1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2,2,2]octane bis(tetrafluoroborate) as novel and efficient reagent for the conjugate addition of indoles to α,β-unsaturated ketones

Article abstract of DOI:10.1246/cl.2007.1056

Indoles undergo smooth conjugate addition with α,β-unsaturated ketones in the presence of 10 mol % Selectfluor under extremely mild conditions to afford the corresponding Michael adducts in high to quantitative yields with 1,4-selectivity. Copyright

Full text of DOI:10.1246/cl.2007.1056

1056
Chemistry Letters Vol.36, No.8 (2007)
1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2,2,2]octane Bis(tetrafluoroborate)
as Novel and Efficient Reagent for the Conjugate Addition
of Indoles to ꢀ,ꢁ-Unsaturated Ketones
J. S. Yadav,ꢀ B. V. Subba Reddy, A. Raju, K. Ravindar, and Gakul Baishya
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received April 2, 2007; CL-070345; E-mail: yadavpub@iict.res.in)
Indoles undergo smooth conjugate addition with ꢀ,ꢁ-unsat-
urated ketones in the presence of 10 mol % SelectfluorÔ under
extremely mild conditions to afford the corresponding Michael
adducts in high to quantitative yields with 1,4-selectivity.
O
O
SelectfluorTM
CH3CN, r.t.
+
N
H
N
H
1
2
3a
Scheme 1.
The conjugate addition of indoles to ꢀ,ꢁ-unsaturated
ketones constitutes a key reaction in the total synthesis of
complex natural products such as hapalindole. The hapalindole
alkaloids isolated from the blue-green algae Hapalosiphon fon-
tinalis. They exhibit potent antibacterial and antimycotic activi-
ty.1 Consequently, numerous methods have been reported for the
conjugate addition of indoles to electron-deficient olefins
through the activation of enones by Lewis acids.2,3 Asymmetric
version of Michael addition of indole to ꢀ,ꢁ-unsaturated ketones
has also been reported using proline-derived chiral amines to
produce enantiomerically enriched indole derivatives.4 Typical-
ly, these Michael reactions are performed under the influence of
strong bases such as alkali metal alkoxides or hydroxides.5 The
strong basic conditions often lead to a number of undesirable
side reactions such as aldol reaction, ester solvolysis, base-
induced rearrangements such as retro-Claisen or retro-Michael
reactions and polymerization reactions. Subsequently, Lewis
acids are found to catalyze the Michael reactions under mild
conditions.6,7 Since indoles and their derivatives have become
increasingly useful and important in the field of drugs and
pharmaceuticals, the developments of simple and efficient
approaches are desirable.
Recently, SelectfluorÔ has been introduced commercially
as a user-friendly electrophilic fluorinating agent (Figure 1).
SelectfluorÔ is readily available at low cost and is easy to
handle and also retains its activity even in the presence of
amines.8 More recently, SelectfluorÔ has been employed as an
efficient Lewis acid catalyst for the one-pot allylation of imines
and for the hydrolysis of acetals, dithia-acetals and tetrahydro-
pyranyl ethers9 and also for the cleavage of epoxides with thio-
cyanates.10 However, there have been no examples of the use of
SelectfluorÔ as a catalyst for the conjugate addition of indoles to
ꢀ,ꢁ-unsaturated ketones.
catalyst for the conjugate addition of indoles to ꢀ,ꢁ-unsaturated
ketones to produce 3-substituted indoles in high to quantitative
yields under mild conditions.12 Accordingly, treatment of indole
(1) with methyl vinyl ketone (2) in the presence of 10 mol %
SelectfluorÔ resulted in the formation of 4-(3-indolyl)-2-buta-
none (3a) in 90% yield (Scheme 1).
The reaction proceeded efficiently in acetonitrile at room
temperature with high 1,4-selectivity. The reaction went to com-
pletion in a short time (3.0 h). Encouraged by the results obtained
with indole and methyl vinyl ketone, we turned our attention
to various indoles and electron-deficient alkenes. Interestingly,
various enones including chalcones underwent 1,4-addition with
a range of indoles under these reaction conditions to afford the
corresponding 3-alkylated indoles, the yields were generally
high to quantitative in few hours. Like enones, other electron-
deficient alkenes such as 1-[2-nitro-(E)-1-ethenyl]benzene also
afforded the Michael adduct in excellent yields (Entry N). In the
absence of catalyst, the reactions did not proceed even after
long reaction times (10–20 h). No by-products arising from
1,2-addition or bis-addition was observed. Moreover, the reac-
tions were clean and high yielding in some cases quantitative.
