Organocatalytic aldol reaction of indole-3-carbaldehydes with ketones: Synthesis of chiral 3-substituted indoles

Article abstract of DOI:10.1016/j.tetlet.2013.06.056

An efficient aldol reaction of indole-3-carbaldehydes with ketones is described. O-TBS-protected l-threonine promoted the aldol addition of ketones to indole-3-carbaldehydes affording 3-indolylmethanols with good to excellent yields and diastereoselectivi

Full text of DOI:10.1016/j.tetlet.2013.06.056

Tetrahedron Letters 54 (2013) 4653–4655
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Organocatalytic aldol reaction of indole-3-carbaldehydes
with ketones: synthesis of chiral 3-substituted indoles
a
a
a
a
a
a
Qi-Xiang Guo a, , Wei Wen , Li-Na Fu , Shun-En Zhang , Lan-Xi Zhang , Yu-Wan Liu , Biao Xu ,
⇑
Yan Xiong b
a School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
b School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient aldol reaction of indole-3-carbaldehydes with ketones is described. O-TBS-protected L-thre-
Received 20 March 2013
Revised 29 May 2013
Accepted 13 June 2013
Available online 20 June 2013
onine promoted the aldol addition of ketones to indole-3-carbaldehydes affording 3-indolylmethanols
with good to excellent yields and diastereoselectivities, and excellent enantioselectivities.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Aldol reaction
Indolylmethanol
Asymmetric synthesis
3-Substituted indole
Chiral indole units are common in many biologically active nat-
ural and unnatural compounds.1 Recently, the preparation of opti-
cally active indole derivatives has attracted much attention,2 and
the development of asymmetric methodologies for constructing in-
dole derivatives is currently a hot topic in organic synthesis.3
Among the large number of biologically active compounds and nat-
ural indole products, the optically active 3-substituted indoles
have been synthesized and investigated extensively.3a There are
two main methods for preparing chiral 3-substituted indoles.
One is the catalytic asymmetric addition of indoles to various elec-
3-indolylmethanols with excellent enantioselectivities and
diastereoselectivities.
We investigated the reaction between indole-3-carbaldehyde
1a and cyclohexanone 2a, catalyzed by L-phenylalanine, in DMSO.
The desired product 4a was not obtained (Table 1, entry 1) because
of the electron-rich properties of 1a. However, when an electron-
withdrawing group (benzenesulfonyl) was introduced on the
nitrogen atom of 1a, the reaction smoothly proceeded, and affor-
ded the desired product 4b in moderate yield, with excellent dia-
stereoselectivity and good enantioselectivity (Table 1, entry 2).
Encouraged by these experimental results, we evaluated various
catalysts, including natural amino acids and modified amino acids
3a and 3b (Table 1, entries 2–8). The natural amino acids promoted
this reaction and efficiently controlled the stereochemistry of 4b,
but the yields were moderate (Table 1, entries 2–6). O-protected
trophiles, such as a
,b-unsaturated compounds,4a imines,4b and car-
bonyl compounds.4c The other is the catalytic asymmetric addition
of various nucleophiles to 3-functionalized indoles, such as 3-ind-
olylmethanols,5,6 3-vinylindoles,7 and 3-indolylnitroalkenes.8 Sur-
prisingly, indole-3-carbaldehydes, which are simple 3-
functionalized indoles, have not yet been used in the organocata-
lytic synthesis of chiral 3-substituted indoles.9 This may be be-
cause the electron-rich indole ring decreases the electrophilicity
of an indole-3-carbaldehyde, making activation by organocatalysts
difficult.4b We believe that the electron-rich properties of indole-3-
carbaldehydes can be changed by introducing suitable protecting
groups. In this Letter, we report the first direct organocatalytic
asymmetric aldol reaction10 of N-benzenesulfonyl-protected in-
dole-3-carbaldehydes with ketones, leading to good yields of chiral
L
-threonines have been successfully used to catalyze aldol and
Mannich reactions.11 When the modified
L
-threonines 3a and 3b
were used as catalysts, the yields of 4b were greatly enhanced,
and the stereochemical outcomes were maintained (Table 1, en-
tries
7 and 8). The catalyst loading could be decreased to
15 mol%, which is lower than that using natural amino acids as cat-
alysts. Further reduction of the catalyst load, greatly reduced the
yields (Table 1, entry 9). The O-TBS-protected L-threonine 3a was
the best catalyst in terms of yield and stereochemical outcome,
and was used to optimize the reaction conditions.
