Efficient synthesis of γ-keto sulfones by NHC-catalyzed intermolecular Stetter reaction

Article abstract of DOI:10.1021/ol301045x

The N-heterocyclic carbene-catalyzed intermolecular Stetter reaction of aldehydes with α,β-unsaturated sulfones allows the atom-economic and selective formation of γ-keto sulfones in good yields. Key to the success of this unique transition-metal-free carbon-carbon bond-forming reaction is the right choice of the NHC precursor and base. The reaction tolerates a broad range of different aldehydes.

Full text of DOI:10.1021/ol301045x

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Efficient Synthesis of γ-Keto Sulfones by
NHC-Catalyzed Intermolecular Stetter
Reaction
Anup Bhunia, Santhivardhana Reddy Yetra, Sachin Suresh Bhojgude, and
Akkattu T. Biju*
Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL),
Dr. Homi Bhabha Road, Pune -411008, India
at.biju@ncl.res.in
Received April 20, 2012
ABSTRACT
The N-heterocyclic carbene-catalyzed intermolecular Stetter reaction of aldehydes with R,β-unsaturated sulfones allows the atom-economic and
selective formation of γ-keto sulfones in good yields. Key to the success of this unique transition-metal-free carbonÀcarbon bond-forming
reaction is the right choice of the NHC precursor and base. The reaction tolerates a broad range of different aldehydes.
The Stetter reaction, the nucleophilic heterocyclic
carbene (NHC)-organocatalyzed umpolung of aldehydes
followed by their reaction with Michael acceptors, consti-
tutes a highly valuable and widely used catalytic protocol
for the synthesis of 1,4-bifunctional compounds such as
1,4-diketones, 4-ketonitriles, and 4-ketoesters, thusleading
to an unnatural functional group distance, which is diffi-
cult to realize using traditional methods.1,2 These reactions
proceed via the formation of nucleophilic acyl anion
intermediates, which can react with various activated,
polarized,3 and even electron neutral4 CÀC double bonds.
Intriguingly, however, whereas the NHC-catalyzed gen-
eration of the Breslow intermediate (A)5 and its subsequent
interception with a variety of Michael acceptors are well
documented (Scheme 1, eq 1),3 the analogous reaction
with R,β-unsaturated sulfones as electrophiles is extremely
rare, presumably due to the formation of undesired side
(1) (a) Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed. Engl.
1973, 12, 81. (b) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. (c)
Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407.
(2) For recent reviews on NHC-organocatalysis, see: (a) Bugaut, X.;
Glorius, F. Chem. Soc. Rev. 2012, 41, 3511. (b) Grossmann, A.; Enders,
D. Angew. Chem., Int. Ed. 2012, 51, 314. (c) Nair, V.; Menon, R. S.; Biju,
A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc. Rev.
2011, 40, 5336. (d) Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res.
2011, 44, 1182. (e) Hirano, K.; Piel, I.; Glorius, F. Chem. Lett. 2011, 40,
786. (f) Chiang, P.-C.; Bode, J. W. RSC Catalysis Series; Royal Society of
Chemistry: Cambridge, 2010; p 339. (g) Moore, J. L.; Rovis, T. Top. Curr.
Chem. 2009, 291, 77. (h) Phillips, E. M.; Chan, A.; Scheidt, K. A.
Aldrichimica Acta 2009, 42, 55. (i) Enders, D.; Niemeier, O.; Henseler, A.
ꢀ
Chem. Rev. 2007, 107, 5606. (j) Marion, N.; Dıez-Gonzalez, S.; Nolan,
S. P. Angew. Chem., Int. Ed. 2007, 46, 2988.
(3) For reviews, see: (a) Read de Alaniz, J.; Rovis, T. Synlett 2009,
1189. (b) Rovis, T. Chem. Lett. 2008, 37, 2. (c) Christmann, M. Angew.
