Synthesis of Geminal Azido-Halo Compounds and α-Azidoalkyl Esters from Aldehydes via α-Azido Alcohols

Article abstract of DOI:10.1021/acs.orglett.7b02380

α-Azido alcohols are generated by treating aldehydes with hydrazoic acid in chloroform. These adducts are transformed into geminal azido-halo compounds through the reaction with phosphorus trichloride or phosphorus tribromide, whereas α-azidoalkyl esters are isolated after interaction with acyl chlorides.

Full text of DOI:10.1021/acs.orglett.7b02380

Letter
pubs.acs.org/OrgLett
Synthesis of Geminal Azido−Halo Compounds and α‑Azidoalkyl
Esters from Aldehydes via α‑Azido Alcohols
Klaus Banert,* Christian Berndt, and Kevin Weigand
Chemnitz University of Technology, Organic Chemistry, Strasse der Nationen 62, 09111 Chemnitz, Germany
S
* Supporting Information
ABSTRACT: α-Azido alcohols are generated by treating aldehydes with
hydrazoic acid in chloroform. These adducts are transformed into geminal
azido−halo compounds through the reaction with phosphorus trichloride or
phosphorus tribromide, whereas α-azidoalkyl esters are isolated after interaction
with acyl chlorides.
lcohols and the azido unit belong to the most important
functional groups in organic chemistry. Especially unusual
structures and new reactions of azides have currently elicited
great research interest.1,2 However, α-azido alcohols of type 5,
the geminal combination of both functionalities, are only
recently known (Scheme 1).3 Such compounds were
azidomethanol 5a instead of the desired product.3 The new
compound 5a was conveniently characterized3 in solution
although it was only postulated to occur as a short-lived
intermediate previously.7 Approximately three decades ago,
several unsuccessful experiments8 to synthesize α-azido
alcohols 5 led to the presumption that hydrazoic acid does
not react with aldehydes readily.9 But 5a was simply available
by mixing solutions of formaldehyde 4a and hydrazoic acid, and
it turned out that all types of aldehydes 4 react with the reagent
HN3 to establish an equilibrium with 5.3 At −50 to −65 °C,
this equilibration is retarded, and thus, hydrazoic acid along
with the solvent and even volatile aldehydes 4 can be removed
in vacuum to get highly enriched or pure α-azido alcohols 5,
which are obtained as less volatile solids or viscous liquids.3,10
When the adduct 5 is liberated from HN3 at room temperature,
however, the rapid equilibration causes complete cleavage of 5,
and only aldehyde 4 remains. In such cases, the formation of 5
from 4 and hydrazoic acid is easily overlooked,11 and this
explains the late discovery of α-azido alcohols.3
A
Scheme 1. Discovery of Azidomethanol 5a and Synthesis of
α-Azido Alcohols 5
The synthesis of adducts 5 from aldehydes and HN3 is
compatible with a variety of other functional groups, such as
olefins, alkynes, allenes, halides, acetals, esters, et al., and can be
combined with several subsequent transformations. Thus, 1,3-
dipolar cycloaddition at the azido group of 5 led to 1,2,3-
triazoles, for example, by copper-free click reaction in the
presence of cyclooctyne. Photolysis of 5 induced liberation of
dinitrogen and gave amides via a proton shift from carbon to
nitrogen or similar migration of the group R.3,10,12
Furthermore, the azido unit in 5 strongly influences the facility
with which the hydroxy group can be oxidized to a carbonyl
group. Hence, oxidation of α-azido alcohols 5 in chloroform at
−20 to −60 °C with the help of pyridinium chlorochromate
produced the corresponding acyl azides in 80−89% yield based
on the aldehydes 4.3 Under such mild reaction conditions,
accidentally discovered after preparing azidochloromethane 2a
and azidobromomethane 3a by treatment of triazide 1 with
anhydrous hydrogen chloride or hydrogen bromide, respec-
tively.4 These products are not available by the simple reaction
of dihalomethanes with azide salts because the desired
nucleophilic substitution is by far slower than the displacement
of the second halogen atom leading to unwanted diazido-
methane.5 When chloroiodomethane was treated with a
substoichiometric amount of hexadecyltributylphosphonium
azide (QN3),6 we hoped to detect intermediate 2a by NMR
monitoring, but were disappointed since only the signals of the
substrate, diazidomethane, and those of Q (hexadecyltributyl-
phosphonium) were observed.4
In an attempt to prepare azidoiodomethane by treatment of
1 with hydrogen iodide under apparently not completely
anhydrous conditions or workup, we surprisingly obtained
Received: August 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02380
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Organic Letters
Letter
Curtius rearrangement did not occur, and even previously
unknown short-lived formyl azide was available from
azidomethanol 5a for the first time.13 Moreover, cleavage of
1,2-diazidoethan-1,2-diol, which is accessible from glyoxal and
hydrazoic acid, gave formyl azide by treatment with periodic
acid.
