Palladium-catalyzed functionalization of indoles with 2-acetoxymethyl- substituted electron-deficient alkenes

Article abstract of DOI:10.1021/jo061546s

New functionalizations of indoles via palladium-catalyzed reaction of indoles and 2-acetoxymethyl-substituted electron-deficient alkenes are reported. It was found that for N-protected indoles the reaction proceeded smoothly in the presence of 5 mol % of

Full text of DOI:10.1021/jo061546s

palladium-catalyzed Heck-type reactions of 3-halo-substituted
indoles5 are two well-established methods for the functional-
ization at the 3-position of the indole nucleus. During the past
several years, palladium-catalyzed intramolecular or intermo-
lecular direct coupling of indoles with alkenes have also been
developed by the utilization of various oxidants to regenerate
the catalytically active Pd(II) species in situ.6 Billups’ group
reported a palladium-catalyzed nonselective allylation of indoles
with allyl acetate, allylic alcohols, or 1,3-dienes, affording a
mixture.7 Recently, the Tamura group has also found that under
the catalysis of palladium, Et3B can promote the C-3-selective
allylation of indoles with a variety of allyl alcohols.8 In both
cases, a π-allylpalladium intermediate may be involved. In our
previous work,9 we have demonstrated an efficient metal- and
halogen-free route to stereoselective synthesis of benzocycles
via TFA-mediated intramolecular Friedel-Crafts reactions of
6-acetoxy-4-alkenylarenes.9a Also, a new functionalization of
indoles via the Pd(OAc)2-catalyzed reaction of indoles with
2-acetoxymethyl-substituted electron-deficient alkenes to afford
3-(2-methoxycarbonyl-2-propenyl)indoles was reported, in which
the â-OAc functional group was used for the regeneration of
Pd(II) species.9c However, this reaction usually needed a long
reaction time and high temperature and suffered from low yield
and poor diversity for the starting indoles. Herein, we wish to
report our recently developed new catalytic systems for the
coupling of indoles with 2-acetoxymethyl-substituted electron-
deficient alkenes.
Palladium-Catalyzed Functionalization of Indoles
with 2-Acetoxymethyl-Substituted
Electron-Deficient Alkenes
Shengming Ma,* Shichao Yu, Zhihua Peng, and Hao Guo
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. China
masm@mail.sioc.ac.cn
ReceiVed July 26, 2006
New functionalizations of indoles via palladium-catalyzed
reaction of indoles and 2-acetoxymethyl-substituted electron-
deficient alkenes are reported. It was found that for N-
protected indoles the reaction proceeded smoothly in the
presence of 5 mol % of Pd(acac)2 and 10 mol % of PPh3 at
80 °C in HOAc, while for N-unprotected indoles, the reaction
was carried out by using 5 mol % of Pd(dba)2 or 2.5 mol %
of Pd2(dba)3‚CHCl3 with 10 mol % of 2,2′-bipyridine as the
catalyst in toluene. This strategy allows the selective instal-
lation of electron-deficient olefin functionality at the 3-posi-
tion of indoles, which might be difficult to obtain by other
methods and can be further elaborated.
(3) (a) Hegedus, L. S. Angew. Chem., Int. Ed. 1988, 27, 1113. (b) Antilla,
J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684.
(c) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030. (d) Ferreira, E.
M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578. (e) Coleman, C. M.;
Oshea, D. F. J. Am. Chem. Soc. 2003, 125, 4054. (f) Bandini, M.; Cozzi,
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Bu¨chi, G.; Mak, C. J. Org. Chem. 1977, 42, 1784-1786. (c) Ranganathan,
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D. A.; Scheidt, K. A.; Frandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem.
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2947-2949. (b) Vaillancourt, V.; Albizati, K. F. J. Am. Chem. Soc. 1993,
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42, 983-985.
Indoles and their derivatives constitute an important class of
biologically active natural products, which play a fundamental
role in bioorganic chemistry.1 For this reason, the efficient
synthesis and functionlization of indoles derivatives2,3 have
attracted the interest of many synthetic chemists. The Lewis
acid catalyzed alkylation between indoles and electrophiles4 and
* To whom correspondence should be addressed. Tel: 86-21 54925147.
Fax: 86-21 64167510.
(1) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New
York, 1970. (b) Sexton, J. E. Indoles, Part 4: The monoterpenoid indole
alkaloids; Wiley: New York, 1983. (c) Sundberg, R. J. Indoles; Academic
Press: London, 1996. (d) Joule, J. A.; Mills, K. Heterocyclic Chemistry,
4th ed.; Blackwell Science: Oxford, 2000.
(6) (a) Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1,
2097. (b) Lu, W.; Jia, C.; Kitamura, T.; Fujiwara, Y. Org. Lett. 2000, 2,
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2004, 126, 10250. (e) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc.
2003, 125, 9578. (f) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem.,
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10.1021/jo061546s CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/01/2006
J. Org. Chem. 2006, 71, 9865-9868
9865

