.D.)
sintered glass fritted Buchner funnel. The solid was extracted with 1:5 ethyl acetate:hexanes in 75 mL
portions by pouring the solvent mixture over the dry solids with vacuum suction to collect the solution
in a round bottom flask. Allow the solids to dry between solvent portions for best separation. The first
1250 mL typically contained 85 - 95% of pure product. The combined eluent was evaporated to dryness
under reduced pressure to afford a dense, white, flakey solid (2.06 g, 90%). If the product was found to
contain non-halogenated contaminants from the previous step, pure halogenated product was easily
obtained by recrystallization from hexanes. The phase transfer catalyst, presumably a mixture of
tetrabutylammonium salts, was recovered by either scooping it out of the filter or by eluting with ethyl
acetate.
3-fluoro-4,5-dimethoxybenzaldehyde (3b). From 3.10 g (11.7 mmol) of 5-fluoro-vanillin (3-chloro-4-
hydroxy-5-methoxybenzaldehyde) methylation afforded 3.27 g (97.5%) of a fluffy, white solid; mp =
51.2–53.0 °C; 1H-NMR (300 MHz, DMSO-d6) ɷ 9.88 (d, J = 1.6 Hz, 1H), 7.48 – 7.43 (m, 2H), 3.92 – 3.90 (m,
6H). ; 19F NMR (282 MHz, DMSO-d6): ɷ -128.87 (d, J = 10.1 Hz). EI-MS m/z: 184 (M+), 169, 155, 137, 125,
113, 95, 83, 70, 59, 50.
14
2-Chloro-3,4-dimethoxybenzaldehyde (3c). From 2.00 g (10.7 mmol) of 2-chloro-isovanillin (2-chloro-3-
hydroxy-4-methoxybenzaldehyde) methylation afforded 1.98 g (92%) of a fluffy, white solid; mp = 68.0-
69.0 °C (recrystallized from hexanes with 78% recovery); 1H-NMR (300 MHz, DMSO-d6): ɷ 10.19 (s, 1H,
CHO), 7.68 (d, J= 8.8 Hz., 1H, Ar-H ), 7.24 (d, J=8.8 Hz., 1H, Ar-H), 3.95 (s, 3H, OMe), 3.79 (s, 3H, OMe); EI-
MS m/z: 203, 202 (M+2), 200 (M+, 100%), 199, 187, 185, 172, 167, 158, 156, 149, 141, 135, 131, 129,
121, 115, 113, 107, 99, 93, 85, 79, 78, 74, 65, 60, 51, 50; UV-Vis: 211.0, 233.6, 282.0 nm.
3-Chloro-4,5-dimethoxybenzaldehyde (3d). From 2.10 g (11.2 mmol) of 5-chloro-vanillin (3-chloro-4-
hydroxy-5-methoxybenzaldehyde) methylation afforded 2.17 g (96%) of dense, white, flakey solid; mp =
54.5-55.5 °C (recrystallized from hexanes with 80% recovery); 1H-NMR (300 MHz, DMSO-d6): ɷ 9.90 (s,
1H, CHO), 7.66 (s, J=1.75 Hz., 1H, Ar-H ), 7.53 (s, J=1.75 Hz., 1H, Ar-H), 3.93 (s, 3H, OMe), 3.87 (s, 3H,
OMe); EI-MS m/z: 202 (M+2), 200 (M+), 199, 187, 185, 171, 159, 157, 149, 141, 135, 131, 129, 121, 116,
114, 107, 99, 94, 93, 85, 79, 78, 77, 74, 65, 60, 51; UV-Vis: 234.8, 268.5, 304.2 nm.
2-Bromo-3,4-dimethoxybenzaldehyde (3e). From 5.09 g (22.0 mmol) 2-bromo-isovanillin (2-bromo-3-
hydroxy-4-methoxybenzaldehyde) methylation afforded 5.19 g (96%) of a dense, white, flakey solid; mp
= 83.0-84.0 °C (no recrystallization); 1H-NMR (300 MHz, DMSO-d6): ɷ 10.11 (s, 1H, CHO), 7.68 (d, J=8.8
Hz., 1H, Ar-H ), 7.27 (d, J=8.8 Hz., 1H, Ar-H), 3.95 (s, 3H, OMe), 3.78 (s, 3H, OMe); EI-MS m/z: 246 (M+2),
245, 244 (M+, 100%), 243, 231, 229, 216, 207, 202, 200, 187, 185, 175, 173, 163, 160, 159, 158, 157,
150, 149, 143, 137, 131, 129, 122, 116, 107, 94, 79,78, 77, 65, 50; UV-Vis: 238.5, 280.1, 299.8 nm.
15
3-Bromo-4,5-dimethoxybenzaldehyde (3f). From 2.50 g (10.8 mmol) of 5-bromo-vanillin (3-bromo-4-
hydroxy-5-methoxybenzaldehyde) methylation afforded 2.47 g (93%) white, fluffy solid; mp = 59.8-61.3
°C; 1H-NMR (300 MHz, DMSO-d6): ɷ 9.89 (s, 1H, CHO), 7.78 (s, 1H, Ar-H ), 7.55 (s, 1H, Ar-H), 3.92 (s, 3H,
OMe), 3.85 (s, 3H, OMe); EI-MS m/z: 247 (M+2), 246, 245 (M+), 244 (100%), 243, 231, 229, 215, 207,
203, 202, 201, 200, 199, 197, 187, 185, 175, 173, 163, 160, 157, 150, 145, 143, 135, 129, 122, 116, 107,
101, 94, 86, 79,78, 73, 63, 51; UV-Vis: 223.8, 272.1, 229.9, 272.8 nm.
2-Iodo-3,4-dimethoxybenzaldehyde (3g). From 2.78g (10 mmol) of 2-iodo-isovanillin (2-iodo-3-hydroxy-
4-methoxybenzaldehyde) methylation afforded 2.65 g (90%) of a dense, white, flakey solid; 1H-NMR
(300 MHz, DMSO-d6): ɷ 9.90 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 3.93 (s, 3H), 3.75 (s,
3H). UV-Vis: 227.5, 292.4 nm.
