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Diazonamide synthetic studies. Reactivity of N-unsubstituted benzofuro[2,3-b]indolines

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Benzofuro[2,3-b]indolines undergo ring opening in the presence of base to generate 3H-indolines. The latter can rearrange into 3-arylindoles through an intramolecular transfer of the methoxycarbonyl moiety from quaternary carbon to oxygen of phenol. The intermediate 3H-indolines can be isolated upon DMAP-catalyzed O-acylation of the phenol moiety with Boc2O.
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Benzofuro[2,3-b]indoline is a core structure in a number
of natural products such as the marine metabolite diazon-
amide A (1), azonazine (2), and voacalgine A (3), a repre-
sentative of the pleiocarpamine family of alkaloids (Fig. 1).
Among them, diazonamide A (1) is an especially important
synthetic target1 because it exerts nanomolar cytotoxicity
against a broad panel of human tumor cell lines.2 Not
surprisingly, the development of methods for the assembly
and further functionalization of benzofuro[2,3-b]indoline
heterocyclic system has been a focus of research efforts.3, 4
A majority of the natural products contains an N-sub-
stituted benzofuro[2,3-b]indoline scaffold and only
diazonamide A (1) possesses the N-unsubstituted tetra-
cyclic core. In the context of diazonamide A total synthe-
sis, this structural feature imposes challenges associated
with a potentially labile nature of the N-unsubstituted
cyclic hemiaminal moiety. Thus, our group5 and Moody6
have observed fragmentation of the benzofuro[2,3-b]-
indoline to indolic side products. For example, during
attempted Suzuki cross coupling of the N-unsubstituted
benzofuro[2,3-b]indoline 4a with boronate 5a in the
presence of base, we obtained 3-arylindole 6a as a major
product (86% yield, Scheme 1, Conditions A). Installation
of an N-MOM protecting group in the benzofuro[2,3-b]-
indoline moiety helped to avoid the fragmentation of the
cyclic hemiaminal in the Suzuki cross coupling and
allowed for the desired biaryl 7a to be isolated in 82%
yield (Scheme 1, Conditions A).7 The formation of the
undesired 3-arylindole 6b was encountered also in the
Stille cross coupling involving the N-unsubstituted
tetracyclic stannane 4b under virtually neutral conditions
Химия гетероциклических соединений 2015, 51(7), 613–620
Лaтвийcкий
инcтитут
opгaничecкoгo
cинтeзa
© 2015 Лaтвийcкий инcтитут opгaничecкoгo cинтeзa
Diazonamide synthetic studies.
Reactivity of N-unsubstituted benzofuro[2,3-b]indolines
Ilga Mutule1, Toms Kalnins1, Edwin Vedejs1,2, Edgars Suna1*
1 Latvian Institute of Organic Synthesis,
21 Aizkraukles St., Riga LV-1006, Latvia; e-mail: edgars@osi.lv
2 Department of Chemistry, University of Michigan,
Ann Arbor, Michigan 48109, U. S. A.; e-mail: edved@umich.edu Submitted June 30, 2015
Accepted July 16, 2015
Benzofuro[2,3-b]indolines undergo ring opening in the presence of base to generate 3H-indolines. The latter can rearrange into 3-aryl-
indoles through an intramolecular transfer of the methoxycarbonyl moiety from quaternary carbon to oxygen of phenol. The inte rmediate
3H-indolines can be isolated upon DMAP-catalyzed O-acylation of the phenol moiety with Boc2O.
Keywords: diazonamide, DMAP, hemiaminal, indole, 3H-indoline.
Figure 1. Benzofuro[2,3-b]indoline motif-containing representa-
tive natural products.
614
(49%, Scheme 1, Conditions B).5a The observed fragmenta-
tion of the cyclic hemiaminals to 3-arylindoles under basic
or neutral cross-coupling conditions prompted us to investi-
gate stability and reactivity of the N-unsubstituted benzo-
furo[2,3-b]indoline 4a.
The hemiaminal rac-4a was found to be stable in CDCl3
solution at room temperature, but addition of Et3N
(2 equiv) resulted in very slow formation of 3-arylindole 8a
(Scheme 2). After 24 h at room temperature only trace
amounts (<5%) of compound 8a were formed and complete
conversion of the hemiaminal rac-4a to indole 8a required
57 days at room temperature. We hypothesized that the
formation of 3-arylindole 8a would proceed through an
initial formation of 3H-indoline intermediate 9a.
Unfortunately, we could not observe the formation of
ring-opening intermediates such as compound 9a by NMR
spectroscopy in the base-facilitated fragmentation of
hemiaminal rac-4a to indole 8a. Possibly, the lifetime of
putative intermediate 9a was too short on the timescale of
the NMR experiment. Therefore, an electrophilic reagent
was sought to trap the intermediate 9a. Boc2O was chosen
as the trapping reagent because it did not react with the
starting benzofuro[2,3-b]indoline rac-4a in the absence of
base (Boc2O in CH2Cl2, rt, 24 h or neat Boc2O, rt, 24 h, or
Boc2O, ZrCl4, MeCN, rt, 24 h). Disappointingly, addition of
Boc2O (2 equiv) to the hemiaminal rac-4a in the presence
of Et3N (2 equiv) in CDCl3 returned no detectable amounts
of O-Boc-protected phenol 9a or any other intermediates
derived from the ring opening of the hemiaminal rac-4a.
