CaSH organocatalysis: Enantioselective Friedel-Crafts alkylation of indoles with α,β-unsaturated aldehydes

Article abstract of DOI:10.1055/s-0029-1217552

Enantioselective Friedel-Crafts alkylation of indole with α,β-unsaturated aldehyde was catalyzed by camphor sulfonyl hydrazine (CaSH) with good enantioselectivity (81-88%). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217552

LETTER
2115
CaSH Organocatalysis: Enantioselective Friedel–Crafts Alkylation of Indoles
with a,b-Unsaturated Aldehydes
E
nantioselective
i
Friede
a
l–Crafts
A
n
lkylation of IndolesTian,a,b Bao-Jian Pei,a Qing-Hua Li,a Hao He,a Ling-Yan Chen,a Xiang Zhou,b Wing-Hong Chan,a
Albert W. M. Lee*a
a
Department of Chemistry, Hong Kong Baptist University, Hong Kong, P. R. of China
Fax +85234117438; E-mail: alee@hkbu.edu.hk
College of Chemistry and Molecular Sciences, Wuhan University, Hubei, P. R. of China
b
Received 1 April 2009
tionality is also an effective organocatalyst. It is well es-
Abstract: Enantioselective Friedel–Crafts alkylation of indole with
a,b-unsaturated aldehyde was catalyzed by camphor sulfonyl hy-
drazine (CaSH) with good enantioselectivity (81–88%).
tablished that by attaching a heteroatom to an amine, its
nucleophilicity will be greatly enhanced.11 We envision
that if another nitrogen atom is attached to the amino func-
tionality (hydrazine) of an organocatalyst, the so-called a-
heteroatom effect could enhance its nucleophilicity.12 The
addition of an electron-withdrawing group such as sulfo-
nyl could further fine tune the extent of the a-effect.
Key words: camphor sulfonyl hydrazine (CaSH), organocatalysis,
indole alkylation, a,b-unsaturated aldehydes
Although the term organocatalysis was only coined in
2000,1 the concept of using small molecules to catalyze
asymmetric transformation has appeared in literatures
even back in the 1970s. The proline-catalyzed intramolec-
ular aldol reaction by Hajos, Parrish, Eder, Sauer, and
Wiechert is an outstanding example.2 In recent years, we
have witnessed an exponential growth in organocatalysis.
It has become a highly dynamic and rapidly growing re-
search field. Together with organometallic and enzymatic
approaches, organocatalysis has emerged as a new power-
ful tool for various asymmetric transformations.3,4 Among
numerous asymmetric carbon–carbon forming reactions,
the Friedel–Crafts alkylation of aromatic substrates with
the a,b-unsaturated carbonyl compounds has received
considerable attention.5 It is not only an important type of
reaction in organic synthesis, but also provides important
building blocks for the synthesis of many natural prod-
ucts.6
To put these concepts into practice, we have recently pre-
pared a series of camphor sulfonyl hydrazines (CaSH)
from camphor sulfonyl chloride by a three-step reaction
sequence with good overall yield (70%, Scheme 1). We
have demonstrated that CaSH are excellent organocata-
lysts in asymmetric Diels–Alder reactions and aza-
Micheal addition.13 In this paper, we report the use of
CaSH 1 (R = Bn) as organocatalyst in Friedel–Crafts
alkylation of indoles with a,b-unsaturated aldehydes.
NH2NH2⋅H2O
N
AcOH–MeOH
S
O
92%
N
SO2Cl
O
H
O
R-X
THF
91–97%
(X = Br, Cl or I)
NaOH, TBAB
Based on the imine formation strategy,7 MacMillan and
co-workers first explored the organocatalytic asymmetric
Friedel–Crafts indole alkylation. Employing chiral imida-
zolidinone salts as organocatalysts, they reported the reac-
tions of indoles, pyrroles, and electron-rich benzenes with
a,b-unsaturated aldehydes.8 The MacMillan-type catalyst
has also been used for the indole alkylation with cyclic
a,b-unsaturated aldehydes.9a Intramolecular Friedel–
Crafts-type indole alkylation reactions have also been in-
vestigated by other groups.9b Further improvements in this
type of organocatalytic Friedel–Crafts indole alkylation
with a,b-unsaturated ketones by new organocatalysts also
appeared recently.10
NH
R
S
N
O
O
CaSH
R = Me, Et, Bu, Bn
N
S
N
R
O
O
Scheme 1 Preparation of the camphor sulfonyl hydrazines (CaSH)
Our investigation started with the reaction between indole
and (E)-crotonaldehyde. We chose trifluoroacetic acid
(TFA, 20 mol%) as the additive and toluene as the solvent.
