A radical procedure for the anti-markovnikov hydroazidation of alkenes

Article abstract of DOI:10.1021/ja2054989

A one-pot procedure for the efficient hydroazidation of alkenes involving hydroboration with catecholborane followed by reaction with benzenesulfonyl azide in the presence of a radical initiator is described. The regioselectivity is controlled by the hydroboration step and corresponds in most cases to an anti-Markovnikov regioselectivity. This procedure is applicable to a wide range of alkenes and gives excellent results with 1,2-disubstituted and trisubstituted alkenes.

Full text of DOI:10.1021/ja2054989

COMMUNICATION
pubs.acs.org/JACS
A Radical Procedure for the Anti-Markovnikov Hydroazidation
of Alkenes
Ajoy Kapat, Andreas K€onig, Florian Montermini, and Philippe Renaud*
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland
S Supporting Information
b
azides. They were surprised to observe the formation of aryl
ABSTRACT: A one-pot procedure for the efficient hydro-
azidation of alkenes involving hydroboration with catechol-
borane followed by reaction with benzenesulfonyl azide in
the presence of a radical initiator is described. The regios-
electivity is controlled by the hydroboration step and
corresponds in most cases to an anti-Markovnikov regios-
electivity. This procedure is applicable to a wide range of
alkenes and gives excellent results with 1,2-disubstituted and
trisubstituted alkenes.
sulfides and noticed the formation of an intermediate with an
IR absorption band at 2100 cmÀ1. However, no alkyl azide was
isolated, and no mechanism was proposed to rationalize this
unexpected result.17
Our previous results with organoboron compounds and
sulfonyl azides encouraged us to investigate the reaction of B-
alkylcatecholboranes with benzenesulfonyl azide in presence of a
radical initiator. The formation of alkyl azides was anticipated. R-
Pinene (1) was selected as a model substrate for optimization of
the reaction conditions. It was hydroborated with 2 equiv of
catecholborane (CatBH) in dichloromethane using N,N-di-
methylacetamide (DMA)18 as a catalyst. After completion of
the hydroboration, the excess CatBH was treated with t-BuOH,
and the solvent was removed. The in situ-generated organobor-
ane was treated at 80 °C with 3 equiv of benzenesulfonyl azide
and 0.1 equiv of di-tert-butylhyponitrite19 as a radical initiator
(Scheme 2). Three different solvents were tested, and the results
are summarized in Table 1. In benzene and 1,2-dichloroethane
(DCE), the organoborane was consumed within 30 min, and the
desired azide 2 was obtained in moderate yield (entries 1 and 2).
In these two solvents, 2 was contaminated with sulfide 3, and
these could not be separated by column chromatography. Since
N,N-dimethylformamide (DMF) proved to be an excellent
solvent in the radical allylation of B-alkylcatecholboranes,15d
the next reaction was run in DMF. We were pleased to observe
a much cleaner reaction and a higher yield (78% isolated yield;
entry 3). Interestingly, the formation of the sulfide 3 was
completely suppressed.
The rationale for this dramatic solvent effect is not clear to
date. We believe that a sulfurizing reagent is generated by
dismutation and decomposition of the chain-reaction side pro-
duct (benzenesulfinyloxy)catecholborane (PhSO2BCat) (see
Scheme 5). DMF may slow the formation of this sulfurizing
agent by stabilizing the PhSO2BCat as a result of its Lewis basic
character.21
The scope and limitations of the optimized procedure were
tested with several alkenes, and the results are summarized in
Scheme 3. Cyclohexene afforded cyclohexyl azide (4) in 57%
isolated yield. The true yield of this transformation was signifi-
cantly higher (g75%; see below), but isolation was inefficient
because of the volatility of the product. Reactions involving other
secondary alkylcatecholboranes generated in situ from the
corresponding trisubstituted alkenes were examined. Azide 5
was obtained from 1-phenylcyclohexene in excellent yield (95%)
mines and their derivatives are privileged structures for drug
A
candidates and are ubiquitous in natural products. The
hydroamination of olefins represents a very attractive approach
for their preparation.1 However, this apparently simple proce-
dure remains a challenging transformation despite a tremendous
amount of recent research activity in this field. Most reported
intermolecular hydroamination processes use transition-metal
catalysts.2 Carreira described a Markovnikov hydrohydrazination
and hydroazidation of alkenes involving a hydrocobaltation
step.3 Anti-Markovnikov hydroamination of alkenes is particu-
larly puzzling,4 and recently, Studer reported a radical-mediated
anti-Markovnikov hydroamination of alkenes.5 The hydroazida-
tion reaction6 is particularly attractive because of the rich
chemistry of organic azides.7
Organoboranes are very useful reagents that are easily pre-
pared by hydroboration of alkenes and very efficiently converted
into alcohols by oxidative treatment.8 Extension of this chemistry
to the formation of CÀN bonds is usually achieved by reacting
the organoboranes with alkyl azides.9 Intra-10 and intermolecular
amination reactions have been reported, but the latter work well
only with highly electrophilic B-alkyldichloro- and -difluorobor-
anes (Scheme 1).9d,11 Other reagents such as chloramine-T and
analogues9e,12 have also been used.13 In this communication, we
report that under carefully conceived conditions, the reaction of
alkylboranes with sulfonyl azides follows a radical pathway
leading to efficient anti-Markovnikov hydroazidation of alkenes.
We recently reported that B-alkylcatecholboranes are extre-
mely useful radical precursors14 that participate in efficient
chain reactions with arenesulfonyl radicals.15 We have also
reported that arenesulfonyl azides are excellent reagents for
the azidation of alkyl radicals generated from halides, dithio-
carbonates, and Barton esters.16 In 1982, Ortiz and Larson
investigated the reaction of trialkylboranes with arenesulfonyl
azides.17 At that time, they anticipated the formation of
sulfonamides according to the mechanism observed with alkyl
Received: June 20, 2011
Published: August 08, 2011
r
2011 American Chemical Society
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|

