Stereoselective synthesis of cyclohexanones via phase transfer catalyzed double addition of nucleophiles to divinyl ketones

Article abstract of DOI:10.1021/jo101713d

Functionalized cyclohexanones are formed in excellent yield and diastereoselectivity from a phase transfer catalyzed double addition of active methylene pronucleophiles to nonsymmetrical divinyl ketones.

Full text of DOI:10.1021/jo101713d

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molecular structure (Figure 1). Therefore, these natural
Stereoselective Synthesis of Cyclohexanones via
Phase Transfer Catalyzed Double Addition of
Nucleophiles to Divinyl Ketones.
products offer themselves as challenging synthetic targets
and have attracted considerable attention.5
Andrew C. Silvanus,† Benjamin J. Groombridge,†
‡
Benjamin I. Andrews, Gabriele Kociok-Kohn, and
†
€
David R. Carbery†,*
†Department of Chemistry, University of Bath, Bath BA2 7AY,
U.K, and ‡GlaxoSmithKline Medicines Research Centre,
Stevenage, Hertfordshire SG1 2NY, U.K.
FIGURE 1. Jiadifenolide 1 and jiadifenin 2.
A number of synthetic routes to functionalized cyclo-
hexanones have been be reported in recent years, underlining
the continued importance of this framework to the synthetic
community. Most notably [4 þ 2] cycloadditions,2a,6 organo-
catalyzed domino annulations,7 Rh(I)-catalyzed Pauson-
Khand,8 Pd-catalyzed intramolecular hydroalkylation,9 and
reductive tandem double Michael cascades.10
d.carbery@bath.ac.uk
Received August 31, 2010
Divinyl ketones (DVKs) are predominantly associated
with the Nazarov reaction.11 However, they also act as com-
petent double electrophiles reacting with a variety of double
nucleophiles.12 The double addition of a methylene pro-
nucleophile is well-known (Scheme 1).13
SCHEME 1. Reaction of a Malonate with a Divinyl Ketone13
Functionalized cyclohexanones are formed in excellent
yield and diastereoselectivity from a phase transfer catalyzed
double addition of active methylene pronucleophiles to non-
symmetrical divinyl ketones.
For example, Kohler reported in 1924 that dibenzylidene
acetone 3a formed meso-cyclohexanone 5a when exposed to
dimethylmalonate and NaOH. The reaction is syn-selective,
with all subsequent reports involving the use of symmetrical
diaryl DVKs, or similar pseudosymmetrical diaryl sub-
stituted ketones, forming syn-diaryl cyclohexanones.14 The
The development of single-pot reactions which allow the
rapid construction of several bonds and stereocenters remains a
considerable challenge in modern organic chemistry.1 In many
instances this strategy can offer a simple and versatile synthesis
of valuable building blocks from inexpensive starting materials.
Highly substituted cyclohexanones and the related cyclo-
hexanols, provide key skeletal components of many natural
products with significant biological and pharmaceutical
importance.2 In particular, a number of important cyclo-
hexanol natural products exist which have a quaternary
center at C-4 (Figure 1). Jiadifenolide 13 and jiadifenin 24
are highly active neurotrophins which possess such a cyclo-
hexanol motif embedded within their compact and complex
(5) For total synthesis of 2, see: (a) Cho, Y. S.; Carcache, D. A.; Tian, Y.;
Li, Y-M; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 14358.
(b) Carcache, D. A.; Cho, Y. S.; Hua, Z.; Tian, Y.; Li, Y-M; Danishefsky,
S. J. J. Am. Chem. Soc. 2006, 128, 1016.
(6) (a) Kim, W. H.; Lee, J. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2009,
131, 12576. (b) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128,
9626.
(7) (a) Pulkkinen, J.; Aburel, P. S.; Halland, N.; Jørgensen, K. A. Adv.
