N-alkylation of phthalimide, carboxamide, and sulfonamides by oxdation-reduction condensation using di-tert-butyl-1,4-benzoquinone and alkyl diphenylphosphinite

Article abstract of DOI:10.1246/cl.2005.142

Various N-alkylamides were obtained in high yields under mild conditions by treating alkyl diphenylphosphinite with phthalimide, carboxamide or sulfonamides in the presence of 2,6-di-tert-butyl-1,4-benzoquinone (DBBQ) by oxdation-reduction condensation. C

Full text of DOI:10.1246/cl.2005.142

1
42
Chemistry Letters Vol.34, No.2 (2005)
N-Alkylation of Phthalimide, Carboxamide, and Sulfonamides By Oxdation–Reduction
Condensation Using Di-tert-butyl-1,4-benzoquinone and Alkyl Diphenylphosphinite
ꢀy;yy
y;yy
and Hidenori Aoki
Teruaki Mukaiyama
Center for Basic Research, The Kitasato Institute, 6-15-5 (TCI), Toshima, Kita-ku, Tokyo 114-0003
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641
y
yy
(Received October 29, 2004; CL-041289)
Table 1. Screening of quinone derivatives on benzylation of
phthalimide
Various N-alkylamides were obtained in high yields under
mild conditions by treating alkyl diphenylphosphinite with
phthalimide, carboxamide or sulfonamides in the presence of
O
Ph POBn (1.1 equiv.)
O
2
2,6-di-tert-butyl-1,4-benzoquinone (DBBQ) by oxdation–reduc-
tion condensation.
Quinone (1.1 equiv.)
CH Cl , rt, 1 h
NH
NBn
2
2
O
O
(
1.0 equiv.)
It was recently reported from our laboratory that a new
type of oxidation–reduction condensation using alkyl diphenyl-
phosphinite (Ph2POR) formed from n-BuLi-treated alcohols
and chlorodiphenylphosphine, 2,6-dimethyl-1,4-benzoquinone
(DMBQ) and carboxylic acids afforded alkyl carboxylates from
alcohols including chiral tertiary ones in good to high yields with
Entry Quinone Yield /% Entry
Quinone Yield /%
t
Bu
1
2
O
O
O
O
52
4
5
O
O
O
28
91
t
inversion of configurations in high levels (up to >99:9% inver-
1
F
F
F
F
Bu
sion). This method was further applied to the synthesis of alkyl
2
2
,1b
3
N.D.
O
aryl ethers,
dialkyl ethers, primary nitriles, and alkyl aryl
4
sulfides. In order to extend the scope of this type of condensa-
tion reaction, our attention was next focused on carbon–nitrogen
bond forming reaction.
t
t
Bu
Bu
Among carbon–nitrogen bond forming reactions via oxida-
tion–reduction condensation, the Mitsunobu alkylation method
that uses alcohols and various nitrogen containing nucleophiles
and a combination of triphenylphosphine and diethyl azodicar-
boxylate under mild conditions is known well. In this type of
N-alkylation, however, nucleophiles are generally limited to
3
O
O
13
6
O
O
N.D.
t
Bu
5
rivatives were examined in order to increase the yield (Entries
3–6). When simple 1,4-benzoquione or 2-tert-butyl-1,4-benzo-
quione was used, the yield was low (Entries 3, 4). Interestingly,
the yield turned to 91% when DBBQ having bulky substituent at
2,6-positions was employed but that nothing was produced when
2,5-di-tert-butyl-1,4-benzoquinone was used (Entries 5, 6).
In order to further confirm the usefulness of DBBQ, N-alkyl-
ations of phthalimide were tried by using 1,4-benzoquione,
DMBQ, or DBBQ (Table 2). As a result, DBBQ gave good re-
sults in condensations of primary, secondary or tertiary alcohols
with phthalimide. It is further noted that the corresponding com-
pound was obtained in 72% yield with perfect inversion on treat-
ing (1R, 2S, 5R)-(–)-(l)-menthyl diphenylphosphinite with
phthalimide at room temperature (Entry 9). In the case of 2-
methy-4-phenyl-2-butanol, the yield of the desired product was
low because ꢀ-eliminations took place faster than N-alkylation
of phthalimide and gave two corresponding olefins (Entry 12).
Next, N-benzylation of amides using DBBQ was studied in
detail (Table 3). As a result, DBBQ was found highly reactive
when amides such as carboxamide and sulfonamides were used.
Finally, the desired N-alkylated compound was obtained in 59%
yield with the use of N-benzyltrifluoroacetamide (pKa ¼ 13:6),
whose yield remained low in the Mitsunobu alkylation reaction
the compounds having nitrogen-hydrogen bond of pKa values
6
which is lower than that of 13 such as sulfonamides or cyclic
7
imides. Recently, Tsunoda et al. reported alkylation reaction
of nucleophiles having higher pKa than 13 which took place like-
wise by using alcohols and cyanomethylenetributylphosphorane
8
9
(CMBP) or cyanomethylenetrimethylphosphorane (CMMP).
Bombrun et al. demonstrated also that CMMP is a reagent of
choice for the N-alkylation of 1H-indole and 9H-carbazole de-
1
0
rivatives with primary, secondary, and tertiary alcohols while
Zaragoza et al. reported cyanomethyphophonium iodides which
are easy to be prepared and are inert to air, water, or alcohols at
room temperature to be good promoters for intermolecular N-al-
1
1
kylation of aliphatic amines with alcohols.
Here, we would like to describe high-yielding preparation of
N-alkylamides by way of a new type of oxdation–reduction con-
densation using alkyl diphenylphosphinite, amides such as
phthalimide, carboxamide, or sulfonamides and 2,6-di-tert-
butyl-1,4-benzoquinone (DBBQ) under mild conditions.
In the first place, N-benzylation of phthalimide with 1.1
equiv. of benzyl diphenylphosphinite was tried by using 1.1
equiv. of DMBQ and the desired product was obtained within
8
1
h in moderate yield at room temperature (Table 1, Entry 1).
(Entry 9).
On the other hand, the corresponding compound was not ob-
tained when tetrafluoro-1,4-benzoquinone was used under the
same conditions (Entry 2). Then, various 1,4-benzoquinone de-
A proposed reaction mechanism is shown in Scheme 1: alkyl
diphenylphosphinite reacted initially with DBBQ to form adduct
1 which in turn transformed to phosphonium salt 2 by the inter-
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.2 (2005)
143
Table 2. Effect of quinone derivatives on N-alkylation of
phthalimide
t
t
Bu
Ph
Ph
OR
O
Ph POR
P
2
Phthalimide
O
t
t
O
n
Bu
BuLi /Hexane
Ph PCl
(
1.0 equiv.)
Quinone
Bu H NR R
1 2
2
NR
O
O
ROH
Ph POR
2
1
THF 0°C − rt, 1 h
CH Cl , rt
2 2
O
Bu
NR R
1
2
Entry Ph POR/equiv.
Quinone /equiv. Time /h Yield /%
t
t
2
R
Bu
Bu
OH
Ph
Ph
O
O
Ph
O
O
1
1,4-Benzoquinone
DMBQ 1.1
DBBQ
19
51
88
9
P
P
OPPh2
OH
R R NR+ Ph
1 2
2
3
4
5
6
Ph
Ph
1
1
t
3
t
1.1
1.1
Bu
Bu
2
1,4-Benzoquinone
DMBQ 1.1
DBBQ
Scheme 1.
47
75
OPPh2
none (0.33 mmol) was added a solution of benzyl diphenylphos-
1
3
phinite (0.33 mmol) in dichloromethane (0.25 mL) at room
temperature under argon atmosphere. The reaction mixture
was stirred for 1.0 h at room temperature. After completion of
the reaction (detected by TLC) it was quenched with water
and the mixture was extracted with dichloromethane. The organ-
ic layers were dried over anhydrous sodium sulfate, filtered and
concentrated. The crude product was purified by preparative
TLC to afford the corresponding N-benzylphthalimide in 91%
yield.
Thus, it is noted that 2,6-di-tert-butyl-1,4-benzoquinone is
the most suitable oxidant for the preparations of N-alkylamides
by way of a new type of oxdation–reduction condensation using
alkyl diphenylphosphinites, quiones, and amides such as phtha-
limide, carboxamide or sulfonamides. Further study on this type
of condensation reaction is now in progress.
