N-heterocyclic carbene-catalyzed domino ring-opening/redox amidation/cyclization reactions of formylcyclopropane 1,1-diesters: Direct construction of a 6-5-6 tricyclic hydropyrido[1,2-a]indole skeleton

Article abstract of DOI:10.1021/jo900650h

(Chemical Equation Presented) Catalyzed by N-heterocyclic carbenes (NHCs), domino ringopening/redox amidation/cyclization reactions of the readily available formylcyclopropane 1,1-diesters with 2-chloro-1Hindole-3- carboaldehydes were reported. This metho

Full text of DOI:10.1021/jo900650h

N-Heterocyclic Carbene-Catalyzed Domino
Ring-Opening/Redox Amidation/Cyclization
Reactions of Formylcyclopropane 1,1-Diesters:
Direct Construction of a 6-5-6 Tricyclic
Hydropyrido[1,2-a]indole Skeleton
Ding Du, Linxia Li, and Zhongwen Wang*
State Key Laboratory of Elemento-Organic Chemistry,
Institute of Elemento-Organic Chemistry, Nankai UniVersity,
Tianjin, 30071, People’s Republic of China
FIGURE 1. Selected typical alkaloids with a hydropyrido[1,2-a]indole
skeleton.
wzwrj@nankai.edu.cn
ReceiVed March 27, 2009
cleophilic substitutions,5 acid-induced cyclizations,6 cycload-
ditions,7 and Pauson-Khand reactions.8 These strategies usually
need multiple steps to construct the additional piperidine
skeleton. Thus, the discovery of new, general, and direct
methods for the construction of such skeleton remains a
formidable challenge in pursuit of efficient and sustainable
chemical processes.
Domino reactions9 are one of the most important methods
for HECCS (highly efficient construction of complex skeleton)
in contemporary organic synthesis. As versatile building blocks
in modern organic syntheses, activated cyclopropanes have
attracted much interest in the field of nucleophilic ring-opening
domino reactions.10 In the research of novel carbon-carbon and
carbon-heteroatom bond-forming reactions, N-heterocyclic
Catalyzed by N-heterocyclic carbenes (NHCs), domino ring-
opening/redox amidation/cyclization reactions of the readily
available formylcyclopropane 1,1-diesters with 2-chloro-1H-
indole-3-carboaldehydes were reported. This methodology
provides an efficient and direct construction of a 6-5-6
tricyclic hydropyrido[1,2-a]indole skeleton, which can be
potentially applied for the synthesis of several types of
polycyclic indole alkaloids.
(3) For some selected examples, please see: (a) Lotter, A. N. C.; Pathak, R.;
Sello, T. S.; Fernandes, M. A.; van Otterlo, W. A. L.; de Koning, C. B.
Tetrahedron 2007, 63, 2263. (b) Khdour, O.; Ouyang, A.; Skibo, E. B. J. Org.
Chem. 2006, 71, 5855. (c) Taga, M.; Ohtsuka, H.; Inoue, I.; Kawaguchi, T.;
Nomura, S.; Yamada, K.; Date, T.; Hiramatsu, H.; Sato, Y. Heterocycles 1996,
42, 251. (d) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc.
1995, 117, 5776. (e) Kato, M.; Ito, K.; Nishino, S.; Yamakuni, H.; Takasugi, H.
Chem. Pharm. Bull. 1994, 42, 2546.
(4) Selected articles include: (a) Magolan, J.; Carson, C. A.; Kerr, M. A.
Org. Lett. 2008, 10, 1437. (b) Bowman, W. R.; Fletcher, A. J.; Pedersen, J. M.;
Lovell, P. J.; Elsegood, M. R. J.; Hernandez Lopez, E.; McKee, V.; Potts, G. B.
Tetrahedron 2007, 63, 191. (c) Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8,
4561. (d) Menes-Arzate, M.; Martnez, R.; Cruz-Almanza, R.; Muchowski, J. M.;
Osornio, Y. M.; Miranda, L. D. J. Org. Chem. 2004, 69, 4001. (e) Tsotinis, A.;
Panoussopoulou, M.; Sivananthan, S.; Sugden, D. Il Farmaco 2001, 56, 725. (f)
Caddick, S.; Shering, C. L.; Wadman, S. N. Tetrahedron 2000, 56, 465. (g)
Fiumana, A.; Jones, K. Tetrahedron Lett. 2000, 41, 4209.
