Reaction of an electrogenerated 'iminium cation pool' with organometallic reagents. Direct oxidative α-alkylation and -arylation of amine derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00128-9

We have developed an efficient direct oxidative α-alkylation and -arylation of carbamates based on the 'cation pool' method. Grignard reagents, organozinc compounds, and organoaluminum compounds are effective as carbon nucleophiles toward iminium cation pools generated by low temperature electrolysis of carbamates.

Full text of DOI:10.1016/S0040-4039(01)00128-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2173–2176
Reaction of an electrogenerated ‘iminium cation pool’ with
organometallic reagents. Direct oxidative a-alkylation and
-arylation of amine derivatives
Seiji Suga, Masayuki Okajima and Jun-ichi Yoshida*
Department of Synthetic Chemistry & Biological Chemistry, Graduate School of Engineering, Kyoto University,
Yoshida Honmachi, Sakyo, Kyoto 606-8501, Japan
Received 28 December 2000; accepted 19 January 2001
Abstract—We have developed an efficient direct oxidative a-alkylation and -arylation of carbamates based on the ‘cation pool’
method. Grignard reagents, organozinc compounds, and organoaluminum compounds are effective as carbon nucleophiles toward
iminium cation pools generated by low temperature electrolysis of carbamates. © 2001 Elsevier Science Ltd. All rights reserved.
Recently we have developed the ‘cation pool’ method,1
which involves the generation and the accumulation of
a relatively unstable carbocation and the subsequent
reaction with a nucleophile under non-oxidative condi-
tions. For example, carbamates are electrochemically
oxidized at low temperature to accumulate the acyli-
minium cation, which is characterized as a solution of a
single cationic species by NMR spectroscopy. The addi-
tion of carbon nucleophiles to the ‘iminium cation pool’
affords the corresponding carbonꢀcarbon bond forma-
tion products in high yields (Scheme 1). The ‘cation
pool’ method provides not only a powerful tool for the
mechanistic studies of the process involving carboca-
tions but also a useful synthetic method that overcomes
the conventional two-step transformation. There is no
need for trapping of a carbocation by a heteroatom
nucleophile such as alcohol, the isolation of the trapped
carbocation, and the regeneration of the carbocation
using a Lewis acid (Scheme 2).2–4
In our previous work, organosilicon compounds such
as allylsilanes and silyl enol ethers were used as carbon
nucleophiles.1 In order to expand the scope of the
‘cation pool’ method, we examined the use of other
organometallic compounds such as Grignard reagents
as carbon nucleophiles. There was no information on
the direct reaction of spectroscopically well-character-
ized acyliminium cations with such organometallics.
Herein we report that alkyl, alkenyl, alkynyl, and aryl
Grignard reagents, as well as alkylzinc and alkylalu-
minum compounds, serve as effective nucleophiles
toward iminium cation pools. The present method pro-
vides a useful method for the introduction of a sub-
stituent at the a-carbon of amine derivatives.5
R3M
low
temperature
electrolysis
R2
R2
R2
Chemical
Process
R1
R1
R1
+
N
N
R3
N
CO2Me
CO2Me
CO2Me
"iminium
cation pool"
Scheme 1. Cation pool method.
Keywords: cation pool; iminium cation; electrochemical oxidation; carbon–carbon bond formation; Grignard reagents.
* Corresponding author. Fax: +81-75-753-5911; e-mail: yoshida@sbchem.kyoto-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00128-9