Chem., Int. Ed. 2005, 44, 2632. For recent examples, see: (d) DiRocco,
D. A.; Noey, E. L.; Houk, K. N.; Rovis, T. Angew. Chem., Int. Ed. 2012,
51, 2391. (e) Fang, X.; Chen, X.; Lv, H.; Chi, Y. R. Angew. Chem., Int.
Ed. 2011, 50, 11782. (f) Um, J. M.; DiRocco, D. A.; Noey, E. L.; Rovis,
T.; Houk, K. N. J. Am. Chem. Soc. 2011, 133, 11249. (g) DiRocco, D. A.;
Rovis, T. J. Am. Chem. Soc. 2011, 133, 10402. (h) Jousseaume, T.; Wurz,
€
(4) (a) Liu, F.; Bugaut, X.; Schedler, M.; Frohlich, R.; Glorius, F.
Angew. Chem., Int. Ed. 2011, 50, 12626. (b) Bugaut, X.; Liu, F.; Glorius,
F. J. Am. Chem. Soc. 2011, 133, 8130. (c) Piel, I.; Steinmetz, M.; Hirano,
€
K.; Frohlich, R.; Grimme, S.; Glorius, F. Angew. Chem., Int. Ed. 2011,
50, 4983. (d) Biju, A. T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49,
9761. (e) Biju, A. T.; Wurz, N. E.; Glorius, F. J. Am. Chem. Soc. 2010,
132, 5970. (f) Hirano, K.; Biju, A. T.; Piel, I.; Glorius, F. J. Am. Chem.
Soc. 2009, 131, 14190. For a recent highlight on this topic, see: (g)
DiRocco, D. A.; Rovis, T. Angew. Chem., Int. Ed. 2011, 50, 7982. For a
related hydroacylation of enol ethers, see: (h) He, J.; Tang, S.; Liu, J.; Su,
Y.; Pan, X.; She, X. Tetrahedron 2008, 64, 8797.
ꢀ
N. E.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1410. (i) Sanchez-
Larios, E.; Thai, K.; Bilodeau, F.; Gravel, M. Org. Lett. 2011, 13, 4942.
(j) DiRocco, D. A.; Oberg, K. M.; Dalton, D. M.; Rovis, T. J. Am.
Chem. Soc. 2009, 131, 10872. (k) Liu, Q.; Rovis, T. Org. Lett. 2009, 11,
2856. (l) Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130,
14066. (m) Enders, D.; Han, J. Synthesis 2008, 3864. (n) Enders, D.; Han,
J.; Henseler, A. Chem. Commun. 2008, 3989. (o) Enders, D.; Bonten,
M. H.; Raabe, G. Synlett 2007, 885.
(5) For the initial report of the concept, see: Breslow, R. J. Am. Chem.
Soc. 1958, 80, 3719.
r
10.1021/ol301045x
XXXX American Chemical Society

products under basic conditions. In 1978, Stetter et al.
