[3+2]-Dipolar cycloaddition reactions of an N-heterocyclic carbene boryl azide

Article abstract of DOI:10.1021/ol300851m

Thermal 1,3-dipolar cycloaddition reactions of 1,3-bis(2,6- diisopropylphenyl)imidazol-2-ylidene dihydridoboron azide occur smoothly with alkynes, nitriles, and alkenes bearing electron-withdrawing groups. New, stable NHC-boryl-substituted triazoles, tetr

Full text of DOI:10.1021/ol300851m

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2690–2693
[3 þ 2]-Dipolar Cycloaddition Reactions of
an N-Heterocyclic Carbene Boryl Azide
†
†
†
Everett Merling, Vladimir Lamm, Steven J. Geib, Emmanuel Lacote,‡,§ and
^
Dennis P. Curran*,†
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260,
^
United States, ICSN CNRS, Batiment 27, Av. de la Terrasse, 9118 Gif-sur-Yvette
Cedex, France, and UPMC Sorbonne Universites, Institut Parisien de Chimie
ꢀ
ꢀ
Moleculaire (UMR CNRS 7201), 4 place Jussieu, C. 229, 75005 Paris, France
curran@pitt.edu
Received April 3, 2012
ABSTRACT
Thermal 1,3-dipolar cycloaddition reactions of 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene dihydridoboron azide occur smoothly with
alkynes, nitriles, and alkenes bearing electron-withdrawing groups. New, stable NHC-boryl-substituted triazoles, tetrazoles, and triazolidines are
formed in good to excellent yields.
Recent studies of N-heterocyclic carbene-boranes
(NHC-boranes) are unearthing a surprisingly rich chem-
istry for compounds that can be viewed as simple Lewis
acid/Lewis base complexes.1 A key feature of many classes
of complexes is that they are stable to air and water and do
not dissociate even under relatively forcing conditions.2
Carbene-boranes are of interest as reagents in organic
synthesis3 and as initiators in polymer chemistry.4 And
the study of carbene-boranes as reactants has led to the
synthesis of diverse stable compounds with unusual boron
substituents and bonding patterns.1,5
† University of Pittsburgh.
‡ ICSN CNRS.
§
ꢀ
UPMC Sorbonne Universites.
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r
10.1021/ol300851m
Published on Web 05/22/2012
2012 American Chemical Society

