Tandem N-alkylation-C-allylation reaction of α-imino esters with organoaluminums and allyltributyltin

Article abstract of DOI:10.1021/ja029639o

On treatment of various α-imino esters with organoaluminum reagents and allyltributyltin in the presence of benzoyl peroxide, the tandem reaction proceeded to give the N-alkylation-C-allylation products in good yields. The tandem N-alkyation-C-cyanation also proceeded using silyl or aluminum cyanide to give the aminonitrile in good yield. Copyright

Full text of DOI:10.1021/ja029639o

Published on Web 03/11/2003
Tandem N-Alkylation-C-Allylation Reaction of r-Imino Esters with
Organoaluminums and Allyltributyltin
Yasuki Niwa and Makoto Shimizu*
Department of Chemistry for Materials, Mie UniVersity, Tsu, Mie 514-8507, Japan
Received December 9, 2002; E-mail: mshimizu@chem.mie-u.ac.jp
Scheme 1
Nucleophilic addition to the nitrogen atom of simple imines is,
in principle, difficult due to the electron negativity of the imino
functionality. Only limited examples have been available for the
nucleophilic addition to the nitrogen atom of R-imino esters.1 We
have focused on the reactivity of R-imino esters and have revealed
several interesting features.2,3 During these studies, we found that
on treatment of the imino ester 1a with diethylaluminum chloride
in the presence of benzoyl peroxide (BPO), diethylation product
2a was obtained (Scheme 1).
Table 1. Tandem N-Ethylation-C-Allylation Reaction under
Various Conditions
This result induced us to explore the intriguing reactivity of the
R-imino esters, and we have now found an unprecedented reaction
for the synthesis of R,R-disubstituted amino acids. This paper
presents a tandem N-alkylation-C-allylation reaction of R-imino
esters using organoaluminum reagents and allyltributyltin.
First, the addition of two different nucleophiles to the imine 1a
was investigated. Allyltributyltin was chosen as a second alkylating
reagent due to its highly nucleophilic nature as well as to the ability
to act as a radical source.4 The results are shown in Table 1. The
imino ester 1a was prepared by condensation of ethyl benzoylfor-
mate with p-anisidine. In DME solution, the reaction of diethyl-
aluminum chloride gave the allylation product 4a in 67% yield along
with the diethylation product 2a in 8% yield (entry 1). The reaction
of ethylaluminum dichloride was more selective, although the yield
was moderate (entry 2). Both the yield and the selectivity were
improved using a mixture of diethylaluminum chloride (1 equiv)
and ethylaluminum dichloride (1 equiv) (entry 3). Regarding the
solvent, propionitrile was found to be the most effective, as it
afforded the allylation product 4a in 73% yield (entries 3-8).
Using optimized conditions, we examined the reaction with
several imino esters 1a-i. The reaction was carried out as
follows: to a solution of BPO and the imino ester in propionitrile
were added Et2AlCl, EtAlCl2, and allyltributyltin successively at
-20 °C. After the starting material disappeared on TLC, a usual
workup followed by purification gave the N-ethylation-C-allylation
products 4a-i. The results are summarized in Table 2. The aliphatic
as well as aromatic imino esters underwent the tandem N-ethyl-
ation-allylation to give the addition products in moderate to good
yields.
entry
EtnAlCl3-n
Et2AlCl
EtAlCl2
Et2AlCl + EtAlCl2
Et2AlCl + EtAlCl2
Et2AlCl + EtAlCl2
Et2AlCl + EtAlCl2
Et2AlCl + EtAlCl2
Et2AlCl + EtAlCl2
solvent
time (h)
4a (%)
2a (%)
1
2
3
4
DME
DME
DME
Et2O
9
8
9
9
9
20
7
8
67
57
73
41
65
22
73
70
8
1
2
6
1
<1
<1
2
5a
6b,c
7
THF
CH2Cl2
EtCN
MeCN
8
a N-Ethylation product 3a was also obtained in 18% yield. b Carried out
from -20 °C to room temperature. c N-Ethylation product 3a was also
obtained in 40% yield.
Table 2. Tandem N-Ethylation-C-Allylation Reaction with Various
R-Imino Esters
entry
R (1)
time (h)
product
yield (%)a
1
2
3
4
Ph (1a)
7
8
7
7
7
7
7
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
75
47
62
63
76
34
50
39
18
oAn (1b)
pAn (1c)
pTol (1d)
5b
6c,d
7e
8
pCl-C6H4 (1e)
2-thienyl (1f)
cyclopropyl (1g)
cHex (1h)
9c
H (1i)
To increase the utility of this tandem alkylation-allylation
reaction, bis(trimethylsilyl)aluminum chloride was used as an initial
N-alkylation reagent,5,6 and the results are summarized in Table 3.
As shown in entry 1, a tandem N-silylation-C-allylation reaction
proceeded with bis(trimethylsilyl)aluminum chloride on heating
the mixture to 50 °C to afford the homoallylamine 5a in 93% yield.
On the other hand, the allylation did not proceed in the absence of
BPO (entry 2). Other R-imino esters could also be used for the
present N-silylation-C-allylation reaction to give the products in
good to excellent yields (entries 3-7).
a Isolated yield. b Et2AlCl (1.5 equiv) and EtAlCl2 (1.5 equiv) were used.
c Carried out from -50 °C to room temperature. d Et2AlCl (2 equiv) was
used. e Carried out from -78 °C to room temperature.
dichloride, N-ethylation product 2a was obtained in 76% yield. After
the N-ethylation, BPO or 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ) with allyltributyltin was added, which actually gave
the desired allylation product 4a. To check the possibility of the
involvement of a radical mechanism, the tandem reaction was
carried out in the presence of galvinoxyl or 1,4-cyclohexadiene as
a radical scavenger. However, the yields did not decrease, indicating
that an ionic mechanism might be involved.
To clarify the reaction mechanism, several reaction conditions
were examined (Scheme 2). When the imino ester 1a was treated
with a mixture of diethylaluminum chloride and ethylaluminum
9
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J. AM. CHEM. SOC. 2003, 125, 3720-3721
10.1021/ja029639o CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Tandem N-Silylation-C-Allylation Reaction
Scheme 4
entry
R
time (h)
product
yield (%)a
1
2b
3
4
5
6
7
Ph (1a)
Ph (1a)
23
25
25
24
24
28
23
5a
5a
5c
5d
5e
5f
93
0c
In conclusion, the tandem N-alkylation-C-allylation and N-alky-
lation-C-cyanation reactions of several R-imino esters with orga-
noaluminums were carried out in good to excellent yields, where
two nucleophiles attacked across the CdN double bond. The tandem
reaction consists of the following three sequences: nucleophilic
addition to the nitrogen atom of the imino ester, oxidation of the
enolate with BPO, and allylation (or cyanation) to the resulting
iminium salt. The synergetic effect of Et2AlCl and EtAlCl2 is of
interest, and we are currently investigating it in more detail.
pAn (1c)
84
83
73
61
58
pTol (1d)
pCl-C6H4 (1e)
2-thienyl (1f)
cyclopropyl (1g)
5g
a Isolated yield. b In the absence of BPO. c The reduction product was
obtained in 57% yield.
Scheme 2
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education, Science,
Sports, Culture, and Technology, Japan.
Supporting Information Available: Experimental procedures and
product characterization for new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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Scheme 3
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On the basis of these results, a possible mechanism of the present
tandem reaction is shown in Scheme 3. First, 1,4-addition of the
ethyl group proceeds at the nitrogen atom of the imino ester to
give an enolate species. The enolate (A) is subsequently oxidized
with BPO (B) to form an iminium salt (C), which is attacked by
allyltributyltin to afford the C-allylation product.
The tandem reaction was also carried out using trimethylsilyl
cyanide instead of allyltributyltin to give the amino nitrile 6 in 83%
yield (Scheme 4). It is interesting to note that in the presence of
BPO, diethylaluminum cyanide acted as both ethylation and
subsequent cyanation reagent to afford the amino nitrile 6 in 73%
yield.7 Although diethylaluminum cyanide has been used as the
cyanide source in Strecker reaction,8 its intriguing behavior as an
ethylating reagent is unknown.
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AlCN/BPO, only a trace of N-ethylation-C-cyanation product was
obtained.
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Oiarbide, M.; Landa, A. J. Org. Chem. 2000, 65, 41. (c) Davis, F. A.;
Portonove, P. S.; Reddy, R. E.; Chiu, Y. J. Org. Chem. 1996, 61, 440.
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