Synthesis of electronically diverse tetraarylimidazolylidene carbenes via catalytic aldimine coupling

Article abstract of DOI:10.1021/ol8012765

(Chemical Equation Presented) A new method for synthesizing symmetrical N-heterocyclic imidazolium salts is described. Catalytic coupling of aldimines with cyanide followed by oxidation gives α-diketimines, which can then be cyclized with formaldehyde in

Full text of DOI:10.1021/ol8012765

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3677-3680
Synthesis of Electronically Diverse
Tetraarylimidazolylidene Carbenes via
Catalytic Aldimine Coupling
James W. Ogle,†,‡ Jubo Zhang,† Joseph H. Reibenspies,† Khalil A. Abboud,‡ and
Stephen A. Miller*,‡
The George and Josephine Butler Laboratory for Polymer Research, Department of
Chemistry, UniVersity of Florida, GainesVille, Florida 32611-7200, and Department of
Chemistry, Texas A&M UniVersity, College Station, Texas 77843-3255
miller@chem.ufl.edu
Received June 5, 2008
ABSTRACT
A new method for synthesizing symmetrical N-heterocyclic imidazolium salts is described. Catalytic coupling of aldimines with cyanide followed
by oxidation gives r-diketimines, which can then be cyclized with formaldehyde in acidic media. This two-step procedure requires no
chromatography and allows the synthesis of electronically diverse 1,3,4,5-tetraarylimidazolylidene carbenes.
The recent popularity of N-heterocyclic carbenes (NHCs)
stems primarily from their utility as ancillary ligands (e.g.,
phosphine analogues) in organometallic complexes and as
metal-free agents for organocatalysis.1 Hundreds of free and
metal-coordinated N-heterocyclic imidazolylidene carbenes
have been reported, but 4,5-diaryl substituted heterocyclic
imidazolylidene carbenes are relatively rare. One example
is that reported by Arduengo et al., who synthesized the
prototypical 1,3,4,5-tetraphenylimidazol-2-ylidene from 1,3,4,5-
tetraphenylimidazol-2-thione.2 Although some insights into
the impact of 4,5-substituents have been reported,3 improved
synthetic methods for such carbenes are necessary for their
comprehensive understanding.
Our group first demonstrated application of the intramo-
lecular cyanide-catalyzed aldimine coupling reaction as a
general route for making heterocycles.4 Herein, we report
the scope and generality of an intermolecular aldimine
coupling reaction followed by cyclization with formaldehyde
for preparing a wide variety of 1,3,4,5-tetraaryl substituted
† Texas A&M University.
‡ University of Florida.
(3) (a) Chianese, A. R.; Li, X.; Janzen, M. C.; Faller, J. W.; Crabtree,
R. H. Organometallics 2003, 22, 1663–1667. (b) Kelly, R. A., III; Clavier,
H.; Giudice, S.; Scott, N. M.; Stevens, E. D.; Bordner, J.; Samardjiev, I.;
Hoff, C. D.; Cavallo, L.; Nolan, S. P. Organometallics 2008, 27, 202–210.
(c) Hillier, A. C.; Sommer, W. J.; Yong, B. S.; Petersen, J. L.; Cavallo, L.;
Nolan, S. P. Organometallics 2003, 22, 4322–4326.
(1) (a) Herrman, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290–1309.
(b) Herrman, W. A.; Kocheer, C. Angew. Chem., Int. Ed. 1997, 36, 2162–
2187. (c) Garrison, J. C.; Youngs, W. J. Chem. ReV. 2005, 105, 3978–
4008. (d) Huang, J. K.; Stevens, E. D.; Nolan, S. P.; Petersen, J. P. J. Am.
Chem. Soc. 1999, 121, 2674–2678. (e) Kamber, N. E.; Jeong, W.;
Waymouth, R. M.; Pratt, R. C.; Lohmeijer, B. G. G.; Hedrick, J. L. Chem.
ReV. 2007, 107, 5813–5840.
(4) (a) Reich, B. J. E.; Justice, A. K.; Beckstead, B. T.; Reibenspies,
J. H.; Miller, S. A. J. Org. Chem. 2004, 69, 1357–1359. (b) Reich, B. J. E.;
Greenwald, E. E.; Justice, A. K.; Beckstead, B. T.; Reibenspies, J. H.; North,
S. W.; Miller, S. A. J. Org. Chem. 2005, 70, 8409–8416.
(2) Arduengo, A. J., III; Goerlich, J. R.; Krafczyk, R.; Marshall, W. J.
Angew. Chem., Int. Ed. 1998, 37, 1963–1965.
10.1021/ol8012765 CCC: $40.75
Published on Web 08/06/2008
2008 American Chemical Society

