Convenient procedure for one-pot conversion of azides to N-monomethylamines

Article abstract of DOI:10.1055/s-2001-14646

One-pot conversion of azides to N-monomethylamines is described. Two optional protocols have been developed, which share the first stage, the reaction of an azide with (CH₃)₃P to generate the corresponding iminophosphorane. This Staudinger intermediate, thus generated, is either methylated with CH₃I and hydrolyzed (method A), or treated with (HCHO)_n and reduced with NaBH₄ (method B), thereby giving the corresponding N-monomethylamine in high yield.

Full text of DOI:10.1055/s-2001-14646

LETTER
1003
Convenient Procedure for One-pot Conversion of Azides to N-Mono-
methylamines
Hirohisa Kato, Ken Ohmori, Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and CREST, Japan Science and Technology Corporation (JST), O-okayama, Me-
guro-ku, Tokyo 152-8551, Japan
E-mail: ksuzuki@chem.titech.ac.jp
Received 1 February 2001
Dedicated to Prof. Ryoji Noyori for his outstanding contribution to organic chemistry.
stage of the synthetic scheme. Although many reports
Abstract: One-pot conversion of azides to N-monomethylamines is
have appeared for the access to such a group via the cor-
described. Two optional protocols have been developed, which
share the first stage, the reaction of an azide with (CH3)3P to gener-
ate the corresponding iminophosphorane. This Staudinger interme-
responding prim-amines,3 they are often hampered by the
problems of competing bis-methylation or inapplicability
diate, thus generated, is either methylated with CH3I and to the multi-functionalized substrates. In order to avoid
hydrolyzed (method A), or treated with (HCHO)n and reduced with
NaBH4 (method B), thereby giving the corresponding N-monome-
thylamine in high yield.
such complication, we became interested in the possibility
of the one-pot conversion of such an azide to the corre-
sponding N-monomethylamine.
Key words: azides, N-monomethylamines, Staudinger reaction,
We describe herein two effective methods for the one-pot
iminophosphorane, aza-Wittig reaction
synthesis of N-monomethylamines from the correspond-
ing azides (Scheme 1), which seem to fulfill the above-
stated criteria. The bottom line is the use of the imino-
An N-monomethylamino group is often embedded as a
phosphorane, which is easily generated from the azides by
structural motif in various biologically active natural
treatment with R3P, actually (CH3)3P (vide infra). The
products, such as pradimicin A (1)1 and the neocarzinosta-
Staudinger intermediate,4 thus generated, is either methy-
lated with CH3I and hydrolyzed (method A), or treated
with paraformaldehyde and reduced with NaBH4 (method
tin chromophore (2).2 In connection with our synthetic ef-
fort directed toward the pradimicin-benanomicin class
antibiotics including 1, we required a method for the facile
B), thereby giving the corresponding N-monomethy-
construction of an N-monomethylamino group from the
lamine in high yield.
azide in a densely functionalized intermediate at the later
R
N
N3
CO2H
3
I
O
NH
(CH3)3P
–N2
HO
O
O
HO
R
P(CH3)3
H3CO
Method A
Method B
(HCHO)n
–(CH3)3P=O
CH3I
O
O
HO
OH
HO
O
O
HO
HO
NCH3
H
CH3
Pradimicin A (1)
OH
R
N
R
N
CH2
+
P(CH3)3
I–
III
O
OH
O
II
O
O
O
hydrolysis
NaBH4
O
–(CH3)3P=O
CH3
R
N
O
H
OCH3
O
4
H3CN
H
HO
OH
Scheme 1
NCS-chromophore (2)
Figure
Synlett 2001, SI, 1003–1005 ISSN 0936-5214 © Thieme Stuttgart · New York

1004
H. Kato et al.
LETTER
Table N-Monomethylamination of Various Azides
(C6H5)3P is the ready solubility of (CH3)3P=O in water,
enabling the easy purification of the products. (CH3)3P is
currently commercially available as a stock solution (1.0
M / toluene).
R-N(H)CH3 4 (Yield/%)
run
1
substrate
method Aa)
method Bb)
76c)
74e)
Method A
N3
3a
Representative procedure for method A is described for
the reaction of the azide 3e: To a solution of 3e (59.3 mg,
0.177 mmol) in CH2Cl2 (1.5 mL) was added a solution of
(CH3)3P in toluene (1.0 M, 0.4 mL) at room temperature.
After stirring for 1.5 h, CH3I (251 mg, 1.77 mmol) in
CH2Cl2 (1.5 mL) was added. After stirring for 3 h at room
temperature, the reaction mixture was concentrated in
vacuo. The residue was dissolved in 1,4-dioxane (2.0 mL)
and aqueous NaOH (2 M, 2 mL), and heated at 100 °C for
1 h. After cooling, the products were extracted with
CH2Cl2 (x5). The combined organic extracts were dried
(K2CO3), and concentrated in vacuo. Purification by pre-
parative silica-gel TLC (CHCl3 / MeOH = 94 / 6) gave 4e5
as colorless oil (49.2 mg, 86%).
O
O
O
68c)
73d)
86d)
81
77
2
3
4
O
N3 O
3b
N3
3c
OBn
OBn
BnO
O
81
The left-side column in the Table shows the application of
this protocol to various azides. In all cases listed, the ini-
tial two stages of the process, i.e. the reaction with
(CH3)3P and the methylation with CH3I, were complete
within 4 h at 25 °C, whereas the hydrolysis of the resulting
phosphonium salt was far more difficult than expected,
which was particularly the case for the sterically hindered
substrates. Thus, in the cases of 3a and 3b, the hydrolysis
was possible simply by heating the phosphonium salt in
aqueous THF (runs 1, 2), the hydrolysis for the cases of
3c–3f was only possible by heating under basic conditions
(1 M NaOH aq., 100 °C, 1 h).
N3
BnO
3d
N3
BnO
O
86d)
5
6
83
76
BnO
OCH3
3e
O
N3
BnO
80d)
BnO
OCH3
3f
Method B
a) (CH3)3P (2.0 eq.) / toluene, CH2Cl2, 25 °C, 1.5 h / CH3I (10 eq.),
CH2Cl2, 25 °C; b) (CH3)3P (2.0 eq.) / toluene, CH2Cl2, 25 °C, 1.5 h /
(HCHO)n (5.0 eq.) / NaBH4 (5.0 eq.), MeOH; c) hydrolysis was per-
formed in aq.THF at 80 °C, 12 h; d) hydrolysis was performed in 2
M NaOH, 1,4-dioxane at 100 °C, 1 h; e) the corresponding N,N-di-
methylamine was obtained in 18% yield.
Representative procedure for method B is described also
for the reaction of the azide 3e: To a solution of 3e (56.8
mg, 0.148 mmol) in CH2Cl2 (1.5 mL) was added a solu-
tion of (CH3)3P in toluene (1.0 M, 0.3 mL) at room tem-
perature. After stirring for 1.5 h, (HCHO)n (22.6 mg,
0.753 mmol) was added. The reaction mixture was stirred
for 6 h at room temperature before treatment with MeOH
(2 mL) and NaBH4 (28 mg, 0.74 mmol) at 0 °C. After stir-
ring for 0.5 h, the reaction was stopped with saturated
aqueous NaHCO3, and extracted with CH2Cl2 (x5). The
combined extracts were dried (K2CO3), and concentrated
in vacuo. Purification by preparative silica-gel TLC
(CHCl3 / MeOH = 94 / 6) gave 4e5 as colorless oil (45.7
mg, 83%).
Although both methods worked well for various sub-
strates, it became apparent that method A is effective for
the less hindered azides, while method B for the hindered
ones. More importantly, method B is particularly suitable
for the application to the multi-functionalized compounds
in terms of the mild reaction conditions, as will be seen in
the following.
Preliminary attempts showed that (CH3)3P, rather than
(C6H5)3P, is the reagent of choice because of the superior
reactivity for generating the key iminophosphorane spe-
cies. The reactivity difference can be roughly grasped by
comparing the time required for the completion of the re-
action with cyclohexyl azide (ca. 0.5 M soln. toluene),
that is, (CH3)3P (1.5 h at 25 °C), (C6H5)3P (12 h at 25 °C
or 5 h at 80 °C). An additional advantage of (CH3)3P over
Gratifyingly, this latter protocol proved applicable to var-
ious substrates as shown in the right column of the Table.
Particularly attractive was that both of the two reaction
stages, i.e. the aza-Wittig reaction and the reduction,
proceeded nicely without respect to, if any, the steric
hindrance of the substrates (cf. method A, vide supra).
Synlett 2001, SI, 1003–1005 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
One-pot Conversion of Azides to N-Monomethylamines
1005
Indeed, application to a model compound 7, correspond- In summary, we have developed a method for the one-pot
ing to the disaccharide portion6 of our target, cleanly gave conversion of azides to N-monomethylamines. Compati-
the N-monomethylated compound 8 in good yield. Partic- bility with diverse functional groups would make the
ularly important is that the reaction conditions proved to present protocol useful in organic synthesis. We are cen-
be mild enough to allow its application to such a base-sen- tering our attention to the total synthesis of pradimicin A
sitive substrate with acyl protecting groups (Scheme 2).
by utilizing this method.
References and Notes
F
(1) Kitamura, M.; Ohmori, K.; Kawase, T.; Suzuki, K. Angew.
Chem., Int. Ed. 1999, 38, 1229–1232, and references therein.
(2) For synthetic studies on this class of natural products, see
a) Myers, A. G.; Liang, J.; Hammond, M.; Harrington, P. M.;
Wu, Y.; Kuo, E. Y. J. Am Chem. Soc. 1998, 120, 5319–5320.
b) Kaneko, T.; Takahashi, K.; Hirama, M. Heterocycles 1998,
47, 91–96, and references therein. In these studies, the N-
monomethylamino group is introduced by the N-methylation
of the prim-amine derivatives with temporary mono-
protection (by Cbz-, CF3CO-) followed by deprotection at any
suitable stage of the synthesis.
(3) Selected examples of the N-monoalkylation of prim-amines
see: a) Olsen, R. K. J. Org. Chem. 1970, 35, 1912–1915.
b) Briggs, E. M.; Brown, G. W.; Jiricny, J.; Meidine, M. F.
Synthesis 1980, 295–296. c) Krishnamurthy, S. Tetrahedron
Lett. 1982, 23, 3315–3318. d) Grieco, P. A.; Bahsas, A. J. Org.
Chem. 1987, 52, 5746–5749, and the references cited therein.
(4) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635–646.
For a review on Staudinger reaction, see: Gololobov, Y. B.;
Kasukhin, L. F. Tetrahedron 1992, 48, 1353–1406.
(5) All new compounds were fully characterized by spectroscopic
means as well as combustion analysis.
(6) Kato, H.; Ohmori, K.; Suzuki, K. Tetrahedron Lett. 2000, 41,
6827–6832.
(7) a) Lambert, P. H.; Vaultier, M.; Carrié, P. J. Chem. Soc.,
Chem. Commun. 1982, 1224–1225. b) Takeuchi, H.;
Yanagida, S-. i.; Ozaki, T.; Hagiwara, S.; Eguchi, S. J. Org.
Chem. 1989, 431–434. For a review on iminophosphorane and
aza-Wittig reaction, see: Wamhoff, H.; Richardt, G.; Stölben,
S. Adv. Heterocycl. Chem. 1995, 64, 159–249.
O
BzO
(HCHO)n
(CH3)3P
O
AcO
AcO
O
CH2Cl2, toluene
N3
then NaBH4
AcO
7
F
O
BzO
O
AcO
AcO
O
NCH3
H
AcO
8
69%
Scheme 2
Currently, we are studying the application of this protocol
for poly-functionalized azides, which will be detailed
elsewhere. However, it is interesting to note here an unex-
pected observation encountered along these lines
(Scheme 3). The -acyloxy azide 5 underwent an intramo-
lecular aza-Wittig reaction7 without regard to the co-exist-
ing paraformaldehyde, giving the oxazoline 6 in good
yield. This suggests not only a limitation of the method,
but at the same time a promising hint to the new synthesis
of heterocycles.
N3
N
(CH3)3P
O
O
Article Identifier:
1437-2096,E;2001,0,SI,1003,1005,ftx,en;Y04001ST.pdf
O
AcO
CH2Cl2, toluene
AcO
AcO
25 °C
OCH3
OCH3
5
6
76%
Scheme 3
Synlett 2001, SI, 1003–1005 ISSN 0936-5214 © Thieme Stuttgart · New York