J. Am. Chem. SOC.1981, 103, 1172-1176
1172
Electroorganic Chemistry. 46. A New Carbon-Carbon Bond Forming Reaction at the a-Position of Amines Utilizing Anodic Oxidation as a Key Step’ Tatsuya Shono,* Yoshihiro Matsumura, and Kenji Tsubata Contribution from the Department of Synthetic Chemistry, Faculty of Engineering, Kyoto University, Yoshida, Sakyo, Kyoto 606, Japan. Received June 23, I980
Abstract: A new carbon-carbon bond forming reaction at the a-position of primary and secondary amines has been exploited. The method involves anodic oxidation of urethanes derived from the primary and secondary amines and subsequent acid-catalyzed reaction of the resulting a-methoxylated urethanes with nucleophiles such as electron-rich olefins and active methylene compounds. The intermediary participation of (carbometh0xy)iminiumions was suggested in the acid-catalyzed reaction. The application to the synthesis of pyrrolidine, piperidine, and tropane alkaloids is also described.
The transformation of an amine (1) to another amine (2) forming a new carbon-carbon bond (C-C) a t the CY position of 1 (eq 1) is an important tool2 in the synthesis of a variety of
Scheme I
-
2
R’N;H2R H
CIC02CH3
anodic
I
co2cr3 7
6 R’ N‘
-
R’NCHZR’
oridn in CH30H
N”
I
I
R2
R2
1
2
I
I
R’, RZ = alkyl group or hydrogen
co2cr3
Nu = nucleophile
8
physiologically important nitrogen-containing compounds. The functionalization of the a position of 1 in advance by converting 1 to intermediates such as imines (3),3iminium ions P A M
M A 4
3
M
I
4
C02CH3
r
u
A.-,
m
I
5
(4),3bp4or acyliminium ions (5)s is necessary for this purpose, though the formation of these intermediates from 1 is not necessarily easy. W e wish to report herein a new efficient method of forming a C-C bond at the CY position of primary and secondary amines ( 6 ) utilizing anodic oxidation6 of urethanes of 6 as a key step. Results and Discussion C-C Bond Forming Reaction Catalyzed by Lewis Acids. Scheme
10
9
in which (carbometh0xy)iminium ions (9) generated from compounds (8) could be presumed to be the possible active intermediates similar to the acyliminium ions (5). According to the method previously described,6 the anodic oxidation of 7 to 8 was performed in 70-80% isolated yields (3-3.5 F/mol of electricity). As shown in Table I, the C - C bond forming reaction was satisfactorily accomplished through prior treatment of 8 (R’= CH3, R2 = H , compound 11) with Lewis acids and subsequent addition of a nucleophile 12 (method A). The addition of Lewis acids into the reaction mixture after 11 and 12 were mixed (method B) resulted in a poor yield of the desired product (13) (eq 2), suggesting the intermediary participation of the iminium ion 9 (R’= CH3, R2 = H).
I
I illustrates our process involving the anodic oxidation of urethanes
COzCH3
(7) and the subsequent acid-catalyzed C-C bond forming reaction
11
+U
-
Lewis acids
12
( I ) Part 45 in this series: Shono, T.; Usui, Y.; Mizutani, T.; Hamaguchi, H. Tetrahedron Lett. 1980, 21, 3073.
(2) Several methods of C C bond formation at the a-position of nitrogen have been exploited; see, for example: (a) Stork, G.; Jacobson, R. M.; Levitz, R. Tetrahedron Lett. 1979, 771. (b) Seebach, D.; Enders, D.; Renger, B. Chem. Ber. 1977, 110, 1852. Renger, B.; Kalinowski, H. -0.; Seebach, D. Ibid. 1977 110, 1866. Seebach, D.; Enders, D.; Dach, R.; Pieter, R. Ibid. 1977, 110, 1879. (c) Shono, T.; Yoshida, K.; Ando, K.; Usui, Y.; Hamaguchi, H. Tetrahedron Lett. 1978, 4819. Shono, T.; Usui, Y.; Mizutani, T.; Hamaguchi, H. Ibid. 1980, 21, 3073. ( 3 ) (a) Quick, J.; Oterson, R. Synthesis 1976, 745. (b) Mathiu, J.; Weill-Raynal, J. “Formation of C-C Bonds”; Gerog Thieme Publishers: Stuttgart, 1979; Vol. 111. (c) Scully, F. E., Jr.; J . Org. Chem. 1980, 45, 1515. (4) Dean, R. T.; Padgett, H. C.; Rapoport, H. J . Am. Chem. SOC.1976, 98,7448. Dean, R. T.; Rapport, H. J . Org. Chem. 1978,43,4183. Csendes, I. G.; Lee, Y. Y.; Padgett, H. C.; Rapoport, H. Ibid. 1979, 44, 4173. ( 5 ) Schoemaker, H. E.; Dijkink, J.; Speckamp, W. N. Tetrahedron 1978, 34, 163. Schoemaker, H. E.; Kruk, C.; Speckamp, W. N. Tetrahedron Lett. 1979, 2437. Hart, D. J. J. Am. Chem. SOC.1980, 102, 397. Danishefsky, S.; Guingant, A,; Prisbylla, M. Tetrahedron Lett. 1980, 21, 2033. (6) Shono, T.; Hamaguchi, H.; Matsumura, Y. J. Am. Chem. SOC.1975, 97, 4264.
0002-7863/81/1503-1172$01.25/0
13
The results obtained under the reaction conditions of the method A using Lewis acids as catalysts are listed in Table 11. Furthermore, dimethyl malonate was found to be effective as a nucleophile (runs 12 and 13). In this new method, regioselective reaction is possible since the anodic oxidation preferentially takes place at the less-substituted a-position7 (eq 3). (7) Similar regioselectivity has generally been observed in the electrochemical and photochemical oxidation of amines, and also in some chemical oxidations.* The effect of @-alkylsubstituents (for example, methyl group in 3-methylpiperidine) on the selectivity has not yet been clarified.
0 1981 American Chemical Society
J. Am. Chem. SOC.,Vol. 103, No. 5, 1981 11 73
A New C-C Bond at the a-Position of Amines
Table I. Reaction of 11 (10 mmol) and 12 (1 1 mmol)
p i n e
I C02CH3
I CO2CH3 14
74%
15
run
acid (mmol)
1 2 3
TiC14 (10.9) TiC1, (3) TiC1, (10.9) BF,.OEt, (10) ZnC1, (3) MsOHb (IO) HCIC
4
5 6
7 COzCH3
16 The potentiality of this method is also demonstrated by the facile transformation of the products to pyrrolidine and piperidine alkaloids (eq 4 and 5 ) or a precursor of tropane alkaloids (eq 6). OSiE
isolated meth- react. react. yield of oda temp, "C time, h 13, % B A A B A A
3.5 1 3.5 4 17.5 3 5
-75 18 -20-rtd -75-rtd 18 -70-rtd -70-rtd
48 47 -100 97 51
