New synthesis of 3-substituted indoles using lithium trimethylsilyldiazomethane

Article abstract of DOI:10.1016/j.tetlet.2004.06.102

Lithium trimethylsilyldiazomethane smoothly reacted with N-tosyl-o-acylanilines to give 3-substituted indoles in good to high yields.

Full text of DOI:10.1016/j.tetlet.2004.06.102

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6303–6305
New synthesis of 3-substituted indoles using lithium
trimethylsilyldiazomethane
Takashi Miyagi, Yoshiyuki Hari and Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 14 May 2004; revised 4 June 2004; accepted 18 June 2004
Abstract—Lithium trimethylsilyldiazomethane smoothly reacted with N-tosyl-o-acylanilines to give 3-substituted indoles in good to
high yields.
ꢀ
2004 Elsevier Ltd. All rights reserved.
1
Indoles have a wide spectrum of biological activities. A
large number of methods for the construction of the
O
C
Me3SiC(Li)N2
2
Me
Me
NH2
indole nucleus have been reported. Among them, the
3d
3
a–c
–Me SiOLi
base-
metal-catalyzed
or Lewis acid- mediated, and transition-
3
3
NH2
–
N2
e–i
cyclization of o-ethynylaniline deriv-
1
a
2
atives is one of the most useful methods. However, there
is still strong demand for new, versatile, and efficient
methods for the construction of the indole nucleus.
Me
Me
We have already demonstrated that the lithium salt of
trimethylsilyldiazomethane (TMSC(Li)N2), prepared
from trimethylsilyldiazomethane (TMSCHN2) with
n-butyllithium (n-BuLi) or lithium diisopropylamide
+
N
NH2
4a (58 %)
H
(
LDA), is quite useful as a reagent for generating alkyl-
3a (23 %)
4
idene carbenes from carbonyl compounds. For exam-
ple, TMSC(Li)N2 smoothly reacts with b-amino
ketones to give 2-pyrrolines, the intramolecular N–H
insertion product, via alkylidene carbene intermediates
in good yields. We thought that this reaction would
be applicable to the synthesis of 3-substituted indoles
Scheme 1.
5
Thus, we found that N-tosyl-o-acylanilines 1 smoothly
reacted with TMSC(Li)N in THF at À78ꢁC for 1h
2
if o-acylanilines were used as substrates. In fact, treat-
ment of TMSC(Li)N with o-aminoacetophenone 1a in
and then at room temperature for 1h to give the corre-
sponding 3-substituted N-tosylindoles 3 in good to high
2
THF gave the desired 3-methylindole 3a in 23% yield,
6
7
yields (Scheme 2). The scope of the new synthesis of
8
but the major product was o-(1-propynyl)aniline 4a
(
3
-substituted N-tosylindoles is summarized in Table 1.
58%) via the alkylidene carbene intermediate 2 (Scheme
). However, protection of the amino group of 1a with
1
N-tosyl-o-acylanilines bearing various R groups such
as alkyl, aryl, and heteroaryl groups were smoothly con-
verted to the corresponding 3-substituted N-tosylindoles
1
tosyl chloride led to a significant improvement of the
yield.
3
(entries 1 and 5–10). In some cases, the alkynes 4 were
also formed as by-products. Analogously, the N-meth-
anesulfonyl derivative 1c afforded the desired indole 3c
in 70% yield (entry 2). In the case of the N-Boc deriva-
tive 1d, the product was a mixture of the corresponding
3d (48%) and the alkyne 4d (28%) with low selectivity
(entry 3). Moreover, although the N-acetyl derivative
Keywords: o-Acylanilines; Alkylidene carbene; Indoles; Intramolecular
N–H insertion; Trimethylsilyldiazomethane.
*
Corresponding author. Tel./fax: +81-52-836-3439; e-mail: aoyama@
phar.nagoya-cu.ac.jp
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.102

6304
T. Miyagi et al. / Tetrahedron Letters 45 (2004) 6303–6305
O
O
R3
R4
R3
R4
R1
NHR2
LDA (2.2 eq.)
THF
R1
+
Me3SiCHN2
(1.2 eq.)
N(Li)R2
+
1
Me3SiC(Li)N2
R1
R1
R3
R4
R3
+
N
R2
R4
NHR2
3
4
Scheme 2.
