Organocatalytic C-H bond arylation of aldehydes to bis-heteroaryl ketones

Article abstract of DOI:10.1021/ja400051d

An organocatalytic aldehyde C-H bond arylation process for the synthesis of complex heteroaryl ketones has been developed. By exploiting the inherent electrophilicity of diaryliodonium salts, we have found that a commercial N-heterocyclic carbene catalyst promotes the union of heteroaryl aldehydes and these heteroaromatic electrophile equivalents in good yields. This straightforward catalytic protocol offers access to ketones bearing a diverse array of arene and heteroarene substituents that can subsequently be converted into molecules displaying structural motifs commonly found in medicinal agents.

Full text of DOI:10.1021/ja400051d

Communication
pubs.acs.org/JACS
Organocatalytic C−H Bond Arylation of Aldehydes to Bis-heteroaryl
Ketones
Qiao Yan Toh, Andrew McNally, Silvia Vera, Nico Erdmann, and Matthew J. Gaunt*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
S
* Supporting Information
ABSTRACT: An organocatalytic aldehyde C−H bond
arylation process for the synthesis of complex heteroaryl
ketones has been developed. By exploiting the inherent
electrophilicity of diaryliodonium salts, we have found that
a commercial N-heterocyclic carbene catalyst promotes the
union of heteroaryl aldehydes and these heteroaromatic
electrophile equivalents in good yields. This straightfor-
ward catalytic protocol offers access to ketones bearing a
diverse array of arene and heteroarene substituents that
can subsequently be converted into molecules displaying
structural motifs commonly found in medicinal agents.
iaryliodonium salts have become an increasingly exploited
class of aryl transfer reagents that frequently behave as
D
aromatic electrophiles.1 This reactivity profile stems from the
electrophilic nature of the iodine(III) center, making it
susceptible to attack from nucleophiles.2 Aryl transfer to nucleo-
philes such as alkoxides and enolates is proposed to occur
through initial attack at iodine followed by ligand coupling and
has resulted in a number of useful carbon−aryl and heteroatom−
aryl bond-forming processes.1,3 Despite this utility, the
development of catalytic processes using diaryliodonium salts
has been dominated by the use of transition metals, which
typically operate via oxidative insertion. The metal−aryl
intermediates are able to function in traditional Pd-catalyzed
cross-couplings or serve as reactive aromatic electrophiles in
Cu-catalyzed reactions with a range of π-nucleophiles.1,4−6
Given the intrinsic electrophilicity of diaryliodonium salts, we
were surprised that a contrasting strategy based on catalytic
generation of carbogenic nucleophiles that react with these aryl
transfer reagents directly to form carbon−aryl bonds (eq 1) has
yet to be fully exploited.7
unexplored means of aryl transfer to form carbon−aryl bonds
to traditionally non-nucleophilic molecules. Moreover, this
straightforward aldehyde C−H bond arylation process forms a
range of complex heteroaryl aryl ketone and bis-heteroaryl
ketone products from readily available starting materials and
should find broad utility in synthetic applications.
Diaryl ketones are multifaceted compounds that function as
components of pharmacophores, photolabels and photo-
sensitizers, organic electronics, and polymers.8a−e Furthermore,
manipulation of the carbonyl group provides a generic entry
into molecules containing bisbenzylic functionality (eq 3). Of
particular importance to medicinal chemists are compounds
Herein we report the successful development of this concept
through an organocatalytic aldehyde C−H arylation process
(eq 2). In this transformation, an N-heterocyclic carbene
(NHC) catalyst reacts with an aldehyde to form a transient
carbogenic nucleophile, which reacts with the diaryliodonium
salt. This combination leads to a potentially useful and as yet
Received: January 3, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja400051d | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
displaying heterobenzylic−benzylic and bis-heterobenzylic
motifs (eq 4).9 Classical methods for the formation of diaryl
ketones include the addition of arylmetal species to carbonyl
compounds10,11 and Friedel−Crafts acylation reactions. How-
ever, the presence of aromatic heterocyles can limit these
strategies, as organometallic reagents can be incompatible with
heteroaromatic nuclei12 and Friedel−Crafts acylations usually
work best with π-rich arenes and sometimes result in isomeric
mixtures. An alternative Cacyl−Caryl bond formation strategy has
been realized through Pd-catalyzed cross-coupling reactions of
activated carboxylic acid derivatives13 and carbonylative
processes.14 More recently, metal-catalyzed C−H arylation of
aldehydes has provided new pathways for the construction of
these molecules.15,16 Related to this strategy, diaryl ketone
formation from aldehydes has been realized using NHC
catalysis17 through reactions with aromatic electrophiles such
as activated aryl halides via SNAr-type reactions18 or with
benzynes.19 Despite the sophistication of these catalytic
methods, the majority of examples form benzophenone
derivatives, and the number of heteroaromatic coupling
partners is limited. Driven by the need for a catalytic method
for regioselective diaryl ketone formation that can incorporate a
broad range of heteroaromatic nuclei, we envisioned that these
challenges could potentially be met through the use of
diaryliodonium salts. These aromatic electrophiles react with
precise regiocontrol upon combination with nucleophiles, are
readily prepared and stable reagents, and can transfer aryl or
heteroaryl groups. Taken together with the reactivity of acyl
anion equivalents, which are readily accessible through the
powerful NHC catalyst activation mode, we speculated that the
reaction of heterocyclic aldehyde 1 with NHC 3 would form
the putative Breslow intermediate I,20 a nucleophilic species
that could attack the iodine(III) center of diaryliodonium salt 2
(eq 2). In the resultant iodane species II, aryl transfer would
constitute the key C−C bond-forming event, affording tertiary
carbinol III. Release of the NHC catalyst would form the
desired bis-heteroaryl ketone 4 and complete the catalytic cycle.
