N-heterocyclic carbene-catalyzed cross-coupling of aromatic aldehydes with activated alkyl halides

Article abstract of DOI:10.1021/ol102626p

N-Heterocyclic carbene-catalyzed umpolung of aldehydes followed by their interception with diarylbromomethanes has been reported. This conceptually novel transition-metal-free cross-coupling of aldehydes with alkyl halides works well at low catalyst loadings and under mild reaction conditions leading to the formation of diaryl acetophenone derivatives in good yields. In addition, α-halo ketones and esters can also be used as aldehyde reaction partners.

Full text of DOI:10.1021/ol102626p

ORGANIC
LETTERS
2011
Vol. 13, No. 1
98-101
N-Heterocyclic Carbene-Catalyzed
Cross-Coupling of Aromatic Aldehydes
with Activated Alkyl Halides
Mohan Padmanaban, Akkattu T. Biju, and Frank Glorius*
Westfa¨lische Wilhelms-UniVersita¨t, NRW Graduate School of Chemistry,
Organisch-Chemisches Institut, Corrensstrasse 40, 48149 Mu¨nster, Germany
glorius@uni-muenster.de
Received October 29, 2010
ABSTRACT
N-Heterocyclic carbene-catalyzed umpolung of aldehydes followed by their interception with diarylbromomethanes has been reported. This
conceptually novel transition-metal-free cross-coupling of aldehydes with alkyl halides works well at low catalyst loadings and under mild
reaction conditions leading to the formation of diaryl acetophenone derivatives in good yields. In addition, r-halo ketones and esters can also
be used as aldehyde reaction partners.
N-Heterocyclic carbenes (NHCs)1 have found widespread
applications as versatile ligands in transition-metal catalysis2
and as organocatalysts in their own right.3 NHC-organo-
catalyzed umpolung reactions of aldehydes can lead to the
formation of nucleophilic acyl anion intermediates, which
can react with various electrophiles, like aldehydes and
ketones,4 imines,5 and activated, polarized CdC double
bonds.6 Intriguingly, however, whereas the NHC-catalyzed
(4) For selected references, see: (a) Enders, D.; Kallfass, U. Angew.
Chem., Int. Ed. 2002, 41, 1743. (b) White, M. J.; Leeper, F. J. J. Org.
Chem. 2001, 66, 5124. (c) Enders, D.; Grossmann, A.; Fronert, J.; Raabe,
G. Chem. Commun. 2010, 46, 6282. (d) Enders, D.; Henseler, A. AdV. Synth.
Catal. 2009, 351, 1749. (e) Enders, D.; Niemeier, O.; Balensiefer, T. Angew.
Chem., Int. Ed. 2006, 45, 1463. (f) Takikawa, H.; Hachisu, Y.; Bode, J. W.;
Suzuki, K. Angew. Chem., Int. Ed. 2006, 45, 3492. (g) Chan, A.; Scheidt,
K. A. J. Am. Chem. Soc. 2006, 128, 4558.
(1) (a) Arduengo, A. J., III. Acc. Chem. Res. 1999, 32, 913. (b)
Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. ReV. 2000,
100, 39. (c) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (d)
Hahn, F. E.; Jahnke, M. C. Angew. Chem., Int. Ed. 2008, 47, 3122. For
recent reviews on the physicochemical properties of NHCs, see: (e) Dro¨ge,
T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 6940. (f) Dro¨ge, T.; Glorius,
F Nachr. Chem. 2010, 58, 112.
(5) For selected references, see: (a) Murry, J. A.; Frantz, D. E.; Soheili,
A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001,
123, 9696. (b) Mennen, S. M.; Gipson, J. D.; Kim, Y. R.; Miller, S. J. Am.
Chem. Soc. 2005, 127, 1654. (c) Li, G.-Q.; Dai, L.-X.; You, S.-L. Chem.
Commun. 2007, 852. (d) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131. (e)
Rommel, M.; Fukuzumi, T.; Bode, J. W. J. Am. Chem. Soc. 2008, 130,
17266.
(2) (a) D´ıez-Gonza´lez, S.; Marion, N.; Nolan, S. P. Chem. ReV. 2009,
109, 3612. (b) Wu¨rtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523. (c)
Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem., Int. Ed.
2007, 46, 2768. Glorius, F., Ed. N-Heterocyclic Carbenes in Transition
Metal Catalysis; Springer: Berlin, 2007. Diez-Gonzalez, S.; Nolan, S. P.
Coord. Chem. ReV. 2007, 251, 874. Nolan, S. P., Ed. N-Heterocyclic
Carbenes in Synthesis; Wiley-VCH: Weinheim, 2006.
(6) For reviews, see: (a) Read de Alaniz, J.; Rovis, T. Synlett 2009, 1189.
(b) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632. For selected
references, see: (c) Read de Alaniz, J.; Kerr, M. S.; Moore, J. L.; Rovis, T.
J. Org. Chem. 2008, 73, 2033. (d) Liu, Q.; Perreault, S.; Rovis, R. J. Am.
Chem. Soc. 2008, 130, 14066. (e) Mattson, E.; Bharadwaj, A. R.; Scheidt,
K. A. J. Am. Chem. Soc. 2004, 126, 2314. (f) Mattson, A. E.; Zuhl, A. M.;
Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4932.
(3) For reviews on NHC-organocatalysis, see: (a) Moore, J. L.; Rovis,
T. Top. Curr. Chem. 2009, 291, 77. (b) Nair, V.; Vellalath, S.; Babu, B. P.
Chem. Soc. ReV. 2008, 37, 2691. (c) Enders, D.; Niemeier, O.; Henseler,
A. Chem. ReV. 2007, 107, 5606. (d) Marion, N.; D´ıez-Gonza´lez, S.; Nolan,
S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (e) Phillips, E. M.; Chan, A.;
Scheidt, K. A. Aldrichim. Acta 2009, 42, 55.
10.1021/ol102626p  2011 American Chemical Society
Published on Web 11/30/2010

