Trapping of azidocarbenium ion: A unique route for azide synthesis

Article abstract of DOI:10.1021/ol5008235

For the first time, a sensitive azidocarbenium ion intermediate has been trapped with various nucleophiles to provide azides in excellent chemoselectivity. This provides a novel approach for the chemoselective synthesis of primary and secondary benzyl azides from aldehydes in a one-pot reaction. Enantioselective nucleophilic addition to the azidocarbenium ion has also been initiated.

Full text of DOI:10.1021/ol5008235

Letter
pubs.acs.org/OrgLett
Trapping of Azidocarbenium Ion: A Unique Route for Azide Synthesis
Suman Pramanik and Prasanta Ghorai*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Indore By-pass Road, Bhauri, Bhopal 462066,
India
S
* Supporting Information
ABSTRACT: For the first time, a sensitive azidocarbenium ion
intermediate has been trapped with various nucleophiles to provide
azides in excellent chemoselectivity. This provides a novel approach
for the chemoselective synthesis of primary and secondary benzyl
azides from aldehydes in a one-pot reaction. Enantioselective
nucleophilic addition to the azidocarbenium ion has also been
initiated.
he α-azidocarbenium ion (IV, Scheme 1) has been well-
Scheme 2. Chemistry of Azidocarbenium Ion Intermediate
T
known in the literature since the middle half of the
Scheme 1. Chemistry of the α-Stabilized Carbenium Ions
many other organic transformations.8 Such azides have been
used as important building blocks for the synthesis of other
classes of molecules, including natural products containing
piperidine9 and the pyrrolidine core.10
In general, the benzyl azides are prepared by nucleophilic
substitution of an appropriate benzyl electrophile with azide
anions. In this context, recently considerable attention has been
paid toward the development of azidation reaction via catalytic
twentieth century as an intermediate in Schmidt and related
rearrangement reactions.1 It has already been well established
that in such an intermediate the α-azido group stabilizes the
carbocation;2 moreover, ab initio calculations have predicted that
the α-azido group can stabilize the α-carbocation better than an
α-OH group, albeit to a reduced extent in comparison to the α-
NH2 group.3 Although there are overwhelming reports for the
trapping of the oxocarbenium ion (I),4 the peroxycarbenium ion
(II),5 and the iminium ion (III)6 for the synthesis of alkoxides,
peroxides, and amines, respectively, the trapping of an analogous
azidocarbenium ion (IV) for the synthesis of azides has never
been developed.1 The real obstacle to surmount in achieving
trapping of the azidocarbenium ion is to stop the Schmidt and
related rearrangements driven by the thermodynamically
favorable loss of molecular nitrogen (N2) gas from the azido
group (Scheme 2a). Here, we envisioned the unprecedented
approach for the trapping of a highly sensitive azidocarbenium
ion intermediate (IV) with numerous nucleophiles to provide a
diverse class of benzylazides from aldehydes with excellent
chemoselectivity (Scheme 2b).
11
1
SN -type (via carbocation intermediate) instead of the
12,13
2
traditional stoichiometric SN -type
reaction pathway. How-
ever, benzyl alcohols11a or alcohol derivatives11b,c with electron-
deficient substituents such as O2N-, CN-, CO2R, etc. are
1
unsuccessful as substrate for such catalytic (SN -type) reactions
because of the instability of the corresponding carbocationic
intermediate (A, Scheme 3). For the same reason, our recently
developed FeCl3-catalyzed synthesis of homoallylic azides, via an
allylation−azidation sequence, also suffer from similar substate
scope.11d Therefore, we aimed that via an azidocarbenium ion
Scheme 3. Benzyl Carbocation vs Azidocarbenium Ion
The benzyl azides are valuable intermediates in organic
synthesis. These are extensively used in biological studies as a
fluorescent probe through its click chemistry.7 Furthermore,
these find application in the synthesis of amines, nitriles and in
Received: February 14, 2014
Published: April 4, 2014
© 2014 American Chemical Society
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Letter
a
(B) pathway would eliminate such limitations; the carbocation
would get stabilized by the α-azido group which might be
sufficient to compensate for the electron-deficiency caused by
electron-withdrawing group on the aryl ring.