It is well known that chiral quaternary ammonium salts activate
the enones effectively to promote the Michael reaction.13 Simi-
larly, enones may be activated by quaternary nitrogen of the
SelectfluorÔ. However, ꢀ,ꢁ-unsaturated nitriles and esters
failed to undergo Michael addition with indoles under identical
conditions. Furthermore, the reaction of indole with sterically
hindered 3-methylcyclohexenone in the presence of 10 mol %
of SelectfluorÔ in refluxing acetonitrile gave low yield (10%).
The scope and generality of this process is illustrated with
respect to various enones and indoles and the results are
summarized in Table 1.
In summary, we have described a simple and highly efficient
protocol for the conjugate addition of indoles to ꢀ,ꢁ-unsaturated
ketones using SelectfluorÔ as novel catalyst. This method
offers several advantages including mild reaction conditions,
high conversions, short reaction times, clean reaction profile,
ease of handling, and ready availability of the catalyst at
low cost, which makes it a useful and attractive process for
the alkylation of indoles with ꢀ,ꢁ-unsaturated system.
As part of our on going programme in developing new
synthetic methodologies for the functionalization of indoles,11
herein we report the use of SelectfluorÔ as a novel and efficient
+
Cl
N
2BF4
+
-
N
F
AR, KR, and GB thank CSIR New Delhi for the award of
fellowships.
Figure 1.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.8 (2007)
1057
Table 1. SelectfluorÔ catalyzed conjugate addition of indoles
to enones
R. Varala, S. R. Adapa, Tetrahedron Lett. 1998, 29, 2477;
M. Bandini, P. Melchiorre, A. Melloni, A. Umani-Ronchi,
Synthesis 2002, 1110; J. S. Yadav, B. V. S. Reddy, B. Gakul,
K. V. Reddy, Tetrahedron 2005, 61, 9541; V. Kumar, S. Kaur,
S. Kumar, Tetrahedron Lett. 2006, 47, 7001; Z.-H. Huang,
J.-P. Zou, W.-Q. Jiang, Tetrahedron Lett. 2006, 47, 7965.
J. F. Austin, D. W. C. Macmillan, J. Am. Chem. Soc. 2002,
124, 172; M. Bandini, M. Fagioli, P. Melchiorre, A. Melloni,
A. Umani-Ronchi, Tetrahedron Lett. 2003, 44, 5843; K. B.
Jensen, J. Thorhange, R. G. Hazel, K. A. Jorgensen, Angew.
Chem., Int. Ed. 2001, 40, 160.
Entry
Indole (1)
Enone (2)
Product (3)a
Time/h Yield/%b
O
O
4
90
92
3.0
2.5
A
B
N
H
N
O
H
O
O
N
N
H
O
H
5
6
E. D. Bergamnn, D. Ginsburg, R. Pappo, Org. React. 1953,
10, 179.
C
D
3.5
4.0
90
89
N
N
O
O
O
O
A. Soriente, A. Spinella, M. DeRosa, M. Giordano, A. Scettri,
Tetrahedron Lett. 1997, 38, 289; H. Kotsuki, K. Arimure, T.
Ohishi, R. Maruzasa, J. Org. Chem. 1999, 64, 3770; G.
Bartoli, M. Bosco, M. C. Bellucci, E. Marcantoni, L. Sambri,
E. Torregiani, Eur. J. Org. Chem. 1999, 617.
S. Kobayashi, Synlett 1994, 689; S. Kobayashi, I. Hachiya,
T. Takabhori, M. Araki, H. Ishitani, Tetrahedron Lett. 1992,
33, 6815; Y. Mori, K. Kakumoto, K. Manabe, S. Kobayashi,
Tetrahedron Lett. 2000, 41, 3107.
N. Shibata, E. Suzuki, T. Asahi, M. Shiro, J. Am. Chem. Soc.
2001, 123, 7001; M. D. Burkart, Z. Zhang, S.-C. Hung, C.-H.
Wong, J. Am. Chem. Soc. 1997, 119, 11743.
J. Liu, C.-H. Wong, Tetrahedron Lett. 2002, 43, 3915; J. Liu,
C.-H. Wong, Tetrahedron Lett. 2002, 43, 4037.
N
H
N
H
E
4.0
90
N
H
N
H
7
O
O
Br
Br
F
4.5
3.5
91
88
N
H
N
H
O
O
8
9
CN
O
O
CN
G
N
H
N
H
4.0
4.0
90
90
H
I
10 J. S. Yadav, B. V. S. Reddy, Ch. S. Reddy, Tetrahedron Lett.
2004, 45, 1291.
