Published on Web 04/04/2013
r2013 American Chemical Society
Vol. 15, No. 8
to 4‑Aminoquinolines, 1H‑Indoles,
Keith C. Coffman, Teresa A. Palazzo, Timothy P. Hartley, James C. Fettinger,
Dean J. Tantillo,* and Mark J. Kurth*
Department of Chemistry, University of California, Davis, One Shields Avenue,
Davis, California 95616, United States
firstname.lastname@example.org (synthetic aspects); email@example.com
Received March 22, 2013
4(1H)-ones from 2-nitrophenyl substituted isoxazoles are reported. When this methodology is applied to 3,5-, 4,5-, and 3,4-bis(2-
nitrophenyl)isoxazoles, chemoselective heterocyclization gives quinolin-4(1H)-ones, and 4-aminoquinolines, exclusively.
(H?H) strategies, wherein a starting heterocycle is trans-
constitute a powerful means to address diversity in dis-
covery chemistry.2We postulate that H?H strategies can
be particularly useful in providing skeletal diversity and
that this approach uniquely complements the more well
an H?H strategy in a variety of indazole f indazolone
studies4and report an extension to isoxazole based systems.
isoxazoles can be selectively reduced to their corresponding
anilines with Zn/HOAc (0 ?C, 5 min) and we set out to
explore the possibility of reducing 2-nitrophenylisoxazoles
to other useful heterocycles with Zn/HOAc. Analysis of the
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Schreiber, S. L. Nature 2009, 457, 153. (g) Thomas, G. L.; Wyatt, E. E.;
Spring, D. R. Curr. Opin. Drug Discovery Dev. 2006, 9, 700.
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ARKIVOC 2006, 7, 395. (c) Guirado, A.; Andreu, R.; Galvez, J.
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A.; Buscemi, S.; Vivona, N.; Pace, A. J. Org. Chem. 2010, 75, 8724.
(3) (a) Galloway, W. R. J. D.; Di? az-Gavil? an, M.; Isidro-Llobet, A.;
Spring, D. R. Angew. Chem., Int. Ed. 2009, 48, 1194. (b) Morton, D.;
Leach, S.; Cordier, C.; Warriner, S.; Nelson, A. Angew. Chem., Int. Ed.
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Chem. 2008, 6, 1149. (d) Kumagai, N.; Muncipinto, G.; Schreiber, S. L.
Angew. Chem., Int. Ed. 2006, 45, 3635.
(4) (a) Conrad, W. E.; Rodriguez, K. X.; Nguyen, H. H.; Fettinger,
J. C.; Haddadin, M. J.; Kurth, M. J. Org. Lett. 2012, 14, 3870. (b)
Conrad,W.E.; Fukazawa,R.;Haddadin,M.J.;Kurth,M.J. Org.Lett.
2011,13, 3138.(c)Donald,M.B.; Conrad,W. E.;Oakdale,J.S.; Butler,
J. D.; Haddadin, M. J.; Kurth, M. J. Org. Lett. 2010, 12, 2524. (d)
Oakdale, J. S.; Solano, D. M.; Fettinger, J. C.; Haddadin, M. J.; Kurth,
M. J. Org. Lett. 2009, 11, 2760.
Comb. Sci. 2012, 14, 280. (b) Butler, J. D.; Coffman, K. C.; Ziebart,
K. T.; Toney, M. D.; Kurth, M. J. Chem.;Eur. J. 2010, 16, 9002.
Org. Lett., Vol. 15, No. 8, 20132063
literature revealed that others had reported related trans-
formations. Specifically, Batra6aet al. reported that a
isoxazole leads to substituted 4-aminoquinolines (10
examples)6and Yamanaka et al. reported that Raney
nickel reduction of 4- or 5-(2-nitrophenyl)isoxazoles can
deliver 3-acylindole7(2 examples) or quinolin-4(1H)-
one7b(1 example) heterocycles, respectively.
