Ring lithiation and functionalization of imidazol-2-ylidene-boranes

Article abstract of DOI:10.1021/ol202516c

N,N′-Dialkyl and N,N′-diaryl imidazol-2-ylidene-boranes and trifluoroboranes are rapidly lithiated at C4 of the imidazole ring, and the resulting intermediates have been quenched with an assortment of electrophiles to provide ring-functionalized imidazol-2-ylidene-boranes. Further deprotonation and functionalization of C5 have been demonstrated. Deboronation of the products by treatment with triflic acid or iodine and then methanol opens a route to C4/C5 functionalized imidazolium salts and imidazol-2-ylidenes.

Full text of DOI:10.1021/ol202516c

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6042–6045
Ring Lithiation and Functionalization of
Imidazol-2-ylidene-boranes
†
Andrey Solovyev, Emmanuel Lacote, and Dennis P. Curran*
‡
,†
^
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260,
United States, and ICSN CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex,
France
curran@pitt.edu
Received September 16, 2011
ABSTRACT
N,N0-Dialkyl and N,N0-diaryl imidazol-2-ylidene-boranes and trifluoroboranes are rapidly lithiated at C4 of the imidazole ring, and the resulting
intermediates have been quenched with an assortment of electrophiles to provide ring-functionalized imidazol-2-ylidene-boranes. Further
deprotonation and functionalization of C5 have been demonstrated. Deboronation of the products by treatment with triflic acid or iodine and then
methanol opens a route to C4/C5 functionalized imidazolium salts and imidazol-2-ylidenes.
N-Heterocyclic carbenes (NHC) and their metal and
main group complexes are important reagents and cata-
lysts for synthesis of molecules and materials alike.1 Rela-
tively stable imidazol-2-ylidenes B (Figure 1) are a popular
class of NHC ligands for the preparation of catalytically
active complexes C with transition metals2 and for the
stabilization of unusual states of main group elements.3
Carbenes B and complexes C lacking substituents on the
ring carbon atoms (R4 = R5 = H) are easily prepared
Figure 1. General structures of imidazolium salts, imidazol-
2-ylidenes, and complexes thereof (formal þ/ꢀ charges on C
from common imidazolium salts A.4
Substitution at C4 and C5 in free imidazol-2-ylidene
carbenes B or carbene complexes C (R4, R5 ¼ H) allows for
tuning steric or electronic properties5 or for attaching a
handle for further functionalization, easier separation, or
recycling. The main strategy to introduce such substituents
is to make suitably substituted acyclic precursors first (e.g.,
1,2-diimines) and then to form the imidazolium ring A.4
and related structures are omitted for simplicity).
Such processes can take several steps and may not be
compatible with a broad range of R4 and R5 groups.
For many substituents R4 and R5, it would be conve-
nient to make more substituted carbenes B or complexes C
from less substituted ones, and ring metalation followed
by electrophilic substitution is an appealing strategy.6
However, the direct application of this strategy to imida-
zolium salts A is complicated because H2 is much more
acidic than H4. Indeed, the acidity of H2 is the basis of
carbene formation.
† University of Pittsburgh.
‡ ICSN CNRS.
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10.1021/ol202516c
Published on Web 10/24/2011
2011 American Chemical Society

Bertrand has used strong bases to functionalize the C4
position of C2-substituted imidazolium salts via so-called
abnormal carbenes,7 and Robinson has deprotonated the
C4 position of the free carbene N,N0-(2,6-diisopropyl-
phenyl)imidazol-2-ylidene.8 The resulting lithio-carbene
was quenched with TMSCl and BH3. Direct borylation
of carbenes by very strong electrophiles is also possible.9
Imidazol-2-ones10 and -2-thiones11 are also useful NHC
precursors that can be functionalized by metalation. Meta-
lated carbene-lanthanide12 and carbene-phosphinidene13
complexes have also been described.