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COMMUNICATION
Scheme 1. Reaction of B-Alkyldichloroboranes with Alkyl
Scheme 3. Hydroazidation of Olefins20
Azides (Cy = Cyclohexyl)11a
Scheme 2. Hydroazidation of r-Pinene (1)
Table 1. Solvent Optimization for the Conversion of 1 to 2
According to Scheme 2
entry
solvent
% yield of 2
2/3b
1
2
3
benzene
DCE
54a
61a
78
14:1
3:1
>50:1c
DMF
a An inseparable mixture of 2 and 3 was isolated; the yield was corrected
according to the measured 2/3 ratio. b Determined by 1H NMR analysis.
c Compound 2 was isolated as a single diastereomer.
a The isolated yield was low because of the volatility of the azide. b The
actual yield was g75% (see Scheme 6). c Hydroboration performed
with (Ph3P)3RhCl as a catalyst. d 6:1 mixture of regioisomers, only
major shown. e Contains unreacted PhSO2N3, yield corrected accord-
ing to NMR.
as a 2.5:1 trans/cis mixture of diastereomers. Traces of 1-azido-1-
phenylcyclohexane (5%) were also observed, indicating that the
hydroboration is not completely regioselective. Isolongifolene,
O-benzylnopol, and O-benzoylcitronellol afforded the expected
azides 6À8 in 62, 78, and 71% yield, respectively. The reaction
worked with unprotected cholesterol, affording azide 9 in
moderate yield (37%). Single diastereomers were detected for
compound 6, 7, and 9. In these three systems, the reaction took
place from the less hindered face of the polycyclic radical
intermediate. As anticipated, 8 was obtained as a 1:1 mixture of
diastereomers (no 1,4-induction in such an acyclic system would
be expected).22 The reaction with the benzylic alkylcatecholbor-
ane obtained by hydroboration of p-methoxystyrene using
(Ph3P)3RhCl as a catalyst23 led to the remarkable formation of
azide 10 in 77% yield with high regioselectivity (21:1). In this
case, the Markovnikov addition was achieved with satisfactory
selectivity. Interestingly, the Markovnikov cocatalyzed hydroazi-
dation developed by Carreira did not proceed with styrene
derivatives.3b All attempts to invert the stereoselectivity by using
different catalysts or performing an uncatalyzed reaction did not
allow inversion of the regioselectivity. Tertiary alkylcatecholbor-
anes obtained by hydroboration of tetrasubstituted alkenes were
also investigated. cis-4,5-Di(benzyloxymethyl)-1,2-dimethylcy-
clohex-1-ene affordsed azide 11 in 93% yield as a 16:4:0.8:0.2
mixture of diastereomers. Hydroboration occurred predomi-
nantly from the less hindered face anti to the two benzyloxy-
methyl groups (20:1 anti/syn), and the relative configuration of
the azidated carbon atom was determined by a rotating-frame
Overhauser effect spectroscopy (ROESY) experiment (see the
Supporting Information). A 4:1 diasterereoselectivity was ob-
served for the azidation step. On the basis of our results with
radicals generated from iodides,16a the hydroazidation of term-
inal olefins (primary alkylcatecholboranes) was expected to be
much less efficient. Nevertheless, satisfactory yields were ob-
tained with 4-phenyl-1-methylenecyclohexane (12, 67%, dr
1.3:1). Similar results were obtained with 1-dodecene (13,
70%) and O-p-chlorobenzoyldec-9-en-1-ol (14, 69%). For these
two monosubstituted terminal alkenes, the regioselectivity of the
hydroboration was not complete, and small amounts of the
corresponding secondary alkyl azides were formed.
The radical nature of the process was demonstrated by the
reaction with (À)-carene (15) which afforded ring-opened azide
16 in 79% yield (Scheme 4). The azidation of primary alkyl
radicals was expected to be a slow process that should allow slow
radical rearrangements to take place before the azidation step.