Table 2. Scope of Aldehydes for Reductive Azidation
Recently, a reductive azidation of carbonyls via tosylhydra-
zones has been developed by Barluenga and co-workers,
providing moderate yields of primary and secondary azides.13
Notably, benzyl azides are not accessible via other methods such
as the reactions of carbon nucleophile with electrophilic azides14
and hydroazidation of alkenes.15
We started our investigation of the direct reductive azidation
choosing 4-nitro benzaldehyde (1a), a challenging substrate for
the SN1-like (via a carbocationic intermediate) reaction
conditions, as a model substrate in the presence of TMS-N3
and Et3SiH as azide and hydride source, respectively
(summarized in Table 1). In the presence of various Lewis acid
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalysts (10 mol %)
yield of 3a (%)
3a:4a
1
2
3
4
5
6
7
8
In(OTf)3
FeCl3
5
8
50:50
9:91
AuCl3
0
0:100
39:61
99:1
Cu(ClO4)2
Sc(OTf)3
AgOTf
23
d
100 (78)
18
14
1
69:31
73:27
42:58
a
1 (1.0 mmol), TMS-N3 (2.8 mmol), Sc(OTf)3 (5 mol %) in CH2Cl2,
at 50 °C (A) or rt (B) or 0 °C (C) for t1 h, then nucleophile 2a was
added at 50 °C for conditions A and B or at rt for condition C and
Bi(OTf)3
Cu(OTf)2
a
b
c
1 (0.3 mmol), TMS-N3 (0.9 mmol), catalyst (0.03 mmol) in CH2Cl2
stirred for t2 h. Isolated yield. Step 1 was carried out at −10 °C
instead of 0 °C. AgOTf (10 mol %) was used. 10 mol % Sc(OTf)3
was used.
d e
at 50 °C for 5 h, then Et3SiH (0.6 mmol) was added, followed by
b
stirring for 24 h. 1H NMR yield of the reaction mixture using
c
acetophenone as an internal standard. Ratios were determined using
d
1H NMR of the reaction mixture. Isolated yields (in parentheses).
respectively, entries 11−13) in good yields. Benzyl as well as
naphthaldehydes are also equally effective for the current process
(entries 14−16). The reductive azidation of heteroaromatic
aldehydes like thiophene-2-carboxaldehyde, N-Boc-indole-3-
carboxaldehyde and chroman-2-en-4-one-3-carbaldehyde also
proceeded smoothly using AgOTf instead of Sc(OTf)3 as catalyst
to furnish the corresponding azides (entries 17−19). Unfortu-
nately, aliphatic aldehydes are not a suitable substrate for
reductive azidation.
After successful reductive azidation, we turned our attention
toward C−C bond formation with azidocarbenium ion for the
synthesis of secondary benzyl azides (Table 3). As shown,
azidocarbenium ion derived from p-MeO benzaldehyde was
trapped with various silanes (2b,c), silyl enol ethers (2d−f), and
silyl ketene acetal (2g) to provide a variety of secondary azides
such as homoallylic azides (6a,b), β-azido carbonyls (6c−e), and
β-azido esters (6f) in good yields and with excellent chemo-
selectivities (entries 1−6, respectively). We extended the present
methodology to silyloxy furan (2h) as nucleophile to provide
vinylogous addition product 6g (entry 7). Notably, most of these
synthesized compounds are unprecedented in the literature.
Further potential utility of such electrophilic α-azidobenzyl
cations generated from diazides was extended to the function-
alization of nucleophilic β-keto esters (as shown in Scheme 4).
For example, β-keto esters of cyclopentanone- (7a,b), indanone-
(7c), and cyclohexanone- (7d) were evaluated and furnished the
corresponding products 8a−f, having an all carbon quaternary
catalysts, the addition of TMSN3 and Et3SiH sequentially
provided the mixture of products containing the desired azide
(3a) along with nitrile (4a) and diazide (5a)16 respectively.
Interestingly, Sc(OTf)3 as catalyst mainly provided the desired
azide (3a) along with the diazide (5a) which further slowly
converted to the azide 3a on longer duration of the reaction.
Since the formation of nitrile (4a) completely ceases on addition
of excess TMS-N3, we preferred to convert the aldehyde to
diazide 5a by adding excess TMSN3 (by TLC) followed by
conversion of diazide 5a to azide 3a by the addition of Et3SiH.
Thus, the chemoselectivity of azidation over nitrile formation
was controlled. Although the reaction proceeds well in a number
of solvents, CH2Cl2 was identified as optimal for both the steps to
proceed with high chemoselectivity.
