Efficient synthesis of o-alkynyl-N-pivaloylanilines from o-acyl-N-pivaloylanilines and lithium trimethylsilyldiazomethane

Article abstract of DOI:10.1016/j.tetlet.2005.12.051

Reaction of o-acyl-N-pivaloylanilines with lithium trimethylsilyldiazomethane efficiently gave the corresponding o-alkynyl-N-pivaloylanilines via alkylidenecarbene intermediates.

Full text of DOI:10.1016/j.tetlet.2005.12.051

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1137–1139
Efficient synthesis of o-alkynyl-N-pivaloylanilines from
o-acyl-N-pivaloylanilines and lithium trimethylsilyldiazomethane
Yoshiyuki Hari, Tomoki Kanie and Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 17 November 2005; revised 30 November 2005; accepted 2 December 2005
Available online 27 December 2005
Abstract—Reaction of o-acyl-N-pivaloylanilines with lithium trimethylsilyldiazomethane efficiently gave the corresponding o-alkyn-
yl-N-pivaloylanilines via alkylidenecarbene intermediates.
Ó 2005 Elsevier Ltd. All rights reserved.
o-Alkynylanilines serve as an important precursor for
the construction of heterocyclic structures, for example,
indole,1,2 quinoline3 and cinnoline skeletons.4 Although
there are a few synthetic methods of o-alkynylanilines,5,6
the practical method would be limited to Sonogashira
coupling reaction between o-iodoanilines and terminal
alkynes.5 Therefore, development of additional syn-
thetic approaches to o-alkynylanilines would be still re-
quired in the field of heterocyclic chemistry.
products) were formed as by-products. On the other
hand, interestingly, under similar conditions, when
o-acetylacetanilide was used as a substrate, the major
product was the rearrangement product, o-(1-propy-
nyl)acetanilide (46%), though the desired indole (21%)
was also obtained.9 These results indicate that the reac-
tion pathway was significantly affected by a substituent
on an amino group. Therefore, we reinvestigated the
reaction of N-acyl-o-acylanilines with TMSC(Li)N2 in
order to yield N-acyl-o-alkynylanilines selectively. This
letter describes our results.
Recently, we have revealed that the lithium salt of tri-
methylsilyldiazomethane (TMSC(Li)N2), a quite useful
reagent for generating alkylidenecarbenes from carbonyl
compounds,7,8 smoothly reacts with o-acyl-N-tosylanil-
ines to selectively give 3-substituted N-tosylindoles (the
intramolecular N–Li insertion products) via alkylidene-
carbene intermediates (Scheme 1).9 In some cases, small
amounts of o-alkynyl-N-tosylanilins (the rearrangement
First, screening of N-substituents was carried out as
shown in Table 1.10,11 As standard reaction conditions,
we employed TMSCHN2 (1.2 equiv) and n-BuLi
(2.2 equiv), in which the latter was used as a base for
the preparation of TMSC(Li)N2 and for deprotonation
of the N–H moiety of a substrate. As expected, reaction
R1
R2
R3
R1
O
N
Ts
Me3SiCHN2 (1.2 eq.)
R2
R3
R2
R3
R1
LDA (2.2 eq.)
C
Li
THF
NHTs
R1
N
R2
R3
Ts
NHTs
Scheme 1. Reaction of o-alkynyl-N-tosylanilines with TMSC(Li)N2.
Keywords: o-Acylanilines; Alkylidenecarbenes; o-Alkynylanilines; Lithium trimethylsilyldiazomethane; Trimethylsilyldiazomethane.
*
Corresponding author. Tel./fax: +81 52 836 3439; e-mail: aoyama@phar.nagoya-cu.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.051

