Synthesis of 2,3-disubstituted indoles via palladium-catalyzed annulation of internal alkynes

Article abstract of DOI:10.1021/jo9803277

The palladium-catalyzed coupling of 2-iodoaniline and the corresponding N-methyl, -acetyl, and -tosyl derivatives with a wide variety of internal alkynes provides 2,3-disubstituted indoles in good-to-excellent yields. The best results are obtained by empl

Full text of DOI:10.1021/jo9803277

7652
J . Org. Chem. 1998, 63, 7652-7662
Syn th esis of 2,3-Disu bstitu ted In d oles via P a lla d iu m -Ca ta lyzed
An n u la tion of In ter n a l Alk yn es
R. C. Larock,* E. K. Yum, and M. D. Refvik
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received February 20, 1998
The palladium-catalyzed coupling of 2-iodoaniline and the corresponding N-methyl, -acetyl, and
-tosyl derivatives with a wide variety of internal alkynes provides 2,3-disubstituted indoles in good-
to-excellent yields. The best results are obtained by employing an excess of the alkyne and a sodium
or potassium acetate or carbonate base plus 1 equiv of either LiCl or n-Bu4NCl, occasionally adding
5 mol % PPh3. The yields with LiCl appear to be higher and more reproducible than those obtained
with n-Bu4NCl. The process is quite general as far as the types of substituents which can be
accommodated on the nitrogen of the aniline and the two ends of the alkyne triple bond. The
reaction is quite regioselective, placing the aryl group of the aniline on the less sterically hindered
end of the triple bond and the nitrogen moiety on the more sterically hindered end. This
methodology readily affords 2-silylindoles, which can be easily protodesilylated, halogenated, or
reacted with alkenes and Pd(OAc)2 to produce 3-substituted indoles, 2-haloindoles, or 2-(1-alkenyl)-
indoles, respectively. The presence of alcohol groups in the alkyne seems to have a particularly
strong directing effect, perhaps due to coordination with palladium. This catalytic process
apparently involves arylpalladium formation, regioselective addition to the C-C triple bond of the
alkyne, and subsequent intramolecular palladium displacement.
In tr od u ction
cycles.10 We wish at this time to report full details on
this very useful new synthetic approach to indoles.11
The palladium-catalyzed, carbo- and heteroannulation
of 1,2-dienes,1 1,3-dienes,2 1,4-dienes,3 and vinylic cyclo-
propanes or cyclobutanes4 by aromatic halides bearing
functional groups in the ortho position has recently
proven to be an extremely versatile method for the
synthesis of a wide variety of heterocycles and car-
bocycles. All of these processes are believed to proceed
by π-allylpalladium intermediates. Although the addi-
tion of arylpalladium compounds to alkynes and subse-
quent intramolecular cyclization has been previously
observed, such processes have generally involved sto-
ichiometric amounts of arylpalladium compounds formed
by ortho-palladation and insertion of more than 1 equiv
of alkyne, followed in many cases by cyclization back onto
the preexisting aromatic ring.5,6 One exception is the
synthesis of N-methylbenzo[d,e]quinolines by the pal-
ladium-catalyzed annulation of internal alkynes by 1-iodo-
8-(dimethylamino)naphthalene.7 In attempting to extend
our annulation chemistry to alkynes,8 we observed and
previously communicated that excellent yields of 2,3-
disubstituted indoles could be obtained from the pal-
ladium-catalyzed coupling of 2-iodoaniline and deriva-
tives with internal alkynes.9 That chemistry has sub-
sequently been employed by others for the synthesis of
potential migraine headache drugs and other hetero-
(6) For the cascade carbopalladation of alkynes, see: (a) Wu, G.;
Lamaty, F.; Negishi, E. J . Org. Chem. 1989, 54, 2507. (b) Negishi, E.
Pure Appl. Chem. 1992, 64, 323. (c) Zhang, Y.; Negishi, E. J . Am. Chem.
Soc. 1989, 111, 3454. (d) Negishi, E.; Harring, L. S.; Owczarczyk, Z.;
Mohamud, M. M.; Ay, M. Tetrahedron Lett. 1992, 33, 3253. (e) Negishi,
E.; Noda, Y.; Lamaty, F.; Vawter, E. J . Tetrahedron Lett. 1990, 31,
4393. (f) Torii, S.; Okumoto, H.; Nishimura, A. Tetrahedron Lett. 1991,
32, 4167. (g) Owczarczyk, Z.; Lamaty, F.; Vawter, E. J .; Negishi, E. J .
Am. Chem. Soc. 1992, 114, 10091. (h) Negishi, E.; Ay, M.; Sugihara,
T. Tetrahedron 1993, 49, 5471. (i) Coperet, C.; Sugihara, T.; Negishi,
E. Tetrahedron Lett. 1995, 36, 1771. (j) Meyer, F. E.; Henniges, H.; de
Meijere, A. Tetrahedron Lett. 1992, 33, 8039. (k) Trost, B. M.; Shi, Y.
J . Am. Chem. Soc. 1992, 114, 791. (l) Meyer, F. E.; Brandenburg, J .;
Parsons, P. J .; de Meijere, A. J . Chem. Soc., Chem. Commun. 1992,
390. (m) Meyer, F. E.; de Meijere, A. Synlett 1991, 777. (n) Meyer, F.
E.; Parsons, P. J .; de Meijere, A. J . Org. Chem. 1991, 56, 6487. (o)
Zhang, Y.; Wu, G.; Agnel, G.; Negishi, E. J . Am. Chem. Soc. 1990, 112,
8590. (p) Coperet, C.; Sugihara, T.; Negishi, E. Tetrahedron Lett. 1995,
36, 1771. (q) Ihle, N. C.; Heathcock, C. H. J . Org. Chem. 1993, 58,
560. (r) Sugihara, T.; Coperet, C.; Owczarczyk, Z.; Harring, L. S.;
Negishi, E. J . Am. Chem. Soc. 1994, 116, 7923.
(7) Beydoun, N.; Pfeffer, M. Synthesis 1990, 729.
(8) For some of our recent alkyne annulation chemistry, see: (a)
Larock, R. C.; Doty, M. J .; Cacchi, S. J . Org. Chem. 1993, 58, 4579. (b)
Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. C. J . Org. Chem.
1995, 60, 3270. (c) Larock, R. C.; Doty, M. J .; Tian, Q.; Zenner, J . M.
J . Org. Chem. 1997, 62, 7536. (d) Larock, R. C.; Tian, Q. J . Org. Chem.
1998, 63, 2002. (e) Larock; R. C.; Doty, M. J .; Han, X. Tetrahedron
Lett. 1998, 39, 5143. (f). Larock, R. C.; Han, X.; Doty, M. J . Tetrahedron
Lett. 1998, 39, 5713. (g) Roesch, K. R.; Larock, R. C. J . Org. Chem.
1998, 63, 5306.
(9) (a) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689.
For subsequent intramolecular versions of this reaction, see: (b) Arcadi,
A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992, 33, 3915. (c) Cacchi,
S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett 1997, 1363.
(10) (a) Wensbo, D.; Eriksson, A.; J eschke, T.; Annby, U.; Gronowitz,
S.; Cohen, L. A. Tetrahedron Lett. 1993, 34, 2823. (b) Chen, C.;
Lieberman, D. R.; Larsen, R. D.; Reamer, R. A.; Verhoeven, T. R.;
Reider, P. J . Tetrahedron. Lett. 1994, 35, 6981. (c) J eschke, T.; Wensbo,
D.; Annby, U.; Gronowitz, S.; Cohen, L. A. Tetrahedron Lett. 1993, 34,
6471. (d) Smith, D. W.; Youcca, F. D.; Yevich, J . P.; Mattson, R. J .;
Williams, A.; Ruediger, E. H.; Combrink, K. D.; Pearce, B. C. European
Patent 0 548 813 A1, 1993. (e) Chen, C.-y.; Lieberman, D. R.; Street,
L. J .; Guiblin, A. R.; Larsen, R. D.; Verhoeven, T. R. Synth. Commun.
1996, 26, 1977. (f) Zhang, H.-C.; Brumfield, K. K.; Maryanoff, B. E.
Tetrahedron Lett. 1997, 38, 2439. (g) Park, S. S.; Choi, J . K.; Yum, E.
K.; Ha, D.-C. Tetrahedron Lett. 1998, 39, 627.
(1) Larock, R. C.; Berrios-Pen˜a, N. G.; Fried, C. A. J . Org. Chem.
1991, 56, 2615.
(2) (a) Larock, R. C.; Berrios-Pen˜a, N.; Narayanan, K. J . Org. Chem.
1990, 55, 3447. (b) Larock, R. C.; Fried, C. A. J . Am. Chem. Soc. 1990,
112, 5882. (c) O’Connor, J . M.; Stallman, B. J .; Clark, W. G.; Shu, A.
Y. L.; Spada, R. E.; Stevenson, T. M.; Dieck, H. A. J . Org. Chem. 1983,
48, 807. (d) Larock, R. C.; Guo, L. Synlett 1995, 465.
(3) Larock, R. C.; Berrios-Pen˜a, N. G.; Fried, C. A.; Yum, E. K.; Tu,
C.; Leong, W. J . Org. Chem. 1993, 58, 4509.
(4) Larock, R. C.; Yum, E. K. Synlett 1990, 529.
(5) For general reviews, see: (a) Maitlis, P. M. J . Organomet. Chem.
1980, 200, 161. (b) Pfeffer, M. Recl. Trav. Chim. Pays-Bas 1990, 109,
567.
10.1021/jo9803277 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/03/1998

Synthesis of 2,3-Disubstituted Indoles
J . Org. Chem., Vol. 63, No. 22, 1998 7653
Ta ble 1. P a lla d iu m -Ca ta lyzed An n u la tion of 4-Octyn e
2-Iod oa n ilin e (Eq 1)
ucts (entries 5 and 6). The addition of 5 mol % of PPh3
also dramatically lowered the yield of indole and in-
creased the amount of apparent multi-insertion products
(entries 7 and 8). Whether PPh3 was present or not, no
indole was formed when the temperature was lowered
to 100 °C (entries 9 and 10).
LiX
PPh3
temp
(°C)
% isoltd
yield of 1
entry
base
X
(equiv) (5 mol %)
1
2
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3 Cl
Na2CO3 Br
Na2CO3
Na2CO3 Cl
Na2CO3 Cl
NaOAc
NaOAc
NaOAc
NaOAc
120
120
120
120
120
120
120
120
100
100
120
120
120
120
120
120
120
100
100
120
120
120
120
120
120
120
120
100
36
80
0
26
56
0
Cl
Br
I
Cl
Cl
Cl
Cl
Cl
Cl
1
3
1
K2CO3 was the next base examined. Although it gave
superior results to KOAc in the absence of other reagents
(compare entries 1 and 11), when 1 equiv of LiCl was
added, the results were inferior to those of KOAc (com-
pare entries 2 and 12). Unlike reactions with KOAc,
however, reactions with K2CO3 and LiBr or LiI (entries
13 and 14) or an additional equivalent of LiCl (entry 15)
actually gave higher yields of indole. The addition of 5
mol % of PPh3 to the reaction employing 1 equiv of LiCl
gave exactly the same yield as the reaction without any
PPh3 (entry 16), but the addition of an additional 1 equiv
of LiCl greatly slowed the reaction and none of the indole
product was observed (entry 17). When the temperature
of the reaction with 1 equiv of LiCl was lowered to 100
°C, an improved yield of 80% was actually obtained (entry
18), but the addition of PPh3 resulted in much of the aryl
iodide being recovered and none of the indole being
obtained (entry 19).
