InBr3-mediated one-pot synthesis of 2-(polyhydroxylatedalkyl)-N- aryl-/-alkylpyrroles from 1,2-cyclopropa-3-pyranone and amines

Article abstract of DOI:10.1021/ol401489x

An efficient one-pot synthesis of polyhydroxyalkyl-substituted pyrroles from 1,2-cyclopropa-3-pyranones with primary amines is reported. With 10% of InBr₃ as the catalyst, both aryl- and alkylamines as well as various 1,2-cyclopropa-3-pyranones

Full text of DOI:10.1021/ol401489x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
InBr3‑Mediated One-Pot Synthesis
of 2‑(Polyhydroxylatedalkyl)‑N‑aryl-/-
alkylpyrroles from 1,2-Cyclopropa-3-
pyranone and Amines
Pingyuan Wang,†,‡ Shanshan Song,§ Zehong Miao,§ Guangfu Yang,*,† and
Ao Zhang*,‡
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan, China, and CAS Key Laboratory
of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory
(SOMCL), and State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica (SIMM), Chinese Academy of Sciences, Shanghai, China
aozhang@mail.shcnc.ac.cn; gfyang@mail.ccnu.edu.cn
Received May 28, 2013
ABSTRACT
An efficient one-pot synthesis of polyhydroxyalkyl-substituted pyrroles from 1,2-cyclopropa-3-pyranones with primary amines is reported. With
10% of InBr3 as the catalyst, both aryl- and alkylamines as well as various 1,2-cyclopropa-3-pyranones are well tolerated. This method is highly
appealing because of its one-pot process, mild reaction conditions, substrate simplicity, and broad substrate scope.
Pyrroles are a unique class of heterocycles commonly
identified in natural products and pharmacological agents.1
Although construction of the pyrrole ring can be realized
by a number of classical synthetic methods, including the
Hantzsch reaction2 and the PaalꢀKnorr synthesis,3,4 many
new approaches have been recently reported leading to
formation of multifunctionalized pyrroles. Among these,
cyclopropanes activated by one or two electron-withdrawing
substituents have attracted tremendous interest for facile
construction of functionalized pyrroles through ring-
opening followed by a cycloaddition process.5ꢀ16 For example,
Charette and co-workers8 reported that cyclopropanes
† Central China Normal University.
‡ CAS Key Laboratory of Receptor Research and Synthetic Organic &
Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia
Medica.
§ State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica.
(2) Hantzsch, A. Ber. 1890, 23, 1474–1483.
(3) Paal, C. Ber. 1885, 18, 367–371.
(4) Knorr, L. Ber. 1885, 18, 299–311.
(1) (a) Battersby, A. R. Nat. Prod. Rep. 2000, 17, 507–526. (b) Walsh,
C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep.
2006, 23, 517–531. (c) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213–
7256. (d) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. Chem. Rev. 2008, 108,
(5) For recent reviews on DꢀA cyclopropanes and their reactivity,
see: (a) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051–3060.
(b) De Simone, F.; Waser, J. Synthesis 2009, 3353–3374. (c) Agrawal, D.;
Yadav, V. K. Chem. Commun. 2008, 6471–6488. (d) Yu, M.; Pagenkopf,
B. L. Tetrahedron 2005, 61, 321–347. (e) Reissig, H.-U.; Zimmer, R.
Chem. Rev. 2003, 103, 1151–1196.
(6) (a) Yu, M.; Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125, 8122–
8123. (b) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099–5101. (c) Yu,
M.; Pantos, G. D.; Sessler, J. L.; Pagenkopf, B. L. Org. Lett. 2004, 6,
1057–1059.
ꢀ
ꢀ
264–287. (e) Kral, V.; Davis, J.; Andrievsky, A.; Kralova, J.; Synytsya,
ꢀ
A.; Pouckova, P.; Sessler, J. L. J. Med. Chem. 2002, 45, 1073–1078. (f)
Bandyopadhyay, D.; Mukherjee, S.; Granados, J. C.; Short, J. D.;
Banik, B. K. Eur. J. Med. Chem. 2012, 50, 209–215. (g) McArthur,
K. A.; Mitchell, S. S.; Tsueng, G.; White, D. J.; Grodberg, J.; Lam, K. S.;
Potts, B. C. J. Nat. Prod. 2008, 71, 1732–1737. (h) Khanna, I. K.; Weier,
R. M.; Yu, Y.; Collins, P. W.; Miyashiro, J. M.; Koboldt, C. M.;
Veenhuizen, A. W.; Currie, J. L.; Seibert, K.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1619–1633.