We began our investigation by using benzoxazole-2-
carboxaldehyde (1a) as a representative heterocyclic substrate
in combination with diphenyliodonium triflate (2a) and a
selection of commonly encountered NHC catalyst precursors 3
(Table 1, entries 1−4). After assessing four commercially
available catalysts, we were delighted to find that triazolium salt
3d, developed by Rovis,21 was the most effective in promoting
the desired bond-forming process to give ketone 4a. This is
consistent with recent reports by Rovis and co-workers demon-
strating the suitability of N-C6F5-substituted triazolium catalysts
in facilitating Stetter reactions of heterocyclic aldehydes.22 Key
results of our optimization included an improvement in yield
when 4-dimethylaminopyridine (DMAP) was used as the base
to generate the carbene (entries 5−10) and the observation
that including a protic additive was beneficial for homogeneity
of the reaction mixture. It is important to emphasize that the reac-
tion employs an equimolar ratio of diphenyliodonium triflate
and aldehyde and uses a commercially available NHC catalyst.
After establishing the optimal reaction conditions, we applied
this new arylation protocol to a series of heterocyclic aldehydes,
producing heteroaryl-phenyl ketones in good yields (Table 2,
4b−l). Aliphatic aldehydes could also be arylated in this process
(4m). Beyond phenyl group transfer, symmetrical diaryl-
iodonium salts displaying a range of substituents could be
incorporated without loss of efficiency (4n−r). Particularly
noteworthy are diaryl ketones that could be selectively formed
Table 1. Evaluation of NHC Catalysts and Bases
a
entry
catalyst
base (equiv)
iPr2NEt (1.0)
yield of 4 (%)
1
2
3a
3b
3c
3d
3d
3d
3d
3d
3d
3d
0
iPr2NEt (1.0)
iPr2NEt (1.0)
iPr2NEt (1.0)
KHMDS (1.0)
K2CO3 (1.0)
17
19
77
70
43
70
79
3
4
5
6
7
DBU (1.0)
8
DMAP (1.0)
b
9
DMAP (1.5)
iPr2NEt (1.5)
DMAP (no iPrOH) (1.5)
98 (91 )
10
11
83
86
3d
a
1
Determined by H NMR analysis using 1,3,5-trimethoxybenzene as
b
an internal standard. Isolated yield.
a
Table 2. Scope of Heteroaryl Aldehydes: Phenylation
a
b
c
d
Isolated yields are shown. At −40 °C. 20 mol % 3d. 15 mol % 3d.
with substitution patterns that are “nonstandard” on the basis
of the principles of Friedel−Crafts acylation reactions (4o−r).
Our next challenge was to apply this method to synthesize
bis-heteroaryl ketones. Compared with their symmetrical
B
dx.doi.org/10.1021/ja400051d | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
counterparts, nonsymmetrical heteroaryliodonium salts would
be advantageous for this purpose because of their relative ease
of synthesis and the more economical use of the transferring
group. Observations from the literature suggested that the more
electron-deficient aryl moiety should be transferred from the
iodine(III) center after nucleophilic attack.3b,23 However, when
we tested salts 2g and 2h, displaying simple phenyl and anisyl
groups, respectively, alongside the pyridyl unit, the selectivity of
the aryl transfer was poor (Scheme 1). Although the sterically
Table 3. Formation of Bis-heteroaryl Ketones: Scope
a
Scheme 1. Selectivity of Aryl Transfer
a
Yield determined by 1H NMR analysis using 1,3,5-trimethoxybenzene
b
c
as an internal standard. Isolated yield. H2O was used instead of
iPrOH.
a
b
Yield of isolated products. Using symmetrical iodonium salt.