When Na2CO3 was employed as the base, the results
were generally inferior to those of KOAc or K2CO3
(entries 20-24). The addition of LiBr or LiI gave lower
yields than LiCl (entries 21 and 22). Only a slight
improvement in yield was observed by adding a second
equivalent of LiCl (entry 23), and this improvement was
negated by the addition of PPh3 (entry 24).
Poor results were also obtained when NaOAc was
employed as the base (entries 25-28). Again, LiBr
proved inferior to LiCl, and the addition of PPh3 had little
effect. Lowering the temperature to 100 °C failed to
provide any of the desired indole product.
4
1
2
3-5
1
2
1
1
5
6
7
+
+
40
36
0
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
+
0
46
60
60
70
68
60
0
Cl
Br
I
Cl
Cl
Cl
Cl
Cl
1
1
1
2
1
2
1
1
1
1
1
2
2
1
1
1
1
+
+
80
0
46
0
20
50
44
38
0
42
0
+
I
+
+
Cl
Br
Cl
Cl
Resu lts a n d Discu ssion
Initial studies were directed toward finding a general
set of reaction conditions that could be applied to a wide
variety of 2-iodoaniline derivatives and alkynes. Since
it appeared that reactions such as that of 2-iodoaniline
itself with relatively unhindered alkynes, such as 4-oc-
tyne, were likely to prove the most difficult, we turned
our attention to optimizing that particular process (eq
1). The following variables were closely examined: the
From these studies, at least with 2-iodoaniline itself,
it appears that the best bases for this annulation process
are KOAc and K2CO3 and that it is highly desireable to
add 1 equiv of LiCl to the reaction. The stoichiometry of
the LiCl salt is also very important. More than one equiv
generally slows down the rate of reaction and sharply
lowers the yield. With KOAc, a temperature of 120 °C
is necessary for the reaction to reach completion in a
reasonable amount of time, whereas K2CO3 can be
employed at a slightly lower temperature of 100 °C. The
addition of PPh3 is generally unnecessary. In studies
with other aryl iodides and alkynes, variations of these
apparently “optimal” conditions have continued to be
explored, because our previous work on this type of
annulation chemistry has shown us that the optimal
reaction conditions can often be highly dependent on the
substrates employed. Many quite satisfactory results
reported later using n-Bu4NCl as the halide salt had been
obtained prior to this optimization study.
Since the annulation of internal alkynes appeared to
be very sensitive to the concentration of the alkyne, we
have also explored the effect of varying the number of
alkyne equivalents used in the reaction. Some of those
results are summarized in Table 2. These reactions were
run using 1 equiv of LiCl in DMF (10 mL per 0.25 mmol
of ArI) at 100 °C for 1 day. In all reactions, reasonable
yields of indole product were obtained using just 1 equiv
of the alkyne, but better yields were possible when 2-5
equiv of alkyne was employed. In subsequent studies,
an excess of alkyne was therefore commonly utilized.
base, the added lithium halide and its stoichiometry, the
presence or absence of PPh3, and the reaction tempera-
ture. All reactions were run on a 0.25-mmol scale, using
5 mol % of Pd(OAc)2 as catalyst, 3 equiv of alkyne, 5 equiv
of base in 10 mL of DMF as solvent for 20 h. Some
results from that study are summarized in Table 1.
KOAc was the first base examined (Table 1, entries
1-10). In the absence of any lithium halide or PPh3 at
120 °C, a 36% yield of 2,3-di-n-propylindole (1) was
obtained (entry 1). The addition of 1 equiv of LiCl, LiBr,
or LiI afforded yields of 80%, 0%, and 26%, respectively
(entries 2-4). The latter two salts appeared to give high
molecular weight products assumed to be multiple inser-
tion products. The use of LiCl is clearly superior and
appears to give more reproducible results than n-Bu4NCl,
although many early results using the latter salt, re-
ported later in Table 3, were obtained prior to this
particular study. Further addition of LiCl resulted in
substantially slower reactions and lower yields plus the
apparent concomitant formation of multi-insertion prod-
(11) For a review of other palladium-based approaches to indoles,
see: Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113.

7654 J . Org. Chem., Vol. 63, No. 22, 1998
Larock et al.
Ta ble 2. Effect of Alk yn e Stoich iom etr y
Having gained an understanding of the factors that
were influencing the heteroannulation process, we sub-
jected 2-iodoaniline and several derivatives, plus a wide
range of internal alkynes, to this process to determine
its scope and limitations (eq 2). All of the work was
°C
carried out using 5 mol % of Pd(OAc)2 and 1 equiv of LiCl
or n-Bu4NCl at 100 °C. Only after considerable work had
been carried out was the superiority of LiCl discovered;
therefore, not all reactions were necessarily run under
optimal conditions. The significant variation in yields
obtained in previous annulation work using different
substrates and bases encouraged us to continue to try a
number of different acetate and carbonate bases and to
occasionally add 5 mol % of PPh3. The effect of added
PPh3 also was not appreciated during much of our early
work. The more volatile the alkyne, the greater the
number of equivalents of alkyne that were employed. The
best results obtained during this study are summarized
in Table 3.
a
b
K2CO3 was employed as the base. KOAc was employed as
the base.
As indicated in Table 3, this approach to 2,3-disubsti-
tuted indoles is very versatile. 2-Iodoanilines with a wide
variety of substitutents on the nitrogen moiety have been
reacted successfully. We have been able to obtain high
yields using 2-iodoaniline, N-methyl-2-iodoaniline, 2-io-
doacetanilide, and N-tosyl-2-iodoaniline. It is particu-
larly noteworthy that 2-iodoacetanilide undergoes this
annulation process with a variety of alkyl and aryl
acetylenes to afford indoles in high yields, because
previous work on the reaction of the ortho-palladation
complex 1 and alkynes demonstrated the exclusive
formation of multi-insertion products (eq 3).12 It is not
A wide variety of alkynes have been successfully
employed in this indole synthesis. Simple unhindered
alkyl-substituted alkynes, such as 4-octyne, afford high
yields of the corresponding indoles. This is quite remark-
able, because this type of unhindered aliphatic alkyne
has failed in much of our other alkyne annulation chemis-
try in which functional groups other than nitrogen have
been employed.8 These relatively unhindered alkynes
appear to be particularly reactive toward insertion6h and
apparently readily undergo multi-insertion processes.
Alkynes bearing a variety of hindered and unhindered
hydroxyalkyl groups can also be utilized (eq 4).14-16
However, migration of the N-acetyl group from nitrogen
to the alcohol group has been observed in some reactions
in which 2-iodoacetanilide was employed as the starting
material (eq 5; Table 3, entries 20 and 23). This obvi-
clear at present if this apparent difference in reactivity
is due to the different halides present in the two reactions
(only Cl versus I and Cl) or some other variable. It is
known that the nature of the halide can have a pro-
nounced effect on the nature of the products in these
alkyne insertion processes.13 2-Bromoaniline and deriva-
tives thereof are unreactive under our reaction condi-
tions, but one might expect that the introduction of
electron-withdrawing groups on the aromatic ring would
increase their reactivity.
(14) For one example of the synthesis of a cinnolinium salt by the
stoichiometric, palladium-promoted heteroannulation of this particular
alkynediol, see: Wu, G.; Rheingold, A. L.; Heck, R. F. Organometallics
1987, 6, 2386.
(15) For the palladium-catalyzed hydroarylation of alkynols, see: (a)
Cacchi, S. Pure Appl. Chem. 1990, 62, 713. (b) Arcadi, A.; Cacchi, S.;
Marinelli, F. Tetrahedron 1985, 41, 5121. (c) Arcadi, A.; Cacchi, S.;
Ianelli, S.; Marinelli, F.; Nardelli, M. Gazz. Chim. Ital. 1986, 116, 725.
(d) Arcadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.; Marinelli, F.;
Pietroni, B. Tetrahedron 1988, 44, 481.
(12) Dupont, J .; Pfeffer, M.; Daran, J .-C.; Gouteron, J . J . Chem. Soc.,
Dalton Trans. 1988, 2421.
(13) (a) Maassarani, F.; Pfeffer, M.; Le Borgne, G. J . Chem. Soc.,
Chem. Commun. 1987, 565. (b) Maassarani, F.; Pfeffer, M.; Le Borgne,
G. Organometallics 1987, 6, 2029.
(16) For the palladium-catalyzed hydrovinylation of alkynols, see:
Arcadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.; Marinelli, F.; Pietroni,
B. Tetrahedron Lett. 1989, 30, 3465.

Synthesis of 2,3-Disubstituted Indoles
J . Org. Chem., Vol. 63, No. 22, 1998 7655
Ta ble 3. An n u la tion of In ter n a l Alk yn es by 2-Iod oa n ilin e a n d Der iva tives (Eq 2)
PPh3 reactn
% isoltd
yield
entry
R1
H
R2
R3
n
chloride
base
(5 mol %)
time (h)
1
2
3
4
5
6
7
8
9
n-Pr
t-Bu
C6H11
i-Pr
n-Pr
Me
Me
Me
Me
CMe2OH
Me
5
5
5
5
5
2
2
2
2
LiCl
K2CO3
Na2CO3
KOAc
K2CO3
K2CO3
Na2CO3
Na2CO3
KOAc
20
24
24
24
24
72
12
24
24
80
82
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
LiCl
+
57
+
+
+
+
62, 25a
Et
62 (60:40)b
CMe2OH
CMe2OH
54
52
70
85
C(Me)dCH2
Et
KOAc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
n-Pr
n-Pr
i-Pr
Et
Ph
CH2OH
CH2OH
CH2CH2OH
CH3CH(OH)CH2
Me3Si
n-Pr
t-Bu
Et
CH(OEt)2
CMe2OH
Ph
Me
n-Bu
Ph
CH2OH
Me3Si
n-Pr
n-Pr
Me
Me
Me
Me
C(Me)dCH2
Me
Me
Me
n-Pr
Me
Me
Me
C(Me)dCH2
Ph
5
5
5
2
2
3
3
2
5
2
2
2
2
2
5
3
5
2
5
2
2
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
LiCl
Na2CO3
NaOAc
NaOAc
Na2CO3
NaOAc
K2CO3
KOAc
Na2CO3
K2CO3
KOAc
K2CO3
NaOAc
KOAc
Na2CO3
K2CO3
KOAc
+
24
12
16
24
20
24
24
24
24
24
24
24
24
12
12
24
24
36
24
24
48
98
81
68
+
+
60
54c
Me
Ac
71
91
67, 26a
30, 28a
75
LiCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
LiCl
n-Bu4NCl
n-Bu4NCl
LiCl
+
+
60d
27
43e
60, 16f
70
Ts
86
86
KOAc
K2CO3
NaOAc
KOAc
60 (50:50)b
28, 28a
45
n-Bu4NCl
n-Bu4NCl
LiCl
K2CO3
60
a
b
Actual isolated yields of two regioisomers. Ratio of regioisomers determined by GC and 1H NMR spectroscopy. c The product is
3-(trimethylsilyl)indole. The product is 2-acetoxymethyl-3-methylindole. e The product is 2-(2-acetoxyethyl)-3-methylindole. f The two
d
products are 2-(2-acetoxypropyl)-3-methylindole and 1-acetyl-3-(2-hydroxypropyl)-2-methylindole, respectively.
ously involves a base-catalyzed, intramolecular transfer
of the acetyl group from nitrogen to oxygen in the
anticipated product; the annulation of 4-hexyn-2-ol is
observed to give a mixture of regioisomers in which acetyl
migration is observed in the product with the hydroxy-
alkyl group in the 2-position, but no migration is seen in
the other regioisomer (eq 6; Table 3, entry 23). It is not
however, that although the yields are not always high,
the reactions may not always have been run under
optimal conditions.
