Efficient domino approaches to multifunctionalized fused pyrroles and dibenzo[ b, e ][1,4]diazepin-1-ones

Article abstract of DOI:10.1021/ol203166c

Efficient domino approaches for the synthesis of multifunctionalized tricyclic fused pyrroles and dibenzo[b,e][1,4]diazepin-1-ones have been established. The reaction pathways were controlled by varying enaminones with different substituted patterns to gi

Full text of DOI:10.1021/ol203166c

ORGANIC
LETTERS
2012
Vol. 14, No. 3
700–703
Efficient Domino Approaches to
Multifunctionalized Fused Pyrroles and
Dibenzo[b,e][1,4]diazepin-1-ones
Bo Jiang,† Qiu-Yun Li,† Hao Zhang,† Shu-Jiang Tu,*,† Suresh Pindi,‡ and Guigen Li*,‡
School of Chemistry and Chemical Engineering and Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Xuzhou Normal University, Xuzhou,
221116, Jiangsu, P. R. China, and Department of Chemistry and Biochemistry,
Texas Tech University, Lubbock, Texas 79409-1061, United States
laotu@xznu.edu.cn; guigen.li@ttu.edu
Received November 26, 2011
ABSTRACT
Efficient domino approaches for the synthesis of multifunctionalized tricyclic fused pyrroles and dibenzo[b,e][1,4]diazepin-1-ones have been
established. The reaction pathways were controlled by varying enaminones with different substituted patterns to give a series of new fused
pyrroles and dibenzo[b,e][1,4]diazepin-1-ones selectively. The complete anti diastereoselectivity was achieved for the first reaction.
Polycyclic fused pyrroles are among the most ubiquitous
heterocycles in nature and often referred to as “privileged
structures” in drug discovery because of their biological
activities such as antibacterial, antiviral, anti-inflammatory,
antitumoral and antioxidant activities.1 In the past several
decades, many methodologies for the synthesis of poly-
cyclic fused pyrroles have been developed; most of them
involved metal-catalyzed cascade cyclization of alkynes,2
rearrangementÀcyclization of alkynol3a and alkynyl
ketones,3b cycloketone annulations,4 and 1,3-dipolar
cycloaddition reactions of muchnone derivatives.5 The
development of new convenient and step-economical ap-
proaches to this family of heterocyclic compounds, pro-
ducing less waste and byproduct, continues to be of considerable
(3) (a) Zhao, X.; Zhang, E.; Tu, Y.-Q.; Zhang, Y.-Q.; Yuan, D.-Y.;
Cao, K.; Fan, C.-A.; Zhang, F.-M. Org. Lett. 2009, 11, 4002–4004. (b)
Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan,
V. J. Am. Chem. Soc. 2007, 129, 9868–9878.
† Xuzhou Normal University.
‡ Texas Tech University.
(4) Nagafuji, P.; Cushman, M. J. Org. Chem. 1996, 61, 4999–5003.
(5) Hershenson, F. M. J. Org. Chem. 1972, 37, 3111–3113. J. Org.
Chem. 1975, 40, 740–743.
(1) (a) Pyrroles, The Synthesis, Reactivity, and Physical Properties of
Substituted Pyrroles, Part II; Jones, R. A., Ed.; Wiley: NewYork, 1992. (b)
Jacobi, P. A.; Coults, L. D.; Guo, J. S.; Leung, S. I. J. Org. Chem. 2000, 65,
205–213. (c) Furstner, A. Angew. Chem., Int. Ed. 2003, 42, 3528–3603.
(6) For key references, see: (a) Reed, S. A.; White, M. C. J. Am.
Chem. Soc. 2008, 130, 3316–3318. (b) Fraunhoffer, K. J.; White, M. C.