r
10.1021/ol401489x
XXXX American Chemical Society

with double activation by nitro and acyl groups can readily
react with arylamines to facilitate N-arylpyrroles (eq a,
Scheme 1). Meanwhile, Kerr’s group reported that cyclo-
propanes doubly activated by two ester groups can react
with nitrones affording N-arylpyrroles after Pd-catalyzed
dehydrocarbonylation and dehydration (eq b, Scheme 1).9
Alternatively, using donorꢀacceptor (DA) cyclopro-
panes5 (e.g., 1) as the dipole precursor, Pagenkopf6 re-
ported a novel [3 þ 2] dipolar cycloaddition with various
nitriles using catalytic TMSOTf to generate N-nonsubsti-
tuted pyrroles 2 (eq c, Scheme 1). These new approaches
not only showcase the power of advances in organic
methodology but also provide pyrroles bearing unique
substitution patterns that are useful for high-throughput-
screening and for further structural manipulation. In our
drug discovery program, we are interested in multisubsti-
tuted pyrroles, especially with N-aryl and N-alkyl substi-
tuents, and the above-mentioned methods either suffer
from multiple reaction steps or are limited in the synthesis
of N-aryl- and N-H-pyrroles. Therefore, new strategies for
versatile synthesis of both N-aryl- and N-alkylpyrroles,
together with simple reaction substrate and a short and
facile reaction process, are still highly useful. To this end,
we recently found that using glucose-derived cyclopropane
ketone 3,16 a substrate lacking the 10-esteric group as
that in 1 and without the trouble of diastereomeric selec-
tivity during its preparation, reacts with various amines
under the catalysis of a Lewis acid to afford N-substituted
pyrroles 5. This strategy represents a versatile method
to access both N-aryl- and N-alkylpyrroles bearing a
C2-(polyhydroxylated alkyl) substituent.
Scheme 1. Recently Reported and Our Newly Discovered
Synthesis of Pyrroles from Cyclopropanes
to that for preparation of 2, the reaction of glucose-derived
cyclopropane 3 (1.0 equiv) with 4-chloroaniline (1.2 equiv)
under 30% TMSOTf at ꢀ78 °C did not occur. Gradually
elevating reaction temperature to rt led to major decom-
position of carbohydrate 3, while pyrrole 5awas isolated as
a minor product in appropriately 10% yield. The structure
of 5a was assigned by all spectroscopic data (1H and
13C NMR, MS, HRMS, HSQC). Meanwhile, HMBC cor-
relations characteristic of structure 5a were also observed
(Scheme 1).
Since there is no report on reactions of carbohydrate-
derived 1,2-cyclopropa-3-pyranones (e.g., 3) with amines,
and compounds 5 are new N-substituted pyrroles with
pharmacological potentials, we decided to optimize the
reaction conditions to enable compounds 5 to be produced
as the major products.
We initially attempted to replace aryl nitriles with
arylamines to react with ester 1; unfortunately, no reaction
was observed. We then employed DA cyclopropane 3
to react with arylamines and speculated that without
assistance of the C10-esteric group as in 1, ring-opening
of cyclopropane 3 at C1ꢀC10 would be difficult; instead,
ring-opening at C1ꢀC2 should be preferred because of the
ring strain, thus leading to a Ferrier-rearrangement prod-
uct 4.17,18 To our surprise, following a procedure similar
With the reaction of cyclopropane 3 and 4-chloroaniline
as the model reaction, we first screened various Lewis
acids (see the Supporting Information). Using BF3 Et2O
as the catalyst, the reaction did not occur at rt, and high
temperature led to decomposition of cyclopropane 3.
Fortunately, 30 mol % of indium halides19 were found to
efficiently promote the reaction and the yield of the prod-
uct was dependent on the acidicity of the indium halides.
(7) Kaschel, J.; Schneider, T. F.; Kratzert, D.; Stalke, D.; Werz, D. B.
Angew. Chem., Int. Ed. 2012, 51, 11153–11156.
(8) Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313–2136.
(9) (a) Humenny, W. J.; Kyriacou, P.; Sapeta, K.; Karadeolian, A.;
Kerr, M. A. Angew. Chem., Int. Ed. 2012, 51, 11088–11091. (b) Lebold,
T. P.; Kerr, M. A. Org. Lett. 2009, 11, 4354–4357. (c) Carson, C. A.;
Kerr, M. A. J. Org. Chem. 2005, 70, 8242–8244.
(10) Morra, N. A.; Morales, C. L.; Bajtos, B.; Wang, X.; Jang, H.;
Wang, J.; Yu, M.; Pagenkopf, B. L. Adv. Synth. Catal. 2006, 348, 2385–
2390.