This point was demonstrated by the efficient 6-exo-trig cycliza-
tion of β-citronellene (17), which exclusively afforded cyclic
azide 18 at a high (3 M) concentration of benzenesulfonyl azide
(Scheme 4).
On the basis of the radical probe experiments, we propose the
following reaction mechanism for hydroazidation (Scheme 5).
Under heating at 80 °C, t-BuONdNOt-Bu decomposes to give
tert-butoxyl radicals that initiate the chain reaction. Reaction of
the B-alkylcatecholborane with a tert-butoxyl radical gives the
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COMMUNICATION
Scheme 4. Azidation Reactions Involving Rearrangement of
the Radical Intermediates
alkenes. The versatility of the azides, which can be easily
prepared, makes this reaction particularly suitable for applica-
tions in natural product synthesis.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures,
b
characterization data, and copies of H and 13C NMR spectra
1
of all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
philippe.renaud@ioc.unibe.ch
Scheme 5. Proposed Mechanism
’ ACKNOWLEDGMENT
This work was supported by the Swiss National Science
Foundation (Grant 20-135087). We thank BASF Corporation
for the generous gift of boron reagents.
’ REFERENCES
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Scheme 6. Sequential HydroborationÀAzidationÀ1,3-Di-
polar Cycloaddition Reaction
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starting alkyl radical and a boronic ester. The radical reacts with
benzenesulfonyl azide to give the alkyl azide and a benzenesul-
fonyl radical, which propagates the chain by homolytic substitu-
tion of the starting B-alkylcatecholborane. This last step produces
1 equiv of PhSO2BCat. Decomposition of PhSO2BCat may be
the origin of the thioethers observed when the reaction was run
in benzene and DCE (see above). The exact nature of the
sulfurizing agent is unknown.
A sequential reaction involving the hydroborationÀazidation
and a Cu(I)-mediated 1,3-dipolar cycloaddition24 with 3-phe-
nylprop-1-yne was investigated next (Scheme 6). The reaction
with cyclohexene afforded 4-benzyl-1-cyclohexyl-1H-1,2,3-tria-
zole (19) in 75% overall yield, confirming that the moderate yield
of 57% observed in the azidation reaction leading to 4
(Scheme 3) resulted from the volatility of this product.
In conclusion, we have developed an unprecedented reaction
between B-alkylcatecholborane and benzenesulfonyl azide that
can be applied to the efficient hydroazidation of alkenes. The
regioselectivity is controlled by the hydroboration and
corresponds in most cases to a formal anti-Markovnikov regios-
electivity. This procedure is applicable to a wide range of alkenes
and gives excellent results with mono-, di-, and trisubstituted
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(20) General azidation procedure: CatBH (0.64 mL, 6.0 mmol)
was added dropwise at 0 °C under nitrogen to a solution of the olefin
(2.0 mmol) and DMA (0.020 mL, 0.2 mmol) in CH2Cl2 (2.0 mL). The
reaction mixture was heated under reflux for 5 h, after which t-BuOH
(0.37 mL, 4.0 mmol) was added at 0 °C to solvolyze the excess CatBH
and the solution was stirred for 15 min at rt. After evaporation of the
solvent under vacuum, DMF (2 mL), PhSO2N3 (1.1 g, 6.0 mmol), and
DTBHN (36 mg, 0.2 mmol) were added, and the solution was stirred at
80 °C. After 2À3 h, the solution turned black, and the reaction mixture
was filtered through a pad of aluminum oxide to eliminate polar boron-
containing residues using Et2O as eluent. The filtrate was washed with
water and dried over Na2SO4. After evaporation of the solvent, the crude
product was purified by flash chromatography.
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