J. Am. Chem. Soc. 2007, 129, 7274–7276. (c) Delcamp, J. H.; White,
M. C. J. Am. Chem. Soc. 2006, 128, 15076–15077. (d) Fraunhoffer, K. J.;
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9032–9033. (e) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White,
M. C. J. Am. Chem. Soc. 2005, 127, 6970–6971. (f) Fraunhoffer, K. J.;
Bachovchin, D. A.; White, M. C. Org. Lett. 2005, 7, 223–226. (g) Chen,
M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346. (h) Reed, S. A.;
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1998, 120, 8305–8314. (e) Jones, R. A.; Bean, G. P. The Chemistry of
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346–349. (b) Kusama, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc.
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r
10.1021/ol203166c
Published on Web 01/19/2012
2012 American Chemical Society

interest and important for modern organic and medicinal
chemistry, particularly, for drug discovery and development.
However, to the best of our knowledge, a one-pot synthesis
of lactonized fused pyrroles via domino reaction involving
intramolecular allylic activation has not been well docu-
mented yet.
Scheme 1
In the meantime, there has been enormous interest in
developing the direct and selective functionalization on
allylic CÀH bonds6,7 including the direct formations of
CÀO bonds.8 These methodologies would provide the
intrinsic advantages, such as step-economy, high chemos-
electivity and easy operation leading to “benign by design”
of green synthesis.9 The design of efficient allylic lactoniza-
tion without the use of metal catalysts has remained as a
challenge at the forefront of organic chemistry.
In the past several years, we and others have developed a
series of domino reactions that provided easy access to
multiple functionalized ring structures of chemical and
pharmaceutical interest.10À12 We also established a new
three-component domino reaction for the synthesis of
multifunctionalized indole derivatives.10f The reaction is
easy to perform simply by mixing readily available car-
boxylic acids, N-aryl enaminones, and arylglyoxal mono-
hydrate under microwave (MW) irradiation. During the
continuation of this project, we found that when N-aryl
enaminones were replaced by N-amino acid counterparts,
the reaction can be directed toward lactonization to form
tricyclic fused pyrrole derivatives that can directly serve for
pharmaceutical research (Scheme 1). In this paper, we
disclose novel domino reactions for the synthesis of
polyfunctionalized and tricyclic fused pyrroles and
dibenzo[b,e][1,4]diazepin-1-ones. The attractive aspect of
the present domino reaction is shown by the fact that the
novel construction of two new rings including pyrrole and
oxazinone skeletons and the direct CÀO bond formation
can be easily achieved via metal-free allylic lactonization in
a one-pot operation.
In the initial experiment, the enaminone 1a which was
derived from glycine and 5,5-dimethylcyclohexane-1,
3-dione was subjected to the reaction with phenylglyoxal
monohydrate (2a) under microwave (MW) irradiation.
Various solvents, such as DMF, benzene, HOAc, EtOH,
HCOOH, and CF3COOH, were employed as reaction
media. Among these solvents, the first two aprotic ones
(DMF and benzene) led to poor yields (<10%) even at an
enhanced temperature of 80 °C under MW irradiation.
The weak protic solvent, EtOH, resulted in product 3a in
38% isolated yield. We found that in acetic acid, 1a was
converted into the product 3a in a good yield (81%). It
turned out that acetic acid can serve not only as a suitable
medium but also as an adequate Bronsted acid promoter
for the present reaction, while the stronger acids, HCOOH
and CF3COOH, led to much lower chemical yields
(<15%).
With these optimized conditions in hand, we next ex-
amined the scope of the reaction by using readily available
and common starting materials. As revealed in Table 1, a
range of tricyclic fused indole derivatives can be formed
under the optimized condition in good to excellent yields
(65À89%). Enaminones derived from three different ami-
no acids (R = H, Me and Et, 1aÀc) were proven to be
suitable for this reaction. Meanwhile, a variety of aryl-
glyoxal monohydrates 2 bearing either electron-withdraw-
ing or electron-donating groups can react with above
enaminones 1aÀc to give corresponding tricyclic fused
pyrrole products 3aÀx (67% À89%). The performed
enaminone substrate 1d can also participate in the reaction
yielding products 3yÀz in good yields of 65À73%. Inter-
estingly, the complete anti diatereoselectivity products
3fÀz was achieved as determined by 1H NMR and X-ray
diffractional analyses. Furthermore, pyrrolo[3,2,1-kl]phe-
noxazin-3(4H)-one 3aa can be readily generated by react-
ing 2-aminophenol-derived enaminone 1e with arylglyoxal
monohydrate under these conditions.