We investigated the yields in various solvents. A higher yield
was obtained in DMSO than in other solvents (Table 1, entry 18).
⇑
Corresponding author.
E-mail address: qxguo@swu.edu.cn (Q.-X. Guo).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.056

4654
Q.-X. Guo et al. / Tetrahedron Letters 54 (2013) 4653–4655
Table 1
Table 2
Catalyst screening and optimization of reaction conditionsa
Substrate scope of indole-3-carbaldehydesa
O
OH
4
O
O
OH
O
CHO
CHO
R1
15 mol% 3a
neat, 20oC
R1
x mol% 3
solvent, 20oC
N
PG
N
N
N
BS
BS
53 hs
PG
2a
1
2a
4a: PG = H
4b: PG = BS
1a: PG = H
1b: PG = BS
Entry
R1, 1
4
Time (h)
Yieldb (%)
drc (anti/syn)
eed (%)
OTBDPS
COOH
OTBS
COOH
1
2
3
4
5
6
7
8
9
10
H, 1b
4b
4c
4d
4e
4f
4g
4h
4i
72
91
92
91
91
91
115
109
71
96
85
66
80
77
85
76
83
76
96
88
94:6
97:3
87:13
87:13
88:12
96:4
93:7
92:8
88:12
90:10
99
99
99
98
2-Me, 1c
5-Me, 1d
5-MeO, 1e
6-Me, 1f
7-Me, 1g
5-Cl, 1h
5-Br, 1i
6-F, 1j
H2N
H2N
3a
3b
>99
>99
97e
97e
98
Entry
Catalyst (x)
Solvent
Yieldb (%)
drc (anti/syn)
eed (%)
1
2
3
4
5
6
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0e
–
–
L
L
L
L
L
L
-Phe (30)
4j
54
57
28
56
52
93:7
98:2
96:4
97:3
99:1
82
92
93
95
>99
-Phe (30)
-Leu (30)
-Thr (30)
-Ser (30)
-Val (30)
1kf
4k
96g
a
b
c
Reaction conditions: 1 (0.2 mmol), 2a (4 mmol), 3a (0.03 mmol), and 20 °C.
Isolated yield.
Determined by 1H NMR.
d
e
F
g
ee of anti-product determined by HPLC analysis on a chiral stationary phase.
0.5 mL DMSO and 10 equiv. 2a were used.
Compound 1k = 1-(phenylsulfonyl)-1H-indole-2-carbaldehyde.
At 0 °C.
7
8
9
3a (15)
3b (15)
3a (10)
3a (15)
3a (15)
3a (15)
3a (15)
3a (15)
3a (15)
3a (15)
3a (15)
3a (15)
3a (15)
3a (15)
DMSO
DMSO
DMSO
Toluene
DMF
NMP
THF
CH2Cl2
CH3OH
H2O
73
67
54
43
67
51
40
58
67
62
42
77
85
77
98:2
96:4
98:2
95:5
97:3
96:4
96:4
95:5
95:5
98:2
95:5
96:4
94:6
90:10
99
98
92
>99
99
99
99
99
99
>99
98f
98g
99h
99g,h
10
11
12
13
14
15
16
17
18
19
20
The substrate scope with ketones was also investigated. Various
ketones, including cyclic ketones and acyclic ketones, were tested
(Table 3). Ketones with six-membered rings afforded the aldol ad-
ducts in high yields and with excellent diastereoselectivities and
enantioselectivities (Table 3, entries 1–4). The diastereoselective
ratio significantly decreased when cyclopentanone 2e was used
DMSO
DMSO
–
–
a
Reaction conditions: 1b (0.2 mmol), 2a (4 mmol), solvent (0.5 mL), BS = PhSO2–,
TBS = tBu(Me)2Si–, TBDPS = tBu(Ph)2Si–.
Table 3
b
Substrate scope of ketonesa
Isolated yield.
Determined by HPLC.
ee of anti-product determined by HPLC analysis on a chiral stationary phase.
Using 1a as reactant.
Used 2 equiv of 2a.
Used 10 equiv of 2a.
Reaction for 72 h.
c
d
O
OH
4
O
CHO
e
15 mol% 3a
neat, 20oC
R2
f
R2
g
R3
N
N
R3
O
h
BS
2
BS
1b
O
N
The yield was increased to 85% when no solvent was used (Table 1,
entry 18). The number of equivalents of ketone used is important
for the yield; for example, the yield decreased to 77% when 10
equiv of cyclohexanone 2a was used in this reaction (Table 1, entry
20).
