InCl3-catalyzed alkylation of aromatic and heteroaromatic compounds with cyclic allylic acetates

Article abstract of DOI:10.1055/s-2006-958418

Various aromatic and heteroaromatic compounds undergo smooth alkylation with cyclic allylic acetates in the presence of 10 mol% of indium trichloride under mild conditions to afford 3-substituted indoles, 2-substituted furan and pyrrole and cyclohexenyl-s

Full text of DOI:10.1055/s-2006-958418

LETTER
3447
InCl -Catalyzed Alkylation of Aromatic and Heteroaromatic Compounds with
3
Cyclic Allylic Acetates
a
a
a
a
a
a
I
J
nCl -Cata
.
lyze
d
A
lkyla
S
tion of Aroma
.
tic and
Hete
Y
roaromatic Compo
a
unds dav,* B. V. Subba Reddy, K. Vishweshwar Rao, P. Purushothama Rao, K. Sarita Raj, A. R. Prasad,
3
b
b
A. Prabhakar, B. Jagadeesh
a
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
b
Centre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 26 July 2006
To expand the scope of these reactions, we have studied
the reaction of cyclic allylic acetates with other aromatic
and heteroaromatic compounds. Now we wish to report
Abstract: Various aromatic and heteroaromatic compounds under-
go smooth alkylation with cyclic allylic acetates in the presence of
1
0 mol% of indium trichloride under mild conditions to afford 3-
substituted indoles, 2-substituted furan and pyrrole and cyclohex- our findings for the alkylation of aromatic and heteroaro-
enyl-substituted arenes in good yields with high selectivity.
matic compounds through S 2-type substitution of cyclic
N
allylic acetates using a catalytic amount of indium trichlo-
ride.
Keywords: indium(III) compounds, cyclic allylic acetates, alkyla-
tion, aromatics
Accordingly, treatment of 2-methylindole (1) with 4-car-
bethoxy-3-methyl-2-cyclohexenyl acetate (2) in the pres-
Lewis acid catalyzed carbon–carbon bond-forming reac- ence of indium trichloride (10 mol%) in 1,2-
tions are of great importance in organic synthesis because dichloroethane afforded 3-(4-carbethoxy-3-methyl-2-cy-
of their high reactivity, selectivity and mild reaction con- clohexenyl)-1H-indole (3b) in 80% yield (Scheme 2).
1
ditions. Indole and its derivatives are found abundantly in
nature and are known to exhibit potent physiological
properties. Consequently, the synthesis and reactions of
2
CO Et
2
CO2Et
indole and its derivatives have attracted great importance
in organic synthesis.3–5 Allylic acetates are well-known
carbon electrophiles capable of reacting with various nu-
cleophiles and their ability to undergo nucleophilic substi-
tution reactions contributes largely to their synthetic
value. However, there are no examples of the C-alkylation
of indoles with cyclic allylic acetates. Recently, indium
InCl3 (10 mol%)
DCE, 80 °C
Me
+
N
H
OAc
Me
1
2
N
H
3b
trichloride has evolved as mild and water-tolerant Lewis Scheme 2
acid imparting high regio-, chemo- and diastereoselectiv-
6
ity in various organic transformations. Compared to con-
O
9
11 12
CH3
8
ventional Lewis acids, indium trichloride has advantages
of water stability, recyclability and operational simplici-
ty. While studying the mechanism of the aminoglycosi-
dation reactions of glycals with aryl amines, we observed
that the reaction of cyclohexenyl acetate and aniline under
the influence of indium tribromide (10 mol%) in dichloro-
ethane at 80 °C afforded 2-(2-cyclohexenyl)aniline8
CH3
7
O
10
H
H
H
Ha
6
7
H
Hb
Hc
f
3
4
H 6'
H5
H5'
H
H
e
2
1
CH3
R
CH3
N
H
H
H
H
O
Hd
H
H
HN
O
H
(
Scheme 1).
CH3
H
H
Figure 1 Characteristic NOE interactions for 3b
InBr3 (10 mol%)
DCE, 80 °C
+
NH2
The NMR studies were carried out for the structural char-
acterization of compound 3b making use of vicinal cou-
pling and two-dimensional experiments like HSQC and
NOESY. For compound 3b the six-membered ring adopts
a half-chair conformation. NOE cross peak between H7–
NH2
OAc
Scheme 1
H5¢, H4–H6 and large coupling J
H7–H6
= 10.0 Hz and
J = 10.3 Hz confirm the half-chair conformation
H4–H5¢
SYNLETT 2006, No. 20, pp 3447–3450
Advanced online publication: 08.12.2006
1
8
.1
2
.2
0
0
6
(Figure 1). The presence of NOE cross peak between
DOI: 10.1055/s-2006-958418; Art ID: D22006ST
Ha–H4, Ha–H10, H1–H5, and H1–H5¢ further supports
©
Georg Thieme Verlag Stuttgart · New York

3
448
J. S. Yadav et al.
LETTER
the assigned structure and that the stereochemistry is
trans. Like entry b (Table 1), other reactions (entries c, d,
i, l–n, Table 1) are highly stereoselective affording the
corresponding products with trans stereochemistry. Simi-
larly, substituted indoles such as 2-methyl- and 7-ethyl-
indole derivatives reacted smoothly with cyclohexenyl
acetates to give the corresponding 3-cyclohexenyl indoles
in good yields (entries a–c, Table 1). Like indole, pyrrole
and furan gave the respective 2-cyclohexenyl pyrrole and
furan derivatives (entries d and e, Table 1, Scheme 3).
EtO2C
InCl3 (10 mol%)
DCE, 80 °C
+
N
N
H
H
CO Et
2
OAc
Scheme 3
OMe
InCl3 (10 mol%)
DCE, 80 °C
+
Similarly, electron-rich arenes underwent smooth alkyla-
tion with cyclohexenyl acetates under the same reaction
conditions to give the respective cyclohexenyl-substituted
arenes (entry h–n, Table 1, Scheme 4).
OMe
OMe
OAc
OMe
OMe
OMe
Scheme 4
Table 1 InCl -Catalyzed Alkylation of Aromatic Compounds with Cyclic Allylic Acetates
3
Entry
Allylic acetate
Nucleophile
Product 3a
Time (h)
3.5
Yield (%)b
75
a
OAc
N
H
Me
Me
N
H
b
OAc
4.0
80
CO2Et
Me
N
H
CO2Et
OAc
Me
N
H
c
CO Et
4.5
3.5
71
75
2
N
H
Et
N
H
CO2Et
OAc
Et
d
Me
N
H
N
H
CO2Et
CO2Et
OAc
e
f
2.5
2.0
72
70
Me
O
O
OAc
NH2
NH2
g
OAc
2.5
72
NH2
NH2
Synlett 2006, No. 20, 3447–3450 © Thieme Stuttgart · New York

LETTER
InCl -Catalyzed Alkylation of Aromatic and Heteroaromatic Compounds
3449
3
Table 1 InCl -Catalyzed Alkylation of Aromatic Compounds with Cyclic Allylic Acetates (continued)
3
Entry
Allylic acetate
Nucleophile
Product 3a
Time (h)
1.0
Yield (%)b
82
h
OAc
OH
OH
MeO
MeO
i
OAc
OH
OH
1.5
75
O
O
O
O
CO2Et
OAc
2
CO Et
j
MeO
MeO
1.5
1.0
81
87
k
OAc
OAc
OMe
MeO
OMe
OMe
MeO
OMe
l
Me
Me
2.5
2.5
2.0
79
80
83
CO2Et
OAc
2
CO Et
m
n
MeO
MeO
CO2Et
OAc
2
CO Et
MeO
MeO
MeO
MeO
CO2Et
CO2Et
a
1
All products were characterized by H NMR, IR and mass spectroscopy.
Yield refers to products isolated after chromatography.
b
In all cases, the reactions proceeded efficiently with high nucleophiles. This method was successful only with
selectivity and were complete within 0.5–4.5 hours. How- cyclic allylic acetates. As solvent, dichloroethane appears
ever, in the absence of the indium chloride, no reaction to give the best results. All the products were character-
1
13
was observed between allylic acetates and aromatic com- ized by H NMR, C NMR, IR, and mass spectroscopy.
pounds. No g-substitution was observed in this case. The The scope and generality of this process was illustrated
acetate group was simply replaced by the nucleophile in with respect to various indoles, pyrrole and arenes and the
SN2 manner. However, pyrrole underwent partial poly- results are presented in Table 1.9
merization when metal triflates were used as catalysts.
In conclusion, we have described a novel and efficient
Pyrrole was also not compatible with conventional Lewis
protocol for the alkylation of aromatic and heteroaromatic
acids such as aluminum chloride or boron trifluoride
compounds through S 2-type substitution of cyclic allylic
N
etherate. This is because of the sensitivity of pyrrole to
acetates using indium trichloride as the catalyst. In addi-
strong acidic conditions. Interestingly, this method is
tion to its efficiency, simplicity and mild reaction condi-
compatible with acid-sensitive substrates such as pyrrole
tions, this method provides good yields of products with
and furan. Other functional groups such as olefins and es-
high selectivity, which makes it a useful and attractive
ters are unaffected. The simple cyclohexyl acetates failed
process for the alkylation of aromatic compounds. It is
to undergo alkylation under similar reaction conditions.
an entirely new synthetic route for the functionalization
Furthermore, acyclic allylic acetates such as 3-phenyl-
of indoles, pyrrole, furan and electron-rich aromatic
(
E)-2-propenyl acetate and (E)-2-butenyl acetate did not
systems.
undergo the expected S 2 substitution with aromatic
N
Synlett 2006, No. 20, 3447–3450 © Thieme Stuttgart · New York

3
450
J. S. Yadav et al.
LETTER
the corresponding cyclohexenyl-substituted aromatic or
References and Notes
heteroaromatic compound in pure form.
(
(
1) Kobayashi, S. Eur. J. Org. Chem. 1999, 15.
2) (a) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1.
Spectral Data for Selected Products:
1
Entry a: H NMR (200 MHz, CDCl ): d = 7.80 (br s, 1 H,
3
(
b) Ninomiya, I. J. Nat. Prod. 1992, 55, 541.
NH), 7.65 (d, J = 8.0 Hz, 1 H), 6.85–7.40 (m, 4 H), 5.60 (br
(
3) (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew.
Chem. Int. Ed. 2004, 43, 550. (b) Austin, J. F.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. (c) Jensen, K.
B.; Thorhange, J.; Hazel, R. G.; Jørgensen, K. A. Angew.
Chem. Int. Ed. 2001, 40, 160.
s, 1 H), 3.65 (br s, 1 H), 2.05 (m, 4 H), 1.75 (s, 3 H), 1.65 (m,
2
7
H). IR (KBr): 3416, 2920, 2857, 1697, 1453, 1338, 1087,
43 cm . EIMS: m/z (%) = 211 (100) [M ], 196 (70), 168
–1
+
(
53), 130 (31), 117 (30), 77 (15), 41 (18). HRMS (LSIMS):
+
m/z [M ] calcd for C H N: 211.1361; found: 211.1359.
Entry b: H NMR (500 MHz, CDCl ): d = 7.70 (br s, 1 H,
1
5
17
(
4) (a) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68,
1
3
2
109. (b) Bartoli, G.; Bartolacci, M.; Bosco, M.; Foglia, G.;
Giuliani, A.; Marcantoni, E.; Sambri, L.; Torregiani, E. J.
Org. Chem. 2003, 68, 4594.
NH), 7.47 (d, J = 7.1 Hz, 1 H, Ha), 7.25 (d, J = 7.1 Hz, 1 H,
Hd), 7.05 (t, J = 7.1 Hz, 1 H, Hc), 7.01 (t, J = 7.1 Hz, 1 H,
Hb), 5.74 (q, J = 2.2 Hz, 1 H, H-10), 4.20 (q, J = 7.2 Hz,
(
(
5) (a) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi,
A. Synlett 2005, 1199. (b) Ma, S.; Yu, S. Tetrahedron Lett.
2
H, H-11), 3.70 (dddd, JH4–H10 = 2.2 Hz, JH4–H5 = 5.6 Hz,
JH4–H5¢ = 10.0 Hz, JH4–H7 = 2.0 Hz, 1 H, H-4), 3.24 (dddd,
JH4–H7 = 2.0 Hz, JH6–H7 = 5.6 Hz, JH6¢–H7 = 10.3 Hz, JH9–H7
2
004, 45, 8419.
=
6) (a) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149.
1
1
1
.1 Hz, 1 H, H-7), 2.36 (s, 3 H, H-1), 2.13 (m, 1 H, H-6),
(
(
b) Babu, G.; Perumal, P. T. Aldrichima Acta 2000, 33, 16.
c) Ghosh, R. Indian. J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2001, 40, 550.
.95–1.98 (m, 2 H, H5, H6¢), 1.76–1.78 (m, 4 H, H5¢, H-9),
13
.29 (t, J = 7.2 Hz, 3 H, H-12). C NMR (75 MHz, CDCl ):
3
d = 135.5 (Ce), 130.1 (C-10), 129.4 (C-2), 126.9 (C=O),
(
7) (a) Yadav, J. S.; Reddy, B. V. S.; Raman, J. V.; Niranjan, N.;
Kumar, S. K.; Kunwar, A. C. Tetrahedron Lett. 2002, 43,
1
1
2
26.9 (Cf), 124.0 (C-8), 120.6 (Cc), 118.8 (Ca), 118.8 (Cb),
15.0 (C-3), 110.2 (Cd), 60.2 (C-11), 46.7 (C-7), 33.2 (C-4),
2
095. (b) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M.
Synlett 2001, 1417. (c) Yadav, J. S.; Sunny, A.; Reddy, B.
V. S.; Sabitha, G. Tetrahedron Lett. 2001, 42, 8063.
7.9 (C-5), 26.8 (C-6), 21.5 (C-9), 14.2 (C-12), 11.6 (C-1).
–1
IR (KBr): 3390, 2924, 2364, 1721, 1458, 1167, 745 cm .
EIMS: m/z (%) = 297 (77) [M ], 282 (35), 207 (27), 182 (47),
+
(
(
8) Yadav, J. S.; Reddy, B. V. S.; Rao, K. V.; Saritha Raj, K.;
Prasad, A. R.; Kiran Kumar, S.; Kunwar, A. C.; Jayaprakash,
P.; Jagannath, B. Angew. Chem. Int. Ed. 2003, 115, 5356.
9) General Procedure: A mixture of cyclic allylic acetate (1
mmol), arene or indole (2 mmol) and/or pyrrole or furan (4
1
67 (18), 147 (100), 97 (15), 84 (73), 43 (65).
1
Entry l: H NMR (200 MHz, CDCl ): d = 6.75 (d, J = 8.0 Hz,
3
1
3
H), 6.55 (d, J = 8.0 Hz, 1 H), 5.30 (br s, 1 H), 3.85 (s, 9 H),
.60 (br s, 1 H), 1.95 (m, 3 H), 1.75 (s, 3 H), 1.65 (m, 3 H).
13
1
C NMR (50 MHz, CDCl , H-decoupled): d = 151.5,
3
mmol) and InCl (10 mol%) in 1,2-dichloroethane (10 mL)
3
142.2, 135.0, 132.9, 126.1, 124.7, 122.6, 107.1, 61.1, 60.6,
was stirred at reflux temperature for the time required to
complete the reaction (Table 1). After complete conversion
as indicated by TLC, the reaction mixture was diluted with
water and extracted with EtOAc (2 × 10 mL). The combined
organic layers were dried over anhyd Na SO , concentrated
5
6.0, 34.7, 31.1, 29.9, 23.9, 21.5. IR (KBr): 3452, 2928,
–1
1601, 1492, 1462, 1280, 1097, 1022, 717 cm . EIMS: m/z
+
(%) = 262 (100) [M ], 247 (43), 219 (20), 203 (17), 167 (10),
+
95 (16), 84 (24), 49 (43). HRMS (LSIMS): m/z [M ] calcd
2
4
for C H O : 262.1569; found: 262.1565.
1
6
22
3
in vacuo and purified by column chromatography on silica
gel (Merck, 100–200 mesh, EtOAc–hexane, 1:9) to afford
Synlett 2006, No. 20, 3447–3450 © Thieme Stuttgart · New York