Reaction of isoquinolinium methylide derivatives with trimethylsilylketene

Article abstract of DOI:10.1016/j.tetlet.2005.12.065

Our investigation on the reaction of isoquinolinium methylide derivatives with trimethylsilylketene (TMS ketene), giving [3+2] cycloadducts, pyrroloisoquinolines, is described. TMS ketene is found to function as the C2 unit introducing reagent in the reaction of isoquinolinium methylide derivatives. Furthermore, the advantage of TMS ketene in comparison with ketene (CH₂CO) is shown.

Full text of DOI:10.1016/j.tetlet.2005.12.065

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1469–1471
Reaction of isoquinolinium methylide derivatives with
trimethylsilylketene
Mayumi Kobayashi, Mika Tanabe, Kazuhiro Kondo and Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 7 November 2005; revised 1 December 2005; accepted 9 December 2005
Abstract—Our investigation on the reaction of isoquinolinium methylide derivatives with trimethylsilylketene (TMS ketene), giving
[3+2] cycloadducts, pyrroloisoquinolines, is described. TMS ketene is found to function as the C2 unit introducing reagent in the
reaction of isoquinolinium methylide derivatives. Furthermore, the advantage of TMS ketene in comparison with ketene
(CH2@C@O) is shown.
Ó 2005 Elsevier Ltd. All rights reserved.
Trimethylsilylketene (TMS ketene) occupies an impor-
tant position, most notably in its service as a masked
ketene (CH2@C@O).1 TMS ketene exhibits milder reac-
tivity than labile ketene and is considered to be more
convenient in view of its easy handling and long-term
storable stability. As part of our program2 directed
toward development of new reactions using TMS
ketene, we herein report our investigation on the reac-
tion of isoquinolinium methylide derivatives with TMS
ketene.
solvent was found to be the most effective combination
for obtaining the desired [3+2] cycloadducts, pyrroloiso-
quinolines, 3a and 4a.5
Having the best conditions, we examined the reaction of
several isoquinolinium salts 1b–d, 5 and 8 as shown in
Scheme 2. Isoquinolinium salts 1b–d with electron-
donating and -withdrawing groups on the isoquinoline
ring were found to be employable, giving the corre-
sponding pyrroloisoquinolines in 63–71% yield. Fur-
thermore, isoquinolinium salts 5 and 8 bearing a
sterically hindered tert-butyl ester group and a methyl
group in the a position of the ester gave the correspond-
ing pyrroloisoquinolines 6/7 and 9 in good yields.
We first investigated the reaction with isoquinolinium
salt 1a as shown in Scheme 1. After intensive screening
of reaction conditions,4 the use of 2.4 equiv of TMS
ketene,3 1.2 equiv of i-Pr2NEt as a base and THF as a
In order to demonstrate the advantage of TMS ketene,
we compared the reactivity of ketene (CH2@C@O) with
that of TMS ketene in reaction with 10. The results are
shown in Scheme 3. The use of ketene with 10 has been
reported by Kato,6 giving product 12, which was formed
by the reaction of two molecules of ketene with one mole-
cule of 10. On the other hand, as expected, the use of
TMS ketene gave the desired pyrroloisoquinoline 11 in
63% yield. In this case, Li2CO3 as a base in place of
i-Pr2NEt was the best.7 Taking the experimental results
independently reached by Kato’s group and ours into
consideration, we could conclude TMS ketene was an
effective reagent.
i-Pr2NEt
(1.2 equiv)
Br-
N+
CO2Et
N+
CO2Et
THF, reflux
2 h
1a
2a
4a
TMS ketene
(2.4 equiv)
N
+
CO2 Et
N
CO2Et
reflux, 24 h
3a
OH
y. 66% (3a/4a = 1 : 1)
OAc
Scheme 1.
The reaction mechanism8 for the formation of hydroxy-
pyrroloisoquinoline 3a and/or acetoxy-pyrroloisoquino-
line 4a may be considered to be as shown in Scheme 4.
*
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.2005.12.065

1470
M. Kobayashi et al. / Tetrahedron Letters 47 (2006) 1469–1471
i-Pr2NEt, THF
reflux, 2 h
Br-
X
X
N
N
X
CO
2Et
CO2Et
N+
CO2Et
+
then, TMSCH=C=O
reflux, 24 h
3
4
1b: X = 5-MeO
1c: X = 6-MeO
1d: X = 5-NO2
OAc
OH
y. 71% (3b/4b = 3 : 1)
y. 64% (3c/4c = 1 : 1)
y. 63% (3d only)
Br-
N+
as above
as above
N
N
CO2t-Bu
OAc
CO2t-Bu
CO2 t-Bu
+
5
6
7
OH
y. 79% (6/7 = 3 : 1)
Br-
N+
CO2Et
N
CO2Et
8
9: y. 63%
O
Scheme 2. Substrate generality.
Acknowledgements
TMSCH=C=O
Li2CO3
Br-
N+
CO2Et
CO2Et
N
We thank the Ministry of Education, Culture, Sports,
Science and Technology, Japan for support.
THF, reflux, 24 h
10
CO2Et
CO2Et
11: y. 63%
O
1) base
2) CH2=C=O, acetone, rt
CO2Et
CO2Et
References and notes
10
N
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,
O
12: y. 64%
O
Scheme 3. Comparison with CH2@C@O.
Nucleophilic attack of carbanion in ylide 2a to TMS
ketene followed by cyclization of the resulting betain
13 produces 14. Desilylation and aromatization and of
14 afford hydroxy-pyrroloisoquinoline 3a. Subsequent
nucleophilic attack of the OH group in 3a to TMS
ketene and then desilylation afford acetoxy-pyrroloiso-
quinoline 4a.
´
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.
In summary, TMS ketene has been found to function
as the C2 unit introducing reagent in the reaction of
isoquinolinium methylide derivatives.9 Work on other
synthetic reactions using TMS ketene is now in progress.
´
´
´
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.
N+
CO2Et
N+
CO2Et
N
CO2Et
2a
TMSCH
-
13
TMS
14
O
TMS
O
O
C
N
N
CO2Et
CO2Et
O
C
TMSCH
3a
4a
OH
OAc
Scheme 4. Possible reaction mechanism.

M. Kobayashi et al. / Tetrahedron Letters 47 (2006) 1469–1471
1471
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. Heterocycles 2001, 55,
2283–2287.
(100). HRMS (M+): m/z calcd for C16H15NO4: 285.1001;
found: 285.1003.
2-Acetoxy-8-methoxy-pyrrolo[2,1-a]isoquinoline-3-carbox-
ylic acid ethyl ester (4c): Yellow needles of mp 138–
141 °C (EtOAc–hexanes). IR (nujol): 1767, 1670 cmÀ1
.
1H NMR (270 MHz, CDCl3): d = 1.40 (t, J = 7.1 Hz, 3H),
2.37 (s, 3H), 3.92 (s, 3H), 4.36 (q, J = 7.1 Hz, 2H), 6.73 (s,
1H), 6.98 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H),
7.16 (dd, J = 8.8, 2.4 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H),
9.19 (d, J = 7.6 Hz, 1H). 13C NMR (67.8 MHz, CDCl3):
d = 14.9, 21.4, 55.8, 60.3, 94.3, 106.6, 107.9, 112.7,
118.0, 118.8, 125.1, 125.4, 129.9, 133.3, 145.5, 159.5,
160.7, 169.2. EIMS: m/z (%) = 327 (70, M+), 239 (100).
HRMS (M+): m/z calcd for C18H17NO5: 327.1107; found:
327.1101.
´
`
3. For preparation of TMS ketene: Valentı, E.; Pericas, M.
A.; Sarratosa, F. J. Org. Chem. 1990, 55, 395–397.
4. The use of Et3N as a base resulted in no reaction. The
results of solvent effects were as follows: toluene (62%
yield), DMF (complex mixtures).
5. Representative procedure: A mixture of 2-ethoxycarbonyl-
methylisoquinolinium bromide (1a) (118 mg, 0.40 mmol)
and i-Pr2NEt (0.0840 mL, 0.480 mmol) in THF (10 mL)
was refluxed for 2 h under argon and then to this mixture
trimethylsilylketene (2.91 mL, 0.960 mmol, 0.330 M in
toluene solution) was added. The reaction mixture was
refluxed for 24 h, diluted with water, and extracted with
EtOAc. The combined organic layer was washed with
brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(hexanes/EtOAc, 30:1 to 10:1) to afford 2-hydroxy-pyr-
rolo[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (3a)
(35.1 mg, 34%) as brown powders and 2-acetoxy-pyr-
rolo[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (4a)
(38.4 mg, 32%) as white powders. The spectral data of 3a
were as follows. Mp 77–78 °C (EtOAc–hexanes). IR
2-Hydroxy-7-nitro-pyrrolo[2,1-a]isoquinoline-3-carboxylic
acid ethyl ester (3d): Orange powders of mp 193–194 °C
1
(EtOAc–hexanes). IR (nujol): 3471, 1682 cmÀ1. H NMR
(270 MHz, CDCl3): d = 1.49 (t, J = 7.1 Hz, 3H), 4.53 (q,
J = 7.1 Hz, 2H), 6.67 (s, 1H), 7.58 (dd, J = 8.0, 8.0 Hz,
1H), 7.66 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H),
8.29 (d, J = 8.0, 1H), 8.86 (br s, 1H). 13C NMR
(67.8 MHz, CDCl3): d = 14.7, 60.9, 90.3, 102.4, 104.8,
121.6, 124.5, 125.5, 126.1, 127.7, 129.0, 132.2, 145.5.
EIMS: m/z (%) = 300 (38, M+), 254 (100). Anal. Calcd for
C15H12N2O5: C, 60.00; H, 4.03; N, 9.33. Found: C, 59.76;
H, 4.14; N, 9.11.
2-Oxo-2H-pyrrolo[2,1-a]isoquinoline-3,3-dicarboxylic acid
diethyl ester (11): A yellow oil. IR (neat): 1732, 1683,
1634 cmÀ1 1H NMR (270 MHz, CDCl3): d = 1.33 (t,
.
J = 7.1 Hz, 6H), 4.35 (q, J = 7.1 Hz, 2H), 4.36 (q,
J = 7.1 Hz, 2H), 5.59 (s, 1H), 6.57 (d, J = 7.3 Hz, 1H),
7.28 (d, J = 7.3 Hz, 1H), 7.45–7.53 (m, 2H), 7.63–7.69 (m,
1H), 7.83 (d, J = 8.1 Hz, 1H). 13C NMR (67.8 MHz,
CDCl3): d = 14.0, 63.6, 78.6, 88.7, 108.0, 121.8, 126.7,
127.4, 127.5, 128.6, 133.3, 134.9, 162.7, 166.8, 183.1.
EIMS: m/z (%) = 327 (59, M+), 209 (100). HRMS (M+):
m/z calcd for C18H17NO5: 327.1107; found: 327.1083.
6. Kato, T.; Chiba, T.; Tanaka, S.; Sasaki, T. Heterocycles
1978, 11, 227–230.
(nujol): 3356, 1638 cmÀ1 1H NMR (270 MHz, CDCl3):
.
d = 1.46 (t, J = 7.1 Hz, 3H), 4.47 (q, J = 7.1 Hz, 2H), 6.50
(s, 1H), 6.79 (d, J = 7.6 Hz,1H), 7.39–7.46 (m, 2H), 7.51–
7.56 (m, 1H), 7.90–7.94 (m, 1H), 8.59 (br s, 1H). 13C NMR
(67.8 MHz, CDCl3): d = 14.6, 60.2, 88.5, 101.5, 110.5,
123.3, 123.6, 124.4, 126.5, 127.0, 127.5, 128.3, 134.0.
EIMS: m/z (%) = 255 (87, M+), 209 (100). HRMS (M+):
m/z calcd for C15H13NO3: 255.0896; found: 255.0929. The
spectral data of 4a were comparable to those reported.10
The spectral data of selected pyrrolo[2,1-a]isoquinoline
derivatives were as follows.
7. Other bases such as pyridine, NaOAc, and NaHCO3 gave
less satisfactory results.
2-Hydroxy-8-methoxy-pyrrolo[2,1-a]isoquinoline-3-carbox-
ylic acid ethyl ester (3c): Yellow plates of mp 173–175 °C
8. We previously demonstrated that the [4+2] cycloaddition
of TMS ketene and a 1,3-diene proceeded by a stepwise
process.2a However, in the case of Scheme 1, a concerted
mechanism might be considered.
9. 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.
1
(EtOAc–hexanes). IR (nujol): 3271, 1636 cmÀ1. H NMR
(270 MHz, CDCl3): d = 1.48 (t, J = 7.1 Hz, 3H), 3.92 (s,
3H), 4.49 (q, J = 7.1 Hz, 2H), 6.46 (s, 1H), 6.85 (d,
J = 7.3 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 7.14 (dd,
J = 8.9, 2.3 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 8.50 (br s,
0.5H), 9.30 (br s, 0.5H). 13C NMR (67.8 MHz, CDCl3):
d = 14.8, 55.4, 60.2, 87.6, 107.5, 110.4, 117.4, 118.1, 125.2,
130.2, 159.3. EIMS (EI): m/z (%) = 285 (48, M+), 239
10. Kato, T.; Chiba, T.; Sasaki, T. Heterocycles 1979, 12, 925–
928.