C
S. Asai et al.
Letter
Synlett
Table 3 N-Monoalkylation of Primary Amides
N,N-dialkyl amides by silica gel column chromatography.
Consequently, the present N-monoalkylation method is
useful from the viewpoint of using stable and easily han-
dled alkylating reagents.
O
O
O
base (1.8 equiv)
R'
R'
PO(OR')3 (3.0 equiv)
NH2
N
N
H
CPME, 115 °C, 24 h
R'
1a
2
3
Acknowledgment
Entry
R′
Solvent
Yielda
We thank the Zeon Corporation for the kind gift of CPME.
1a
2
3
1
2
3
4
5
6
Et
NaOH
BuLi
93
7
NDb
ND
ND
ND
ND
ND
Supporting Information
7
54 (50)c
11
Supporting information for this article is available online at
Bu
Bn
NaOH
BuLi
76
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
4
61 (54)c
NaOH
BuLi
trace
trace
–
d (43)c
d (56)c
References and Notes
–
a Determined by 1H NMR with durene as an internal standard.
b ND = not detected.
(1) For examples of N-monomethyl amide, see: (a) Gate, E. N.;
Threadgill, M. D.; Stevens, M. F. G.; Chubb, D.; Vickers, L. M.;
Langdon, S. P.; Hickman, J. A.; Gescher, A. J. Med. Chem. 1986, 29,
1046. (b) Khire, U. R.; Bankston, D.; Barbosa, J.; Brittelli, D. R.;
Caringal, Y.; Carlson, R.; Dumas, J.; Gane, T.; Heald, S. L.; Hibner,
B.; Johnson, J. S.; Katz, M. E.; Kennure, N.; Kingery-Wood, J.; Lee,
W.; Liu, X.-G.; Lowinger, T. B.; McAlexander, I.; Monahan, M.-K.;
Natero, R.; Renick, J.; Riedl, B.; Rong, H.; Sibley, R. N.; Smith, R.
A.; Wolanin, D. Bioorg. Med. Chem. Lett. 2004, 14, 783. (c) Lahm,
G. P.; Stevenson, T. M.; Selby, T. P.; Freudenberger, J. H.;
Cordova, D.; Flexner, L.; Bellin, C. A.; Dubas, C. M.; Smith, B. K.;
Hughes, K. A.; Hollingshaus, J. G.; Clark, C. E.; Benner, E. A.
Bioorg. Med. Chem. Lett. 2007, 17, 6274. (d) Clegg, N. J.;
Wongvipat, J.; Joseph, J. D.; Tran, C.; Ouk, S.; Dilhas, A.; Chen, Y.;
Grillot, K.; Bischoff, E. D.; Cai, L.; Aparricio, A.; Dorow, S.; Arora,
V.; Shao, G.; Qian, J.; Zhao, H.; Yang, G.; Cao, C.; Sensintaffar, J.;
Wasielewska, T.; Herbert, M. R.; Bonnefous, C.; Darimont, B.;
Scher, H. I.; Smith-Jones, P.; Klang, M.; Smith, N. D.; De
Stanchina, E.; Wu, N.; Ouerfelli, O.; Rix, P. J.; Heyman, R. A.;
Jung, M. E.; Sawyers, C. L.; Hager, J. H. Cancer Res. 2012, 72,
1494. (e) Selby, T. P.; Lahm, G. P.; Stevenson, T. M.; Hughes, K.
A.; Cordova, D.; Annan, I. B.; Barry, J. D.; Benner, E. A.; Currie, M.
J.; Pahutski, T. F. Bioorg. Med. Chem. Lett. 2013, 23, 6341.
(2) For examples of N-monoalkylated amides, see: (a) Sood, A.;
Panchagnula, R. Chem. Rev. 2001, 101, 3275. (b) Constable, D. J.
C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L. Jr.;
Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells,
A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411. (c) Zhang, J.;
Shan, Y.; Pan, X.; He, L. Mini-Rev. Med. Chem. 2011, 11, 920.
(3) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243.
(4) (a) Johnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35, 2169.
(b) Yamawaki, J.; Ando, T.; Hanafusa, T. Chem. Lett. 1981, 10,
1143. (c) Gajda, T.; Zwierzak, A. Synthesis 1981, 1005.
(d) Braddock, D. C.; Cansell, G.; Hermitage, S. A. Chem. Commun.
2006, 2483. (e) Vervisch, K.; D’hooghe, M.; Törnroos, K. W.; De
Kimpe, N. Org. Biomol. Chem. 2009, 7, 3271.
c Isolated yield.
d The 1H NMR yield could not be determined because the 1H NMR spectrum
of the crude mixture was complicated.
give N-methyl-N-phenylbenzamide (5a) in excellent yield
(entries 3 and 4). Phthalimide (4b) was similarly converted
into N-methylphthalimide (5b) in good yield (entries 5 and
6).
Table 4 N-Methylation of Secondary Amides
base (1.8 equiv)
PO(OMe)3 (3.0 equiv)
substrate
product
CPME, 115 °C, 24 h
Entry Substrate
Product
Product
Yielda
1
2
3
4
BzNHMe
NaOH
BuLi
BzNMe2 (3a)
38 (62)b
71 (18)b
quant
BzNHPh
NaOH
BuLi
BzN(Me)Ph (5a)
90 (0)b
O
O
N
Me
NH
5
6
NaOH
BuLi
66 (14)b
O
O
4b
5b
70 (trace)b
a Isolated yield.
b Recovered yield of substrate.
(5) Xia, Q.; Liu, X.; Zhang, Y.; Chen, C.; Chen, W. Org. Lett. 2013, 15,
3326.
(6) Bassindale, A. R.; Parker, D. J.; Patel, P.; Taylor, P. G. Tetrahedron
Lett. 2000, 41, 4933.
(7) (a) Noller, C. R.; Dutton, G. R. J. Am. Chem. Soc. 1933, 55, 424.
(b) Toy, A. D. F. J. Am. Chem. Soc. 1944, 66, 499. (c) Van Dyke
Tiers, G. Acta Chem. Scand. 1998, 52, 1223.
In conclusion, we have accomplished a highly selective
N-monoalkylation of amides by using trialkyl phosphates in
the presence of NaOH or BuLi in CPME, a solvent useful for
chemical processes. Although the selectivity is not perfect,
the desired N-monoalkylated amide derivatives are readily
separated from the recovered substrate and overreacted
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D