O
O
O
O
O
O
O
O
2b
2g
2h
COOEt
2c
2f
2e
2d
Under optimal reaction conditions, we examined the substrate
scope.12 We investigated various substituted indole-3-carbaldehy-
des. We found that catalyst 3a efficiently promoted the reactions of
cyclohexanone 2a with various substituted indole-3-carbaldehy-
des 1, and gave excellent stereochemical control. For example, in-
Entry
2
4
Time (h)
Yieldb (%)
drc (anti/syn)
eed (%)
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
2d
2e
2e
2f
2g
2h
Acetone
4b
4l
72
96
72
94
30
80
72
88
90
97
85
85
94
86
92
88
28
36
94:6
98:2
98:2
97:3
54:46
77:23
87:13
40:60
NDh
99
98e
99
4m
4n
4o
4o
4p
4q
4r
dole-3-carbaldehydes
bearing
electron-donating
groups
98e
96
participated in the reaction and afforded the desired products in
good yields, with good to excellent diastereoselectivities and excel-
lent enantioselectivities (Table 2, entries 2–6). Similar results were
obtained using indole-3-carbaldehydes substituted with electron-
withdrawing groups as acceptors (Table 2, entries 7–9). The yield
increased to 96% when the strong electron-withdrawing group F
was introduced into the indole ring (Table 2, entry 9). We found
that indole-2-carbaldehyde 1k could also undergo this transforma-
tion, leading to chiral 2-indolylmethanol in good yield, with good
diastereoselectivity and excellent enantioselectivity (Table 2, entry
10). To the best of our knowledge, this is the first example of the
synthesis of a chiral 2-indolylmethanol by organocatalysis.13
99f
92
94g
ND
ND
Trace
Trace
4s
ND
a
b
c
Reaction conditions: 1a (0.2 mmol), 2 (4 mmol), and 3a (0.03 mmol).
Isolated yield.
Determined by 1H NMR.
d
e
f
ee of anti-product determined by HPLC analysis on a chiral stationary phase.
0.5 mL DMSO and 10 equiv. 2a were used.
At 0 °C.
ee of syn-product, R2 = R3 = Me.
ND = not determined.
g
h

Q.-X. Guo et al. / Tetrahedron Letters 54 (2013) 4653–4655
4655
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4. Selected examples (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
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(c) Li, H.; Wang, Y.-Q.; Deng, L. Org. Lett. 2006, 8, 4063.
R1
H
N
OTBS
R3
N
Bs
O
H
O
R2
O
H
Transition State I (TS I)
5. (a) Guo, Q.-X.; Peng, Y.-G.; Zhang, J.-W.; Song, L.; Feng, Z.; Gong, L.-Z. Org. Lett.
2009, 11, 4620; (b) Song, L.; Guo, Q.-X.; Li, X.-C.; Tian, J.; Peng, Y.-G. Angew.
Chem., Int. Ed. 1899, 2012, 51; (c) Xu, B.; Guo, Z.-L.; Jin, W.-Y.; Wang, Z.-P.; Peng,
Y.-G.; Guo, Q.-X. Angew. Chem., Int. Ed. 2012, 51, 1059.
Figure 1. The plausible transition state.
6. (a) Guo, C.; Song, J.; Huang, J.-Z.; Chen, P.-H.; Luo, S.-W.; Gong, L.-Z. Angew.
Chem., Int. Ed. 2012, 51, 1046; (b) Song, J.; Guo, C.; Adele, A.; Yin, H.; Gong, L.-Z.
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as the donor (Table 3, entry 5). When this reaction was carried out
at a lower temperature, the diastereoselectivity ratio increased to
77:23 (Table 3, entry 6). The cycloheptanone 2f yield was only
28% (Table 3, entry 7). Acyclic ketones were not good reaction part-
ners; for example, butanone reacted with 1a to give the aldol prod-
uct in 36% yield with poor diastereoselectivity (Table 3, entry 8),
but 3-pentanone and acetone did not react with 1a efficiently (Ta-
ble 3, entries 9 and 10).
The relative and absolute configurations of 4b (S, R) were deter-
mined by X-ray crystallography (see the Supplementary data).14
The stereochemistries of the other aldol products were assigned
by comparison with 4b.