(7) For representative examples of sp3 CÀH bond functionalization,
see: (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 56–57. (b) Li, Z.;
Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928–
8933. (c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810–11811. (d)
Li, Z.; Cao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2007, 46, 6505–6507. (e)
Zhang, Y.; Li, C.-J. Angew. Chem., Int. Ed. 2006, 45, 1949–1952. (f) Li,
Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968–6969. (g) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2005, 127, 3672–3673. (h) Zhang, Y.; Li, C.-J. J. Am.
Chem. Soc. 2006, 128, 4242–4243. (i) Stuart, D. R.; Fagnou, K. Science
2007, 316, 1172–1175. (j) Dwight, T. A.; Rue, N. R.; Charyk, D.;
Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137–3139.
(8) Lee, J. M.; Park, E. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc.
2008, 130, 7824–7825.
(9) (a) Winterton, N. Green Chem. 2001, 3, G73–G75. (b) Anastas,
P. T.; Warner, J. C. Green Chemistry Theory and Practice; Oxford
University Press: New York, 1998.
(10) (a) Jiang, B.; Li, C.; Shi, F.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G.
J. Org. Chem. 2010, 75, 2962–2965. (b) Jiang, B.; Tu, S.-J.; Kaur, P.;
Wever, W.; Li, G. J. Am. Chem. Soc. 2009, 131, 11660–11661. (c) Jiang,
B.; Wang, X.; Shi, F.; Tu, S.-J.; Ai, T.; Ballew, A.; Li, G. J. Org. Chem.
2009, 74, 9486–9489. (d) Li, G.; Wei, H. X.; Kim, S. H.; Carducci, M. D.
Angew. Chem., Int. Ed. 2001, 40, 4277–4280. (e) Ma, N.; Jiang, B.;
Zhang, G.; Tu, S.-J.; Wever, W.; Li, G. Green Chem. 2010, 12, 1357–
1361. (f) Jiang, B.; Yi, M.-S.; Shi, F.; Tu, S.-J.; Pindi, S.; McDowell, P.;
Li, G. Chem. Commun. 2011, 808–810.
(11) For domino reactions and atom economic synthesis see refs 11
and 12: (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions
in Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Tietze, L. F.; Brazel,
C. C.; Hoelsken, S.; Magull, J.; Ringe, A. Angew. Chem., Int. Ed. 2008, 47,
5246–5249. (c) Trost, B. M. Science 1991, 254, 1471–1477. (d) Padwa, A.
Chem. Soc. Rev. 2009, 38, 3072–3081. (e) Padwa, A.; Bur, S. K. Tetra-
hedron 2007, 63, 5341–5378.
(12) (a) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 15051–15053. (b) Lu, M.; Zhu, D.; Lu, Y.;
Hou, Y.; Tan, B.; Zhong, G. Angew. Chem., Int. Ed. 2008, 47, 10187–
10191. (c) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos,
A. L. J. Am. Chem. Soc. 2009, 131, 1753–1765. (d) Yang, J. W.; Fonseca,
M. T. H.; List, B. J. Am. Chem. Soc. 2005, 127, 15036–15037.
As usual, this reaction is easy to perform simply by
mixing enaminones 1 and arylglyoxal monohydrates 2 in
HOAc under microwave irradiation and exhibits the great
Org. Lett., Vol. 14, No. 3, 2012
701

Table 1. Domino Synthesis of Polycyclic Fused Pyrroles 3 under
MWa
Figure 1. X-ray structure of 3p.