It is especially noteworthy that a wide variety of silyl-
substituted alkynes have been successfully employed in
this annulation process.17 The reaction conditions are
sufficiently mild that desilylation is not usually a prob-
lem. However, when the hindered acetylene bis(trim-
ethylsilyl)acetylene is annulated, the sole product ob-
served is 3-(trimethylsilyl)indole (eq 8; Table 3, entry 14).
obvious why the product of the reaction of 2-iodoaceta-
nilide and 4-methyl-4-penten-2-yn-1-ol (entry 21) appar-
ently fails to undergo acetyl migration (unless we mis-
assigned the regiochemistry of this product), although the
product is only obtained in low yield.
The silyl-substituted indoles are versatile intermedi-
ates for the synthesis of a variety of other substituted
indoles (eq 9). For example, protonolysis could be ac-
The chemoselectivity of this annulation process is
apparently very high, because we have been able to
annulate 4-methyl-4-penten-2-yn-1-ol (Table 3, entry 21)
and 2,5-dimethyl-5-hexen-3-yn-2-ol (Table 3, entries 8
and 29) without any evidence for the corresponding
products of alkene substitution (eq 7). It should be noted,
complished in 87% isolated yield by reacting 1-acetyl-3-
(17) For the palladium-catalyzed hydroarylation of silylalkynes, see
ref 15a and Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1986,
27, 6397.

7656 J . Org. Chem., Vol. 63, No. 22, 1998
Larock et al.
methyl-2-(trimethylsilyl)indole with AlCl3 in CH2Cl2 for
1 h at 0 °C, followed by an aqueous workup. Protonolysis
could also be effected in 80% isolated yield using aqueous
HF in CH3CN. Refluxing with n-Bu4NF in 9:1 THF/
MeOH failed to provide the hydrogen-substituted prod-
uct. Although 3-monosubstituted indoles can be synthe-
sized from 2-iodoanilines by N-allylation and subsequent
intramolecular palladium-catalyzed cyclization,18 this
approach provides a useful, expeditious alternative and
has proven valuable in establishing the regiochemistry
of the annulation process.
The 2-silylindoles also undergo a variety of other
synthetically useful substitution processes (eq 9). Thus,
halogenation provides a convenient route to 2-halo-3-
substituted indoles. The 2-silylindoles can also be re-
acted with Pd(OAc)2 and alkenes, such as methyl vinyl
ketone or ethyl acrylate, to afford the corresponding 2-(1-
alkenyl)indoles. This appears to be one of the few
successful applications of arylsilanes in the Heck reaction
and the only one to use a heterocyclic silane and Pd-
(OAc)2.19
It was a bit surprising that the annulation of the aryl-
substituted alkynes 1-phenylpropyne and diphenylacety-
lene by 2-iodoaniline afforded only messy reactions
exhibiting a multitude of products. Numerous single-
and multi-insertion products of these alkynes and ortho-
palladation compounds have been reported,20-22 and both
alkynes have provided high yields of a single product in
many of our other alkyne annulation processes.8 How-
ever, the reactions of 2-iodoacetanilide and 1-phenylpro-
pyne (Table 3, entry 19) and N-tosyl-2-iodoaniline and
diphenylacetylene (Table 3, entry 30) both afforded the
anticipated indoles in fair-to-good yields.
dimethyl-2-pentyne (t-Bu vs Me) by either 2-iodoaniline
(Table 3, entry 2) or N-tosyl-2-iodoaniline (Table 3, entry
26) affords a single product, the 2-tert-butyl-3-methylin-
dole, in excellent yields of 82% and 86%, respectively.
Complete regioselectivity is also observed when annu-
lating 1-cyclohexylpropyne (Cy vs Me; Table 3, entry 3).
However, 4-methyl-2-pentyne (i-Pr vs Me) afforded two
regioisomeric products in a 71:29 ratio for 2-iodoaniline
(Table 3, entry 4) and 72:28 for 2-iodoacetanilide (Table
3, entry 17). The regioselectivity is somewhat dependent
on the nature of the substituent on the nitrogen and the
precise reaction conditions. 2-Pentyne (Et vs Me) gave
a mixture of regioisomers in ratios of approximately 50:
50 to 60:40 for 2-iodoaniline (Table 3, entry 5), 2-iodoac-
etanilide (entry 18), and N-tosyl-2-iodoaniline (Table 3,
entry 27). The structures of the isomers in these latter
mixtures could be easily assigned by the chemical shift
of the methyl group.
Alcohol-containing alkynes exhibited a very interesting
regiochemistry. In view of the substantial difference in
steric effects at the two ends of the C-C triple bond, it
was not too surprising that complete regioselectivity was
observed in the annulation of the tertiary alkynols
2-methyl-3-pentyn-2-ol (CMe2OH vs Me; Table 3, entry
7), 2,5-dimethyl-5-hexen-3-yn-2-ol (CMe2OH vs isopro-
penyl; Table 3, entries 8 and 29), and 1-(1-butynyl)-
cyclohexanol (1-hydroxycyclohexyl vs Et; Table 3, entry
9). However, even the primary alcohols 2-butyn-1-ol
(CH2OH vs Me; Table 3, entry 20), 3-pentyn-1-ol (CH2-
CH2OH vs Me; Table 3, entry 22), and 4-methyl-4-penten-
2-yn-1-ol (CH2OH vs isopropenyl; Table 3, entry 21) gave
exclusively one product, although the yield was not
always very high. It appears that there is either an
electronic effect or, probably more likely, a chelation
effect of the hydroxyl group which results in that sub-
stituent ending up in the 2-position of the resulting
indole. An analogous directing effect of hydroxyl groups
has been observed in the palladium-catalyzed hydroary-
lation of propargylic alcohols.15b-d
This annulation process is quite regioselective, gener-
ally significantly more so than the related palladium-
catalyzed hydroarylation process, which often produces
mixtures of regioisomers (eq 10).15-17,22 This is perhaps
In contrast, while the less hindered primary alcohol
3-pentyn-1-ol (CH2CH2OH vs Me; Table 3, entry 22) gives
a single product, the more highly branched secondary
alcohol 4-hexyn-2-ol (CH2CHOHCH3 vs Me; Table 3,
entry 23), which might therefore be expected to be even
more regioselective, afforded a 79:21 mixture of regioi-
somers when allowed to react with 2-iodoacetanilide. This
suggests that the latter alkyne, possessing a more
hindered alcohol group, is less able to coordinate to
palladium during the alkyne insertion step and therefore
gives a mixture of regioisomers more reminiscent of
4-methyl-2-pentyne or other simple aliphatic alkynes
with little steric difference between the two ends of the
alkyne.
due to chelation of the palladium in our arylpalladium
intermediates by the neighboring nitrogen, which reduces
the overall reactivity and increases the steric hindrance
of these intermediates toward alkyne insertion. As noted
elsewhere,6h the rates and regiochemistry of these alkyne
insertion processes appear to be controlled primarily by
steric effects. Not too surprisingly, the annulation of 4,4-
(18) (a) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291.
(b) Odle, R.; Blevins, B.: Ratcliff, M.; Hegedus, L. S. J . Org. Chem.
1980, 45, 2709.
(19) For prior Heck chemistry with PhSiMe3, see: Akhrem, I. S.;
Chistovalova, N. M.; Mysov, E. I.; Vol’pin, M. E. J . Organomet. Chem.
1974, 72, 163.
(20) For insertion products of 1-phenylpropyne, see refs 7 and 13b
and (a) Bahsoun, A.; Dehand, J .; Pfeffer, M.; Zinsius, M.; Bouaoud,
S.-E.; Le Borgne, G. J . Chem. Soc., Dalton Trans. 1979, 547. (b)
Maassarani, F.; Pfeffer, M.; Le Borgne, G. Organometallics 1987, 6,
2043.
The failure of the diethyl acetal of 2-butynal to exhibit
any regioselectivity at all would seem to argue against
electronic effects playing any major role in this annula-
tion process (eq 11; Table 3, entry 28). Apparently, steric
(21) For insertion products of diphenylacetylene, see refs 5, 7, 12,
13b, 14 and (a) Kalinin, V. N.; Usatov, A. V.; Zakharkin, L. I. Izv. Akad.
Nauk SSSR, Ser. Khim. 1984, 1646. (b) Dupont, J .; Pfeffer, M. J .
Organomet. Chem. 1987, 321, C13. (c) Wu, G.; Geib, S. J .; Rheingold,
A. L.; Heck, R. F. J . Org. Chem. 1988, 53, 3238. (d) Wu, G.; Rheingold,
A. L.; Geib, S. J .; Heck, R. F. Organometallics 1987, 6, 1941. (e) Wu,
G.; Rheingold, A. L.; Heck, R. F. Organometallics 1986, 5, 1922. (f)
Maassarani, F.; Pfeffer, M. J . Chem. Soc., Chem. Commun. 1986, 488.
(22) For the palladium-catalyzed hydroarylation and hydrovinyla-
tion of diphenylacetylene, see ref 16 and Cacchi, S.; Felici, M.; Pietroni,
B. Tetrahedron Lett. 1984, 25, 3137.
effects in this alkyne are not very important either.

Synthesis of 2,3-Disubstituted Indoles
J . Org. Chem., Vol. 63, No. 22, 1998 7657
The aryl group in 1-phenylpropyne (Ph vs Me) was
observed to have a pronounced directing effect. The
annulation of this alkyne by 2-iodoacetanilide afforded
a good yield of a single product, which matched the
literature characterization of 1-acetyl-3-methyl-2-phe-
nylindole23 (Table 3, entry 19). This result is consistent
with the high regioselectivity generally observed in
alkyne insertion processes of this alkyne7,13b,20a,b and the
directive effect of aryl groups in general in the palladium-
catalyzed hydroarylation process.15b,c,16
having a similar powerful directing effect, because only
one product is formed, albeit in low yield (Table 3, entry
21).