Table 1. Preparation of 3-substituted N-tosylindoles
1
R
2
R
3
R
4
R
Entry
Substrate
Conditions
Yield (%)
a
1
1b
1c
1d
1e
1f
Me
Me
Ts
Ms
Boc
Ac
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
H
H
H
H
H
H
H
H
À78ꢁC, 1hfirt, 1h
À78ꢁC, 1hfirt, 2h
À78ꢁC, 1hfirt, 2h
À78ꢁC, 1hfi0ꢁC, 5h
À78ꢁC, 1hfirt, 1.5h
À78ꢁC, 1hfirt, 1h
À78ꢁC, 1hfirt, 1h
À78ꢁC, 1hfirt, 1h
À78ꢁC, 1hfirt, 1h
À78ꢁC, 1hfirt, 1h
À78ꢁC, 1hfirt, 1h
À78ꢁC, 1hfirt, 1h
81 (3b)+8 (4b)
70 (3c)+10 (4c)
48 (3d)+28 (4d)
2
b
3
b
Me
Me
c
4
–– (3e)+46 (4e)
d
78 (3f)+nd (4f)
5
6
7
8
9
Me
–OCH
2
O–
1g
1h
1i
n-Bu
Ph
H
H
Cl
H
H
H
H
H
H
H
H
H
68 (3g)+29 (4g)
d
91 (3h)+nd (4h)
d
87 (3i)+nd (4i)
Ph
1j
2-Furyl
2-Pyridyl
H
63 (3j)+30 (4j)
d
64 (3k)+nd (4k)
10
11
12
1k
1l
d
85 (3l)+nd (4l)
d
79 (3m)+nd (4m)
1m
H
–CH@CHCH@CH–
a
b
c
3
b (78%) and 4b (8%) were obtained when n-BuLi was used as a base.
Me SiCHN (2equiv) and n-BuLi (2equiv) were used.
-Methylindole 3a (21 %) was obtained and 3e could not be detected.
3
2
3
d
Not detected.
1
e also reacted with TMSC(Li)N to give the indole 3a
2
References and notes
(
21%), formed by hydrolysis of the first produced N-
acetylindole during work-up, the major product was
the alkyne 4e (46%) (entry 4). It is known that hydrogen
has a high migratory aptitude for alkylidene carbene
rearrangement giving alkynes. Interestingly, however,
the aldehydes 1l and 1m preferentially gave the corre-
sponding indoles 3l and 3m in high yields, respectively,
and no alkynes could be detected (entries 11 and 12).
In these reactions, THF was found to be the reaction
solvent of choice. No reaction occurred under the above
1. For a review; see: Sundberg, R. J. Indoles; Academic:
London, 1996.
2
. For reviews; see: (a) Pindur, U.; Adam, R. J. Heterocycl.
Chem. 1988, 25, 1–8; (b) Gribble, G. W. J. Chem. Soc.,
Perkin Trans. 1, 2000, 1045–1075, and references cited
therein.
6
,9
3
. For recent works in the area, see: (a) Arcadi, A.; Cacchi,
S.; Fabrizi, G.; Marinelli, F. Synlett, 2000, 647–649; (b)
Dai, W.-M.; Guo, D.-S.; Sun, L.-P. Tetrahedron Lett.
2001, 42, 5275–5278; (c) Koradin, C.; Dohle, W.; Rodri-
guz, A. L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59,
1571–1587; (d) Hiroya, K.; Itoh, S.; Ozawa, M.; Kana-
mori, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43,
reaction conditions when Et O was used as a solvent
2
because of the poor solubility of substrates. Both LDA
and n-BuLi could be used as a base. The tosyl group
of 3 can be easily removed with 10% aqueous sodium
hydroxide in refluxing ethanol to give 3-substituted
1
277–1280; (e) Takeda, A.; Kamijo, S.; Yamamoto, Y.
J. Am. Chem. Soc. 2000, 122, 5662–5663; (f) Yasuhara, A.;
Takeda, Y.; Suzuki, N.; Sakamoto, T. Chem. Pharm. Bull.
1
0
indoles.
2
002, 50, 235–238; (g) Cacchi, S.; Fabrizi, G.; Lamba, D.;
Marinelli, F.; Parisi, L. M. Synthesis, 2003, 728–734; (h)
Kamijo, S.; Sasaki, Y.; Yamamoto, Y. Tetrahedron Lett.
In conclusion, the present method using TMSCHN2
makes possible the efficient conversion of N-tosyl-o-
1
2
004, 45, 35–38; (i) Olivi, N.; Spruyt, P.; Peyrat, J.-F.;
1
acylanilines into 3-substituted indoles and will provide
added flexibility in indole synthesis.
Alami, M.; Brion, J.-D. Tetrahedron Lett. 2004, 45,
2607–2610.
. (a) Hari, Y.; Tanaka, S.; Takuma, Y.; Aoyama, T. Synlett,
4
2
003, 2151–2153; (b) Miyabe, R.; Shioiri, T.; Aoyama, T.
