Direct oxidative carbon-carbon bond formation using the cation pool method. 1. Generation of iminium cation pools and their reaction with carbon nucleophiles

Article abstract of DOI:10.1021/ja9920112

We have developed a method that involves the generation of a cation pool using low-temperature electrolysis, and then its reaction with nucleophiles under non-oxidative conditions. This one-pot method solves problems associated with conventional oxidative generation of cations and their in situ reaction with nucleophiles, and provides an efficient method for direct oxidative carbon-carbon bond formation. As an example of this method, generation of cation pools from carbamates by low-temperature electrolysis (-72°C) and their reactions with carbon nucleophiles such as allylsilanes, enol silyl ethers, and enol acetates were examined and the desired products were obtained in good yields. Aromatic compounds and 1,3-dicarbonyl compounds can also be utilized as carbon nucleophiles. The present method was also applied to combinatorial parallel synthesis using a robotic synthesizer.

Full text of DOI:10.1021/ja9920112

9546
J. Am. Chem. Soc. 1999, 121, 9546-9549
Direct Oxidative Carbon-Carbon Bond Formation Using the “Cation
Pool” Method. 1. Generation of Iminium Cation Pools and Their
Reaction with Carbon Nucleophiles
Jun-ichi Yoshida,* Seiji Suga, Shinkiti Suzuki, Naoya Kinomura, Atsushi Yamamoto, and
Kazuyuki Fujiwara
Contribution from the Department of Synthetic Chemistry & Biological Chemistry,
Graduate School of Engineering, Kyoto UniVersity, Kyoto 606-8501, Japan
ReceiVed June 14, 1999
Abstract: We have developed a method that involves the generation of a “cation pool” using low-temperature
electrolysis, and then its reaction with nucleophiles under non-oxidative conditions. This one-pot method solves
problems associated with conventional oxidative generation of cations and their in situ reaction with nucleophiles,
and provides an efficient method for direct oxidative carbon-carbon bond formation. As an example of this
method, generation of cation pools from carbamates by low-temperature electrolysis (-72 °C) and their reactions
with carbon nucleophiles such as allylsilanes, enol silyl ethers, and enol acetates were examined and the desired
products were obtained in good yields. Aromatic compounds and 1,3-dicarbonyl compounds can also be utilized
as carbon nucleophiles. The present method was also applied to combinatorial parallel synthesis using a robotic
synthesizer.
The oxidative deprotonation of organic compounds to gener-
Scheme 1. Oxidative Generation of a Carbocation and Its
Reaction with a Carbon Nucleophile in Situ
ate carbocations1 followed by their reactions with carbon
nucleophiles is one of the most straightforward approaches to
carbon-carbon bond formation (Scheme 1). This transformation
contrasts with the transformations starting from compounds
having a leaving group (Scheme 2), and serves as an efficient
method for carbon-carbon bond formation.
This type of transformation is, however, generally rather
difficult to achieve for the following reasons. Extensive studies
have been carried out for the generation of carbocations from
C-H compounds using superacids.2 For synthetic purposes,
however, milder reaction conditions which are compatible with
various functional groups are needed. To this end, electrochemi-
cal and chemical reactions have been developed.3 In these cases
the oxidative generation of a carbocation often needs to be
carried out in the presence of a nucleophile, because the
carbocations generated are generally not stable to the reaction
conditions used. Nucleophiles, especially carbon nucleophiles,
are, however, often easily oxidized during the course of
oxidative generation of the carbocation, although electrochemi-
cal or chemical oxidative cyanations have been achieved in the
presence of the cyanide ion.4
Scheme 2. Non-Oxidative Generation of a Carbocation and
Its Reaction with a Carbon Nucleophile in Situ
Scheme 3. Two-Step Procedure for Carbon-Carbon Bond
Formation Involving Temporary Trapping of a Oxidatively
Generated Carbocation
To avoid these problems, the two-step transformation shown
in Scheme 3 is usually used to achieve an oxidative carbon-
carbon bond formation.3 In the first step, the carbocation is
generated in the presence of an excess amount of a heteroatom
nucleophile (X-) of high oxidation potential such as methanol.
The nucleophile immediately traps the carbocation intermediate.