The reaction of 2-iodoacetanilide and 4-hexyn-2-ol gave
two isomeric products (Table 3, entry 23). In the major
product, according to the IR and 1H NMR spectra, the
OH has disappeared and has been replaced by an acetate
ester and an NH [1H NMR δ 2.28 (CH3), 8.10 (NH)]. This
product is believed to be 2-(2-acetoxypropyl)-3-methylin-
dole on the basis of the chemical shift of the methyl group
and the assumption that acetyl migration is more likely
to occur when the alcohol group is located on a side chain
in the 2-position rather than the 3-position. The minor
product retains the hydroxyl group and possesses a
The annulation of 1-(trimethylsilyl)alkynes was found
to be completely regioselective. In all cases examined,
even for 3-trimethylsilyl-2-propyn-1-ol (Me3Si vs CH2OH;
Table 3, entry 13) and 1-(trimethylsilyl)-2-phenylethyne
(Me3Si vs Ph; Table 3, entry 12), the sole product
observed was the 2-(trimethylsilyl)indole. This is not
surprising considering the importance of steric effects
observed earlier in our studies using simple aliphatic
alkynes, such as 4-methyl-2-pentyne, and the high regi-
oselectivity observed previously in the palladium-cata-
lyzed hydroarylation of these same trimethylsilyla-
lkynes.17
1
methyl group further upfield in the H NMR spectrum
[1H NMR δ 1.75 (OH), 2.60 (CH3)]. It is known that the
methyl in the 1H NMR spectrum of 3-methylindole is
further upfield than the methyl in 2-methylindole. Thus,
this isomer appears to be 1-acetyl-3-(2-hydroxypropyl)-
2-methylindole. The GCMS fragmentation patterns for
these two isomers are consistent with these assignments;
the major product has a base peak at M - 59 (loss of
OAc), while the minor isomer has a base peak at M - 43
(loss of Ac).
The regiochemical assignments of the products ob-
tained from the annulation of unsymmetrical alkynes are
based on the following arguments. The annulation of 4,4-
dimethyl-2-pentyne by 2-iodoaniline and 2-iodobenzal-
dehyde affords the corresponding known indole24 and
indenone,8a respectively, in which the tert-butyl group
resides in the 2-position. The major product from the
The reaction of 3-pentyn-1-ol and 2-iodoacetanilide
produces a single product in which the acetyl group has
again migrated (Table 3, entry 22). The 1H NMR
spectrum indicates the presence of the indole NH and
the absence of an OH group. The position of the methyl
group is more consistent with a 3-methylindole. This
product is assigned the structure 2-(2-acetoxyethyl)-3-
methylindole, which is consistent with the strong prefer-
ence for hydroxyalkyl groups to locate in the 2-position
and the tendency of such groups to migrate an acetyl
group. It is logical that the tertiary hydroxyalkyl-
substituted acetylenes frequently employed in this
study would provide indoles in which this more hindered
group resides exclusively in the 2-position. All of these
assignments are consistent with the strong directing
effect of the hydroxyl group observed in the palladium-
catalyzed hydroarylation of these same alcohol-containing
alkynes.15b-d,17
Trimethylsilyl-substituted alkynes always afford a
single indole product in which the silyl group resides in
the 2-position. This is true whether the other end of the
alkyne bears a Me (Table 3, entries 10 and 24), an n-Bu
(entry 11), a Ph (entry 12), or a CH2OH (entry 13). This
regiochemistry is consistent with previous work on the
palladium-catalyzed hydroarylation of silylalkynes17 and
more recent applications of our heteroannulation chem-
istry by others.10a-c The most convincing proof of this
regiochemistry is found in the many compounds that
have been desilylated to known products. For example,
the protodesilylation of 3-methyl-2-(trimethylsilyl)in-
dole28 (entry 10), 3-phenyl-2-(trimethylsilyl)indole29 (entry
12), and 1-acetyl-3-methyl-2-(trimethylsilyl)indole30 (en-
try 24) all afford the corresponding known indoles.
Bromination of the latter silylindole also provided a
known bromoindole.31 Desilylation of the 2-trimethylsilyl
1
annulation of 2-pentyne by 2-iodoaniline matched the H
and 13C NMR spectra previously reported for 2-ethyl-3-
methylindole.25 It is also known that a methyl group in
the 3-position of an indole occurs in the 1H NMR
spectrum at approximately δ 2.3, which is upfield from
a methyl group in the 2-position. On the basis of these
observations, it is therefore concluded that the exclusive
or predominant indole obtained from the annulation of
simple, unsymmetrical aliphatic alkynes always has the
more hindered alkyl group in the 2-position.
The annulation of 1-phenylpropyne by 2-iodoacetanil-
ide afforded a single product known to have the phenyl
group in the 2-position and the methyl group in the
3-position.23 In the annulation of this same alkyne by
2-iodophenol,8b a mixture of benzofurans is obtained in
which the minor regioisomer is the known 2-methyl-3-
phenylbenzofuran.26 Thus, 1-phenylpropyne consistently
gives annulation products in which the aryl group resides
in the 2-position. Analogous regiochemistry has been
observed previously in the insertion of this alkyne into
cyclopalladation adducts.7,13b,20a,b
The regiochemistry of the alkynol annulation products
has been assigned as follows. The annulation of 2-butyn-
1-ol by 2-iodoacetanilide (Table 3, entry 20) affords a
known compound27 in which the acetyl group has mi-
grated to the alcohol, thus establishing the powerful
directing effect of the hydroxyl group. It is assumed that
the hydroxyl group in 4-methyl-4-penten-2-yn-1-ol is
(23) Itahara, T. J . Org. Chem. 1985, 50, 5272.
(24) Ito, Y.; Kobayashi, K.; Seko, N.; Saegusa, T. Bull. Chem. Soc.
J pn. 1984, 57, 73.
(25) Naruse, Y.; Ito, Y.; Inagaki, S. J . Org. Chem. 1991, 56, 2256.
(26) Cardillo, G.; Cricchio, R.; Merlini, L. Tetrahedron 1971, 27,
1875.
(28) Pouchert, C. Aldrich Library of NMR Spectra, Edition II, Vol.
2, Compound 519-D.
(29) Russell, G. A.; Yao, C.-F.; Tashtoush, H. I.; Russell, J . E.;
Dedolph, D. F. J . Org. Chem. 1991, 56, 663.
(30) Pindur, U.; Flo, C.; Akgu¨n, E.; Tunali, M. Liebigs Ann. Chem.
1986, 1621.
(27) Gassman, P. G.; Campbell, G. A.; Mehta, G. Tetrahedron 1972,
28, 2749.
(31) Hino, T.; Nakamura, T.; Nakagawa, M. Chem. Pharm. Bull.
1975, 23, 2990.

7658 J . Org. Chem., Vol. 63, No. 22, 1998
Larock et al.
Sch em e 1
F igu r e 1. Steric effects on the regiochemistry of alkyne
insertion.
the aryl iodide are expected to undergo relatively rapid
oxidative addition. These first and third steps are well
known and integral to a wide variety of Pd(0)-catalyzed
processes. Whereas alkene coordination to palladium
species has been well studied, analogous alkyne chem-
istry has received little attention and can only be
surmised as a necessary prerequisite to alkyne insertion.
Less hindered alkynes are known to insert more readily
than more hindered alkynes.6h syn-Addition of the
arylpalladium compound to the alkyne has been estab-
lished for the analogous palladium-catalyzed hydroary-
lation process15c and assumed in many other alkyne
insertion processes.5-8
Although it has been stated that the insertion of
unsymmetrical alkynes into an arylpalladium bond pro-
ceeds to place the less hindered group next to palladium,5b
this has not been our observation or that of Cacchi in
the palladium-catalyzed hydroarylation and hydroviny-
lation of unsymmetrical alkynes.15a Indeed, all of our
results are quite the contrary. It appears to us that the
controlling factor in these insertion processes may be the
steric hindrance present in the developing carbon-carbon
bond or the orientation of the alkyne immediately prior
to syn-insertion of the alkyne into the aryl palladium
bond. Alkyne insertion occurs so as to generate the least
steric strain in the vicinity of the shorter, developing
carbon-carbon bond rather than the longer carbon-
palladium bond (Figure 1). It may also be important that
the alkyne adopts the orientation indicated in the pen-
tacoordinate complex illustrated in Scheme 1. The
arylpalladium bond and the alkyne must be parallel and
cis-coordinated in order for the syn-addition to occur.
Consequently, the alkyne may adopt an orientation in
which the more sterically demanding group is situated
away from the sterically encumbered aryl group. Analo-
gous regiochemistry is observed in the insertion of
alkynes into the carbon-manganese bond.34 Some evi-
dence apparently exists for the reversibility of such
insertion processes,35 although we think this is unlikely
in our system.
group during the annulation of bis(trimethylsilyl)acety-
lene by 2-iodoaniline is observed to give the known
compound 3-(trimethylsilyl)indole24 (entry 14). Previous
annulations of 1-(trimethylsilyl)propyne by 2-iodobenz-
aldehyde,8a methyl 2-iodobenzoate,8b and methyl 2-(trif-
luoromethanesulfonyloxy)cyclopentenecarboxylate32 have
all afforded silyl-substituted products in which the silyl
group resides next to the functional group present in the
starting material, as proven by desilylation to known
compounds. The annulation of 4-trimethylsilyl-3-butyn-
1-ol by a 4-substituted 2-iodoaniline has also recently
been shown to produce 2-silylindoles, indicating that the
steric hindrance of the silyl group exerts a more powerful
directing effect than the alcohol group.10b We assume
that this is also true for 3-trimethylsilyl-2-propyn-1-ol,
for which a single silylindole is obtained in good yield
(entry 13). Analogous regiochemistry has recently been
reported in the heteroannulation of this same alkyne by
2-iodoheteroaromatic amines.10a
This indole synthesis presumably proceeds via (1)
reduction of the Pd(OAc)2 to Pd(0), (2) coordination of the
chloride33 to form a chloride-ligated zerovalent palladium
species, (3) oxidative addition of the aryl iodide to Pd(0),
(4) coordination of the alkyne to the palladium atom of
the resulting arylpalladium intermediate and subsequent
regioselective syn-insertion into the arylpalladium bond,
(5) nitrogen displacement of the halide in the resulting
vinylic palladium intermediate to form a six-membered,
heteroatom-containing palladacycle, and (6) reductive
elimination to form the indole and regenerate Pd(0)
(Scheme 1). The chloride ligation step has been proposed
by Amatore to explain various kinetic phenomena as-
sociated with the oxidative addition of aryl iodides to Pd-
(0) species.33 The subsequent stabilized Pd(0) species and
The pronounced directive effect of neighboring alcohol
groups on the regiochemistry of alkyne insertion would
appear to be the result of coordination of the alcohol to
the palladium during the insertion step (eq 12). An
analogous directive effect of hydroxyl groups has been
observed in the palladium-catalyzed hydroarylation of
propargylic alcohols.15b-d,17
(32) Larock, R. C.; Doty, M. J ., work in progress.