generation of the Breslow intermediate (A)7 and its subse-
quent interception with sp2-carbon centered electrophiles are
well documented,3 the analogous reaction with sp3-carbon-
centered electrophiles is extremely rare,8 and the NHC-
catalyzed umpolung addition of aldehydes to diarylbro-
momethane derivatives are, to the best of our knowledge,
unknown (Scheme 1).9 Very recently, the NHC-mediated
Table 1. Optimization of the Reaction Conditionsa
Scheme 1. NHC-Catalyzed Umpolung of Aldehydes
variation of the
standard conditionsa
yield of
3ab (%)
entry
1
2
none
5 instead of 4
99
5
3
4
6 instead of 4
7 instead of 4
45
0
5
8 instead of 4
0
6
7
8
9
10
11
12
13
DBU instead of K2CO3
Et3N instead of K2CO3
KOt-Bu instead of K2CO3
Cs2CO3 instead of K2CO3
1,4-dioxane instead of THF
DME instead of THF
Et2O instead of THF
0.2 equiv of K2CO3 instead of
1.2 equiv K2CO3
80
16
22
99
52
87
2
alkylation of aromatic aldehydes with benzyl halides was
reported by Du, Deng, et al.8a Herein, we report the NHC-
catalyzed umpolung of aldehydes, followed by their alky-
lation using alkyl halides, leading to the formation of
acetophenone derivatives.
28
14
0.05 equiv 4 and 1.1 equiv of
K2CO3, 3 h
0.05 equiv 4 and 1.1 equiv of
82
15
98 (93)c
Our present study commenced with the exposure of
4-chlorobenzaldehyde 1a and (bromomethylene)dibenzene
2a with thiazolium salt 410 and 1.2 equiv of K2CO3 in THF.
To our delight, a facile reaction occurred leading to the
formation of diphenylethanone derivative 3a in excellent
yield (based on 1H NMR analysis of the crude product, Table
1, entry 1). This NHC has been designed by us for the dual
NHC/Pd catalysis,10a which we recently applied successfully
in the hydroacylation of unactivated alkenes,11a alkynes,11b
arynes,11c and formaldehyde.11,12 Remarkably, in contrast
to this NHC, other common NHCs derived from 5-8 are
far less effective (entries 2-5).13 The use of bases such as
DBU, Et3N, and KOt-Bu furnished reduced yield of the
product (entries 6-8), but Cs2CO3 maintained the reactivity,
Cs2CO3, 3 h
a Standard conditions: 1 (0.25 mmol), NHC·HX (10 mol %), K2CO3
(1.2 equiv), THF (2.5 mL), rt and 2 h. b The yields were determined by 1H
NMR analysis of crude products using CH2Br2 as the internal standard.
c Isolated yield in parentheses.
affording 3a in excellent yield (entry 9). The use of other
solvents such as 1,4-dioxane, DME, or Et2O was not found
to be beneficial (entries 10-12). Additionally, the reaction
carried out using catalytic amounts of base considerably
reduced the yield of product (entry 13) indicating that excess
of base is needed for excellent conversion. Finally, reducing
the catalyst loading to 5 mol % of 4 and 1.1 equiv of Cs2CO3
maintained the reactivity, affording product 3a in 93%
isolated yield (entry 15).
With these optimized reaction conditions in hand, we
examined the substrate scope of this NHC-organocatalyzed
umpolung/alkylation reaction (Scheme 2). The parent system
worked well, and a variety of electron-withdrawing and
electron-donating groups at the 4-position of the ring are well
tolerated, leading to the formation of alkylated products in
62-93% (3a-g) although electron-rich substrates needed
higher catalyst loading for efficient conversion. Moreover,
3-substituted aldehydes and disubstituted aldehydes resulted
in the smooth conversion to the product (3h-l). Interestingly,
the transformation of terephthalaldehyde resulted in the
formation of dialkylated product in 63% yield. Furthermore,
this novel alkylation reaction of aldehydes is not only limited
(7) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. For the formation
and use of conjugate Breslow intermediates, see: (b) Glorius, F.; Burstein,
C. Angew. Chem., Int. Ed. 2004, 43, 6205. (c) Sohn, S. S.; Rosen, E. L.;
Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370.
(8) For a related very recent report using stoichiometric amounts of NHC,
see: (a) Lin, L.; Li, Y.; Du, W.; Deng, W.-P. Tetrahedron Lett. 2010, 51,
3571. (b) Singh, P.; Singh, S.; Rai, V. K.; Yadav, L. D. S. Synlett 2010,
2649. (c) He, J.; Zheng, J.; Liu, J.; She, X.; Pan, X. Org. Lett. 2006, 8,
4637. (d) Stetter, H.; Schmitz, P. H.; Schreckenberg, M. Chem. Ber. 1977,
110, 1971. For an NHC-catalyzed Heck-type reaction, see: (e) Fischer, C.;
Smith, S. W.; Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 1472.
(9) For a recent report on the R-alkylation of aldehydes using diaryl
bromomethanes, see: Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. J. Am.
Chem. Soc. 2010, 132, 9286.
(10) (a) Lebeuf, R.; Hirano, K.; Glorius, F. Org. Lett. 2008, 10, 4243.
(b) Hirano, K.; Piel, I.; Glorius, F. AdV. Synth. Catal. 2008, 350, 984.
(11) (a) Hirano, K.; Biju, A. T.; Piel, I.; Glorius, F. J. Am. Chem. Soc.
2009, 131, 14190. (b) Biju, A. T.; Wurz, N. E.; Glorius, F. J. Am. Chem.
Soc. 2010, 132, 5970. (c) Biju, A. T.; Glorius, F. Angew. Chem., Int. Ed.
2010, 45, DOI: 10.1002/anie.201005490
(12) Kuhl, N.; Glorius, F. Chem. Commun. 2011, DOI: 10.1039/
c0cc02416c
.
.
(13) For details, see the Supporting Information.
Org. Lett., Vol. 13, No. 1, 2011
99

Based on the widely accepted mechanistic proposal for
the benzoin and Stetter reaction,5c,15 we envisaged using
benzoin as a masked aldehyde equivalent. Treatment of
benzoin with 2a employing 10 mol % of 4 and 1.2 equiv
of Cs2CO3 furnished 1,2,2-triphenylethanone 3c in 55%
yield, indicating the reversibility of the formation of
Breslow intermediate under the present reaction conditions
(Scheme 4).
Scheme 2
.
NHC-Catalyzed Alkylation of Aldehydes: Variation
of the Aldehyde Moietya
Scheme 4. Reaction Using Benzoin Instead of Benzaldehyde
a General conditions: 1 (1.0 mmol), 2a (1.0 mmol), 4 (5 mol %), Cs2CO3
(1.1 mmol), THF (10 mL), 25 °C, and 3 h. b Using 20 mol % of 4 and 1.4
equiv of Cs2CO3. c Reaction was run for 24 h.
A mechanistic rationale for the reaction may be advanced
along the following lines (Scheme 5). Following the revers-
Scheme 5. Possible Mechanistic Pathways
to the formation of triphenylethanones. Gratifyingly, het-
erocyclic aldehydes also worked well leading to the forma-
tion of the desired products (3m,n) in good to excellent
yields. It is important to note, however, that in preliminary
experiments aliphatic aldehydes and 2-substituted benzal-
dehydes failed to undergo this transformation under the
standard reaction conditions.
In view of these interesting results, we further investigated
the scope of the reaction using various differently substituted
diarylbromomethanes (Scheme 3). Gratifyingly, both electron-
Scheme 3.
Variation of Diaryl Bromomethane Moietya
ible formation of Breslow intermediate A, the nucleophilic
enaminol can attack the diaryl bromomethane in a concerted
fashion via the five-membered transition state B or via a
backside attack (B′) resembling the SN2 displacement to
furnish the alkoxide intermediate D. Alternatively, a stepwise
SN1 pathway involving the formation of a diphenylmethyl
carbonium ion can also be invoked (intermediate C), where
the carbonium ion will be eventually attacked by A leading
to alkoxide D. Liberation of NHC from D completes the
catalytic cycle and results in the formation of the diaryl
acetophenone derivatives.
a General conditions: 1 (1.0 mmol), 2a (1.0 mmol), 4 (5 mol %), Cs2CO3
(1.1 mmol), THF (10 mL), 25 °C, and 3 h. b Starting material 2o contained
small amounts of an impurity. c Reaction was run for 24 h. d 1H NMR yield
of the product.
withdrawing and electron-donating groups at the 4- and 4′-
position of the aromatic ring of 2 are well tolerated, leading
to the formation of versatile R,R-diaryl acetophenone deriva-
tives amenable for further functional group manipulations14
in 74-95% yield (3o-s). Interestingly, the cyclic 9-bro-
mofluorene also afforded the desired product in 60% yield.
(14) See, for example: (a) Popielarz, R.; Arnold, D. R. J. Am. Chem.
Soc. 1990, 112, 3068. (b) Churruca, F.; SanMartin, R.; Carril, M.; Urtiaga,
M. K.; Solans, X.; Tellitu, I.; Dom´ınguez, E. J. Org. Chem. 2005, 70, 3178.
(15) (a) Enders, D.; Han, J.; Henseler, A. Chem. Commun. 2008, 3989.
(b) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007,
129, 3520
.
100
Org. Lett., Vol. 13, No. 1, 2011

Further insightful experiments seem to favor the stepwise
pathway. Reactions carried out using benzyl bromide 9a as
the electrophile in the alkylation reaction did not furnish any
alkylated product, although 9a is known as powerful elec-
trophile in SN2-type reactions (Table 2, entry 2).16 In
Scheme 6. Utility of R-Bromo Esters and R-Bromo Ketone
Table 2. Electrophile Competition Experiments
In conclusion, we have uncovered a transition-metal-free
NHC-organocatalyzed alkylation reaction of aldehydes via
the umpolung of aldehydes leading to the formation of
acetophenone, ꢀ-diketone, and ꢀ-keto ester derivatives.
Considering the widespread application of NHCs in orga-
nocatalysis, the present methodology represents a rare case
of the addition of Breslow intermediate to sp3-carbon
centered electrophiles. Further studies should be directed
toward improved understanding of the mechanism, expanding
the scope, and developing asymmetric variants of this
transformation.
entry 2a (equiv) 9a (equiv) yield of 3aa (%) yield of 10aa (%)
1
2
3
1
0
1
0
1
1
98
0
66
0
0
0
a
1
The yields were determined by H NMR analysis of crude products
using CH2Br2 as the internal standard.
competition experiments carried out using 2a and 9a, the
product 3a was observed in 66% yield, and no alkylated
product derived from 9a was observed (entry 3). Thus, the
absence of reactivity of 9a is not due to catalyst deactivation,
since the formation of 66% of 3a clearly demonstrated that
the catalyst maintained reactivity.13
Furthermore, this novel NHC-catalyzed alkylation of
aldehydes via the umpolung strategy is not limited to
diarylbromomethane derivatives. In addition, R-bromo esters
and an R-bromo ketone were also successfully employed as
the electrophilic coupling partner leading to the formation
of ꢀ-keto esters and ꢀ-diketone in moderate to good yields
(Scheme 6).
Acknowledgment. Generous financial support by the
Fonds der Chemischen Industrie, the Deutsche Forschungs-
gemeinschaft (DFG), the International NRW Graduate
School of Chemistry (fellowship for M.P.), and the Alexander
von Humboldt Foundation (fellowship for A.T.B.) is grate-
fully acknowledged. The research of F.G. is supported by
the Alfried Krupp Prize for Young University Teachers of
the Alfried Krupp von Bohlen and Halbach Foundation.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) For more details, see the Supporting Information of ref 9.
OL102626P
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