3-Iodo-4,5-dimethoxybenzaldehyde (3h). From 2.78g (10 mmol) of 5-iodo-vanillin (3-iodo-4-hydroxy-5-
methoxybenzaldehyde) methylation afforded 2.83 g (97%) of a white, fluffy solid; 1H-NMR (300 MHz,
DMSO-d6): ɷ ). 1H NMR (300 MHz, CDCl3) ɷ 10.40 (d, J = 2.4 Hz, 1H), 8.48 (t, J = 2.1 Hz, 1H), 8.07 (d, J =
1.8 Hz, 1H), 4.49 (d, J = 2.3 Hz, 3H), 4.44 (d, J = 2.4 Hz, 3H). EI-MS m/z: 292 (M+), 277, 264, 245, 233, 221,
206, 189, 177, 166, 150, 135, 122, 107, 94, 77, 62, 51; UV-Vis: 228.1, 297.5 nm.
Nitroaldol (Henry) reactions
Method A: General procedure for nitroaldol reaction. Aldehyde (4 mmol) was added to a round bottom
flask containing a solution of 0.3 g (4 mmol, 1 eq.) of ammonium acetate (fresh commercial solid works
well, however it must be recrystallized from glacial acetic acid if it appears wet) dissolved in 1.1 mL (20
mmol, 5 eq.) of nitromethane, 3.0 mL (56 mmol, 14 eq.) of glacial acetic acid, and small number of 3Å
molecular sieves. The flask was attached to a condenser with septum and the assembly was lowered
into a sand bath. The reaction mixture was allowed to gently reflux at 90–100 °C with stirring for one
hour. After removing the molecular sieves, the resulting bright yellow solution was partitioned between
10 mL of brine and extracted with 3 x 25 mL portions of ethyl acetate. Organic extracts were combined
and rinsed with 3 X 50 mL portions of deionized water, dried over MgSO4, vacuum filtered, and
concentrated under vacuum to afford a dense yellow crystalline solid. Unless otherwise specified, all
isolated products were free of starting material, side products, and ammonium acetate by 1H-NMR and
16
HPLC-UV. If further purification is required due to the presence of minor side products, the nitrostyrene
may be recrystallized by dissolving in minimal methanol and adding distilled water at room temperature.
All reported melting points were from crude isolated solid.
2
2
+
2
2
2
12
&+12
1+&+2
&+&22+
UHIOX[ KU1
))
5-fluoro-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4b). 145 mg (0.78 mmol) of 3-fluoro-4,5-
dimethoxybenzaldehyde (3b) was reacted following Nitroaldol Reaction Method A. The reaction was
maintained at 95-100 °C for 1.5 hours resulting in a bright yellow solution. Isolation afforded a dense,
flakey bright yellow crystalline solid (175 mg, 98%). 1H NMR (300 MHz, DMSO-d6): ɷ 8.28 (d, J = 13.6 Hz,
1H), 8.06 (d, J = 13.6 Hz, 1H), 7.52–7.43 (m, 2H), 3.90–3.85 (m, 6H). 19F NMR (282 MHz, DMSO-d6): ɷ -
130.54 (d, J = 11.1 Hz).
2-chloro-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4c). 803 mg (4.00 mmol) of 2-Chloro-3,4-
dimethoxybenzaldehyde (3c) was reacted following Nitroaldol Reaction Method A. The reaction was
maintained at 89-90 °C for one hour resulting in a bright yellow solution. Isolation afforded a dense,
flakey bright yellow crystalline solid (973 g, 99%). mp = 84.6-88.1 °C (lit. 88-91 °C 21); 1H-NMR (300 MHz,
DMSO-d6): ɷ 8.23 (s, 2H, C=CH), 7.88 (d, J=9.29 Hz, 1H, Ar-H), 7.20 (d, J=9.29 Hz., 1H, Ar-H), 3.93 (s, 3H,
OMe), 3.78 (s, 3H, OMe); 1H-NMR (300 MHz, CDCl3): 8.40 (d, J= 13.70 Hz., 1H, C=CH), 7.60 (d, J=13.70
Hz., 1H, C=CH), 7.40 (d, J=8.83 Hz., 1H, Ar-H), 6.90 (d, J=8.83 Hz., 1H, Ar-H), 3.97 (s, 3H, OMe), 3.91 (s,
3H, OMe); UV-Vis: 253, 351 nm.
5-chloro-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4d). 804 mg (4.00 mmol) of 3-Chloro-4,5-
dimethoxybenzaldehyde (3d) was reacted following Nitroaldol Reaction Method A. The reaction was
maintained at 89-90 °C for one hour resulting in resulting in a bright yellow solution. Isolation afforded a
dense, flakey bright yellow crystalline solid a fluffy, bright yellow crystalline solid 900 mg (92%). mp =
17
149.4-155.5 °C; 1H-NMR (300 MHz, DMSO-d6): ɷ 8.32 (d, J=13.62 Hz., 1H, C=CH), 8.07 (d, J=13.62 Hz.,
1H, C=CH), 7.64 (s, 1H, Ar-H), 7.59 (s, 1H, Ar-H), 3.90 (s, 3H, OMe), 3.82 (s, 3H, OMe); UV-Vis: 248.2,
335.0 nm.
2-bromo-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4e). 800 mg (3.26 mmol) of 2-Bromo-3,4-
dimethoxybenzaldehyde (2e) was reacted following Nitroaldol Reaction Method A. The reaction was
maintained at 100 °C for one hour resulting in resulting in a bright yellow solution. Isolation afforded a
dense yellow crystalline solid 933 mg (99%). mp = 84.9-87.8 °C; 1H-NMR (300 MHz, DMSO-d6): ɷ 8.26 (d,
J=13.35 Hz., 1H, C=CH), 8.19 (d, J=13.35 Hz., 1H, C=CH), 7.87 (d, J= 9.14 Hz., 1H, Ar-H), 7.22 (d, J= 9.14
Hz., 1H, Ar-H), 3.93 (s, 3H, OMe), 3.77 (s, 3H, OMe); UV-Vis: 257.4, 355.0 nm.