Hydropyrido[1,2-a]indole is a 6-5-6 tricyclic core skeleton
existing in a large class of naturally bioactive polycyclic indole
alkaloids (Figure 1).1 Great efforts to construct such skeleton
have been documented, and most of the typical strategies started
from the indole skeleton, and the additional piperidine ring was
built through transition-metal-catalyzed C-C bond formation,2
intra/intermolecular condensations,3radical cyclizations,4nu-
(5) Selected articles include: (a) Morales, C. L.; Pagenkopf, B. L. Org. Lett.
2008, 10, 157. (b) Tanino, H.; Fukuishi, K.; Ushiyama, M.; Okada, K.
Tetrahedron 2004, 60, 3273.
(1) Selected references include: (a) Kam, T.-S.; Sim, K.-M.; Pang, H.-S.;
Koyano, T.; Hayashi, M.; Komiyama, K. Bioorg. Med. Chem. Lett. 2004, 14,
4487. (b) Kam, T.-S.; Subramaniam, G.; Lim, K.-H.; Choo, Y.-M. Tetrahedron
Lett. 2004, 45, 5995. (c) Kam, T.-S.; Sim, K.-M.; Lim, T.-M. Tetrahedron Lett.
2000, 41, 2733. (d) van Beek, T. A.; Verpoorte, R.; Baerheim Svendsen, A.
Tetrahedron 1984, 40, 737. (e) Ohmoto, T.; Koike, K. The Alkaloids; Academic
Press: New York, 1989; Vol. 36, pp 135-170. (f) Bonjoch, J.; Sole, D. Chem.
ReV. 2000, 100, 3455. (g) Pilarcik, T.; Havlicek, J.; Hajicek, J. Tetrahedron
Lett. 2005, 46, 7909, references cited therein.
(2) Some selected examples include: (a) Li, G.; Huang, X.; Zhang, L. Angew.
Chem., Int. Ed. 2008, 47, 346. (b) Liu, J.; Shen, M.; Zhang, Y.; Li, G.;
Khodabocus, A.; Rodriguez, S.; Qu, B.; Farina, V.; Senanayake, C. H.; Lu, B. Z.
Org. Lett. 2006, 8, 3573. (c) Jafarpour, F.; Lautens, M. Org. Lett. 2006, 8, 3601.
(d) Fayol, A.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 4203. (e) Bressy, C.;
Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148. (f) Siebeneicher,
H.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 2003, 42, 3042. (g) Nakanishi,
M.; Mori, M. Angew. Chem., Int. Ed. 2002, 41, 1934. (h) Faust, R.; Garratt,
P. J.; Jones, R.; Yeh, L.-K. J. Med. Chem. 2000, 43, 1050.
(6) (a) Tanaka, M.; Sagawa, S.; Hoshi, J.; Shimoma, F.; Yasue, K.; Ubukata,
M.; Ikemoto, T.; Hase, Y.; Takahashi, M.; Sasase, T.; Ueda, N.; Matsushita,
M.; Inaba, T. Bioorg. Med. Chem. 2006, 14, 5781. (b) Bennasar, M.-L.; Zulaica,
E.; Alonso, Y.; Vidal, B.; Vazquez, J. T.; Bosch, J. Tetrahedron: Asymmetry
2002, 13, 95.
(7) (a) Haider, N.; Kaferbock, J. Tetrahedron 2004, 60, 6495. (b) Gharago-
zloo, P.; Lazareno, S.; Miyauchi, M.; Popham, A.; Birdsall, N. J. M. J. Med.
Chem. 2002, 45, 1259. (c) Bodwell, G. J.; Li, J. Angew. Chem., Int. Ed. 2002,
41, 3261. (d) Eichberg, M. J.; Dorta, R. L.; Lamottke, K.; Vollhardt, K. P. C.
Org. Lett. 2000, 2, 2479. (e) Beccalli, E. M.; Broggini, G.; La Rosa, C.; Passarella,
D.; Pilati, T.; Terraneo, A.; Zecchi, G. J. Org. Chem. 2000, 65, 8924.
(8) Prez-Serrano, L.; Domnguez, G.; Prez-Castells, J. J. Org. Chem. 2004,
69, 5413.