parent complex 1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene borane 1. Treatment of 1 with triflic acid gives a
solution-stable triflate 2 that can be displaced in situ to
produce unusual functionalized NHC-borane compounds
3 including boryl azides, nitroboranes, boryl nitrites, boryl
nitriles, and boryl isonitriles, among others.6
of heteroatom-substituted azides, notably with tin10aꢀc and
sulfonyl10d azides, are also well-known.
In contrast, to the best of our knowledge, there are
no known cycloaddition reactions of boron-substituted
azides, doubtless because such azides have been so rare.11
Here we report that a prototypical NHC-boryl azide 4
behaves as an electron-rich [1,3]-dipole in cycloaddition
reactions with electron-poor alkynes, alkenes, and nitriles
to provide remarkably stable NHC-boryl triazoles, triazo-
lidines, and tetrazoles.
Cycloaddition reactions were conducted with 1,3-bis-
(2,6-diisopropylphenyl)imidazol-2-ylidene borane azide 4
because simple safety guidelines project that it will not be
explosive.12 On a gram scale, 4 was conveniently prepared
by reaction of 1 with iodine (0.5 equiv, makes NHC-BH2I
in quantitative yield) and then addition of sodium azide in
DMSO. After purification by flash chromatography, 4 was
isolated in 76% yield (Scheme 1).
Scheme 1. Gram-Scale Synthesis of 4 and Preliminary Cy-
cloaddition Reactions with Ethyl Propiolate
Figure 1. NHC-boranes 2 bearing good leaving groups (here,
triflate) are easily made, and the leaving groups can be displaced
to make unusual heteroatom-functionalized NHC-boranes 3
that are surprisingly stable.
Similar chemistry can also be done with easily generated
boryl iodide and bromide analogs of triflate 2 as well.
Because such functionalized boranes 3 are rare, little is
known about their chemistry.
We selected boryl azides (3, Nuc = N3) for initial study
because the azides are easy to prepare and handle.6 We
were also intrigued because azides are commonly reduced
by boranes, but NHC-boryl azides bearing adjacent BꢀH
bonds are stable. Will this stability translate to onward
reaction products derived from boryl azides?
The boron atom of an NHC-borane is often compared
to a tetravalent carbon atom because the two are isoelectronic.
The quintessential reaction of carbon-substituted azides7 is a
Huisgen [1,3]-dipolar cycloaddition,8 one of the most valuable
“click reactions”.9 An assortment of cycloaddition reactions
Azide 4 melts to a clear liquid at 180ꢀ183 °C.6 It bubbles
(N2 release?) at ∼270 °C and then turns from yellow to
brown above 300 °C. It is also stable to heating alone in
toluene at 110 °C overnight. Even so, all reactions were
conducted behind safety shields as a standard precaution.
In a preliminary experiment, 4 (30 mg, 0.07 mmol) and
ethyl propiolate 5a (2 equiv) were dissolved in C6D6 and
reaction progress was followed by 1H NMR spectroscopy.
A new singlet at 6.53 ppm (imidazolyl protons Hi) of 5a
grewinasthestarting singletof4 (6.33ppm) decreased, but
the conversion reached only about 50% after 1.5 days at rt.
A similar reaction at 80 °C was complete after 4 h. Simple
solvent evaporation and flash chromatography provide
the stable NHC-boryl triazole 6a as the only apparent
regioisomer in 93% yield. A larger scale experiment (100
mg, 0.23 mmol) was conducted in the more practical
solvent toluene at 110 °C, giving 6a in 94% isolated yield.
Boryl triazole 6a is a robust, stable compound that is
convenient to handle. The crystal structure, shown in
(6) Solovyev, A.; Chu, Q.; Geib, S. J.; Fensterbank, L.; Malacria, M.;
^
Lacote, E.; Curran, D. P. J. Am. Chem. Soc. 2010, 132, 15072–15080.
€
(7) (a) Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 44, 5188–5240. (b) Organic azides: Synthesis and
€
applications; Brase, S., Banert, K., Eds.; Wiley: Chichester, 2010.
(8) Lwowski, W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Vol. 1, pp 559ꢀ652.
(9) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004–2021.
(10) (a) Sisido, K.; Nabika, K.; Isida, T.; Kozima, S. J. Organomet.
Chem. 1971, 33, 337–346. (b) Kozima, S.; Itano, T.; Mihara, N.; Sisido,
K.; Isida, T. J. Organomet. Chem. 1972, 44, 117–126. (c) Hitomi, T.;
Kozima, S. J. Organomet. Chem. 1977, 127, 273–280. (d) Pocar, D.;
Ripamonti, M. C.; Stradi, R.; Trimarco, P. J. Heterocycl. Chem. 1977,
14, 173–181.
(11) The closest relative of 4 is Me3NꢀBH2N3, which has been
reported to explode at 200 °C. (a) Miller, N. E.; Chamberland, B. L.;
Muetterties, E. L. Inorg. Chem. 1964, 3, 1064–1065. (b) Skillern, K. R.;
Kelly, H. C. Inorg. Chem. 1977, 16, 3000–3005. Trivalent azido boranes
are more common. See for example: (c) Bettinger, H. F.; Filthaus, M.;
Neuhaus, P. Chem. Commun. 2009, 2186–2188. (d) Bettinger, H. F.;
Filthaus, M.; Bornemann, H.; Oppel, I. M. Angew. Chem., Int. Ed. 2008,
47, 4744–4747.
€
(12) Keicher, T.; Lobbecke, S. In Organic Azides: Synthesis and
€
Applications; Brase, S., Banert, K., Eds.; Wiley: Chichester, 2010, pp 1ꢀ28.
Org. Lett., Vol. 14, No. 11, 2012
2691

Figure 2, demonstrates that 6a is the 1,4-regioisomer
resulting from addition of the azide nitrogen bearing the
boron atom to the β-carbon of ethyl propiolate. At
shielded by one of the dipp rings14) were confirmed by
X-ray crystallography (see Figure 2).
˚
1.567(5) A, the NꢀB bond of 6a is longer than comparable
bonds in carbon-substituted triazoles. For example, the
corresponding NꢀC bond in an analogous N-benzyl-sub-
Table 1. Dipolar Cycloaddition Reactions of Boryl Azide 4 with
Substituted Alkynes 5bꢀ5i
13
˚
stituted triazole is 1.471(2) A.
Figure 2. X-ray crystal structures of cycloadducts 6a and 6f.
Table 1 summarizes the results of cycloaddition reac-
tions of 4 with other electron-poor alkynes 5bꢀi bearing
carbonyl or phenyl substituents. (Formal changes are
omitted on these and the subsequent structures.) Similar
results were observed in reactions of 4 with methyl pro-
piolate 5b, 3-butyn-2-one 5c, and dimethyl- and diethyla-
cetylene dicarboxylate 5d,e. Single products;1,4-
disubstituted (6b,6c) or 1,4,5-trisubstituted tetrazoles
(6d,6e);were isolated in yields ranging from 84% to 94%
(entries 1ꢀ5).
Disubstituted alkynes with only one carbonyl group
(ethyl but-2-ynoate 5f, methyl 3-phenylpropiolate 5g,
and 4-phenylbut-3-yn-2-one 5h) were less reactive and gave
two regioisomers 6fꢀh and 7fꢀh. These reactions took
about 7 days at 110 °C in toluene but still gave good
total yields. The regioisomeric triazoles 6f/7f from the
butynoate reaction were formed with high selectivity (96/4)
and were partially separated. We obtained 19% of pure 6f
and 67% of a mixture of 6f and 7f in a 95/5 ratio (entry 6).
The corresponding triazoles 6g and 7g from methyl
3-phenylpropiolate were formed with lower selectivity but
were well separated. We isolated 54% of 6g and 27% of 7g
(entry 8). Likewise the products 6h and 7h from 4-phenyl-
but-3-yn-2-one were separable and were isolated in 61%
and 28% yields (entry 9; the crystal structure of 6his shown
in the Supporting Information (SI)).
a 80 °C in C6D6, followed by 1H NMR spectroscopy; 110 °C in
toluene; 180 °C, microwave in benzotrifluoride. b NHC = 1,3-(2,6-
diisopropylphenyl)imidazol-2-ylidene. c Isolated yields after flash chro-
matography unless otherwise indicated. d NMR yield in C6D6.
Control experiments (see SI) provided no evidence for
thermal cycloreversion or 1,3-boryl shift. So we believe
that the isomer ratios are kinetically controlled.
When the carbonyl group was removed, we still ob-
served reasonable reactivity for phenyl-substituted alkynes
like (4-bromophenyl)ethyne 5i (entry 11). However, unlike
the other monosubstituted alkynes 5aꢀc, the reaction now
produced a small amount of the 1,5-regioisomer 7i (8%)
along with the major 1,4-regioisomer 6i (50%). Results
from a few alkyl-substituted alkynes were much less
encouraging (see SI). Reactions were dramatically slower
and sometimes not clean. Attemptsatcoppercatalysis with
several of the poorly reactive substrates did not give
significantly improved results.
The major regioisomer 6fꢀh in each case has the carbo-
nyl directing group on C4 of the triazole. The positions of
the substituents were initially assigned by a shielding trend
in the 1H NMR spectra, and both the structure of 6f and
the origin of the trend (protons on the C5 substituent are
(13) Huang, C.-C.; Wu, F.-L.; Lo, Y. H.; Lai, W.-R.; Lin, C.-H. Acta
Crystallogr., Sect. E 2010, 66, o1690.
(14) For example, the imidazole CH3 group resonates at 2.27 ppm
In contrast, microwave reactions can reduce reaction
times dramatically for less reactive alkynes. Again due to
when it is on C4 (7f) and 1.78 ppm when it is on C5 (6f).
2692
Org. Lett., Vol. 14, No. 11, 2012