However, the equilibration of 4/HN3 and 5 has to be taken
into account when transformations of 5 are planned. In the
presence of a base, for example, hydrazoic acid is completely
consumed to form a salt, and the equilibrium is totally shifted
from 5 to 4. Herein, we describe esterification of 5 with the
help of acyl chlorides and the synthesis of geminal azido−halo
compounds 2 and 3 from 5 and phosphorus trihalide (Table 1).
of the products, especially those of azides with low molecular
mass, must also be taken into account.19 Thus, we treated not
only most of the azides 2 and 3 but also the compounds 9, 10,
13, 14, 17, 19e, and 20e with cyclooctyne in dichloromethane
or hexane and obtained the corresponding 1H-1,2,3-triazoles in
good to excellent yields. These cycloadducts, for example, 7, 8,
and 11, are stable and can easily be utilized to characterize the
original azides.
The products 2 and 3 show the quality of substrates with a
halide leaving group combined with an adjacent azido donor
unit. Consequently, high reactivity, comparable to that of α-
halo ethers, is observed. This reactivity can be used in
substitution and elimination reactions as depicted in Schemes
2 and 3, respectively. Treatment of 3d or 3f with N,N,N′,N′-
Table 1. Synthesis of Geminal Azido−Halo Compounds 2
and 3 from Aldehydes 4 via α-Azido Alcohols 5
Scheme 2. Reactions of Geminal Azido−Halo Compounds 2
and 3
a
a
compd
R
yield of 2 (%)
yield of 3 (%)
b
b
a
b
c
d
e
f
H
56
67
b
c
Me
66
−
−
b
c
Et
65
CH2Cl
CCl3
CO2Et
Bn
42
42
49
48
50
54
b
c
g
90
−
a
b
Isolated yields based on 4 unless stated otherwise. Yield determined
c
by 1H NMR and based on 4. Unstable product, decomposition
leading to nitrile 6.
Very few examples of products, for which structures 214 or 315
were assigned, are known in literature.16 But to the best of our
knowledge, a general method to prepare such compounds has
not been reported so far. Obviously, the access to 2a and 3a
from the special precursor 1 cannot be transfused from these
parent compounds to create a general synthesis of geminal
azido−halo products. On the other hand, several compounds of
type 2 were analyzed in theoretical studies.17
tetramethylguanidinium azide (TMGA) in chloroform led to
the corresponding geminal diazides 9d and 9f, which are
known16,21 compounds. Obviously, the reactivity of the geminal
azido−halo moiety is significantly higher than that of the CH2−
Cl group of 3d in this substitution reaction. Exposure of 3e or
3f to an excess of tetrabutylammonium thiocyanate in
chloroform gave only incomplete consumption of the starting
compounds and low yields of 10e and 10f, respectively. Even
after extended reaction times, 30−31% of 3e or 3f were
recovered. Most probably, the substrates form equilibria with
the desired products.22
The vinyl azides 12−14 and 17 were generated when we
reacted geminal azido−halo compound 2g, 2d, or 3d with
potassium tert-butoxide in diethyl ether. The known23 product
12 was isolated in 74% yield as a cis/trans mixture (1:9). In the
cases of enazides 13, 14, and 17, characterization was
performed only partially and in solution because of the
explosive and volatile properties of these products. After
treatment with cyclooctyne, however, the corresponding
cycloadducts 15, 16, and 18 were utilized to isolate stable
derivatives, which were conveniently characterized.24
When we treated freshly distilled aldehydes 4 with 2 equiv of
hydrazoic acid18,19 in chloroform,20 first at −5 °C and then at
room temperature for 2 h, the α-azido alcohols 5 were formed.
These products were liberated from solvent and an excess of
HN3 in vacuum (0.005 mbar) at −50 to −55 °C, which led also
to removal of unreacted 4 in the case of more volatile
substrates. The residue was resolved in precooled (−50 °C)
chloroform, and after addition of 3 equiv of phosphorus
trihalide, the mixture was stirred for 1 h and then at ambient
temperature for 12 h. The latter reaction conditions were
changed to −30 °C and 12 h for the less stable products 2b,c,g.