(33) Amatore, C.; J utand, A.; Suarez, A. J . Am. Chem. Soc. 1993,
115, 9531.
(34) Liebeskind, L. S.; Gasdaska, J . R.; McCallum, J . S.; Tremont,
S. J . J . Org. Chem. 1989, 54, 669.
(35) See ref 41 in ref 5b above.

Synthesis of 2,3-Disubstituted Indoles
J . Org. Chem., Vol. 63, No. 22, 1998 7659
(CDCl3) δ 2.24 (s, 3 H), 6.48 (dd, 1 H, J ) 7.5, 1.5 Hz), 7.34
(m, 1 H), 7.41 (br s, 1 H), 7.78 (d, 1 H, J ) 7.5 Hz), 8.21 (d, 1
H, J ) 8.3 Hz).
By the proper choice of reaction conditions, we are
apparently able to minimize the amount of multiple
alkyne insertion. The overall concentration of the reac-
tants, the presence and/or absence of chloride, bromide
and iodide ions, as well as PPh3; the nature and steric
effects of the substituents on the alkyne termini, and
perhaps the solvent polarity all appear to play a signifi-
cant role in this process. We note again the remarkable
difference between our results using 2-iodoacetanilide
and 1-phenylpropyne (Table 3, entry 19) and simple
aliphatic alkynes (Table 3, entries 16-18) versus those
reported previously using 2-butyne and diphenylacety-
lene in which multiple insertion predominated (eq 3).12
The final steps of this process are presumed to be
palladacycle formation and subsequent reductive elimi-
nation. Although we have no actual proof for the
intermediacy of such palladacycles, a closely related
heterocyclic arylpalladium amide has been recently
reported and shown to undergo analogous thermal reduc-
tive elimination to form the corresponding aromatic
nitrogen heterocycle.36 The presence of iodide (from the
starting aryl halide) may be critical to the reductive
elimination step. Pfeffer points out that the presence of
an iodide ligand in such palladium complexes promotes
formation of the carbon-nitrogen bond, perhaps due to
its poorer σ-donor properties compared to those of
chloride, a feature that has been shown to be crucial to
reductive elimination processes involving palladium.5b,13a
As noted previously, one equivalent of chloride appears
to dramatically favor indole formation, whereas ad-
ditional equivalents of chloride significantly slow the
process and appear to favor multiple alkyne insertion.
The latter process becomes an increasing problem when
LiBr, LiI, and/or PPh3 are added.
N-Meth yl-2-iod oa n ilin e. N-Methyl-2-iodoaniline was pre-
pared by a procedure reported by Harrison.38 In a flame-dried
100-mL round-bottom flask, 2-iodoaniline (2.25 g, 10.3 mmol)
was dissolved in 30 mL of dry THF. The resulting solution
was cooled to -78 °C under N2, 1.6 M MeLi (6.25 mL, 10 mmol)
was added dropwise, and the resulting solution was stirred
at -78 °C for 30 min. To the solution was added Me2SO4 (1.90
g, 15.1 mmol), and stirring was continued for 10 min at -78
°C. The solution was then warmed to rt and stirred for 2 h,
followed by acidification with 10% HCl. The reaction mixture
was diluted with ether, and the aqueous layer was removed.
The ether extract was stirred with 30 mL of concd NH4OH for
30 min. The aqueous layer was removed, and the organic
phase was washed with 20 mL of water and 30 mL of brine,
dried with MgSO4, and concentrated. Distillation at 101-105
°C (2.0 mmHg) yielded 2.03 g (8.7 mmol, 87%) of N-methyl-
1
2-iodoaniline: IR (neat) 3410 (NH) cm-1; H NMR (CDCl3) δ
2.80 (s, 3 H), 4.0 (br s, 1 H), 6.20-6.80 (m, 4 H); HRMS calcd
for C7H8IN 232.9702, found: 232.9702.
1-(Tr im eth ylsilyl)-2-p h en yleth yn e. Under N2, n-BuLi
(1.5 M in hexane, 10.5 mL, 15.8 mmol) was added to a solution
of PhCtCH (1.45 g, 14.3 mmol) in dried THF (10 mL) at 0 °C
over 10 min. The mixture was stirred for 1.5 h, and HMPA
(2.8 mL) containing Me3SiCl (3.0 g, 28 mmol) was slowly
added. The mixture was stirred overnight at rt. The reaction
mixture was poured into a mixture of ice and pentane (20 mL).
The organic layer was separated, and the aqueous layer was
extracted with pentane (20 mL). The combined organic layer
was washed with brine (10 mL), dried, and concentrated. The
crude product was distilled in a vacuum to give 1.9 g (65%) of
1-(trimethylsilyl)-2-phenylethyne: bp 63 °C, 2 mmHg; 1H NMR
(CDCl3) δ 0.22 (s, 9 H), 7.27 (m, 3 H), 7.45 (m, 2 H). This
material is now available from the Aldrich Chemical Co.
1-(Tr im eth ylsilyl)-1-h exyn e. This compound was pre-
pared by the same procedure used for the synthesis of
1-(trimethylsilyl)-2-phenylethyne. A 70% yield of the desired
product was obtained: 1H NMR (CDCl3) δ 0.11 (s, 9 H), 0.85
(t, 3 H, J ) 5.1 Hz), 1.46 (m, 4 H), 2.18 (t, 2 H, J ) 6.3 Hz).
This material is now available from the Aldrich Chemical Co.
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Het-
er oa n n u la tion of Alk yn es. Pd(OAc)2 (0.0125 mmol), LiCl
(0.5 mmol) or n-Bu4NCl (0.5 mmol), the appropriate base (2.50
mmol), the aryl iodide (0.50 mmol), the alkyne (0.50-2.50
mmol), DMF (10 mL), and where indicated PPh3 (0.025 mmol)
were added to a 4-dram vial equipped with a stirring bar and
Teflon-lined screwcap. After being heated for the appropriate
time at 100 °C, the reaction mixture was diluted with ether
and washed with saturated aqueous NH4Cl and H2O. The
organic layer was dried over MgSO4. The reaction mixture
was filtered and concentrated, and the product was purified
by flash column chromatography using hexanes-ethyl acetate.
The following compounds were prepared using the above
general procedure.
Exp er im en ta l Section
Gen er a l. All proton and carbon nuclear magnetic reso-
nance spectra were recorded at 300 and 75.5 MHz, respec-
tively. Flash chromatography was carried out on 230-400
mesh silica gel. Gas chromatographic analyses were carried
out on an OV-101 packed column. All melting points are
uncorrected.
Rea gen ts. All chemicals were used directly as obtained
from commercial sources unless otherwise noted. Pd(OAc)2
was donated by Kawaken Fine Chemicals Co., Ltd., and
J ohnson Matthey, Inc. Anhydrous n-Bu4NCl (Lancaster Syn-
thesis Inc.), DMF and LiCl (Fisher Scientific Co.), 2-iodoaniline
and PPh3 (Aldrich Chemical Co. Inc.), and most alkynes
(Farchan Scientific Co.) were purchased from commercial
sources. The other aryl iodides and alkynes were prepared
as follows.
2,3-Di-n -p r op ylin d ole (Ta ble 3, en tr y 1): slightly yellow
2-Iod oa ceta n ilid e. 2-Iodoacetanilide was prepared by a
procedure reported by Berrios-Pen˜a.37 2-Iodoaniline (5.48 g,
25 mmol) was dissolved in 150 mL of Et2O. Et3N (3.51 mL)
was added, and the solution was cooled to 0 °C. AcCl (2.55 g,
25.2 mmol) dissolved in 15 mL of Et2O was added dropwise.
After 1 hr of stirring at 0 °C, the reaction mixture was allowed
to reach rt and then stirred overnight. Filtration (to remove
Et3N•HCl), followed by concentration of the filtrate, afforded
5.25 g (80%) of a white solid. Recrystallization from Et2O
afforded 4.9 g (75%) of colorless needles: mp 109-111 °C; IR
1
oil; IR (neat) 3412 (NH) cm-1; H NMR (CDCl3) δ 1.02 (m, 6
H), 1.72 (m, 4 H), 2.73 (m, 4 H), 7.15 (m, 2 H), 7.29 (m, 1 H),
7.56 (m, 1 H), 7.70 (br s, 1 H); 13C NMR (CDCl3) δ 14.2, 14.5,
23.4, 24.3, 26.5, 28.3, 110.4, 112.2, 118.5, 119.0, 120.9, 129.0,
135.3, 135.4; HRMS calcd for C14H19N 201.1518, found 201.1512.
Anal. Calcd for C14H19N: C, 83.58; H, 9.45. Found: C, 83.44;
H, 9.11.
2-ter t-Bu tyl-3-m eth ylin d ole24 (Ta ble 3, en tr y 2): slightly
yellow oil; 13C NMR (CDCl3) δ 10.2, 29.3, 32.1, 105.2, 110.1,
1
(CDCl3) 3407 (NH), 3026 (ArH), 1697 (CdO) cm-1; H NMR
117.7, 118.9, 120.8, 130.4, 133.7, 141.6; HRMS calcd for
1
C
13H17N 187.1361, found 187.1361. IR and H NMR data are
consistent with previously reported data.24
(36) (a) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1995, 117,
4708. (b) Louie, J .; Hartwig, J . F. Tetrahedron Lett. 1995, 36, 3609. (c)
Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1997, 119, 8232. (d)
Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J . Am. Chem. Soc. 1997,
119, 8451.
2-Cycloh exyl-3-m eth ylin d ole (Ta ble 3, en tr y 3): slightly
yellow oil; IR (neat) 3425 (NH) cm-1; 1H NMR (CDCl3) δ 1.0-
(37) Berrios-Pen˜a, N. G. Ph.D. Dissertation, Iowa State University,
Ames, IA, 1989.
(38) Harrison, L. W. Ph.D. Dissertation, Iowa State University,
Ames, IA, 1984.

7660 J . Org. Chem., Vol. 63, No. 22, 1998
Larock et al.
2.0 (m, 10 H), 2.30 (s, 3 H), 2.95 (m, 1 H), 7.10 (m, 2 H), 7.25
(m, 1 H), 7.50 (m, 1 H), 7.80 (br s, 1 H); 13C NMR (CDCl3) δ
8.4, 26.1, 26.7, 32.8, 35.8, 105.3, 110.2, 118.0, 118.9, 120.7,
129.3, 134.8, 139.7. This compound decomposes fairly rapidly;
so no further data was obtained.
28.3, 29.4, 34.6, 111.0, 119.1, 119.2, 122.3, 126.3, 129.0, 132.7,
138.4; HRMS calcd for C15H23NSi 245.1600, found 245.1596.