TABLE 1. Optimization of Reaction Conditions for the
Pd-Catalyzed Coupling of 1a with
Methyl 2-(Acetoxymethyl)acrylate 2a
TABLE 3. Optimization of Reaction Conditions for the
Pd-Catalyzed Coupling of N-Methylindole 1k with Methyl
(2-Acetoxymethyl)acrylate 2a
entry
solvent
time (h)
yielda (%)
ligand,
(mol %)
time
(h)
yield of
entry
cat.
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(PhCN)2Cl2
[Pd(η3-C3H5)Cl]2
Pd(acac)2
Pd(acac)2
Pd(acac)2
solvent
3kaa (%)
1
2
3
4
5
6
7
8c
tert-amyl alcohol
isopropyl alcohol
tert-butyl alcohol
toluene
35
35
35
35
19
19
19
12
17
66
64
1
2
3
4
5
6
7
8
9
dppp (5)
dppe (5)
HOAc
HOAc
HOAc
HOAc
HOAc
THF
DMSO
DCE
HOAc
10
10
10
11
11
14
19
19
23
53
46
28
20
64
70
26
73
84b
96 (81b)
48
dppb (5)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
EtOH
1,3-dichloropropane
THF
toluene
0
78
84b
a The yield was determined by 1H NMR spectra using CH2Br2 as the
internal standard. b Isolated yield. c 2.5 mol % of Pd2(dba)3·CHCl3 was used
as the catalyst.
Pd(acac)2
a The yield was determined by 1H NMR spectra using CH2Br2 as internal
standard. b Isolated yield.
TABLE 2. Pd-Catalyzed Coupling of Indoles 1 with Methyl
2-(Acetoxymethyl)acrylate 2a
SCHEME 1
indoles 1
entry
R1
R2
time (h)
yield of 3 (%)
1
2
3
4
5
6
7
8
9a
4-BnO (1b)
5-BnO (1c)
6-BnO (1d)
4-Br (1e)
5-Br (1f)
6-Br (1g)
5-Me (1h)
5-MeO (1i)
H (1j)
H
H
H
H
H
H
H
H
Me
12
12
12
10
10
10
12
10
23
76 (3ba)
72 (3ca)
74 (3da)
72 (3ea)
69 (3fa)
68 (3ga)
73 (3ha)
76 (3ia)
67 (3ja)
In addition, the reaction is not limited to methyl 2-acetoxym-
ethyl acrylate 2a. 3-acetoxymethyl-3-buten-2-one 2b, 2-phe-
nylsulfonyl-2-propenyl acetate 2c, and 2-acetoxymethyl acry-
lonitrile 2d are also effective, affording 3ab, 3ac, and 3ad in
79%, 75%, and 71% yields, respectively (Scheme 1).
However, when 1-methylindole 1k was reacted with 2-(ac-
etoxymethyl)acrylate 2a under similar reaction conditions, only
a 23% yield of coupling product 3ka was obtained (eq 1). Thus,
a new protocol for the reaction of N-protected indoles was
desired.
a 5 mol % of Pd(dba)2 and 10 mol % of bpy were used.
Pd(dba)2 or Pd2(dba)3‚CHCl3/bpy(2,2′-bipyridine)-Cata-
lyzed Coupling of Indoles with 2-Acetoxymethyl-Substituted
Electron-Deficient Alkenes. After trying several combinations
of various palladium species and ligands, we examined the
reaction of indole (1a) with methyl 2-acetoxymethyl acrylate
2a using Pd(dba)2 or Pd2(dba)3‚CHCl3 and 2,2′-bipyridine9c as
the catalyst in different solvents (entries 1-8, Table 1). The
reactions in tert-amyl alcohol, i-PrOH, t-BuOH, EtOH, and THF
afforded the desired coupling product 3aa in moderate yields
(entries 1-3, 5, and 7, Table 1). However, the corresponding
reaction in toluene at 80 °C in the presence of Pd(dba)2 or Pd2-
(dba)3‚CHCl3 afforded 3aa in good isolated yields (entries 4
and 8, Table 1). Thus, in the following cases, the reaction was
conducted at 80 °C in toluene using 5 mol % of Pd(dba)2 or
2.5 mol % of Pd2(dba)3‚CHCl3 and 10 mol % of 2,2′-bipyridine
as the catalyst.
Pd(acac)2/PPh3-Catalyzed Coupling of N-Protected Indoles
with 2-Acetoxymethyl-Substituted Electron-Deficient Alk-
enes. In an initial attempt, we examined the reaction of 1k with
methyl 2-acetoxymethyl acrylate 2a in acetic acid under several
7
combinations of Pd(acac)2 with monodentate or bidentate
phosphine ligands: When bidentate phosphine ligands, such as
dppp, dppe, or dppb, were used, the product 3ka was obtained
in 53%, 46%, and 28% yields, respectively (Table 3, entries
1-3). However, to our delight, when 10 mol % of Ph3P was
used, the desired cross-coupled product 3ka was obtained in
84% isolated yield (Table 1, entry 9). Next, various palladium
complexes were screened for the effectiveness in the above
transformation. The results showed that Pd(PhCN)2Cl2 and
A variety of indoles were next examined to generate the
desired coupling products 3 under the standard conditions. The
results are summarized in Table 2. The yield of this reaction is
generally good. It is interesting to note that a bromo substituent
is compatible under the cross-coupling conditions (Table 2,
entries 4-6).
9866 J. Org. Chem., Vol. 71, No. 26, 2006

SCHEME 2
SCHEME 3
TABLE 4. Pd-Catalyzed Coupling of N-Protected Indoles 1 with
2-Acetoxymethyl-Substituted Electron-Deficient Alkenes 2
indole
3). In addition, it should be noted that no isomerization was
observed between 2e and 2g. A similar reaction of 1k with 2f
afforded 3kf in 45% yield.
On the basis of these results, a Pd(0)-catalyzed mechanism
is proposed for this reaction (Scheme 4). The oxidative addition
reaction of the allylic acetate with Pd(0) forms the π-allylic
palladium intermediate 4.10 Its reaction with indole via the Heck-
type reaction or the direct attack of the nucleophilic 3-position
of indole would form the product.
entry
R1
R2
EWG
time (h)
yield (%)
1
2
3
4
5
6
7
8
H
H
H
2-Me
6-BnO
H
Bu (1l)
CO2Me (2a)
CO2Me (2a)
CO2Me (2a)
CO2Me (2a)
CO2Me (2a)
COMe (2b)
SO2Ph (2c)
CN (2d)
9
18
15
10
11
22.5
11
16
81 (3la)
74 (3ma)
82 (3na)
72 (3oa)
75 (3pa)
79 (3kb)
76 (3kc)
75 (3kd)
allyl (1m)
Bn (1n)
Me (1o)
Me (1p)
Me (1k)
Me (1k)
Me (1k)
H
H
In summary, we have developed two protocols for the Pd-
catalyzed C-3 regiospecific functionalization of indoles with
2-acetoxymethyl-substituted electron-deficient alkenes. Although
it is still too early to exclude the Pd(II) mechanism completely,
this reaction will be useful in organic synthesis due to the
potentials of indoles.
[Pd(η3-C3H5)Cl]2 did catalyze the formation of 3ka but with
lower efficiency as compared with Pd(acac)2 (Table 3, entries
4, 5, and 9). Then, the coupling reaction of 1-methylindole 1k
with 2-acetoxymethyl acrylate 2a in the presence of 5 mol %
of Pd(acac)2 and 10 mol % of PPh3 as the catalyst in different
solvents was investigated. Among the solvents tested, toluene,
DME, 1,4-dioxane, DMF, and tert-amyl alcohol were ineffective
for the coupling reaction while THF or 1,2-dichloroethane gave
relatively better results (Table 3, entries 6 and 8). The reaction
in HOAc afforded 3ka in the highest yield (Table 3, entry 9).
Thus, in following cases, the reaction was conducted at 80 °C
in HOAc using 5 mol % of Pd(acac)2 and 10 mol % of PPh3 as
the catalyst. However, it was strange to find that when indole
1a and allyl acetate were subjected to the similar reaction
conditions or the conditions used in Table 2, no reaction
occurred, which was different from what was reported (Scheme
2).7
The scope of the Pd(acac)2/PPh3-catalyzed coupling reaction
is demonstrated by the reaction of N-protected indoles 1k-p
with 2-acetoxymethyl-substituted electron-deficient alkenes 2a-
d. The results are presented in Table 4. Indoles 1, in which the
nitrogen was protected with various substituents, including butyl,
methyl, allyl, and benzyl, reacted with 2a to give 3 in good
yields (entries 1-5, Table 4). In a similar way, 2-acetoxymethyl-
3-buten-2-one 2b, 2-phenylsulfonyl-2-propenyl acetate 2c, and
2-cyanopropenyl acetate 2d reacted with 1k in the presence of
5 mol % of Pd(acac)2 to afford the corresponding products 3kb,
3kc, and 3kd in 79%, 76%, and 75% yields, respectively (entries
6-8, Table 4).
Experimental Section
1. Pd2(dba)3‚CHCl3/bpy-Catalyzed Coupling of Indoles with
2-Acetoxymethyl-Substituted Electron-Deficient Alkenes. Syn-
thesis of 3-(2′-Methoxycarbonyl-2′-propenyl)indole (3aa). Typi-
cal Procedure. A dried reaction tube equipped with a magnetic
stirring bar was charged with indole 1a (59 mg, 0.5 mmol), methyl
2-(acetoxymethyl)acrylate (96 mg, 0.6 mmol), Pd2(dba)3‚CHCl3
(12.9 mg, 2.5 mol %), 2,2′-bipyridine (7.8 mg, 10 mol %), and
toluene (1 mL). Then the reaction was heated at 80 °C with stirring
for 12 h as monitored by TLC. Filtration of the reaction mixture
through a small pad of silica gel (Et2O), concentration, and
purification of the dark oil by flash chromatography on silica gel
(eluent: ethyl acetate/petroleum ether ) 1:5) afforded 3aa as a
1
yellow solid (90 mg, 84%): mp 69-71 °C (hexane); H NMR
(CDCl3, 300 MHz) δ 8.04 (bs, 1 H), 7.53 (d, J ) 7.5 Hz, 1 H),
7.36 (d, J ) 8.1 Hz, 1 H), 7.19 (t, J ) 8.4 Hz, 1 H), 7.10 (t, J )
8.1 Hz, 1 H), 7.03 (d, J ) 2.4 Hz, 1 H), 6.20 (s, 1 H), 5.49 (s, 1
H), 3.78 (s, 2 H), 3.76 (s, 3 H); 13C NMR (CDCl3, 75.4 MHz) δ
167.8, 139.3, 136.2, 127.2, 125.6, 122.8, 121.9, 119.2, 119.0, 112.6,
111.1, 51.9, 27.5 ppm; MS (70 eV) m/z 215 (M+, 100); IR (neat)
ν 3378, 1697, 1628, 1433, 1424, 1310, 1287, 1141, 745 cm-1
HRMS calcd for C13H13NO2 215.09462, found 215.09223.
;
2. Pd(acac)2/PPh3-Catalyzed Coupling of N-Protected Indoles
with 2-Acetoxymethyl-Substituted Electron-Deficient Alkenes.
Synthesis of 3-(2′-Methoxycarbonyl-2′-propenyl)-1-methylin-
Although no reaction was observed between indole 1a and
1- or 3-substituted 2-(methoxycarbonyl)allylic acetates 2e or
E-2g, the reactions of 2e and 2g with indole 1k afforded the
same product 3ke in 66% and 51% yields, respectively (Scheme
(10) (a) Mandai, T.; Matsumoto, T.; Tsuji, J. Tetrahedron Lett. 1993,
34, 2513. (b) Al-Masum, M.; Meguro, M.; Yamamoto, Y. Tetrahedron Lett.
1997, 38, 6071. We thank one of the reviewers for the suggestion on some
parts of this mechanism and these two references.
J. Org. Chem, Vol. 71, No. 26, 2006 9867