NHCs. Although the intermolecular cyanide-catalyzed aldi-
mine coupling reaction of aromatic Schiff bases was first
studied in 1928,5 few reports since then have applied this
reaction toward further synthesis. Our success with the
intramolecular variant prompted us to further investigate
more practical uses of cyanide-catalyzed aldimine coupling,
and it soon became apparent that NHC synthesis could
readily be accomplished by reviving the original intermo-
lecular method. Somewhat related to our approach, Kison
and Opatz have recently reported the synthesis of highly
substituted unsymmetrical 1,2-diamines and 1,2-diimines via
cross-coupling of R-aminonitriles with N-sulfonyliminess
leading to imidazolium salts and imidazolylidenes.6
Our approach employing aldimine coupling reactions may
be superior for preparing R-diketimine substrates because
the corresponding R-diketones generally condense with the
second amine equivalent only under rather stringent reaction
conditions.7 Furthermore, it is well-known that the cognate
cyanide-catalyzed benzoin condensation is quite sensitive to
the aromatic aldehyde substrates and further oxidation of
benzoin to make R-diketone compounds requires relatively
harsh conditions.4a,8
Table 1. Cyanide-Catalyzed Aldimine Coupling Reactions to
Prepare Symmetrical R-Diketiminesa
temp time yield
entry
Ar
Ar′
(°C)
(h)
(%)b
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
Ph
4-MeC6H4
4-FC6H4
4-CF3C6H4
4-MeOC6H4
Ph
4-MeC6H4
Ph
4-NO2C6H4
4-NMe2C6H4
4-CF3C6H4
4-CF3C6H4
4-MeC6H4
1-naphthyl
Ph
Ph
Ph
Ph
Ph
25
25
25
25
25
25
80
80
25
80
25
25
80
25
25
25
24
40
20
20
24
22
36
24
24
120
18
24
48
24
24
24
54
78
67
65
57
51
40
28
-
-
31
55
4-FC6H4
4-MeC6H4
4-MeOC6H4
Ph
c
d
Ph
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
Ph
Sixteen aromatic aldimines with varying C-aryl and N-aryl
substituents were prepared and subjected to cyanide-catalyzed
C-C coupling conditions (Table 1, 1a-1p). The aldimine
substrates were combined with 20 mol % of NaCN catalyst
in dry DMF, and the conversion to intermediate ene-diamines
c
-
9e
d
2-OH,3-MeOC6H3 4-MeC6H4
Ph 2,4,6-Me3C6H2
-
0
1
a The reaction was conducted under N2; the crude coupling product
was isolated first then oxidized with 1,4-benzoquinone (see the Supporting
Information). b Isolated yield. c Imine starting materials were unreactive;
some unidentified products were produced. d Trace amount of reaction
(<5%) observed by 1H NMR; no isolation was attempted. e The NMR yield
at about 90% purity was 30%; starting material could not efficiently be
removed from the product by crystallization.
was monitored by H NMR spectroscopy. Following sub-
sequent oxidation with 1,4-dibenzoquinone, most substrates
afforded the targeted diketimines (2a-2h, 2k, 2l, 2n).
The results from Table 1 delineate the scope of the
aldimine coupling strategy. The reaction is halted by the
phenolic functionality (1o). Compounds 1i and 1m both gave
a mixture of products, indicating that this methodology is
intolerant of the nitro functionality. What little product that
was observed in these reactions indicated that a mixture of
cyanide addition products was likely produced, both with
and without oxidation. Nonetheless, several electron-poor
substrates reacted favorably, as demonstrated by 2c, 2d, 2f,
2k, and 2l. The very electron-rich 1j likely cannot form the
initially required carbanion which is necessary to react in
the benzoin condensation-like mechanism. This is consistent
with diminished stability of the benzyl anion, generally
thought to be the nucleophilic intermediate generated fol-
lowing cyanide addition to the aldimine and subsequent
tautomerization.9 In general, the reaction appears to work
well for both electron-rich and electron-poor rings that are
between the nitro and amino extremes but generally gives
higher yields for electron-poor rings. Additionally, steric bulk
tends to slow or stop the reaction, as demonstrated by the
naphthyl (1n) and mesityl (1p) substrates.
Although Becker discussed the effect of reaction conditions
on the aldimine coupling reaction in 1970,9b his principal
characterization method was fluorescence spectroscopy. Our
studies allow additional understanding since NMR readily
shows the intermediates that form before oxidation and more
conclusively quantifies the products. While the initial ene-
diamine coupling products were claimed by Becker to be
oxidized easily in air,9b 1a in DMF with 20% NaCN under
dry airsemploying a variety of temperature and solvent
conditionssfor 24 h resulted in, at most, a 9:1 mixture of
ene-diamine to R-diimine. 1,4-Benzoquinone was found to
be a competent oxidant for converting the ene-diamines to
R-diimines; for example, one equivalent (relative to 1a)
provided the diimine 2a within minutes (monitored by
NMR), while simply stirring the reaction open to air afforded
2a in only 50% yield after 24 h. 1,4-Benzoquinone failed as
an in situ oxidant to convert the ene-diamine to diimines
apparently because of unwanted reaction with sodium
cyanide. However, we found that simple dilution of the
reaction mixture with dichloromethane followed by extraction
with water is sufficient to remove NaCN and DMF, which
allowed us to skip isolation of the ene-diamine intermediate.
(5) Strain, H. H. J. Am. Chem. Soc. 1928, 50, 2218–2223.
(6) Kison, C.; Opatz, T. Synthesis 2006, 21, 3727–3738.
(7) (a) Siegfeld, M. Chem. Ber. 1892, 25, 2600–2601. (b) Reddelien,
G. Chem. Ber. 1914, 46, 2718–2723. (c) Bock, H.; tom Dieck, H. Chem.
Ber. 1967, 100, 228–246.
(8) (a) Ide, W. S.; Buck, J. S. Org. React. 1948, 4, 269–304. (b) Jose,
B.; Unni, M. V. V.; Prathapan, S.; Vadakkan, J. J. Synth. Commun. 2002,
32, 2495–2498. (c) Weiss, M.; Appel, M. J. Am. Chem. Soc. 1948, 70,
3666–3667.
(9) (a) Kuebrich, J. P.; Schowen, R. L.; Wang, M.; Lupes, M. E. J. Am.
Chem. Soc. 1971, 93, 1214–1220. (b) Becker, H.-D. J. Org. Chem. 1970,
35, 2099–2102.
3678
Org. Lett., Vol. 10, No. 17, 2008

Our results are consistent with Becker’s conclusion that
DMF is a good solvent for aldimine coupling. Our previous
study on the ring-closing of dialdimines to form heterocycles
showed that intramolecular aldimine coupling also performs
well in MeOH or the biphasic CH2Cl2/H2O system using
Bu4NI as a phase transfer agent. Ethanol is a common solvent
for the benzoin reaction; however, no intermolecular aldi-
mine coupling could be achieved using NaCN in alcohols
or in the biphasic CH2Cl2/H2O/Bu4NI system for those
substrates attempted (1a and 1g). For several substrates (1a,
1c, 1e, and 1g), the reaction was sensitive to air, water,
(including wet DMF not previously dried over MgSO4), or
even residual MeOHslowering the yield or altogether
preventing reactivity. Alternative solvents were not explored
for the remaining substrates.
As imidazolium salts are important precursors for NHC
synthesis, several different procedures have been reported
for converting R-diimines to imidazolium salts. Arduengo10
originally reported a strategy for cyclizing R-diimines with
formaldehyde equivalents which has been fruitful in generat-
ing a variety of imidazolium salts. From the diimines 2a-2h,
we modified Noels’ procedure11 (based on Arduengo’s
strategy) to prepare imidazolium chlorides by reaction with
paraformaldehyde and anhydrous HCl. Our yields, albeit low,
are similar to those previously reported via this method
(Table 2). The imidazolium salts 3a-3h have been synthe-
NHCs can be directly prepared by deprotonation of the
imidazolium chloride salt with KOtBu using the typical
method reported in the literature.10-12 Free carbene com-
pounds from 3b and 3e have thus been prepared and
characterized by 1H and 13C NMR spectroscopy. The carbene
carbons can be verified with peaks resonating around 220
ppm in the 13C NMR spectra.
Alternatively, the imidazolium chloride salts can be
directly transformed into the silver(I) chloride carbene species
by refluxing with silver oxide in methylene chloride. Silver
carbene complexes 4a, 4c, 4e, 4f, and 4h were targeted for
synthesis because of their electronically diverse substituents.
These complexes were prepared and isolated as colorless
needles which are neither air nor moisture sensitive. X-ray
crystallography confirmed the anticipated structures, and
these are illustrated in Figure 1.
Table 2. Formation of Tetraarylimidazolium Salts and Tetraaryl
N-Heterocyclic Silver Carbenes
2f3 time
yield 3
δ
1H 3
yield 4
Ag-C
entry
(h)
(%)a
CHb
(%)a
(Å)c
a
b
c
d
e
f
12
18
18
18
12
18
36
24
b
22
33
12
16
32
33
29
31
10.81
10.85
9.85
80
-
75
-
55
88
-
2.079
-
2.087
-
2.051
2.070
-
9.78
10.58
10.88
10.63
10.58
Figure 1. Silver carbene complexes 4a, 4c, 4e, 4f, and 4h depicted
with 50% probability ellipsoids.
g
h
80
2.079
a Isolated yields. 1H NMR shift of the imidazolium ring proton.
c Determined by X-ray crystallography (see the Supporting Information).
Although silver NHCs are useful for transmetalation to
generate other organometallic species, they have few inherent
uses.13 We sought a catalytically active system bearing
classical NHCs that could be modified to include our novel
carbenes for comparative investigations. Both the electronic
sized, purified, and fully characterized by NMR, mass
spectrometry, and, in the case of 3d, single-crystal X-ray
analysis (see the Supporting Information).
(10) Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.;
Goerlich, J. N.; Marshall, W. J.; Unverzagt, M. Tetrahedron 1999, 55,
14523–14534.
(11) Delaude, L.; Szypa, M.; Demonceau, A.; Noels, A. F. AdV. Synth.
Catal. 2002, 344, 749–756
.
Org. Lett., Vol. 10, No. 17, 2008
3679