1138
Y. Hari et al. / Tetrahedron Letters 47 (2006) 1137–1139
Table 1. Reaction of o-acetyl-N-acylanilines
O
Me
+
Me
Me3SiCHN2 (1.2 eq.)
n-BuLi (2.2 eq.)
Me
Solvent, -78 C, 2-3 h
˚
N
R
NHR
NHR
1
2
3
Entry
R
Solvent
Yield (%)b
1
2
Bz (a)
THF
THF
THF
THF
THF
Et2O
62 (2a)+4 (3a)+3c
56 (2b)
p-MeOPhCO (b)
o-MePhCO (c)
Piv (d)
Piv (d)
Piv (d)
3c
4
38 (2c)+9c
74 (2d)+8 (3d)
69 (2d)+10 (3d)
61 (2d)+16 (3d)
5a
6
a n-BuLi (1.2 equiv) was used.
b Isolated yield.
c Yield of 3-methylindole.
a
Table 2. Reaction of o-acyl-N-pivaloylanilines 1 with TMSC(Li)N2
of TMSC(Li)N2 with 1a–d bearing a benzoyl, p-meth-
oxybenzoyl, o-methylbezoyl or pivaroyl group as N-sub-
stituents in THF smoothly proceeded and the desired
o-(1-propynyl)anilides 2a–d were preferentially obtained
in all cases (entries 1–4). Among them, 1d bearing a
bulky pivaroyl group gave the best result (entry 4).
Interestingly, in this reaction, the use of a reduced
amount of n-BuLi also afforded 2d in good yield (entry
5). This result indicates that there might be equilibrium
between TMSC(Li)N2 and the N–Li form of the amide.
Very recently, it has been reported that the use of Et2O,
having lower ET-value12 than that of THF, as solvent
increases the ratio of the alkyne to the indole in the reac-
tion of TMSC(Li)N2 with o-aminobenzophenone.13
However, reaction with 1d in Et2O led to a less effective
result (entry 6).
O
R1
Me3SiCHN2 (1.2 eq.)
n-BuLi (2.2 eq.)
R2
R3
R2
R3
R1
THF, -78 C, 2-3 h
˚
NHPiv
NHPiv
1
2
Entry Substrate R1
R2
R3
Yield
(%)
1
2
3
4
5
6
7
8
1e
1f
n-Bu
i-Pr
H
H
H
H
H
H
H
H
H
H
H
H
H
82 (2e)
76 (2f)
50 (2g)
50 (2h)
58 (2i)b
84 (2j)
63 (2k)b
56 (2d)c
51 (2l)d
64 (2m)
82 (2n)
1g
1h
1i
Ph
2-Pyridyl
2-Furyl
Me
Me
Me
H
i-Pr
i-Pr
1j
1k
1l
–OCH2O–
I
I
Me
Me
H
H
H
H
9
1l
Under the most efficient reaction conditions as shown in
entry 4 of Table 1, generality of the reaction was inves-
tigated (Table 2).11 Reaction of TMSC(Li)N2 with 1e
and 1f bearing alkanoyl groups, such as pentanoyl and
isobutyryl groups, as an acyl moiety, successfully affor-
ded the desired o-alkynyl-N-pivaloylanilines 2e and 2f
as the sole isolable product in 82% and 76% yields,
respectively (entries 1 and 2). Similarly, the formyl deriv-
ative 1g gave 2g in 50% yield (entry 3). Substrates 1h–j
bearing aroyl groups also underwent the reaction with
TMSC(Li)N2 giving the corresponding 2h–j (entries 4–
6). Especially, 2-furyl derivative 1j gave the high yield
(84%). Although reaction of the p-iodoanilide 1l also
proceeded, the product was the deiodinated alkynylani-
lide 2d, not the p-iodo derivative 2l, resulting from
iodine–lithium exchange reaction (entry 8). However, the
use of the reduced amount of n-BuLi described above
led to a significant improvement of the reaction and
the desired 2l was obtained in 51% yield without forma-
tion of 2d (entry 9). This reaction will be valuable since
the synthesis of (o-alkynyl)iodoanilines by Sonogashira
reaction of diiodoanilines with terminal alkynes is usu-
ally difficult. Other substrates 1m–o also gave the corre-
sponding alkynes 2m–o in 63–82% yields (entries 10–12).
10
11
12
1m
1n
1o
–CH@CH–CH@CH– 63 (2o)
a In all cases, 3-substituted indole was not obtained.
b Substrates 1i and 1k were recovered in 6% and 7% yields,
respectively.
c The desired iodo derivative 2l was not obtained.
d n-BuLi (1.2 equiv) was used.
o-alkynyl-N-pivaloylanilines. This method would pro-
vide a new and efficient synthetic access to o-alkynyl-
anilines, which are useful precursors for construction
of heterocyclic skeletons. Moreover, this result and our
previous report9 are noteworthy in demonstrating that
the difference between tosyl and pivaloyl groups as
N-substituents of o-acylanilines in reaction with
TMSC(Li)N2 would bring about divergent reaction of
their alkylidenecarbene intermediates, namely, N–Li
insertion reaction and rearrangement reaction.
Acknowledgements
In conclusion, we have found that o-acyl-N-pivaloylan-
ilines reacted with TMSC(Li)N2 to selectively give
This work was financially supported by a Grant-in-Aid
for Scientific Research (KAKENHI) (to T.A.), and a