Carbene-boranes14 are an increasingly valuable class of
synthetic reagents15 and polymerization co-initiators,16
spurring demand for ring-functionalized variants. Such
boranes are very stable, and their BꢀH protons are weakly
basic, not acidic.17 Cavel observed fluorine promoted H/D
exchange on the imidazolylidene rings of an unusual bis-
carbene trifluoroborane under forcing conditions (100 °C,
100 h).18 Later, we described the first example of a ring-
metalated carbene trihydridoborane (see below).19 And
recently Roesky reported the deprotonation of dipp-Imd-
Figure 2. Proposed generation and trapping of lithiated car-
bene-boranes (top) and a clue that such reactions were possible
(bottom).
BH3 (1d) by BuLi and solved the crystal structure of the
lithiated intermediate (2 with R = H, R0 = dipp).20
Here we show that direct lithiation of N,N0-disubstituted
imidazol-2-ylidene-boranes 1 is a general reaction that has
significant preparative value. Onward reactions of the
resulting lithiated intermediates 2 with electrophiles (E)
to form diverse new ring-substituted carbene-boranes 3 are
studied (Figure 2, top). Repeat metalation and functiona-
lization of C5 to give 4 are also demonstrated. Sample
deboronation reactions prove the principle that lithiated
reagent 2 is the synthetic equivalent of the imaginary
“deprotonated imidazolium ion” synthon.
We recently developed a procedure for reductive lithia-
tion of boronꢀhalide bonds of such complexes by reaction
of boryl iodide 5 with lithium di-tert-butylbiphenylide
(Figure 2, bottom).19 Trapping of this intermediate with
ethyloxirane provided the expected B-alkylated product 6
in 34% yield with substantial amounts (30%) of a bis-B/C-
alkylated product 7, evidently a secondary product derived
from deprotonation of 6 at C4.
(7) Mendoza-Espinosa, D.; Donnadieu, B.; Bertrand, G. J. Am.
Chem. Soc. 2010, 132, 7264–7265.
(8) (a) Wang, Y.; Xie, Y.; Abraham, M. Y.; Wei, P.; Schaefer, H. F.;
Schleyer, P. v. R.; Robinson, G. H. J. Am. Chem. Soc. 2010, 132, 14370–
14372. (b) Wang, Y.; Xie, Y.; Abraham, M. Y.; Wei, P.; Schaefer, H. F.;
Schleyer, P. v. R.; Robinson, G. H. Organometallics 2011, 30, 1303–
1306.
(9) For a recent example, see: Kronig, S.; Theuergarten, E.;
Holschumacher, D.; Bannenberg, T.; Daniliuc, C. G.; Jones,
P. G.; Tamm, M. Inorg. Chem. 2011, 50, 7344–7359.
(10) Llopart, C. C.; Ferrer, C.; Joule, J. A. Can. J. Chem. 2004, 82,
1649–1661.
(11) Arduengo, A. J., III; Bannenberg, T. P.; Tapu, D.; Marshall,
W. J. Chem. Lett. 2005, 34, 1010–1011.
(12) Arnold, P. L.; Liddle, S. T. Organometallics 2006, 25, 1485–1491.
(13) Wang, Y.; Xie, Y.; Abraham, M. Y.; Gilliard, R. J.; Wei, P.;
Schaefer, H. F.; Schleyer, P. v. R.; Robinson, G. H. Organometallics
2010, 29, 4778–4780.
(14) Curran, D. P.; Solovyev, A.; MakhloufBrahmi, M.; Fensterbank,
L.; Malacria, M. Angew. Chem. Int. Ed. 2011, 50, 10294ꢀ10317.
(15) (a) Ueng, S.-H.; Makhlouf Brahmi, M.; Derat, E.; Fensterbank,
^
L.; Lacote, E.; Malacria, M.; Curran, D. P. J. Am. Chem. Soc. 2008, 130,
10082–10083. (b) Chu, Q.; Makhlouf Brahmi, M.; Solovyev, A.; Ueng,
^
S.-H.; Curran, D.; Malacria, M.; Fensterbank, L.; Lacote, E. Chem.;
Eur. J. 2009, 15, 12937–12940. (c) Monot, J.; Makhlouf Brahmi, M.;
Ueng, S.-H.; Robert, C.; Desage-El Murr, M.; Curran, D. P.; Malacria,
Preliminary experiments showed that BuLi was a con-
venient base for deprotonation. Table 1 shows the results
of lithiation and silylation of a series of imidazolylidene
complexes NHC-BH3 (1aꢀe) bearing different N-substi-
tuents. The carbene-boranes are all known and readily
available. In a typical experiment, 1 equiv of BuLi was
added to a solution of diiPr-Imd-BH3 1a in THF. After
5 min, the resulting anion was quenched by addition of
1.1 equiv of trimethylsilyl chloride. Standard workup and
flash chromatography provided C4-silylated product 8a in
93% isolated yield (entry 1).
Good yields of C4-silylated products were obtained with
several N-alkyl (entries 1ꢀ3) and N-aryl (entries 4ꢀ5)
substituted imidazol-2-ylidene-boranes. The products of
the reactions 8aꢀe are generally stable white solids that are
^
M.; Fensterbank, L.; Lacote, E. Org. Lett. 2009, 11, 4914–4917. (d)
^
Ueng, S.-H.; Fensterbank, L.; Lacote, E.; Malacria, M.; Curran, D. P.
Org. Biomol. Chem. 2011, 9, 3415–3420. (e) Ueng, S.-H.; Fensterbank,
^
L.; Lacote, E.; Malacria, M.; Curran, D. P. Org. Lett. 2010, 12, 3002–
3005.
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Curran, D. P.; Malacria, M.; Fensterbank, L.; Lacote, E.; Lalevee, J.
Macromolecules 2010, 43, 2261–2267. (b) Tehfe, M.-A.; Monot, J.;
Makhlouf Brahmi, M.; Bonin-Dubarle, H.; Curran, D. P.; Malacria,
^
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M.; Fensterbank, L.; Lacote, E.; Lalevee, J.; Fouassier, J.-P. Polym.
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Chem. 2011, 2, 625–631.
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Inorg. Chim. Acta 2003, 352, 143–150. (b) Clyburne observed a close
contact in the crystal structure of 1,3-dimesitylimidazol-2-ylidene-bor-
ane between the BꢀH bond of one complex and the C4ꢀH bond of
another, implying that the latter bond might be acidic. Ramnial, T.;
Jong, H.; McKenzie, I. D.; Jennings, M.; Clyburne, J. A. C. Chem.
Commun. 2003, 1722–1723.
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^
M.; Lacote, E.; Curran, D. P. J. Am. Chem. Soc. 2010, 132, 15072–
15080.
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^
D. P.; Robert, M.; Fensterbank, L.; Malacria, M.; Lacote, E. Angew.
ꢁ
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Chem. Int. Ed. 2010, 49, 9166–9169.
Stalke, D. Eur. J. Inorg. Chem. 2011, 3686–3689.
Org. Lett., Vol. 13, No. 22, 2011
6043

Table 1. Reactions of Deprotonated NHC-BH3 Complexes with
TMSCl
Table 2. Reactions of Deprotonated NHC-BH3 Complexes 1a,d
with Electrophiles
a After purification by flash chromatography. b Residual 1d (about 10%)
was not separable in this case.
a After purification by flash chromatography. b The reaction was
quenched with methanol. c 5 equiv. d NMR yield: the product and
residual starting material were inseparable.
readily handled in ambient lab conditions. Unlike the
corresponding imidazolium salts or free carbenes, they
can conveniently be purified by flash chromatography.
The only significant side product in these reactions was
recovered starting material, which was typically present at
the level of 10% or less. This could be separated from the
silylated products by chromatography in most cases, but
not in the case of 1d/8d, whose diisopropylphenyl substi-
tuents make both compounds very nonpolar.
Scheme 1. Lithiation and Electrophilic Trapping of Carbene
Complex 14 with Boron Trifluoride
Table 2 summarizes the results of a series of experiments
with diiPr-Imd-BH3 1a and dipp-Imd-BH3 1d that begin
to outline the scope of the electrophilic trapping reaction.
The isolated yields after purification by flash chromato-
graphy are reported. Like TMSCl, benzaldehyde is an
excellent trapping reagent to give 9a,d (entry 1, 88% and
82%). And ethyloxirane can also be used to form 10a,d
(entry 2, 40% and 60%), as anticipated by the results in
Figure 2.
Primary alkyl bromides give alkylation products 11a,d
and 12a in variable yields (entries 3, 4), although even these
yields are perhaps surprising given that no transmetalation
was attempted. An azide substituent, potentially useful
for downstream click chemistry, survives the reaction and
purification (entry 3). Furthermore, the products 11a,d are
stable, so evidently carbene-boranes do not directly reduce
alkyl azides. Reactions with diphenylphosphinyl chloride
gave expected phosphorylated products 13a (33%) and
13d (75%) (entry 5).
Boron trifluoride (BF3) complexes can also be metalated
and functionalized, as shown by the two reactions with
dipp-Imd-BF3 14 in Scheme 1. Metalation of 14 was again
conducted with BuLi for 5 min and then the electrophile
(TMSCl or ethyloxirane) was added, followed by workup
and flash chromatography. Silylated product 15 was iso-
lated in 85% yield, though it again could not be separated
from some unreacted 14because both are so nonpolar. The
product of reaction with ethyl oxirane 16 was readily iso-
lated in pure form in 66% yield. These results with the BF3
complexes are comparable to the BH3 analogs (8d, Table 1,
entry 4; 10d, Table 2, entry 2).
transformation came as a surprise. Metalation of 1a as
usual followed by addition of 4-toluenesulfonyl chloride
(TsCl) provided thedichloride17in45% yield based on 1a.
Evidently, the lithiated carbene-borane sees TsCl as a
chlorinating agent,21 not a sulfonylating agent. Further,
the initially formed monochlorinated product is presum-
ably deprotonated by the remaining lithiated carbene-
borane to lead to the dichlorinated product 17. Thus, the
yield of 17 based on BuLi is 90%.
Carbene-boranes can also be treated with excess BuLi
followed by addition of bis-electrophiles. For example,
treatment of 1d with 3 equiv of BuLi followed by addition
ofbromide 18providedthe interesting tetracycle20in67%
isolated yield. A similar reaction of 1d with homologue 19
provided the corresponding eight-membered ring analog
21, though only in 8% yield.
Finally, the monofunctionalized products can also be
deprotonated and functionalized a second time. For ex-
ample, metalation of 12a (the product of Table 2, entry 4)
followed by addition of benzaldehyde gave 22 in 61%
isolated yield. Broad signals in the 1H NMR spectrum of
22 that sharpen on heating show evidence of dynamic
(21) (a) Slocum, D. W.; Gierer, P. L. J. Org. Chem. 1976, 41, 3668–
3673. (b) Ketcha, D. M.; Lieurance, B. A.; Homan, D. F. J.; Gribble,
G. W. J. Org. Chem. 1989, 54, 4350–4356. (c) Brummond, K. M.;
Gesenberg, K. D. Tetrahedron Lett. 1999, 40, 2231–2234. (d) Voinov,
M. A.; Grigor’ev, I. A. Tetrahedron Lett. 2002, 43, 2445–2447.
Scheme 2 shows selected results for the double functio-
nalization at both C4 and C5, which could be accom-
plished in either one or two steps. The first one-step
6044
Org. Lett., Vol. 13, No. 22, 2011

Scheme 2. Examples of One-Pot and Stepwise Double Func-
tionalization Reactions
Scheme 3. Deboronation of a Functionalized Carbene-Borane
23 with Triflic Acid and Methanol
to provide triazole-substituted NHC-borane 26. Treatment
of 26 with triflic acid and methanol gave salt 27 in 92% yield.
These preliminary results suggest that alkylation and
deboronation of NHC-boranes will provide an attractive
alternative to traditional routes to functionalized imida-
zolium salts.
Scheme 4. Deboronations Functionalized Carbene-Boranes 11d
and 26
processes, which we attribute to slow rotation of either the
C5ꢀCH(OH)Ph bond or the N1ꢀi-Pr bond.
Our principal interest is in the actual carbene-borane
products of these reactions. However, such products could
also be convenient precursors of imidazolium salts and, in
turn, carbenes and carbene complexes. The use of boranes
as protecting/activating groups for carbenes is analogous
with some uses of phosphine-boranes.22 In both cases,
the last step is a deboronation. We previously observed that
treatment of dipp-Imd-BH3 1d with I2 or TfOH produced
NHC-BH2I or NHC-BH2OTf complexes.17 In the presence
ofwater (ormethanol), these compoundswereobservedby
NMR spectroscopy to undergo fast hydrolysis (or metha-
nolysis) to the corresponding imidazolium salts.
To follow up on these leads, we first prepared bromoalkyl-
substituted NHC-borane 23 by the usual alkylation reac-
tion with 1,6-dibromohexane (64% yield, see Table 2 for
conditions). Reaction of 23 with 1 equiv of triflic acid
followed by addition of excess methanol and workup
provided hygroscopic imidazolium salt 24 in essentially
quantitative yield (Scheme 3).
We then looked at combining deboronation and click
chemistry with azide 11d (Scheme 4). Here we also initially
evaluated whether iodine could be used in place of triflic
acid. In a first approach, treatment of 11d with 0.6 equiv of
iodine followed by methanolysis did not give the target
azide, but instead provided amino-substituted imidazo-
lium salt 25 in 81% yield. Apparently, the boryl iodide
(NHC-BH2I) or some other in situ generated borane23
reduced the azide during the deboronation.
Insummary, wedevelopeda simple procedurefor the C4
or C4,5 functionalization of imidazol-2-ylidene-borane
complexes by lithiation (5 min, rt) and electrophile trap-
ping. Handling and purification are facilitated because the
reaction products are generally stable to air, water, and
chromatography. This opens the way for the preparation
of carbene-borane reagents possessing improved reactiv-
ity, solubility, separation, or other properties. Moreover,
the functionalizedproducts are precursors for the synthesis
of C4 or C4,5 substituted imidazolium salts, free carbenes,
and their complexes that are otherwise challenging to
prepare.
Acknowledgment. We thank the U.S. National Science
Foundation (CHE-0645998) and the French Centre
National de la Recherche Scientifique for funding. A.S.
thanks the University of Pittsburgh for Andrew Mellon
and Goldblatt Predoctoral Fellowships. Dr. Anne
Reversing the order of the steps, we reacted azide 11d
with p-bromophenylethyne under Cu-catalyzed click con-
ditions (CuSO4, sodium ascorbate, tert-butanol/water)24
ꢂ
Boussonniere, University of Pittsburgh, made the sample
of dipp-Imd-BF3.
(22) Staubitz, A.; Robertson, A. P. M.; Sloan, M. E.; Manners, I.
Chem. Rev. 2010, 110, 4023–4078.
(23) Lindsay, D. M.; McArthur, D. Chem. Commun. 2010, 46, 2474–
2476.
(24) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210–
216.
Supporting Information Available. Procedures, charac-
terization of new compounds, and the reactions with
other electrophiles. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 22, 2011
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