and steric characteristics of Ir(1,5-cyclooctadiene)NHC
systems have been very extensively studied in the literature
in recent years by Crabtree and Nolan.3,14 Routes to generate
these species are also well established. Scheme 1 shows our
Scheme 2. Initial Studies of Transfer Hydrogenation Using
Ir[COD](tetraphenylNHC) Chloride (5a)
Scheme 1
.
Strategy for the Synthesis of Ir(COD)NHC Chloride
Complexes from Imidazolium Salts
rather simple. It does not require heating (to 80 °C) or
dynamic removal of acetone. Also, our catalyst has the
longevity to attain 100% conversion, whereas catalyst
mortality has limited most previous efforts to about 70-90%
conversion.
In conclusion, we have extended our intramolecular
cyanide-catalyzed aldimine coupling strategy to the inter-
molecular coupling of several readily available, electronically
variable diarylaldimines. The functional group tolerance of
this reaction was fairly broad and has allowed the synthesis
of a novel family of electronically diverse tetraarylimida-
zolylidene carbenes. The silver chloride carbenes are readily
generated as air-stable compounds. In addition, metalation
of the imidazolium salts is facile and can form catalytically
useful iridium NHC complexes, which we have applied to
transfer hydrogenation reactions. Future work will assess the
importance of the carbene electronic tunability on this and
other homogeneous catalytic reactions.
initial strategy to generate the complexes parallel to the
method of Crabtree. Our preliminary studies have shown that
we can synthesize iridium complex 5a in 68% yields
importantly, with no chromatographic isolation steps.
The catalytic activity of iridium NHC complexes is well-
known.15 One of the simplest systems for assessing catalytic
activity is transfer hydrogenation.16 In the application of 5a,
we have found very good catalytic activity in the transfer
hydrogenation of acetophenone to R-hydroxyethylbenzene
(Scheme 2), as 100% conversion is obtained in 12 h and,
separately, a turnover frequency (TOF) of 41 h-1 is obtained
in the first hour. This compares well with most iridium NHC
complexes, although some are known to have a TOF of
150-174 h-1 for acetophenone.17 However, the comparison
is notably more favorable considering that our procedure is
Acknowledgment. Funding was provided by the Robert
A. Welch Foundation (No. A-1537) and the National Science
Foundation (CAREER CHE-0548197). K.A.A. wishes to
acknowledge the National Science Foundation and the
University of Florida for funding the purchase of X-ray
analysis equipment.
(12) Jafarpour, L.; Nolan, S. P. Organometallics 2000, 19, 2055–2057.
(13) For examples of transmetalation and antimicrobial activity for some
silver NHC carbenes, see ref lc.
Supporting Information Available: Synthetic details,
NMR spectra, and X-ray structural data (CIF files) for 3d,
4a, 4c, 4e, 4f, and 4h. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Serena Fantasia, S.; Petersen, J. L.; Jacobsen, H.; Cavallo, L.; Nolan,
S. P. Organometallics 2007, 26, 5880–5889.
(15) Crabtree, R. H. Platinum Metals ReV. 2006, 50, 171–176.
(16) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300–1308.
(17) (a) Hodgson, R.; Douthwaite, R. E. J. Organomet. Chem. 2005,
690, 5822–5831. (b) Kownacki, I.; Kubicki, M.; Szubert, K.; Marciniec,
B. J. Organomet. Chem. 2008, 693, 321–328.
OL8012765
3680
Org. Lett., Vol. 10, No. 17, 2008