The unreacted hemiaminal rac-4a (<5% conversion) was
the only species observed after 24 h at rt. However, we were
pleased to see that addition of catalytic amounts (10 mol %)
of DMAP to the mixture of hemiaminal rac-4a, Boc2O, and
Et3N brought about a rapid conversion of the starting
hemiaminal rac-4a (>95% after 30 min at rt) and formation
of O-Boc-phenol 10a as a major product (66%) together
with N-Boc-indole 11a* (18%, Scheme 3).
Importantly, a control experiment without added Boc2O
(hemiaminal rac-4a, 5 equiv of Et3N, and 0.5 equiv of
DMAP in CDCl3 at room temperature) showed only
unreacted hemiaminal rac-4a after 24 h (<5% conversion).
Chem. Heterocycl. Compd. 2015, 51(7), 613–620 [Химия гетероцикл. соединений 2015, 51(7), 613–620]
Scheme 1
Fragmentation of N-unsubstituted benzofuro[2,3-b]indolines 4a,b
Scheme 2
Base-mediated fragmentation of hemiaminal rac-4a
Scheme 3
* Isolated compound 11a was converted to N-deprotected
indole 8a under thermal conditions (PhMe, 160°C, 30 min)8 to
confirm the structural assignment for compound 8a, which was
based on the NMR experiments.
Ring opening of the hemiaminal rac-4a in the presence of Boc2O
615
Evidently, DMAP-catalyzed trapping of the equilibrating
ring-opened intermediate 9a with Boc2O to form O-Boc-
phenol 10a facilitates fragmentation of the benzofuro[2,3-b]-
indoline rac-4a by shifting the equilibrium between
compounds 4a and 9a toward the latter.
Surprisingly, DMAP-catalyzed transformation of the
hemiaminal rac-4a to O-Boc-phenol 10a and indole 11a
proceeded even without the added triethylamine. Thus,
10 mol % of DMAP effected the complete conversion of
the benzofuro[2,3-b]indoline rac-4a within 1.5 h (Table 1,
entry 1). Apparently, the facile formation of O-Boc-phenol
10a is achieved by tert-butoxide, the strong base formed in
situ in the reaction of DMAP with Boc2O.* Notably, electron-
releasing substituents at position 7 of the benzofuro[2,3-b]-
indoline (rac-4c X = Me and rac-4d X = 2-MeC6H4)
considerably slowed down the rearrangement of the corres-
ponding hemiaminals (from 1.5 to 72 h; entries 2, 3).
Furthermore, the formation of 3-arylindoles 11c,d was not
observed for these substrates and 3H-indoles 10c,d were
the only products. In sharp contrast, 7-cyanobenzofuro[2,3-b]-
indoline rac-4e did not undergo ring opening under stan-
dard conditions (entry 4). Instead, N-Boc-protected hemi-
aminal 12e was isolated in almost quantitative yield (98%).
The isolation of O-Boc phenols 10a,c,d provide eviden-
ce that the ring opening of the benzofuro[2,3-b]indolines
4a,ce is the first step of the multistep rearrangement
process (Scheme 4). Presumably, electron-withdrawing
substituents (X = CN) in the benzofuro[2,3-b]indoline
rac-4e stabilize the tetracyclic system and prevent the ring
opening to form compound 9e. Hence, DMAP-catalyzed
N-acylation of benzofuro[2,3-b]indoline rac-4e with Boc2O
affords the ring-closed N-Boc hemiaminal 12e. Other
benzofuro[2,3-b]indolines rac-4a,c,d apparently lack the
stabilization by substituent and exist in the equilibrium
with the corresponding phenols 9a,c,d. For these sub-
strates, N-acylation rates with Boc2O are presumably
slower compared to the competing O-acylation of the
corresponding opened forms 9a,c,d. Possibly, diminished
N-acylation rates of the benzofuro[2,3-b]indolines rac-4a,c,d
compared to rac-4e are the result of steric hindrance around
the nitrogen atom introduced by ortho substituents X. Since a
CN group is the smallest substituent in the series, increased
steric hindrance imposed by other substituents (X = Me,
2-MeC6H4, Br) may account for reduced rates of the
catalytic N-acylation of tetracycles rac-4a,c,d with Boc2O.
Hence, the competing DMAP-catalyzed O-acylation with
Boc2O facilitates the opening of the benzofuro[2,3-b]-
indolines rac-4a,c,d to form 3H-indolines 10a,c,d.
In the absence of external electrophile such as Boc2O
phenols 9 may undergo an intramolecular acyl transfer via
tetrahedral intermediate 13 with indole acting as a good
leaving group to form the N-unsubstituted indole 14.