Heterocycles 2002, 57, 1313–1318; (c) Sakai, A.; Aoyama,
T.; Shioiri, T. Tetrahedron Lett. 2000, 41, 9455–9458; For
a review: (d) Shioiri, T.; Aoyama, T. In Science of
Synthesis; Fleming, Ed.; Georg Thieme: Suttgart, 2002;
Vol. 4, pp 569–577.
Acknowledgements
This work was financially supported by a Grant-in-Aid
for Scientific Research (KAKENHI) (to T.A.).

T. Miyagi et al. / Tetrahedron Letters 45 (2004) 6303–6305
6305
5
. Yagi, T.; Aoyama, T.; Shioiri, T. Synlett, 1997,
063–1064.
. Alkyl aryl ketones and aldehydes smoothly react with
TMSC(Li)N to give the corresponding homologous
alkynes via the alkylidene carbene intermediates in good
to moderate yields, see: (a) Miwa, K.; Aoyama, T.; Shioiri,
T. Synlett, 1994, 107–108; (b) Miwa, K.; Aoyama, T.;
Shioiri, T. Synlett, 1994, 461–462.
7.00 (1H, m), 7.18–7.27 (4H, m), 7.56 (1H, d, J=8Hz),
7.65 (2H, d, J=8Hz). HRMS (EI): Calcd for
C H NO S, 327.1293. Found, 327.1287. 3h: H (CDCl ):
1
1
6
1
9
21
2
3
2
d 2.34 (3H, s), 7.22 (2H, d, J=8Hz), 7.29 (1H, d,
J=8Hz), 7.33–7.39 (2H, m), 7.43–7.49 (2H, m), 7.60 (2H,
d, J=8Hz), 7.69 (1H, s), 7.76–7.82 (3H, m), 8.05 (1H, d,
J=8Hz). HRMS (EI): Calcd for C H NO S, 347.0980.
2
1
17
2
1
3
Found, 347.0981. 3i: H (CDCl ): d 2.35 (3H, s), 7.23 (2H,
7
. Representative procedure (entry 1 in Table 1): To a
solution of LDA, prepared from diisopropylamine
d, J=8Hz), 7.30–7.40 (2H, m), 7.43–7.49 (2H, m), 7.53–
7.57 (2H, m), 7.69–7.72 (2H, m), 7.78 (2H, d, J=8Hz),
(
0
111mg, 1.1mmol) and n-BuLi (1.59M in hexane,
.69mL, 1.1mmol) in THF (5mL), was added dropwise
TMSCHN (1.61M in hexane, 0.37mL, 0.6mmol) at
À78ꢁC under N , and the mixture was stirred at 78ꢁC for
7.97 (1H, d, J=9Hz). HRMS (EI): Calcd for
S,381.0590. Found, 381.0617. 3j:
1
H
C
(CDCl
21
H
16ClNO
2
2
3
): d 2.32 (3H, s), 6.50–6.51 (1H, m), 6.65 (1H, d,
J=3Hz), 7.21 (2H, d, J=8Hz), 7.28–7.39 (2H, m), 7.48
2
2
(
0min.
A solution of o-(N-tosylamino)acetophenone
(1H, s), 7.79 (2H, d, J=8Hz), 7.86–7.88 (2H, m), 8.03
(1H, d, J=8Hz). HRMS (EI): Calcd for C19
145mg, 0.5mmol) in THF (5mL) was then added to the
H
15NO
3
S,
1
above mixture at À78ꢁC. The mixture was stirred at
À78ꢁC for 1h and then at room temperature for 1h. After
the reaction was quenched with water, the mixture was
extracted with AcOEt. The organic extracts were washed
with H O and saturated brine, dried over MgSO , and
concentrated in vacuo. The residue was purified by silica
gel column chromatography (Fuji Silysia, PQS 60B,
hexane–AcOEt=15:1) to give 3b (116mg, 81%) and 4b
337.0773. Found, 337.0774. 4j: H (CDCl ): d 2.35 (3H, s),
3
6.47 (1H, s), 6.67 (1H, d, J=3Hz), 7.04–7.09 (1H, m),
7.17 (2H, d, J=8Hz), 7.28–7.36 (2H, m), 7.48 (1H, s),
7.62 (1H, d, J=8Hz), 7.67 (2H, d, J=8Hz). HRMS (EI):
Calcd for C H NO S, 337.0773. Found, 337.0775. 3k:
2
4
19 15
3
1
H (CDCl ): d 2.32 (3H, s), 7.07 (1H, t, J=8Hz), 7.14
3
(2H, d, J=8Hz), 7.29–7.35 (2H, m), 7.41–7.48 (2H, m),
7.60–7.76 (5H, m), 8.65 (1H, d, J=4Hz). HRMS (EI):
Calcd for C H N O S, 348.0932. Found, 348.0926. 3l:
1
2
(
1
12mg, 8%). 3b: mp 108–109ꢁC (AcOEt–hexane) (lit. mp
2
0
16
2
2
1
1
04–106ꢁC). 4b: H (CDCl
.94–7.00 (1H, m), 7.17–7.24 (4H, m), 7.53 (1H, d,
3
): d 2.06 (3H, s), 2.37 (3H, s),
3
Ref. 15. 3m: H (CDCl ): d 2.29 (3H, s), 6.76 (1H, d,
6
J=8Hz), 7.67 (2H, d, J=8Hz). HRMS (EI): Calcd for
C H NO S, 285.0823. Found, 285.0816.
