Enantioselective NHC-Catalyzed [3+3] Annulation of α-Bromoenals with 2-Aminobenzimidazoles

Article abstract of DOI:10.1021/acs.orglett.9b04054

A chiral carbene-catalyzed [3+3] annulation of α-bromoenals with 2-aminobenzimidazoles providing pyrimido[1,2-a]benzimidazoles has been described. This protocol features a broad scope and good functional group tolerance. Biological studies indicated that the formed pyrimido[1,2-a]benzimidazole exhibited moderate cytotoxic activity against tumor cells.

Full text of DOI:10.1021/acs.orglett.9b04054

pubs.acs.org/OrgLett
Letter
Enantioselective NHC-Catalyzed [3+3] Annulation of α‑Bromoenals
with 2‑Aminobenzimidazoles
Yangxi Xie, Luoyuan Li, Shaofa Sun,* Zijun Wu, Ming Lang, Di Jiang, and Jian Wang*
Cite This: https://dx.doi.org/10.1021/acs.orglett.9b04054
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A chiral carbene-catalyzed [3+3] annulation of α-bromoenals with 2-aminobenzimidazoles providing pyrimido[1,2-
a]benzimidazoles has been described. This protocol features a broad scope and good functional group tolerance. Biological studies
indicated that the formed pyrimido[1,2-a]benzimidazole exhibited moderate cytotoxic activity against tumor cells.
ver the past few decades, N-heterocyclic carbene
(NHC) organocatalysis has received a great deal of
Scheme 1. Strategies for NHC-Catalyzed [3+n] Annulation
and Biologically Important Benzoimidazoles
O
attention in synthetic chemistry.1 To date, a series of NHC-
bound intermediates (e.g., Breslow intermediate,2 acyl anion
equivalent,1j,3 homoenolate,4 etc.1c,k,5) have been developed
and utilized in NHC-catalyzed organic transformations. In
particular, the NHC-bounded α,β-unsaturated acyl azo-
liums1k,5c have broadly participated in [3+n] annulation
reactions1k,5c,6−8 (Scheme 1a). Notably, the nucleophiles used
in these reactions mostly belong to “C” synthons.6,7 Only a
few “N” nucleophiles have been successfully explored in such
annulations.8 In 2013, the group of Hui reported a NHC-
catalyzed cascade reaction via the use of 2′-aminophenyle-
none as the “N” nucleophile.8a Later, Chi et al. disclosed a
[3+2] annulation of activated hydrazines with α,β-unsaturated
acyl azoliums.8b Recently, Du8c and our group8d independ-
ently reported an example of NHC-catalyzed [3+4]
annulation of α-bromoenals with o-aryleneamines. The groups
of Chi and Biju independently reported a NHC-catalyzed
[3+3] annulation of thioamides with α-bromoenals for
enantioselective synthesis of thiazinones.8f,g Thus, the
development of catalytic annulation of “N” nucleophiles
with NHC-bounded α,β-unsaturated acyl azoliums remains a
highly significant reaction.
Herein, we report an unprecedented NHC-catalyzed [3+3]
annulation of α-bromoenals with 2-aminobenzimidazoles
(Scheme 1c). The resulting pyrimido[1,2-a]benzimidazole
structures are useful scaffolds present in several pharmaceut-
icals such as the HCV inhibitor, magenta, and CRF1 receptor
antagonist (Scheme 1d).9
Received: November 13, 2019
We commenced the study with the model reaction of 2-
bromoenal (1a) and 2-aminobenzimidazole (2a). Chiral
triazolium catalysts A−H were screened first. To our delight,
https://dx.doi.org/10.1021/acs.orglett.9b04054
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
indanol-derived triazolium catalyst A10 delivered the product
3a in 46% yield with 15% ee (Table 1, entry 1). However,
catalyst B11 (Ar = C6F5) exhibited almost no reactivity (Table
1, entry 2). In addition, L-phenylalanine-derived triazolium
catalyst C12 or D13 also gave poor results (Table 1, entry 3 or
4, respectively). To gain a deeper understanding of a catalyst
skeleton, morpholinone-derived triazolium catalysts E−H14,15
were then screened. Catalyst E14 gave a moderate 59% ee and
30% yield (Table 1, entry 5). Gratifyingly, morpholinone-
derived triazolium catalyst G,15b bearing an N-2,6-
(MeO)2C6H3 substituent, afforded 3a in 71% yield and 93%
ee (Table 1, entry 7). Further investigation of bases and
solvents showed that K2HPO4 and acetone were proven to be
an ideal base and medium (Table 1, entry 10, 81% yield, 93%
ee).