To illustrate the potential utility of our new process, we
demonstrated how bis-heteroaryl ketones can be converted into
enantioenriched molecules (eq 5). Ellman imine formation
hindered mesityl salt 2i resulted in selective formation of bis-
heteroaryl ketone 4s, the yield was low. This was surprising, as
sterically demanding aryl groups tend to undergo preferential
aryl transfer.24 In searching for an alternative, we wondered
whether nonsymmetrical uracil−aryl iodonium salts25 could be
adapted to our purposes. Uracil−pyridine salt 2j was readily
prepared,26 and when it was subjected to the reaction
conditions, ketone 4s was formed exclusively in 75% yield.
While a precise rationale for the aryl transfer selectivity is
unclear, these results suggest that the usual rules governing
selectivity do not operate during this process.
Using uracil−heteroaryl iodonium salts, we were able to
demonstrate further the value of this process by constructing a
range of bis-heteroaryl ketones (Table 3). Five-membered
heteroaryl aldehydes performed well, resulting in high yields of
bis-heteroaryl ketone products (4t−v). Six-membered hetero-
aryl aldehydes showed slightly lower reactivity but nevertheless
combined productively with 2j to form the desired products in
synthetically useful yields (4w−y). The transfer of the pyridyl
group was observed as the only detectable outcome in all cases.
We also found that a variety of uracil−heteroaryl iodonium salts
were compatible with the new coupling process to heteroaryl
aldehydes; electron-deficient heteroarenes (4z−ab) and an
electron-rich thiophene derivative (4ac) were accommodated
well by this protocol. Important pharmacophores such as
azaindoles could also be incorporated into bis-heteroaryl
ketones (4ad). Finally, in a surprising outcome, the uracil
motif was selectively transferred when uracil−3-(N-methylpyrazole)
iodonium triflate was tested as a coupling partner, further reflecting
the subtle balance of factors influencing aryl transfer (vide
supra).
from 4t (not shown),27 addition of MeMgBr in high yield and
diastereoselectivity (92% yield, >20:1 dr), and auxiliary cleavage
furnished optically active amine hydrochloride salt (+)-6 in a
simple three-step sequence.28
In summary, we have developed a catalytic C−H arylation
process for the formation of complex heteroaryl ketones via the
combination of diaryliodonium salts and NHC catalysis. The
process operates under mild conditions, involves simple
experimental protocols, uses a commercially available NHC
catalyst, and encompasses a range of high-value heterocyclic
systems. We therefore believe that this method will be
appealing to practitioners of medicinal chemistry. Studies of
the mechanism of the process, including the aryl transfer
selectivity, as well as the application of diaryliodonium salts in
other catalytic systems are ongoing and will be reported in due
course.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
C
dx.doi.org/10.1021/ja400051d | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(13) (a) Haddach, M.; McCarthy, J. R. Tetrahedron Lett. 1999, 40,
3109. (b) Bumagin, N. A.; Korolev, D. N. Tetrahedron Lett. 1999, 40,
3057. (c) Gossen, L. J.; Ghosh, K. Angew. Chem., Int. Ed. 2001, 40,
3458. (d) Liebeskind, L.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
(e) Wang, D.; Zhang, Z. Org. Lett. 2003, 5, 4645. (f) Kunchithapatham,
K.; Eichman, C. C.; Stambuli, J. P. Chem. Commun. 2011, 47, 12679.
(g) Schmink, J. R.; Krska, S. W. J. Am. Chem. Soc. 2011, 133, 19574.
For a review, see: (h) Dieter, R. K. Tetrahedron 1999, 55, 4177.
(14) For representative examples, see: (a) Heck, R. F. J. Am. Chem.
Soc. 1968, 90, 5546. (b) Ishiyama, T.; Kizaki, H.; Hayashi, T.; Suzuki,
A.; Miyaura, N. J. Org. Chem. 1998, 63, 4726. (c) Li, H.; Yang, M.; Qi,
Y.; Xue, J. Eur. J. Org. Chem. 2011, 2662. (d) Couve-Bonnaire, S.;
Carpentier, J.-F.; Mortreux, A.; Castanet, Y. Tetrahedron 2003, 59,
2793. For reactions involving diaryliodonium salts, see refs 4c and 4d
and: (e) Zhou, T.; Chen, Z.-C. Synth. Commun. 2002, 32, 3431.