reported the first NHC-catalyzed addition of aldehydes to
vinyl sulfones (eq 2).6 Surprisingly, however, the product
was not the expected γ-keto sulfone but was a 1:1 mixture
of 1,4-diketone and γ-disulfone. The NHC-catalyzed um-
polung addition of aldehydes to vinyl sulfones leading to
the formation of γ-keto sulfones, the intermolecular hy-
droacyalation of R,β-unsaturated sulfones, are, to the best
of our knowledge, unknown (eq 3). Herein, we report the
NHC-catalyzed intermolecular Stetter reaction of R,β-
unsaturated sulfones leading to the formation of γ-keto
sulfones. It is important to note, however, that keto
sulfones are attractive synthetic targets, since they are
potent and selective 11β-hydroxysteroid dehydrogenase
type I inhibitors.7
Table 1. Optimization of the Reaction Conditionsa
Scheme 1. NHC-Catalyzed Stetter Reaction
Our present study commenced with the treatment of
4-chlorobenzaldehyde 1a and phenyl vinyl sulfone 2a with
the thiazolium salt 6 originally developed by Glorius et al.8
and 15 mol % of t-BuOK. Delightfully, a facile reaction
occurred leading to the formation of the γ-ketosulfone 3a
other common NHCs derived from 7À10 are far less
effective (entries 2À5). Other bases such as K2CO3,
Na2CO3, Et3N, and DBU furnished the desired product
3a in reduced yields (entries 6À9), and solvents other than
1,4-dioxane resulted in inferior reactivity and/or selectivity
(entries 10À12). Thereactionissluggish at60°C (entry 13),
and the yield of 3a was reduced considerably when the
amount of 6 and t-BuOK was reduced (entry 14). Finally,
increasing the amount of 1a to 1.4 equiv and reducing the
reaction time to 22 h improved the reactivity, with 3a
obtained in 81% yield (entry 15).10 Under the optimized
conditions, the symmetric 1,4-diketone 4a was isolated in
8% yield and no disulfone 5a was formed.
With these optimized reaction conditions in hand, we
then examined the substrate scope of this unique inter-
molecular Stetter reaction (Scheme 2). The unsubstituted
parent system worked well, and a variety of electron-
donating and -withdrawing groups at the 4-position of
the aromatic ring were well tolerated, leading to γ-keto
1
in 56% yield (based on H NMR spectroscopy, Table 1,
entry 1). Interestingly, under this condition, the undesired
side products 4a and 5a derived from the base-induced
elimination of the sulfonyl group of 3a was observed in low
yields. We believethatthekey tosuccessmightbetheuse of
a strong base, which will be mostly protonated by the
thiazolium salt 6 so that a minimum amount of free base
that might induce the elimination in 3a is present in the
reaction medium.9 Remarkably, in contrast to this NHC,
(6) (a) Stetter, H.; Bender, H.-J. Angew. Chem., Int. Ed. Engl. 1978,
17, 131. (b) Stetter, H.; Bender, H.-J. Chem. Ber. 1981, 114, 1226.
(7) (a) Trivedi, S.; Patidar, P. C.; Chaurasiya, P. K.; Pawar, R. S.;
Patil, U. K.; Singour, P. K. Der Pharma Chemica 2010, 2, 369. (b) Xiang,
J.; Ipek, M.; Suri, V.; Tam, M.; Xing, Y.; Huang, N.; Zhang, Y.; Tobin,
J.; Mansour, T. S.; McKew, J. Bioorg. Med. Chem. 2007, 15, 4396.
€
(8) (a) Piel, I.; Pawelczyk, M. D.; Hirano, K.; Frohlich, R.; Glorius,
F. Eur. J. Org. Chem. 2011, 5475. (b) Lebeuf, R.; Hirano, K.; Glorius, F.
Org. Lett. 2008, 10, 4243. See also: (c) Padmanaban, M.; Biju, A. T.;
Glorius, F. Org. Lett. 2011, 13, 5624. (d) Padmanaban, M.; Biju, A. T.;
Glorius, F. Org. Lett. 2011, 13, 98. (e) Kuhl, N.; Glorius, F. Chem.
Commun. 2011, 47, 573.
(9) For a similar observation in an intermolecular Stetter reaction,
see ref 3h.
(10) For details, see the Supporting Information.
B
Org. Lett., Vol. XX, No. XX, XXXX

that in preliminary experiments β-substituted R,β-unsatu-
rated sulfones failed to undergo this transformation under
the optimized reaction conditions.
Scheme 2. NHC-Catalyzed Synthesis of γ-Ketosulfones: Var-
iation of the Aldehyde Moietya
Scheme 3. NHC-Catalyzed Synthesis of γ-Ketosulfones: Var-
iation of the Sulfone Moietya
a The yield of the 1,4-diketone 4a is in parentheses. bReaction run
using 1.4 equiv of 1a. cReaction run using 1.0 equiv of 1a.