CaSH 1 which has very good catalytic effect in asymmet-
ric Diels–Alder reactions was chosen as the organocata-
lyst. Although indole disappeared after six hours at –40
°C, only trace amount of the desired product 3 was detect-
ed (Table 1, entry 1). When electron-withdrawing group
such as mesylate, benzoyl, and propyonyl was attached to
indole, the reactivities of these N-substituted indoles were
decreased to the extent that there were no reactions even
at room temperature (Table 1, entries 2–4). To our delight,
In the reported Lewis base approaches, the key function-
alities in these organocatalysts are either primary or
secondary amines. We report here that hydrazine func-
SYNLETT 2009, No. 13, pp 2115–2118
x
x
.x
x
.2
0
0
9
Advanced online publication: 10.07.2009
DOI: 10.1055/s-0029-1217552; Art ID: W04809ST
© Georg Thieme Verlag Stuttgart · New York

2116
T. Tian et al.
LETTER
N-methylindole started to show some promising results. observed that with larger alkyl substituent on the b-posi-
Alkylated product 3 was isolated in moderate yield with tion of the unsaturated aldehydes, the reactions were
60% ee after 9 hours at –40 °C (Table 1, entry 5). For the slower with lower yields but higher ee (Table 2, entries 1–
ease of handling, aldehyde 314 was reduced with NaBH4 4). It is possibly due to the steric effect. For aryl-substitut-
directly to alcohol 4, which is more polar and can be sep- ed a,b-unsaturated aldehydes, moderate yields, and up to
arated easily by flash chromatograph on silica gel. We 88% ee were achieved (Table 2, entries 5–7). When the
tried different solvents [Et2O, CH2Cl2, CCl4, and i-PrOH– unsaturated aldehyde was substituted with a strong elec-
CH2Cl2 (15% v/v)] for this reaction. However, both the tron-donating group (OMe), the reaction was very slow
yields and the enantioselectivities were poor as compared even at room temperature (Table 2, entry 8).
with using toluene (Table 1, entries 6–9). Finally, we
moved to N-benzyl indole and found it afforded much bet-
In summary, we have demonstrated for the first time that
camphor sulfonyl hydrazine (CaSH) is an efficient orga-
ter result in terms of yield (60%) and ee (78%, Table 1,
nocatalyst for enantioselective Friedel–Crafts alkylation
entry 10). When the less acidic trichloroacetic acid (TCA)
of N-benzyl indole with a,b-unsaturated aldehydes with
good enantioselectivity. The investigation of the other
was used as the additive, the result was slightly inferior
(Table 1, entry 11). Increased the amount of catalyst and
CaSH-catalyzed enantioselective transformations is in
TFA to 30 mol%, the yield and ee were improved to 71%
progress.
and 81%, respectively (Table 1, entry 12).
With the optimized reaction conditions in hand, we then
examined the scope of this CaSH 1 catalyzed alkylation of
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
N-benzyl indole with various a,b-unsaturated alde-
hydes.15 The results are summarized in Table 2.16 It was
Table 1 Friedel–Crafts Alkylation of Indoles with (E)-Crotonaldehyde Catalyzed by CaSH 1
NH
S
N
Ph
S
O
CHO
NaBH4
O
CH2OH
(20 mol%)
CaSH 1
CHO
+
TFA (20 mol%)
N
N
N
R1
R1
R1
2
3
4
Entry
1
R1
H
Solvent
Temp (°C)
–40
Time (h)
Yield (%)a
ee (%)b,c
toluene
toluene
toluene
toluene
toluene
Et2O
6
<10
n.r.
n.r.
n.r.
53
–
2
Ms
Bz
–40 to r.t.
–40 to r.t.
–40 to r.t.