(11) Morales, C. L.; Pagenkopf, B. L. Org. Lett. 2008, 10, 157–159.
(12) Li, W.; Shi, M. J. Org. Chem. 2008, 73, 4151–4154.
(13) Moustafa, M. M. A. R.; Pagenkopf, B. L. Org. Lett. 2010, 12,
3168–3171.
(14) Parsons, A. T.; Smith, A. G.; Neel, A. J.; Johnson, J. S. J. Am.
Chem. Soc. 2010, 132, 9688–9692.
(15) Sathishkannan, G.; Srinivasan, K. Org. Lett. 2011, 13, 6002–
6005.
(16) (a) Sridhar, P. R.; Venukumar, P. Org. Lett 2012, 14, 5558–5561.
(b) Batchelor, R.; Harvey, J. E.; Teesdale-Spittle, P.; Hoberg, J. O.
Tetrahedron Lett. 2009, 50, 7283–7285. (c) Cousins, G. S.; Hoberg, J. O.
Chem. Soc. Rev. 2000, 29, 165–174.
3
(18) For recent examples involving oxepanes, see: (a) Batchelor, R.;
Hoberg, J. O. Tetrahedron Lett. 2003, 44, 9043–9045. (b) Batchelor, R.;
Harvey, J. E.; Northcote, P. T.; Teesdale-Spittle, P.; Hoberg, J. O.
J. Org. Chem. 2009, 74, 7627–7632. (c) Hewitt, R. J.; Harvey, J. E. J. Org.
Chem. 2010, 75, 955–958. (d) Hewitt, R. J.; Harvey, J. E. Chem.
Commun. 2011, 47, 421–423. (e) Sridhar, P. R.; Seshadri, K.; Reddy,
G. M. Chem. Commun. 2012, 48, 756–758.
(19) Contributions from our group involving InBr3 as the catalyst:
(a) Li, F.; Ding, C.; Wang, M.; Yao, Q.; Zhang, A. J. Org. Chem. 2011,
76, 2820–2827. (b) Du, C.; Li, F.; Zhang, X.; Hu, W.; Yao, Q.; Zhang, A.
J. Org. Chem. 2011, 76, 8833–8839. (c) Wang, P.; Wang, M.; Zhang, X.;
Yang, G.; Zhang, A. Tetrahedron 2012, 68, 5386–5390.
(17) Ferrier, R. J.; Prasad, N. J. J. Chem. Soc., Chem. Commun. 1969,
570–575.
B
Org. Lett., Vol. XX, No. XX, XXXX

Figure 2. N-Alkyl-2-(polyhydroxylkyl)pyrroles.
or phenylethylamine also took part in the reaction very well
and afforded corresponding pyrroles 5n and 5o in 86%
and 73% yield, respectively. Similarly, cyclohexylamine
and propylamine were also suitable substrates, and the
corresponding N-alkylpyrroles 5p and 5q were obtained in
84% and 89% yields, respectively.
Meanwhile, representative variations in the carbohy-
drate-derived cyclopropane substrates were also explored.
As listed in Scheme 2, cyclopropane ketones 6ꢀ8 were
prepared by cylopropanation of corresponding glycals16
and subjected to reaction with benzylamine under cataly-
sis of InBr3 (10%) in refluxing CH2Cl2. All three reac-
tions proceeded nicely and generated the corresponding
N-benzylpyrroles 9ꢀ11 in 63ꢀ95% yields. These results
further illustrate the generality of this novel strategy.
Figure 1. N-Aryl-2-(polyhydroxylkyl)pyrroles.
The strongest acid InBr3 afforded compound 5a in highest
yield of 82%. Meanwhile, it was found that in the refluxing
CH2Cl2 (40 °C), the amount of Lewis acid loading could be
reduced from 0.3 to 0.1 equiv (based on cyclopropane 3)
without significant effect on the yield. In addition, some
other Lewis acids, e.g., Dy(OTf)3 and Yb(OTf)3, were also
investigated, but lower yields were obtained.
On the basis of the results obtained above, 10% of InBr3
was the optimal catalyst (in refluxing CH2Cl2), and the
expected N-arylpyrrole 5a was successfully obtained as the
major product in 80% isolated yield. With this encoura-
ging result, we next evaluated the scope of the reaction
by reacting cyclopropane 3 with various arylamines. As
shown in Figure 1, all arylamines used herein took part in
the reactions smoothly and yielded the expected N-aryl-
substituted pyrroles 5aꢀl in 55ꢀ92% yield. Arylamines
with electron-donating groups generally gave slightly
higher yields (5c, 5f, 5h, 5i vs 5d, 5e). Arylamine with a
morpholinyl substituent also gave good yield (5i, 92%).
