Extremely simple but long overlooked: Generation of α-Azido alcohols by hydroazidation of aldehydes

Article abstract of DOI:10.1002/anie.201003246

Discovered by accident: Just because an example of a simple substructure cannot be found in literature does not mean that corresponding compounds are not readily accessible. α-Azido alcohols like 1-azidoethanol have now been prepared and isolated. Copyright

Full text of DOI:10.1002/anie.201003246

Communications
DOI: 10.1002/anie.201003246
Azido Alcohols
Extremely Simple but Long Overlooked: Generation of a-Azido
Alcohols by Hydroazidation of Aldehydes**
Klaus Banert,* Christian Berndt, Samia Firdous, Manfred Hagedorn, Young-Hyuk Joo,
Tobias Rꢀffer, and Heinrich Lang
Dedicated to Professor Harald Gꢀnther on the occasion of his 75th birthday
Cyanohydrins 6 are easily formed from aldehydes 1 and
hydrogen cyanide and have proved to be highly useful
substrates in synthesis (Scheme 1).[1] In contrast, the reaction
acetals or enol ethers and then isolated and characterized.
This led to the presumption that hydrazoic acid does not react
with aldehydes readily.[9a]
Since we did not question this statement or at least did not
doubt the elusiveness of a-azido alcohols 2, we obtained
evidence for these compounds incidentally. By treatment of
triazide 7 with anhydrous hydrogen halide, we prepared
azidochloromethane (8) and azidobromomethane (9) besides
diazide 10 (Scheme 2).[10] The desired products are inter-
Scheme 1. a-Azido alcohols 2 postulated as short-lived intermediates.
of 1 with hydrazoic acid to prepare a-azido alcohols 2 is
completely unknown. Attempts to generate 2 by methanolysis
of silyl ethers 3 led only to 1.[2] a-Azido alcohols of type 2 have
been discussed as short-lived intermediates in the solvolysis of
diazides 4, which also yielded the final products 1.[3] Proto-
nation of 2 at N-a leads to an intermediate that is generally
accepted to explain the mechanism of the Schmidt reaction.[4]
Recently, in situ formation of azidomethanol (2a) was
postulated in the reaction of formaldehyde and sodium
azide in the presence of acetic acid. This reaction was
completed by copper(I)-catalyzed cycloaddition at terminal
alkynes to give 1,2,3-triazoles.[5] In all of these cases, there is
no spectroscopic proof of intermediates 2, whereas com-
pounds of types 3[2,6] and 4[7,8] and also a-azido ethers 5[8,9] can
be prepared easily from precursors 1 or the corresponding
Scheme 2. Synthesis of azidomethanol (2a).
mediates in the nucleophilic substitution of the corresponding
dihalomethanes to generate 10 but could not be detected in
these transformations.[10,11] Whereas 8 was isolated as an
explosive colorless liquid, 9 was less stable and thus charac-
terized only in solution.[10] When 7 was reacted with hydrogen
iodide in chloroform under apparently not completely
anhydrous conditions, we surprisingly got azidomethanol
(2a), which we analyzed by NMR and IR spectroscopy
(Table 1). Its structure was additionally confirmed by treat-
ment with cyclooctyne[12] and isolation of the stable product
11a, which resulted from 1,3-dipolar cycloaddition followed
by rearrangement (see also Figure 1 for the molecular
structure of 11a based on X-ray diffraction analysis).
Solutions of 2a in chloroform showed only small proportions
of the cleavage products 1a and hydrazoic acid. Thus, it is
logical that the equilibrium of 1a/HN3 and 2a favors the a-
azido alcohol, which is very easily available by simply mixing
1a and hydrazoic acid in chloroform.[13]
[*] Prof. Dr. K. Banert, C. Berndt, S. Firdous, Dr. M. Hagedorn,
Dr. Y.-H. Joo
Chemnitz University of Technology, Organic Chemistry
Strasse der Nationen 62, 09111 Chemnitz (Germany)
Fax: (+49)371-531-21229
E-mail: klaus.banert@chemie.tu-chemnitz.de
Homepage: http://www.tu-chemnitz.de/chemie/org/indexe.html
Dr. T. Rꢀffer, Prof. Dr. H. Lang
Chemnitz University of Technology, Inorganic Chemistry
Strasse der Nationen 62, 09111 Chemnitz (Germany)
[**] We gratefully acknowledge financial support from the Deutsche
Forschungsgemeinschaft (Ba 903/12-1). S.F. thanks DAAD for a
fellowship. We are grateful to Christoph Mꢀller and Dr. Jens Wutke
for experimental support.
This approach to a-azido alcohols 2 can be transferred to
electron-poor aldehydes like 1v,cc,dd,ee as well as to simple
aliphatic or even aromatic aldehydes (Table 2). When 0.6m
solutions of hydrazoic acid and 1e in chloroform were mixed
in different ratios, the corresponding Job plot showed a
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003246.
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Table 1: Selected spectroscopic data of a-azido alcohols.[a]
maximum proportion of 2e in the case of equimolar starting
2a 1H NMR:
d=4.31 (t, 3J=8.0 Hz, OH), 4.59 ppm (d, 3J=8.0 Hz)
materials. Thus, a 1:1 adduct of type 2 forms, which was also
supported unequivocally by H NMR data (see the Support-
1
1
13C NMR:
d=75.50 ppꢀm1 (t, JCH =163.1 Hz)
~
IR (CDCl3): n=3453 cm (OH), 2137 (N3)
ing Information). Specifically, the vicinal coupling resulting
from OH and CH groups and the presence of diastereotopic
protons or other diastereotopic groups (see, for example,
2e,g,h,i,k,u) as a consequence of the stereogenic center of 2
exclude diazides 4 and trimers of 1 (1,3,5-trioxanes). Also
13C NMR data can be used to distinguish between 2, 4, and
1,3,5-trioxanes (Table 1). The latter were generated very
slowly from some of the aldehydes like 1b,c,d, whereas
diazides 4 were detected as side products when 1b or 1c were
treated with hydrazoic acid in water or when 1l was subjected
to hydrazoic acid and p-toluenesulfonic acid. Hydrazoic acid
did not add to nonactivated C–C double or triple bonds (see
the cases m,n,o,p,dd, and ee), and we did not observe either
cleavage of esters or acetals, or nucleophilic substitution of
halides. Thus, 1q and 1r led to equilibria with 2q and 2r,
respectively, but not to diazide 2s, which was generated from
1s. In contrast to aldehydes 1g,h,i, cyclopropanecarbaldehyde
did not react observably with hydrazoic acid. We assume that
the three-membered ring stabilizes the partial positive charge
at the carbonyl carbon atom, reduces the electrophilicity, and
increases the thermodynamic stability of the aldehyde.
Similar arguments can be utilized to explain the low
proportion of 2 ff in equilibrium with 1 ff and hydrazoic acid.
Using weighed samples of 1 and titrated solutions of
hydrazoic acid in CDCl3 and with the help of 1H NMR
spectra, we determined the equilibrium constant K for some
of the reactions depicted in Table 2. Small values of K were
found in case of aromatic substrates 1 ff,gg,hh,ii, whereas
electron-poor aldehydes such as 1q, 1v, and 1cc led to higher
values of K (Table 3). Thus, the K values of 2 behave similarly
to those of the corresponding aldehyde hydrates,[14] but there
is no strict correlation. Aldehydes with branching at the
a position like 1e gave slightly lower values than the linear
isomers such as 1d. Such a steric effect may also account for
the K value resulting from 1v, which is only a little higher than
that of 1q, although the trichloromethyl group is a stronger
acceptor. An intramolecular hydrogen bond in 2gg can
explain the greater K value of 1gg relative to that of isomeric
1hh. At lower temperatures (ꢀ258C versus 208C), we
2b 1H NMR[b]: d=1.44 (d, 3J=5.6 Hz, 3H, H2), 3.55 (d, br.,
3J=6.0 Hz, 1H, OH), 5.07 ppm (dq, 3J=6.0 Hz,
3J=5.6 Hz, 1H, H1)
13C NMR[b]: d=21.89 (q, C2), 82.65 ppm (d, C1)
2j 1H NMR[c]: d=2.88 (dd, 2J=13.6 Hz, 3J=5.6 Hz, 1H, H2), 2.96
3
(dd, 2J=13.6 Hz, J=5.2 Hz, 1H, H2’), 3.38
3
3
(d, br., J=8.4 Hz, 1H, OH), 5.11 (ddd, J=8.4 Hz,
3J=5.6 Hz, 3J=5.2 Hz, 1H, H1), 7.20–7.40 ppm
(m, 5H, Ph)
13C NMR[c]: d=42.50 (t, C2), 86.02 (d, C1), 127.17 (s, Cipso),
128.55 (d, Cortho), 129.72 (d, Cmeta), 134.77 ppm
(d, Cpara
)
[a] 1H and 13C NMR spectra were recorded in CDCl3 at 218C and 400 and
100 MHz, respectively; for additional data, see the Supporting Informa-
tion. [b] Measured at ꢀ508C. [c] Measured at ꢀ558C.
Figure 1. Molecular structure of 11a determined by single-crystal X-ray
diffraction analysis.
Table 2: Definition of substituent R in aldehydes 1 and a-azido alcohols
2.
=
a H
m CH2CH2C(Me) CH2
y (CH2)3Br
= =
b Me
c Et
d Pr
e iPr
n CH2CH C CH2
z (CH2)3OTs
Table 3: Equilibrium constants K for 1+HN3 Q2.[a]
ꢁ
o CH2CH2C CH
aa CH2CH2CMe2N3
bb CH2CH2CMe2Br
cc CO2Et
dd CO2CH2CH CH2
ee CO2CH2C CH
1/2
K [Lmolꢀ1
]
T [8C]
1/2
K [Lmolꢀ1
]
T [8C]
ꢁ
p (CH2)3C CH
q CH2Cl
r CH2Br
s CH2N3
a
b
c
d
e
g
h
i
10.1ꢂ1.1
20.0
21.2
21.2
20.8
21.0
19.8
20.3
21.0
21.1
21.3
ꢀ25.0
21.0
n
q
t
v
cc
ff
gg
hh
hh
ii
0.92ꢂ0.06
12.5ꢂ1.3
20.3
20.3
19.5
21.4
20.0
22.0
20.2
20.4
=
f tBu
0.93ꢂ0.12
0.59ꢂ0.03
0.42ꢂ0.10
0.27ꢂ0.05
0.42ꢂ0.02
0.30ꢂ0.01
0.33ꢂ0.02
0.59ꢂ0.07
1.89ꢂ0.02
5.87ꢂ0.08
0.40ꢂ0.09
ꢁ
g cBu
h cPent
i cHex
j Bn
k CHPh2
l CH2CH2Ph
0.76ꢂ0.06
13.5ꢂ1.1
t CH2P+Ph3 Clꢀ
u CH(OMe)2
v CCl3
w CH2CH2N3
x (CH2)3N3
ff Ph
gg C6H4-2-NO2
hh C6H4-4-NO2
ii C6H3-2,4-(NO2)2
ca. 620
0.0028ꢂ0.0002
0.0205ꢂ0.0002
0.0163ꢂ0.0009
0.0487ꢂ0.0009
0.1176ꢂ0.0004
12.8ꢂ1.0
j
ꢀ25.0
j[b]
j
20.2
kk
kk
20.5
ꢀ25.0
k
ca. 340
[a] Determined in CDCl3 by 1H NMR spectroscopy. Substituents R of
compounds 1 and 2 are defined in Table 2. [b] Determined in [D6]DMSO.
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observed significantly higher K values (see 1j, 1hh, and 1kk).
More polar solvents like DMSO led also to greater propor-
tions of the a-azido alcohols 2.
Like 2a, the azide 2cc furnished a stable 2H-1,2,3-triazole
of type 11 upon reaction with cyclooctyne (Scheme 4). In
contrast to 11cc, product 11v is unstable and tends to cleave
into 1v and 4,5,6,7,8,9-hexahydrocycloocta-1,2,3-triazole. A
Glyoxal (1jj) reacted with two equivalents of hydrazoic
acid to afford a mixture of meso- and rac-2jj (ca. 1:1). For this
transformation, a K value of (85.9 ꢂ 2.2) L2 molꢀ2 (CDCl3,
19.88C) was calculated. Treatment of hydrazoic acid with
chiral carbohydrates bearing an aldehyde unit also furnished
two anomers. For example, 2kk was formed as 2.5:1 mixture
of a-azido alcohols, whereas nearly equal proportions of
anomers 2ll (ca. 4:3) resulted from aldehyde 1ll. Because
equilibria are fast at room temperature, these diastereomeric
products should be generated under thermodynamic control.
At ꢀ50 to ꢀ658C, the equilibrations of 1/HN3 and 2 were
retarded. Thus, hydrazoic acid along with the solvent and
even the aldehydes 1a–f,q,v could be removed in vacuum
because the corresponding adducts 2 were less volatile. The
residues were dissolved in precooled solvents to give solutions
of pure or highly enriched a-azido alcohols 2. Some of these
products (2a–d) could be observed as solids or viscous liquids
at low temperature. The best yields of 2 were achieved when
the equilibrium was established at reduced temperature, for
example at ꢀ258C in the refrigerator, before the volatile
compounds were removed in vacuum at even lower temper-
atures.
When the a-azido alcohol was liberated from hydrazoic
acid at room temperature, the rapid equilibration caused
complete cleavage of 2. In such a case, only the aldehyde
remained, and the formation of 2 from 1 and hydrazoic acid
could be overlooked easily.[15] Treatment of acrolein (12) with
an excess of hydrazoic acid was reported several times to
afford the azide 1w, but the generation of diazide 2w was not
noticed,[16,17] although it can be registered quite simply by
NMR methods (Scheme 3). In 1910, vinyl azide (13) in water
Scheme 4. Reactions of a-azido alcohols 2. The substituents R are
defined in Table 2.
slow intramolecular 1,3-dipolar cycloaddition transformed 2p
into the heterocycle 15p. On irradiation with a mercury high-
pressure lamp, a-azido alcohols lost dinitrogen to give amides
18 and 19 most probably via intermediates 16 and 17,
respectively. The two types of products, for example
18cc,dd,ee and 19cc,dd,ee, could be easily separated by
chromatography. Thus, the results of the photolysis of 2 are
different from those of the known[2] thermolysis of 3, which
takes place exclusively with a proton shift to generate the
corresponding N-(trimethylsilyl)carboxamides. Oxidation of
a-azido alcohols 2 with pyridinium chlorochromate (PCC) in
chloroform led under very mild conditions to acyl azides
20b,c,j,k,q,cc,ff,gg,ii (80–89% yield based on 1) without
inducing Curtius rearrangement. The starting material 2jj
afforded the known[20] oxalic acid diazide at ꢀ508C (82%
yield of isolated product based on HN3), and 2d was oxidized
by PCC at the same temperature to provide butyryl azide
Scheme 3. Generation of a-azido alcohols from starting materials 12
and 13.
was subjected to bromine to prepare dibromide 14. Owing to
the explosive course of the reaction, however, 14 could not be
characterized and 1r was the only product identified.[18] Quite
recently, it has been shown that 14 can be synthesized
conveniently and quantitatively, when 13 is exposed to
bromine in organic solvents at low temperature.[19] We treated
14 with wet dimethyl sulfoxide to get a-azido alcohol 2r in
equilibrium with 1r/HN3, which could also be reached by
mixing 1r and hydrazoic acid.
1
(97% yield based on H NMR data). In control experiments
under the latter conditions, it was shown that a mixture of
butyric acid, hydrazoic acid, and PCC did not generate
butyryl azide. On the other hand, 1d and PCC alone (without
HN3) did not produce butyric acid at such low temperatures.
Thus, our method for the preparation of acyl azides from
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Although we have investigated only a few reactions of a-
azido alcohols up to now, we assume that these compounds
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Received: May 28, 2010
Revised: August 30, 2010
Published online: November 25, 2010
Keywords: alcohols · aldehydes · azides · equilibrium reactions ·
.
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