–40
72
72
48
9
–
3
–
4
propionyl
Me
–
5
60
40
43
54
40
78
70
81
6
Me
–40
18
9
30
7
Me
CH2Cl2
CCl4
–40
38
8
Me
–40
24
20
20
30
20
34
9
Me
i-PrOH–CH2Cl2
toluene
–40
49
10
11d
12e
Bn
–40
60
Bn
toluene
–40
55
Bn
toluene
–40
71
a Isolated yield of alcohol 4.
b Determined by chiral HPLC (Chiracel AD-H) of the alcohol 4.
c Absolute configuration was assigned by comparison of the chiral HPLC chromatographs with the literature reported data.8
d TCA was used instead of TFA.
e Conditions: 30 mol% CaSH 1 and 30 mol% TFA.
Synlett 2009, No. 13, 2115–2118 © Thieme Stuttgart · New York

LETTER
Enantioselective Friedel–Crafts Alkylation of Indoles
2117
Table 2 Friedel–Crafts Alkylation of N-Benzyl Indole with a,b-Unsaturated Aldehydes Catalyzed by CaSH 1
R2
R2
NH
Ph
S
N
CHO
O
CH2OH
O
NaBH4
CaSH 1 (30 mol%)
CHO
R2
+
TFA (30 mol%)
toluene, –40 °C
N
N
N
(3.0 equiv)
Bn
Bn
Bn
5
6
Entry
R2
Me
Et
Time (h)
20
Yield (%)a
ee (%)b
81
1
2
3
4
5
6
7
8
71
67
63
46
50
49
49
<20
28
84
Pr
36
87
Bu
Ph
36
88
30
87
4-ClC6H4
30
88
4-BrC6H4
4-MeOC6H4
20
88
72
–
a Isolated yields of the alcohols 6.
b Determined by chiral HPLC analysis of the alcohols 6.
Jørgensen, K. A. . Angew. Chem. Int. Ed. 2003, 42, 1498.
(d) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.
(e) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 2458.
Acknowledgment
Financial support from the Faculty Research Grant (FRG/07-08/II-
64) and General Research Fund of the Research Grant Council are
gratefully acknowledged.
(8) (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 1172. (b) Paras, N. A.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2001, 123, 4370. (c) Paras, N. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894.
(d) Huang, Y.; Walji, A. M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 15051.
(9) (a) King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura,
R.; Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437.
(b) Li, C.-F.; Liu, H.; Liao, J.; Cao, Y.-J.; Liu, X.-P.; Xiao,
W.-J. Org. Lett. 2007, 9, 1847.
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2007, 5, 816. (b) Bartoli, G.; Bosco, M.; Melchiorre, P. Org.
Lett. 2007, 9, 1403.
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6154. (b) Cavill, J. L.; Elliott, R. L.; Evans, G.; Jones, I. L.;
Platts, J. A.; Ruda, A. M.; Tomkinson, N. C. O. Tetrahedron
2006, 62, 410.
References and Notes
(1) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243. (b) A similar term ‘organic
catalysis’ first appeared in the German literature:
Langenbeck, W. Fortschr. Chem. Forsch. 1966, 6, 301.
(2) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed.
Engl. 1971, 10, 496. (b) Hajos, Z. G.; Parrish, D. R. J. Org.
Chem. 1974, 39, 1615.
(3) (a) Alessandro, D.; Alessandro, M. Angew. Chem. Int. Ed.
2008, 47, 4638. (b) List, B. Chem. Rev. 2007, 107, 5413.
(c) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43,
5138. (d) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T.
Chem. Rev. 2003, 103, 2985. (e) Dalko, P. I.; Moisan, L.
Angew. Chem. Int. Ed. 2001, 40, 3726.
(12) (a) Cavill, J. L.; Peters, J. U.; Tomkinson, N. C. O. Chem.
Commun. 2003, 728. (b) Gupta, R. R.; Kumar, M.; Gupta,
V. Heterocyclic Chemistry, Vol. 3; Springer: Heidelberg,
1999. (c) Lemay, M.; Ogilvie, W. W. Org. Lett. 2005, 7,
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71, 4663. (e) Lemay, M.; Aumand, L.; Ogilvie, W. W. Adv.
Synth. Catal. 2007, 349, 441.
