B(C6F5)3-catalyzed synthesis of benzylic azides

Article abstract of DOI:10.1080/00397911.2017.1350277

B(C₆F₅)₃ was found to catalyze the reaction between trimethylsilyl azide and benzylic acetates. Secondary and tertiary benzylic acetates were competent substrates in this reaction providing the azide products in moderate t

Full text of DOI:10.1080/00397911.2017.1350277

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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B(C F ) -catalyzed synthesis of benzylic azides
6
5 3
Michael S. Wrigley & Timothy J. Barker
To cite this article: Michael S. Wrigley & Timothy J. Barker (2017): B(C F ) -catalyzed synthesis of
6
5 3
benzylic azides, Synthetic Communications, DOI: 10.1080/00397911.2017.1350277
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1350277
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Date: 19 July 2017, At: 23:40

B(C F ) -catalyzed synthesis of benzylic azides
6
5 3
Michael S. Wrigley
Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC, USA
Timothy J. Barker
Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC, USA
Address correspondence to Timothy J. Barker, Department of Chemistry and Biochemistry,
College of Charleston, Charleston, SC 29424, USA
ABSTRACT
Graphical Abstract
KEYWORDS
Introduction
Alkyl azides are useful intermediates in synthetic organic chemistry and participate in a
[
1]
[2]
myriad of reactions. An azide can also be easily reduced to the corresponding amine. Copper-
catalyzed azide-alkyne cycloadditions (CuAAC) to form triazoles are another reaction of great
1

[
3]
synthetic interest. CuAAC reactions have been employed in bioconjugation and material science
to great effect due to the ease of performing this reaction.[4]
There are several known routes to benzyl azides. The Mitsunobu reaction can directly
convert benzylic alcohols into azides.[5,6] Alcohol derivatives such as acetate and silyl-protected
alcohols have also been shown to react with trimethylsilyl azide in the presence of Lewis acid
[
7]
catalysts. More recently, other methods using Lewis acid catalysts have been reported to convert
[
8]
benzylic alcohols to azides. A drawback to these methods is that some Lewis acid catalysts have
been reported to promote formation of dimeric ether side products when secondary benzylic
alcohols are employed as electrophiles.[9] We were interested in examining
tris(pentafluorophenyl)borane as a catalyst for an azidation reaction.
Tris(pentafluorophenyl)borane (B(C
6
F
5
3
) ) has been a catalyst of recent interest due to its
unique reactivity as a Lewis acid.[10] It has been employed successfully for the reduction of
alcohols to alkanes and reductive cleavage of ethers, as well as the reduction of carboxylic acids
and ketones to alkanes in the presence of silanes.[11] The combination of B(C
also been used in the hydrosilylation of alkenes.[12] Additionally, allylsilanes have been employed
F
5
6
3
) and silanes has
as carbon nucleophiles with B(C
6
F
5
)
3
as a catalyst with benzyl and propargyl acetate
electrophiles.[13] We wanted to examine the viability of B(C
F
5
6
3
) as a Lewis acid catalyst with
trimethylsilyl amine nucleophiles. Mechanistically, this reaction was of interest due to the potential
for forming a new Lewis acid-base pair with an amine nucleophile (Scheme 1).
Azidoborane and azidoborates have previously been studied in detail.[14] Crystal structures
+
–
[15]
of [Me
4
N] [B(C
6
F
5
)
3
(N
3
)] and related compounds have been reported.
While a stable
azidoborate is known and fully characterized, no reactivity with electrophiles of this anion is
known to the best of our knowledge. In the course of our studies we sought to determine the
2

viability of a B(C
6
F
5
)
3
/TMSN Lewis acid-base pair as an intermediate in reactions between
3
benzylic acetates and trimethylsilyl azide (TMSN ).
3
Results and Discussion
We began our investigations with the secondary benzyl acetate 1a and TMSN
pleased to observe complete consumption of the starting acetate under the reaction conditions in
Scheme 2. Representative examples of Brønsted and Lewis acids (PTSA and BF ·OEt ) provided
3
. We were
3
2
little to no desired product under the reaction conditions (entries 2 and 3). Switching the azide
nucleophile to sodium azide provided none of the desired product (entry 4). This result suggests
the necessity for the trimethylsilyl moiety and its possible role as a Lewis acid in this reaction. A
Boc-protected alcohol was found to provide the product in the same efficiency as the acetate
derivative (entry 6). Using the alcohol as the substrate provided the product in a respectable 71%
yield. A reaction with two equivalents of TMSN did not go to completion (entry 9). A reaction
3
time of 6 h was insufficient for the starting material to be consumed (entry 10).
The scope of benzylic acetates compatible with this reaction was next examined (Scheme
3
). Both secondary and tertiary benzylic acetates were good substrates for this transformation and
1
provided clean conversion to the azide products as determined by H NMR of the unpurified
reaction mixture. Substrate 3e with an electron donating substituent at the 4-position provided the
product in 82% yield. The cyclic azide 3f was provided in excellent yield under these reaction
conditions. A substrate with a ring deactivating 4-bromo substituent in 3g did not go to completion
in 24 hours resulting in a diminished yield. Benzhydrol was a good substrate providing the desired
azide 3h in 96% yield, revealing that the acetate group was not required for highly activated
substrates. Reactions to form products 3j, 3k, and 3l provided no product, confirming the need for
a secondary or tertiary benzylic carbocation intermediate in this reaction.
3