Notably, for phenol 9a, the intramolecular acyl transfer
from carbon to oxygen to afford compound 14a was a
competing side reaction (yield 15%, Table 1, entry 1) to
DMAP-catalyzed intermolecular O-acylation with the
excess of Boc2O (2 equiv). Possibly, the better leaving
group ability of the 7-bromoindole moiety compared to
7-methyl- and 7-(2-methylphenyl)-substituted analogs
ensures sufficiently rapid decomposition of the putative
tetrahedral intermediate 13a to form compound 14a
(Scheme 4). It should be noted that in the presence of
DMAP/Boc2O anionic versions of intermediates rac-4a,ce
and 9a,ce could also be involved,9 but they are not
illustrated in the Scheme 4 for simplicity.
In summary, the fragmentation reaction of benzofuro-
[2,3-b]indolines rac-4a,ce has been studied. They undergo
ring opening to the corresponding phenols 9a,c,d in the
presence of a base such as Et3N or DMAP/Boc2O.9 The
intermediate phenols 9a,c,d can be isolated upon DMAP-
catalyzed O-acylation with Boc2O. Without the added
Chem. Heterocycl. Compd. 2015, 51(7), 613–620 [Химия гетероцикл. соединений 2015, 51(7), 613–620]
Entry Hemiaminal* X Product yield**, %
Reaction time, h 10a,ce 11a,ce 12a,ce
1 4a Br 1.5 85*** 15***
2 4c Me 72 91
3 4d 2-MeC6H4 72 81
4 4e CN 20 98
* Racemic, diastereomerically pure hemiaminals 4a,ce were used.
** Isolated yields.
*** Yields established by 1H NMR spectroscopy.
Table 1. Influence of substituents on the fragmentation of hemiaminals rac-4a,ce
* As has been demonstrated by Hassner,9 the reaction of DMAP with
Boc2O produces ion pair: N-Boc-pyridinium tert-butoxycarboxylate.
The tert-butoxycarboxylate decomposes to CO2 and the strong base
tert-butoxide.
616
Boc2O, phenols 9 undergo an intramolecular transfer of the
methoxycarbonyl group via the tetrahedral intermediate 13
with indole acting as a good leaving group to form
O-methoxycarbonyl phenols 14. The proposed mechanism
differs from an alternative base-mediated pathway sug-
gested by Moody for N-substituted benzofuro[2,3-b]-
indolines,6 which would involve an initial hydrolysis of
ester 15 by aqueous base, followed by decarboxylation of
the intermediate carboxylic acid 16 with concomitant
formation of N-substituted aromatic indole 17 (Scheme 5).
According to the mechanism proposed by Moody,
phenolate acts as a good leaving group resulting in the
formation of O-unsubstituted N-protected phenol 17 as the
fragmentation product. It should be noted, that we observed
the formation of N-unsubstituted O-methoxycarbonyl-
phenols 6a and 14a with the methoxycarbonyl moiety
originating from the ester moiety at the quaternary carbon
in the starting benzofuro[2,3-b]indolines, hence suggesting
that our mechanism differs from that of Moody. Therefore,
benzofuro[2,3-b]indolines may undergo fragmentation to
3-arylindoles by two alternative mechanisms, depending on
the reaction conditions.
Experimental
IR spectra were recorded on a Shimadzu IR Prestige21
FTIR spectrometer in thin film. 1H and 13C NMR spectra
were recorded at ambient temperature on a Varian Mercury
NMR spectrometer (400 and 100 MHz, respectively) in
CDCl3 with TMS as internal standard. High-resolution
mass spectra (ESI) were obtained on a Waters Tof Synapt
GSi mass spectrometer. Preparative HPLC was performed
on a Waters SunFireTM Prep Silica OBDTMm, 30 × 100 mm,
mobile phase 10% EtOAc in petroleum ether, flow rate
35 ml/min. Analytical thin-layer chromatography (TLC)
was performed on precoated silica gel F-254 plates
(Merck).
Unless otherwise noted, all chemicals were used as
obtained from commercial sources and all reactions were
performed under argon atmosphere in an oven-dried (120°C)
glassware. Toluene was distilled from sodium/benzo-
phenone prior the use. Anhydrous 1,4-dioxane (Acros),
N,N-dimethylacetamide (Acros), and toluene were degassed
by multiple freeze-pump-thaw cycles, and handled using
Schlenk technique. Anhydrous CH2Cl2 was obtained by
passing commercially available solvent through activated
alumina columns. Commercially available anhydrous
K3PO4 was heated at 250°C for 3 h and stored in a glove
box under argon atmosphere.