(13) (a) He, H.; Pei, B.-J.; Chou, H.-H.; Tian, T.; Chan, W.-W.;
Lee, A. W.-M. Org. Lett. 2008, 10, 2421. (b) Langlois, Y.;
Petit, A.; Remy, P.; Scherrmann, M. C.; Kouklovsky, C.
Tetrahedron Lett. 2008, 49, 5576. (c) Chen, L.-Y.; He, H.;
Pei, B.-J.; Chan, W. H.; Lee, A. W. M. Synthesis 2009, 1573.
(14) Aldehyde 3 (R1 = Me): 1H NMR (400 MHz, CDCl3): d =
9.75 (s, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.31 (m, 1 H), 7.26
(m, 1 H), 7.14 (m, 1 H), 6.84 (s, 1 H), 3.75 (s, 3 H), 3.68 (m,
(4) (a) Notz, W.; Tanaka, F.; Barbas, C. F. III. Acc. Chem. Res.
2004, 37, 580. (b) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2006, 45, 1520.
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2903.
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Chem. Int. Ed. 2004, 43, 550. (b) Austin, J. F.; Kim, S.-G.;
Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5482.
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Synlett 2009, No. 13, 2115–2118 © Thieme Stuttgart · New York

2118
T. Tian et al.
LETTER
1 H), 2.87 (m, 1 H), 2.71 (m, 1 H), 1.43 (d, J = 6.8 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): d = 203.1, 137.4, 126.8,
125.4, 121.9, 119.3, 119.0, 109.6, 51.2, 32.9, 26.1, 21.9 ppm.
Alcohol 4 was obtained by NaBH4 reduction. Alcohol 4
(R1 = Me): 1H NMR (400 MHz, CDCl3): d = 7.64 (dd,
J = 8.0, 0.8 Hz, 1 H), 7.30 (dd, J = 7.2, 0.8 Hz, 1 H), 7.23 (m,
1 H), 7.10 (m, 1 H), 6.85 (s, 1 H), 3.75 (s, 3 H), 3.66 (m, 1
H), 3.22 (m, 1 H), 2.06 (m, 1 H), 1.96 (m, 1 H), 1.40 (d,
J = 6.8 Hz, 3 H) ppm.
1 H), 1.98 (m, 2 H), 1.74 (m, 2H), 0.83 (t, J = 7.0 Hz, 3 H)
ppm.
Compound 6 (R2 = Pr): 1H NMR (400 MHz, CDCl3): d =
7.69 (d, J = 8.0 Hz, 1 H), 7.33–7.24 (m, 4 H), 7.18 (m, 1 H),
7.17–7.06 (m, 3 H) 6.93 (s, 1 H), 5.29 (s, 2 H), 3.62 (m, 2 H),
3.05 (m, 1 H), 2.03 (m, 2 H), 1.18 (m, 2 H), 1.30 (m, 2 H),
0.88 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
d = 138.0, 137.1, 128.9, 127.8, 127.7, 126.7, 125.6, 121.8,
119.9, 119.0, 118.9, 110.0, 61.9, 50.0, 39.0, 38.9, 33.6, 21.0,
14.4 ppm.
(15) General Experimental Procedure for CaSH 1 Catalyzed
Friedel–Crafts Reaction of Indoles with a,b-Unsaturated
Aldehydes
Compound 6 (R2 = Bu): 1H NMR (400 MHz, CDCl3): d =
7.66 (d, J = 7.6 Hz, 1 H), 7.30–7.22 (m, 4 H), 7.14 (t, J = 7.6
Hz, 1 H), 7.09–7.03 (m, 3 H), 6.90 (s, 1 H), 5.27 (s, 2 H),
3.59 (m, 2 H), 3.01 (m, 1 H), 2.00 (m, 2 H), 1.78 (m, 2 H),
1.23 (m, 4 H), 0.83 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100
MHz, CDCl3): d = 138.0, 137.1, 128.9, 127.8, 127.7, 126.7,
125.6, 121.8, 119.9, 119.0, 110.0, 61.9, 50.0, 39.0, 36.3,
33.8, 30.2, 23.0, 14.3 ppm.