2174
S. Suga et al. / Tetrahedron Letters 42 (2001) 2173–2176
R2
R2
R1
R2
R2
N
R2
R1
+
Lewis
Acid
R1
N
R1
R3M
R1
+
CO2Me
+
R3
CO2Me
OMe
CO2Me
"trapped
N
N
N
CO2Me
CO2Me
MeOH
(solvent)
MeOH
iminium cation"
isolated
Scheme 2. Conventional two-step method.
diethylamine were also found to be effective for the
reaction with Grignard reagents.
We initially examined the reactions of the electrogener-
ated iminium cation pools with Grignard reagents. A
typical procedure is as follows. Methyl pyrrolidinecar-
boxylate was anodically oxidized in CH2Cl2 at −72°C to
generate the ‘iminium cation pool’.6 After completion
of the electrolysis (2.5 F/mol was consumed), 2 equiv.
of phenylmagnesium bromide in ether was added and
the mixture was stirred at the same temperature for 10
min. The work up followed by chromatography gave
methyl 2-phenylpyrrolidinecarboxylate in 79% yield
(Eq. (1)). In marked contrast to the reaction with
Grignard reagents, the reactions with alkyllithium were
not practically useful. For example, the reaction with
phenyllithium in hexane led to the formation of the
desired compound only in very low yield (4%). Proba-
bly higher basicity of organolithium compounds caused
the decomposition of the iminium cation via b-proton
elimination.
The reaction of the ‘iminium cation pool’ and benzyl-
magnesium halide exhibited an interesting feature.
Three isomeric products were formed as a mixture, as
shown in Eq. (2). The formation of the coupling prod-
ucts at aromatic o- and p-carbons suggests that the
mechanism involves the initial electron transfer from
the Grignard reagent to the iminium cation to generate
benzyl radical, although the detailed mechanism has
not been clarified as yet.
Other organometallic compounds such as organozinc7
and organoaluminum8 reagents are also effective as
carbon nucleophiles. For example, diethylzinc, ethyl-
zinc iodide, triethylaluminum, and diethylaluminum
chloride readily react with the iminium cation pool
generated from methyl pyrrolidinecarboxylate to give
the ethylated product in good to moderate yields (Table
2). Low basic character of organozinc and organoalu-
minum reagents, which might suppress the competing
elimination process, seems to be responsible for the
success of the reactions.4d This tendency is consistent
with the known softness of iminium cations.9
M
-2e, -H+
-72 oC
N
N
+
N
CO2Me
CO2Me
CO2Me
M = MgBr : 79%
M = Li:
4%
(1)
In summary, we have developed an efficient direct
oxidative carbonꢀcarbon bond formation at the a-posi-
tion of carbamates based on the ‘cation pool’ method.
The present findings open a rich variety of synthetic
applications of the iminium cation pool method, espe-
cially in the field of synthesis of alkaloids. Further
investigations using other organometallic reagents and
mechanistic studies are in progress.
The reactions with other Grignard reagents having a
primary, secondary alkyl and ally groups also took
place smoothly, as shown in Table 1. Alkenyl, alkynyl,
and homoallyl magnesium halides can also be utilized
although the yields are moderate. Aryl magnesium
halides, such as phenylmagnesium bromide and o- or
p-substituted phenylmagnesium bromides, are also
added to the iminium cation smoothly to give the
corresponding arylated compounds. It is worth noting
that p-fluorophenylmagnesium bromide, having an
electronegative group on the aromatic ring, could be
utilized. The result overcomes our previous work in
which only highly electron-rich aromatic compounds
can be utilized as carbon nucleophiles.1 Other cation
pools generated from the carbamates of piperidine and
Acknowledgements
This research was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan.
MgCl
-2e, -H+
-72 oC
CO2Me
/Et2O
-72 oC, 20 min
+
+
:
N
N
N
N
N
+
(2)
CO2Me
CO2Me
CO2Me
CO2Me
:
66
20
14
Total yield 47%

S. Suga et al. / Tetrahedron Letters 42 (2001) 2173–2176
2175
Table 1. Reaction of Grignard reagents to electrogenerated ‘iminium cation pool’a
nucleophileb
product
substrate
% yield c
65%
EtMgCl / Et2O
N
N
CO2Me
CO2Me
67%
57%
n-BuMgCl / Et2O
MgCl / Et2O
N
CO2Me
N
CO2Me
45%
68%
54%
N
MgBr / THF
MgBr
CO2Me
/ Et2O
N
CO2Me
MgBr / Et2O
N
CO2Me
Ph
58%
63%
Ph
MgBr / THF,Et2Od
N
CO2Me
MgBr / Et2O
N
CO2Me
69%
MgBr / Et2O
MgBr / Et2O
MgBr / Et2O
N
CO2Me
OMe
F
MeO
61%
66%
N
CO2Me
F
N
CO2Me
N
PhMgBr / Et2O
72%
CO2Me
N
CO2Me
57%
50%
PhMgBr / Et2O
N
N
CO2Me
CO2Me
MgBr / Et2O
N
CO2Me
a After the electrolysis (2.5 F/mol based on the carbamates), a carbon nucleophile (2 equiv.) was added to the ‘cation pool’ thus generated at
−72°C. b Et2O or THF solutions of Grignard reagents were used. Grignard reagents were purchased or prepared from corresponding organic
halides. c Isolated yield. d Phenylacetylenylmagnesium chloride was prepared by treating phenylacetylene in THF with C2H5MgBr at room
temperature for 4 h.