With these optimized reaction conditions identified, we
examined the reductive azidation of a wide variety of aldehydes
as summarized in Table 2. Both electron-deficient and electron-
rich aldehydes are effective for the current reaction. Aromatic
aldehydes with other electron-deficient substituents such as m-
O2N, p-CN, p-EtO2C, m-F3C, 3,5-di-F3C, fluoro, chloro, bromo,
and phenyl react at rt to 50 °C to provide the desired benzyl
azides (3b−j, entries 2−10) in good yields with excellent
chemoselectivity. Further, aromatic aldehydes with electron-rich
substituents such as methyl, methoxy, and benzyloxy react even
more smoothly to provide the desired products (3k−m,
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Letter
a
Table 3. Scope of Nucleophiles for the Synthesis of Azides
Scheme 5. Preliminary Result of Enantioselective Variant
a
Scheme 6. Benzyl Carbocation vs Azidocarbenium Ion
a
1
Yields are based on H NMR studies of reaction mixture.
Sc(OTf)3 catalyst, following the previous protocol (path a), the
in situ formed homoallyl alcohol/silyl ether intermediates (9a/
b) did not convert to the corresponding azide 6h. These results
reflect the difficulty in the formation of the corresponding
carbocation A. On the other hand, the current azidation followed
by allylation using the same catalysts (path b) provided the
desired azide 6h. The easy formation of azidocarbenium ion
intermediate B most likely enabled this process.
a
1l (1.0 mmol), TMSN3 (2.8 mmol), and Sc(OTf)3 (10 mol %) were
stirred at 0 °C in CH2Cl2 for 8 min, nucleophile (2.0 mmol) was
added, the temperature was increased to rt, and the mixture was stirred
b
c
for time t. Isolated yield. The yield in parentheses refers to the
reaction when carried out from gem-diazide 5l instead of 1l (see the
Supporting Information).
a c
−
Scheme 4. Synthesis of β-Azidodicarbonyls
Furthermore, a common azide ion inhibition experiment was
carried out to observe the effect of TMS-N3 in the above reaction
(Scheme 7). We observed that the substitution of diazide (5n)
Scheme 7. Common Azide Ion Inhibition Experiment
a
7 (0.5 mmol), gem-diazide (5, 0.75 mmol), Cu(OTf)2 (10 mol %) in
b
c
CH2Cl2, 0 °C for 15 min, then at rt. Isolated yield. dr was
d
determined from the 1H NMR of the reaction mixture. Reaction was
carried out at 50 °C.
with allyl-TMS is much slower in the presence of excess amount
of TMS-N3. An excess of TMS-N3 likely surrounds the in situ
formed azidocarbenium ion (through a “contact ion pair”2c)
which prevents the nucleophilic attack by the allylic anion. This is
also an indirect indication for a stepwise reaction mechanism
through the generation of an α-azidocarbenium ion followed by
nucleophilic addition reaction.
The plausible mechanism for the current reaction is proposed
in Scheme 8. Azidation of the aldehyde using TMS-N3 forms an
α-azidosilyl ether (C) which undergoes further azidation to give
carbon center α to the azidobenzyl group, in good yields and with
excellent chemoselectivity. To our surprise, isolated diazides (5)
instead of in situ formed diazides (as was the case in Table 3)
provided better yields; moreover, Cu(OTf)2 showed superior
reactivity instead of Sc(OTf)3 as catalyst in this particular case.
Next, we became interested in examining the enantioselective
variant of the above developed reactions. As shown in Scheme 5,
a preliminary attempt to provide the proof of concept has been
investigated using catalytic Cu(OTf)2 in the presence of catalytic
iPr-PHOX (L), as chiral ligand, providing an enantioselective
C(sp3)−CH(N3)Ar product (8d-crl) in good yield (68%) and
with acceptable enantioselectivity (∼40% ee).
Scheme 8. Proposed Reaction Mechanism
The advantage of the current azidation−allylation sequence
over our previous report of an allylation−azidation sequence of
aldehydes (1a)11d has also been demonstrated (summarized in
Scheme 6). As shown, in the presence of FeCl3, as well as
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Experimental procedures, characterization data, and copies of
NMR spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: pghorai@iiserb.ac.in.
Notes
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A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.; Grabowski, E. J.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by BRNS, DAE, India, through a
DAE Young Scientist Research Award Grant. We are grateful to
IISER Bhopal for additional support. We are thankful to Dr.
Deepak Chopra for his assistance. S.P. thanks CSIR, New Delhi,
India, for a fellowship.
(13) For reductive azidation, see: Barluenga, J.; Tomas
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