(15) (a) Pucheault, M.; Darses, S.; Genet, J.-P. J. Am. Chem. Soc.
2004, 126, 15356. (b) Huang, Y.-C.; Majumdar, K. K.; Cheng, C.-H. J.
Org. Chem. 2002, 67, 1682. (c) Qin, C.; Chen, J.; Wu, H.; Cheng, J.;
Zhang, Q.; Zuo, B.; Su, W.; Ding, J. Tetrahedron Lett. 2008, 49, 1884.
(d) Satoh, T.; Itaya, T.; Miura, M.; Nomura, M. Chem. Lett. 1996, 823.
(e) Xia, M.; Chen, Z.-C. Synth. Commun. 2000, 30, 531.
(16) For other notable metal-catalyzed processes, see: (a) Zhou, C.;
Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302. (b) Duplais, C.;
Bures, F.; Sapountzis, I.; Korn, T. J.; Cahiez, G.; Knochel, P. Angew.
Chem., Int. Ed. 2004, 43, 2968.
(17) For reviews from some of the pioneers in NHC catalysis, see:
(a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606.
(b) Moore, J. L.; Rovis, T. Top. Curr. Chem. 2010, 291, 77. (c) Phillips,
E. M.; Chan, A.; Scheidt, K. A. Aldrichchimica Acta 2009, 42, 55.
(d) Chiang, P.-C.; Bode, J. W. In N-Heterocyclic Carbenes as Organic
Catalysts: From Laboratory Curiosities to Efficient Synthetic Tools; Díez-
AUTHOR INFORMATION
■
Corresponding Author
mjg32@cam.ac.uk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Leverhulme Trust (A.M.), the Spanish
Government (S.V.), and the EPSRC and ERC (M.J.G) for
fellowships and VCI for a scholarship (N. E.). We acknowledge
the EPSRC Mass Spectrometry Service (University of
Swansea).
REFERENCES
■
(1) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052.
(2) (a) Varvoglis, A. The Organic Chemistry of Polycoordinated Iodine;
VCH: New York, 1992. (b) Varvoglis, A. Hypervalent Iodine in Organic
Synthesis; Academic Press: London, 1997. (c) Ochiai, M. Top. Curr.
Chem. 2003, 224, 5.
(3) For examples, see: (a) Beringer, F. M.; Daniel, W. J.; Galton, S.
A.; Rubin, G. J. Org. Chem. 1966, 31, 4315. (b) Oh, C. H.; Kim, J. S.;
Jung, H. H. J. Org. Chem. 1999, 64, 1338. (c) Chen, K.; Koser, G. F. J.
Org. Chem. 1991, 56, 5764. (d) Iwama, T.; Birman, V. B.; Kozmin, S.
A.; Rawal, V. H. Org. Lett. 1999, 1, 673. (e) Lubinkwowski, J. J.;
Knapczyk, J. W.; Calderon, J. L.; Petit, L. R.; McEwen, W. E. J. Org.
Chem. 1975, 40, 3010. (f) Jalalian, N.; Ishikawa, E. E.; Silva, L. F.;
Olofsson, B. Org. Lett. 2011, 13, 1552.
(4) For examples of cross-coupling-type processes, see: (a) Zhu, M.;
Song, Y.; Cao, Y. Synthesis 2007, 853. (b) Zhu, M.; Zhao, Z.; Chen, R.
Synthesis 2008, 2680. (c) Kang, S.-K.; Ho, P.-S.; Yoon, S.-K.; Lee, J.-C.;
Lee, K.-J. Synthesis 1998, 823. (d) Kang, S.-K.; Lee, H.-W.; Jang, S.-B.;
Ho, P.-S. J. Org. Chem. 1996, 61, 4720.
́
Gonzalez, S., Ed.; Royal Society of Chemistry: Cambridge, U.K., 2010;
pp 399−435. (e) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41,
3511.
(18) (a) Miyashita, A.; Matsuda, H.; Iijima, C.; Higashino, T. Chem.
Pharm. Bull. 1990, 38, 1147. (b) Suzuki, Y.; Ota, S.; Fukuta, Y.; Ueda,
Y.; Sato, M. J. Org. Chem. 2008, 73, 2420.
(19) Biju, A. T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 9761.
