Boron perturbed click reactions prompt aromatic C-H activations

Article abstract of DOI:10.1002/anie.201402567

The reaction of boron alkynes and boron azides leads to rare N ₃BC heterocycles resulting from aromatic C-H activation of benzene and toluene. While subsequent treatment with PMe₃ gave the P-B adduct with the exocyclic boron, reactio

Full text of DOI:10.1002/anie.201402567

Angewandte
Chemie
DOI: 10.1002/anie.201402567
Cyclization
À
Boron Perturbed Click Reactions Prompt Aromatic C H
Activations**
Daniel Winkelhaus and Douglas W. Stephan*
Abstract: The reaction of boron alkynes and boron azides
the 1,3-dipolar cycloaddition reaction of the boron azide,
leads to rare N3BC heterocycles resulting from aromatic C H
Cy2BN3, with electron-poor acetylenes.[10] Herein, we report
the unusual and uncatalyzed reaction of bis(pentafluorophe-
nyl)boron-substituted alkynes and azides leading to an
exceptional five-membered BCN3 heterocycle by the activa-
tion of the corresponding aromatic solvent. Moreover,
mechanistic considerations for the formation of this remark-
able reaction are presented.
À
activation of benzene and toluene. While subsequent treatment
À
with PMe3 gave the P B adduct with the exocyclic boron,
reaction with PtBu3 effected deprotonation of the heterocycle
to give the corresponding phosphonium salt.
C
lick chemistry, as coined by Sharpless in 2001,[1] refers to
ꢀ
a set of reactions which allow the easy formation of molecules
in a quick and reliable way. Such reactions are characterized
by high yields of the desired product with relatively few by-
products, and exhibit a high functional-group tolerance. This
strategy is a powerful synthetic tool to generate a large library
of compounds and has found application in the pharmaceut-
ical industry, materials science, and other industries.[2] Many
different reactions fulfill these criteria, including nucleophilic
ring-opening reactions, additions to carbon–carbon multiple
bonds, non-aldol carbonyl chemistry, and cycloaddition
reactions.[1] The latter includes the model and most prominent
example for click chemistry: the 1,3-dipolar cycloaddition of
alkynes and azides to yield 1,2,3-triazoles. The thermal variant
was first described by Huisgen[3] and requires elevated
temperatures and often produces mixtures of regioisomers.
This disadvantage was overcome with a copper- and, later,
ruthenium-catalyzed cycloaddition reaction which provides
selectively one regioisomer. In the case of the copper-
catalyzed[4] variant, only terminal alkynes can be utilized,
whereas both terminal and internal alkynes can be involved in
the ruthenium-catalyzed[5] reaction. Although a number of
The bis(pentafluorophenyl)boron alkyne (F5C6)2BC
CPh[7g] (1) was prepared according to the literature procedure
[11]
ꢀ
by the reaction of (PhC C)2SnMe2 and (F5C6)2BCl. Alter-
natively, 1 can also be synthesized directly from in situ
generated lithium acetylide and (F5C6)2BCl in 76% yield. The
[12]
reaction of the 1 with (F5C6)2BN3
(2) in benzene and
toluene, leads to the formation of the new air- and moisture-
sensitive N3BC-heterocycles 3 and 4para/4ortho, respectively
(Scheme 1). These products are isolated as red or orange
powders in 73–77% yield.
boron-substituted azides (R2BN3)[6] and alkynes (RC CBR2,
ꢀ
R = alkyl or aryl)[7] have been reported, only a few examples
of their application in click chemistry are known. Harrity
et al. described the cycloaddition of an alkynylborante with
benzyl azide leading to a boron substituted 1,2,3-triazole.[8]
ꢀ
The first cycloaddition reaction of a boron azide with C C
bonds was described by Curran et al. to give N-heterocyclic
carbene boryl triazoles.[9] Recently, we extended this scope to
Scheme 1. Reactions of 1 and 2 in benzene and toluene.
[*] Dr. D. Winkelhaus, Prof. Dr. D. W. Stephan
Department of Chemistry, University of Toronto
80 St. George St, Toronto, Ontario M5S3H6 (Canada)
E-mail: dstephan@chem.utoronto.ca
1
The H NMR spectrum of 3 shows a broad resonance at
d = 12.42 ppm attributed to an NH fragment as well as
multiplets at d = 7.51, 7.29, 7.22, 7.14, and 6.82 ppm, all of
which integrate to a total of ten protons which are assignable
to two phenyl groups. 1H/1H COSY, 1H/13C HSQC, and 1H/13C
HMBC data confirm this assignment. In the 11B NMR
spectrum of 3 a broad and a sharp resonance are observed
at d = 48.5 and À6.0 ppm, respectively while the 19F NMR
signals are detected at d = À131.4 (o-C6F5), À132.1 (o-C6F5),
Prof. Dr. D. W. Stephan
Chemistry Department-Faculty of Science
King Abdulaziz University
Jeddah 21589 (Saudi Arabia)
[**] D.W.S. gratefully acknowledges the financial support of the NSERC
of Canada and the award of a Canada Research Chair.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402567.
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Angewandte
Communications
À149.7 (p-C6F5), À157.0 (p-C6F5), À161.8 (m-C6F5), and
À164.7 ppm (m-C6F5). The separation of resonances attribut-
able to the m- and p-C6F5 groups are indicative for the
presence of one tricoordinated and one tetracoordinated
boron atom.[13]
The NMR spectra of the heterocycle 4 show the presence
of two isomeric species; the major isomer being a symmetrical
substituted toluene isomer, 4para, and a minor species with an
unsymmetrical substitution pattern at toluene (4ortho). The
1H NMR spectrum exhibits two broad NH resonances for the
two isomers at d = 12.53 (4para) and 12.16 ppm (4ortho), in
a ratio of 1:0.56. The toluene methyl groups of the two
isomers were detected as singlets at d = 2.41 and 2.05 ppm. 13
C
1
and two-dimensional NMR spectral data (1H/1H-COSY, H/
1
13C-HSQC, H/13C-HMBC, and HSQC TOCSY) correspond
with this assignment. The 11B NMR spectrum of 4 exhibits two
signals similar to those of 3 at d = 48.6 and À6.0 ppm while the
19F NMR spectrum shows two sets of signals in regions similar
to those seen for 3. Again the intensity was consistent with the
4para and 4ortho isomers in a ratio of 1:0.56.
Subsequent treatment of 3 and 4 with the Lewis base
PMe3 in toluene led to the formation of the Lewis acid-base
adducts 5 and 6, respectively (Scheme 1). These compounds
were isolated in 92–93% yield as yellow solids. The 1H NMR
spectrum shows resonances attributable to the NH fragment
of 5, 6para, and 6ortho, and are shifted upfield to d = 10.76, 10.78,
and 10.37 ppm, respectively. The Lewis adducts 5, 6para, and
6ortho show broad signals in the 31P{1H} NMR spectra at d =
À5.7, À5.7, and À5.9 ppm, respectively. In the 11B NMR
spectrum resonances for 5 and 6 are observed at d = À4.3 (for
5 and 6) and d = À5.2 (for 5) and d = À5.1 ppm (for 6) with
the latter signals exhibiting a P–B coupling constant of 86 and
77 Hz for 5 and 6, respectively. The 19F NMR spectra of 5 and
6 exhibit very broad signals for the fluorine atoms of the
pentafluorophenyl groups, at ambient temperature (258C).
These broad signals are attributed to restricted rotation of the
Figure 1. POV-ray depiction of 5 (top) and 6para (bottom). Hydrogen
atoms are omitted for clarity.
(in 6para), whereas the exocyclic B(2)-N(3) single bond lengths
are 1.573(5) (in 5) and 1.577(4) ꢀ (in 6para). The C(1)-N(1)
bonds within the heterocycle 5 and 6para have a length of
1.417(4) and 1.414(4) ꢀ, respectively, thus suggesting some
degree of delocalization. The B(1)-C(1) distances in 5 and
6para of 1.632(5) and 1.626(5) ꢀ, are typical of B–C single
bonds.[15] The C(1)-B(1)-N(3) bond angles in 5 and 6para are
95.6(3) and 95.3(2)8, respectively, and reflect the impact of the
constrained five-membered ring.
À
C6F5 groups around the P B bond. In the case of 6 decreasing
the temperature to À408C slows this molecular motion, thus
revealing three sets of signals in a ratio of 1:0.4:0.16. These
signals are assigned to the major isomer 6para, and the two
rotamers of the minor isomer 6ortho
.
The nature of the adducts of the heterocycles were
subsequently confirmed with X-ray crystallographic studies of
5 and 6para as single crystals were obtained from a CH2Cl2
solution (Figure 1). These compounds feature a rare N3BC
framework, as only a handful of heterocycles, fused with an
icosahedral carborane anion, have been described in the
literature.[14] In the case of 5 the N3BC framework is
essentially planar with the N(1)-B(1)-C(1)-N(3) torsion
angle being 2.38. In contrast, the corresponding N3BC core
in 6para deviates slightly from this planarity with a N(1)-B(1)-
C(1)-N(3) torsion angle of 8.28. The N(1)-N(2) and N(2)-N(3)
bonds exhibit similar lengths of 1.307(4) and 1.301(4) ꢀ in 5
and 1.310(3) and 1.291(3) ꢀ in 6para. These values are larger
than a typical N–N double bond (1.20 ꢀ)[15] and shorter than
a typical N–N single bond (1.48 ꢀ).[15] These observations are
consistent with a delocalized bonding pattern at the three
nitrogen atoms. The B(1)-N(3) bond lengths within the
heterocycles are found to be 1.634(5) (in 5) and 1.640(4) ꢀ
The mechanism for the formation of 3 and 4 is thought to
involve initial coordination of the boron azide to the boron
alkyne (Scheme 2). This coordination is consistent with
inhibition of the formation of 3 by the addition of BCl3, as
BCl3 competes with 1 effectively and precludes reaction of
1 with 2. Following coordination of 1 and 2, nucleophilic
addition of the a-alkynyl carbon atom to the terminal azide
nitrogen atom leads to the mesomeric carbocation
(Scheme 2). This prompts electrophilic aromatic substitution
À
À
of the solvent, thus resulting in C C and N H bond
formation, ultimately yielding the heterocycles 3 and 4para
and 4ortho. The regiochemistry of the aromatic substitution to
À
the exocyclic carbon atom results in C C bond formation
trans to the B(C6F5)2 fragment. It is thought that this
regiochemistry is guided by the proximity of the proton
accepting nitrogen atom. In the case of toluene, electrophilic
aromatic substitution proceeds at either the para or ortho
positions, thus affording the two isomers. Performance of the
2
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Scheme 2. Proposed mechanism for formation of 3.