selectivities and moderate yields (3l−n). Even the presence of
an alkyl group or ester group at the β-position of 2-bromoenal
afforded the product with moderate to good yields (3o and
3p).
a
Table 1. Optimization of the Reaction Conditions
With the optimized reaction conditions in hand, we
examined the generality of the reaction with various 2-
bromoenals. As shown in Scheme 2, substituents at the para
b
c
entry
catalyst
base
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
A
B
C
D
E
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DBU
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
CH2Cl2
CH3CN
acetone
acetone
acetone
46
trace
57
trace
30
55
71
24
34
81
39
69
65
84
80
57
15
−
11
a
Scheme 2. Scope of α-Bromoenals
−
59
77
93
40
<5
93
85
88
85
92
92
91
F
G
H
G
G
G
G
G
G
G
G
9
10
11
12
13
14
d
15
d,e
16
a
Reaction conditions: 1a (0.15 mmol), 2a (0.1 mmol), catalyst (20
mol %), base (0.15 mmol), solvent (1.0 mL), room temperature, 4 Å
b
molecular sieves, 12 h. Isolated yield after flash column
c
chromatography. Enantiomeric ratio (ee) determined by chiral
d
e
HPLC. With 10 mol % catalyst G. Without 4 Å molecular sieves.
Further investigation of the scope of 2-aminobenzimidaoles
was conducted (Scheme 3). 5,6-Disubstituted 2-amino-
benzimidaoles afforded the corresponding products with
good to excellent enantioselectivities (4a−c). 1H-Naphtho-
[2,3-d]imidazol-2-amine gave corresponding product 4f in
83% yield and 92% ee. 4-Substituted 2-aminobenzimidaoles
afforded only one major isomer, probably attributed to the
adjacent steric effect (4d and 4e). 5-Substituted 2-amino-
benzimidaoles regularly generated two regioisomers with an
almost 1:1 ratio (4g−k). 2-Aminoimidazole was also
compatible in the reaction (4l). The absolute configuration
of 3m was determined by single-crystal X-ray analysis, and
that of the other products was assigned by analogy.16
a
Reaction conditions: 1 (0.15 mmol), 2a (0.1 mmol), catalyst G (10
mol %), K2HPO4 (0.15 mmol), acetone (1.0 mL), room temperature,
4 Å molecular sieves, 12−72 h. On a 0.2 mmol scale. Catalyst E was
used.
b
c
As indicated in Scheme 4a, a gram-scale synthesis of 3a (10
mmol) was conducted. No loss of chemical yield or
enantioselectivity was detected in the reaction. Reduction of
3a via LiAlH4 was then carried out, affording 1,2,3,4-
tetrahydropyrimido[1,2-a]benzimidazole 5 in 73% yield with
no loss of enantioselectivity (Scheme 4b).
A mechanistic pathway is postulated as illustrated in
Scheme 5. The reaction starts with the generation of NHC-
bounded α,β-unsaturated acyl azolium I by the addition of
NHC precatalyst G to α-bromoenal 1a in the presence of a
base. Addition of I to 2a results in an adduct II that
(3a−e), ortho (3h), or meta (3f and 3g) position of the β-
phenyl group as well as electron-withdrawing (3d, 3e, 3g, and
3h) or electron-donating (3b, 3c, and 3f) groups are all well
tolerated, affording the corresponding products in moderate
to good yields (75−82%) and high to excellent enantiose-
lectivities (≥90%). Electron rich arene gave 3k in a good
yield (84%) with an excellent ee (97%). Naphthyl-substituted
2-bromoenals were compatible in the system (3i and 3j).
Additionally, a set of heteroaromatic rings were tolerated and
offered their corresponding products with excellent enantio-
B
https://dx.doi.org/10.1021/acs.orglett.9b04054
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a
pathway that involves the aza-nucleophilic conjugate addition
to the β-position of acyl azolium intermediate followed by
cyclization cannot be ruled out.
Scheme 3. Scope of 2-Aminobenzimidazoles
The compounds synthesized were tested for their in vitro
cytotoxic activity against various human/murine tumor cell
lines, such as A549, HeLa, U87MG, and CT26 (see the
Supporting Information). The results indicate that compound
3o effectively inhibited the growth of U87MG cells in
contrast with other tested compounds. In brief, biological
studies suggest that the pyrimido[1,2-a]benzimidazole ex-
hibited moderate cytotoxic activity.
In summary, a new protocol for the rapid synthesis of 3,4-
dihydropyrimido[1,2-a]benzimidazole-2(1H)-ones via NHC
catalysis has been developed. This protocol features good
functional group tolerance, broad scope, and mild conditions.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04054.
Experimental procedures, product characterization, and
copies of NMR spectra (PDF)
a
Reaction conditions: 1a (0.15 mmol), 2 (0.1 mmol), catalyst G (10
mol %), K2HPO4 (0.15 mmol), acetone (1.0 mL), room temperature,
4 Å molecular sieves, 12−72 h.
Accession Codes
CCDC 1963978 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 4. Gram-Scale Synthesis and Synthetic
Transformation
AUTHOR INFORMATION
■
Corresponding Authors
Shaofa Sun − Hubei University of Science and
Technology, Hubei, China
Jian Wang − Hubei University of Science and Technology,
Hubei, China, and Tsinghua University, Beijing, China;
orcid.org/0000-0002-3298-6367;
Scheme 5. Postulated Mechanism
Email: wangjian2012@tsinghua.edu.cn
Other Authors
Yangxi Xie − Tsinghua University, Beijing, China
Luoyuan Li − Tsinghua University, Beijing, China
Zijun Wu − Tsinghua University, Beijing, China
Ming Lang − Tsinghua University, Beijing, China
Di Jiang − Tsinghua University, Beijing, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04054
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation
of China (21871160 and 21672121), the “Thousand Plan”
Youth Program of China, and the Bayer Investigator Fellow
for their generous financial support.
undergoes an intramolecular aza-nucleophilic addition to
furnish intermediate III. Finally, product 3a is produced by
regenerating NHC catalyst G. In addition, another plausible
C
https://dx.doi.org/10.1021/acs.orglett.9b04054
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Chem. 2018, 2018, 2958−2962. (e) Mukherjee, S.; Shee, S.; Poisson,
T.; Besset, T.; Biju, A. T. Org. Lett. 2018, 20, 6998−7002. (f) Liu,
C.; Wu, S.; Xu, J.; Chen, L.; Zheng, P.; Chi, Y. R. Org. Lett. 2019,
21, 9493−9496. (g) Ghosh, A.; Barik, S.; Biju, A. T. Org. Lett. 2019,
21, 8598−8602. (h) Xie, Y. X.; Wang, J. Chem. Commun. 2018, 54,
4597−4600.
(9) (a) Seth, P. P.; Miyaji, A.; Jefferson, E. A.; Sannes-Lowery, K.
A.; Osgood, S. A.; Propp, S. S.; Ranken, R.; Massire, C.; Sampath,
R.; Ecker, D. J.; Swayze, E. E.; Griffey, R. H. J. Med. Chem. 2005, 48,
7099−7102. (b) Parsons, J.; Castaldi, M. P.; Dutta, S.; Dibrov, S.
M.; Wyles, D. L.; Hermann, T. Nat. Chem. Biol. 2009, 5, 823−825.
(c) Kojima, T.; Mochizuki, M.; Takai, T.; Hoashi, Y.; Morimoto, S.;
Seto, M.; Nakamura, M.; Kobayashi, K.; Sako, Y.; Tanaka, M.;
Kanzaki, N.; Kosugi, Y.; Yano, T.; Aso, K. Bioorg. Med. Chem. 2018,
26, 2229−2250.
REFERENCES
■
(1) For selected recent reviews of NHC catalysis, see:
(a) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51,
314−325. (b) Chen, X.-Y.; Ye, S. Org. Biomol. Chem. 2013, 11,
7991−7998. (c) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc.
Rev. 2013, 42, 4906−4917. (d) Mahatthananchai, J.; Bode, J. W. Acc.
Chem. Res. 2014, 47, 696−707. (e) Hopkinson, M. N.; Richter, C.;
Schedler, M.; Glorius, F. Nature 2014, 510, 485−496. (f) Connon, S.
J. Angew. Chem., Int. Ed. 2014, 53, 1203−1205. (g) Menon, R. S.;
Biju, A. T.; Nair, V. Chem. Soc. Rev. 2015, 44, 5040−5052.
(h) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis,
T. Chem. Rev. 2015, 115, 9307−9387. (i) Wang, M. H.; Scheidt, K.
A. Angew. Chem., Int. Ed. 2016, 55, 14912−14922. (j) Menon, R. S.;
Biju, A. T.; Nair, V. Beilstein J. Org. Chem. 2016, 12, 444−461.
(k) Zhang, C.; Hooper, J. F.; Lupton, D. W. ACS Catal. 2017, 7,
2583−2596. (l) Mukherjee, S.; Biju, A. T. Chem. - Asian J. 2018, 13,
2333−2349.
(10) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 8418−8420.
(11) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876−
8877.
(2) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719−3726.
(3) Selected reviews: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res.
2004, 37, 534−541. (b) de Alaniz, J. R.; Rovis, T. Synlett 2009,
2009, 1189−1207. (c) Albanese, D.; Gaggero, N. Catalysts 2018, 8,
181.
(12) Chiang, P.-C.; Rommel, M.; Bode, J. W. J. Am. Chem. Soc.
2009, 131, 8714−8718.
(13) Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130,
14066−14067.
(4) Selected reviews: (a) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu,
C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc. Rev. 2011, 40,
5336−5346. (b) Menon, R. S.; Biju, A. T.; Nair, V. Chem. Soc. Rev.
2015, 44, 5040−5052.
(14) Strand, R. B.; Helgerud, T.; Solvang, T.; Dolva, A.; Sperger, C.
A.; Fiksdahl, A. Tetrahedron: Asymmetry 2012, 23, 1350−1359.
(15) (a) Goodman, C. G.; Walker, M. M.; Johnson, J. S. J. Am.
Chem. Soc. 2015, 137, 122−125. (b) Liu, F.; Bugaut, X.; Schedler,
(5) Selected reviews: (a) Vora, H. U.; Wheeler, P.; Rovis, T. Adv.
Synth. Catal. 2012, 354, 1617−1639. (b) Chen, J.; Huang, Y. Sci.
China: Chem. 2016, 59, 251−254. (c) Mondal, S.; Yetra, S. R.;
Mukherjee, S.; Biju, A. T. Acc. Chem. Res. 2019, 52, 425−436.
(6) Selected examples, when Nu1 = “C” and Nu2 = “O”: (a) Ryan,
S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009, 131,
14176−14177. (b) Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P.
G.; Bode, J. W. J. Am. Chem. Soc. 2010, 132, 8810−8812.
(c) Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P.; Bode, J. W.
J. Am. Chem. Soc. 2010, 132, 8810−8812. (d) De Sarkar, S.; Studer,
A. Angew. Chem., Int. Ed. 2010, 49, 9266−9269. (e) Yetra, S. R.;
Kaicharla, T.; Kunte, S. S.; Gonnade, R. G.; Biju, A. T. Org. Lett.
2013, 15, 5202−5205. (f) Mo, J. M.; Shen, L.; Chi, Y. R. Angew.
Chem., Int. Ed. 2013, 52, 8588−8591. (g) Ni, Q.; Song, X.; Raabe,
G.; Enders, D. Chem. - Asian J. 2014, 9, 1535−1538. (h) Yetra, S. R.;
Mondal, S.; Suresh, E.; Biju, A. T. Org. Lett. 2015, 17, 1417−1420.
(i) Li, G. T.; Gu, Q.; You, S. L. Chem. Sci. 2015, 6, 4273−4278.
(j) Xu, J. Y.; Zhang, W. G.; Liu, Y. S.; Zhu, S. Z.; Liu, M.; Hua, X.;
Chen, S. Y.; Lu, T.; Du, D. RSC Adv. 2016, 6, 18601−18606.
(7) Selected examples, when Nu1 = “C” and Nu2 = “N”:
(a) Wanner, B.; Mahatthananchai, J.; Bode, J. W. Org. Lett. 2011,
13, 5378−5381. (b) Kravina, A. G.; Mahatthananchai, J.; Bode, J. W.
Angew. Chem., Int. Ed. 2012, 51, 9433−9436. (c) Yetra, S. R.;
Bhunia, A.; Patra, A.; Mane, M. V.; Vanka, K.; Biju, A. T. Adv. Synth.
Catal. 2013, 355, 1089−1097. (d) Cheng, J. J.; Huang, Z. J.; Chi, Y.
R. Angew. Chem., Int. Ed. 2013, 52, 8592−8596. (e) Chen, X. Y.;
Gao, Z. H.; Song, C. Y.; Zhang, C. L.; Wang, Z. X.; Ye, S. Angew.
Chem., Int. Ed. 2014, 53, 11611−11615. (f) Zhang, H. M.; Jia, W.
Q.; Liang, Z. Q.; Ye, S. Asian J. Org. Chem. 2014, 3, 462−465.
(g) Zhang, Z. M.; Zeng, X. F.; Xie, D. B.; Chen, D. D.; Ding, L. Y.;
Wang, A. N.; Yang, L. M.; Zhong, G. F. Org. Lett. 2015, 17, 5052−
5055. (h) Ni, Q. J.; Xiong, J. W.; Song, X. X.; Raabe, G.; Enders, D.
Synlett 2015, 26, 1465−1469. (i) Yi, L.; Zhang, Y.; Zhang, Z. F.;
Sun, D.; Ye, S. Org. Lett. 2017, 19, 2286−2289. (j) Chen, Q.; Zhu,
T. S.; Majhi, P. K.; Mou, C. L.; Chai, H. F.; Zhang, J. J.; Zhuo, S. T.;
Chi, Y. R. Chem. Sci. 2018, 9, 8711−8715. (k) Jiang, D.; Dong, S.;
Tang, W.; Lu, T.; Du, D. J. Org. Chem. 2015, 80, 11593−11597.
(8) (a) Zhang, H. R.; Dong, Z. W.; Yang, Y. J.; Wang, P. L.; Hui,
X. P. Org. Lett. 2013, 15, 4750−4753. (b) Wu, X. X.; Liu, B.; Zhang,
Y. X.; Jeret, M.; Wang, H. L.; Zheng, P. C.; Yang, S.; Song, B. A.;
Chi, Y. R. Angew. Chem., Int. Ed. 2016, 55, 12280−12284. (c) Fang,
C.; Cao, J.; Sun, K. W.; Zhu, J. D.; Lu, T.; Du, D. Chem. - Eur. J.
2018, 24, 2103−2108. (d) Lang, M.; Wang, J. Wang, J. Eur. J. Org.
̈
M.; Frohlich, R.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 12626−
12630. (c) Nakano, Y.; Lupton, D. W. Angew. Chem., Int. Ed. 2016,
55, 3135−3139.
(16) CCDC 1963978 (3m) contains the supplementary crystallo-
graphic 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.
D
https://dx.doi.org/10.1021/acs.orglett.9b04054
Org. Lett. XXXX, XXX, XXX−XXX