N-heterocyclic carbene-catalyzed cross-coupling of aldehydes with arylsulfonyl indoles

Article abstract of DOI:10.1021/ol9013238

3-(1-Arylsulfonylalkyl)indoles as electrophiles in the N-heterocyclic carbene-catalyzed umpolung reaction of aldehydes were realized for the first time. This intermolecular Stetter-type reaction features the commercially available catalyst and mild reacti

Full text of DOI:10.1021/ol9013238

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3182-3185
N-Heterocyclic Carbene-Catalyzed
Cross-Coupling of Aldehydes with
Arylsulfonyl Indoles
Yi Li, Fu-Qiang Shi, Qing-Li He, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@mail.sioc.ac.cn
Received April 30, 2009
ABSTRACT
3-(1-Arylsulfonylalkyl)indoles as electrophiles in the N-heterocyclic carbene-catalyzed umpolung reaction of aldehydes were realized for the
first time. This intermolecular Stetter-type reaction features the commercially available catalyst and mild reaction conditions, providing r-(3-
indolyl) ketone derivatives in high yields for a wide range of substrates.
The umpolung reactions catalyzed by N-heterocyclic
carbenes (NHC) provide an unconventional access to
various important target molecules.1,2 It is widely accepted
that these umpolung reactions proceed through the addition
of “Breslow intermediate” (Figure 1) to some electrophilic
reagents, such as aromatic aldehydes, namely the benzoin
reaction,3 and Michael acceptors, namely the Stetter reac-
tion.4 Recently, several electrophilic reagents such as ke-
tones,5 aziridines,6 nitroalkenes,7 haloheteroarenes,8 and
imines9 have also been realized as suitable acceptors for the
acyl anion during the umpolung reaction, highly broadening
the reaction scope. Apparently, novel types of electrophilic
receptors suitable for the umpolung reaction are highly
desirable and would increase the versatility of this umpolung
approach.
Figure 1. 3-(1-Arylsulfonylalkyl)indole and the Breslow intermedi-
ate.
This work was inspired by recent elegant studies of Petrini
and co-workers that 3-(1-arylsulfonylalkyl)indoles are dem-
onstrated good electrophilic precursors.10 The sulfonyl
moiety at the benzylic position of 3-substituted indoles serves
as a good leaving group, which allows the generation of an
electrophilic species under basic conditions (Figure 1). The
intermediate generated in situ equals an active R,ꢀ-unsatur-
ated imine, and we envision that this electrophilic intermedi-
ate might be a suitable acyl receptor in the NHC-catalyzed
umpolung reaction. Previously, Stetter utilized gramine as
an electrophile in a cyanide-catalyzed umpolung reaction of
(1) For reviews, see: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res.
2004, 37, 534. (b) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326.
(c) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43,
5130. (d) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632. (e) Zeitler,
K. Angew. Chem., Int. Ed. 2005, 44, 7506. (f) Marion, N.; D´ıez-Gonza´lez,
S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (g) Enders, D.;
Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606
.
10.1021/ol9013238 CCC: $40.75
Published on Web 07/06/2009
 2009 American Chemical Society

aldehyde, and the desired R-(3-indolyl) ketone was afforded
in only moderate yield.11 Recently, Scheidt reported that the
reaction of a stoichiometrically generated acyl anion with a
silyl-protected gramine derivative led to the formation of
R-(3-indolyl) ketone.12 To our knowledge, there is no report
on NHC-catalyzed reaction with this electrophilic intermedi-
ate generated in situ. Given the fact that indoles exist
extensively as the structure core of biologically active natural
products and pharmaceutical compounds,13 the significance
of developing a new synthetic method for indole derivatives
is obvious.14 Fortunately, after screening the reaction condi-
tions, the cross-coupling reaction of aldehydes with arylsul-
fonyl indoles has been realized with a readily available
thiazolium salt. In this paper, we report the preliminary
results.
For the exploratory studies, we selected the reaction
between benzaldehyde 1a and sulfonylindole 2a, using DBU
(1, 8-diazabicyclo[5.4.0]undec-7-ene) as the base. Our studies
began with an initial examination of different readily
available NHC precursors. The results are summarized in
Table 1. Although imidazolium salt 4 and triazolium salts 5
(2) For recent examples on NHC as umpolung catalysts, see: (a) Phillips,
E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. Chem., Int. Ed.
2007, 46, 3107. (b) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129,
13798. (c) Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem.
