Rhodium-catalyzed tandem aldol condensation-Robinson annulation between aldehydes and acetone: Synthesis of 3-methylcyclohexenones

Article abstract of DOI:10.1016/j.tetlet.2014.09.093

A simple catalytic, redox-neutral access to 3-methylcyclohexenones has been developed via rhodium catalysis in the presence of an amine additive and Ag₂CO₃. This process utilized simple aldehydes and acetone as substrates and tolerates a variety of functional groups. Disubstituted phenols were isolated in moderate yields when Cu(OAc)₂ was employed as an oxidant.

Full text of DOI:10.1016/j.tetlet.2014.09.093

Tetrahedron Letters 55 (2014) 6399–6402
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rhodium-catalyzed tandem aldol condensation–Robinson
annulation between aldehydes and acetone: synthesis
of 3-methylcyclohexenones
Fen Wang a, Yuchen Liu a,b, Zisong Qi a, Wei Dai b, Xingwei Li a,
⇑
a Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116023, China
b School of Chemistry and Biological Sciences, Zhejiang Normal University, Jinhua 321004, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2014
Revised 12 September 2014
Accepted 19 September 2014
Available online 28 September 2014
A simple catalytic, redox-neutral access to 3-methylcyclohexenones has been developed via rhodium
catalysis in the presence of an amine additive and Ag2CO3. This process utilized simple aldehydes and
acetone as substrates and tolerates a variety of functional groups. Disubstituted phenols were isolated
in moderate yields when Cu(OAc)2 was employed as an oxidant.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Rhodium catalysis
3-Methylcyclohexenones
Phenol
Robinson annulation
Transition metal catalysis has witnessed significant contribu-
tions to the construction of C–C bonds leading to molecular com-
plexity.1 This strategy is especially useful in synthetic chemistry
when simple starting materials were utilized and the product
was accessed in a tandem process. This is facilitated by transition
metals owing to their diversified roles in sequentially mediating
intrinsically different steps.2
Cyclohexenones are known to exhibit important biological
activities as antitumor agents, food additive, and pheromones.3 In
particular, 3-methylcyclohexenones have been widely found as a
key structural motif in natural products and in pharmaceuticals.4
Conventionally, 3-methylcyclohexenones were prepared by Hage-
mann condensation and Knoevenagel condensation under rather
harsh conditions.5 Alternatively, Martinez and coworkers devel-
oped a reductive synthesis of 3-methylcyclohexenones via cycliza-
tion of heavily functionalized dihydropyrines.6 Organocatalysis has
been employed as an important method in the synthesis of 3-meth-
ylcyclohexenones, as has been reported by List7 and Wu and Lin.8
However, previously reported systems suffered from utilization of
either less readily accessible starting materials or limited substrate
scope. For example, while Wu and Lin have demonstrated the
important organocatalytic synthesis of such products starting from
an aldehyde and acetone under mild conditions,8 the aldehyde
seems limited to electron-poor ones since lower yields were
obtained for those bearing electron-donating groups. Metal-
mediated/catalyzed synthesis of 3-methylcyclohexenones has been
reported, but only in a few examples. Gagosz reported a two-step
synthesis of 3-methylcyclohexenones via Au-catalyzed cyclization
of alkene-functionalized propargyl acetate followed by base treat-
ment.9 Lanthanide complexes are known as viable catalysts for
the synthesis of 3-methylcyclohexenones starting from enones
and ketones.10 Despite the progress, it is necessary to develop
new methods for the efficient synthesis of 3-methylcyclohexenon-
es, preferentially starting from simple substrates.
During our studies of Rh(III)-catalyzed C–H activation/coupling
reactions, we found that in many cases Rh(III) complexes exhibited
quite unique properties as a Lewis acid.11 As a continuation of our
interest in Rh(III) catalysis, we aim to extend coupling reactions to
systems other than C–H activation.12 We now report rhodium-cat-
alyzed synthesis of 3-methylcyclohexenones via aldol reaction-
Robinson annulation between aldehydes and acetone (Scheme 1).
We initiated our studies with the screening of the conditions for