5-bromo-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4f). 975.0 mg (4 .00 mmol) of 3-Bromo-4,5-
dimethoxybenzaldehyde (3f) was reacted following Nitroaldol Reaction Method A. The reaction was
maintained at 90 °C for one hour resulting in resulting in a bright yellow solution. Isolation afforded a
fluffy, bright yellow crystalline solid (1.075 g, 94%). mp =150-153.2 °C; 1H-NMR (300 MHz, DMSO-d6): ɷ
8.32 (d, J=13.5 Hz., 1H, C=CH), 8.06 (d, J=13.5 Hz., 1H, C=CH), 7.76 (s, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 3.89
(s, 3H, OMe), 3.81 (s, 3H, OMe); UV-Vis: 211.6, 245.8, 335.7 nm.
5-Iodo-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4h). 1.16 g (3.97 mmol) of 2-Iodo-3,4-
dimethoxybenzaldehyde was reacted following Nitroaldol Reaction Method A. The reaction was
maintained at 100 °C for one hour resulting in resulting in a bright yellow solution. Isolation afforded a
dense yellow crystalline solid 1.105 g (83%). 1H NMR (300 MHz, DMSO-d6): ɷ 8.35 (d, J = 13.6 Hz, 1H),
8.09 (d, J = 13.6 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H); UV-Vis:
220.2, 358.6, 369.9 nm.
18
2
2
+
2
2
2
12
&+12
1+&+2
&+&22+
UHIOX[ KU1
3,4-dimethoxy-1-(2-nitrovinyl)benzene (4i). 10.00 g (60.2 mmol) of 3,4-dimethoxybenzaldehyde was
reacted following Nitroaldol Reaction Method A. The reaction was maintained at 100 °C for one hour
resulting in resulting in a bright yellow solution. Isolation afforded a flakey yellow crystalline solid 12.18
g (97%). 1H-NMR (300 MHz, DMSO-d6): ɷ 8.16 (d, J = 13.3 Hz, 1H), 8.03 (d, J= 13.5 Hz, 1H), 7.48 (s, 1H),
7.30 (d, 1.7 Hz, 1H), 6.85 (d, J = 1.7 Hz, 1H), 3.82 (s, 3H). UV-Vis: 217.7, 259.9, 376 nm.
Method B: General nitroaldol reaction procedure with free phenols.
Aldehyde (20 mmol) and ammonium acetate (10 mmol) were mixed in 70 mL of nitromethane in a
sealed glass high-pressure reaction vessel (Ace glass 8648 pressure vessels with 5846 PTFE plugs). The
reaction was mixed by magnetic stirring while immersed in an oil bath maintained at the temperature
and time specified for each compound. Caution: This reaction builds-up pressure, use of a blast shield is
recommended. After the stated time, the vessel was allowed to cool to room temperature before
opening. The reaction mixture was transferred to a round bottom flask (solids were dissolved in ethyl
acetate when necessary). The organic layer was washed with a small amount of brine, dried over MgSO4,
vacuum filtered, and evaporated to dryness under reduced pressure. All isolated products were free of
starting material, side products, and ammonium acetate by 1H-NMR and HPLC-UV. If further purification
was required, products may be recrystallized from ethanol.
Notes on nitroaldol condensation in the presence of phenol moieties.
This method represents a general procedure for large scale nitroaldol condensation in the presence of
unprotected phenol moieties. High yield nitroaldol condensation with the halogenated phenol 2-bromo-
5-hydroxy-4-methoxybenzaldehyde with catalytic ammonium acetate has been previously reported at
reflux temperature (105 °C)8. However, in our hands this procedure did not yield high conversion for our
aldehydes (5-fluoro-vanillin was the notable exception). Instead, reflux with phenols generally achieved
30–60% completion as monitored by HPLC. When allowed to react for longer times, significant amounts
of unidentified side products accumulated.
Heating the reaction in sealed high-pressure glassware at 130–160 °C, above the boiling point of
nitromethane, represents a general improvement over reflux. All reactions were generally complete
after 60 minutes. Although this method worked well for nitroaldol condensation in the presence of free
phenols, it requires significant excess of nitromethane (900–1500 equivalents), which makes large scale
application somewhat cost prohibitive. Moreover, the free phenol was not suitable our specific
application. For these reasons, Method B was not explored further, but other researchers may find it to
19
be a useful option for overcoming the problem of incomplete nitrostyrene reaction with less-reactive
aldehydes and ketones. See Table S1 for results.
This method is similar to the high-yield, microwave-assisted nitroaldol condensation described by
Rodríguez and Pujol.9 Using the identical (CEM Discover microwave system outfitted with external
infrared temperature monitoring), their procedure provided near quantitative conversion of
halogenated aldehydes 6b6f. However, we were unable to scale the reported procedure beyond 2
mmols. Microwave reactions in sealed reaction vessels at 4 mmol scale generated side products and
incomplete conversion. Low conversion to nitrostyrene product was observed when a 10 mmol at ca.
105 °C in an open round bottom flask. We found that this inability to scale-up was due to instrument
problems with accurate monitoring and control of the reaction temperature for a large scale reaction
with only infrared thermometer monitoring in this model microwave reactor. For successful reactions,
the instrument reported the reaction temperature as 90 °C, however we found that the internal
temperature was actually around 130 °C, above the boiling point of nitromethane. We concluded that
the microwave reactor was actually maintaining the conditions of our Method B and not the 90 °C
temperature indicated by the instrument’s infrared thermometer.