Further insightful experiments shed light on the mecha-
nism of this unique transformation (Scheme 4). In the
context of the widely accepted mechanistic proposal for
the benzoin and Stetter reaction,12 benzoin was subjected
to the optimized reaction conditions. This reaction returned
the desired γ-keto sulfone 3b in 58% yield (eq 4). Addition-
ally, upon quenching the reaction under optimized condi-
tions after 2 h, the 4-chlorobenzoin 11 was observed as the
major product in 64% yield along with the desired product in
35% yield (eq 5). These observations indicate the reversi-
bility of the formation of benzoin as well as the Breslow
intermediate under the present reaction conditions.
a General conditions: 2a (1.0 mmol), 1 (1.4 mmol), 6 (20 mol %),
t-BuOK (15 mol %), 1,4-dioxane (2.0 mL), 70 °C, and 22 h. Yields of
isolated products are given. bReaction was run for 30 h. cYield based on
recovered 2a. dThe product was inseparable from the corresponding
f
diketone; NMR yield given. eReaction was run for 18 h. Reaction
was run for 15 h. gReaction run on 0.5 mmol scale using 5.0 equiv of
n-propanal.
Scheme 4. Studies on the General Reaction Pathway
sulfones in 62À92% yield (3aÀi). Moreover, 3-substituted
aldehydes resulted in the smoothconversion tothe product
(3j, 3k). Although 2-substituted benzaldehydes result in
significantly lower yields in NHC-organocatalysis, 2-fluoro-
benzaldehyde and 1-naphthaldehyde still provided a
moderate yield of the corresponding product (3l, 3m).
Furthermore, 2-naphthaldehyde as well as disubstituted
aldehyde worked well (3n, 3o). Interestingly, challenging
aldehydes such as ferrocenecarboxaldehyde as well as
heterocyclic aldehydes also furnished moderate to good
yields of the desired products, further expanding the scope
of this intermolecular Stetter reaction (3pÀs).11 Addition-
ally, this novel hydroacylation reaction is not limited
to aromatic aldehydes. Gratifyingly, aliphatic aldehydes
also worked well leading to the formation of the desired
products (3tÀv) in moderate to good yields.
a Isolated yield. bDetermined by 1H NMR analysis (DMSO-d6) of
crude products using CH2Br2 as the internal standard.
The mechanistic rationale for this intermolecular Stetter
reaction may be advanced as follows (Scheme 5).13 The
reaction is initiated by the addition of NHC to aldehyde
generating the terahedral intermediate, which undergoes
proton transfer to form the nucleophilic Breslow inter-
mediate (A). Thisacylanionequivalentcan attackthevinyl
In view of these interesting results, we further investi-
gated the scope of the reaction using various alkyl sub-
stituted R,β-unsaturated sulfones (Scheme 3). Gratifyingly,
alkyl and vinyl substituents at the sulfone moiety are well
tolerated leading to the formation of γ-keto sulfones 3wÀx
in moderate to excellent yields. It is noteworthy, however,
(12) (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. (c) Li, G.-Q.; Dai, L.-X.; You, S.-L. Chem. Commun.
2007, 852. For an NHC-catalyzed process with irreversible benzoin
formation, see: (d) Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.;
Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696.
(13) For a theoretical investigation of the mechanism of the Stetter
reaction, see: Hawkes, K. J.; Yates, B. F. Eur. J. Org. Chem. 2008, 5563.
(11) With pyridine 4-carboxaldehyde, 5% of the disulfone 5a was
also isolated.
Org. Lett., Vol. XX, No. XX, XXXX
C

sulfone 2 in a concerted fashion2d,4,14,15 via the five-
membered transition state B to furnish the alkoxide inter-
mediate D. Alternatively, a stepwise pathway involving
the formation of the intermediate C can also be invoked.