reaction of 1 and 2 in a 1:1 mixture of C6H6 and C6D6 showed
formation of 50% product of the protio product 3. The
absence of an isotope effect infers the rate-determining step
Figure 2. POV-ray depiction of 7. Hydrogen atoms are omitted for
clarity.
À
in the formation of 3 is not the C H activation. This data
suggests cyclization from the adduct of 1 and 2 is rate
determining. It is also noteworthy that the corresponding
proceed by the classical click reaction to give a triazole
derivative. Instead, exceptional N3BC heterocycles are
[7g]
ꢀ
reaction of (F5C6)2BC CtBu
position, presumably a result of the inability of a correspond-
ing carbocation.
with 2 led only to decom-
À
formed by cyclization and C H activation of the correspond-
ing aromatic solvent. These heterocycles react with less
sterically demanding Lewis bases like PMe3 to yield classical
P/B adducts at the exocyclic boron. In contrast, the more
sterically encumbered Lewis base PtBu3 effects deprotona-
tion, thus providing access to BCN3-heterocyclic salts. Cur-
rent efforts are aimed at targeting the synthesis of related
The compounds 3 and 4 also react with PtBu3 to give the
yellow powders 7 and 8, respectively, in almost quantitative
yield (Scheme 1). The 1H NMR spectrum of 7 shows a doublet
at d = 5.18 ppm with a characteristic P–H coupling of 437 Hz.
The 31P{1H} signal at d = 58.18 ppm is consistent with the
formation of the cation [HPtBu3]+. In the 11B NMR spectrum
two resonances are observed at d = 39.2 and À11.2 ppm. The
19F NMR spectrum of the phenyl-substituted compound (7)
shows signals at d = À132.1 (o-C6F5), À162.6 (p-C6F5), and
À167.5 ppm (o-C6F5), which are attributable to the tetracoor-
dinated boron atom. Furthermore, 19F signals for the two C6F5
groups at the tricoordinated boron atom are observed at d =
À
systems, which are capable of such C H activations, and
exploring further reactivities of these remarkable hetero-
cycles.
CCDC 987434, 987435, and 987436 contain the supple-
mentary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
À131.7
(o-C6F5),
À132.9
(o-C6F5),
À156.3
(p-C6F5), À156.6 (p-C6F5), and À164.3 ppm (2-m-C6F5). The
corresponding data for the toluene-substituted salt 8 are
similar. These spectra show additional signals attributable to
the para and ortho isomers in a ratio of 1:0.47.
Received: February 18, 2014
Published online: && &&, &&&&
À
Keywords: alkynes · azides · boron · C H activation ·
heterocycles
Crystals of 7, obtained from a concentrated benzene
solution, allowed confirmation of the nature of this salt by X-
ray crystallography (Figure 2). The N(1)-N(2) bond within the
five-membered ring system has a length of 1.260(3) ꢀ while
the N(1)-N(2) is 1.420(2) ꢀ. The boron–nitrogen bond length
within the heterocycle has a value of 1.587(3) ꢀ, which is
clearly shorter than the corresponding bond in the neutral 4.
The exocyclic N(3)-B(2) bond has some double bond
character typical of an aminoborane with a length of
1.390(3) ꢀ [cf. 1.372(2) ꢀ in (C6F5)2BNMe2.[16]] The parame-
ters of the cation [HPtBu3] are unexceptional.
.
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Cyclization
D. Winkelhaus,
D. W. Stephan*
&&&& — &&&&
Boron Perturbed Click Reactions Prompt
À
Aromatic C H Activations
Click on B: The reaction of bis(penta-
fluorophenyl)boron alkynes and azides
leads to unusual N3BC heterocycles (see
subsequent treatment of the heterocycle
À
with PMe3 gave the P B adduct, reaction
with PtBu3 effected deprotonation to
generate the corresponding phospho-
nium salt.
À
scheme) resulting from aromatic C H
activation of benzene and toluene. While
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!