3-P h en yl-2-(tr im eth ylsilyl)in d ole (Ta ble 3, en tr y 12):
1
pale yellow oil; IR (CDCl3) 3472 (NH) cm-1; H NMR (CDCl3)
δ 0.27 (s, 9 H), 7.15 (t, 1 H, J ) 6.6 Hz), 7.27 (t, 2 H, J ) 7.2
Hz), 7.45 (m, 5 H), 7.62 (d, 1 H, J ) 7.8 Hz), 8.19 (br s, 1 H);
13C NMR (CDCl3) δ -0.2, 110.9, 114.6, 119.7, 120.0, 122.8,
126.7, 128.0, 128.2, 128.6, 128.7, 136.7, 138.0; HRMS calcd
for C17H19NSi 265.1289, found 265.1288.
2-Isop r op yl-3-m eth ylin d ole a n d 3-Isop r op yl-2-m eth -
ylin d ole (Ta ble 3, en tr y 4). 2-Isop r op yl-3-m eth ylin d ole:
colorless oil; Rf ) 0.70 (6:1 hexanes/ethyl acetate); IR (neat)
3422 (NH), 3057 (ArH) cm-1; 1H NMR (CDCl3) δ 1.35 (d, 6 H,
J ) 6.9 Hz), 2.29 (s, 3 H), 3.40 (m, 1 H), 7.14 (m, 2 H), 7.30
(m, 1 H), 7.51 (m, 1 H), 7.75 (br s, 1 H); 13C NMR (CDCl3) δ
22.5, 22.6, 25.9, 105.4, 110.4, 118.2, 119.1, 121.0, 129.6, 135.0,
140.4; HRMS calcd for C12H15N 173.1205, found 173.1207.
3-Isop r op yl-2-m eth ylin d ole: slightly yellow oil; Rf ) 0.55
(6:1 hexanes/ethyl acetate); IR (neat) 3406 (NH), 3059 (ArH)
3-(Hyd r oxym eth yl)-2-(tr im eth ylsilyl)in d ole (Ta ble 3,
en tr y 13): white solid; mp 156-158 °C; IR (CDCl3) 3474 (OH),
3382 (NH) cm-1; 1H NMR (CDCl3) δ 0.44 (s, 9 H), 1.50 (br s, 1
H), 4.95 (s, 2 H), 7.15 (m, 2 H), 7.40 (d, 1 H, J ) 7.8 Hz), 7.76
(d, 1 H, J ) 8.1 Hz), 8.20 (br s, 1 H); 13C NMR (DMSO-d6) δ
-0.2, 55.1, 111.2, 118.3, 118.8, 121.3, 124.3, 128.1, 134.9, 138.4;
HRMS calcd for C12H17NOSi 219.1079, found 219.1081.
3-(Tr im eth ylsilyl)in d ole24 (Ta ble 3, en tr y 14): yellow oil;
13C NMR (CDCl3) δ -0.8, 115.6, 118.1, 119.9, 120.8, 122.5,
128.9, 138.5, 138.9; HRMS calcd for C11H15NSi 189.0974, found
1
cm-1; H NMR (CDCl3) δ 1.40 (d, 6 H, J ) 6.9 Hz), 2.36 (s, 3
H), 3.16 (m, 1 H), 7.06 (m, 2 H), 7.22 (m, 1 H), 7.55 (br s, 1 H),
7.64 (d, 1 H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 12.1, 23.0, 25.9,
110.2, 114.7, 118.6, 119.9, 120.4, 129.5, 135.3, 138.9; HRMS
calcd for C12H15N 173.1205, found 173.1206.
1
189.0971. IR and H NMR data are consistent with previously
reported data.24
2-E t h yl-3-m et h ylin d ole a n d 3-E t h yl-2-m et h ylin d ole
(Ta ble 3, en tr y 5): slightly yellow oil; IR (neat, 1.5:1 mixture)
3401 (NH), 3057 (ArH) cm-1; 1H NMR (CDCl3, 1.5:1 mixture)
δ 1.30 (m, 6 H), 2.32 (s, 3 H), 2.39 (s, 3 H), 2.80 (q, 4 H), 7.15
(m, 4 H), 7.28 (m, 2 H), 7.55 (m, 2 H), 7.60-7.70 (br s, 2 H);
13C NMR (CDCl3, 60:40 mixture) δ 8.3, 11.3, 14.0, 15.4, 15.5,
17.3, 19.3, 105.9, 110.1, 113.6, 117.9, 118.8, 120.6, 120.7, 124.1,
128.3, 129.3, 129.3, 129.5, 134.1, 135.1, 136.5; HRMS calcd
for C11H13N 159.1048, found 159.1051.
2,3-Bis(1-h yd r oxy-1-m eth yleth yl)in d ole (Ta ble 3, en tr y
6): slightly yellow oil; IR (neat) 3450 (OH), 3416 (NH), 3061
(ArH) cm-1; 1H NMR (CDCl3) δ 1.83 (s, 12 H), 2.03 (br s, 2 H),
7.30 (m, 2 H), 7.49 (d, 1 H, J ) 8.1 Hz), 7.74 (d, 1 H, J ) 7.5
Hz), 8.80 (br s, 1 H); 13C NMR (CDCl3) δ 30.7 (overlapped),
69.7 (overlapped), 97.2, 111.1, 119.8, 120.5, 121.8, 128.4, 135.8,
145.8; HRMS calcd for C14H19NO 233.1417, found 233.1417.
2-(1-Hyd r oxy-1-m eth yleth yl)-3-m eth ylin d ole (Ta ble 3,
en tr y 7): slightly yellow oil; IR (neat) 3431 (OH), 3352 (NH)
cm-1; 1H NMR (CDCl3) δ 1.67 (s, 6 H), 2.03 (br s, 1 H), 2.33 (s,
3 H), 7.10 (m, 2 H), 7.38 (d, 1 H, J ) 6.0 Hz), 7.49 (d, 1 H, J
) 7.5 Hz), 8.45 (br s, 1 H); 13C NMR (CDCl3) δ 9.5, 30.0, 70.7,
103.7, 110.6, 118.9, 121.2, 127.1, 130.0, 133.5, 140.0; HRMS
calcd for C12H15NO 189.1154, found 189.1153.
1-Met h yl-2,3-d i-n -p r op ylin d ole (Ta b le 3, en t r y 15):
1
slightly yellow oil; H NMR (CDCl3) δ 1.19 (m, 6 H), 1.85 (m,
4 H), 2.92 (m, 4 H), 3.86 (s, 3 H), 7.35 (m, 3 H), 7.74 (d, 1 H,
J ) 7.8 Hz); 13C NMR (CDCl3) δ 14.3, 14.6, 23.7, 24.7, 26.8,
26.9, 29.7, 108.7, 111.8, 118.5, 118.6, 120.6, 128.0, 136.8, 137.0;
HRMS calcd for C15H21N 215.1674, found 215.1674. Anal.
Calcd for C15H21N: C, 83.72; H, 9.77. Found: C, 83.75; H,
9.83.
1-Acet yl-2,3-d i-n -p r op ylin d ole (Ta b le 3, en t r y 16):
slightly yellow oil; IR (neat) 1703 (CdO) cm-1 1H NMR
;
(CDCl3) δ 1.04 (m, 6 H), 1.67 (m, 4 H), 2.68 (t, 2 H, J ) 7.5
Hz), 2.78 (s, 3 H), 3.01 (t, 2 H, J ) 7.8 Hz), 7.23 (m, 2 H), 7.52
(m, 1 H), 7.78 (m, 1 H); 13C NMR (CDCl3) δ 14.3, 14.5, 23.3,
23.8, 26.2, 27.8, 29.1, 114.6, 118.9, 120.2, 122.7, 128.5, 131.0,
135.7, 138.3, 170.1; HRMS calcd for C16H21N 243.1623, found
243.1619.
1-Acetyl-2-isop r op yl-3-m eth ylin d ole a n d 1-Acetyl-3-
isop r op yl-2-m eth ylin d ole (Ta ble 3, en tr y 17). 1-Acetyl-
2-isop r op yl-3-m eth ylin d ole: pale yellow oil; Rf ) 0.75 (4:1
hexanes/ethyl acetate); IR (neat) 3059 (ArH), 1701 (CdO) cm-1
;
1H NMR (CDCl3) δ 1.42 (d, 6 H, J ) 7.2 Hz), 2.29 (s, 3 H),
2.73 (s, 3 H), 3.75 (m, 1 H), 7.25 (m, 2 H), 7.47 (m, 1 H), 7.67
(m, 1 H); 13C NMR (CDCl3) δ 9.7, 21.4, 27.0, 27.9, 113.6, 114.7,
118.0, 122.3, 123.3, 131.6, 134.8, 142.8, 170.7; HRMS calcd
for C14H17N 215.1310, found: 215.1310. 1-Acetyl-3-isop r o-
p yl-2-m eth ylin d ole: pale yellow oil; Rf ) 0.65 (4:1 hexanes/
2-(1-Hydr oxy-1-m eth yleth yl)-3-isopr open ylin dole (Table
3, en tr y 8): pale yellow solid; mp 122-123 °C; IR (CDCl3) 3543
1
(OH), 3362 (NH), 1641 (CdC) cm-1; H NMR (CDCl3) δ 1.56
(s, 6 H), 2.03 (s, 3 H), 2.35 (br s, 1 H), 4.90 (d, 1 H, J ) 1.2
Hz), 5.25 (d, 1 H, J ) 1.2 Hz), 7.02 (m, 2 H), 7.16 (d, 1 H, J )
8.1 Hz), 7.36 (d, 1 H, J ) 7.8 Hz), 8.45 (br s, 1 H); 13C NMR
(CDCl3) δ 25.6, 31.2, 71.3, 110.8, 113.7, 117.4, 119.2, 119.6,
121.8, 128.9, 133.8, 139.3, 140.5; HRMS calcd for C14H17NO
215.1310, found 215.1310.
ethyl acetate); IR (neat) 3060 (ArH), 1700 (CdO) cm-1 1H
;
NMR (CDCl3) δ 1.42 (d, 6 H, J ) 7.2 Hz), 2.57 (s, 3 H), 2.73 (s,
3 H), 3.12 (m, 1 H), 7.23 (m, 2 H), 7.67 (m, 1 H), 7.95 (m, 1 H);
13C NMR (CDCl3) δ 14.3, 21.9, 25.3, 27.7, 114.9, 119.7, 122.3,
123.1, 125.0, 129.0, 131.1, 137.0, 170.3; HRMS calcd for
C
14H17N 215.1310, found: 215.1309.
3-Eth yl-2-(1-h yd r oxycycloh exyl)in d ole (Ta ble 3, en tr y
9): white solid; mp 89-90 °C; IR (neat) 3487 (OH), 3315 (NH)
1-Acetyl-2-eth yl-3-m eth ylin d ole a n d 1-a cetyl-3-eth yl-
2-m eth ylin d ole (Ta ble 3, en tr y 18). 1-Acetyl-2-eth yl-3-
m eth ylin d ole: yellow oil; IR (neat) 1696 (CdO) cm-1; 1H NMR
(CDCl3) δ 1.24 (t, 3 H, J ) 7.2 Hz), 2.33 (s, 3 H), 2.79 (s, 3 H),
3.07 (q, 2 H, J ) 7.2 Hz), 7.28 (m, 2 H), 7.49 (m, 1 H), 7.79 (m,
1 H); 13C NMR (CDCl3) δ 8.3, 14.4, 21.9, 27.6, 114.4, 118.4,
120.7, 122.6, 123.4, 131.4, 135.3, 139.5, 169.8; HRMS calcd
for C13H15NO 201.1154, found 201.1159. 1-Acetyl-3-eth yl-
1
cm-1; H NMR (CDCl3) δ 1.27 (t, 3 H, J ) 7.5 Hz), 1.65-1.86
(m, 6 H), 2.27 (m, 2 H), 2.45 (m, 2 H), 2.85 (q, 2 H, J ) 7.5
Hz), 6.05 (br s, 1 H), 7.14 (m, 2 H), 7.28 (t, 1 H, J ) 8.1 Hz),
7.59 (d, 1 H, J ) 6.9 Hz), 7.77 (br s, 1 H); 13C NMR (CDCl3) δ
16.2, 21.7, 21.9, 24.5, 38.0, 72.2, 110.8, 111.2, 118.6, 119.0,
121.3, 129.6, 133.9, 140.1; HRMS calcd for C14H15NO2 243.1623,
found 243.1620.
2-m eth ylin d ole: yellow oil; IR (neat) 1695 (CdO) cm-1 1H
;
3-Meth yl-2-(tr im eth ylsilyl)in d ole (Ta ble 3, en tr y 10):
slightly yellow oil; IR (neat) 3439 (NH) cm-1; 1H NMR (CDCl3)
δ 0.27 (s, 9 H), 2.32 (s, 3 H), 7.05 (m, 2 H), 7.23 (d, 1 H, J )
7.8 Hz), 7.48 (d, 1 H, J ) 7.8 Hz), 7.76 (br s, 1 H); 13C NMR
(CDCl3) δ -0.7, 10.7, 110.9, 118.8, 119.2, 120.4, 122.4, 130.7,
133.0, 138.2; HRMS calcd for C12H17NSi 203.1130, found
203.1125.
NMR (CDCl3) δ 1.17 (t, 3 H, J ) 7.8 Hz), 2.53 (s, 3 H), 2.67 (q,
2 H, J ) 7.8 Hz), 2.69 (s, 3 H), 7.23 (m, 2 H), 7.45 (m, 1 H),
7.95 (m, 1 H); 13C NMR (CDCl3) δ 14.2, 14.5, 17.1, 27.5, 115.1,
118.1, 120.7, 122.7, 123.5, 130.2, 132.9, 135.9, 170.2; HRMS
calcd for C13H15NO 201.1159, found 201.1157.
1-Acetyl-3-m eth yl-2-p h en ylin d ole23 (Ta ble 3, en tr y 19):
pale yellow crystals; mp 81-82 °C (lit.23 mp 80.5-81.5 °C); IR
3-n -Bu tyl-2-(tr im eth ylsilyl)in d ole (Ta ble 3, en tr y 11):
(CDCl3) 3063 (ArH), 1687 (CdO) cm-1 13C NMR (CDCl3) δ 9.4,
;
1
pale yellow oil; IR (CDCl3) 3439 (NH) cm-1; H NMR (CDCl3)
27.8, 116.4, 118.3, 118.9, 123.6, 125.4, 128.6, 128.8 (2 C), 130.3,
133.7, 135.0, 136.9, 171.1; HRMS calcd for C17H15NO 249.1154,
found 249.1154. Anal. Calcd for C17H15NO: C, 81.92; H, 6.17.
Found: C, 82.35; H, 6.35. 1H NMR data is consistent with
previously reported data.23
δ 0.26 (s, 9 H), 0.87 (t, 3 H, J ) 7.2 Hz), 1.36 (m, 2 H), 1.53
(m, 2 H), 2.72 (t, 2 H, J ) 7.8 Hz), 6.96 (t, 1 H, J ) 5.1 Hz),
7.05 (t, 1 H, J ) 4.2 Hz), 7.19 (d, 1 H, J ) 8.1 Hz), 7.50 (d, 1
H, J ) 7.5 Hz), 7.69 (br s, 1 H); 13C NMR (CDCl3) δ -0.3, 14.3,

Synthesis of 2,3-Disubstituted Indoles
J . Org. Chem., Vol. 63, No. 22, 1998 7661
2-(Acetoxym eth yl)-3-m eth ylin d ole27 (Ta ble 3, en tr y
14.4, 15.0, 17.4, 19.8, 21.5, 114.6, 115.0, 116.0, 118.2, 118.2,
122.2, 123.1, 123.3, 123.7, 123.9, 129.6, 129.7, 131.5, 131.8,
136.1, 136.3, 136.4, 138.8, 144.3, 144.4.
20): pale yellow solid; mp 88-89 °C (lit.27 mp 90-92 °C); IR
1
(CDCl3) 3398 (NH), 3059 (ArH), 1717 (CdO) cm-1; H NMR
(CDCl3) δ 2.07 (s, 3 H), 2.37 (s, 3 H), 5.22 (s, 2 H), 7.20 (m, 3
H), 7.53 (d, 1 H, J ) 7.8 Hz), 8.40 (br s, 1 H); 13C NMR (CDCl3)
δ 8.6, 21.5, 57.8, 111.1, 111.8, 119.4, 119.5, 123.0, 128.3, 129.0,
135.9, 172.4; HRMS calcd for C12H13NO2 203.0946, found
203.0943.
1-Acetyl-2-(h ydr oxym eth yl)-3-isopr open ylin dole (Table
3, en tr y 21): pale yellow oil; IR (neat) 3383 (OH), 1701 (Cd
O) cm-1; 1H NMR (CDCl3) δ 1.50 (br s, 1 H), 2.10 (s, 3 H), 2.68
(s, 3 H), 4.77 (s, 2 H), 5.27 (d, 1 H, J ) 1.5 Hz), 5.53 (d, 1 H,
J ) 1.5 Hz), 7.32 (m, 2 H), 7.71 (m, 1 H), 8.21 (d, 1 H, J ) 7.5
Hz); 13C NMR (CDCl3) δ 24.6, 26.4, 55.9, 116.0, 119.4, 119.8,
120.0, 123.7, 125.4, 129.0, 136.5, 136.9, 139.3, 170.6; HRMS
calcd for C14H15NO2 229.1103, found 229.1101.
2-F or m yl-3-m eth yl-1-tosylin d ole Dieth yl Aceta l a n d
3-F or m yl-2-m eth yl-1-tosylin d ole Dieth yl Aceta l (Ta ble 3,
en tr y 28). 2-F or m yl-3-m eth yl-1-tosylin d ole d ieth yl a c-
eta l: yellow oil; IR (neat) 1369 (SO2), 1202 (SO2) cm-1; 1H NMR
(CDCl3) δ 1.41 (t, 6 H, J ) 6.9 Hz), 2.45 (s, 3 H), 2.58 (s, 3 H),
3.80 (m, 4 H), 6.84 (s, 1 H), 7.29 (d, 2 H, J ) 7.8 Hz), 7.41 (m,
2 H), 7.59 (d, 1 H, J ) 7.5 Hz), 7.92 (d, 2 H, J ) 8.1 Hz), 8.29
(d, 1 H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 10.1, 15.4, 21.7, 68.2,
98.4, 115.4, 119.3, 120.9, 123.6, 125.3, 127.0, 129.5, 131.7,
133.5, 135.7, 136.5, 144.5; HRMS calcd for
C21H25NSO4
387.1504, found: 387.1494. 3-F or m yl-2-m eth yl-1-tosylin -
d ole d ieth yl a ceta l: yellow oil; IR (neat) 1391 (SO2), 1199
1
(SO2) cm-1; H NMR (CDCl3) δ 1.35 (t, 6 H, J ) 6.9 Hz), 2.50
(s, 3 H), 2.81 (s, 3 H), 3.70 (m, 4 H), 5.85 (s, 1 H), 7.36 (m, 4
H), 7.81 (d, 2 H, J ) 9.6 Hz), 8.01 (d, 1 H, J ) 7.8 Hz), 8.34 (d,
1 H, J ) 7.8 Hz); 13C NMR (CDCl3) δ 13.3, 15.4, 21.7, 61.5,
98.7, 114.4, 118.0, 121.0, 123.7, 124.1, 126.5, 128.8, 129.8,
2-(2-Acet oxyet h yl)-3-m et h ylin d ole (Ta b le 3, en t r y
22): pale yellow oil; IR (CDCl3) 3398 (NH), 3059 (ArH), 1717
1
(CdO) cm-1; H NMR (CDCl3) δ 2.10 (s, 3 H), 2.27 (s, 3 H),
3.06 (t, 2 H, J ) 6.9 Hz), 4.31 (t, 2 H, J ) 6.9 Hz), 7.13 (m, 2
H), 7.27 (m, 1 H), 7.51 (m, 1 H), 7.97 (br s, 1 H); 13C NMR
(CDCl3) δ 8.6, 21.2, 26.1, 63.8, 108.5, 110.5, 118.5, 119.3, 121.2,
129.2, 130.9, 135.6, 171.1; HRMS calcd for C13H15NO2 217.1103,
found 217.1102.
130.0, 135.3, 136.4, 144.8; HRMS calcd for
387.1504, found 387.1508.
C21H25NSO4
3-Isop r op en yl-2-(1-h yd r oxy-1-m et h ylet h yl)-1-t osylin -
d ole (Ta ble 3, en tr y 29): slightly yellow oil; IR (neat) 3479
(OH), 1366 (SO2), 1188 (SO2) cm-1; 1H NMR (CDCl3) δ 1.62 (s,
3 H), 1.66 (s, 3 H), 2.28 (s, 3 H), 2.32 (s, 3 H), 2.66 (br s, 1 H),
4.79 (s, 1 H), 5.24 (s, 1 H), 6.8-7.4 (m, 8 H); 13C NMR (CDCl3)
δ 21.7, 26.0, 31.0, 32.0, 71.9, 115.1, 120.6, 122.4, 123.2, 124.5,
126.8, 127.1, 128.7, 129.6, 135.4, 136.4, 136.7, 140.9, 144.7;
HRMS calcd for C21H23NO2 369.1399, found 369.1396.
2,3-Dip h en yl-1-t osylin d ole (Ta ble 3, en t r y 30): white
solid; mp 173-174 °C; IR (neat) 3070 (ArH), 3040 (ArH), 1387
(SO2), 1180 (SO2) cm-1; 1H NMR (CDCl3) δ 2.26 (s, 3 H), 7.0-
7.5 (m, 17 H), 8.41 (d, 1 H, J ) 8.4 Hz); 13C NMR (CDCl3) δ
21.4, 116.1, 119.9, 124.1, 124.7, 124.7, 125.0, 126.8, 127.1,
128.1, 128.3, 129.2, 129.7, 130.3, 130.8, 132.0, 132.5, 135.2,
136.7, 137.2, 144.5. Anal. Calcd for C27H21NO2S: C, 76.57;
H, 5.00. Found: C, 76.57; H, 5.05.