Elimination of NHC from D completes the catalytic cycle
furnishing the γ-keto sulfones.
of 20 mol % 6 under basic conditions afforded the
1,4-diketone 12 in 88% yield. The reaction proceeds via
the DBU induced elimination of the sulfonyl group from
3a generating the enone intermediate, which undergoes
an intermolecular Stetter reaction with 1c leading to the
formation of 12 (Scheme 6). It should be noted that
the unsymmetrical 1,4-diketone 12 can easily be conver-
ted into 2,5-disubstituted pyrroles and furans using the
PaalÀKnorr cyclization reaction.17
Scheme 5. Proposed Mechanistic Pathways
Scheme 6. NHC-Catalyzed Synthesis of Unsymmetrical
1,4-Diketones
In conclusion, we have uncovered a transition-metal-
freeNHC-organocatalyzedintermolecular Stetter reaction
of aldehydes with R,β-unsaturated sulfones leading to the
efficient formation of γ-keto sulfones in good yields. The
product formation took place in spite of various selectivity
issues under basic conditions. Further studies on expand-
ing the scope of the reaction and exploring the synthetic
utility of R,β-unsaturated sulfones in challenging organo-
catalytic reactions are ongoing in our laboratory.
The synthetic utility of the γ-keto sulfones has been
demonstrated by the efficient NHC-catalyzed synthesis of
2,3-unsubstituted unsymmetrical 1,4-diketones.16 Thus
treatment of 3a with p-tolualdehyde 1c in the presence
(14) For an early report mentioning the concerted mechanism in an
intramolecular Stetter reaction analogous to reverse Cope elimination,
see: (a) Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284.
For the investigation of the mechanism of an intramolecular Stetter
reaction, see: (b) Moore, J. L.; Silvestri, A. P.; Read de Alaniz, J.;
DiRocco, D. A.; Rovis, T. Org. Lett. 2011, 13, 1742.
Acknowledgment. Generous financial support from
CSIR-NCL (in the form of a start-up grant for a new
faculty to A.T.B.), CSIR-New Delhi (for the award of
Junior Research Fellowship to A.B., S.R.Y., and S.S.B.) is
gratefully acknowledged. We thank Dr. P. R. Rajamohanan
(CSIR-NCL) for the NMR spectra and Ms. B. Santhakumari
(CSIR-NCL) for the HRMS data.
(15) For analogous transformations proceeding through a five-mem-
bered transition state, see: (a) Roveda, J.-G.; Clavette, C.; Hunt, A. D.;
Gorelsky, S. I.; Whipp, C. J.; Beauchemin, A. M. J. Am. Chem. Soc.
2009, 131, 8740. (b) Moran, J.; Gorelsky, S. I.; Dimitrijevic, E.; Lebrun,
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M.-E.; Bedard, A.-C.; Seguin, C.; Beauchemin, A. M. J. Am. Chem. Soc.
2008, 130, 17893.
(16) For selected reports, see: (a) Shen, Z.-L.; Goh, K. K. K.;
Cheong, H.-L.; Wong, C. H. A.; Lai, Y.-C.; Yang, Y.-S.; Loh, T.-P.
J. Am. Chem. Soc. 2010, 132, 15852. (b) Zhdankin, V. V.; Mullikin, M.;
Tykwinski, R.; Berglund, B.; Caple, R.; Zefirov, N. S.; Kozmin, A. S.
J. Org. Chem. 1989, 54, 2605. (c) Stetter, H.; Lorenz, G. Chem. Ber. 1985,
118, 1115.
(17) (a) Knorr, L. Chem. Ber. 1884, 17, 1635. (b) Paal, C. Chem. Ber.
1885, 18, 367. (c) Amarnath, V.; Anthony, D. C.; Amarnath, K.;
Valentine, W. M.; Wetterau, L. A.; Graham, D. G. J. Org. Chem.
1991, 56, 6924–6931.
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.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX