Stereospecific synthesis of sec- and tert-alkyl azides from alcohols and trimethylsilyl azide by a new type of oxidation-reduction condensation using phenyl diphenylphosphinite and trimethylsilylmethyl azide

Article abstract of DOI:10.1246/cl.2008.1072

A novel method for the preparation of alkyl azides from alcohols and trimethylsilyl azide by a new type of oxidation-reduction condensation using phenyl diphenylphosphinite and trimethylsilylmethyl azide is described. Chiral secondary and tertiary alcohols are converted into the corresponding chiral azides with almost complete inversion of configuration under mild and neutral conditions. Copyright

Full text of DOI:10.1246/cl.2008.1072

1072
Chemistry Letters Vol.37, No.10 (2008)
Stereospecific Synthesis of sec- and tert-Alkyl Azides from Alcohols and Trimethylsilyl Azide
by a New Type of Oxidation–Reduction Condensation
Using Phenyl Diphenylphosphinite and Trimethylsilylmethyl Azide
Teruaki Mukaiyama,Ã1 Kiichi Kuroda,2 Yuji Maruyama,3 and Yujiro HayashiÃ2
1Center for Basic Research, Kitasato University, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
2Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
3Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received August 5, 2008; CL-080760; E-mail: mukaiyam@abeam.ocn.ne.jp)
A novel method for the preparation of alkyl azides from
alcohols and trimethylsilyl azide by a new type of oxidation–
reduction condensation using phenyl diphenylphosphinite and
trimethylsilylmethyl azide is described. Chiral secondary and
tertiary alcohols are converted into the corresponding chiral
azides with almost complete inversion of configuration under
mild and neutral conditions.
from alcohols and trimethylsilyl azide by a new type of oxida-
tion–reduction condensation using phenyl diphenylphosphinite
and an azide compound as oxidant.
In order to find the most suitable azidation reagent, a reac-
tion using tertiary alcohol 1a in the presence of phenyl diphenyl-
phosphinite (PhOPPh2) and benzyl azide was first examined
(Table 1, Entries 1–3). The reaction using tetrabutylammonium
azide (Bu4NN3) did not afford the desired azide 2a while 2a was
obtained in a low yield when DPPA was used. In the case of
TMSN3, the yield of 2a increased up to moderate yield and
therefore TMSN3 was chosen as a reagent for this azidation.
Next, various azide compounds were examined to find the suit-
able oxidant (Entries 4–6). Then, the use of ethyl azidoacetate
and 1-azidoadamantane was shown to lower the yield of 2a
while trimethylsilylmethyl azide gave 2a in high yield.
After a suitable azidation reagent and an oxidant were
chosen, condensation reactions of various chiral alcohols with
TMSN3 were tried in order to examine the scope of this reaction
under the optimized conditions (Table 2). A reaction of chiral
secondary alcohol 1b proceeded smoothly to afford the corre-
sponding azide in quantitative yield with complete inversion
of stereochemistry (Entry 1). The reaction of secondary alcohol
with an ꢀ-ester group 1c also afforded the inverted azide in
high yield (Entry 2). When benzylic alcohol such as (S)-1-(2-
naphthyl)ethanol (1d) was employed, the desired product was
obtained in high yield with high enantiomeric excess though
optical purity was lowered slightly (Entry 3). Further, more hin-
dered tertiary alcohols were employed for substrates so as to in-
vestigate potential application of this reaction to the asymmetric
construction of quaternary carbon (Entries 4 and 5). Then, the re-
action of chiral tert-alcohol with an ꢀ-ester group 1e proceeded
smoothly to afford the corresponding azide in high yield with
Conversion of alcohols to their corresponding azides1 is one
of the most important functional group transformations in organ-
ic synthesis.2 The most fundamental method known for azidation
is the Mitsunobu reaction,3 using hydrogen azide as an azide
source.4 The applicability of this reaction is limited owing to
the use of highly toxic and explosive hydrogen azide and
therefore alternative methods using diphenyl phosphorazidate
(DPPA)5 or zinc azide/bis-pyridine complex6 are commonly
used. Further, methods using DPPA/DBU,7 p-NO2DPPA/
DBU,8 and so forth9 have been reported more recently. In these
reactions, primary and secondary alcohols are the most suitable
substrates, and chiral secondary alkyl azides are formed from
chiral secondary alcohols with complete inversion of configura-
tion by an SN2 displacement. On the other hand, sterically
hindered tertiary alcohols are known not to be converted to the
corresponding tertiary alkyl azides.10
It was also reported from our laboratory that the oxidation–
reduction condensation11 of tertiary alkyl diphenylphosphinites
(ROPPh2), that were prepared from the corresponding tert-alco-
hols, with trimethylsilyl azide (TMSN3) gave the corresponding
azides (R–N3) in the presence of methoxybenzoquinone.12 It is
noted that a chiral tert-alcohol is converted into the correspond-
ing chiral tert-alkyl azide with inversion of configuration. How-
ever, in the case of tert-alcohol with an ꢀ-ester group, azidation
that affords an ꢀ,ꢀ-disubstituted ꢀ-amino acid derivative does
not proceed efficiently.