A few alkenes with electron-withdrawing groups were
also surveyed, and the products from reactions with methyl
acrylate, dimethyl fumarate, cyclopent-2-en-1-one, and per-
fluoro-1-heptene are shown in the lower part of Figure 3.
Reactions with methyl acrylate and perfluoroheptene gave
single regioisomers 11 (89%), and 14 (55%) with the
electron-withdrawing group at position 4 of the triazolidene
ring. Reactions with dimethyl fumarate and 2-cyclopenten-
1-one gave single stereoisomers, trans (12, 67%) and cis (13,
40%), respectively. The crystal structure of 13 was solved
and is shown in the SI. A cycloaddition reaction with
dimethyl maleate gave the same product 12 as from dimethyl
fumarate, but the reaction was much slower and less clean.
From this result, it is clear that the cis maleate is less reactive
than trans fumarate, but it is not clear whether the isomer-
ization that ultimately produces 12 occurs before or after
cycloaddition of the maleate. Again, standard alkenes
(including norborene) were not very reactive toward 4.
In summary, prototypical NHC-boryl azide 4 undergoes
dipolar cycloaddition reactions with an assortment of alkyne,
nitrile, and alkene dipolarophiles, provided that the dipolar-
ophiles are substituted with at least one electron-withdrawing
group. It thus seems likely that NHC-boryl azides are Type
III dipoles according to the Sustman classification,17 with the
important frontier orbital interaction occurring between the
HOMO of the dipole and the LUMO of the dipolarophile.
This picture of NHC-boryl as a good inductive electron-
donating group is consistent with the radical chemistry, ionic
chemistry, and electrochemistry of NHC-boranes.1
The boryl azide is different in cycloaddition behavior
from azides bearing electron-withdrawing groups (sulfonyl
azides, for example) and also different from typical carbon-
substituted azides. Phenyl azide (PhN3), for example, is a
classic Type II dipole whose cycloaddition reactions are
accelerated by both an electron-donating and -withdrawing
substituent on alkenes and alkynes.17 Tin azides10aꢀc might
be more comparable to boryl azides because tin is also an
electron donor. Even so, cycloadducts of tin azides often
experience a thermal 1,2- or 1,3-tin shift, and such adducts
are readily destannylated. But the products of cycloaddition
of 4 are very stable; no evidence of a boryl shift has yet been
obtained, and deborylation does not occur under typical
ambient and chromatographic conditions.
Figure 3. Reaction conditions, product structures, and yields for
cycloadditions of 4 with nitriles (top) and alkenes (bottom).
NHC is 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene. a5%
of the 1,4-regioisomer was also isolated.
safety concerns, we limited these reactions to a small scale.
First, a 10 mg sample of 4 was heated alone in a microwave
in benzotrifluoride15 (C6H5CF3) for 1 h at 180 °C. No
unusual pressure or temperature increase was observed.
After cooling, the solvent was removed and the sample 4
was recovered intact as assessed by a 1H NMR spectrum.
Microwave reactions in benzotrifluoride with 4 (30 mg)
and either 5f (entry 7) or 5h (entry 10) provided the
expected regioisomeric adducts in comparable yields to
the standard heating reactions. There was small erosion in
regioselectivity at 180 °C compared to the conductive
heating experiments at 110 °C (compare entries 6 and 7),
but reaction times were much shorter, decreasing from 1
week to 2 and 3.5 h (compare entries 6/7 and 9/10).
Observations during cycloaddition experiments of 4
with nitriles as dipolarophiles were qualitatively similar
to those with alkynes. Azide 4 did not react rapidly in
thermal reactions with acetonitrile and benzonitrile. How-
ever, nitriles substituted with electron-withdrawing groups
gave 1,5-disubstituted tetrazoles upon heating. Products
and yields from cycloadditions with tosyl cyanide
(8, 39%), dichloroacetonitrile (9, 38%16), and perfluorohep-
tanenitrile (10, 87%) are shown in the top part of Figure 3.
All these products were isolated by chromatography and
are stable white solids. The crystal structure of 10 is shown
in the SI. The cycloaddition with tosyl cyanide also gave a
small amount (5%) of the 1,4-regioisomer.
Acknowledgment. We thank the U.S. National Science
Foundation, theFrenchAgenceNationale delaRecherche
(grant ANR-11-BS07-008, NHCX), and CNRS for fund-
ing this work. We thank Prof. Louis Fensterbank (UPMC)
for helpful discussions.
Supporting Information Available. Contains complete
experimental details and copies of NMR spectra of all
cycloadducts. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) (a) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450–451.
(b) Maul, J. J.; Ostrowski, P. J.; Ublacker, G. A.; Linclau, B.; Curran,
D. P. In Modern Solvents in Organic Synthesis; Knochel, P., Ed.; Topics in
Current Chemistry; Springer-Verlag: Berlin, 1999; Vol. 206, pp 80ꢀ104.
(16) Yields as high as 84% were obtained for this adduct, but the
reported yield is more typical. We suspect that the product is reductively
dechlorinated.
(17) Huisgen, W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Vol. 1, pp 1ꢀ176.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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