Methyl 2-(benzyloxy)-7-methyl-6,10b-dihydro-5aH-
benzofuro[2,3-b]indole-10b-carboxylate (4c). N-MOM-
protected hemiaminal rac-4a7 (25 mg, 0.055 mmol) and
PdCl2(dppf) (2.1 mg, 0.0025 mmol) were placed into a 5 ml
pressure vial and suspended in anhydrous dioxane (1.0 ml)
under nitrogen atmosphere. Then dimethylzinc (1.2 M
Chem. Heterocycl. Compd. 2015, 51(7), 613–620 [Химия гетероцикл. соединений 2015, 51(7), 613–620]
Scheme 4
Working mechanism for DMAP-catalyzed fragmentation of benzofuro[2,3-b]indolines rac-4a,ce
Mechanism suggested by Moody
Scheme 5
617
solution in toluene, 83 µl, 0.10 mmol) was added and the
resulting clear yellow solution was heated in an oil bath at
100°C for 1 h. The off-white precipitate was filtered
through a pad of Celite and the pad was washed with
EtOAc (25 ml). The filtrate was washed with water (10 ml)
and the layers were separated. The aqueous layer was back-
extracted with EtOAc (2×10 ml) and the combined organic
extracts were washed with brine, dried over Na2SO4, and
concentrated (rotary evaporator). The residue was purified
on silica gel column using gradient elution from 2% EtOAc
in petroleum ether to 25% EtOAc in petroleum ether to
afford colorless oil (15 mg) comprising a mixture of
MOM-protected and MOM-deprotected products. To
achieve complete cleavage of the N-MOM protecting group
in the product, the isolated mixture of products was
dissolved in MeOH (2 ml) and aqueous concentrated HCl
(50 µl) was added. The colorless solution was stirred at
room temperature for 5 h, basified with aqueous sat. NaHCO3
solution to pH 7 and extracted with CH2Cl2 (3 × 10 ml). The
combined organic extracts were washed with brine, dried
over Na2SO4, and concentrated (rotary evaporator). Column
chromatography on silica gel using gradient elution from
2% EtOAc in petroleum ether to 25% EtOAc in petroleum
ether afforded the product as colorless oil (9 mg, 47%,
Fig. 2). Rf 0.43 (petroleum ether – EtOAc, 5:4). IR spectrum,
ν, cm–1: 3395 (NH), 1736 (C=O). 1H NMR spectrum,
δ, ppm (J, Hz): 7.45–7.30 (6H, m); 7.27 (1H, dd, J = 2.7,
J = 0.4); 6.95 (1H, ddd, J = 7.5, J = 1.2, J = 0.7); 6.86 (1H,
d, J = 3.5); 6.78 (1H, dd, J = 8.7, J = 2.7); 6.75 (1H, t,
J = 7.5); 6.72 (1H, dd, J = 8.7, J = 0.4); 5.00 (2H, s); 4.88
(1H, d, J = 3.5); 3.80 (3H, s); 2.16 (3H, s). 13C{1H} NMR
spectrum, δ, ppm: 170.3; 153.8; 152.7; 146.1; 137.3; 130.5;
128.7; 128.1; 127.8; 127.7; 126.8; 121.8; 120.4; 119.5;
115.8; 112.1; 110.2; 100.3; 71.3; 66.6; 53.2; 16.9.
Found, m/z: 388.1542 [M+H]+. C24H22NO4. Calculated, m/z:
388.1549.
Methyl 2-(benzyloxy)-7-(ortho-tolyl)-6,10b-dihydro-
5aH-benzofuro[2,3-b]indole-10b-carboxylate (4d). N-MOM
-protected rac-4a7 (50 mg, 0.11 mmol), ortho-tolylboronic
acid pinacolyl ester (26 mg, 0.12 mmol), (PCy3)2Pd(η2-O2)7
(14 mg, 20 mol %), and oven-dried K3PO4 (85 mg,
0.44 mmol) were weighed into a 5 ml pressure vial in a
glove box (argon atmosphere). Anhydrous degassed
toluene (2.5 ml) was added, and the reaction mixture was
heated in an oil bath at 110°C for 18 h, then diluted with
EtOAc (15 ml) and washed with water (15 ml). The
aqueous layer was back-extracted with EtOAc (15 ml).
Combined organic extracts were washed with brine, dried
over Na2SO4, filtered, and concentrated (rotary evaporator).
Column chromatography on silica gel using gradient
elution from 2% EtOAc in petroleum ether to 25% EtOAc
in petroleum ether afforded product as yellow oil (38 mg)
comprising a mixture of MOM-protected and MOM-
deprotected products according to 1H NMR. To achieve
complete cleavage of N-MOM protecting group in the
product, the mixture of products was dissolved in MeOH
(3 ml) and aqueous concentrated HCl (100 µl) was added.
The reaction mixture was stirred at room temperature for
20 h, then basified to pH 7 using aqueous saturated
NaHCO3 solution and extracted with CH2Cl2 (3 × 15 ml).
The combined organic extracts were washed with brine,
dried over Na2SO4, and concentrated (rotary evaporator).