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S. Suga et al. / Tetrahedron Letters 42 (2001) 2173–2176
Table 2. Reaction of organozinc and organoaluminum
reagents to the ‘iminium cation pool’ generated from
methyl pyrrolidinecarboxylatea
Pergamon Press: Oxford, 1991; Vol. 1, pp. 355–396; (b)
Kleinman, E. F.; Volkmann, R. A. In Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I., Eds. Reac-
tion of allyl and propargyl/allenic organometallics with
imine and iminium ions. Pergamon Press: Oxford, 1991;
Vol. 2, pp. 975–1006; (c) Hiemstra, H.; Speckamp, W. N.
In Comprehensive Organic Synthesis; Trost, B. M.; Flem-
ing, I., Eds. Addition to N-acyliminium ion. Pergamon
Press: Oxford, 1991; Vol. 2, pp. 1047–1082; (d) Speckamp,
W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817–
3856; (e) Bloch, R. Chem. Rev. 1998, 98, 1407–1438. See
also the following very recent papers: (f) Choucair, B.;
Le´on, H.; Mire´, M.-A.; Lebreton, C.; Mosset, P. Org. Lett.
2000, 2, 1851–1853; (g) Agami, C.; Couty, F.; Evano, G.
Org. Lett. 2000, 2, 2085–2088; (h) Millot, N.; Piazza, C.;
Avolio, S.; Knochel, P. Synthesis 2000, 941–948; (i) Mal-
danar, A. O.; Pilli, R. A. Tetrahedron Lett. 2000, 41,
7843–7846.
Nucleophilea
% Yield
Et2Zn/hexane
EtZnI/Et2Ob
Et3Al/hexane
Et2AlCl/hexane
74
65
72
55
a Hexane or Et2O solutions of the organometallic compounds were
used.
b Ethylzinc iodide was prepared by addition of ethyl iodide to zinc/
copper couple.
References
1. (a) Yoshida, J.; Suga, S.; Suzuki, S.; Kinomura, N.;
Yamamoto, A.; Fujiwara, K. J. Am. Chem. Soc. 1999, 121,
9546–9549; (b) Suga, S.; Suzuki, S.; Yamamoto, A.;
Yoshida, J. J. Am. Chem. Soc. 2000, 122, 10244–10245.
2. Two-step procedures via electrochemical oxidation, see: (a)
Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc.
1981, 103, 1172–1176; (b) Shono, T. Tetrahedron 1984, 40,
811–850; (c) Malmberg, M.; Nyberg, K. Acta Chem.
Scand., Ser. B 1979, 33, 69–72; (d) Mori, M.; Kagechika,
K.; Sasai, H.; Shibasaki, M. Tetrahedron 1991, 47, 531–
540; (e) Li, W.; Moeller, K. D. J. Am. Chem. Soc. 1996,
118, 10106–10112; (f) Danielmeier, K.; Schierle, K.; Steck-
han, E. Tetrahedron 1996, 52, 9743–9754. Enantiomerically
enriched methylphenidate was prepared using chiral Evans
imides as nucleophiles: (g) Matsumura, Y.; Kanda, Y.;
Shirai, K.; Onomura, O.; Maki, T. Org. Lett. 1999, 1,
175–178.
3. Two-step procedures via chemical oxidation, see: (a)
Murahashi, S.; Naota, T.; Kuwabara, T.; Saito, T.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1990,
112, 7820; (b) Naota, T.; Nakato, T.; Murahashi, S.
Tetrahedron Lett. 1990, 31, 7475–7478; (c) Murahashi, S.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2443–2465. See also
the oxidative introduction of alkoxy, azide, and cyano
group to the a-carbon of amides: (d) Han, G.; LaPorte, M.
G.; McIntosh, M. C.; Weinreb, S. M. J. Org. Chem. 1996,
61, 9483–9493; (e) Magnus, P.; Hulme, C.; Weber, W. J.
Am. Chem. Soc. 1994, 116, 4501–4502; (f) Chen, C.-K.;
Hortmann, A. G.; Marzabadi, M. R. J. Am. Chem. Soc.
1988, 110, 4829–4831.
5. The deprotonation–substitution sequence is also well
known as an efficient method for the introduction of a
substituent at the a-carbon of amide derivatives: Beak, P.;
Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S.
Acc. Chem. Res. 1996, 29, 552–560 and references cited
therein.
6. The anodic oxidation was normally carried out in an
H-type divided cell (4G glass filter) equipped with a car-
bon felt anode (Nippon Carbon JF-20-P7, ca. 320 mg,
dried at 250°C/1 mmHg for 1 h before use) and a pla-
tinium plate cathode (40×20 mm). In the anodic chamber
was placed a solution of substrate (0.4 mmol) in 0.3 M
Bu4NBF4/CH2Cl2 (8.0 mL). In the cathodic chamber were
placed 0.3
M Bu4NBF4/CH2Cl2 (8.0 mL) and trifl-
uoromethanesulfonic acid (0.4 mmol). The constant cur-
rent electrolysis (8 mA) was carried out at −72°C with
magnetic stirring until 2.5 F/mol of electricity was con-
sumed.
7. A review for addition of oganozinc reagents to car-
bonꢀnitrogen multiple bond, see: Erdik, E. Organozinc
Reagent in Organic Synthesis; CRC Press: Boca Raton,
1996; Chapter 5.
8. Reaction of a-alkoxy amide with trialkylaluminum has
been reported: (a) Kim, M. Y.; Starrett, J. E.; Weinreb, S.
M. J. Org. Chem. 1981, 46, 5383–5389; (b) Yamazaki, N.;
Suzuki, H.; Kibayashi, C. J. Org. Chem. 1997, 62, 8280–
8281; (c) Yamazaki, N.; Kibayashi, C. Tetrahedron Lett.
1997, 37, 4623–4626; (d) Yamazaki, N.; Suzuki, H.; Aoy-
agi, S.; Kibayashi, C. Tetrahedron Lett. 1996, 37, 6161–
6164.
4. Excellent reviews for organometallic addition to iminium
.
ions and imines, see: (a) Volkmann, R. A. In Comprehen-
sive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.
Nucleophilic addition to imines and imine derivatives.
9. (a) Agami, C.; Couty, F.; Hamon, L.; Puchot, K. Tetra-
hedron Lett. 1992, 33, 3645–3646; (b) Mayr, H.; Ofial, A.
R. Tetrahedron Lett. 1997, 38, 3503–3506.