The actually mechanism of this reaction is still unclear. We
thought the selectivity of this reaction was realized through a sim-
ilar transition state (TS I) to that reported by Córdova and co-work-
ers (Fig. 1).15
In conclusion, we present an efficient aldol reaction of ketones
with indole-3-carbaldehydes, catalyzed by O-TBS-protected L-thre-
8. Chen, J.; Geng, Z.-C.; Li, N.; Huang, X.-F.; Pan, F.-F.; Wang, X.-W. J. Org. Chem.
2013. http://dx.doi.org/10.1021/jo304945.
9. Selected examples of using indole-3-carbaldehydes as acceptors in asymmetric
organometallic catalysis: (a) Gao, X.; Townsend, I. A.; Drische, M. J. J. Org. Chem.
2011, 76, 2350; (b) Leighty, M. W.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc.
2012, 134, 15223; (c) Hassan, A.; Zbieg, J. R.; Krische, M. Angew. Chem., Int. Ed.
2011, 50, 3493; (d) Lipshutz, B. H.; Papa, P. Angew. Chem., Int. Ed. 2002, 41,
4580; (e) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667.
10. For review, see: Heravi, M. M.; Asadi, S. Tetrahedron: Asymmetry 2012, 23, 1431;
The selected pioneering work of organocatalytic asymmetric aldol reactions,
see: (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395;
(b) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-
D. J. Am. Chem. Soc. 2003, 125, 5262.
11. (a) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. Adv. Synth. Catal. 2007, 349, 812; (b)
Cheng, L.; Wu, X.; Lu, Y. Org. Biomol. Chem. 2007, 5, 1018; (c) Guo, Q.-X.; Liu, Y.-
W.; Li, X.-C.; Zhong, L.-Z.; Peng, Y.-G. J. Org. Chem. 2012, 77, 3589.
12. Typical procedure: A 10 mL dried tube was charged with indole-3-carbaldehyde
1b (0.2 mmol), 2a (4 mmol), and catalyst 3a (0.03 mmol) at 20 °C. The mixture
was vigorously stirred and the reaction progress was monitored via TLC. After
the completion of the reaction, two drops of saturated NH4Cl solution were
added to quench the reaction. The organic layer was separated and the water
phase was extracted by EtOAc. The organic phase was combined and dried by
Na2SO4. The product 4b (85%) was obtained by flash chromatography
onine 3a. Our method is a good choice for synthesizing chiral 3-
indolylmethanols and 2-indolylmethanols. All the products have
excellent enantioselectivities, and good to excellent diastereoselec-
tivities and yields.
(petroleum:AcOEt = 4:1) as a white solid: ½a D20
ꢀ
= +3.8 (c 0.052, CH3CH2OH);
1H NMR (300 MHz, CDCl3) d (ppm) 7.99 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 7.4 Hz,
2H), 7.69 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 9.0 Hz, 2H), 7.43 (t, J = 7.2 Hz, 2H), 7.35–
7.30 (m, 1H), 7.22 (d, J = 7.1 Hz, 1H), 5.05 (d, J = 8.5 Hz, 1H), 4.05 (s, 1H), 2.84
(dd, J = 15.0, 10.1 Hz, 1H), 2.50 (d, J = 13.3 Hz, 1H), 2.43–2.32 (m, 1H), 2.08 (s,
1H), 1.79–1.47 (m, 4H), 1.37–1.29 (m, 1H); 13C NMR (75 MHz, CDCl3) d (ppm)
215.4, 138.0, 135.5, 133.9, 129.3, 129.1, 126.8, 125.0, 124.0, 123.4, 122.4, 121.0,
113.7, 68.6, 55.8, 42.7, 31.0, 27.7, 24.7; HRMS(ESI): calcd for C21H21NNaO4S
(M++Na): 406.1083, found: 406.1067.
Acknowledgements
We are grateful for the financial support from NSFC (21272002)
and the Program for New Century Excellent Talents in Universities
(NCET-12-0929). Professor Xiong is grateful for the financial sup-
port from Chongqing University (Nos. CDJRC10220004 and
CDJZR11220005).
13. Selected examples of synthesizing chiral 2-indolylmethanols by
organometallic catalysis, see: (a) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.;
Tan, Z.; Tang, W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.; Yee, N. K.;
Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600; (b) Kim, I. S.; Ngai, M.-Y.;
Krische, M. J. J. Am. Chem. Soc. 2008, 130, 14891.
Supplementary data
14. CCDC 926458 (4b) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
15. Ma, G.; Bartoszewicz, A.; Ibrahem, I.; Córdova, A. Adv. Synth. Catal. 2011, 353,
3114.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
06.056.
References and notes
1. Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489.