Purification of the residue on the silica gel column using
gradient elution from 2% EtOAc in petroleum ether to 25%
EtOAc in petroleum ether afforded the biaryl 4d as color-
less oil (17 mg, 33%, Fig. 3). Rf 0.53 (petroleum ether –
EtOAc, 5:2). IR spectrum, ν, cm–1: 3394 (N–H), 1733
(C=O). 1H NMR spectrum, δ, ppm: 7.49 (1H, d, J = 7.6);
7.47–7.33 (5H, m); 7.32 (1H, d, J = 2.7); 7.28–7.20 (4H,
m); 7.00 (1H, dd, J = 7.6, J = 1.1); 6.85 (1H, t, J = 7.6);
6.80 (1H, dd, J = 8.7, J = 2.7); 6.77 (1H, d, J = 2.7); 6.71
(1H, d, J = 8.7); 5.03 (2H, s); 4.83 (1H, s); 3.84 (3H, s);
2.18 (3H, s). 13C{1H} NMR spectrum, δ, ppm: 170.2;
153.8; 152.9; 145.3; 137.6; 137.3; 136.6 (br. s); 130.6;
130.3; 129.9 (br. s); 128.7; 128.1; 128.0; 127.8; 126.7
(br. s); 126.2; 123.4 (br. s); 123.3; 119.7; 115.8; 112.0;
110.2; 99.9; 71.3; 66.5; 53.3; 20.1. Found, m/z: 464.1861
[M+H]+. C30H26NO4. Calculated, m/z: 464.1862.
Methyl 2-(benzyloxy)-7-cyano-6,10b-dihydro-5aH-
benzofuro[2,3-b]indole-10b-carboxylate (4e). N-MOM-
protected rac-4a7 (100 mg, 0.20 mmol), Pd2(dba)3 (9.2 mg,
0.005 mmol), dppf (11.1 mg, 0.10 mmol), and Zn(CN)2
(16.6 mg, 0.14 mmol) were weighed into a 5 ml pressure
vial and anhydrous degassed DMA (2.5 ml) was added
under nitrogen. The suspension was stirred at 110°C for
2 h, filtered through a pad of Celite, and the pad was
washed with EtOAc (30 ml). The filtrate was washed with
water (2 × 15 ml), brine, dried over Na2SO4, and concen-
trated (rotary evaporator). Purification of a brown oily
residue on silica gel column using gradient elution from
7% EtOAc in petroleum ether to 56% EtOAc in petroleum
ether was followed by additional purification on prepara-
tive TLC using 25% acetone in petroleum ether and
afforded methyl 2-(benzyloxy)-7-cyano-6-(methoxymethyl)-
Chem. Heterocycl. Compd. 2015, 51(7), 613–620 [Химия гетероцикл. соединений 2015, 51(7), 613–620]
Figure 2. 1H and 13C NMR assignment for compound 4c. Figure 3. 1H and 13C NMR assignment for compound 4d.
618
6,10b-dihydro-5aH-benzofuro[2,3-b]indole-10b-carboxy-
late as a brownish oil (46 mg, 53%). Rf 0.37 (petroleum
ether – EtOAc, 5:2). IR spectrum, ν, cm–1: 2222 (C≡N),
1738 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 7.69 (1H,
ddd, J = 7.5, J = 1.2, J = 0.5); 7.43–7.30 (6H, m); 7.17 (1H,
d, J = 2.6); 6.86–6.76 (4H, m); 5.39 (1H, d, J = 10.9); 5.04
(1H, d, J = 10.9); 5.00 (2H, s); 3.82 (3H, s); 3.47 (3H, s).
13C{1H} NMR spectrum, δ, ppm: 169.0; 154.2; 152.3;
147.9; 137.0; 134.0; 130.3; 128.9; 128.7; 128.2; 127.7;
126.8; 120.2; 117.7; 116.5; 111.9; 110.9; 103.1; 92.1; 77.1;
71.3; 63.6; 55.3; 53.6. Found, m/z: 411.1344 [M–CH3O]+.
C25H19N2O4. Calculated, m/z: 411.1345.
The N-MOM-protected hemiaminal from above (40 mg,
0.09 mmol) was dissolved in MeOH (2 ml), aqueous
concentrated HCl (300 µl) was added, and the reaction
mixture was stirred at room temperature for 36 h, then
basified with aqueous saturated NaHCO3 to pH 7 and
extracted with CH2Cl2 (3 × 10 ml). The combined organic
extracts were washed with brine, dried over Na2SO4, and
concentrated (rotary evaporator). The residue was purified
on silica gel column using gradient elution from 7% EtOAc
in petroleum ether to 60% EtOAc in petroleum ether to
afford compound 4e as a colorless solid (18 mg, 56%, Fig. 4).
Rf 0.38 (petroleum etherEtOAc, 5:4). IR spectrum, ν, cm–1:
3335 (N–H), 2224 (C≡N), 1728 (C=O). 1H NMR spectrum,
δ, ppm (J, Hz): 7.65 (1H, d, J = 7.5); 7.44–7.31 (5H, m);
7.29 (1H, dd, J = 7.9, J = 1.1); 7.19 (1H, d, J = 2.6); 6.88
(1H, d, J = 2.2); 6.83 (1H, dd, J = 8.8, J = 2.6); 6.78 (1H, t,
J = 7.7); 6.77 (1H, d, J = 8.8); 5.75 (1H, s); 5.01 (2H, s);
3.83 (3H, s). 13C{1H} NMR spectrum, δ, ppm: 169.2;
154.1; 152. 6; 150.6; 137.0; 131.7; 128. 9; 128.7; 128.3;
128.2; 127.7; 126.6; 119.7; 116.7; 116.4; 111.7; 110.8;
99.3; 91.8; 71.3; 66.0; 53.6. Found, m/z: 399.1326 [M+H]+.