The “trapped carbocation” is separated and then is used for the
regeneration of the carbocation under non-oxidative conditions.
Thus, the treatment of the “trapped carbocation” with a Lewis
acid in the presence of a carbon nucleophile gives the desired
carbon-carbon bond formation product.
(1) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Ley,
S., Eds.; Pergamon Press: Oxford, 1991; Vol. 7 (Oxidation).
(2) For example: (a) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1995,
34, 1393-1405. (b) Stable Carbocation Chemistry; Prakash, G. K. S.,
Schleyer, P. v. R., Eds.; Wiley-Interscience: New York, 1997.
(3) For an electrochemical example, 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.; Steckhan, E. Tetrahedron 1996, 52, 9743-9754. For an example using
Ru catalyzed oxidation, see: Naota, T.; Nakato, T.; Murahasi, S. Tetrahe-
dron Lett. 1990, 31, 7475-7478.
This two-step procedure is tedious in comparison with the
direct reaction shown in Scheme 1. Therefore, we searched for
10.1021/ja9920112 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/25/1999

Direct OxidatiVe Carbon-Carbon Bond Formation
J. Am. Chem. Soc., Vol. 121, No. 41, 1999 9547
Scheme 4. The Oxidative Carbon-Carbon Bond Formation
of N-(Methoxycarbonyl)pyrrolidine (1) with
Allyltrimethylsilane (2)
Figure 1. “Cation pool” method for oxidative carbon-carbon bond
formation.
Table 1. Effect of the Temperature on the Electrolysis of 1a
a general method for the direct reaction of oxidatively generated
carbocation intermediates with carbon nucleophiles to achieve
the carbon-carbon bond formation, and found that a “cation
pool” method is quite effective for this type of transformation
(Figure 1). In the “cation pool” method, carbocations are
generated and accumulated in relatively high concentration by
electrochemical oxidation at low temperature. In the next step,
the carbocations are allowed to react with nucleophiles. This
one-pot method has an advantage over conventional processes
because nucleophiles that might be otherwise oxidized during
an in situ process can be used without any difficulty. In addition,
there is no need for temporary trapping of the carbocation
intermediate, isolation of the “trapped carbocation”, or a Lewis
acid promoted regeneration of the carbocation.
temp (°C)
conversion (%)
yieldb (%)
-72
-47
-25
0
100
100
84
77
61
82
78
31
10
5
20
a After the electrolysis (2.5 F/mol based on 1), the “cation pool” of
3 thus generated was allowed to react with 2 (2 equiv). b Determined
by GC analysis.
of the desired product 4 in only 7% yield. Probably 2 was
oxidized preferentially because 75% of 1 was recovered
unchanged. The oxidation potential of the product 4 (Eox ) 1.90
V) was very close to that of 1 implying that overoxidation of 4
would also be a problem for this reaction, although the
overoxidized products were not detected. It is also noteworthy
that the electrochemical oxidation of 1 in the absence of 2 at
room temperature followed by the addition of 2 gave a complex
mixture, probably because iminium cation 3 decomposed during
the electrolysis (vide infra).
We report herein the principle of the “cation pool” method
and its application to the oxidative carbon-carbon bond forming
reactions of nitrogen-containing compounds. The usefulness of
this tool for both conventional and combinatorial organic
syntheses is examined.