Synth. Catal. 2004, 346, 1077. (b) Gryko, D. Tetrahedron: Asymmetry 2005,
16, 1377. (c) Wang, J.; Ma, A.; Ma, D. Org. Lett. 2008, 10, 5425. (d) Hayashi,
Y.; Toyoshima, M.; Gotoh, H.; Ishikawa, H. Org. Lett. 2009, 11, 45.
(e) Enders, D.; Erdmann, N.; Raabe, G. Synthesis 2010, 2271.
(8) Jiao, L.; Lin, M.; Zhuo, L.-G.; Yu, Z.-X. Org. Lett. 2010, 12, 2528.
(9) Wang, X.; Pei, T.; Han, X.; Widenhoefer, R. A. Org. Lett. 2003, 5,
2699.
(10) Kamenecka, T. M.; Overman, L. E.; Ly Sakata, S. K. Org. Lett.
2002, 4, 79.
(11) (a) Pellissier, H. Tetrahedron 2005, 61, 6479. (b) Tius, M. A. Eur. J.
Org. Chem. 2005, 2193.
(12) For selected heteroatom double additions to divinyl ketones, see:
(a) Rosiak, A.; Hoenke, C.; Christoffers, J. Eur. J. Org. Chem. 2007, 4376.
(b) Radha Krishna, P.; Sreeshailam, A. Tetrahedron Lett. 2007, 48, 6924.
(c) Rosiak, A.; Frey, W.; Christoffers, J. Eur. J. Org. Chem. 2006, 4044.
(d) Rosiak, A.; Christoffers, J. Synlett 2006, 1434. (e) Reddy, D. B.; Reddy,
A. S.; Padmavathi, V. Synth. Commun. 2001, 31, 3429. (f) Brenstrum, T.;
Clattenburg, J.; Britten, J.; Zavorine, S.; Dyck, J.; Robertson, A. J.;
McNulty, J.; Capretta, A. Org. Lett. 2006, 8, 103.
(1) (a) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1. (b) Nicolaou, K. C.;
Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993. (c) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (d) Little, R. D.;
Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I. Org. React. 1995, 47,
315. (e) Ho, T. L. Tandem Organic Reactions; John Wiley: New York, 1992.
(f) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
(2) (a) Jiang, J.; Bunda, J. L.; Doss, G. A.; Chicchi, G. G.; Kurtz, M. M.;
Tsao, K.-L. C.; Tong, X.; Zheng, S.; Upthagrove, A.; K.; Samuel, K.;
Tschirret-Guth, R.; Kumar, S.; Wheeldon, A.; Carlson, E. J.; Hargreaves,
R.; Burns, D.; Hamill, T.; Ryan, C.; Krause, S. M.; Eng, W.; DeVita, R. J.;
Mills, S. G. J. Med. Chem. 2009, 52, 3039. (b) Bui, T.; Barbas, C. F.
Tetrahedron Lett. 2000, 41, 6951.
(3) Kubo, M.; Okada, C.; Huang, J.-M.; Harada, K.; Hioki, H.; Fukuyama,
Y. Org. Lett. 2009, 11, 5190.
(4) Yokoyama, R.; Huang, J.-M.; Yang, C.-S.; Fukuyama, Y. J. Nat.
Prod. 2002, 65, 527.
(13) Kohler, E. P.; Helmkamp, R. W. J. Am. Chem. Soc. 1924, 46, 1267.
DOI: 10.1021/jo101713d
r
Published on Web 10/13/2010
J. Org. Chem. 2010, 75, 7491–7493 7491
2010 American Chemical Society

Silvanus et al.
JOCNote
TABLE 1. Optimisation Studya
TABLE 2. Divinyl Ketone Substrate Scope
entry
R
Ar
product yield (%) dr 5 (anti/syn)a
entry
base
iPrNEt2
DBU
NaOMe
NaOH
KOH
solvent
time (h) yield 5b (%)
dr 5bb
1
2
3
4
5
6
7
8
Me Ph
5b
5c
5d
5e
5f
98
64
90
89
93
82
58
88
85
82b
86c
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
93:7
1
2
3
4
5
6
7
8
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
24
24
24
24
24
24
0c
-
-
91:9
nd
nd
>95:5
>95:5
71:29
75:25
86:14
>95:5
Me 4-OMeC6H4
Me 2-ClC6H4
Me 4-ClC6H4
Me 4-MeC6H4
Me 3-MeC6H4
Me 2-furyl
0c,d
11c
5c
3c
5g
5h
5i
CsOH H2O
3
19c
98
75
95
92
84
CsOH H2Oe PhMe
0.5
Me 2-pyridyl
3
nPr
Cy
Ph
Ph
5j
CsOH H2Oe CH2Cl2
0.5
0.5
0.5
0.5
9
10
11
3
9
10
11
CsOH H2Oe CH3CN
5k
5b
3
CsOH H2Oe Et2O
Me Ph
>95:5
3
CsOH H2Oe hexane
aMeasured by 1H NMR analysis of crude reaction mixture.
3
bAttempted at 85 °C for 24 h. cConducted on 5 mmol scale for 5 h.
aGeneral reaction conditions: base (10 mol %), [1 M] at 25 °C.
bMeasured by H NMR analysis of crude reaction mixture. Reaction
conversion: measured by 1H NMR analysis of crude reaction mixture.
dEnone 6a recovered in 99%. en-Bu4NBr (5 mol %) additive used.
1
c
desired cyclohexanone was observed when CsOH was uti-
lized with tetrabutylammonium bromide phase transfer
catalyst in toluene solvent (entry 6). This led to a dramatic
improvement in reaction efficiency with complete conversion
observed in under 30 min when compared with the absence
limited substrate scope and inherent symmetry of the prod-
ucts suggests a reaction of limited applicability in a stereo-
selective target-orientated context.
n
of Bu4NBr (entry 5). Application of these phase transfer
We felt the potential of this annulation had not been fully
realized regarding divinyl ketone scope and stereochemical
control.15 Indeed, similar concerns had prompted our recent
studies concerning a highly diastereoselective annulation of
nonsymmetrical DVKs and indoles.16 Herein we report
studies concerning the double addition of a range of methy-
lene pronucleophiles to nonsymmetrical DVKs. DVK 3b
was chosen as the initial substrate for examination as each
enone terminus is sterically and electronically differentiated.
Accordingly, dimethyl malonate was exposed to a range of
bases at catalytic loadings, with toluene initially examined
(Table 1).17
Organonitrogen bases were found to be largely ineffective
at catalyzing the desired reaction (entries 1-2). However,
DBU catalyzed the formation of the monoaddition product
6a (entry 2). This observation confirmed the order of the
stepwise double addition as initial intermolecular addition to
the Me-substituted enone followed by subsequent cycliza-
tion onto the Ph-substituted enone. Catalytic loadings of
sodium methoxide and hydroxide bases were also found to
be unsuccessful (entries 3-6). However, the formation of the
conditions in other common organic solvents provided no
significant improvement to either yield or reaction rate
(entries 7-10). Unexpectedly, the anti-diastereomer was
observed to form in this reaction as ascertained by 1D and
2D 1H NMR spectroscopy. Furthermore, these studies
suggested the phenyl group had adopted an axial disposition,
in contrast to the syn-selectivity reported in all diaryl systems
reported in the literature.14
With optimized reaction conditions developed, the scope
of the DVK was subsequently examined (Table 2).
The reaction of dimethyl malonate provided access to anti-
substituted cyclohexanones. In all instances, methyl-aryl
substituted DVKs reacted efficiently and with high diaste-
reoselectivity. This reaction allowed for the incorporation of
heteroaryl substitution upon the cyclohexanone ring (entries
7-8). In contrast, replacing the methyl group by a cyclohexyl
unit led to a dramatic reduction in reactivity with a slight
reduction in diastereoselectivity (entry 10). Importantly, this
reaction is amenable to being conducted on a larger scale
with a 5 mmol scale reaction forming 5b in 86% (entry 11).