A close comparison of the yields between products 5f
(89%) and 5k (60%) indicated that the steric effect in
arylamines played a role and ortho-substituted substrates
gave lower yields.
Scheme 2. Reactions of Benzylamine with Cyclopropanes 6ꢀ8
To rationalize the reaction outcomes, we proposed a
tentative mechanism. As shown in Scheme 3, treating
ketone 3 with an appropriate aryl- or alkylamine would
generate imine I.7 Ring expansion of the iminocyclopro-
pane I followed by an intramolecular nucleophilic attack
of the imino-N to the C1 of the oxonium ion16,18 would yield
species III. Ring cleavage followed by dehydrogenation
would finally deliver pyrroles 5.
To further explore the limitation of the amine substrates
and to expand the diversity of the products, we then
investigated the reactions of cyclopropane 3 with various
alkylamines. It was found that all the reactions using
alkylamines proceeded readily, and the expected products
were obtained in even higher yields. As shown in Figure 2,
reactions of cyclopropane 3 with benzylamine yielded
N-benzylpyrrole 5m in 93% yield. (R)-2-Methylbenzylamine
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 1. Cytotoxicity of Selected Compounds Against Cancer
Cell Lines20,21
Scheme 3. Proposed Mechanism
IC50 (μM)
compd
5b
KB
KB/VCR
A549
14.71
10.99
10.05
77.84
1.88
8.37
7.80
20.56
12.07
13.66
84.72
4.61
5o
5n
7.65
11
57.99
54.39
etoposide
5b, 5o, and 5n were much more potent than pyrrole 11,
with IC50 values around 10 μM, indicating that the poly-
hydroxyalkyl substituents on the pyrroles are important.
In summary, we have reported an efficient one-pot
synthesis of polyhydroxylalkyl-substituted N-alkyl- and
N-alkylpyrroles from 1,2-cyclopropa-3-pyranones with
both aryl- and alkylamines with 10% of InBr3 as the
catalyst. This method is highly appealing due to the
substrate simplicity, mild reaction conditions, broad sub-
strate scope, and cheap catalyst. The resulting pyrroles
show moderate cytotoxicity against several cancer cell lines
and would serve as compound templates worthy of further
structural modification.
According to our proposed mechanism, the 7-hydroxy
group in product 5b was derived directly from the carbo-
hydrate substrate 3; therefore, the absolute configuration
of C7 should be R same as that in 3. To confirm the
diastereomeric purity of 5, pyrrole 5b was oxidized to
ketone using the DessꢀMartin reagent and then subjected
to NaBH4 reduction to regenerate the alcohol products as
a diastereomeric mixture (see the Supporting Information).
With the newly resulting diastereomeric mixture as the
comparison, the diastereomeric ratio of compound 5b was
determined to be 99.0%.
Acknowledgment. This work was supported by grants
from the Distinguished Young Scholars of Chinese NSF
(81125021), National Science & TechnologyMajor Project
on “Key New Drug Creation and Manufacturing Program”,
China (2012ZX09103-101-035, 2012ZX09301001-001).
Supporting grants from the “Interdisciplinary Cooperation
Team” Program for Science and Technology Innovation
(CAS), and grant from the State Key Laboratory of
Drug Research (SIMM1302KF-08), Shanghai Institute of
Materia Medica were also appreciated.
The cytotoxicity of representative pyrrole compounds
5b, 5o, 5n, and 11, as well as clinical anticancer drug
etoposide (as positive control),20,21 was evaluated against
several cancer cell lines, including humanlung cancer A549
cells, squamous carcinoma KB cells, vincristine-resistant
KB/VCR cells, and human lung cancer H460 cells, and
the results are summarized in Table 1. Compared to the
potency of etoposide, our new synthetic pyrroles showed
moderate activity in all the four cancer cells, but slightly
higher sensitivity toward vincristine-resistant KB/VCR
cell was observed for the pyrroles, opposite from the
selectivity profile of etoposide. In addition, compounds
Supporting Information Available. Experimental details
and full spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Manzo, S. G.; Zhou, Z.; Wang, Y.-Q.; Marinello, J.; He, J.-X;
Li, Y.-C.; Ding, J.; Capranico, G.; Miao, Z.-H. Cancer Res. 2012, 72,
5363–5373.
(21) Wang, D.; Song, S.; Tian, Y.; Xu, Y.; Miao, Z.; Zhang, A. J. Nat.
Prod. 2013, 76, 974–978.
The authors declare no competing financial interest.
D
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