Table S1a
D H
2
+
52
52
;
;
D H
52
52
;
;
12
Product R1 R
2 X
1 X
2 conversionb
(isolated yield)
6a CH3 H H F 100% (98%)
6b H CH3 Cl H 99.6% (97%)
6c CH3 H H Cl 94% (95%)
6d H CH3 Br H 96% (94%)
6e CH3 H H Br 99.6% (84%)
6f CH3 H H I 98% (92%)
a. Yields for nitroaldol condensation of aldehydes with
unprotected phenol moieties by Method B.
b. Conversion was estimated from disappearance of initial
amount of starting material by HPLC.
20
5-Fluoro-vanillin nitrostyrene (2-fluoro-6-methoxy-4-(2-nitrovinyl)phenol) (6a). 1.70 g (10.0 mmol) of 2-
fluoro-isovanillin (2-fluoro-3-hydroxy-4-methoxybenzaldehyde) was reacted following Nitroaldol
Reaction Method B at 140 – 150 °C for 60 minutes resulting in a yellow/orange solution. After
evaporation of VROYHQW, 2.10 g (98% yeild) of 6a was collected as a yellow solid without the need for
further purification. 1H NMR (300 MHz, DMSO-d6): ɷ 8.09 (dd, J = 45.6, 13.3 Hz, 2H), 7.41 (d, J = 11.6 Hz,
1H), 7.35 (s, J = 11.8 Hz, 1H), 3.85 (s, 3H). 19F NMR (282 MHz, DMSO-d6): ɷ -135.35 (d, J = 11.5 Hz).
2-Chloro-isovanillin nitrostyrene (2-chloro-6-methoxy-3-(2-nitrovinyl)phenol) (6b). 1.87 g (10.0 mmol)
of 2-chloro-isovanillin (2-chloro-3-hydroxy-4-methoxybenzaldehyde) was reacted following Nitroaldol
Reaction Method B at 150 – 160 °C for 45 minutes resulting in a yellow/orange solution. After
evaporation of solvent, 2.22 g (97%) of 6b was collected as a yellow solid without the need for further
purification. 1H-NMR (300 MHz, acetone-6): ɷ 8.71(s, 1H, OH), ɷ 8.38 (d, J= 13.5 Hz., 1H, C=CH), ɷ 7.94
(d, J= 13.5 Hz., 1H, C=CH), ɷ 7.55 (d, J= 8.5 Hz.,1H, Ar-H), ɷ 7.10 (d, J=8.5 Hz.,1H, Ar-H), ɷ 4.00 (s, 3H,
OMe); UV-Vis: 212, 261, 368 nm.
2
+2
+
2
&O
2
+2
&O
12
&+12
1+&+2
 PLQ
  &
5-chloro-vanillin-nitrostyrene (2-chloro-6-methoxy-4-(2-nitrovinyl)phenol) (6c). 1.86 g (10.0 mmol) of 2-
chloro-isovanillin (2-chloro-3-hydroxy-4-methoxybenzaldehyde) was reacted following Nitroaldol
Reaction Method B at 150 – 160 °C for approximately 80 minutes resulting in a yellow/orange solution.
After evaporation of solvent, 2.17 g (95%) was collected as a powdery, reddish/orange solid without the
need for further purification. UV-Vis: 210.4, 253.7, 366.8 nm.
21
2-bromo-isovanillin-nitrostyrene (2-bromo-6-methoxy-3-(2-nitrovinyl)phenol) (6c). 230 mg (1.00 mmol)
of 2-bromo-isovanillin (2-bromo-3-hydroxy-4-methoxybenzaldehyde) was reacted following Nitroaldol
Reaction Method B with 38 mg (0.5 mmol, 0.5 eq.) of ammonium acetate in ~50.0 mL (931 mmol, 931
eq.) of nitromethane at 150-160 °C for 60 minutes resulting reddish/orange solution. After evaporation
of solvent, 258 mg (94%) was collected as a powdery, bright yellow/orange solid without further
purification. 1H-NMR (300 MHz, acetone-d6): ɷ 8.85 (s, 1H, OH), 8.42 (d, J= 13.5 Hz., 1H, C=CH), 7.90 (d,
J= 13.5 Hz., 1H, C=CH), 7.56 (d, J= 8.5 Hz.,1H, Ar-H), 7.12 (d, J=8.5 Hz.,1H, Ar-H), 4.00 (s, 3H, OMe); UV-
Vis: 211.0, 264.2, 368.6 nm.
5-Bromo-vanillin nitrostyrene ((E)-2-bromo-6-methoxy-4-(2-nitrovinyl)phenol) (6d). 2.31 g (10.0 mmol)
of 5-bromo-vanillin (3-bromo-4-hydroxy-5-methoxybenzaldehyde) was reacted following Nitroaldol
Reaction Method B at 150 – 160 °C for 60 minutes resulting reddish/orange solution. After evaporation
of solvent, 2.31 g (84%) was collected as a powdery, reddish/orange solid without the need for further
purification. UV-Vis: 212.3, 253.1, 367.4 nm.
5-iodo-vanillin-nitrostyrene (2-iodo-6-methoxy-4-(2-nitrovinyl)phenol) (6f). 556 mg (2.0 mmol) of 5-
iodo-vanillin (3-iodo-4-hydroxy-5-methoxybenzaldehyde) was reacted following Nitroaldol Reaction
Method B with 77 mg (1.0 mmol, 0.5 eq.) of ammonium acetate in ~40.0 mL of nitromethane at 150 –
160 °C for 60 minutes resulting reddish/orange solution. After evaporation of solvent, 590 mg (92%) was
collected as a powdery, bright yellow/orange solid without further purification. UV-Vis: 220, 370, 258
nm.
22
Reduction reactions
General procedure for Zn-HCl reduction of nitrostyrenes.
For every 1.0 mmol of nitrostyrene, 2 mL of methanol, 800 mg of zinc dust (12 mmol), and 2 mL of 37%
HCl (24 mmol) were used. Methanol was vigorously stirred in an ice bath maintained <0 °C (ice/NaCl or
freezer-chilled commercial antifreeze). HCl, zinc dust, and nitrostyrene were slowly added over the
course of 30 minutes in alternating small portions taking care that the temperature did not rise above 0
°C. For large-scale reactions (>25 mmol), HCl was added continuously by syringe pump. After addition
was complete, any solids on the side were washed into the solution with a small amount of methanol.