The anti-diastereoselectivity of this tandem-sequence was
confirmed by X-ray crystallography of cyclohexanone 5c
which also confirmed the axial positioning of the aryl group
and equatorial disposition of the methyl group (see Support-
ing Information).
(14) There has been a single example of an anti-selective double addition
ꢀ
of dimethyl malonates to dibenzylidene acetone, see: Gomez-Bengoa, E.;
Cuerva, J. M.; Mateo, C.; Echavarren, A. M. J. Am. Chem. Soc. 1996, 118,
8553.
(15) (a) Li, J-T; Xu, W-Z; Chen, G-F; Li, T.-S. Ultrason. Sonochem. 2005,
12, 473. (b) Khurana, J. M.; Arora, R.; Satija, S. Heterocycles 2007, 71, 2709.
(c) Padmavathi, V.; Balaiah, A.; Reddy, D. B. J. Heterocycl. Chem. 2002, 39,
649. (d) Padmavathi, V.; Reddy, B. J. M.; Subbaiah, D. R. C. V.; Padmaja, A.
Indian J. Chem. B 2006, 45B, 808. (e) Padmavathi, V.; Basha, S. M.; Chinna,
D. R.; Subbaiah, V.; Reddy, T. V. R.; Padmaja, A. J. Heterocycl. Chem.
2005, 42, 797. (f) Zhang, D.; Xu, X.; Tan, J.; Liu, Q. Synlett 2010, 917.
Having assessed the scope of divinyl ketone electrophile,
this methodology was in turn examined with respect to
pronucleophile (Table 3).
A range of pronucleophiles reacted smoothly with 3b to
form cyclohexanone products in good yield. The use of
symmetrical pronucleophiles resulted in excellent yields
and diastereoselctivities (entries 1-3). In contrast, the use of
nonsymmetrical active methylene nucleophiles formed dia-
stereomeric mixtures (entries 4-7). Symmetrical methylene
pronucleophiles gave excellent levels of trans-diastereo-
selectivity. In general, more acidic pronucleophiles
€
(16) Silvanus, A. C.; Heffernan, S. J.; Liptrot, D. J.; Kociok-Kohn, G.;
Andrews, B. I.; Carbery, D. R. Org. Lett. 2009, 11, 1175.
(17) Toluene was initially chosen as solvent due to strong literature
precedent of stereoselective phase transfer-catalysed Michael reactions.
For reviews of enantioselective phase transfer catalysis, see: (a) Maruoka,
K.; Ooi, T. Chem. Rev. 2003, 103, 3013. (b) Ooi, T.; Maruoka, K. Angew.
Chem., Int. Ed. 2007, 46, 4222. (c) Lygo, B.; Andrews, B. I. Acc. Chem. Res.
2004, 37, 518.
7492 J. Org. Chem. Vol. 75, No. 21, 2010

Silvanus et al.
JOCNote
TABLE 3. Pronucleophile Scope
after extensive 1D- and 2D-NMR spectroscopy. Therefore,
complex cyclohexanones with multiple stereocenters are
rapidly accessible from divinylketone substrates.
This tandem phase-transfer catalyzed reaction has also
allowed access to contiguous quaternary centers. Reaction of
dimethyl terminated divinyl ketone 3m and dimethyl malo-
nate under the developed conditions forms cyclohexanone 5s
in good yield (Scheme 3).