C24H19N2O4. Calculated, m/z: 399.1345.
4-(Benzyloxy)-2-[3-(2-methyloxazol-5-yl)-1-(triiso-
propylsilyl)-1H,1'H-[4,7'-biindol]-3'-yl]phenyl methyl
carbonate (6a). A hemiaminal rac-4a7 (100 mg, 0.22 mmol),
N-TIPS indolyl boronate 5a7 (106 mg, 0.22 mmol),
(PCy3)2Pd(η2-O2)7 (30 mg, 20 mol %), and an oven-dried
K3PO4 (188 mg, 0.88 mmol) were weighed into an oven-
dried pressure vial in a glove box (argon atmosphere).
Anhydrous degassed dioxane (4 ml) was added, and the
reaction mixture was heated in an oil bath at 100°C for
20 h, then diluted with EtOAc (25 ml) and washed with
water (25 ml). The aqueous layer was back-extracted with
EtOAc (25 ml). Combined organic extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated
(rotary evaporator). Column chromatography on silica gel
using gradient elution from 5% acetone in hexanes to 25%
acetone in hexanes afforded the product 6a as off-white
foam (130 mg, 86%, Fig. 5). Rf 0.19 (petroleum ether –
EtOAc, 5:2). IR spectrum, ν, cm–1: 3421 (N–H), 1763
(C=O). 1H NMR spectrum, δ, ppm (J, Hz): 8.16 (1H, d,
J = 1.5); 7.60 (1H, dd, J = 6.6, J = 2.7); 7.56 (1H, dd,
J = 7.5, J = 1.5); 7.49–7.38 (5H, m); 7.38–7.29 (5H, m);
7.16 (1H, d, J = 8.9); 7.06–6.98 (2H, m); 6.90 (1H, dd,
J = 8.9, J = 3.1); 6.16 (1H, s); 5.12 (2H, s); 3.70 (3H, s);
1.80 (3H, s); 1.75 (3H, septet, J = 7.5); 1.20 (18H, d,
J = 7.5). 13C{1H}NMR spectrum, δ, ppm: 159.9; 156.7;
154.4; 145.7; 142.1; 142.0; 136.9; 135.0; 132.2; 131.0;
129.1; 128.7; 128.0; 127.4; 127.1; 125.6; 125.0; 123.7;
123.2; 122.9; 122.5; 122.3; 120.0; 118.5; 116.3; 113.8;
113.3; 111.8; 107.2; 70.4; 55.3; 18.2; 13.0; 12.8. Found,
m/z: 726.3351 [M+H]+. C44H48N3O5Si. Calculated, m/z:
726.3363.
4-(Benzyloxy)-2-(7-bromo-1H-indol-3-yl)phenyl methyl
carbonate (8a). A solution of hemiaminal rac-4a7 (10 mg,
0.022 mmol) in CDCl3 (0.7 ml) was placed in NMR tube
and Et3N (6 µl, 0.044 mmol) was added. The solution was
kept at room temperature and progress of the reaction was
monitored by 1H NMR. Full conversion to the starting
hemiaminal bromide rac-4a was observed after 57 days.
For structure assignment and compound characterization
purposes, the indole 8a was synthesized from N-Boc-indole
11a. Accordingly, a solution of N-Boc-indole 11a (30 mg,
0.054 mmol) in toluene (2.0 ml) was heated at 160°C in a
closed 5 ml pressure vial for 30 h, then the solvent was
evaporated and the brownish solid residue was purified on
silica gel column using gradient elution from 7% EtOAc in
petroleum ether to 60% EtOAc in petroleum ether. Indole
8a was obtained as colorless foam (23 mg, 94%, Fig. 6).
Rf 0.38 (petroleum etherEtOAc, 5:2). IR spectrum, ν, cm–1:
3422 (N–H), 1761 (C=O). 1H NMR spectrum, δ, ppm
(J, Hz): 8.48 (1H, s); 7.55 (1H, d, J = 8.0); 7.47–7.32 (7H,
m); 7.22 (1H, d, J = 3.0); 7.19 (1H, d, J = 8.9); 7.01 (1H, t,
J = 7.8); 6.95 (1H, dd, J = 8.9, J = 3.0); 5.12 (2H, s); 3.70
(3H, s). 13C {1H} NMR spectrum, δ, ppm: 156.9; 154.4;
142.3; 137.0; 135.9; 128.8; 128.5; 128.2; 127.6; 127.5;
124.9; 124.3; 123.4; 121.7; 119.4; 116.7; 114.0; 113.6; 105.0;
Chem. Heterocycl. Compd. 2015, 51(7), 613–620 [Химия гетероцикл. соединений 2015, 51(7), 613–620]
Figure 4. 1H and 13C NMR assignment for compound 4e.
Figure 5. 1H and 13C NMR assignment for compound 6a.
619
70.6; 55.5. Found, m/z: 452.0479 [M+H]+. C23H19BrNO4.
Calculated, m/z: 452.0497.