(9) Some reviews include: (a) Tieze, L. F. Chem. ReV. 1996, 96, 115. (b)
Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195. (c) Bunce,
R. A. Tetrahedron 1995, 51, 13103. (d) Nicolaou, K. C.; Edmonds, D. J.; Bulger,
P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (e) Pellissier, H. Tetrahedron
2006, 62, 1619. (f) Pellissier, H. Tetrahedron 2006, 62, 2143.
10.1021/jo900650h CCC: $40.75
Published on Web 05/07/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4379–4382 4379

TABLE 1. Optimization of the Reaction Conditionsa
SCHEME 1. NHC-Catalyzed Ring-Opening Redox
Reactions of Activated FCPs
conv of yield of
time (h) 1 (%)b 3a (%)c
entry
1
cat.
sol.
base
1
2
3
4
5
6
7
8
9d
1a
A-D/F,G THF DBU
10
16
18
16
18
24
20
18
20
40
40
40
20
<10
<30
65
<10
70
0
<20
44
NR
39
40
<20
<20
48
54
60
1a
1a
1a
1a
1a
1a
1a
1a
E/H/I
H
THF DBU
PhMe DBU
PhMe Et3N
PhMe K2CO3
PhMe Cs2CO3
PhMe NaH
PhMe t-BuOK
PhMe DBU
PhMe DBU
PhMe DBU
PhMe DBU
PhMe DBU
H
H
H
H
H
H
H
H
68
<40
<40
62
84
85
10d 1a
11d e 1a
,
12d e 1b
H
H
77
<20
55
NR
,
13d e 1c/1d
,
carbenes (NHCs) have been efficiently applied as organocata-
lysts in a large number of umpolung chemical transformations.11
Under catalysis of NHCs, activated formylcyclopropanes (FCPs)
can undergo ring-opening-based redox esterification and ami-
dation processes (Scheme 1).12 Recently, we have reported a
NHC-catalyzed domino reaction of 1,1-diactivated FCPs (with
intermediate I as a formal 1,2-dipole) with salicylaldehyde, by
which the coumarin skeleton can be directly constructed
(Scheme 1).13 However, continuing effort to utilize intermediate
II as a formal 1,4-dipole in organic syntheses follows our
research interests. We envision that the reactions of intermediate
II with 2-chloro-1H-indole-3-carboaldehyde would afford in-
termediate III, which would undergo subsequent intramolecular
nucleophilic substitution to construct a 6-5-6 tricyclic py-
rido[1,2-a]indole skeleton (Scheme 1). Herein we report this
new type of domino ring-opening/redox amidation/cyclization
reaction.
a Reaction conditions: 1.0 equiv of 1, 2.0 equiv of 2a, 40 mol % of
the catalyst, and 2.0 equiv of the base, 60-70 °C, N2 atmosphere.
b Determined by recovered 1. c Isolated yields based on 1. d Anhydrous
MgSO4 was added as an additive. e 3.0 equiv of 2a was added.
2-chloro-1H-indole-3-carboaldehyde 1a in THF using DBU as
a base. NHCs generated in situ from precursors A-D and F,G
provided no desired product 3a with low conversion of 1a (Table
1, entry 1), while NHCs from precursor E, H, or I exhibited
certain catalytic activity (Table 1, entry 2). Further screening
of the reaction conditions suggested toluene, DBU (2.0 equiv),
and catalyst H (40 mol %) as the optimal solvent, base, and
catalyst, respectively (Table 1, entries 3-8). The addition of
various nucleophilic co-catalysts commonly employed in acy-
lation reactions, including HOBT, DMAP, ortho-nitrophenol,
and imidazole,12 failed to improve the reaction. However, slight
improvement in the conversion of 1a and the yield was observed
with prolonged reaction time and using anhydrous MgSO4 as
an additive (Table 1, entries 9 and 10). Increasing the amount
of 2a to 3.0 equiv could also slightly improve the yield to 60%
with 85% conversion of 1a, and this condition was selected as
the optimal one (Table 1, entry 11). Notably, the leaving group
X in 1 had no great impact on the reaction. Comparing to
substrate 1a (X ) Cl), a similar result was observed for 1b (X
) Br) (Table 1, entry 12). It was surprising that no desired
reactions happened for substrates 1c and 1d (Table 1, entry 13),
indicating the significance of the formyl group. The structure
of 3a was established by spectroscopic analysis and further
confirmed by single-crystal X-ray analysis.14
We initiated our investigations by examining the efficiency
of various NHCs for the reaction of FCP 1,1-diester 2a with
(10) Some reviews include: (a) Danishefsky, S. Acc. Chem. Res. 1979, 12,
66. (b) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C. Chem. ReV. 1989,
89, 165. (c) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151. (d) Yu,
M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (e) Wenkert, E. Acc. Chem.
Res. 1980, 13, 27. A recent example includes: (f) Tanaka, M.; Ubukata, M.;
Matsuo, T.; Yasue, K.; Matsumoto, K.; Kajimoto, Y.; Ogo, T.; Inaba, T. Org.
Lett. 2007, 9, 3331.
(11) For reviews, please see: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res.
2004, 37, 534. (b) Marion, N.; Diez-Gonzalez, S.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2007, 46, 2988. (c) Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV.
2007, 107, 5606.
(12) (a) Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021. (b)
Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798. (c) Vora, H. U.;
Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796. (d) Ibrahem, I.; Zhao, G.-L.;
Rios, R.; Vesely, J.; Sunden, H.; Dziedzic, P.; Cordova, A. Chem.sEur. J. 2008,
14, 7867. (e) Vesely, J.; Zhao, G.-L.; Bartoszewicz, A.; Cordova, A. Tetrahedron
Lett. 2008, 49, 4209.
With the optimal conditions in hand, we turned our attention
to investigating the scope of substrates 1 and 2 (Table 2).
4380 J. Org. Chem. Vol. 74, No. 11, 2009

TABLE 2. Investigation of the Reaction Scopea
SCHEME 2. Reactions of 2-Chloro-1H-benzimidazole 4 and
2-Chloro-1,4-dihydroquinoline-3-carbaldehyde 6 with 2a
entry
1
R1
2
R2 R3 conv of 1 (%)b yield of 3 (%)c
1
2
3
4
5
6
7
8
1a
H
2a Et
2a Et
2a Et
2a Et
2a Et
2a Et
2a Et
2a Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
85
75
78
72
53
>90
88
81
>90
56
59
80
68
59
60
<30
3a, 60
3d, 41
3e, 52
3f, 50
3g, 33
3h, 70
3i, 76
3j, 72
3k, 74
NR
3l, 37
3m, 58
3n, 50
3o, 40
3p, 36
NR
1e 5-Cl
1f 5-Br
1g 5-I
1h 6-Cl
1i
1j 5-Et
1k 5-i-Pr
1l
1m 7-Me
1n 4,6-Me2 2a Et
1j 5-Et
1a
5-Me
9
5-OMe 2a Et
10
11
12
13
14
15
16
2a Et
2b Me
2b Me
2c i-Pr
2d Et
H
1j 5-Et
1j 5-Et
1j 5-Et
2e Et
a Reaction conditions: 1.0 equiv of 1, 3.0 equiv of 2, 40 mol % of cat
H, and 2.0 equiv of DBU, anhydrous MgSO4, PhMe, 60-70 °C, 40 h,
N2 atmosphere. b Determined by recovered 1. c Isolated yields based
on 1.
SCHEME 3. Potential Application to the Synthesis of a
Tronocarpine Substructure
Substituents on the phenyl ring of substrate 1 significantly
affected the yields as well as the conversions. Substrates 1
substituted with electron-withdrawing groups at the 5-position
(Table 2, entries 2-4) reacted with 2a in low to moderate yields
and conversions, while substrates 1 with electron-donating
groups at the 5-position resulted in good yields and conversions
(Table 2, entries 6-9). Substrates 1h and 1n with substituents
at the 6-position both gave unexplainable decreased yields and
conversions (Table 2, entries 5 and 11). The reaction between
1m and 2a afforded no desired product, which was probably
due to the steric effect of the methyl group at the 7-position
(Table 2, entry 10). Several substrates 2 were also examined.
Compared to those of 2a, reactions of 2b were less effective
because of its high volatility (Table 2, entries 12 and 13). The
reaction of more sterically hindered 2c resulted in decreased
yield (Table 2, entry 14). While substrate 2d with methyl
substituted at the 3-position gave the desired product 3p,
substrate 2e with phenyl substituted at the 3-position did not
work (Table 2, entries 15 and 16).
The reaction of 2-chloro-1H-benzimidazole 4 with 2a was
also found to be applicable to the synthesis of imidazole-fused
piperidone 5, although in 63% conversion and 40% yield
(Scheme 2). Several other heteroaromatic compounds have also
been tested. 2,4,5-Tribromo-1H-imidazole decomposed quickly
under the reaction condition without desired product. The
reaction of 5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde was
very complex. It was interesting that, instead of undergoing
redox amidation, the reaction of 2-chloro-1,4-dihydroquinoline-
3-carbaldehyde 6 with 2a gave redox esterification product 7
in quantitative yield, the mechanism of which was probably via
a domino ring-opening/esterification/ aromatization process
(Scheme 2).
The potential application of this method is illuminated by
the synthesis of the tetracyclic subunit of tronocarpine (Scheme
3). Product 3n obtained from 1a and 2b was treated with MeNO2
to give nitroalkene 8 (63% yield), which could be transformed
into 9 by the reported method.15 Tetracyclic product 9 contains
four of the five rings of tronocarpine as well as suitable
functionality for potential conversion to this natural product.
In conclusion, we have demonstrated a novel domino ring-
opening/redox amidation/cyclization reaction between 2-chloro-
1H-indole-3-carboaldehydes and the readily available FCP 1,1-
diesters. This methodology provides an efficient and direct
access to a 6-5-6 tricyclic hydropyrido[1,2-a]indole skeleton.
Additionally, the application of this method to synthesize the
tetracyclic core skeleton of the natural product tronocarpine has
also been illustrated. Further investigation of the reaction scope
is currently underway.
Experimental Section
General Procedure for the Synthesis of 3: To an oven-dried
50 mL three-necked glassware were charged 150 mg of anhydrous
(13) Du, D.; Wang, Z. Eur. J. Org. Chem. 2008, 4949.
(14) See Supporting Information, and CCDC-719430 (3a) contains 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.
(15) The synthesis of compound 9 from 8 has been accomplished: Mahboobi,
V. S.; Burgemeister, T.; Kastner, F. Arch. Pharm. 1995, 328, 29.
J. Org. Chem. Vol. 74, No. 11, 2009 4381

MgSO4 and 56 mg (0.14 mmol) of catalyst H. 2-Chloro-1H-indole-
3-carboaldehydes 1 (0.35 mmol), 2-formylcyclopropane-1,1-dicar-
boxylates 2 (1.05 mmol), 8 mL of dry toluene, and 105 µL (0.70
mmol) of DBU were then added sequentially under a positive
pressure of nitrogen. The reaction mixture was heated to 60-70
°C for 40 h. The mixture was filtered, and the filtrate was evaporated
in vacuo. The residue was purified by silica gel chromatography
to afford products 3 and recovered materials 1.
3a: 85% conv, 60% yield; white solid, mp 84-86 °C; Rf ) 0.26
(silica gel, ethyl acetate/petroleum ether ) 1:4); 1H NMR (400 M,
CDCl3) δ 10.22 (s, 1H), 8.51 (d, J ) 8.0 Hz, 1H), 8.34 (d, J ) 7.2
Hz, 1H), 7.40-7.46 (m, 2H), 4.22-4.38 (m, 4H), 3.03 (t, J ) 6.4
Hz, 2H), 2.78 (t, J ) 6.4 Hz, 2H), 1.28 (t, J ) 7.2 Hz, 6H); 13C
NMR (75 M, CDCl3) δ 186.9, 167.9, 167.7, 140.1, 134.6, 126.7,
126.3, 125.8, 121.8, 119.6, 116.5, 63.5, 55.5, 30.9, 29.3, 13.8;
HRMS (ESI) calcd for C19H19NO6 (M + Na)+ 380.1105, found
380.1110; IR (KBr) ν 2992, 2862, 1751, 1735, 1664, 1551, 1455,
1387, 1311, 1239, 1220, 1187, 1141, 1075, 1015, 986, 947, 863,
831 cm-1
.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20572045) and the Ministry of
Education of China (RFDF20070055022) for financial support.
Supporting Information Available: Detailed experimental
procedure and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO900650H
4382 J. Org. Chem. Vol. 74, No. 11, 2009