Results and Discussions
The “cation pool” method solved these problems. The
electrochemical oxidation of 18 was carried out in CH2Cl2 using
a graphite felt anode at -72 °C in the absence of 2. At this
temperature, the iminium cation 3 was accumulated without
decomposition. Although the conventional electrolysis is usually
carried out at much higher temperature because the conductivity
of the solution generally decreases with decrease of the
temperature, the tuning of the electrolysis conditions such as
the concentrations of the substrate and the electrolyte, and
additives (see the Supporting Information) enabled us to perform
the preparative electrolysis at such a low temperature. After the
electrolysis was completed, 2 (2 equiv) was added to the newly
generated “iminium cation pool” containing 3 to obtain the
desired carbon-carbon bond formation product 4 in 82% yield
(method A). The yield of 4 decreased dramatically with the
increase of temperature of the electrolysis (Table 1), indicating
that the reaction temperature was essential for the accumulation
of the cation. It was difficult to suppress the decomposition of
3 at temperatures higher than ca. -50 °C. In addition to the
yield the conversion of 1 also decreased with increasing
electrolysis temperature. Presumably, the decomposition product
derived from 3 was also oxidized to consume the electricity,
although the decomposition product was not identified. The
choice of the supporting electrolyte was also important for the
low-temperature electrolysis to generate the “cation pool”. The
use of Bu4NBF4 as the supporting electrolyte gave the highest
We chose carbamates as precursors of cations because
oxidation of the carbon adjacent to the nitrogen atom to generate
the corresponding iminium cation is well-established as a
biomimetic type oxidation and enjoys various applications in
organic synthesis.5,6 As carbon nucleophiles, we first examined
allylsilanes because their reactions with carbocations are also
well-established.7 The reaction of N-(methoxycarbonyl)pyrro-
lidine (1) with allyltrimethylsilane (2) is representative (Scheme
4). Compound 1 (oxidation potential Eox ) 1.91 V vs Ag/AgCl
in 0.1 M Bu4NClO4/CH2Cl2) is less easily oxidized than
compound 2 (Eox ) 1.75 V). As a matter of fact, the oxidation
of a mixture of 1 and 2 equiv of 2 under electrolytic conditions
(divided cell at room temperature) gave rise to the formation
(4) As an exception, direct introduction of CN- has been achieved
because the oxidation potential of CN- is relatively high. It is also
noteworthy that the CN group is strongly electron-withdrawing so that the
oxidation potential of the product is expected to be much higher than the
starting material. Electrochemical cyanation: (a) Chiba, T.; Tanaka, Y. J.
Org. Chem., 1977, 42, 2973-2977. Chemical oxidative cyanation: (b) Chen,
C.-K.; Hortmann, A. G.; Marzabadi, M. R. J. Am. Chem. Soc. 1988, 110,
4829-4831. Some amines having very low oxidation potentials, such as
dimethylmesidine, could exceptionally be substrates for the electrooxidative
C-C bond formation: (c) Renaud, R. N.; Be´rube´, D.; Stephens, C. J. Can.
J. Chem. 1983, 61, 1379-1382.
(5) Electrochemical R-oxidation of amine derivatives: (a) Shono, T.
Electroorganic Chemistry as a New Tool in Organic Synthesis; Springer-
Verlag: Berlin, 1984. Transition metal promoted R-oxidation of amine
derivatives: (b) Murahashi, S. Angew. Chem., Int. Ed. Engl. 1995, 34,
2443-2465.
(6) Reviews for the synthetic utility of acyliminium cation, see: (a)
Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-4416. (b)
Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I. Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 1047-
1082. (c) Zaugg, H. E. Synthesis 1984, 85-110. (d) Zaugg, H. E. Synthesis
1984, 181-212.
(8) The conventional electrochemical oxidation of carbamates using
methanol as a nucleophile has been developed: (a) Shono, T.; Hamaguchi,
H.; Matsumura, Y. J. Am. Chem. Soc. 1975, 97, 4264-4268. (b) Shono,
T.; Matsumura, Y.; Tsubata, K. Org. Synth. 1985, 63, 206-213. The
oxidative R-methoxylation of amides has also been reported: (c) Ross, S.
D.; Finkelstein, M.; Peterson, R. C. J. Am. Chem. Soc. 1966, 80, 4657-
4660. (d) Nyberg, K.; Servin, R. Acta Chem. Scand., Ser. B 1976, 30, 640-
642.
(7) For example: (a) Sakurai, H. Pure Appl. Chem. 1982, 54, 1-22. (b)
Chan, T. H.; Fleming, I. Synthesis 1979, 761-786.

9548 J. Am. Chem. Soc., Vol. 121, No. 41, 1999
Yoshida et al.
Table 2. Thermal Stability of the “Cation Pool” of 3 after the
Table 4. Direct Carbon-Carbon Bond Formation of Carbamate 1
with Aromatic Compounds and 1,3-Dicarbonyl Compounds Using
the “Cation Pool” Method
Electrolysisa
temp (°C)
conversion (%)
yieldb (%)
-72
-47
-25
0
100
100
100
100
100
82
80
83
81
76
20
a After the electrolysis (2.5 F/mol based on 1), the “cation pool” of
3 thus generated was kept at the designated temperature for 0.5 h and
then was allowed to react with 2 (2 equiv). b Determined by GC
analysis.
Table 3. Direct Carbon-Carbon Bond Formation of Carbamates
with Allylsilanes, Enol Silyl Ethers, and Related Compounds Using
the “Cation Pool” Methoda
a Method B: After the electrolysis (2.5 F/mol based on 1) at -72
°C, the “cation pool” thus generated and a solution of an aromatic
compound (1 equiv) were added simultaneously to an empty reaction
flask cooled at -72 °C. The reaction was completed immediately.
Method C: To the “cation pool” thus generated was added an excess
amount of an aromatic compound or a 1,3-dicarbonyl compound, and
the mixture was stirred at 0 °C for 24 h. b Isolated yields.
a After the electrolysis (2.5 F/mol based on the carbamates) at -72
°C, the carbon nucleophile (2 equiv) was added at the same temperature
to the “cation pool” thus generated, and then the reaction mixture was
stirred for 30-120 min to give the product (method A). b A carbon
nucleophile was added to the “cation pool” at -28 °C. c Determined
by GC analysis. d The reaction using a robotic synthesizer was carried
out at 0 °C. The dash means that the reaction was not tried.
electrolysis shown in Table 1. There seems to be significant
difference between the stability of 3 during the electrolysis and
that after the electrolysis, although the mechanistic details have
not been clarified as yet.
It is important to know the nature of the “cation pools”
generated by the low-temperature electrolysis. Are they ionic
compounds or covalent compounds? To gain insight into this
point, the “cation pool” generated by low-temperature elec-
trolysis of 1 in CD2Cl2 was analyzed by NMR spectroscopy.10
1H NMR spectroscopy exhibited a single set of signals at 2.45,
3.54, 4.09, 4.45, and 9.38 ppm at 0 °C. These signals did not
yield of 4 among the electrolytes examined (PF6- (48%), OTf-
-
(59%), and ClO4 (5%)). The stability of 3 and its reactivity
toward 2 were also dependent upon the nature of the counter-
anion derived from the supporting electrolyte.9
The thermal stability of the “cation pool” was also studied.
Thus, the electrolysis of 1 was carried out at -72 °C (ca. 3.5
h). After the electrolysis was completed, the “cation pool” was
allowed to warm to a second temperature. After being kept there
for 0.5 h, the carbocation was then allowed to react with 2 at
the same temperature. As shown in Table 2, the “cation pool”
of 3 is rather stable at temperatures lower than 0 °C. This
observation contrasts sharply with the temperature effect of the
(10) NMR study of iminium cations have been reported: (a) Yamamoto,
Y.; Nakada, T.; Nemoto, H. J. Am. Chem. Soc. 1992, 114, 121-125. (b)
Kodama, Y.; Okumura, M.; Yanabu, N.; Taguchi, T. Tetrahedron Lett. 1996,
37, 1061-1064. (c) Mayr, H.; Ofial, A. R.; Wu¨rthwein, E.-U.; Aust, N. C.
J. Am. Chem. Soc. 1997, 119, 12727-12733 and references therein. It has
been reported that the covalent structure exhibits the signal at 7.9 ppm in
1H NMR spectroscopy: (d) Bose, A. K.; Spiegelman, G.; Manhas, M. S.
Tetrahedron Lett. 1971, 3167-3170.
(9) For the effect of the counteranion on reactivity, see: Yamaguchi,
R.; Hatano, B.; Nakayasu, T.; Kozima, S. Tetrahedron Lett. 1997, 38, 403-
406.

Direct OxidatiVe Carbon-Carbon Bond Formation
J. Am. Chem. Soc., Vol. 121, No. 41, 1999 9549
change significantly when the temperature was decreased to -80
°C, indicating that a single species was generated by the low-
temperature electrolysis. The chemical shifts of the signals were
consistent with the structure of the iminium cation. The chemical
shift of the methine proton at 9.38 ppm indicated that this species
was an iminium cation and not a covalently bonded intermediate.
In 13C NMR spectroscopy the “cation pool” exhibited a single
signal at 193.36 ppm at 0 °C due to the methine carbon. This
value also suggests the presence of a strong positive charge at
the carbon, again supporting the formation of the “cation pool”
as a solution of a single ionic species. Currently it is difficult
to distinguish whether the iminium cation is a free ion or an
ion pair.
The generality of the “cation pool” method was demonstrated
by the results shown in Table 3. The reaction of the “cation
pool” of 3 generated from 1 with other allylsilanes such as
2-cyclopentenyltrimethylsilane and 2-cyclohexenyltrimethylsi-
lane took place smoothly indicating the effectiveness of
substituted allylsilanes as nucleophiles. The reaction with other
carbon nucleophiles such as enol silyl ethers and enol acetates
also proceeded smoothly to give the corresponding carbon-
carbon bond formation products. The “cation pools” of other
iminium ions were also generated from carbamates derived from
piperidine and diethylamine, and they were effective for the
carbon-carbon bond formation.
Aromatic compounds and 1,3-dicarbonyl compounds (Table
4) can also be utilized as carbon nucleophiles. In the case of
aromatic compounds with high reactivity such as 1,3,5-tri-
methoxybenzene, a solution of the cation and a solution of a
nucleophile (1 equiv) were added simultaneously to an empty
reaction vessel (method B) to avoid undesired side reactions
such as polyalkylation. In the case of less reactive aromatic
compounds such as 1,3,5-trimethylbenzene, a solution of the
cation was added to an aromatic compound (excess amount)
and the mixture was stirred at 0 °C for 24 h (method C). For
the reaction with 1,3-dicarbonyl compounds such as dimethyl
malonate and acetylacetone (2,4-pentanedione), method C was
employed.
Figure 2. Combinatorial parallel synthesis based on the “cation pool”
method.
the carbon-carbon bond formation. The yields of the products
were essentially the same as those obtained by the one-pot
reactions with manual operation as shown in Table 3. The
present results demonstrate the potentiality of the parallel
synthesis based on the “cation pool” method and open a new
aspect of automated solution-phase combinatorial synthesis.12
Conclusion
The “cation pool” method described in this paper provides a
new, efficient procedure for direct oxidative carbon-carbon
bond formation. This methodology, which involves first the
generation of a cation pool using low-temperature electrolysis
and second a reaction of the cation pool with nucleophiles under
non-oxidative conditions, solved problems associated with
conventional oxidative generation of cations and their in situ
reactions with nucleophiles. The present method can also be
applied to solution-phase combinatorial parallel synthesis using
a robotic synthesizer. This concept will hopefully make
significant contributions to carbocation chemistry and open a
new aspect of organic synthesis using carbocations.
In addition to using the “cation pool” method for conventional
organic synthesis, it was also applied to solution-phase com-
binatorial parallel synthesis.11 The opportunities for variation
in the source of “cation pools” and nucleophiles in this work
enabled the direct synthesis of a variety of coupling products.
Thus, the substrate was subjected to low-temperature electrolysis
to generate the “cation pool” which was then divided into several
portions as shown in Figure 2. The portions were each allowed
to react with different nucleophiles to give the corresponding
coupling products. To demonstrate the feasibility of this concept,
the “cation pool” of 3 generated from 1 was delivered to several
reaction vessels cooled at 0 °C using a robotic synthesizer. To
each vessel was added a different nucleophile to accomplish
Acknowledgment. This research was supported by a Grant-
in-Aid for Scientific Research from Monbusho. We thank Tecan
Japan Ltd. for giving us opportunities to use a robotic
synthesizer.
Supporting Information Available: Experimental details
including conditions for electrolysis and spectroscopic data of
the products (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA9920112
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509. (c) Studer, A.; Hadida, S.; Ferritto, R.; Kim. S.-Y.; Jeger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823-826. (d) Cheng, S.; Commer, D.
D.; Williams, J. P. Myers, P. L.; Boger, D. L. J. Am. Chem. Soc. 1996,
118, 2567-2573 and references therein.
(11) For example: (a) Borman, S. Chem. Eng. News 1996 (February
12), 28-73. (b) Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96,
555-600. (c) Borman, S. Chem. Eng. News 1997 (February 24), 43-62.
(d) Borman, S. Chem. Eng. News 1999 (March 3), 33-48. (e) Dagani, R.
Chem. Eng. News 1999 (March 3) 51-60 and references therein.