Ring opening of the hemiaminal rac-4a in the pre-
sence of Boc2O. The hemiaminal rac-4a7 (880 mg,
1.64 mmol) was dissolved in anhydrous CH2Cl2 (70 ml)
under nitrogen atmosphere, and the resulting solution was
cooled to 0°C. Then, Et3N (3.4 ml, 24.6 mmol) was added
dropwise, followed by Boc2O (892 mg, 4.10 mmol) and
DMAP (50 mg, 0.40 mmol). The colorless solution was
stirred at room temperature for 30 min, then the solvent
was evaporated and the residue was purified on silica gel
column (80 ml SiO2, mobile phase 30% EtOAc in
petroleum ether) to afford a mixture of O-Boc-phenol 10a
and N-Boc-indole 11a. These two products were separated
on the preparative HPLC.
Methyl 3-{5-(benzyloxy)-7-bromo-2-[(tert-butoxy-
carbonyl)oxy]phenyl}-3H-indole-3-carboxylate (10a) was
obtained as a colorless foam (597 mg, 66%, Fig. 7). Rf 0.47
(petroleum ether – EtOAc, 5:2). IR spectrum, ν, cm–1: 1761
(C=O), 1743 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 8.27
(1H, s); 7.62 (1H, d, J = 8.0); 7.45 (1H, d, J = 7.5); 7.34–7.17
(7H, m); 6.93 (1H, dd, J = 9.0, J = 3.0); 6.32 (1H, d, J = 3.0);
4.87 (1H, ABq, JAB = 12.0); 4.86 (1H, ABq, JAB = 12.0);
3.70 (3H, s); 1.55 (9H, s). 13C{1H} NMR spectrum, δ, ppm:
170.3; 168.6; 156.3; 154.1; 151.2; 143.5; 136.7; 136.1;
133.1; 128.5; 128.0; 127.3; 126.1; 123.9; 115.5; 115.1;
113.9; 84.0; 71.5; 70.3; 53.0; 27.6. Found, m/z: 574.0834
[M+Na]+. C28H26BrNNaO6. Calculated, m/z: 574.0841.
tert-Butyl 3-{5-(benzyloxy)-7-bromo-2-[(methoxy-
carbonyl)oxy]phenyl}-1H-indole-1-carboxylate (11a) was
obtained as a colorless oil (167 mg, 18%, Fig. 8). Rf 0.53
(petroleum ether – EtOAc, 5:2). IR spectrum, ν, cm–1: 1763
(C=O), 1738 (C=O). 1H NMR spectrum, δ, ppm (J, Hz):
7.62 (1H, s); 7.55 (1H, dd, J = 7.8, J = 1.0); 7.46–7.32 (6H,
m); 7.21 (1H, d, J = 8.9); 7.11 (1H, d, J = 3.0); 7.08 (1H, t,
J = 7.8); 7.01 (1H, dd, J = 8.9, J = 3.0); 5.11 (2H, s); 3.71
(3H, s); 1.67 (9H, s). 13C{1H} NMR spectrum, δ, ppm:
156.8; 154.5; 148.4; 142.6; 136.8; 134.1; 133.0; 130.3;
128.9; 128.2 (2 peaks overlapping); 127.6; 126.8; 124.4;
123.6; 119.5; 117.0; 116.3; 115.1; 108.1; 84.7; 70.6; 55.5;
28.1. Found, m/z: 452.0484 [M–(CH3)3COC(O)+2H]+.
C23H19BrNO4. Calculated, m/z: 452.0497.
Methyl 3-{5-(benzyloxy)-2-[(tert-butoxycarbonyl)oxy]-
phenyl}-7-methyl-3H-indole-3-carboxylate (10c). A solution
of hemiaminal 4c (20 mg, 0.052 mmol, Fig. 9) in CDCl3
(0.7 ml) was placed in NMR tube and DMAP (0.64 mg,
0.0052 mmol) was added, followed with Boc2O (28 mg,
0.130 mmol). The clear colorless solution was kept at room
temperature and progress of the reaction was monitored by
1H NMR. Complete conversion of the starting hemiaminal
4c was observed after 72 h. The solution was poured onto
the silica gel column and purified using CH2Cl2 as a mobile
phase to afford product 10c (23 mg, 91%) as a yellowish
oil. Rf 0.45 (petroleum ether – EtOAc, 5:2). IR spectrum,
ν, cm–1: 1761 (C=O), 1733 (C=O). 1H NMR spectrum, δ,
ppm (J, Hz): 8.20 (1H, s); 7.35 (1H, dd, J = 7.2, J = 1.0);
7.34–7.22 (7H, m); 7.22 (1H, d, J = 9.0); 6.92 (1H, dd,
J = 9.0, J = 3.0); 6.37 (1H, d, J = 3.0); 4.86 (2H, s); 3.70
(3H, s); 2.61 (3H, s); 1.58 (9H, s). 13C{1H} NMR spectrum,
δ, ppm: 169.6; 168.4; 156.5; 154.5; 151.6; 144.0; 134.5;
134.9; 131.8; 131.3; 128.7; 128.2; 127.7; 127.4; 127.2;
123.9; 122.5; 115.0; 114.2; 84.0; 70.5; 70.3; 53.1; 27.9;
17.0. Found, m/z: 510.1886 [M+Na]+. C29H29NNaO6. Cal-
culated, m/z: 510.1892.