The procedure of workup was also dependent on the stability
and volatility of the products 2 and 3. Isolation of these
substances after conventional workup with water and pentane/
diethyl ether was possible for 2d−f and 3d−f and gave
moderate yields (Table 1). In the case of less robust and/or
highly volatile products, we avoided aqueous workup and
complete removal of the solvent because of the decay or
evaporation loss of the substances. The unwanted decom-
position of geminal azido−halo compounds 2 and 3 to generate
nitriles 6 was excessive for bromides 3b,c,g, which could not be
detected even by NMR spectroscopy. The explosive properties
Esterification of α-azido alcohols 5 is possible with the help
of acyl chlorides and leads to isolable products 19 and 20
(Table 2). After removal of hydrazoic acid and aldehyde 4 in
B
DOI: 10.1021/acs.orglett.7b02380
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Organic Letters
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Scheme 3. Synthesis of Vinyl Azides from Geminal Azido−
Table 2. Synthesis of α-Azidoalkyl Esters 19 and 20 from
Aldehydes 4 via α-Azido Alcohols 5
a
Halo Compounds
a
b
b
compd 4
R
method
yield of 19 (%)
yield of 20 (%)
b
b
b
c
c
c
e
e
e
f
Me
A
B
C
A
B
C
A
B
C
A
B
34
44
34
23
23
54
70
100
−
−
−
10
Me
Me
Et
−
−
−
12
12
15
13
15
Et
Et
CCl3
CCl3
CCl3
CO2Et
CO2Et
79
f
100
a
Method A included enrichment of 5 by removal of HN3 and 4; the
equilibration mixture of 4/HN3 and 5 was utilized in Method B; in the
case of Method C, a one-pot procedure with 4, acyl chloride, H2SO4,
b
and NaN3 was used. Isolated yields based on 4.
with cyclooctyne to prepare the corresponding 1H-1,2,3-
triazoles.24
The syntheses of α-azidoalkyl esters by alternative methods is
known in literature.26 But the access to these compounds is
often described for single and special examples only, and the
desired products are formed as mixtures with other substances
in many cases.27 To date, simple aldehydes have not been
utilized to prepare α-azidoalkyl esters.
In summary, we have shown that geminal azido−halo
compounds 2 and 3 as well as α-azidoalkyl esters 19 and 20
can easily be prepared from aldehydes 4 via α-azido alcohols 5.
We assume that the adducts 5 can also be used to synthesize
other products with rare combinations of geminal functional
groups. Thus, we hope α-azido alcohols 5 will further enrich
the multifarious chemistry of organic azides.
a
Isolated yields based on 2d, 2g, and 3d.
vacuum, we first treated solutions of highly enriched adducts 5
with acetyl chloride or pivaloyl chloride (Method A). However,
it turned out that this purification of 5 was not necessary, and
even significantly better yields of 19 were achieved in some
cases by using the equilibration mixture of 4/HN3 and 5 for the
reaction with the acyl chloride (Method B). A one-pot
procedure, starting with aldehyde 4 in chloroform at −35 °C
and successive addition of acyl chloride, concentrated sulfuric
acid, and sodium azide, was also successful to prepare 19 and
20 via intermediate formation of 5 (Method C). In this
procedure, additional handling of solutions of explosive and
toxic hydrazoic acid18,19,25 was not necessary, and a
substoichiometric amount of sulfuric acid was adequate to
produce the reagent from sodium azide because hydrogen
chloride as a second strong acid is generated in the
esterification step. From simple aldehydes such as 4b and 4c
acetates 19 (R′ = Me) were synthesized with moderate yields
via α-azido alcohols 5b,c, whereas good to excellent yields of
acetates resulted from electron-poor substrates such as 4e and
4f. However, the sterically hindered pivaloyl chloride gave only
low yields of the corresponding esters 20b,e,f (R′ = t-Bu). In all
cases, α-azidoalkyl esters 19 and 20 were isolated as colorless
liquids, and the products 19e and 20e were additionally treated
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02380.
Experimental details for new reactions and analytical data
of new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: klaus.banert@chemie.tu-chemnitz.de.
ORCID
Klaus Banert: 0000-0003-2335-7523
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by funding from the Deutsche
Forschungsgemeinschaft (BA 903/12/1-3). We thank Dr. S.
■
C
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Organic Letters
Letter
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D
DOI: 10.1021/acs.orglett.7b02380
Org. Lett. XXXX, XXX, XXX−XXX