Soc. 2008, 130, 2416. (d) Seayad, J.; Patra, P. K.; Zhang, Y.-G.; Ying,
J. Y. Org. Lett. 2008, 10, 953. (e) Wong, F. T.; Patra, P. K.; Seayad, J.;
Zhang, Y.; Ying, J. Y. Org. Lett. 2008, 10, 2333. (f) He, M.; Bode, J. W.
J. Am. Chem. Soc. 2008, 130, 418. (g) Rommel, M.; Fukuzumi, T.; Bode,
J. W. J. Am. Chem. Soc. 2008, 130, 17266. (h) He, M.; Beahm, B. J.; Bode,
J. W. Org. Lett. 2008, 10, 3817. (i) Maki, B. E.; Scheidt, K. A. Org. Lett.
2008, 10, 4313. (j) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130,
2740. (k) Phillips, E. M.; Wadamoto, M.; Roth, H. S.; Ott, A. W.; Scheidt,
K. A. Org. Lett. 2009, 11, 105. (l) Wang, L.; Thai, K.; Gravel, M. Org.
Lett. 2009, 11, 891. (m) Yang, L.; Tan, B.; Wang, F.; Zhong, G. J. Org.
Chem. 2009, 74, 1744. For recent examples on NHC as nucleophilic
catalysts, see: (n) He, L.; Jian, T.-Y.; Ye, S. J. Org. Chem. 2007, 72, 7466.
(o) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett. 2008, 10,
277. (p) Zhang, Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chem.sEur. J. 2008, 14,
8473. (q) Huang, X.-L.; He, L.; Shao, P.-L.; Ye, S. Angew. Chem., Int. Ed.
2009, 48, 192. (r) Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith,
A. D. Org. Biomol. Chem. 2008, 6, 1108. (s) Campbell, C. D.; Duguet, N.;
Gallagher, K. A.; Thomson, J. E.; Lindsay, A. G.; O’Donoghue, A. C.;
Smith, A. D. Chem. Commun. 2008, 3528. (t) Thomson, J. E.; Campbell,
C. D.; Concellon, C.; Duguet, N.; Rix, K.; Slawin, A. M. Z.; Smith, A. D.
J. Org. Chem. 2008, 73, 2784. (u) Thomson, J. E.; Kyle, A. F.; Gallagher,
K. A.; Lenden, P.; Concellon, C.; Morrill, L. C.; Miller, A. J.; Joannesse,
C.; Slawin, A. M. Z.; Smith, A. D. Synthesis 2008, 17, 2805.
Table 1. Screening the Catalysts for the Reaction of
Benzaldehyde 1a with Arylsulfonylindole 2aa
(3) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. (b) Sheehan, J.;
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H.; Foss, F. W., Jr.; Breslow, R. J. Am. Chem. Soc. 2008, 130, 12590.
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Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284. (f) Enders, D.;
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entry
catalyst
time (h)
convn (%)b
1
2
3
4
5
6
4
5
6
7
8
9
48
48
48
2
48
48
N.R.
N.R.
N.R.
85
17
N.R.
a Reaction conditions: 1a/2a/DBU ) 1.2/1/1.2, 0.1 M of 2a in THF at
b
1
25 °C. Determined by H NMR.
and 6 are reported to be suitable catalysts for the umpolung
reactions, none of them displays catalytic activities here
(entries 1-3, Table 1). We are delighted to find that the
commercially available thiazolium salt 7 is capable of
catalyzing the reaction to give the desired product in an 85%
yield (entry 4, Table 1). However, the catalyst derived from
thiazolium salt 8 gave the product in only 17% yield despite
the structural similarity between 8 and 7. The reaction with
the thiazolium salt 9 failed to give any product (entry 6, Table
1).
(6) Liu, Y.-K.; Li, R.; Yue, L.; Li, B.-J.; Chen, Y.-C.; Wu, Y.; Ding,
L.-S. Org. Lett. 2006, 8, 1521.
(7) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am.
Chem. Soc. 2006, 128, 4932.
(8) (a) Suzuki, Y.; Ota, S.; Fukuta, Y.; Ueda, Y.; Sato, M. J. Org. Chem.
2008, 73, 2402. (b) Suzuki, Y.; Toyota, T.; Imada, F.; Sato, M.; Miyashita,
A. Chem. Commun. 2003, 1314.
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J. J.; Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696. (b) Mennen, S. M.;
Gipson, J. D.; Kim, Y. R.; Miller, S. J. J. Am. Chem. Soc. 2005, 127, 1654.
(c) Li, G.-Q.; Dai, L.-X.; You, S.-L. Chem. Commun. 2007, 852.
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2006, 8, 4093. (b) Palmiei, A.; Petrini, M. J. Org. Chem. 2007, 72, 1863.
(c) Ballini, R.; Palmiei, A.; Petrini, M.; Shaikh, R. R. AdV. Synth. Catal.
2008, 350, 129. (d) Shaikh, R. R.; Mazzanti, A.; Petrini, M.; Bartoli, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8707.
(13) (a) Bosch, J.; Bennasar, M.-L. Synlett 1995, 587. (b) Faulkner, D. J.
Nat. Prod. Rep. 2002, 19, 1. (c) Agarwal, S.; Caemmerer, S.; Filali, S.;
Froehner, W.; Knoell, J.; Krahl, M. P.; Reddy, K. R.; Knoelker, H.-J. Curr.
Org. Chem. 2005, 9, 1601. (d) O’Connor, S. E.; Maresh, J. J. Nat. Prod.
Rep. 2006, 23, 532.
(11) (a) Stetter, H.; Schmitz, P. H.; Schreckenberg, M. Chem. Ber. 1977,
110, 1971. (b) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407.
(12) Mattson, A. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 4508.
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Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199.
Org. Lett., Vol. 11, No. 15, 2009
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As summarized in Table 2, different solvents and bases
have been examined for the reaction. Several common
Table 3. Substrate Scope for the Reaction of Aldehydes with
Arylsulfonylindolesa
Table 2. Optimizing the Conditions for the Reaction of
Benzaldehyde 1a with Arylsulfonylindole 2aa
entry
1, R1
1a, Ph
2, R2, R3, R4, R5
2a, Ph, H, H, H
3, yield (%)b
1
3aa, 99
3ba, 69
3ca, 99
3da, 99
3ea, 99
3fa, 99
3ga, 99
3ha, 99
3ia, 99
3ja, 99
3ka, 99
3la, 95
3ma, 62
3na, 54
3ab, 87
3ac, 99
3ad, 66
3ae, 37
3af, 97
3ag, 80
3ah, 99
3ai, 79
N.R.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1b, 4-MeC6H4
1c, 4-CF3C6H4
1d, 4-BrC6H4
1e, 4-FC6H4
1f, 4-ClC6H4
1g, 3-ClC6H4
1h, 2-ClC6H4
1i, 3-MeC6H4
1j, 1-naphthyl
1k, 2-furyl
2a, Ph, H, H, H
2a, Ph, H, H, H
2a, Ph, H, H, H
2a, Ph, H, H, H
2a, Ph, H, H, H
2a, Ph, H, H, H
2a, Ph, H, H, H
2a, Ph, H, H, H
2a, Ph, H, H, H
2a, Ph, H, H, H
2a, Ph, H, H, H
entry
solvent
base
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DABCO
Et3N
DIEA
K2CO3
Cs2CO3
KOtBu
time (h)
convn (%)b
1
2
3
4
5
6
7
8
THF
2
4
10
48
48
1
85
>95
89
N.R.
N.R.
93
69
20
44
32
CH2Cl2
toluene
Et2O
DMF
CH3CN
dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1
1l, 2-thienyl
1m, PhCH2CH2 2a, Ph, H, H, H
48
48
48
4
0.5
48
9
1n, n-C3H7
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1a, Ph
2a, Ph, H, H, H
10
11
12
13
2b, 4-BrC6H4, H, H, H
2c, 4-ClC6H4, H, H, H
2d, 4-MeOC6H4, H, H, H
2e, n-C3H7, H, H, H
2f, Ph, Me, H, H
>95
>95
complex
a Reaction conditions: 1a/2a/base ) 1.2/1/1.2, 0.1 M of 2a in solvent
b
1
at 25 °C. Determined by H NMR.
2g, Ph, Ph, H, H
2h, Ph, H, 4-Me, H
2i, Ph, H, 6-Br, H
2i, Ph, H, H, Me
solvents such as THF, CH2Cl2, toluene, CH3CN, and dioxane
all led to the formation of the product 3aa in good to
excellent conversions (entries 1-3, 6, and 7, Table 2). No
reaction occurs in ether probably due to the poor solubility
of 2a (entry 4, Table 1). CH3CN was chosen as the optimal
solvent since the reaction in CH3CN proceeded to completion
in 1 h with excellent yield (entry 6, Table 1). Among the
bases tested, Cs2CO3 gave the best result (>95% conversion)
in 0.5 h (entries 6 and 8-13, Table 2).
Under the optimized reaction conditions [10 mol % of
thiazolium salt 7, 120 mol % of Cs2CO3, in CH3CN at room
temperature], a variety of aromatic or aliphatic aldehydes
and substituted 3-(1-arylsulfonylalkyl)indoles have been
explored to examine the generality of the reaction. The results
are listed in Table 3.
a Reaction conditions:1/2/Cs2CO3 ) 1.2/1/1.2, 0.1 M of 2 in CH3CN at
25 °C. b Isolated yields.
electronic nature of the indole core had little influence on
the outcome of the reaction, and generally high yields were
obtained (entries 19-22, Table 3). Notably, N-methyl-
substituted 2 gives no desired product (entry 23, Table 3).
A preliminary study on the enantioselective version of this
methodology was carried out (Scheme 1). In the presence
Scheme 1
.
Enantioselective Reaction of Benzaldehyde 1a with
Phenylsulfonylindole 2a
As listed in Table 3, the method proved to be suitable for
a wide range of aryl aldehydes (up to 99% yield). It is worth
noting that the aromatic aldehydes with substituent on the
ortho-position (entry 8, Table 3) or bulky 1-naphthaldehyde
(entry 10, Table 3) went well in all cases. Excellent yields
were obtained for the heteroaryl aldehydes as well (entries
11 and 12, Table 3). To our delight, the aliphatic aldehydes
were also tolerated, and this is not usual for the benzoin-
type reaction (entries 13 and 14, Table 3). Using benzalde-
hyde, structural variation in the 3-(1-arylsulfonylalkyl)
indoles was then examined. As to the substituents R2,
aromatic ones with either an electron-withdrawing group or
an electron-donating group show much better reactivity than
the alkyl substituent (entries 15-18, Table 3). The steric and
of 10 mol % of the chiral NHC catalyst derived from the
triazolium salt 10,15 the reaction of benzaldehyde 1a and
3-(1-arylsulfonylalkyl)indole 2a gave 3aa in 36% conversion
and 97% ee. To determine the absolute configuration of the
3184
Org. Lett., Vol. 11, No. 15, 2009

could lead to intermediate III by reacting with the
electrophilic intermediate IV generated from 2 under the
basic condition. Upon proton transfer, intermediate III will
give intermediate V, which could further release the
carbene catalyst I and product 3.
Scheme 2. Proposed Catalytic Cycle
In summary, we have developed an efficient NHC-
catalyzed intermolecular Stetter-type reaction with a novel
electrophile generated from 3-(1-arylsulfonylalkyl)indoles,
providing a facile access to relevant 3-indolyl derivatives.
The reaction features the commercially available catalyst
and mild reaction conditions. Further studies on the design
of new chiral catalysts for the reaction and application of
the methodology in organic synthesis are currently un-
derway.
Acknowledgment. We thank the National Natural Science
Foundation of China (20872159, 20732006), National Basic
Research Program of China (973 Program 2009CB825300),
the Chinese Academy of Sciences, and the Science and
TechnologyCommissionofShanghaiMunicipality(07pj14106,
07JC14063) for generous financial support.
Supporting Information Available: Experimental pro-
cedures and analysis data for 3, and the crystallographic data
of compound (S)-3da. This material is available free of
charge via the Internet at http://pubs.acs.org.
product, the crystal structure of enantiopure 3da was ob-
tained,16 and a single-crystal X-ray analysis determined its
configuration as S.17 Although more efficient NHC catalysts
need to be developed for a better reactivity, these results
serve as a proof of concept for developing a highly efficient
asymmetric version of the current reaction.
A plausible catalytic cycle was proposed as illustrated
in Scheme 2. Carbene I is generated by deprotonation of
thiazolium salt in the presence of base. I reacts with
aldehyde 1 to give the Breslow intermediate II, which
OL9013238
(15) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 14,
5725.
(16) The enantiopure 3da was obtained by semi-preparative HPLC
(Chiralpark IC).
(17) CCDC 735894 contains the supplementary crystallographic data
for (S)-3da. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk /data request/cif.
Org. Lett., Vol. 11, No. 15, 2009
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