TFA (0.15 mmol) was added to a solution of CaSH 1 (0.15
mmol) in toluene (1 mL). The solution was stirred for 20 min
and then cooled to –40 °C. The a,b-unsaturated aldehyde
(1.5 mmol) was then added. After stirring for another 20
min, the N-substituted indole (0.5 mmol) was added. The
reaction was stirred until complete consumption of the
indoles as determined by TLC. MeOH (2 mL) was added to
the reaction mixture followed by NaBH4 (3.0 mmol). The
mixture was warmed to 0 °C and stirred for 20 min. The
reaction was quenched by H2O and extracted with EtOAc.
The organic solution was dried over anhyd Na2SO4. The
product 6 was purified by silica gel chromatography (PE–
EtOAc, 4:1). The ee was determined by chiral HPLC
(Chiracel AD-H) of the alcohol 6 (5% i-PrOH in hexane
as eluent, 1 mL min–1).
Compound 6 (R2 = Ph): 1H NMR (400 MHz, CDCl3): d =
7.52 (m, 1 H), 7.38–7.07 (m, 12 H), 7.03 (m, 2 H), 5.30 (s, 2
H), 4.44 (t, J = 7.6 Hz, 1 H), 3.68 (m, 2 H), 2.48 (m, 1 H),
2.29 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): d = 145.1,
138.0, 237.2, 129.0, 128.7, 128.1, 127.9, 127.8, 126.9,
126.4, 125.6, 122.1, 120.0, 119.3, 119.1, 109.9, 61.5, 50.2,
39.4, 39.0 ppm.
Compound 6 (R2 = 4-ClC6H4): 1H NMR (400 MHz, CDCl3):
d = 7.41 (d, J = 8.0 Hz, 1 H), 7.33–7.22 (m, 8 H), 7.15 (m, 3
H), 7.01 (m, 2 H), 5.29 (s, 2 H), 4.40 (t, J = 7.6 Hz, 1 H), 3.64
(m, 2 H), 2.43 (m, 1 H), 2.22 (m, 1 H) ppm. 13C NMR (100
MHz, CDCl3): d = 143.6, 137.8, 137.2, 131.9, 129.4, 129.0,
128.7, 127.8, 127.6, 126.8, 125.5, 122.2, 119.8, 119.4,
118.5, 110.0, 61.2, 50.2, 38.8, 38.7 ppm.
(16) Spectroscopic Data of Products 6 (Table 2)
Compound 6 (R2 = Me): 1H NMR (400 MHz, CDCl3): d =
7.74 (dd, J = 7.6, 0.8 Hz, 1 H), 7.33 (m, 4 H), 7.21 (m, 4 H),
6.96 (s, 1 H), 5.29 (s, 2 H), 3.30 (m, 2 H), 3.27 (m, 1 H), 2.08
(m, 1 H), 1.95 (m, 1H), 1.44 (d, J = 7.2 Hz, 3 H) ppm. 13
C
NMR (100 MHz, CDCl3): d = 138.0, 137.1, 129.0, 127.7,
127.6, 126.9, 124.6, 122.0, 121.1, 119.8, 119.1, 110.0, 61.7,
50.1, 40.6, 27.9, 22.1 ppm. HRMS (MALDI-TOF): m/z
calcd for C19H22NO [M + H]+: 280.1696; found: 280.1695.
Compound 6 (R2 = Et): 1H NMR (400 MHz, CDCl3): d =
7.64 (d, J = 7.6, Hz, 1 H), 7.25 (m, 4 H), 7.14 (m, 1 H), 7.06
(m, 3 H) 6.88 (s, 1 H), 5.24 (s, 2 H), 3.56 (m, 2 H), 2.93 (m,
Compound 6 (R2 = 4-BrC6H4): 1H NMR (400 MHz, CDCl3):
d = 7.40 (m, 3 H), 7.37–7.18 (m, 6 H), 7.15–7.07 (m, 3 H),
6.99 (m, 2 H), 5.28 (s, 2 H), 4.38 (t, J = 8.0 Hz, 1 H), 3.62
(m, 2 H), 2.43 (m, 1 H), 2.22 (m, 1 H) ppm. 13C NMR (100
MHz, CDCl3): d = 144.1, 137.8, 137.2, 131.7, 129.8, 129.0,
127.8, 127.6, 126.8, 125.5, 122.2, 120.0, 119.8, 119.4,
118.4, 110.0, 61.2, 50.2, 38.8, 38.7 ppm.
Synlett 2009, No. 13, 2115–2118 © Thieme Stuttgart · New York

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