(20) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
(21) (a) Kerr, M. S.; Alaniz, J. R.; Rovis, T. J. Org. Chem. 2005, 70,
5725. (b) Rovis, T. Chem. Lett. 2008, 37, 2. (c) Mahattananchai, J.;
Bode, J. W. Chem. Sci. 2012, 3, 192.
(5) For Pd(II/IV), see: Deprez, N. R.; Sanford, M. S. Inorg. Chem.
2007, 46, 1924 and references therein.
(6) For Cu, see: (a) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am.
Chem. Soc. 2008, 130, 8172. (b) Phipps, R. J.; Gaunt, M. J. Science
2009, 323, 1593. (c) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2011, 133, 4260. (d) Ryan, J. H.; Stang, P. J. Tetrahedron Lett.
1997, 38, 5061. (e) Lockhart, T. P. J. Am. Chem. Soc. 1983, 105, 1940.
(f) Beringer, F. M.; Geering, E. J.; Kuntz, I.; Mausner, M. J. Phys.
Chem. 1956, 60, 141.
(22) Dirocco, D. A.; Oberg, K. M.; Dalton, D. M.; Rovis, T. J. Am.
Chem. Soc. 2009, 131, 10872.
(23) (a) Beringer, F. M.; Forgione, P. S.; Yudis, M. D. Tetrahedron
1960, 8, 49. (b) Ochiai, M.; Shu, T.; Nagaoka, T.; Kitagawa, Y. J. Org.
Chem. 1997, 62, 2130.
(24) (a) Lancer, K. M.; Wiegand, G. H. J. Org. Chem. 1976, 41, 3360.
(b) Carroll, M. A.; Wood, R. A. Tetrahedron 2007, 63, 11349.
(c) Petersen, T. B.; Khan, R.; Olofsson, B. Org. Lett. 2011, 13, 3462.
(25) Roh, K. R.; Kim, J. Y.; Kim, Y. H. Chem. Lett. 1998, 1095.
(26) Preparation of 2j:
(7) Norrby, P.-A.; Peterson, T. B.; Bielawski, M.; Oloffson, B.
Chem.Eur. J. 2010, 16, 8251.
(8) (a) Bosca,
́
F.; Miranda, M. A. J. Photochem. Photobiol., B 1998, 43,
, G.; Prestwich, G. D. Biochemistry 1994, 33, 5661.
1. (b) Dorman
́
(c) Wilkinson, F. Adv. Photochem. 1964, 3, 241. (d) Sharmoukh, W.;
Ko, K. C.; Noh, C.; Lee, J. Y.; Son, S. U. J. Org. Chem. 2010, 75, 6708.
(e) Maeyama, K.; Yamashita, K.; Saito, H.; Aikawa, S.; Yoshida, Y.
Polym. J. 2012, 44, 315.
(9) (a) Chen, C.; Reamer, R. A; Chilenski, J. R.; McWilliams, C. J.
Org. Lett. 2003, 5, 5039. (b) Ruck, R. T.; Huffman, M. A.; Stewart, G.
W.; Cleator, E.; Kandur, W. A.; Kim, M. M.; Zhao, D. Org. Process Res.
Dev. 2012, 16, 1329. (c) Schmidt, F.; Stemmler, R. T.; Rudolph, J.;
Bolm, C. Chem. Soc. Rev. 2006, 35, 454. (d) Walsh, D. A.; Moran, H.
W.; Shamblee, D. A.; Welstead, W. J.; Nolan, J. C.; Sancilio, L. F.;
Graffl, G. J. Med. Chem. 1990, 33, 2296. (e) Salvi, L.; Kim, J. G.; Walsh,
P. J. J. Am. Chem. Soc. 2009, 131, 12483.
(27) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600.
(10) (a) Shirley, D. A. Org. React. 1954, 8, 28. (b) March, J. Advanced
Organic Chemistry, 3rd ed.; Wiley: New York, 1985; pp 433−435 and
824−827. (c) Larock, R. C. Comprehensive Organic Transformations;
VCH: New York, 1989; p 685. (d) O’Neil, B. T. In Comprehensive
Organic Synthesis; Trost, B., Fleming, I.; Eds; Pergamon Press: Oxford,
U.K., 1991; Vol. 1, p 397.
(28) See the Supporting Information for additional examples.
(11) Katoh, T.; Ohmori, O.; Iwasaki, K.; Inoue, M. Tetrahedron 2002,
58, 1289.
(12) McGill, C. K.; Rappa, A. Adv. Heterocyl. Chem. 1988, 44, 1.
D
dx.doi.org/10.1021/ja400051d | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX