In ter ven tion of P h en on iu m Ion in Ritter
Rea ction s
SCHEME 1
Tse-Lok Ho* and Rong-J ie Chein
Department of Applied Chemistry, National Chiao Tung
University, Hsinchu, Taiwan, Republic of China
would not be observed for the alternative unrearranged
product structure. Similar evidence was obtained for 5a .
These results indicate a rearrangement pathway for the
formation of the dihydroisoquinolines and definitely rule
out direct participation of the nitriles to assist departure
of the chlorine atom. Accordingly, two possible mecha-
nisms remain to be considered: a 1,2-aryl shift to give
more stable carbocationic intermediates, or phenonium
ion formation. To differentiate these possibilities, we
prepared 4 from methyl phenylacetate via reduction with
Received October 21, 2003
Abstr a ct: The transformation of phenylethyl chloride to
,4-dihydroisoquinolines is shown to proceed via phenonium
ion. The evidence comes from a study of dideuterated ana-
logue 4, and the monomethylated and dimethylated com-
pounds 2 and 3.
3
LiAlD
chloride with SOCl
4
and conversion of the dideuterated alcohol to the
gave
2
. The reaction with PhCN‚SnCl
4
The Ritter reaction involves the generation of relatively
stable carbocations from alcohols or alkenes and trapping
of the cations in situ by nitriles to provide, after hydroly-
sis, amide products.1
a product that is shown to be a mixture of 6a and 6b.
-3
In view of the structural requirements for the cationic
precursors, we were intrigued by the report4 of Lora-
Tamayo et al. that describes the formation of 1-substi-
tuted-3,4-dihydroisoquinolines from reaction of 1-chloro-
2
-phenylethane 1 with cyanides in the presence of SnCl
4
.
1
The H NMR spectrum displays a pair of signals at δ 2.71
These authors implicitly asserted an assisted ionization
of the chloride to form N-(2-phenylethyl)nitrilium species,
which rapidly cyclized (Scheme 1). In our opinion, this
interpretation is tenuous and intervention of a phe-
nonium ion5 is more likely.
To verify our conjecture, we investigated the behavior
of 1-chloro-2-phenylethane analogues 2 and 3 and the
dideuterio derivative 4.
and 3.76, and integration data suggest a 1:1 ratio within
experimental error. Thus our results strongly argue for
the intervention of a phenonium ion intermediate at least
in the case of the parent substrate 1, and indeed explain
,6
the peculiar reactivity of the 2-phenylethyl chlorides as
contrary to other primary alkyl halides.7
Exp er im en ta l Section
Gen er a l Meth od s. NMR spectra were recorded with CDCl
3
1
13
as solvent, at 300 and 74 MHz respectively for H and
C
absorption. Chemical shifts are in ppm relative to 0 for TMS.
F or m a tion of 3,4-Dih yd r oisoqu in olin es.4 A mixture of
chloride 1, 2, 3, or 4 and MeCN or PhCN (2.1 mmol each) was
placed in a flask fit with a rubber septum and a condenser, and
4
SnCl (2 mmol) was added through a syringe to the stirred
mixture. After the exothermic reaction subsided, the mixture
was heated in an oil bath at 110-130 °C for 3 h. It was cooled,
basified with 20% NaOH, and extracted with ether. The ethereal
layer was extracted with 20% HCl, neutralized with an aqueous
solution with NaOH, and extracted with ether. On evaporation
of the dried ethereal extract, 3,4-dihydroisoquinoline derivatives
were obtained in 45-55% yield.
When 2 and 3 were submitted to the reaction condi-
tions described by Lora-Tamayo et al., we obtained
products corresponding to structure 5 only. Thus, the 13
C
NMR spectrum of 5b indicates the presence of a quater-
,3-Dim eth yl-3,4-d ih yd r oisoqu in olin e8 (5a ). H NMR δ
,9
1
1
1
.35 (3H, d, J ) 6.6 Hz), 2.35 (3H, d, J ) 2.1 Hz), 2.45 (1H, dd,
(
3) J ohnson, F.; Madronero, R. Adv. Heterocycl. Chem. 1996, 6, 95-
1
9
6
46.
(4) Lora-Tamayo, M.; Madronero, R.; Munoz, G. G. Chem. Ber. 1960,
3, 289-297.
(
5) Olah, G. A.; Porter, R. D. J . Am. Chem. Soc. 1971, 93, 6877-
887.
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98, 6284-6289.
7) Meerwein, H.; Lasch, P.; Wersch, R.; Spille, J . Chem. Ber. 1956,
9, 209-224.
8) Gray, N. M.; Cheng, B. K.; Mick, S. J .; Lair, C. M.; Contreras, P.
nary carbon atom that is attached to an amine nitrogen
(
(δ 53.4) and NOE study showed a proximal relationship
(
between a CH (δ 2.63) and a peri-H (δ 7.07). Such effect
2
8
(
(
1) Ritter, J . J .; Minieri, P. P. J . Am. Chem. Soc. 1948, 70, 4045-
048.
2) Krimen, L. I.; Cota, D. J . Org. React. 1969, 17, 213-325.
C. J . Med. Chem. 1989, 32, 1242-1248.
(9) Grunewald, G. L.; Galdwell, T. M.; Li, Q.; Criscione, K. R. Bioorg.
Med. Chem. 1999, 7, 869-880.
4
1
(
0.1021/jo035561y CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/30/2003
J . Org. Chem. 2004, 69, 591-592
591
Ho, Tse-Lok
