Cycloaddition reactions of trimethylsilylketene with 8-azaheptafulvenes and 6-amino-1-azafulvenes

Article abstract of DOI:10.3987/com-00-s(i)18

Trimethylsilylketene smoothly reacts with 8-azaheptafulvenes to give 3,3a-dihydro-3-trimethylsilyl-1-azaazulen-2(1H)-ones, the [8+2] cycloadducts, in excellent yields. Furthermore, trimethylsilylketene also undergoes the [6+2] cycloaddition reaction with 6-amino-1-azafulvenes to afford 1H-pyrrolizin-3(2H)-ones.

Full text of DOI:10.3987/com-00-s(i)18

HETEROCYCLES, Vol. 54, No. 1, 2001, pp. 209 - 215, Received, 19th April, 2000
CYCLOADDITION REACTIONS OF TRIMETHYLSILYL-
KETENE WITH 8-AZAHEPTAFULVENES AND 6-
†
AMINO-1-AZAFULVENES
*
Kiyo Takaoka, Toyohiko Aoyama, and Takayuki Shioiri
*
Faculty of Pharmaceutical Sciences, Nagoya City University
Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Abstract- Trimethylsilylketene smoothly reacts with 8-azaheptafulvenes to give
3,3a-dihydro-3-trimethylsilyl-1-azaazulen-2(1H)-ones, the [8+2] cycloadducts, in
excellent yields. Furthermore, trimethylsilylketene also undergoes the [6+2]
cycloaddition reaction with 6-amino-1-azafulvenes to afford 1H-pyrrolizin-3(2H)-
ones.
1
2
Heterocumulenes have been reported to react with 8-azaheptafulvenes and 6-amino-1-azafulvenes to
give the corresponding [8+2]- and [6+2] cycloadducts, respectively. For example, ketenes such as
phenylketene, diphenylketene, and chloroketene react with 8-azaheptafulvenes to give 3,3a-dihydro-1-
1a,e
azaazulen-2(1H)-ones.
Reaction of ketenes with 6-amino-1-azafulvenes also proceeds to afford 2,3-
2b
dihydro-1H-pyrrolizin-3-ones.
To our knowledge, however, there is no report dealing with reaction
of silylketenes, an electron-rich ketene, with azafulvene derivatives.
We have already revealed that silylketenes can be effectively used as heterodienophiles for the [4+2]
3
cycloaddition reaction with electron-rich 1,3-dienes or o-quinodimethanes and as dienophiles for the
4
[4+2] cycloaddition reaction with acyl isocyanates.
5
Our continued interest in the reactivities of
silylketenes has led us to investigate the reaction of trimethylsilylketene (TMSCH=C=O) with 8-
azaheptafulvenes and 6-amino-1-azafulvenes.
We have found that TMSCH=C=O smoothly reacts with 8-(p-methylphenyl)-8-azaheptafulvene (1a) in
refluxing chloroform to give 3,3a-dihydro-3-trimethylsilyl-1-azaazulen-2(1H)-one (2a), the [8+2]
cycloadduct, in high yield together with a small amount of the desilylated product (3a), as shown in Table
(Run 1). The stereochemistry of C-3 and C-3a positions of 2a was determined to be trans by Noe
1a
1
experiments and coupling constants (J = 4 Hz) between C-3 and C-3a protons on its H NMR spectra.
Under similar reaction conditions, 8-(p-bromophenyl)- (1b) and 8-(p-methoxyphenyl)-8-azaheptafulvene
(1c) also gave the corresponding 1-azaazulen-2(1H)-ones (2b,c) in excellent yields, respectively (Runs
4,5). Both benzene and ethyl acetate can be used as a reaction solvent (Runs 2,3). In contrast to the
6
results with 8-azaheptafulvenes, the reaction of TMSCH=C=O with tropones was completely inactive.
†
Dedicated to Prof. Shô Itô on the occasion of his 77th birthday.

Table. Reaction of Trimethylsilylketene with 8-Azaheptafulvenes (1)
Ar
N
Ar
N
Me SiCH=C=O
3
Ar
O
O
+
N
H
SiMe
3
3
1
2
Yield(%)
Ar
3
Run
Solvent
2
CHCl
p-MeC H (a)
6
3
1
2
3
4
4
86
86
85
85
10
6
p-MeC H (a)
6
4
benzene
AcOEt
p-MeC H (a)
4
6
8
p-BrC H (b)
6
CHCl
4
3
5
p-MeOC H (c)
6
CHCl
3
5
4
72
7
The trimethylsilyl group of 2a was easily removed by treatment with tetrabutylammonium fluoride (TBAF)
7
to give the compound (3a) which was dehydrogenated with chemical manganese dioxide (CMD) to
afford 1-(p-methylphenyl)-1-azaazulen-2(1H)-one (4), as shown in Scheme 1.
Ar
Ar
Ar
N
N
N
TBAF
CMD
O
O
O
THF
73%
benzene
88%
H
SiMe
3
3a
4
Ar = p-MeC H
6
2a
4
Scheme 1
The mechanism of the formation of 2 may be as shown in Scheme 2. In analogy with the reaction of
1e
ketenes with 1, nucleophilic attack of the nitrogen atom of 1 to the central carbon of TMSCH=C=O
gives the betaine intermediate (5) which cyclizes to give the [8+2] cycloadduct (2).
Ar
Ar
N
O
C
C
-
N
Ar
O
+
O
N
H
SiMe
H
SiMe
H
SiMe
3
3
3
1
2
5
Scheme 2

Tropone tosylhydrazone (1d) has also been reported to undergo [8+2] cycloaddition reaction with
1e,8
ketenes,
but the reaction with TMSCH=C=O afforded a mixture of N-trimethylsilylacetylhydrazone
(6) and its desilylated product (7), and no cycloadduct was obtained (Scheme 3).
Me SiCH=C=O
3
NNTs
+
3
NNTs
COCH
NNHTs
CHCl
3
COCH SiMe
2
3
1d
6
7
14%
27%
Scheme 3
Next, the reaction of TMSCH=C=O with 6-amino-1-azafulvenes was investigated. TMSCH=C=O also
reacted with 6-pyrrolidino-1-azafulvene (9) generated by thermal decomposition of dipyrrolo[1,2-a:1’,2’-
d]pyrazine (8) to give 1-pyrrolidino-1H-pyrrolizin-3(2H)-one (11) in excellent yield which was formed
by desilylation of the first produced [6+2] cycloadduct (10) with water (Scheme 4). Although the
reaction of ketenes with 1-azafulvenes giving 1H-pyrrolizin-3(2H)-ones has been reported, the yields are
2b
low to moderate.
Me SiCH=C=O
3
N
N
N
N
Δ
N
CH N
N
CHCl
3
N
O
SiMe
3
9
10
8
N
H O
2
N
- Me SiOH
87%
3
Scheme 4
O
11
In conclusion, trimethylsilylketene (TMSCH=C=O) smoothly reacts with 8-azaheptafulvenes and 6-amino-
1-azafulvenes to give the corresponding 3,3a-dihydro-1-azaazulen-2(1H)-one and 2,3-dihydro-1H-
pyrrolizin-3-ones in excellent yields, respectively. The synthetic reactions developed here will open a
new possibility for the use of trimethylsilylketene as a building block for heterocycles.
EXPERIMENTAL
General : Melting points were determined on a YAMATO MP-21 apparatus and a YAMATO micro melting
point apparatus (hot plate). All melting points were uncorrected. IR spectra were measured on a
SHIMADZU FTIR-8100 spectrophotometer. NMR spectra were measured on a JEOL EX-270
spectrometer referred to tetramethylsilane (TMS) or CHCl as an internal standard in CDCl . MS spectra
3
3

were obtained on a JEOL JMS-SX 102A spectrometer. Flash column chromatography was performed
on silica gel (Silica Gel 60 particle size 40-63 µm, MERCK).
Preparation of 1-azaazulen-2(1H)-ones (2 and 3)
9
General procedure : A mixture of 1 (0.5 mmol) and TMSCH=C=O in CHCl (5 mL) was stirred at
3
reflux for 12 h under argon. After concentration in vacuo, the residue was purified by flash column
chromatography on silica gel to give 2 and 3.
3,3a-Dihydro-1-(p-methylphenyl)-3-trimethylsilyl-1-azaazulen-2(1H)-one (2a)
dihydro-1-(p-methylphenyl)-1-azaazulen-2(1H)-one (3a)
and
3,3a-
Prepared from 1a (98 mg, 0.5 mmol) and TMSCH=C=O (77 mg, 0.68 mmol). Pale yellow crystals 2a
(133 mg, 86%) and pale yellow crystals 3a (12 mg, 10%), purified by flash column chromatography on
silica gel (hexane : AcOEt = 5:1 to 3:1).
nujol
-1
cm : 1705, 1634, 1250, 860, 843.
1
Compound (2a) : mp 128-130℃ (hexane). IR ν
H
max
NMR (CDCl ) δ : 0.20 (9H, s), 2.37 (3H, s), 2.39 (1H, d, J = 3.96 Hz), 2.77-2.79 (1H, m), 5.09 (1H,
3
dd, J = 3.96, 9.23 Hz), 5.34 (1H, d, J = 5.94 Hz), 6.12-6.26 (2H, m), 6.39-6.45 (1H, m), 7.08 (2H, d,
J = 8.25 Hz), 7.24 (2H, d, J = 8.25 Hz). Anal. Calcd for C H NOSi : C ; 73.74, H ; 7.49, N ;
19 23
4.53. Found : C ; 73.58, H ; 7.48, N ; 4.42.
nujol
-1
cm : 1723, 1632, 1516, 1370, 1252.
1
Compound (3a) : mp 134-136℃. IR ν
max
(CDCl ) δ : 2.38 (1H, s), 2.77 (1H, dd, J = 4.29, 17.82 Hz), 3.00-3.04 (1H, m), 3.23 (1H, dd, J =
H NMR
3
10.55, 17.82 Hz), 5.18 (1H, dd, J = 3.63, 8.91 Hz), 5.35 (1H, d, J = 5.61 Hz), 6.15-6.27 (2H, m),
6.35-6.42 (1H, m), 7.13 (2H, d, J = 8.25 Hz), 7.27 (2H, d, J = 8.25 Hz). Anal. Calcd for
C H NO : C ; 80.98, H ; 6.37, N ; 5.93. Found : C ; 81.21, H ; 6.43, N ; 5.93.
16 15
3,3a-Dihydro-1-(p-bromophenyl)-3-trimethylsilyl-1-azaazulen-2(1H)-one (2b)
dihydro-1-(p-bromophenyl)-1-azaazulen-2(1H)-one (3b)
and
3,3a-
Prepared from 1b (130 mg, 0.5 mmol) and TMSCH=C=O (83 mg, 0.73 mmol). Orange crystals 2b
(158 mg, 85%) and orange crystals 3b (8 mg, 5%), purified by flash column chromatography on silica gel
(hexane : AcOEt = 5:1 to 3:1).
nujol
-1
cm : 1705, 1628, 1611, 1538, 1250,
Compound (2b) : mp 118 - 120℃ (hexane). IR ν
1
max
H NMR (CDCl ) δ : 0.20 (9H, s), 2.40 (1H, d, J = 3.96 Hz), 2.75-2.78 (1H, m), 5.09 (1H, dd,
843.
3
J = 3.96, 9.24 Hz), 5.39 (1H, d, J = 5.61 Hz), 6.13-6.18 (1H, m), 6.23-6.29 (1H, m), 6.40-6.46 (1H,
m), 7.11 (2H, d, J = 8.58 Hz), 7.57 (2H, d, J = 8.58 Hz). Anal. Calcd for C H NOBrSi : C ;
18 20
53.75, H ; 5.38, N ; 3.74. Found : C ; 53.73, H ; 5.46, N ; 3.48.
nujol -1
cm : 1717, 1634, 1487, 1252, 1067.
1
Compound (3b) : mp 137 - 140℃. IR ν
max
(CDCl ) δ : 2.78 (1H, dd, J = 4.63, 18.16 Hz), 2.99-3.03 (1H, m), 3.23 (1H, dd, J = 10.89, 18.16
H NMR
3
Hz), 5.18 (1H, dd, J = 3.96, 9.24 Hz), 5.38 (1H, d, J = 6.27 Hz), 6.17-6.27 (2H, m), 6.29-6.44 (1H,
79
m), 7.16 (2H, d, J = 8.58 Hz), 7.60 (2H, d, J = 8.58 Hz). HRMS Calcd for C H NO
15 12
Br :
81
301.0103. Found : 301.0080. HRMS Calcd for C H NO Br : 303.0083. Found : 303.0082.
15 12

3,3a-Dihydro-1-(p-methoxyphenyl)-3-trimethylsilyl-1-azaazulen-2(1H)-one
3,3a-dihydro-1-(p-methoxyphenyl)-1-azaazulen-2(1H)-one (3c)
(2c)
and
Prepared from crude 1c (87 mg, 0.41 mmol) and TMSCH=C=O (70 mg, 0.61 mmol). Apale yellow oil
2c (96 mg, 72%) and pale orange crystals 3c (7 mg, 7%), purified by flash column chromatography on
silica gel (hexane : AcOEt = 5:1 to 3:1).
neat -1
cm :1713, 1632, 1514, 1248, 848.
1
Compound (2c) : IR ν
max
H NMR (CDCl ) δ : 0.20 (9H,
3
s), 2.39 (1H, d, J = 3.96 Hz), 2.77-2.79 (1H, m), 3.82 (3H, s), 5.09 (1H, dd, J = 3.96, 9.24 Hz), 5.31
(1H, d, J = 6.59 Hz), 6.11-6.26 (2H, m), 6.39-6.45 (1H, m), 6.96 (2H, d, J = 8.91 Hz), 7.12 (2H, d, J
= 8.91 Hz). HRMS Calcd for C H NO Si : 325.1499. Found : 325.1498.
19 23
nujol -1
2
1
Compound (3c) : IR ν
max
cm : 1717, 1636, 1538, 1250, 1034.
H NMR (CDCl ) δ : 2.77
3
(1H, dd, J = 4.29, 18.15 Hz), 3.01-3.05 (1H, m), 3.22 (1H, dd, J = 10.55, 17.81 Hz), 3.83 (3H, s),
5.17 (1H, dd, J = 3.63, 8.90 Hz), 5.34 (1H, d, J = 5.61 Hz), 6.15-6.27 (2H, m), 6.36-6.42 (1H, m),
6.98 (2H, d, J = 8.91 Hz), 7.17 (2H, d, J = 8.91 Hz). HRMS Calcd for C H NO : 253.1104.
16 15
2
Found : 253.1103.
3,3a-Dihydro-1-(p-methylphenyl)-1-azaazulen-2(1H)-one (3a)
The azaazulene (2a) (91 mg, 0.29 mmol) was dissolved in THF (1 mL) and tetrabutylammonium fluoride
(184 mg, 0.58 mmol) was added. After being stirred at rt for 30 min, the mixture diluted with ether (50
mL) was washed with saturated brine (30 mL×3), dried over MgSO , and concentrated in vacuo. The
4
residue was purified by flash column chromatography on silica gel (hexane : AcOEt = 4 : 1) to give 3a (50
mg, 73%) as pale yellow crystals, which was identified by spectroscopic comparison with the authentic
sample.
1-(p-Methylphenyl)-1-azaazulene-2(1H)-one (4)
Amixture of 3a (71 mg, 0.3 mmol) and CMD (261 mg, 3 mmol) in benzene (3 mL) was stirred at rt for
12 h. The insoluble materials were filtered through the pad of celite, and washed with AcOEt. The
combined organic solvent was concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexane : AcOEt = 1 : 2) to give 4 (62 mg, 88%) as red crystals, mp 117-
1e
119℃ (AcOEt) (lit., 116-117℃). IR ν
nujol
-1
cm : 1682, 1588, 1532, 1514, 1483, 1256, 1205.
max
H NMR (CDCl ) δ : 2.44 (3H, s), 6.17 (1H, s), 6.74 (1H, d, J = 9.11 Hz), 6.81-7.06 (3H, m), 7.23
1
3
(2H, d, J = 8.24 Hz), 7.36 (2H, d, J = 8.24 Hz), 7.43 (1H, d, J = 11.21 Hz). Anal. Calcd for
C H NO : C ; 81.68, H ; 5.57, N ; 5.95. Found : C ; 81.56, H ; 5.61, N ; 5.75.
16 13
Tropone
N-trimethylsilylacetyl-p-tosylhydrazone
(6)
and
tropone
N-acetyl-p-
tosylhydrazone (7)
10
A mixture of 1d (137 mg, 0.5 mmol) and TMSCH=C=O (79 mg, 0.69 mmol) in CHCl (3 mL) was
3
stirred at reflux for 12 h under argon. After concentration in vacuo, the residue was purified by flash
column chromatography on silica gel (hexane : AcOEt = 3:1 to 2:1 to 1:1) to give 6 as a pale yellow oil (53
mg, 27%) and 7 as pale yellow crystals (22 mg, 14%).

ν
CHCl
-1
cm : 1680, 1639, 1360, 1252, 1169, 1086, 854.
1
Compound (6) : IR
H NMR
max
(CDCl ) δ : -0.04 (9H, s), 2.04 (2H, s), 2.41 (3H, s), 6.62-6.84 (5H, m), 7.00-7.05 (1H, m), 7.29
3
3
(2H, d, J = 8.24 Hz), 7.91 (2H, d, J = 8.24 Hz). HRMS Calcd for C H N O SSi : 373.1042.
18 21 2 3
Found : 373.1044.
nujol
-1
cm : 1690, 1640, 1223, 1088,
Compound (7) : mp 147-149℃ (AcOEt-hexane). IR ν
1
max
H NMR (CDCl ) δ : 2.07 (3H, s), 2.43 (3H, s), 6.66-6.88 (4H, m), 7.05-7.10 (1H, m), 7.23-
1001.
3
7.29 (1H, m), 7.32 (2H, d, J = 8.58 Hz), 7.93 (2H, d, J = 8.58 Hz). HRMS Calcd for
C H N O S : 316.0883. Found : 316.0883.
16 16 2 3
1-Pyrrolidino-1H-pyrrolizin-3(2H)-one (11).
2a
A mixture of dipyrrolo[1,2-a: 1’, 2’-d]pyrazine (8) (74 mg, 0.25 mmol) and TMSCH=C=O (85 mg,
0.74 mmol) in CHCl (5 mL) was stirred at reflux for 4 h. After concentration in vacuo, the residue was
3
purified by flash column chromatography on silica gel (AcOEt) to give 11 (83 mg, 87%) as an orange oil.
neat
-1
cm : 1759, 1624, 1566, 1464, 1397, 1294, 1277, 1088.
1
IR ν
max
H NMR (CDCl ): 1.79-1.93
3
(4H, m), 2.55-2.59 (2H, m), 2.70-2.73 (2H, m), 2.99 (1H, dd, J = 2.97, 18.47 Hz), 3.21 (1H, dd, J =
7.26, 18.48 Hz), 4.20 (1H, dd, J = 2.97, 7.26 Hz), 6.14 (1H, d, J = 3.3 Hz), 6.47-6.57 (1H, m), 7.05
(1H, d, J = 2.31 Hz). Anal. Calcd for C H N O : C ; 69.45, H ; 7.42, N ; 14.72. Found: C;
11 14 2
69.32, H; 7.60, N; 14.48.
REFERENCES AND NOTES
1. a) K. Yamamoto, S. Kajigaeshi, and S. Kanemasa, Chem. Lett., 1977, 91. b) K. Yamamoto, S.
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1992, 34, 1415. e) K. Ito, K. Saito, and K. Takahashi, Bull. Chem. Soc. Jpn., 1992, 65, 812.
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Kobayashi, S. Kajigaeshi, and S. Kanemasa, Heterocycles, 1976, 4, 1281.
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Aoyama, and T. Shioiri, Tetrahedron, 1997, 53, 225.
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Aoyama, J. Heterocycl. Chem., 1999, 36, 1555.
6. Tropones have been reported to react with ketenes to give the [8+2] cycloadducts, see a) J. Ciabattoni
and H. W. Anderson, Tetrahedron Lett., 1967, 3377; b) T. Asao, N. Morita, and N. Iwagame, Bull.
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8. S. Kajigaeshi, S. Matsuoka, S. Kanemasa, and M. Noguchi, J. Heterocycl. Chem., 1986, 23, 49.
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S. Kanemasa, Synthesis, 1997, 202.
10. W. M. Jones and C. L. Ennis, J. Am. Chem. Soc., 1969, 91, 6391.