N
H
N
H
O
O
11 J. S. Yadav, B. V. S. Reddy, P. M. Reddy, Ch. Srinivas,
Tetrahedron Lett. 2002, 43, 5185; J. S. Yadav, B. V. S. Reddy,
G. Satheesh, Tetrahedron Lett. 2003, 44, 8331; J. S. Yadav,
B. V. S. Reddy, G. Satheesh, Tetrahedron Lett. 2004, 45,
3673.
Br
Br
N
H
N
H
Ph O
O
3.0
3.0
90
91
J
N
H
Ph
12 General procedure. A mixture of indole (1 mmol) and ꢀ,ꢁ-
unsaturated ketone (1 mmol) and SelectfluorÔ (10 mol %) in
acetonitrile (10 mL) was stirred at room temperature for the
appropriate time (Table 1). After completion of the reaction,
as indicated by TLC, The solvent was evaporated under
reduced pressure. Then, the resulting product was directly
charged onto a small silica gel column and eluted with a
mixture of ethyl acetate: n-hexane (1.5:8.5) to afford pure 3-
substituted indoles. Spectral data for selected products: 3a.
White solid, mp 94–95 ꢁC; IR (KBr). ꢂ 3329, 3047, 2936,
2841, 1702, 1595, 1503, 1437, 1361, 1227, 1159, 1061, 934,
N
H
Ph O
Ph O
Ph O
O
K
L
Ph
N
N
O
O
Br
Br
4.0
3.5
90
95
Ph
Ph
N
H
N
H
Ph
M
N
Ph
N
H
N
H
1
859, 746 cmꢂ1; H NMR (200 MHz, CDCl3): ꢃ 2.50 (s, 3H),
Ph
NO
2
2.80 (t, 2H, J ¼ 7:5 Hz), 3.04 (t, 2H, J ¼ 7:5 Hz), 6.95 (d,
1H, J ¼ 2:5 Hz), 7.00–7.18 (m, 2H), 7.22–7.32 (m, 1H),
7.50 (d, 1H, J ¼ 7:0 Hz), 7.90 (brs, 1H, NH); 13C NMR
(50 MHz, CDCl3): ꢃ 20.1, 30.5, 44.6, 113.8, 116.1, 118.2,
119.0, 120.6, 122.4, 127.6, 130.7, 208.3; EI-MS m=z (%).
187 (Mþ 32), 130 (100), 115 (10), 77 (12), 43 (48). 3n. Yellow
solid, mp 100–101 ꢁC, IR (KBr). ꢂ 3418, 3066, 2997, 2834,
1599, 1546, 1491, 1443, 1409, 1376, 1329, 1258, 1218,
3.0
92
NO
2
Ph
N
H
N
H
aAll products were characterized by 1H NMR, IR, and mass
spectrometry. Isolated and unoptimized yield.
b
References and Notes
1
1109, 1094, 1018, 967, 851, 743, 697 cmꢂ1
;
1H NMR
R. E. Moore, C. Cheuk, G. M. L. Patterson, J. Am. Chem.
Soc. 1984, 106, 6456.
(200 MHz, CDCl3): ꢃ 4.90–5.08 (m, 2H), 5.20 (t, 1H,
J ¼ 7:0 Hz), 6.96 (d, 1H, J ¼ 2:2 Hz), 7.05–7.40 (m, 8H),
7.50 (d, 1H, J ¼ 8:0 Hz), 8.00 (brs, 1H, NH); 13C NMR
(50 MHz, CDCl3): ꢃ 40.8, 78.5, 110.9, 118.8, 120.1, 121.8,
123.0, 126.4, 127.8, 128.1, 129.2, 135.9, 140.1; EI-MS m=z
(%). 266 (Mþ 100), 219 (37), 206 (21), 178 (11), 158 (47),
130 (16), 105 (24), 77 (31), 51 (26).
2
N. Srivastave, B. K. Banik, J. Org. Chem. 2003, 68, 2109;
M. Bandini, P. G. Cozzi, M. Giacomini, P. Melchiorre, S.
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Bartoli, M. Bartolacci, M. Bosco, G. Foglia, A. Giuliani, E.
Marcantoni, L. Sambri, E. Torregiani, J. Org. Chem. 2003,
68, 4594.
3
P. Harrington, M. A. Kerr, Can. J. Chem. 1998, 76, 1256;
P. Harrington, M. A. Kerr, Synlett 1996, 1047; M. M. Alam,
13 R. Ceccarelli, S. Insogna, M. Bella, Org. Biomol. Chem. 2006,
4, 4281.
Published on the web (Advance View) July 21, 2007; doi:10.1246/cl.2007.1056