This backdrop, coupled with the H?H potential of this
strategy, led us to explore this topic further, focusing
initially on using M (= Zn or Fe) in HOAc to trans-
form (2-nitrophenyl)isoxazoles into quinolines/indoles/
quinolin-4(1H)-ones with subsequent studies exploring
the outcomes of reducing bis(2-nitrophenyl)isoxazoles
under these same conditions. We began by preparing
(2-nitrophenyl)isoxazole 1a (Scheme 1) and found that
Fortunately, we found that Fe powder in neat HOAc at
120 ?C resulted in reductive heterocyclization to 4-amino-
quinoline 2a in 77% yield. To extend this methodology,
(Br2, CCl4,99% yield) and subsequent Fe/HOAc reduc-
tion delivered 3-bromo-4-aminoquinoline (2b). Attempts
to combine this 1b f 2b H?H transformation with sub-
sequent o-haloaniline-based coupling reactions failed.
These reductive heterocyclizations of 1a and 1b proceed
by the green aniline NH2attacking the isoxazole-derived
We next prepared isoxazole 1c by reacting 2-bromo-N-
hydroxybenzimidoyl chloride with 2-nitrophenylacety-
lene.8Fe/HOAc reduction of isoxazole 1c gave 2-(2-
bromophenyl)-4-quinolin-4(1H)-one 3c in 44% yield. We
NBS (HOAc, cat. H2SO4). Fe/HOAc reduction of 1d gave
3-bromo-2-phenyl-4-quinolin-4(1H)-one 3d (44% yield).
[f 5H-indolo[3,2-b]quinolin-11(10H)-one] failed. The re-
aniline NH2attacking the isoxazole-derived imine carbon.
With these calibrating results in hand, wherein both the
carbonyl and imine carbons can serve as the reactive
electrophile, our next objective was to evaluate whether
presumed intermediate 7 (Scheme 2) would undergo
chemoselective heterocyclization of the red aniline NH2
onto the imine or onto the carbonyl carbon. Each hetero-
cyclization of 6 would deliver a different 3-acylindole
whenR16¼ R2. Toaddressthiscompetitionquestion,both
isomers of 6 (a and b) were prepared by the base-mediated
condensation of the appropriate chlorooxime 4 with the
appropriate 1-(2-nitrophenyl)alkan-2-one 5 (f 6a; f 6b).
gave only indole 8b in 60% yield (see X-ray in Supporting
Although intermediate 7 has several possible tautomeric
forms that are all likely accessible under the reaction
conditions12and may display different modes of reactiv-
ity, the observed chemoselectivity is complete. Although
we are not certain which tautomeric form (or protonated
form thereof) of 7 preferentially reacts in the systems
described herein, we formulate our discussion around
the β-iminocarbonyl 7a.
To test the limits of imine vs carbonyl chemoselectivity,
6c was prepared (Scheme 3). Our reasoning was that a
Scheme 1. H?H Chemistry of 3- and 5-(2-Nitrophenyl)-
Scheme 2. H?H Chemistry of 4-(2-Nitrophenyl)isoxazole
(6) (a) Singh, V.; Yadav, G. P.; Maulik, P. R.; Batra, S. Synthesis
2006, 12, 1995. (b) Casnati, G.; Quilico, A.; Ricca, A.; Finzi, P. V.
Tetrahedron Lett. 1966, 7, 233. (c) Thomson, I.; Torssell, K. B. G. Acta
Chem. Scand. 1995, 49, 53.
(7) (a) Uchiyama, D.; Yabe, M.; Kameyama, H.; Sakamoto, T.;
Kondo, Y.; Yamanaka, H. Heterocycles 1996, 43, 1301. (b) Sakamoto,
T.; Kondo, Y.; Uchiyama, D.; Yamanaka, H. Tetrahedron 1991, 47,
(8) (a) Guggenheim, K. G.; Butler, J. D.; Painter, P. P.; Lorsbach,
B. A.; Tantillo, D. J.; Kurth, M. J. J. Org. Chem. 2011, 76, 5803.
(b) Meng, L.; Lorsbach, B. A.; Sparks, T. C.; Fettinger, J. C.; Kurth,
M. J. J. Comb. Chem. 2010, 12, 129.
(9) For a review of Buchwald chemistry, see: Fischer, C.; Koenig, B.
Beilstein J. Org. Chem. 2011, 7, 59.
(10) CCDC 926644 (8b), 926905 (10a), and 926645 (10b) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(11) See Supporting Information for explanation of chemoselectivity.
were computed (B3LYP/6-31þG(d,p); see SI for complete details).
It was determined that 7c had the lowest overall energy, while 7a and 7b
were 10.1 and 5.2 kcal/mol higher, respectively.