7
8
1,4-Benzoquinone
DMBQ 2.0
N.D.
a
1
22
OPPh2
a
9
2.0
DBBQ
72
10
11
12
1,4-Benzoquinone
DMBQ 2.0
DBBQ
N.D.
13
Ph
OPPh2
12
2.0
24
aThe corresponding compound was obtained with perfect inver-
sion.
Table 3. Effect of quinone derivatives on N-benzylation of
various amides
Quinone (1.1equiv.)
This study was supported in part by the Grant of the 21st
Century COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
Ph POBn (1.1equiv.)
2
R R NH
R R NBn
1
2
1
2
CH Cl , rt, 1 h
2
2
(
1.0 equiv.)
References and Notes
Entry
R R NH
Quinone
Yield /%
1
2
1
a) T. Shintou, K. Fukumoto, and T. Mukaiyama, Bull. Chem.
Soc. Jpn., 77, 1569 (2004). b) T. Shintou, W. Kikuchi, and T.
Mukaiyama, Bull. Chem. Soc. Jpn., 76, 1645 (2003). c) T.
Mukaiyama, T. Shintou, and K. Fukumoto, J. Am. Chem.
Soc., 125, 10538 (2003).
1
2
3
1,4-Benzoquinone
DMBQ
79
94
97
TsNHBoc
a
(
pK 5.1)
a
DBBQ
4
5
6
7
8
1,4-Benzoquinone
DMBQ
3
21
2
3
T. Shintou and T. Mukaiyama, J. Am. Chem. Soc., 126, 7359
(2004).
T. Mukaiyama, K. Masutani, and Y. Hagiwara, Chem. Lett., 33,
TsNHMe
(
pK 11.7)
a
DBBQ
88
1
192 (2004).
1,4-Benzoquinone
DMBQ
Trace
4
59
4
5
6
T. Mukaiyama and K. Ikegai, Chem. Lett., 33, 1522 (2004).
O. Mitsunobu, Synthesis, 1981, 1.
a) M. L. Edwards, D. M. Stemerick, and J. R. McCarthy,
Tetrahedron, 50, 5579 (1994). b) I. Koppel, J. Koppel, F.
Degerbeck, L. Grehn, and U. Ragnarsson, J. Org. Chem., 56,
7172 (1991).
CF CONHBn
3
(
pK 13.6)
a
9
DBBQ
aSee Ref. 12.
action with amides such as phthalimide, carboxamide and sulfo-
namides. An intramolecular attack of the amide anion to the car-
bon atom adjacent to an oxygen atom of the alkoxy group afford-
ed the corresponding N-alkylamides along with diphenylphos-
phiric acid 4-hydroxy-3,5-di-tert-butylphenyl ester 3. The high
activity of DBBQ in this reaction may be attributed to the two
bulky substituents of DBBQ which prevented the occurrence
of side reactions caused by phenoxy anion generated by the at-
tack of alkyl diphenylphosphinite to DBBQ.
7
8
a) Z. J. Jia, Synlett, 1999, 565. b) M. A. Walker, J. Org. Chem.,
6
0, 5352 (1995).
T. Tsunoda, F. Ozaki, and S. Ito, Tetrahedron Lett., 35, 5081
1994).
(
9 S. Ito and T. Tsunoda, Pure Appl. Chem., 71, 1053 (1999).
10 A. Bombrun and G. Casi, Tetrahedron Lett., 43, 2187 (2002).
11 F. Zaragoza and H. Stephensen, J. Org. Chem., 66, 2518 (2001).
12 I. Koppel, J. Koppel, I. Leito, V. Pihl, L. Grehn, and U.
Ragnarsson, J. Chem. Res., Synop., 1994, 212.
Typical experimental procedure is as follows: To a mixture
of phthalimide (0.3 mmol) and 2,6-di-tert-butyl-1,4-benzoqui-
13 Preparation of various alkyl diphenylphosphinites: See Ref. 1
or 4.
Published on the web (Advance View) December 25, 2004; DOI 10.1246/cl.2005.142