2-(2-Acetoxyp r op yl)-3-m eth ylin d ole a n d 1-Acetyl-3-(2-
h yd r oxyp r op yl)-2-m eth ylin d ole (Ta ble 3, en tr y 23). 2-(2-
Acetoxyp r op yl)-3-m eth ylin d ole: yellow oil; IR (neat) 3401
1
(NH), 3059 (ArH), 1718 (CdO) cm-1; H NMR (CDCl3) δ 1.28
(d, 3 H, J ) 6.3 Hz), 2.09 (s, 3 H), 2.28 (s, 3 H), 3.00 (m, 2 H),
5.18 (m, 1 H), 7.13 (m, 2 H), 7.28 (t, 1 H, J ) 7.2 Hz), 7.52 (d,
1 H, J ) 7.5 Hz), 8.10 (br s, 1 H); 13C NMR (CDCl3) δ 8.8,
19.5, 21.6, 32.8, 70.9, 108.9, 110.5, 118.4, 119.1, 121.5, 129.1,
130.6, 135.6, 170.2; HRMS calcd for C14H17NO2 231.1260, found
231.1262. 1-Acetyl-3-(2-h yd r oxyp r op yl)-2-m eth ylin d ole:
1
yellow oil; IR (CDCl3) 3383 (OH), 1701 (CdO) cm-1; H NMR
(CDCl3) δ 1.30 (d, 3 H, J ) 6.3 Hz), 1.75 (br s, 1 H), 2.60 (s, 3
H), 2.72 (s, 3 H), 2.83 (d, 2 H, J ) 6.6 Hz), 3.10 (m, 1 H), 7.30
(m, 2 H), 7.50 (m, 1 H), 7.90 (m, 1 H); 13C NMR (CDCl3) δ
15.0, 23.3, 27.8, 34.1, 68.1, 115.1, 115.2, 118.7, 122.1, 123.2,
124.1, 130.8, 134.6, 170.4; HRMS calcd for C14H17NO2 231.1260,
found 231.1263.
1-Acetyl-3-m eth yl-2-(tr im eth ylsilyl)in d ole (Ta ble 3, en -
tr y 24): yellow solid; mp 65-67 °C; IR (CDCl3) 1693 (CdO)
cm-1; 1H NMR (CDCl3) δ 0.35 (s, 9 H), 2.35 (s, 3 H), 2.77 (s, 3
H), 7.20-7.33 (m, 2 H), 7.52 (d, 1 H, J ) 7.5 Hz), 7.62 (d, 1 H,
J ) 7.5 Hz); 13C NMR (CDCl3) δ 2.8, 11.3, 26.5, 113.6, 119.5,
122.5, 124.8, 129.4, 134.0, 136.6, 137.1, 169.0; HRMS calcd
for C14H19NOSi 245.1236, found 245.1237.
1-Acetyl-3-m eth ylin d ole.30 1-Acetyl-3-methyl-2-(trimeth-
ylsilyl)indole (51 mg, 0.25 mmol) and AlCl3 (33 mg, 0.25 mmol)
were added to 5 mL of CH2Cl2, and the reaction mixture was
stirred for 30 min at 0 °C. Water was added, and the reaction
mixture was extracted with ether, dried over MgSO4 and
concentrated. Flash column chromatography using 4:1 hex-
ane/ethyl acetate afforded 38 mg of crystalline product (87%
yield): mp 66-67 °C (lit.30 mp 66 °C); 13C NMR (CDCl3) δ 9.6,
23.8, 116.4, 118.2, 118.7, 122.1, 123.2, 125.0, 131.3, 135.7,
168.1; HRMS calcd for C11H11NO 173.0841, found 173.0842.
1
IR and H NMR data are consistent with previously reported
data.30
2,3-Di-n -p r op yl-1-tosylin d ole (Ta ble 3, en tr y 25): pale
yellow oil; IR (neat) 1366 (SO2), 1186 (SO2) cm-1 1H NMR
;
1-Acetyl-2-br om o-3-m eth ylin d ole. 1-Acetyl-3-methyl-2-
(trimethylsilyl)indole (51 mg, 0.25 mmol) and NBS (89 mg, 0.50
mmol) were dissolved in 5 mL of CH2Cl2 and refluxed for 30
min. The reaction mixture was concentrated and purified by
flash chromatography using 4:1 hexane/ethyl acetate to give
44 mg (70%) of crystalline product: mp 61-62 °C (lit.31 mp
49-50.5 °C); IR (CDCl3) 1699 (CdO) cm-1; 1H NMR (CDCl3) δ
2.26 (s, 3 H), 2.83 (s, 3 H), 7.27 (m, 2 H), 7.43 (d, 1 H, J ) 7.8
Hz), 8.20 (d, 1 H, J ) 7.8 Hz); 13C NMR (CDCl3) δ 10.5, 28.1,
107.5, 118.1, 118.1, 120.8, 123.5, 125.2, 129.4, 137.0, 169.8.
This compound rapidly decomposed, so no mass spectrum or
elemental analysis could be obtained.
Ethyl(E)-3-(1-Acetyl-3-methyl-2-indolyl)acrylate. 1-Acetyl-
3-methyl-2-(trimethylsilyl)indole (102 mg, 0.50 mmol), ethyl
acrylate (100 mg, 1.0 mmol), palladium acetate (112 mg, 0.50
mmol), and 10 mL of DMF were added to a 4-dram vial
equipped with a stirring bar and Teflon-lined screwcap. After
being heated for 2 d at 100 °C, the reaction mixture was diluted
with ether, washed with saturated aqueous NH4Cl and H2O,
dried over MgSO4, filtered, concentrated, and purified by flash
column chromatography using 4:1 hexane/ethyl acetate to
afford 102 mg (75%) of a crystalline solid: mp 70-71 °C; IR
(CDCl3) 3022 (CdCH), 1705 (CdO), 1630 (CdC) cm-1; 1H NMR
(CDCl3) δ 1.36 (t, 3 H, J ) 7.2 Hz), 2.37 (s, 3 H), 2.67 (s, 3 H),
4.31 (q, 2 H, J ) 7.2 Hz), 6.10 (d, 1 H, J ) 15.9 Hz), 7.25-7.42
(CDCl3) δ 0.87 (t, 3 H, J ) 7.5 Hz), 1.00 (t, 3 H, J ) 7.2 Hz),
1.57 (m, 2 H), 1.76 (m, 2 H), 2.29 (s, 3 H), 2.59 (t, 2 H, J ) 7.8
Hz), 2.95 (t, 2 H, J ) 7.5 Hz), 7.11 (d, 2 H, J ) 7.8 Hz), 7.23
(m, 2 H), 7.38 (d, 1 H, J ) 6.9 Hz), 7.53 (d, 2 H, J ) 8.4 Hz),
8.17 (d, 1 H, J ) 8.4 Hz); 13C NMR (CDCl3) δ 13.2, 14.9, 22.3,
23.0, 24.3, 26.2, 26.7, 114.2, 117.6, 119.6, 122.7, 124.4, 125.0,
127.2, 128.4, 130.5, 131.1, 136.8, 144.2; HRMS calcd for C21H25
NSO2 355.1606, found 355.1600.
-
2-ter t-Bu t yl-3-m et h yl-1-t osylin d ole (Ta b le 3, en t r y
26): pale yellow oil; IR (neat) 1399 (SO2), 1177 (SO2) cm-1
1H NMR (CDCl3) δ 1.85 (s, 9 H), 2.38 (s, 3 H), 2.40 (s, 3 H),
7.09 (d, 2 H, J ) 8.7 Hz), 7.28 (d, 2 H, J ) 4.2 Hz), 7.34 (m, 1
H), 7.42 (d, 2 H, J ) 8.4 Hz), 8.18 (d, 1 H, J ) 4.8 Hz); 13C
NMR (CDCl3) δ 12.6, 21.4, 31.8, 35.9, 117.9, 118.9, 124.3, 124.4,
124.6, 126.7, 128.3, 132.4, 135.0, 139.6, 143.6, 147.2; HRMS
calcd for C20H23NSO2 341.1450, found 341.1446.
;
2-Eth yl-3-m eth yl-1-tosylin d ole a n d 3-Eth yl-2-m eth yl-
1-tosylin d ole (Ta ble 3, en tr y 27): pale yellow oil; IR (neat,
1
50:50 mixture) 3068 (ArH), 1371 (SO2), 1188 (SO2) cm-1; H
NMR (CDCl3, 1:1 mixture) δ 1.13 (t, 3 H, J ) 7.5 Hz), 1.27 (t,
3 H, J ) 7.2 Hz), 2.14 (s, 3 H), 2.31 (s, 3 H), 2.33 (s, 3 H), 2.53
(s, 3 H), 2.60 (q, 2 H, J ) 7.5 Hz), 3.01 (q, 2 H, J ) 7.2 Hz),
7.23 (m, 8 H), 7.38 (m, 2 H), 7.60 (q, 4 H, J ) 8.4 Hz), 8.18 (d,
2 H, J ) 7.8 Hz); 13C NMR (CDCl3, 50:50 mixture) δ 8.7, 12.5,

7662 J . Org. Chem., Vol. 63, No. 22, 1998
Larock et al.
(m, 2 H), 7.54 (d, 1 H, J ) 7.8 Hz), 7.89 (d, 1 H, J ) 15.9 Hz),
8.07 (d, 1 H, J ) 8.4 Hz); 13C NMR (CDCl3) δ 10.4, 14.4, 27.4,
60.7, 115.2, 119.7, 121.3, 121.9, 123.4, 126.4, 130.6, 131.3,
135.5, 136.5, 166.4, 169.9; HRMS calcd for C14H17NO3 271.1208,
found 271.1206.
(E)-4-(1-Acetyl-3-m eth yl-2-in d olyl)-3-bu ten -2-on e. This
compound was obtained as a yellow oil in 50% isolated yield
from the reaction of 1-acetyl-3-methyl-2-(trimethylsilyl)indole
and methyl vinyl ketone using the same method reported
above for the synthesis of ethyl (E)-3-(1-acetyl-3-methyl-2-
indolyl)acrylate: IR (neat) 1695 (CdO), 1653 (CdO), 1603 (Cd
C) cm-1; 1H NMR (CDCl3) δ 2.37 (s, 3 H), 2.42 (s, 3 H), 2.72 (s,
3 H), 6.36 (d, 1 H, J ) 16.2 Hz), 7.34 (m, 2 H), 7.57 (d, 1 H, J
) 9.0 Hz), 7.83 (d, 1 H, J ) 16.2 Hz), 7.94 (d, 1 H, J ) 8.4 Hz);
13C NMR (CDCl3) δ 10.5, 27.4, 27.5, 114.8, 119.9, 122.2, 123.5,
126.4, 129.7, 130.9, 131.8, 134.9, 136.4, 170.0, 198.0; HRMS
calcd for C15H15NO2 241.1103, found 241.1105.
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health for their generous finan-
cial support and J ohnson Matthey, Inc., and Kawaken
Fine Chemicals Co., Ltd., for the palladium acetate.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H or 13C
NMR spectra (59 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9803277