Recently, a newer type of oxidation–reduction condensa-
tion13,14 by using a combination of phenyl diphenylphosphinite
(PhOPPh2) and an azide compound as oxidant15 was reported
from our laboratory, which was applied to the stereospecific syn-
thesis of sulfides from alcohols and 2-sulfanyl-1,3-benzothiazole
as a sulfur nucleophile. In this reaction, chiral tert-alcohols with
an ꢀ-ester group are converted into the corresponding chiral tert-
alkyl sulfides with inversion of configuration. In order to extend
the utility of this type of reaction, stereospecific azidation of al-
cohols including tert-alcohols with an ꢀ-ester group was next
studied.
Table 1. Optimization of reaction conditionsa
PhOPPh2 (2.0 equiv)
Oxidant (2.0 equiv)
Me OH
Ph CO2Me
Me N3
Ph CO2Me
Azide
Toluene, rt, 48 h
1a (1.0 equiv)
(2.0 equiv)
2a
Entry
Azide
Oxidant
Yield/%b
1c
2c
3
4
5
Bu4NN3
DPPA
N3CH2Ph
N3CH2Ph
N3CH2Ph
N3CH2CO2Et
AdN3
N.D.
34
57
9
12
82
TMSN3
6
N3CH2TMS
aThe solution of PhOPPh2 and oxidant was stirred at 80 ꢀC for
20 min, followed by addition of alcohol and azide at rt. bIsolated
In this communication, we would like to describe a new
method for stereospecific synthesis of sec- and tert-alkyl azides
c
yield. The reaction time was 24 h.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.10 (2008)
1073
Table 2. Azidation of various chiral alcohols
Ph Ph
PhO P
Ph Ph
PhO P N R
TMS N3
PhOPPh2 RN3
(R = CH2TMS)
PhOPPh2 (2.0 equiv)
TMSCH2N3 (2.0 equiv)
N
R
R1 OH
R1 N3
R2 R3
N2
TMSN3
(2.0 equiv)
ROH
Iminophosphorane
R2 R3
Toluene, rt, 5 h
1b-1f
2b-2f
Ph Ph
Ph
Yield/%a
(%ee)
PhO
R1 OH
R2 R3
P
N R
R1 N3
R2 R3
'' Inversion''
Ph
Entry
1
1
Product 2
O
P
N R
TMS
R1
O
TMS
Ph2P N R
TMS
H OH
Me
H
N3
Me
N3
PhOH
quant
(>99)b
R2
R3
1b
N3
Ph
Ph
A
B
H OH
H
N3
CO2Et
H N3
Me
98
Scheme 2.
(>99)c
2
3
1c
1d
Ph
CO2Et
Ph
K. K. was granted a Research Fellowship of Japan Society
for the Promotion of Science for Young Scientist.
H
OH
Me
85
(97)b
References and Notes
1
For a review of organic azides, see: S. Brase, C. Gil, K. Knepper,
¨
Me OH
Et CO2Bn
Me N3
Et CO2Bn
V. Zimmermann, Angew. Chem., Int. Ed. 2005, 44, 5188.
a) B. M. Trost, I. Fleming, Comprehensive Organic Synthesis,
Pergamon Press, New York, 1991, Vol. VI, p. 76. b) S. Hanessian,
Preparative Carbohydrate Chemistry, Marcel Dekker, New York,
1997, Chap. 5, 90.
a) O. Mitsunobu, Synthesis 1981, 1. b) D. L. Hughes, Org. React.
1992, 42, 335. c) R. Dembinski, Eur. J. Org. Chem. 2004, 2763.
d) T. Y. S. But, P. H. Toy, Chem. Asian J. 2007, 2, 1340.
H. Loibner, E. Zibral, Helv. Chim. Acta 1976, 59, 2100.
B. Lal, B. N. Pramanik, M. S. Manhas, A. K. Bose, Tetrahedron
Lett. 1977, 18, 1977.
4d,e
84
1e
1f
2
(96)f
Me OH
Ph CO2Me
Me N3
Ph CO2Me
86
5d,g,h
(>99)b
3
aIsolated yield. bThe ratio of enantiomer was determined by HPLC
analysis after reducing the azide to amine. cThe ratio of enantiomer
was determined by HPLC analysis. dPhOPPh2 (3.0 equiv), tri-
methylsilylmethyl azide (3.0 equiv), TMSN3 (3.0 equiv) were used.
eThe reaction time was 24 h. fRef. 16. gThe reaction time was 48 h.
hRef. 17.