Efforts to expand the scope to other trimethylsilyl amine nucleophiles were unsuccessful.
Trimethylsilyl)isocyanate was unreactive under the conditions. The starting benzylic acetate was
(
consumed in a reaction with (trimethylsilyl)isothiocyanate, but provided a complex mixture of
products that was not separable by column chromatography.
NMR experiments were performed to detect the presence of a Lewis acid-base pair between
the catalyst B(C
6
F
5
)
3
and TMSN
3
(Figure 1). In C
6
D
, a series of 19F experiments revealed
6
chemical shifts consistent with the Lewis-acid base complex proposed in Scheme 1. Adding one
19
equivalent of TMSN
indicative of coordination of the TMSN
the unpaired species. Next an excess of the TMSN
conditions and force the equilibrium to the Lewis acid-base pair. This addition resulted in a major
3
relative to the catalyst resulted in a small shift in all three F signals,
, but suggested that this species was in equilibrium with
was added that would be similar to the reaction
3
3
1
9
species with F shifts at -134.1 (o), -154.3 (p) and -162.6 (m) ppm as well as additional peaks
from presumable side products. The narrowing of the distance between the para and meta peak
resonances is indicative of a change from a neutral 3 coordinate geometry to a anionic four
coordinate geometry around the boron.[11d,16] Additionally, these peaks are close to those reported
+
N
]– (-135.3 (o), -161.6 (p), and -166.7 (m) ppm).[15] This data suggests a shift
for [Me
4
N] [BC
6
F
5
3
in equilibrium to favor the Lewis acid-base adduct, but that this reaction is fast and reversible.
Conclusion
We have developed a B(C
6
F
5
3
) -catalyzed synthesis of benzylic azides. Secondary and
tertiary benzylic esters were found to react under these reaction conditions. These reactions
provide the azide products in moderate to high yields with no observable side products. This report
provides evidence of an intermediate Lewis acid-base pair of B(C
6
F
5
)
3
/TMSN and its use in a
3
4

productive transformation to generate carbon-nitrogen bonds. We plan to further examine the
reactivity of this Lewis acid-base pair with additional electrophiles.
Experimental Section
NMR spectra were recorded on a Bruker 400 MHz spectrometer. NMR data were collected
°
at 25 C. Proton chemical shifts are reported in ppm (δ) relative to the respective solvent resonance
(
CDCl
doublet (d), triplet (t), quartet (q), multiplet (m)], coupling constants [Hz], integration). Carbon
chemical shifts are reported in ppm (δ) relative to the respective solvent resonance (CDCl , δ 77.16
3
δ 7.26). Data are reported as follows: proton chemical shift (multiplicity [singlet (s),
3
ppm). Acetate substrates were prepared via sodium boron hydride reduction of commercially
available aromatic ketones with subsequent acylation according to known procedures.[17,18]
(azidomethylene)dibenzene 3j was prepared using the standard procedure using commercially
available benzyhydrol as the substrate. B(C
6
F
5
3
) was purchased from Strem.
General procedure
In a nitrogen glovebox, Tris-pentafluorophenyl borane (7.7 mg, 0.015 mmol, 0.05 equiv)
and a stir bar were added to a flame-dried RBF. The RBF was then placed under an argon
atmosphere. Starting substrate 1a (49 mg, 0.75 mmol, 1.0 equiv) was added to a four mL vial and
diluted with THF (1 mL). To the vial solution TMSN (120 μL, 0.90 mmol, 3.0 equiv) was added.
3
The vial contents were transferred via syringe to the RBF and allowed to stir for 24 hours at room
temperature. THF was removed under reduced pressure and the product purified by flash
chromatography. Flash chromatography was performed using a 1” diameter column, 5 cm of SiO
2
gel and a mobile phase of pentane:ether (98:2) to provide 35 mg (80% yield) of the azide product
5

3
a.[19] 1H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.33 (m, 5H), 4.64 (q, J = 6.6 Hz, 1H), 1.56
1
3
(
d, J = 6.6 Hz, 3H). C NMR (101 MHz, CDCl ) δ 141.00, 128.90, 128.25, 126.50, 61.23, 21.70.
3
Acknowledgments
The College of Charleston is acknowledged for financial support. The NMR spectrometer
at the College of Charleston is supported by the National Science Foundation under Grant No.
429308.
1
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[
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[
[
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1
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[
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2
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6

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[
[
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6
F
5
)
3
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4
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7

Table 1. Optimization of conditions
Entry
Change from Standard Conditions Yield (%)a
1
2
3
4
None
88
0
TsOH as catalyst
BF3.0(Et)2 as catalyst
0
NaN3 instead of TMSN3, no
B(C6F5)3, no Ar
0
5
6
7
8
9
NaN3 instead of TMSN3
OBoc insted of OAc
OCOCF3 instead of OAc
OH instead of OAc
0
88
25
71
84
62
63
TMSN3 (2.0 equiv)
1
1
0
1
Toluene instead of THF
Reaction time = 6h
a
1
Yield obtained by H NMR using 1,4-dimethoxybenzene as an internal standard.
8

Table 2. Substrate scope
9

1
9
19
19
Figure 1. F NMR Spectra of B(C
6
F
5
)
3
and TMSN
3
. A. F of B(C
6
F
5
)
3
B. F of B(C
(40 equiv)
6
F
5
3
) (1
1
9
equiv_ and TMSN
3
(1 equiv) C. F of of B(C (1 equiv_ and TMSN
6
F
5
)
3
3
1
0

Scheme 1. Lewis acid-base pairs
1
1