All starting material was consumed within one hour of complete reagent addition as monitored by HPLC
and observed by complete disappearance of the initial yellow color. At this point, an intermediate and
the phenethylamine product generally dominate the mixture as observed by HPLC. The intermediate is
typically converted to product after 4 hours of total stirring at 0 °C. The reaction is typically complete 4–
6 hours after the yellow color has disappeared. The reaction may stir for as long as 16 hours in a 4 °C
refrigerator without significant formation of side products. If HPLC is not available to monitor the
reaction, we suggest adding an additional 200 mg of zinc dust (3 mmol) and 0.6 mL (7 mmol) of
concentrated HCl for every 1.0 mmol of nitrostyrene after 5 hours and stir for an additional hour to
ensure complete reaction. Once complete, the excess solid zinc was removed by filtration through filter
paper. Note that filtering through celite, silica gel, or alumina at this stage leads to product
decomposition. The solution was made basic by dropwise addition of saturated sodium hydroxide in
methanol, while maintaining the temperature below 5 °C, until the pH was greater than 11 by pH paper.
Next, 10 mL of CHCl3 was added (per mmol of reactant). Solid anhydrous MgSO4 was added to dry the
organic layer. The organic extract was filtered by filter paper. The remaining paste was extracted two
more times with CHCl3 and filtered. The combined organic extracts were evaporated in vacuo to yield
phenethylamine as an amber oil. In cases when an oil was not obtained at the final step, the material
was dissolved in minimal CHCl3 and the remaining inorganic salts were completely precipitated by
addition of diethyl ether. After filtration and evaporation, a salt-free oil was obtained.
The phenethylamine products may be converted to solid HCl salts by dissolving the free base in minimal
cold diethyl ether, carefully adding one equivalent of concentrated HCl, and evaporating to dryness
under vacuum.
23
5-fluoro-3,4-dimethoxy-phenethylamine (5b). 750 mg (3.3 mmol) of compound 4b was reacted
following the general procedure for Zn-HCl reduction to yield 766 mg (83%) as an oil. 1H NMR (300 MHz,
methanol-d4): ɷ 6.85 – 6.68 (m, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.20 (t, J = 7.5 Hz, 2H), 2.93 (t, J = 7.6 Hz,
2H). 19F NMR (282 MHz, methanol-d4): ɷ -132.92 (d, J = 10.4 Hz). HRMS (C10H16NO2F+): calc. 200.1086
[M+H]+; found 200.1088.
2-chloro-3,4-dimethoxy-phenethylamine (5c). 517 mg (2.4 mmol) of compound 4c was reacted
following the general procedure for zinc reduction to yield 434 mg (74%) as an oil. 1H NMR (300 MHz,
methanol-d4) ɷ 7.01 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.5 Hz 1H), 3.82 (s, 3H), 3.79 (s, 3H), 2.94 (d, J = 5.6
Hz, 2H), 2.83 (d, J = 5.4 Hz, 2H). HRMS (C10H15NO2Cl+): calc. 216.0791 [M+H]+; found 216.0795.
5-chloro-3,4-dimethoxy-phenethylamine (5d). 487 mg (2.0 mmol) of compound 4d was reacted
following the general procedure for zinc reduction to yield 376.5 mg (87%) as a yellow oil. 1H NMR (300
MHz, methanol-d4) ɷ 6.93 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 1.9 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.14 (t, J =
7.5 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H). HRMS (C10H15NO2Cl+): calc. 216.0791 [M+H]+; found 216.0791.
2-bromo-3,4-dimethoxy-phenethylamine (5e). 288 mg (1.0 mmol) of compound 4e was reacted
following the general procedure for zinc reduction to yield 201.3 mg (77%) as yellow oil. 1H NMR (300
MHz, methanol-d4) ɷ 6.96 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H), 3.88 (s, 3H), 2.97 (dd, J
= 10.4, 3.8 Hz, 2H), 2.84 (dd, J = 10.5, 3.9 Hz, 2H). 13C NMR (75 MHz, methanol-d4) ɷ 146.93, 143.65,
126.48, 121.82, 121.78, 114.61, 40.61, 32.20. HRMS (C10H15NO2Br+): calc. 260.0286 and 262.0266
[M+H]+; found 260.0288 262.0267.
24
5-bromo-3,4-dimethoxy-phenethylamine (5f). 288 mg (1.0 mmol) of compound 4f was reacted
following the general procedure for zinc reduction to yield 216.1 mg (83%) as a yellow colored solid. 1H
NMR (300 MHz, methanol-d4) ɷ 7.10 (d, J = 1.9 Hz, 1H), 6.96 (d, J = 1.9 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H),
3.19 (t, J = 7.6 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H). HRMS (C10H15NO2Br+): calc. 260.0286 and 262.0266
[M+H]+; found 260.0292 and 262.0277.
Catechol demethylation reactions
Method A. General demethylation procedure by HBr reflux. For every 1 mmol of mono- or dimethoxy-
phenethylamine, 10 mL of concentrated (37%) HBr was refluxed for 20 minutes to degas any dissolved
oxygen. The top of the condenser was closed off from the atmosphere and connected to an oil bubbler.
The methoxy phenol ether was added and the mixture was refluxed for 3 hours. The excess
hydrobromic acid was removed by vacuum and the resulting product was dissolved in methanol (15 mL)
and evaporated to dryness under vacuum. This step was repeated again using methanol (15 mL),
followed by H2O (15 mL), and finally methanol (15 mL). After the final evaporation the product was
placed in a vacuum desiccator overnight to yield dopamine analogs as their hydrobromide salts. Slow
diffusion of ether into an isopropanol solution works well to recrystallize the products if analytical purity
is required for further applications. However, recovery is significantly lower.