1
J=4Hz), 7.17 (2H, d, J=8Hz), 7.39–7.48 (2H, m), 7.67
(1H, d, J=4Hz), 7.77 (2H, d, J=8Hz), 7.88 (1H, d,
J=7Hz), 7.97–7.99 (2H, m), 8.44 (1H, s). HRMS (EI):
6
15
2
1
8
. 3c: Ref. 13. 4c: H (CDCl
.02 (1H, br s), 7.06–7.11 (1H, m), 7.27–7.33 (1H, m), 7.40
1H, d, J=8Hz), 7.56 (1H, d, J=8Hz). HRMS (EI): Calcd
3
): d 2.13 (3H, s), 3.00 (3H, s),
2
Calcd for C19H15NO S, 321.0823. Found, 321.0822.
7
(
9. Gallo, M. M.; Hamilton, T. P.; Schaefer, H. F., III. J. Am.
Chem. Soc. 1990, 112, 8714–8719.
for C H NO S, 209.0510. Found, 209.0513. 3d: Ref. 14.
2
10. For example, a mixture of compound 3b (143mg,
0.50mmol), 10% aqueous NaOH (4mL), and EtOH
(12mL) was refluxed for 24h to give 3a (99%), which
was identified by comparison of their spectroscopic data
with the authentic sample.
1
0
11
1
d: H (CDCl
4
m), 7.22–7.27 (1H, m), 7.32 (1H, d, J=8Hz), 8.10 (1H, d,
3
): d 1.54 (9H, s), 2.15 (3H, s), 6.89–6.95 (1H,
J=8Hz). HRMS (EI): Calcd for C H NO , 231.1259.
2
1
4
17
1
3
Found, 231.1259. 4e: H (CDCl ): d 2.16 (3H, s), 2.23 (3H,
s), 6.97–7,03 (1H, m), 7.25–7.31 (1H, m), 7.35 (1H, d,
J=8Hz), 7.91 (1H, br s), 8.36 (1H, d, J=8Hz). HRMS
11. The starting N-tosyl-o-acylanilines (1f, 1i, and 1j) were
easily prepared from o-(N-tosylamino)benzaldehyde by
treatment with the corresponding organolithium reagents,
followed by oxidation of the resulting benzylalcohols with
(
EI): Calcd for C H NO, 173.0841. Found, 173.085. 3f:
11 11
1
H (CDCl
1H, s), 7.21 (2H, d, J=8Hz), 7.49 (1H, s), 7.70 (2H, d,
J=8Hz). HRMS (EI): Calcd for C17 S, 329.0722.
Found, 329.0716. 3g: H (CDCl ): d 0.93 (3H, t, J=7Hz),
3
): d 2.15 (3H, s), 2.34 (3H, s), 5.96 (2H, s), 6.78
1
6
(
2
MnO (CMD, chemical manganese dioxide).
H15NO
4
12. Kikugawa, Y. Synthesis 1981, 460–461.
13. Wenkert, E.; Moeller, P. D. R.; Piettre, S. R.; McPhail, A.
T. J. Org. Chem. 1987, 52, 3404–3409.
14. Liu, R.; Zhang, P.; Gan, T.; Cook, J. M. J. Org. Chem.
1997, 62, 7447–7456.
15. Illi, V. O. Synthesis 1979, 136.
1
3
1
.30–1.44 (2H, m), 1.60–1.71 (2H, m), 2.32 (3H, s), 2.64
2H, t, J=8Hz), 7.18 (2H, d, J=8Hz), 7.21–7.29 (3H, m),
.46 (1H, d, J=7Hz), 7.72 (2H, d, J=8Hz), 7.97 (1H, d,
J=8Hz). HRMS (EI): Calcd for C H NO S, 327.1293.
(
7
1
9
21
2
1
Found, 327.1292. 4g: H (CDCl
1
3
): d 0.93 (3H, t, J=7Hz),
.37–1.63 (4H, m), 2.36 (3H, s), 2.39–2.44 (2H, m), 6.94–
16. Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.;
Anzai, M.; Ando, A.; Shioiri, T. Synlett 1998, 35–36.