Y. Hari et al. / Tetrahedron Letters 47 (2006) 1137–1139
1139
0.69 ml, 1.1 mmol) was added dropwise at À78 °C under
argon atmosphere and the mixture was stirred at À78 °C
for 20 min. A solution of 1d (108 mg, 0.5 mmol) in THF
(3 ml) was then added to the above mixture at À78 °C.
The whole mixture was stirred at À78 °C for 2 h. After
addition of water, the mixture was extracted with AcOEt.
The organic extracts were washed with water and brine,
dried over NaSO4 and concentrated in vacuo. The residue
was purified by column chromatography on silica gel using
hexane–AcOEt (20:1) as eluent to give N-pivaloyl-o-(1-
propynyl)aniline 2d (80 mg, 74%) and 3-methyl-N-piva-
loylindole 3d (8.6 mg, 8%).
Grant-in-Aid for The Japan Securities Scholarship
Foundation (to Y.H.).
References and notes
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7.92 (2H, dd, J = 1.0 and 8.0 Hz), 8.57 (1H, d,
J = 8.0 Hz), 8.84 (1H, br s). Compound 2b, 1H NMR
(CDCl3) d: 2.19 (3H, s), 3.88 (3H, s), 6.98–7.06 (3H, m),
7.31–7.41 (2H, m), 7.88 (2H, d, J = 8.5 Hz), 8.55 (1H, d,
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J = 7.5 Hz), 7.26–7.36 (2H, m), 8.40–8.43 (2H, m). Com-
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pound 2e, H NMR (CDCl3) d: 0.96 (3H, t, J = 7.0 Hz),
1.35 (9H, s), 1.46–1.54 (2H, m), 1.62 (2H, q, J = 7.0 Hz),
2.51 (2H, t, J = 7.0 Hz), 6.99 (1H, t, J = 8.0 Hz), 7.27 (1H,
t, J = 8.0 Hz), 7.35 (1H, d, J = 8.0 Hz), 8.38–8.43 (2H, m).
Compound 2f, 1H NMR (CDCl3) d: 1.50 (6H, d,
J = 7.0 Hz), 1.53 (9H, s), 3.07 (1H, sept, J = 7.0 Hz),
7.17 (1H, t, J = 7.5 Hz), 7.42–7.50 (1H, m), 7.54 (1H, d,
J = 7.5 Hz), 8.57 (1H, br s), 8.61 (1H, d, J = 8.0 Hz).
Compound 2g, 1H NMR (CDCl3) d: 1.34 (9H, s), 3.54
(1H, s), 7.03 (1H, t, J = 8.0 Hz), 7.36 (1H, t, J = 8.0 Hz),
7.45 (1H, d, J = 8.0 Hz), 8.35 (1H, br s), 8.45 (1H, d,
J = 8.0 Hz). Compound 2h, 1H NMR (CDCl3) d: 1.36
(9H, s), 7.06 (1H, t, J = 8.0 Hz), 7.34 (1H, d, J = 8.0 Hz),
7.38–7.40 (3H, m), 7.49–7.55 (3H, m), 8.42 (1H, br s), 8.48
(1H, d, J = 8.0 Hz). Compound 2i, 1H NMR (CDCl3)
d: 1.37 (9H, s), 7.06 (1H, t, J = 7.0 Hz), 7.20–7.29 (1H, m),
7.38 (1H, t, J = 8.0 Hz), 7.48–7.55 (2H, m), 7.71 (1H,
t, J = 8.0 Hz), 8.47–8.50 (2H, m), 8.64 (1H, br s).
Compound 2j, 1H NMR (CDCl3) d: 1.35 (9H, s), 6.44
(1H, dd, J = 2.0 and 3.5 Hz), 6.68 (1H, d, J = 3.5 Hz),
7.03 (1H, t, J = 8.0 Hz), 7.34 (1H, t, J = 8.0 Hz), 7.44–7.46
(2H, m), 8.34 (1H, br s), 8.45 (1H, d, J = 8.0 Hz).
Compound 2k, 1H NMR (CDCl3) d: 1.25 (9H, s), 2.05
(3H, s), 5.85 (2H, s), 6.69 (1H, s), 7.94 (1H, s), 8.25 (1H, br
3. (a) Li, H.; Yang, H.; Petersen, J. L.; Wang, K. K. J. Org.
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1
s). Compound 2l, H NMR (CDCl3) d: 1.22 (9H, s), 2.04
(3H, s), 7.45 (1H, d, J = 9.0 Hz), 7.54 (1H, s), 8.08 (1H, d,
J = 9.0 Hz), 8.22 (1H, br s). Compound 2m, 1H NMR
(CDCl3) d: 1.27 (9H, s), 2.19 (3H, s), 3.43 (1H, s), 7.08
(1H, d, J = 8.5 Hz), 7.17 (1H, s), 8.17 (1H, br s), 8.23 (1H,
1
d, J = 8.5 Hz). Compound 2n, H NMR (CDCl3) d: 1.22
(6H, d, J = 7.0 Hz), 1.25 (9H, s), 2.17 (3H, s), 2.77 (1H,
sept, J = 7.0 Hz), 6.98 (1H, d, J = 8.0 Hz), 7.08 (1H, s),
1
8.19–8.23 (2H, m). Compound 2o, H NMR (CDCl3) d:
1.26 (6H, d, J = 7.0 Hz), 1.31 (9H, s), 2.82 (1H, sept,
J = 7.0 Hz), 7.25 (1H, t, J = 7.0 and 8.0 Hz), 7.33 (1H, t,
J = 7.0 and 8.0 Hz), 7.57 (1H, d, J = 8.0 Hz), 7.68 (1H, d,
J = 8.0 Hz), 7.80 (1H, s), 8.44 (1H, br s), 8.85 (1H, s).
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10. Typical procedure (entry 4 in Table 1). To a stirred
solution of TMSCHN2 (1.7 M in hexane, 0.37 ml,
0.6 mmol) in THF (3 ml), n-BuLi (1.6 M in hexane,