4
5
6
7
M. C. Viaud, P. Rollin, Synthesis 1990, 130.
A. S. Thompson, G. R. Humphrey, A. M. DeMarco, D. J. Mathre,
E. J. J. Grabowski, J. Org. Chem. 1993, 58, 5886.
Me N3
Ph CO2Me
2f
Me NH2
Ph CO2Me
96%, >99%ee
8
9
M. Mizuno, T. Shioiri, Chem. Commun. 1997, 2165.
a) A. Saito, K. Saito, A. Tanaka, T. Oritani, Tetrahedron Lett.
1997, 38, 3955. b) C. Yu, B. Liu, L. Hu, Org. Lett. 2000, 2,
1959. c) N. Iranpoor, H. Firouzabadi, B. Akhlaghinia, N.
Nowrouzi, Tetrahedron Lett. 2004, 45, 3291.
H2, Pd/C
EtOAc, rt
Scheme 1.
10 For a recent example of preparation of tert-alkyl azides via the
Markovnikov addition of an azide anion, see: J. Waser, B. Gaspar,
H. Nambu, E. M. Carreira, J. Am. Chem. Soc. 2006, 128, 11693.
11 For reviews of oxidation–reduction condensation, see: a) T.
Mukaiyama, H. Yamabe, Chem. Lett. 2007, 36, 2. b) T.
Mukaiyama, K. Ikegai, H. Aoki, W. Pluempanupat, K. Masutani,
Proc. Jpn. Acad., Ser. B 2005, 81, 103. c) T. Mukaiyama,
Angew. Chem., Int. Ed. 2004, 43, 5590.
12 a) K. Kuroda, Y. Hayashi, T. Mukaiyama, Tetrahedron 2007, 63,
6358. b) K. Kuroda, N. Kaneko, Y. Hayashi, T. Mukaiyama,
Chem. Lett. 2006, 35, 1432.
13 K. Kuroda, Y. Maruyama, Y. Hayashi, T. Mukaiyama, Chem. Lett.
2008, 37, 836.
14 K. Kuroda, Y. Hayashi, T. Mukaiyama, Chem. Lett. 2008, 37, 592.
15 For oxidation–reduction condensation using azides as oxidant, see:
a) H. Aoki, K. Kuroda, T. Mukaiyama, Chem. Lett. 2005, 34, 1266.
b) T. Mukaiyama, K. Kuroda, H. Aoki, Chem. Lett. 2005, 34, 1644.
c) S. Torii, H. Okumoto, M. Fujikawa, M. A. Rashid, Chem.
Express. 1992, 7, 933.
high enantiomeric excess (Entry 4). Similarly, chiral benzylic
alcohol with an ꢀ-ester group 1f gave the desired product in high
yield with complete inversion of stereochemistry (Entry 5).
Since the chiral tert-alkyl azide 2f was converted to the cor-
responding chiral ꢀ-tertiary amine in high yield by hydrogena-
tion, a concise method for the preparation of chiral amines from
the corresponding alcohols was established (Scheme 1).
A plausible reaction mechanism is shown in Scheme 2: a
reaction of phenyl diphenylphosphinite (PhOPPh2) and tri-
methylsilylmethyl azide gave initially the corresponding imino-
phosphorane which in turn resulted in the formation of inter-
mediate A by subsequent N-silylation with trimethylsilyl azide.
The following nucleophilic attack of an alcohol to the positively
charged phosphorus atom led to an intermediate B. Finally, a
nucleophilic attack of the azide anion (N3À) to its phosphonium
part via SN2 manner gave the inverted azide.
Thus, a new method for the preparation of sec- or tert-alkyl
azides from the corresponding alcohols and trimethylsilyl azide
by a new type of oxidation–reduction condensation using phenyl
diphenylphosphinite and trimethylsilylmethyl azide is establish-
ed. It is noted that chiral tert-alkyl azides were formed from the
corresponding chiral alcohols with almost complete inversion
of configuration under mild and neutral conditions. This is the
first example of the stereospecific synthesis of an inverted chiral
tert-alkyl azide prepared directly from a chiral tert-alcohol by an
SN2 displacement.
16 The ratio of enantiomer 2e was determined by HPLC analysis after
converting the azide to 1,4-disubstituted 1,2,3-triazole on treat-
.
ment with phenylacetylene in the presence of CuSO4 5H2O and
sodium ascorbate.
17 Typical experimental procedure is as follows (Table 2, Entry 5): to
PhOPPh2 (0.60 mmol) in dry toluene (0.30 mL) was added tri-
methylsilylmethyl azide (0.60 mmol) at rt under Ar atmosphere.
After this mixture was stirred for 20 min at 80 ꢀC, alcohol 1f
(0.20 mmol) in dry toluene (0.60 mL) and TMSN3 (0.60 mmol)
were added at rt. The reaction mixture was stirred at rt for 48 h
and the crude product was purified by preparative TLC to afford
the corresponding azide 2f (86% yield).
Published on the web (Advance View) September 13, 2008; doi:10.1246/cl.2008.1072