Copper(II) bromide-catalyzed conjugate addition of indoles to α,β-enones

Article abstract of DOI:10.1080/00397910500518940

Copper(II) bromide was found to be an efficient catalyst for the conjugate addition of indoles to α,β-enones in acetonitrile at room temperature. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500518940

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Copper(II) Bromide–Catalyzed Conjugate
Addition of Indoles to α,β‐Enones
a
Sandip K. Nayak
a
Bio‐organic Division , Bhabha Atomic Research Centre , Mumbai, India
Published online: 24 Feb 2007.
To cite this article: Sandip K. Nayak (2006) Copper(II) Bromide–Catalyzed Conjugate Addition of Indoles
to α,β‐Enones, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:9, 1307-1315, DOI: 10.1080/00397910500518940
To link to this article: http://dx.doi.org/10.1080/00397910500518940
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Synthetic Communications , 36: 1307–1315, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500518940
Copper(II) Bromide–Catalyzed Conjugate
Addition of Indoles to a,b-Enones
Sandip K. Nayak
Bio-organic Division, Bhabha Atomic Research Centre, Mumbai, India
Abstract: Copper(II) bromide was found to be an efficient catalyst for the conjugate
addition of indoles to a,b-enones in acetonitrile at room temperature.
Keywords: Conjugate addition, copper(II) bromide, a,b-enone, indole
The simple and direct method for the synthesis of 3-alkyl indoles
involves the conjugate addition of indoles to a,b-unsaturated carbonyl
[1]
[2]
compounds in the presence of protic or Lewis acids. However, the
acid-catalyzed conjugate addition of indoles requires careful control of
acidity to prevent side reactions such as dimerization or polymerization,
whereas Lewis acid–catalyzed reactions involve toxic and expensive
[
3]
reagents coupled with long reaction times.
develop a mild and cheap catalyst for these reactions. A recent report
We felt a need to
[3g]
on the samarium triodide
–
catalyzed alkylation of indoles
prompted us to report our results on the conjugate addition of indoles
to a,b-enones catalyzed by copper(II) bromide to furnish 3-alkylated
indole (Scheme 1).
2
of 15 mol% of CuBr in acetonitrile reacted smoothly within 15 min at
-Methylindole (1b) with benzylideneacetophenone (2a) in the presence
2
ambient temperature to afford 3-(2-methyl-3-indolyl)-1,3-diphenyl-propan-
l-one (3a) in 83% yield. To test the generality of the protocol, the reactions
Received in India September 26, 2005
Address correspondence to Sandip K. Nayak, Bio-organic Division, Bhabha Atomic
Research Centre, Mumbai 400 085, India. Fax: þ91(22)25505151; E-mail: sknayak@
magnum.barc.ernet.in
1
307

1
308
S. K. Nayak
Scheme 1. R ¼ H, Me; R
1
¼ H, alkyl, aryl; R ¼ alkyl, aryl.
2
were also carried out using several other a,b-unsaturated carbonyl compounds
such as benzylideneacetone (2a–g), giving rise to Michael adducts (3b–j) in
good yields (Table 1). Because of extensive polymerization, however,
reactions of 1a and 1b with methyl vinyl ketone (2f ) furnished the correspond-
ing adducts 3g and 3h in modest yields (Table 1, entries 7 and 8). Interestingly,
reactions of 1a and 1b with dibenzylideneacetone (2h) (with 2:1 molar ratio)
in the presence of 30 mol% CuBr gave bis-alkylated products 3k and 3l
2
respectively (Table 1, entries 11 and 12). All the compounds were fully
1
13
characterized by IR, H NMR, C NMR, and MS data by comparison with
the known compounds.
In summary, wehave demonstrated thatCuBr is an efficientand mild Lewis
2
acid catalyst for alkylation of indole/2-methyl indole with a,b-unsaturated
carbonyl compounds.
Melting points were taken on a Fisher-Johns melting-point apparatus
and are uncorrected. The FT-IR spectra were scanned with a Jasco FT-
1
IR spectrophotometer. The H NMR and
13
C NMR spectra were
recorded with a Bruker AC 200 (200-MHz) spectrometer. Mass spectra
were recorded with a Shimadzu GC-MS QP 5050A mass spectrometer.
All reactions were carried out under an argon atmosphere Acetonitrile
was dried and distilled over P O . Compounds 2a–d and 2h were
2
5
[4]
prepared following the literature procedure. Compounds 1a, 1b, 2e–g,
and CuBr were used as received from Fluka.
2
EXPERIMENTAL
Typical Experimental Procedure
A solution of indole 1 (3.0 mmol), a,b-unsaturated carbonyl compounds 2
(
(
3.0 mmol), and CuBr2 (0.45 mmol, 0.1 g, 15 mol%) in dry acetonitrile
10 ml) was stirred at room temperature for an appropriate time (see
Table 1). The mixture was concentrated, diluted with water and ethylacetate,
and filtered over Celite. The filtrate was extracted with ethylacetate and dried
(
(
Na SO ). Removal of solvent followed by silica-gel chromatography
2 4
hexane/ethyl acetate 85:15) afforded 3.

a,b
Table 1. CuBr
2
-catalyzed conjugate addition of indoles to a,b-enones
c
Entry
Nucleophile Electrophile
Product
Time (h)
0.25
Yield (%)
83
1
2
3
0.25
0.33
72
82
4
0.33
73
(continued)

Table 1. Continued
Entry Nucleophile
c
Electrophile
Product
Time (h)
Yield (%)
5
0.33
55
6
0.5
54
7
8
0.25
0.25
45
39

9
0.33
90
1
1
1
0
1
2
0.33
0.50
0.50
68
65
52
a
Reaction conditions: indole/2-methylindole (3.0 mmol), a,b-enone (3.0 mmol), and CuBr
entries 1–10).
2
(0.45 mmol) in acetonitrile at ambient temperature
(
b
Reaction conditions: indole/2-methylindole (2.0 mmol), a,b-enone (1.0 mmol), and CuBr (0.3 mmol) acetonitrile at ambient temperature (entries
2
11 and 12).
c
Isolated and unoptimized yields.

1
312
Data
-(2-Methyl-3-indolyl)-1,3-diphenyl-propan-1-one (3a)
Solid, mp 179–1808C; IR (KBr): 3367, 3024, 1684, 1618, 1460, 699 cm
S. K. Nayak
[3c]
3
2
1
;
1
H NMR (200 MHz, CDCl ): d ¼ 7.89 (d, 2 H, J ¼ 7.8 Hz), 7.51 (br s, 1 H,
3
NH), 7.00–7.48 (m, 12 H), 5.11 (t, 1 H, J ¼ 7.0 Hz), 3.94 (dd, 2 H, J ¼ 2.7,
1
3
7
1
1
2
.3 Hz), 2.39 (s, 3 H); C NMR (50 MHz, CDCl ): d ¼ 199.3, 144.1,
3
37.0, 135.4, 132.8, 131.7, 128.4, 128.2, 127.9, 127.4, 127.3, 125.8, 120.5,
18.9, 113.2, 110.5, 43.5, 36.7, 11.9.; EIMS: m/z ¼ 339 (M ), 234, 221,
þ
20, 216, 146, 128.
[3c]
3-(3-Indolyl)-1,3-diphenyl-propan-l-one (3b)
21 1
Solid, mp 130–1328C; IR (KBr): 3399, 3019, 1676, 1457, 700 cm ; H NMR
(
200 MHz, CDCl ): d ¼ 7.92–7.95 (m, 3 H), 7.00–7.54 (m, 13 H), 5.07 (t, 1
3
1
3
H, J ¼ 7.2 Hz), 3.77 (m, 2 H); C NMR (50 MHz, CDCl ): d ¼ 198.6, 144.2,
3
1
1
37.0, 136.6, 133.0, 128.5, 128.4, 128.0, 127.8, 126.6, 126.3, 122.0, 121.4,
19.5, 119.3, 119.1, 111.1, 45.2, 38.2; EIMS: m/z ¼ 325 (M ), 246, 220, 206.
þ
[3c]
4-(2-Methyl-3-indolyl)-4-phenyl-butan-2-one (3c)
21 1
Solid, mp 108–1098C; IR (KBr): 3400, 3010, 1712, 1620, 1461, 700 cm ; H
NMR (200 MHz, CDCl ): d ¼ 7.79 (br s, 1 H, NH), 6.96–7.47 (m, 9 H), 4.86
3
(
t, 1 H, J ¼ 6.7 Hz), 3.38 (dq, 2 H, J ¼ 8.3, 16.2 Hz), 2.42 (s, 3 H), 2.01 (s, 3
1
3
H); C NMR (50 MHz, CDCl ): d ¼ 208.3, 143.9, 135.4, 135.8, 128.2, 127.3,
3
1
25.8, 120.6, 118.9, 112.8, 110.5, 48.2, 36.7, 30.7, 11.9; EIMS: m/z ¼ 277
þ
(
M ), 234, 217, 143, 129, 102.
3-(2-Methyl-3-indolyl)-1-(3-methoxyphenyl)-3-(4-chlorophenyl)-
propan-1-one (3d)
21 1
Thick oil; IR (KBr): 3369, 3015, 1682, 1598, 1461 cm ; H NMR (200 MHz,
CDCl ): d ¼ 7.81 (br s, 1 H, NH), 7.03–7.49 (m, 12 H), 5.05 (t, 1 H,
3
1
3
J ¼ 7.0 Hz), 3.94–3.77 (m, 2 H), 3.73 (s, 3 H), 2.39 (s, 3 H); C NMR
(
50 MHz, CDCl ): d ¼ 198.9, 159.5, 142.5, 138.1, 135.3, 131.7, 131.3,
3
1
1
29.4, 128.7, 128.1, 126.9, 120.6, 120.6, 119.5, 119.0, 118.6, 112.7, 111.9,
10.5, 55.0, 43.2, 36.2, 11.7; EIMS: m/z ¼ 404 (M ), 254, 216, 135, 82.
þ
Anal. calcd. for C H ClNO :C, 74.34; H, 5.49; N, 3.47. Found: C, 74.45;
22
2
5
2
H, 5.58; N, 3.56.

Addition of Indoles to a,b-Enones
1313
3-(2-methyl-3-indolyl)-1-(3-methoxyphenyl)-3-(4-methoxyhenyl)-
propan-1-one (3e)
21 1
Thick oil; IR (KBr): 3377, 3008, 1682, 1598, 1461, 1035 cm ; H NMR
(
(
(
200 MHz, CDCl ): d ¼ 7.38 (br s, 1 H, NH), 6.78–7.50 (m, 12 H), 5.04
3
t, 1 H, J ¼ 7.0 Hz), 3.39–4.01 (m, 2 H), 3.75 (s, 3 H), 3.72 (s, 3 H), 2.37
1
3
s, 3 H); C NMR (50 MHz, CDCl ): d ¼ 199.3, 159.6, 157.5, 138.5,
3
1
1
2
3
36.2, 135.4, 131.6, 129.4, 128.4, 127.3, 120.5, 119.5, 118.9, 113.5, 111.9,
10.4, 55.1, 55.0, 43.7, 36.1, 11.7; EIMS: m/z ¼ 399 (M 2 1), 369, 277,
þ
35, 217, 204, 191. Anal. calcd. for C H CNO : C, 78.17; H, 6.31; N,
25
2
6
3
.51. Found: C, 78.26; H, 6.21; N, 3.59.
[3c]
-(2-Methyl-3-indolyl)cyclohexan-l-one (3f )
3
21 1
Solid, mp 91–928C; IR (KBr): 3380, 3014, 2939, 1703, 1619; 1459 cm ; H
NMR (200 MHz, CDCl ): d ¼ 7.83 (br s, 1 H, NH), 7.65–7.68 (m, 1 H),
3
7
.03–7.30 (m, 3 H), 2.92–3.28 (m, 2 H), 1.65–2.52 (m, 7 H), 2.33 (s, 3
1
3
H); C NMR (50 MHz, CDCl ): d ¼ 212.2, 135.3, 130.2, 126.7, 120.6,
3
1
18.8, 113.4, 110.6, 48.1, 41.3, 37.2, 31.3, 25.9, 11.8; EIMS: m/z ¼ 227
þ
(M ), 184, 170, 107, 83, 69.
[3b]
4
-(2-Methyl-3-indolyl)-butan-2-one (3g)
21 1
Thick oil; IR (KBr): 3478, 3018, 1713, 1456, 1216 cm ; H NMR (200 MHz,
CDCl ): d ¼ 7.80 (br s, 1 H, NH), 7.07–7.44 (m, 4 H), 2.96 (t, 2 H,
3
1
3
J ¼ 7.1 Hz), 2.76 (t, 2 H, J ¼ 7.2 Hz), 2.38 (s, 3 H), 2.10 (s, 3 H); C NMR
(
50 MHz, CDCl ): d ¼ 209.2, 135.2, 131.2, 128.1, 120.8, 118.9, 117.6,
3
þ
1
12.6, 110.3, 110.1, 44.1, 30.1, 18.3, 11.4; EIMS: m/z ¼ 201 (M ), 143,
1
35, 121, 110, 97, 70.
[
3b]
4
-(3-Indolyl)-butan-2-one (3h)
1
Solid, mp 70–718C; H NMR (200 MHz, CDCl ): d ¼ 7.95 (br s, 1 H, NH),
3
7
2
2
2
.78 (d, 1 H, J ¼ 7.5 Hz), 6.99–7.38 (m, 4 H), 3.09 (t, 2 H, J ¼ 7.4 Hz),
1
3
.85 (t, 2 H, J ¼ 7.3 Hz), 2.14 (s, 3 H); C NMR (50 MHz, CDCl ): d ¼
3
11.1, 209.1, 136.2, 127.0, 121.8, 121.5, 119.1, 118.5, 114.8, 111.2, 43.9,
9.9, 19.2; EIMS: m/z ¼ 187 (M ), 149, 135, 110, 97, 82, 69.
þ
[3f]
-(2-Methyl-3-indolyl)-1,4-naphthaquinone (3i)
2
21 1
Solid, mp 182–1848C; IR (KBr): 3328, 3018, 1667, 1593, 1454 cm ; H
NMR (200 MHz, CDCl ): d ¼ 8.51 (br s, 1 H, NH), 8.12–8.21 (m, 2 H),
3
7
.47–7.78 (m, 2H), 7.51–7.53 (m, 1 H), 7.09–7.25 (m, 4 H), 2.41 (s, 3 H);
1
3
C NMR (50 MHz, CDCl ): d ¼ 185.3, 184.8, 144.4, 137.2, 135.4, 134.5,
3

1
314
S. K. Nayak
1
1
33.7, 133.5, 132.7 132.2, 127.6, 126.9, 125.9, 122.1, 120.8, 110.7, 107.1,
þ
3.7; EIMS: m/z ¼ 287 (M ), 286, 270, 269.
[3f]
2
-(3-Indolyl)-1,4-naphthaquinone (3j)
21 1
Solid, mp 178–1798C; IR (KBr): 3328, 3018, 1667, 1593, 1454 cm ; H
NMR (200 MHz, CDCl ): d ¼ 8.75 (br s, 1 H, NH), 8.10–8.30 (m, 4 H),
3
7
1
.71–7.76 (m, 2 H), 7.25–7.41 (m, 4 H).
[3a]
,5-Bis(3-indolyl)-1,5-diphenyl-pentan-3-one (3k)
Solid, inseparable mixture of dl and meso isomers; IR (KBr): 3402, 3018,
2
1 1
1
707, 1618, 1455, 701 cm ; H NMR (200 MHz, CDCl ): d ¼ 7.82 (br s,
3
2
H, NH), 6.97–7.37 (m, 18 H), 6.67–6.73 (m, 2 H), 4.78 (t, 2 H,
1
3
J ¼ 7.5 Hz), 3.07–3.20 (m, 4 H); C NMR (50 MHz, CDCl ): d ¼ 208.6,
3
2
4
08.5, 143.9, 143.8, 136.3, 128.3, 127.5, 126.2, 121.7, 119.2, 118.0, 111.2,
9.6, 49.6, 37.9.
1,5-Bis(2-methyl-3-indolyl)-1,5-diphenyl-pentan-3-one (3l)
Brown solid, inseparable mixture of dl and meso isomers; IR (KBr): 3422,
3
2
027, 1709, 1618, 1418, 1217, 700 cm ; H NMR (200 MHz, CDCl ):
1
1
3
d ¼ 7.66 (br s, 2 H, NH), 6.97–7.34 (m, 18 H), 4.76 (t, 2 H, J ¼ 7.0 Hz),
1
.04–3.43 (m, 4 H), 2.21 (s, 2 H), 2.10 (s, 4 H); C NMR (50 MHz,
3
3
CDCl ): d ¼ 211.2, 209.2, 143.9, 143.8, 135.3, 131.8, 128.1, 127.3, 119.2,
3
119.0, 112.9, 112.6, 110.4, 48.2, 47.9, 36.6, 11.8, 11.6.
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