2-fluoro-dopamine-HBr (1a). Following the general procedure above (Method A), 0.250 g (1.26 mmol) of
2-fluoro-3,4-dihydroxy-phenethylamine was reacted as above to yield 0.330 g (104%) of 1a as a white
powdery solid. NMR revealed that there were significant no organic contaminants, however quantitative
NMR analysis revealed that the product was 87.9% pure by mass, thus the recovered yield was 91%. 1H
NMR (300 MHz, DMSO-d6): ɷ 9.40 (s, 1H), 9.00 (s, 1H), 7.87 (s, 3H), 6.57-6.49 (m, 2H), 2.97-2.90 (m, 2H),
2.80-2.75 (m, 2H). 13C NMR (75 MHz, CDCl3): ɷ 151.01 (d, J = 237.9 Hz), 146.97 (d, J = 5.6 Hz), 133.85 (d, J
= 14.3 Hz), 119.45 (d, J = 5.4 Hz), 115.15 (d, J = 14.1 Hz), 111.47 (d, J = 2.6 Hz), 40.42 (s), 31.17 (s). 19F
NMR (282 MHz, DMSO-d6): ɷ -143.69 (dd, J = 6.2, 1.2 Hz). HRMS (C8H11NO2F+): calc. 172.0774 [M+H]+;
found 172.0772.
25
5-fluoro-dopamine-HBr (1b). Following the general procedure above, 0.290 g (1.3 mmol) of 2-fluoro-3-
hydroxy-4-methoxyphenethylamine hydrochloride was reacted as above to yield 0.347 g (105%) of 1b as
powdery solid. NMR revealed that there were no organic contaminants, however quantitative NMR
analysis revealed that the product was 85.3% pure by mass, thus the recovered yield was 89.6%. 1H
NMR (300 MHz, DMSO-d6): ɷ 9.47 (s, 1H), 8.92 (s, 1H), 7.81 (s, 3H), 6.55-6.53 (m, J = 1.8 Hz, 1H), 6.50-
6.48 (m, J = 1.4 Hz, 2H), 3.04 – 2.85 (m, 2H), 2.78 – 2.62 (m, 2H). 1H NMR (300 MHz, CDCl3): ɷ 7.87 (s,
5H), 6.52 (dd, J = 11.3, 1.8 Hz, 1H), 6.48 (d, J = 1.4 Hz, 1H), 3.02 – 2.90 (m, 2H), 2.74 – 2.62 (m, 2H). 13C
NMR (75 MHz, DMSO-d6): ɷ 152.41 (d, J = 237.2 Hz), 148.10 (d, J = 6.3 Hz), 132.34 (d, J = 14.3 Hz),
127.92 (d, J = 8.8 Hz), 112.31 (s), 107.17 (d, J = 19.3 Hz), 40.43 (s), 32.74 (s). 19F NMR (282 MHz, DMSO-
d6): ɷ -135.23 (dd, J = 11.2, 1.2 Hz). HRMS (C8H11NO2F+): calc. 172.0774 [M+H]+; found 172.0774.
Method B: General demethylation procedure by BBr3. Halogenated-3,4-dimethoxy-phenethylamine (1.0
mmol) was dissolved in minimal dry DCM (2 mL, dried over 3Å molecular sieves) and cooled to 0 °C by
ice bath under nitrogen atmosphere. After cooling, BBr3 in DCM (2.2 mL, 1 M solution) was added slowly
via syringe to prevent vigorous reaction. The reaction was allowed to warm to room temperature and
stirred for 1.5 hours. After this time, all reactions were observed to be complete by HPLC. If the reaction
was incomplete, extra 0.2-1.0 equivalents of BBr3 may be added. The reaction mixture was cooled again
in an ice bath, quenched by slow addition of dry MeOH (dried over 3Å molecular sieves), and allowed to
stir for 10 minutes. The resulting solution was concentrated in vacuo. The products were extracted by
washing first with Et2O and then dry MeOH to remove any borane byproducts and the leftover oil was
dried under vacuum. The product can be precipitated by dissolving the oil in minimal acetonitrile
followed by addition of minimal Et2O until precipitation occurs.
2-chloro-dopamine. 0.169 g (0.78 mmol) was reacted as above to yield 0.130 g (88.19%) of 1b as a
yellow oil. 1H NMR (300 MHz, methanol-d4): ɷ 6.81 – 6.71 (m, 2H), 3.16 (d, J = 5.1 Hz, 1H), 3.12 – 2.98
(m, 1H). 13C NMR (75 MHz, methanol-d4): ɷ 145.44, 142.13, 125.24, 120.66, 120.45, 113.35, 39.30,
30.78. HRMS (C8H11NO2Cl+): calc. 188.0478 and 190.0449 [M+H]+; found 188.0474 and 190.0446.
5-chloro-dopamine. 0.221 g (1 mmol) was reacted as above to yield 0.191 g (98.9%) of 1d as a yellow oil.
1H NMR (300 MHz, methanol-d4): ɷ 6.75 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 1.9 Hz, 1H), 3.14 (t, J = 7.6 Hz,
2H), 2.82 (t, J = 7.6 Hz, 2H). 13C NMR (75 MHz, methanol-d4): ɷ 148.13, 142.24, 129.52, 122.02, 121.46,
26
115.25, 41.96, 33.67. HRMS (C8H11NO2Cl+): calc. 188.0478 and 190.0449 [M+H]+; found 188.0481 and
190.0450.
2-bromo-dopamine. 0.201 g (0.77 mmol) was reacted as above to yield 0.171 g (94.8%) of 1e as a yellow
oil. 1H NMR (300 MHz, methanol-d4): ɷ 6.73 (q, J = 8.2 Hz, 2H), 3.20 – 3.09 (m, 1H), 3.08 – 2.97 (m, 1H).
13C NMR (75 MHz, methanol-d4): ɷ 146.93, 143.65, 126.48, 121.82, 121.78, 114.61, 40.61, 32.20. HRMS
(C8H11NO2Br+): calc. 231.9973 and 233.9953 [M+H]+; found 231.9975 and 233.9956.