Chem. Heterocycl. Compd. 2015, 51(7), 613–620 [Химия гетероцикл. соединений 2015, 51(7), 613–620]
Figure 6. 1H and 13C NMR assignment for compound 8a.
Figure 7. 1H and 13C NMR assignment for compound 10a.
Figure 8. 1H and 13C NMR assignment for compound 11a.
Figure 9. 1H and 13C NMR assignment for compound 10c.
620
Methyl 3-{5-(benzyloxy)-2-[(tert-butoxycarbonyl)oxy]-
phenyl}-7-(ortho-tolyl)-3H-indole-3-carboxylate (10d).
To a solution of hemiaminal 4d (30 mg, 0.065 mmol) in
anhydrous CH2Cl2 (4 ml) under nitrogen atmosphere, DMAP
(0.8 mg, 0.0065 mmol) and Boc2O (36 mg, 0.16 mmol)
were added. The clear colorless solution was stirred at
room temperature for 72 h. The solvent was evaporated and
the residue was purified on silica gel column using gradient
elution from 2% EtOAc in petroleum ether to 25% EtOAc
in petroleum ether to afford the product 10d as yellow oil
(30 mg, 82%, Fig. 10). Rf 0.49 (petroleum ether EtOAc,
5:2). IR spectrum, ν, cm–1: 1760 (C=O), 1742 (C=O).
1H NMR spectrum, δ, ppm (J, Hz): 8.21 (1H, s); 7.55 (1H,
dd, J = 6.4, J = 2.3); 7.43–7.27 (11H, m); 7.24 (1H, d,
J = 9.0); 6.96 (1H, dd, J = 9.0, J = 3.0); 6.44 (1H, d,
J = 3.0); 4.90, 4.88 (2H, ABq, J = 12.0); 3.73 (3H, s); 2.19
(3H, s); 1.57 (9H, s). 13C{1H} NMR spectrum, δ, ppm:
169.5; 169.3; 156.6; 154.3; 153.8; 151.7; 144.0; 138.1;
136.5; 136.4; 135.7; 135.2; 131.3; 130.3; 128.8; 128.3;
128.0; 127.7; 127.4; 127.2; 125.7; 124.0; 124.0; 115.1;
114.2; 70.6; 70.2; 53.1; 27.9; 20.6. Found, m/z: 586.2222
[M+Na]+. C35H33NO6Na. Calculated, m/z: 586.2206.
6-tert-Butyl 10b-methyl 2-(benzyloxy)-7-cyano-6H-
[1]benzofuro[2,3-b]indole-6,10b(5aH)-dicarboxylate (rac-12e).
A solution of hemiaminal rac-4e (15 mg, 0.038 mmol) in
CDCl3 (0.7 ml) was placed in NMR tube and DMAP (0.46 mg,
0.0038 mmol) was added, followed with Boc2O (21 mg,
0.094 mmol). The clear colorless solution was kept at room
temperature and progress of the reaction was monitored by
1H NMR spectroscopy. Complete conversion of the starting
hemiaminal 4e was observed after 20 h. The solution was
poured onto the silica gel column and purified using
CH2Cl2 as a mobile phase to afford rac-12e as a yellowish
oil (16 mg, 83%, Fig. 11). Rf 0.38 (petroleum ether –
EtOAc, 5:2). IR spectrum, ν, cm–1: 2231 (C≡N), 1811
(C=O), 1742 (C=O). 1H NMR spectrum, δ, ppm (J, Hz):
7.72 (1H, d, J = 7.7); 7.55 (1H, d, J = 7.8); 7.44–7.30 (5H,
m); 7.22 (1H, d, J = 2.5); 7.14 (1H, dd, J = 7.7, J = 7.8);
7.13 (1H, s); 6.82 (1H, dd, J = 8.8, J = 2.5); 6.77 (1H, d,
J = 8.8); 5.01 (2H, s); 3.84 (3H, s); 1.67 (9H, s).
13C{1H} NMR spectrum, δ, ppm: 168.5; 154.2; 152.4;
151.3; 142.2; 136.9; 134.6; 133.1; 129.1; 128.8; 128.2;
127.7; 126.1; 124.9; 116.9; 116.4; 111.7; 110.7; 102.4;
100.2; 85.1; 71.3; 63.7; 53.8; 28.2. Found, m/z: 499.1850
[M+H]+. C29H27N2O6Na. Calculated, m/z: 499.1869.
We thank European Social Fund (Project No.
1DP/1.1.1.2.0/13/APIA/VIAA/006) for financial support of
this research. E. Vedejs thanks InnovaBalt project for
funding.
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Chem. Heterocycl. Compd. 2015, 51(7), 613–620 [Химия гетероцикл. соединений 2015, 51(7), 613–620]
Figure 10. 1H and 13C NMR assignment for compound 10d.
Figure 11. 1H and 13C NMR assignment for compound 12e.
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