Unexpectedly cyclized products by reaction of N-tosyliminoisoquinolinium ylides with trimethylsilylketene

Article abstract of DOI:10.1016/j.tetlet.2007.07.106

The reaction of N-tosyliminoisoquinolinium ylides with trimethylsilylketene as a C2 unit introducing reagent, giving unexpected [3+2] cycloadducts, pyrazolo[5,1-a]isoquinolines, is described.

Full text of DOI:10.1016/j.tetlet.2007.07.106

Tetrahedron Letters 48 (2007) 7019–7021
Unexpectedly cyclized products by reaction of
N-tosyliminoisoquinolinium ylides with trimethylsilylketene
Mayumi Kobayashi, Kazuhiro Kondo and Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 28 June 2007; revised 17 July 2007; accepted 20 July 2007
Available online 27 July 2007
Abstract—The reaction of N-tosyliminoisoquinolinium ylides with trimethylsilylketene as a C2 unit introducing reagent, giving
unexpected [3+2] cycloadducts, pyrazolo[5,1-a]isoquinolines, is described.
Ó 2007 Elsevier Ltd. All rights reserved.
Table 1. Optimization of reaction conditions
Trimethylsilylketene (TMS ketene) occupies an impor-
tant position, most notably in its service as a masked
TMSCH=C=O
(1.2 mol equiv)
ketene (CH2@C@O).1 TMS ketene exhibits milder reac-
+
N
tivity than labile ketene and is more convenient in view
of its easy handling and long-term storable stability. We
have already demonstrated that TMS ketene, as a C2
unit introducing reagent, is quite useful for the construc-
tion of various heterocycles.2 For instance, TMS ketene
smoothly reacts with isoquinolinium methylides to give
[3+2] cycloadducts, pyrroloisoquinolines.2i As extension
of this work, we planned to investigate the reaction of
tosyliminoisoquinolinium ylides 1, aza-analogs of iso-
quinolinium methylides, with TMS ketene.
N
NTs base (3 mol equiv)
N
-
2a
1a
reflux, 24 h
N
NTs
O
3
Entry
Solvent
THF
Base
Yield (%) of 2a
1
None
No reaction
2
3
4
5
6
7a
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
None
Complex mixture
Complex mixture
Complex mixture
63
50
47
The reaction of tosyliminoisoquinolinium ylide 1a with
1.2 mol equiv of TMS ketene3 was examined under var-
ious reaction conditions. The selected results are shown
in Table 1. As can be seen, some trends are apparent.
First, non-base, and the use of pyridine exhibiting weak
basicity and K2CO3 were not particularly effective at all.
Second, the use of Et3N and i-Pr2NEt allowed ylide 1a
and TMS ketene to react. After completion of the
reaction, usual work-up and purification afforded the
unexpectedly cyclized product 2a, pyrazolo[5,1-a]iso-
quinoline: our expected product 3 was not produced in
detectable amounts. The structure of 2a was unambigu-
ously determined by comparison of sample 2a, which
was prepared independently by Hosomi and Tominaga’s
method.4 The physical data of 2a were as follows.
Yellow powders of mp 61 °C (EtOAc): lit.5 62 °C. IR
Pyridine
K2CO3
Et3N
i-Pr2NEt
Et3N
a The reaction was performed at 110 °C.
(270 MHz, CDCl3): d = 6.92 (d, J = 8.2 Hz, 1H), 6.93
(s, 1H), 7.45–7.54 (m, 2H), 7.65 (br d, J = 7.7 Hz, 1H),
7.95 (d, J = 1.6 Hz, 1H), 8.03 (br d, J = 8.2 Hz, 1H),
8.21 (d, J = 7.4 Hz, 1H). 13C NMR (67.8 MHz, CDCl3):
d = 97.3, 111.9, 123.5, 124.4, 126.2, 126.9, 127.4, 127.6,
128.5, 138.1, 140.9. EIMS: m/z (%) = 168 (100, M+).
Anal. Calcd for C11H8N2: C, 78.55; H, 4.79; 16.66.
Found: C, 78.72; H, 5.00; 16.44. Thus, Et3N as a base
and aromatic solvent were found to be the most effective
combination for obtaining unexpected [3+2] cyclo-
adduct 2a (entry 5).
(CHCl3): m = 1484, 1435, 1371 cmÀ1
.
1H NMR
*
Corresponding author. E-mail: aoyama@phar.nagoya-cu.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.106

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M. Kobayashi et al. / Tetrahedron Letters 48 (2007) 7019–7021
Table 2. Substrate generality
References and notes
5
4
TMSCH=C=O
(2.4 mol equiv)
6
1. (a) Colvin, E. W. Silicon in Organic Synthesis; Butter-
worths: London, 1985, Chapter 14, pp 174–177; (b)
Leobach, J. L.; Danheiser, R. L. In Encyclopedia of
Reagents for Organic Synthesis; Paquett, L. A., Ed.; John
Wiley & Sons: Chichester, 1995; Vol. 7, pp 5266–5268; (c)
Pommier, A.; Kocienski, P.; Pons, J.-M. J. Chem. Soc.,
Perkin Trans. 1 1998, 2105–2118; (d) Shioiri, T.; Takaoka,
K.; Aoyama, T. J. Heterocycl. Chem. 1999, 36, 1555–1563;
For recent selected examples, see: (e) Evans, D. A.; Janey,
R
+
R
N
N
7
Et3N (6 mol equiv)
reflux, 24 h
N
NTs
2
-
1
Entry
R
Solvent
Time (h)
Yield (%)
1a
2a
3
4
5
4-Br (1b)
5-NO2 (1c)
6-F (1d)
6-Me (1e)
6-MeO (1f)
Toluene
Toluene
Toluene
Toluene
Xylene
48
48
24
24
72
72
75 (2b)
79 (2c)
71 (2d)
62 (2e)
71 (2f)
14 (2g)
´
J. M. Org. Lett. 2001, 3, 2125–2128; (f) Rosse, G.; Gerber,
F.; Specklin, J.-L.; Hubschwerlen, C. Synlett 2001, 538–
540; (g) Ponomarev, S. V.; Zolotareva, A. S.; Ezhov, R.
N.; Kuznetsov, Yu. V.; Petrosyan, V. S. Russ. Chem. Bull.,
Int. Ed. 2001, 50, 1093–1096; (h) Holland, A. W.;
Bergman, R. G. Inorg. Chem. 2002, 341, 99–106; (i)
Fournier, L.; Gaudel-Siri, A.; Kocienski, P. J.; Pons, J.-M.
6
6,7-di-MeO (1g)
Xylene
a The reaction temperature was 80 °C.
´
´
´
Synlett 2003, 107–111; (j) Ungvari, N.; Kegl, T.; Ungvary,
F. J. Mol. Catal. A: Chem. 2004, 219, 7–11.
2. (a) Ito, T.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1993,
34, 6583–6586; (b) Takaoka, K.; Aoyama, T.; Shioiri, T.
Synlett 1994, 1005–1006; (c) Takaoka, K.; Aoyama, T.;
Shioiri, T. Tetrahedron Lett. 1996, 37, 4973–4976; (d)
Takaoka, K.; Aoyama, T.; Shioiri, T. Tetrahedron Lett.
1996, 37, 4977–4978; (e) Matsumoto, T.; Takaoka, K.;
Aoyama, T.; Shioiri, T. Tetrahedron 1997, 53, 225–236; (f)
Takaoka, K.; Aoyama, T.; Shioiri, T. Tetrahedron Lett.
1999, 40, 3017–3020; (g) Takaoka, K.; Aoyama, T.;
Shioiri, T. Heterocycles 2001, 54, 209–215; (h) Arai, S.;
Sakurai, T.; Asakura, H.; Fuma, S.; Shioiri, T.; Aoyama,
T. Heterocycles 2001, 55, 2283–2287; (i) Kobayashi, M.;
Tanabe, M.; Kondo, K.; Aoyama, T. Tetrahedron Lett.
2006, 47, 1469–1471.
+
N+
N
N
NTs
O-
NTs
NTs
O
5
-
1a
TMSCH C O
Scheme 1.
4
TMS
TMS
The substrate generality of this unexpected reaction is
shown in Table 2. The reactions were performed with
2.4 mol equiv of TMS ketene and 6 mol equiv of Et3N,
because the yields of the reactions in Table 2 with
1.2 mol equiv of TMS ketene and 3 mol equiv of Et3N
were moderate or low.6 Tosyliminoisoquinolinium
ylides 1b–f bearing electron-withdrawing substituents
such as fluoro and nitro groups, and electron-donating
substituents such as mono-methoxy and methyl groups
on the isoquinoline ring were found to be employable,
giving the corresponding pyrazolo[5,1-a]isoquinolines
2b–f in 62–79% yield.7 Unfortunately, ylide 1g bearing
strong electron-donating substituents such as di-meth-
oxy groups gave 2g in 14% yield. The reaction mecha-
nism8 for the formation of unexpected [3+2]
cycloadduct 2 including the deoxygenation and detosy-
lation steps9 (from 5 to 2) is not clear at the present time.
But we are tempted to assume that the initial step is a
stepwise process as follows: nucleophilic attack of ylide
1 to TMS ketene followed by cyclization of the resulting
betaine 4 produces 5 (Scheme 1), because we previously
demonstrated that the [4+2] cycloaddition of TMS
ketene and a 1,3-diene proceeded by a stepwise
process.2a
´
`
3. For preparation of TMS ketene: Valentı, E.; Pericas, M.
A.; Sarratosa, F. J. Org. Chem. 1990, 55, 395–397.
4. Tominaga, Y.; Ichihara, Y.; Mori, T.; Kamio, C.; Hosomi,
A. J. Heterocycl. Chem. 1990, 27, 263–268.
5. Huisgen, R.; Grashey, R.; Krischke, R. Liebigs Ann.
Chem. 1977, 506.
6. The results for the reactions with 1.2 mol equiv of TMS
ketene and 3 mol equiv of Et3N were as follows: 2b (y.
40%), 2c (52%), 2d (55%), 2f (23%).
7. The synthesis of 2b bearing a nitro group using Hosomi
and Tominaga’s method4 was not efficient, although the
efficiency for the synthesis of 2a was similar to our method
(Scheme 2).
8. For a recent example of the 1,3-dipolar cyclization of N-
ylides, see: Fang, X.; Wu, Y.-M.; Deng, J.; Wang, S.-W.
Tetrahedron 2004, 60, 5487–5493, and references cited
therein.
9. A fragment of p-acetoxytoluene in the reaction mixture,
which was quenched with Ac2O, was observed by LC–MS.
10. The N-p-tosyliminoisoquinolinium ylides 1a–g were easily
prepared by the standard tosylation of 6.
-O3S
In summary, the reaction of N-tosyliminoisoquinolin-
ium ylides with TMS ketene as a C2 unit introducing
reagent has been found to give unexpected [3+2]
cycloadducts, pyrazolo[5,1-a]isoquinolines.10–12
R
+
N
NH2
6
11. Representative procedure for cyclization: a mixture of N-p-
tosyliminoisoquinolinium ylide (1a) (50.0 mg, 0.168 mmol)
and Et3N (0.07 mL, 0.50 mmol) and trimethylsilylketene
(0.45 mL, 0.20 mmol, 0.45 M in toluene solution) in
toluene (2.0 mL) was refluxed for 24 h, allowed to cool,
and directly concentrated. The residue was purified
Acknowledgement
We thank the Ministry of Education, Culture, Sports,
Science and Technology, Japan, for support.

M. Kobayashi et al. / Tetrahedron Letters 48 (2007) 7019–7021
7021
by silica gel column chromatography (hexanes–EtOAc,
7:1) to afford pyrazolo[5,1-a]isoquinoline (2a) (17.9 mg,
63%).
129.26, 136.91, 141.96. EIMS: m/z (%) = 213 (100, M+).
For 2f: Orange powders of mp 104–105 °C (EtOAc–
hexane). IR (CHCl3): m = 1485, 1472, 1437 cmÀ1 1H
.
12. Selected spectral data are as follows. For 2c: Orange
powders of mp 180–182 °C (EtOAc–hexane). IR (CHCl3):
NMR (270 MHz, CDCl3): d = 3.93 (s, 3H), 6.85–6.87
(m, 1H), 6.92 (d, J = 7.4 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H),
7.18 (dd, J = 8.7, 2.5 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H),
8.00 (d, J = 8.7 Hz, 1H), 8.23 (d, J = 7.4 Hz, 1H). 13C
NMR (67.8 MHz, CDCl3): d = 55.47, 96.24, 108.23,
111.61, 117.21, 118.63, 125.16, 126.70, 130.27, 138.38,
141.16, 159.13. EIMS: m/z (%) = 198 (100, M+).
1
m = 1371, 1339, 1211 cmÀ1. H NMR (270 MHz, CDCl3):
d = 7.09 (br d, J = 2.2 Hz, 1H), 7.67 (dd, J = 8.1, 8.1 Hz,
1H), 7.77 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H),
8.24 (br d, J = 8.1 Hz, 1H), 8.38 (br d, J = 8.1 Hz, 1H),
8.42 (d, J = 8.1 Hz, 1H). 13C NMR (67.8 MHz, CDCl3):
d = 98.84, 105.97, 121.83, 124.54, 126.22, 126.70, 129.03,
X
X
X
-O3S
MeO
CO2Me
+
1) NaOH
N
N
N
NH2
Et3N, EtOH
N
2) PPA
N
MeO2C
2a (X=H); y. 77%
X=H; y. 60%
X=NO2; y. 10%
2b (X=NO2); y. 24%
Scheme 2.