5-bromo-dopamine. 0.216 g (0.8 mmol) was reacted as above to yield 0.175 g (90.8%) of 1f as a yellow
oil. 1H NMR (300 MHz, methanol-d4): ɷ 6.90 (d, J = 2.0 Hz, 1H), 6.72 (s, 1H), 3.11 (d, J = 8.0 Hz, 2H), 2.86
– 2.79 (m, 2H). 13C NMR (75 MHz, methanol-d4): ɷ 146.25, 128.70, 123.32, 115.24, 114.58, 109.51,
40.52, 32.33. HRMS (C8H11NO2Br+): calc. 231.9973 and 233.9953 [M+H]+; found 231.9972 and 233.9958.
2-iodo-dopamine (1g). 2-iodo-3,4-dimethoxy-phenethylamine (0.5 mmol) was dissolved in minimal dry
DCM (2 mL) and cooled to 0 oC under inert atmosphere. After cooling BBr3 in DCM (1.1 mL, 1 M solution)
was added slowly to prevent vigorous reaction. After addition the reaction was stirred at room
temperature for 1.5 hours. Progress was monitored by HPLC. Reaction mixture was quenched with
sieve-dried MeOH and allowed to stir for 10 minutes. The solution was concentrated under lowered
atmosphere. Product was extracted by washing the concentrated solid with Et2O to remove any borane
byproducts and the leftover white powder was dried under vacuum to yield 2-iodo-dopamine (99.5%).
1H NMR (300 MHz, methanol-d4): ɷ 6.78 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 3.10 (s, 2H), 3.07 (d, J
= 4.6 Hz, 2H). 13C NMR (75 MHz, methanol-d4): ɷ 145.88, 143.51, 130.33, 120.63, 114.62, 89.33, 39.61,
37.44. HRMS (C8H11NO2I+): calc. 279.9835 [M+H]+; found 279.9835.
27
5-iodo-dopamine (1h). 5-iodo-3,4-dimethoxy-phenethylamine(1 mmol) was dissolved in minimal dry
DCM (4 mL) and cooled to 0 oC under inert atmosphere. After cooling BBr3 in DCM (2.2 mL, 1 M solution)
was added slowly to prevent vigorous reaction. After addition the reaction was stirred at room
temperature for 1.5 hours. Progress was monitored by HPLC. Reaction mixture was quenched with
sieve-dried MeOH and allowed to stir for 10 minutes. The solution was concentrated under lowered
atmosphere. Product was extracted by washing the concentrated solid with Et2O and dry MeOH to
remove any borane byproducts and the leftover white powder was dried under vacuum to yield 5-iodo-
dopamine (98%). Additional precipitation of the dopamine product can be performed from ACN. 1H
NMR (300 MHz, methanol-d4): ɷ 6.99 (d, J = 1.6p Hz, 1H), 6.66 (d, J = 1.5p Hz, 1H), 2.89-2.98 (m, 2H),
2.63-2.70 (m, 2H). 13C NMR (75 MHz, DMSO-d6): ɷ 145.06, 144.49, 130.18, 128.54, 116.03, 85.33, 31.88,
26.50. HRMS (C8H11NO2I+): calc. 279.9835 [M+H]+; found 279.9835.
Preparation of 2-iodo-3,4-dimethoxy-phenethylamine (5g)
(2-iodo-3,4-dimethoxyphenyl)methanol. 3,4-dimethoxy-5-iodo-benzaladehyde (2.92g, 10 mmol) was
dissolved in minimal EtOH and stirred in an ice bath. After the entire solid had dissolved, NaBH4 (3.4g,
~10 mmol) was added to the mixture. The reaction progress was monitored by HPLC. After, 1.5 hours
the complete reaction mixture was concentrated under vacuum to half its original volume and poured
into a separating funnel containing water. The aqueous layer was extracted three times with DCM. It
was then concentrated to give the final product as yellow oil (2.79 g, 9.5 mmol). 1H NMR (300 MHz,
CDCl3): ɷ 7.40 – 7.27 (m, 1H), 7.02 (d, J = 1.7 Hz, 1H), 4.53 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H). UV-Vis:
216.5, 278.9 nm.
(2-iodo-3,4-dimethoxyphenyl)chloromethane. (2-iodo-3,4-dimethoxyphenyl)methanol (2.79 g, 9.5
mmol) obtained from the previous reaction was dissolved in CH2Cl2 and cooled to 0 °C in an ice bath. To
the reaction an excess of thionyl chloride (3 mL) was added dropwise. After one hour, the reaction was
concentrated in vacuo and dissolved in CH2Cl2. The organic layer was washed with water and brine. The
organic layer was concentrated again under vacuum to afford a yellow oil (2.92 g, 8.55 mmol, 90%)
28
which crystalized upon standing. HPLC analysis of the crude reaction mixture indicated that ~10% of the
starting material did not react during the chlorination procedure. 1H NMR (300 MHz, DMSO-d6): ɷ 7.36
(dd, J = 8.4, 3.3 Hz, 1H), 7.09 (dd, J = 8.5, 3.2 Hz, 1H), 4.80 (d, J = 3.2 Hz, 2H), 3.86 – 3.80 (m, 3H), 3.72 –
3.66 (m, 3H). UV-Vis: 220.0, 281.4 nm.
(2-iodo-3,4-dimethoxyphenyl)acetonitrile. (2-iodo-3,4-dimethoxyphenyl)chloromethane (2.66 g, 8.55
mmol) was dissolved in 150 mL of DMSO and allowed to stir. Sodium cyanide was added in excess to the
mixture and allowed to stir for 2.5 hours. After the reaction was checked by HPLC the mixture was
poured into a separating funnel and extracted with diethyl ether three times and washed with brine.
The product was concentrated under vacuum to afford a white crystalline solid (2.24 g, 8.52 mmol,
99.6%). 1H NMR (300 MHz, DMSO-d6): ɷ 7.27 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 3.96 (d, J = 15.8
Hz, 5H), 3.83 (s, 7H). UV-Vis: 215.9, 285.7 nm.
2-iodo-3,4-dimethoxy-phenethylamine (5g). (2-iodo-3,4-dimethoxyphenyl)acetonitrile (0.151 g, 0.5
mmol) from previous step was dissolved in minimal dry THF (1 mL) and transferred into an oven dried
three neck flask fitted with a reflux condenser. Borane in THF (1 M, 2.2 mL, 1.1 eq per methoxy group)
was added slowly to the mixture over of a time period of 10 minutes. The reaction mixture was then
refluxed overnight at 55 °C. The progress was monitored by HPLC. Once the reaction was complete, the
mixture was cooled to 0 °C and quenched with addition of H2O (1 mL) and concentrated HCl (5 mL).
After stirring for an additional hour, the mixture was diluted with H2O (25 mL) and made basic by
addition of concentrated NaOH. The mixture was then extracted three times with 97:3 DCM:MeOH and
concentrated in vacuo to yield the product (0.48 mmol, 96%). To purify, the basic extract was dissolved
in cold Et2O with stirring, concentrated HCl was added dropwise to precipitate the product as an HCl
salt. Filtration afforded a white solid 95% yield. 1H NMR (300 MHz, methanol-d4): ɷ 7.06 (dd, J = 10.8,
8.4 Hz, 1H), 6.98 (dd, J = 8.4, 3.4 Hz, 1H), 5.51 (s, 3H), 3.88 – 3.83 (m, 3H), 3.80 – 3.76 (m, 3H), 3.27 (t, J =
7.2 Hz, 1H), 2.95 – 2.77 (m, 3H). HRMS (C10H15NO2I+): calc. 308.0148 [M+H]+; found 308.0156. UV-Vis:
212.9, 279.5 nm.
Preparation of 5-iodo-3,4-dimethoxy-phenethylamine (5h)
29
(5-iodo-3,4-dimethoxyphenyl)methanol. 3, 4-dimethoxy-5-iodo-benzaladehyde (2.92 g, 10 mmol) was
dissolved in minimal EtOH and stirred in an ice bath. After the entire solid had dissolved NaBH4 (3.4 g,
~10 mmol) was added to the mixture. The progress was monitored by HPLC. After, 1.5 hours the
complete reaction mixture was concentrated under vacuum to half its volume and poured into a
separating funnel containing water. Aqueous layer was extracted three times with DCM. It was then
concentrated to give the final product as yellow oil (2.79 g, 9.5 mmol). 1H NMR (300 MHz, DMSO-d6): ɷ
7.40 – 7.27 (m, 1H), 7.02 (d, J = 1.7 Hz, 1H), 4.53 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H). UV-Vis: 214.7, 285.1
nm.
(5-iodo-3,4-dimethoxyphenyl)chloromethane. (5-iodo-3,4-dimethoxyphenyl)methanol (2.78 g, 9.4
mmol) obtained from the previous reaction was dissolved in DCM and cooled to 0 oC in an ice bath. To
the reaction an excess of thionyl chloride was added dropwise. After one hour the reaction was
concentrated in vacuo and dissolved in DCM. The organic layer was washed with H2O and brine. The
organic layer was again concentrated in vacuo to afford a yellow colored oil (2.92 g, 8.55 mmol) which
crystalized on standing. 1H NMR (300 MHz, DMSO-d6): ɷ 7.36 (dd, J = 8.4, 3.3 Hz, 1H), 7.09 (dd, J = 8.5,
3.2 Hz, 1H), 4.80 (d, J = 3.2 Hz, 2H), 3.86 – 3.80 (m, 3H), 3.72 – 3.66 (m, 3H). UV-Vis: 218.9, 283.8 nm.
(5-iodo-3,4-dimethoxyphenyl)acetonitrile. The product from the previous reaction (2.92 g, 8.55 mmol)
was dissolved in 150 mL of DMSO and allowed to stir. Sodium cyanide was added in excess (4.9 g, 10
mmol) to the mixture and allowed to stir for 2.5 hours. The reaction mixture was poured into a
separatory funnel and extracted with diethyl ether three times and washed with brine. The product was
concentrated in vacuo to give a white crystalline solid (2.24 g, 7.4 mmol). 1H NMR (300 MHz, DMSO-d6):
ɷ 7.31 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.69 (s, 2H). UV-Vis: 216.5,
285.7 nm.
30
5-iodo-3,4-dimethoxy-phenethylamine (5h). 3,4-dimethoxy-5-iodo-benzylnitrile (0.156 g, 0.5 mmol) was
dissolved in minimal dry THF (1 mL) and transferred into a dry three neck flask with a reflux condenser.
Borane in THF (1M, 2 mL) was added slowly to the mixture over of a time period of 10 minutes. The
reaction mixture was then refluxed at 55 °C for two hours. Progress was monitored by HPLC. Once the
reaction was complete the mixture was cooled to 0 °C and quenched with addition of H2O (1 mL) and
concentrated HCl (5 mL). After stirring for an additional hour the mixture was diluted with H2O (25 mL)
and made basic by addition of concentrated NaOH. Mixture was then extracted three times with DCM
and concentrated under vacuum to yield the product (0.147 g, 0.48 mmol). 1H NMR (300 MHz, CDCl3): ɷ
7.22 (s, 1H), 6.74 (s, 1H), 5.32 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H). HRMS (C10H15NO2I+): calc. 308.0148
[M+H]+; found 308.0151. UV-Vis: 214.1, 284.4 nm.
31
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... The target compounds were synthesized by the Pictet-Spengler reaction of a substituted phenethylamine with isatin or a substituted isatin. The precursors, 3,4-dimethoxyphenethylamine and 3,4,5trimethoxyphenethylamine were prepared as previously described for related amphetamine analogues [46], while 3-hydroxyphenethylamine was obtained from the demethylation of commercially available 3-methoxyphenethylamine [47]. The N-alkylation of isatin and its analogues has also been reported [48]. ...
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