2064Org. Lett., Vol. 15, No. 8, 2013
electron density into the imine of 7 and reduce its electro-
philicity. Treating 6c with Fe/HOAc at 120 ?C resulted in
the formation of two indole products, 10a and 10b in a
combined yield of 96% and in a 60:40 ratio, respectively.
Thus, even in this “reactivity-skewed” case, the aniline
NH2prefers to attack the imine (9a f 10a), in contrast to
Yamanaka’s one asymmetrical example.7aThe structures
of 10a and 10b were established by X-ray crystallography
With these Fe/HOAc-mediated (2-nitrophenyl)isoxaz-
ole f 4-aminoquinoline/indole/quinolin-4(1H)-one H?H
results in hand, we next explored the reductive heterocycli-
zation chemistry of 3,5-, 3,4-, and 4,5-bis(2-nitrophenyl)-
reductive heterocyclization of 3,5-bis-(2-nitrophenyl)-
isoxazole 11 (Scheme 4) could produce quinolin-4(1H)-
one (w heterocyclization to 12 involving the imine via 12a)
and/or 4-aminoquinoline (w heterocyclization to 13 in-
volving the carbonyl via 13a) products. To probe this
question, 11 was synthesized.
Reductive heterocyclization of 11 with Fe/HOAc
gave quinolin-4(1H)-one 12 (22% isolated þ several uni-
dentified spots in the crude TLC); we suspected that
in situ formation of acetic anhydride and subsequent
N-acylation(s) of the reaction products complicated this
reaction mixture.13It was found that changing the acid
source from HOAc to aq. NH4Cl increased the yield of 12
to56%.Thus,11, uponreduction,leads tochemoselective
attack by the blue aniline NH2onto the imine carbon
(12a f 12) to the complete exclusion of the green aniline
NH2onto the carbonyl carbon (13a f 13). Importantly,
no 4-aminoquinoline 13 was detected in either reaction.14
Again, understanding the heterocyclization reactivity
of bis(2-nitrophenyl)isoxazole derived intermediates is
complicated by the viability of various β-iminocarbonyl
tautomers, their numerous conformations and configura-
tions, multiple possible hydrogen bonding arrays, the
effects of different conjugation pathways on the acidity/
basicity (and, potentially, iron-binding ability) of key
functional groups, and different tether lengths between
potential nucleophiles and electrophiles (6-exo-trig vs
5-exo-trig).15Despite these complications, the H?H re-
ductive heterocyclizations depicted in Schemes 2 and 4
each proceed to give only one new heterocyclic product.
The complete imine vs carbonyl chemoselectivity ob-
served for 11 suggested that 3,4-bis(2-nitrophenyl)-
isoxazole 14 (Scheme 5) should produce 3-acyl-1H-indole
17 (and, perhaps, its condensation analogue 18). To test
condensed with N-hydroxy-2-nitrobenzimidoyl chloride
(NaH in dry THF). Reductive heterocyclization of 14
withFe/HOAc gavenone of the anticipated imine-derived
indole 17; rather, 4-aminoquinoline 15 and its acylated
Obtaining 16 supports the suspected in situ formation
of acetic anhydride under these conditions.13Since neither
indole 17 or 18 was obtained, we believe that this hetero-
cyclization is prevented because the imine in 17a (f 17)
suffers deactivation by conjugation with the green aniline
NH2(similar to 6c; Scheme 3). Accepting that as an
explanation for no formation of 17, why was 4-aminoqui-
noline 15 formed to the complete exclusion of indole 19?
red nitro moiety) is the most basic site in the bis-reduction
intermediate derived from 14: this nitrogen’s lone pair is
not delocalized into the β-iminocarbonyl system whereas
the green aniline NH2would be. Consequently, in acetic
acid at 120 ?C, the red aniline is protonated (see 15a in
Scheme 5) and not available for the required nucleophilic
attack. Indeed, this factor may also explain the lack of
formation of 17.
These insights with 14 led us to predict that reductive
heterocyclization of the final system in this series, i.e.,
4,5-bis-(2-nitrophenyl)isoxazole 20 (Scheme 6), should
produce quinolin-4(1H)-one 21a (w reductive heterocycli-
blue conjugatedanilineNH2) viaintermediate20a.Totest
Scheme 3. H?H Chemistry of 4-(2-Nitrophenyl)isoxazole
Scheme 4. H?H Chemistry of 3,5-Bis(2-nitrophenyl)isoxazole
(13) For related studies, see: (a) Yamada, Y.; Segawa, M.; Sato, F.;
Kojima, T.; Sato, S. J. Mol. Catal. A: Chem. 2011, 346, 79. (b) Karimi,
E.; Teixeira, I. F.; Ribeiro, L. P.; Gomez, A.; Lago, R. M.; Penner, G.;
Kycia, S. W.; Schlaf, M. Catal. Today 2012, 190, 73. (c) Squibb, E. R.
J. Am. Chem. Soc. 1895, 17, 187 and references cited therein.
(14) HRMS calculated for 12 [C15H12N2O þ H]þ, 237.1022; found,
237.1030. HRMS results along with NMR spectra confirmed the
identity of 12. Fortunately, 13 has one less proton ([M þ H]þ:
236.1182) leading to the conclusion that one product was formed
(15) The results of quantum chemical calculations on model systems
can be found in the SI.
Org. Lett., Vol. 15, No. 8, 20132065
this prediction, 20 was synthesized by condensation of
phenyl)ethanone (NaH in dry THF). Fe/HOAc reduction
of 20 proceeded to give quinolin-4(1H)-ones 21a and 21b
(87% total yield) in a 1:1.1 ratio, respectively, confirming
formation of acetic anhydride in situ.13Importantly, in-
doles 22 and 23 were not obtained as their formation
is precluded by formation of the protonated red aniline
Since the assignment of structure 21a was complicated
spectra and the same mass, chemical shift calculations
(using the multistandard approach)16were performed
usingDFT17(see SI for details).Meanabsolutedeviations
1H NMR. The MAD for the13C NMR were 2.8, 4.8, and
lowest and within the range typically found for correctly
assigned structures,16suggesting that 21a is indeed the
product of the reduction.19
In this work, we have shown that Fe/HOAc reduction
of (2-nitrophenyl)- and bis(2-nitrophenyl)isoxazoles leads
with great chemoselectivity to a variety of useful hetero-
cycles via heterocycle?heterocycle (H?H) transforma-
tions. Although the reactivities of the systems described
above are influenced by many factors, often juxtaposed in
effect, twoempiricalguidelinesfor predictingthe products
in these systems have emerged: (1) chemoselective hetero-
cyclization onto the imine carbon is preferred unless it is
the lessbasicNH2isthe favored nucleophile. These guide-
lines will, no doubt, prove useful in facilitating the design
of additional H?H synthetic reactions of this type.
Acknowledgment. We thank the Tara K. Telford Fund
for Cystic Fibrosis Research at UC Davis, the National
Institutes of Health (GM0891583, DK072517, and
RR1973), and the National Science Foundation [CHE-
0443516/0449845/9808183, and DBIO-722538 for NMR
spectrometers, CHE-0840444 for the Dual source X-ray
diffractometer, CHE-030089 for computer support] for
generous support. We also thank Kelli M. Gottlieb
(University of California, Davis) for collection of HRMS
data and Mike Lodewyk (University of California, Davis)
for his advice with the calculations.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data for all new compounds,
material is available free of charge via the Internet at
Scheme 6. H?H Chemistry of 4,5-Bis(2-nitrophenyl)isoxazoleScheme 5. H?H Chemistry of 3,4-Bis(2-nitrophenyl)isoxazole
(16) Lodewyk, M.; Siebert, M. R.; Tantillo, D. J. Chem. Rev. 2012,
(18) Figures are in the SI.
(19) Typical 3-acylindole
quinolin-4-ones are ∼175 ppm. The carbonyl shift from the reduction
quinolin-4-one 21a was formed in the reduction. For indole related
examples, see: (a) Stokes, B. J.; Liu, S.; Driver, T. G. J. Am. Chem. Soc.
2011, 113, 4702. (b) Guchhait, S. K.; Kashyap, M.; Kamble, H. J. Org.
Chem. 2011, 76, 4853. For quinolin-4-one related examples, see: (c)
Ravi, V. K.; Xue, C. Tetrahedron 2006, 62, 9365.
13C CdO shifts are ∼190 ppm, while
The authors declare no competing financial interest.