After the synthesis of tricyclic fused pyrroles was
achieved, we turned our attention to the formation of
dibenzo[b,e][1,4]diazepin-1-ones that are another family
of building blocks of pharmaceutical importance by using
benzene-1,2-diamine-derived enaminones to replace their
amino acid counterparts. Pleasantly, we found that the
reactions of arylglyoxal monohydrates (2a, 2c, 2f, and 2g)
with 3-(2-aminophenylamino)-5,5-dimethylcyclohex-2-en-
ones (1eÀg) can smoothly occur in acetic acid under the
above condition to give multifunctionalized dibenzo[b,e]-
[1,4]diazepin-1-ones 4. The reactions can proceed to com-
pletion within shorter periods of 12À18 min at 60 °C
(Scheme 2). As summarized in Table 2 the reaction also
showed a great substrate, scope in which a series of electron-
deficient or electron-withdrawing groups can be attached
aromatic rings of 3-(2-aminophenylamino)-5,5-dimethylcy-
clohex-2-enones. The same situation existed for arylglyoxal
monohydrates substrates to give good to excellent yields of
76À88% (4aÀi). For vicinal diamino moieties, both bro-
mide and chloride were proven to tolerate the microwave
irradiation at 60 °C. These functional groups provide many
opportunities for further manipulations via cross-couplings.
Similar to our previous domino processes,10aÀc the
present two new reactions showed the following attractive
characteristics: (1) the reaction can be performed at fast
reaction rates and be finished within 12À36 min; (2) energy
and manpower are saved for potential industrial produc-
tion; (3) water is formed as the major byproduct, which
belongs to environmentally friendly chemistry; (4) the
convenient workup is needed via simple filtration since
the products directly precipitate out of solution after
the reaction mixtures are diluted with cold water,
which belongs to GAP chemistry;14 (5) readily available
starting materials of enaminones15 and arylglyoxal
monohydrates16 can be employed. Besides the fact that
up to two new rings including pyrrole and oxazinone
a Reagents and conditions: HOAc (1.5 mL), 80 °C, microwave
heating. b Time (min). c Isolated yields.
substrate scope with respect to a range of enaminones and
arylglyoxal monohydrates. In all cases, the complexity of
resulting products from this new domino synthesis illus-
trates the remarkable chemo- and regioselectivity of the
cyclic sequence originated from very simple and easily
accessible starting materials. The resulting functionalities
of these tricyclic fused pyrroles offer a great flexibility for
further structural modifications. These amino lactone
analogs are directly useful for drug design, discovery,
and development and for peptide/protein mimetic re-
search. For example, after the ester group is carefully
hydrolyzed, a series of special N-protected R-amino acids
can be obtained; concurrently, a hydroxyl group is at-
tached onto the six-membered enaminone rings.13
The structural elucidation with stereo- and regiochem-
istry was unambiguously determined by NMR analysis
and X-ray diffraction analysis of single crystals that were
obtainedby slowevaporation ofthesolvent, asrepresented
by the case of [1,4]oxazino[2,3,4-hi]pyrroles 3p (Figure 1).
(14) For Group-Assistant-Purification chemistry, see: (a) Kaur, P.;
Pindi, S.; Wever, W.; Rajale, T.; Li, G. Chem. Commun. 2010, 46, 4330–
4332. (b) Kaur, P.; Pindi, S.; Wever, W.; Rajale, T.; Li, G. J. Org. Chem.
2010, 75, 5144–5150. (c) Kattuboina, A.; Li, G. Tetrahedron Lett. 2008,
49, 1573–1577. (d) Kattuboina, A.; Kaur, P.; Ai, T.; Li, G. Chem. Biol.
Drug Des. 2008, 71, 216–223. (e) Kattuboina, A.; Kaur, P.; Nguyen, T.;
Li, G. Tetrahedron Lett. 2008, 49, 3722–3724. (f) Kaur, P.; Nguyen, T.;
Li, G. Eur. J. Org. Chem. 2009, 912–916.
(13) (a) Paquette, L. A. J. Org. Chem. 1964, 29, 3447–3449. (b)
Paquette, L. A.; Broadhurst, M. J. J. Org. Chem. 1973, 38, 1886–1893.
(c) Sato, E.; Ikeda, Y.; Kanaoka, Y. Lieb. Ann. Chem. 1989, 8, 781–788.
702
Org. Lett., Vol. 14, No. 3, 2012

the intermediate A toward dehydration to yield imine-
isomeric enaminones B, which subsequently undergo intra-
molecular cyclization leading to hydroindoles C. The
7-position of hydroindoles C can be activated to form an
electrophilic center for coupling with carboxylic acid to
give the final products, tricyclic fused pyrroles 3.
Scheme 2
Scheme 3
Table 2. Domino Synthesis of Dibenzo[b,e][1,4]diazepin-1-ones
4 under MWa
entry
4
R3
Ar
time, min yieldb/%
1
2
3
4
5
6
7
8
9
4a, H (1e)
4b H (1e)
4c H (1e)
4d Cl (1f)
4e Cl (1f)
phenyl (2a)
12
14
18
14
14
18
16
17
14
85
84
80
84
81
76
87
82
88
4-chlorophenyl (2c)
4-tolyl (2g)
phenyl (2a)
4-bromophenyl (2f)
4-tolyl (2g)
4f
Cl (1f)
4g Me (1 g) phenyl (2a)
4h Me (1 g) 4-chlorophenyl (2c)
4i
Me (1 g) 4-tolyl (2g)
In conclusion, novel domino reactions have been estab-
lished for the synthesis of polyfunctionalized and tricyclic
fused dibenzo[b,e][1,4]diazepin-1-one and pyrrole deriva-
tives that are important building blocks for organic synth-
esis and medicinal chemistry. The reaction is easy to
perform simply by mixing common reactants under micro-
wave irradiation. The reaction can be performed to
completion within 12À36 min with water as the major
byproduct. The complete anti diastereoselectivity was
achieved for the formation of tricyclic fused pyrrole deri-
vatives. The workup and purification are convenient with-
out the need of using traditional purifications of chromatog-
raphy and recrystallization.
a Reagents and conditions: HOAc (1.5 mL), 60 °C, microwave
heating. b Isolated yield.
skeletons were formed in a one-pot operation without
using any metal catalysts or promoters, this rapid and
efficient synthesis is truly rare, interesting and useful in
organic chemistry, which was made possible by microwave
irradiation while normal heating led to very limited success.
The mechanisms of these chemoselective domino reactions
are proposed and shown in Scheme 3. An initial nucleophilic
reaction of enaminones with protonated arylglyoxal mono-
hydrates affords intermediate A. The key divergent steps in
the present domino pathways depend on the nucleophilicity
of amino group on the phenyl ring and carboxylic acid
functionality. With the stronger nucleophilicity, NH2 group
prefers to undergo second nucleophilic substitution of pro-
tonated arylglyoxal monohydrate and results in polysubsti-
tuted dibenzo[b,e][1,4]diazepin-1-ones 4. The weak nucleo-
philicity of hydroxy moiety from carboxylic acid can direct
Acknowledgment. We are grateful for financial support
from the NSFC (Nos. 20928001, 21072163, 21002083, and
21102124) and PADA of Jiangsu Higher Education In-
stitutions, Jiangsu Science and Technology Support Pro-
gram (No. BE2011045), Robert A. Welch Foundation
(D-1361), and NIH (R21DA031860-01). We thank
Mr. Patrick McDowell for his assistance.
(15) The preparation of enaminones, see: (a) Tu, S. J.; Li, C. M.; Li,
G.; Cao, L. J.; Shao, Q. Q.; Zhou, D. X.; Jiang, B.; Zhou, J. F.; Xiao, M.
J. Comb. Chem. 2007, 9, 1144–1148. (b) Bhosale, R. S.; Suryawanshi,
P. A.; Ingle, S. A.; Lokhande, M. N.; More, S. P.; Mane, S. B.; Bhosale,
S. V.; Pawar, R. P. Synlett 2006, 933–935.
(16) For the preparation of arylglyoxal monohydrates, see: (a)
Wang, K.; Shi, W.; Jia, J.; Chen, S., M.; Ma, H., M. Talanta 2009, 77,
1795–1799. (b) Fodor, G.; Kovacs, O. J. Am. Chem. Soc. 1949, 71, 1045–
1048.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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