SCHEME 4
dole. Typical Procedure. A dried reaction tube equipped with a
magnetic stirring bar was charged with indole 1k (131 mg, 1.0
mmol), methyl 2-acetoxymethyl acrylate 2a (160 mg, 1.0 mmol),
Pd(acac)2 (15 mg, 5 mol %), PPh3 (26 mg, 10 mol %), and HOAc
(0.5 mL). Then the reaction was heated at 80 °C with stirring for
23 h as monitored by TLC. Filtration of the reaction mixture through
a small pad of silica gel (Et2O), concentration, and purification of
the dark oil by flash chromatography on silica gel (eluent: ethyl
acetate/petroleum ether ) 1:5) afforded 192 mg (84%) of 3ka: oil;
1H NMR (300 MHz, CDCl3) δ 7.51 (d, J ) 7.8 Hz, 1 H), 7.28 (d,
J ) 7.8 Hz, 1 H), 7.21 (t, J ) 7.8 Hz, 1 H), 7.09 (t, J ) 7.8 Hz,
1 H), 6.87 (s, 1 H), 6.18 (s, 1 H), 5.51-5.46 (m, 1 H), 3.75 (s, 5
H), 3.73 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 167.6, 139.5, 136.9,
127.5, 127.4, 125.3, 121.3, 119.0, 118.6, 110.9, 109.0, 51.6, 32.3,
27.4; IR (neat) 1720, 1631 cm-1; MS m/z 229 (M+, 100); HRMS
m/z (MALDI) calcd for C14H15NO2Na+(M+ + Na) 252.0995, found
252.1000.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20121202 and 20332060)
is greatly appreciated.
Supporting Information Available: Experimental procedures
and compound characterization. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO061546S
9868 J. Org. Chem., Vol. 71, No. 26, 2006