SCHEME 3. Contiguous Quaternary Center Formationa
aMeasured by 1H NMR analysis of crude reaction mixture. bReaction
conducted in CH2Cl2. cMajor diastereomer isolable and relative config-
aIntermediate enone 6b isolated in 25%.
d
uration confirmed by NOESY 1H NMR spectroscopy. Minor diaste-
In this instance, the initial intermolecular Michael reaction
is found to occur at the Ph-substituted enone moiety before
continuing through a slower intramolecular Michael reac-
tion as gauged by the isolation of enone 6b.
reomer confirmed as epimeric at C-4 quaternary center as confirmed
by 1D- and 2D-1H NMR analysis. eMajor diastereomer not defined, dr
value stated.
In conclusion, an operationally simple, high-yielding and
stereoselective double Michael addition to nonsymmetrical
divinyl ketones has been developed. Substrate scope and
reactivity trends have been investigated.
Experimental Section
Representative Procedure of Phase Transfer-Catalyzed Double
Michael Reactions; Synthesis of 5b. To a vigorously stirring
solution of dimethyl malonate (665 μL, 5.3 mmol) and divinyl
ketone 3b (910 mg, 5.3 mmol) in toluene (0.5 M, 10 mL) was
FIGURE 2. Major diastereomer of 5n-p with key NOE interac-
tions.
added nBu4NBr (85 mg, 0.27 mmol, 5 mol %) and CsOH H2O
3
(79 mg, 0.53 mmol, 10 mol %) at room temperature. The
reaction mixture was allowed to stir until TLC analysis showed
complete consumption of the starting reagents (5 h). The reac-
tion was quenched by diluting with CH2Cl2 (15 mL) and passing
through a short pad of silica. The solvent was removed in vacuo
and crude material purified by flash chromatography (SiO2, 8:1
petrol/EtOAc) to afford 5b as a clear oil (1.381 g, 4.56 mmol,
86%, dr > 95:5). FTIR (film/cm-1) υma1x: 3628 (w), 2953 (s),
2849 (m), 1754 (s), 1727 (s), 1611 (m). H NMR (500 MHz,
CDCl3) δH 7.23-7.28 (3H, m), 7.04-7.06 (2H, m), 4.03 (1H, dd,
J=7.0, 4.6 Hz), 3.80 (3H, s), 3.46 (3H, s), 3.31 (1H, ddd, J =
15.8, 7.0, 0.8 Hz), 2.96 (1H, dqd, J = 12.0, 6.7, 4.5 Hz), 2.73 (1H,
ddd, J = 15.6, 4.5, 1.7 Hz), 2.68 (1H, ddd, J = 15.8, 4.6, 1.7 Hz),
2.29 (1H, ddd, J = 15.6, 12.0, 0.8 Hz), 1.10 (3H, d, J = 6.7 Hz).
13C NMR (125 MHz, CDCl3) δC 209.8, 170.8, 169.7, 140.4,
128.7, 128.3, 127.6, 61.7, 52.3, 51.9, 46.3, 45.5., 43.9, 32.6, 18.8.
HRMS (ES) calcd for C17H20O5 (m/z M þ Hþ): 305.1389.
Found 305.1373.
demonstrated lowered reactivity, presumably a reflection of
reduced nucleophilicity of the respective conjugate base as
exemplified by the double addition of a β-keto ester pronucleo-
phile (entry 5). Full conversion in this instance took 48 h
compared to the short reaction times with malonate and mal-
onitrile pronucleophiles (entries 1-2). The major isomers of
5n-p were isolated after chromatography with the relative
configuration confirmed by 1H NOESY spectroscopy (Figure 2).
Efforts have been made to form three stereocenters by
employing trisubstututed divinyl ketones (Scheme 2).
SCHEME 2. Formation of Three Stereocentres
Acknowledgment. The authors are grateful to the EPSRC
and GSK for studentship funding (ACS).
Divinyl ketone 3l was observed to offer significantly
reduced reactivity when compared to the corresponding
disubstituted system 3b. Ultimately, only two diastereomers
from a possible four were observed after 30 h and were iso-
lated in 63%, with the major anti,anti-diastereomer deduced
Supporting Information Available: Experimental proce-
dures, compound characterization data, and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 21, 2010 7493