the rhodium-catalyzed coupling of benzaldehyde with acetone
(solvent) in the presence of a primary amine with Ag2CO3 being
an oxidant (100 °C). Our initial objective was to convert the alde-
hyde functionality to an imine, a better directing group which
may allow ortho C–H activation and functionalization. To our sur-
prise, although a reaction occurred, NMR analyses of the isolated
product revealed no C–H bond activation. Instead, two equivalents
of acetone were incorporated and the product (2a) was identified
⇑
Corresponding author. Tel./fax: +86 411 8437 9737.
E-mail address: xwli@dicp.ac.cn (X. Li).
http://dx.doi.org/10.1016/j.tetlet.2014.09.093
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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F. Wang et al. / Tetrahedron Letters 55 (2014) 6399–6402
O
O
O
R
CH2O
CO2R
CO2R
CO2R
R
O
a.
O
R
CH2I2
CO2R
O
O
La(OPri)3 (20 mol%)
50 oC, 30 min
O
b.
c.
Ph
Ph
O
Lysine-Imidazole
O
2
O2N
n-pentane
O2N
O
O
OAc
OAc
1-1% Au(I), MeOH
2-K2CO3, MeOH
K2CO3, MeOH
d.
Ph
OMe
Ph
Ph
Scheme 1. Access to 3-methylcyclohexenones.
Table 1
Optimization studiesa,b
[RhCp*(MeCN)3](SbF6)2
(4.5 mol%)
O
+
Ph CHO
+
Ph
O
Ag2CO3 (2 equiv)
PhCH(Me)NH2 (1.2 equiv)
120 oC, 24 h
Ph
O
1
2a
3a
Entry
Change from standard conditions
Yield (%)
2a
3a
1
2
3
4
5
6
7
None
76
nd
<5
65
nd
10
40
5
74
71
10
69
40
42
No Rh(III) catalyst was used
80 °C
100 °C
No Ag2CO3 was used
PhCH(Me)NH2 (0.2 equiv)
14 h
a
Standard conditions: benzaldehyde (0.3 mmol), [RhCp⁄(MeCN)3](SbF6)2 (4.5 mol %),
a-methylbenzylamine (0.36 mmol),
Ag2CO3 (0.6 mmol), acetone (3 mL), 120 °C, 24 h.
b
Isolated yield after column chromatography.
as a disubstituted cyclohexenone on the basis of NMR spectroscopy
and mass spectrometry (Table 1). Screening studies indicated that
Ag2CO3 is necessary because when it was omitted, the aldol con-
densation product (3a) was obtained as the major one (Table 1,
entry 5). Thus the Ag2CO3 is probably best described as a base addi-
tive. The rhodium catalyst also proved necessary because in the
absence of the catalyst, 3a was also detected as the major product
(entry 2). Although PhCH(Me)NH2 is not incorporated, it is neces-
sary in a stoichiometric amount because lowering its amount to
20 mol % only afforded 2a in 10% yield (entry 6). The reaction tem-
perature has some effects; increasing the temperature to 120 °C
gave rise to a slightly increased yield, but lowering the tempera-
ture to 80 °C afforded the aldol condensation side product 3a as
the major one (entries 1, 3 and 4). In contrast, when the rhodium
catalyst was replaced by other Lewis acid such as In(OTf)3 and
Zn(OTf)2, no desired reaction occurred. Thus the optimal condi-
tions consist of the following parameters (entry 1): benzaldehyde,
Ag2CO3 (2 equiv), PhCH(Me)NH2 (1.2 equiv), RhCp⁄(MeCN)3]
(SbF6)2 (4.5 mol %), and acetone (solvent) at 120 °C for 24 h.13
With the establishment of the optimized conditions, we next
explored the scope and limitation of this transformation (Table 2).
A variety of benzaldehydes bearing electron-donating (2e, 2g, 2h,
and 2i), -withdrawing (2b and 2f), and halogen (entry 2c, 2d, and
2j) groups at the meta and para positions underwent smooth
coupling with acetone in consistently good yields (45–76%). The
presence of halogen substituent should readily allow further func-
tionalization of the coupled products. In contrast, ortho substitu-
ents have significant influence on the reactivity. o-Tolualdehyde
reacted with poor efficiency and selectivity, and no analytically
pure product could be isolated. In contrast, o-chlorobenzaldehyde
coupled to give the desired enone 2j in 45% isolated yield. The reac-
tion seems limited to acetone and switching to 3-pentanone only
gave rise to poor conversion, indicative of the limitation of this sys-
tem. Besides using protio acetone, acetone-d6 is also applicable and

F. Wang et al. / Tetrahedron Letters 55 (2014) 6399–6402
6401
Table 2
Substrate scopea,b
[RhCp*(MeCN)3](SbF6)2
(4.5 mol%)
O
Ar CHO
+
Ag2CO3 (2 equiv)
PhCH(Me)NH2 (1.2 equiv)
120 oC, 24 h
Ar
O
1
2
O
O
O
O
O
F
O2N
Cl
2a, 76%
2b,
2d
59%
70%
2c,
2g,
2k,
61%
62%
64%
MeO
O
O
O
O
O
O
MeO
Me
F3C
Me
2e,
2f
, 64%
71%
2h, 53%
2l, 68%
Cl
O
O
S
2i, 60%
2j,
45%
66%
O
O
O
O
O
O
S
O
S
2m,
64%
2n,
2o,
73%
2p, 71%
N
2q
, 72%
a
Reaction conditions: aldehyde (0.3 mmol), [RhCp⁄(MeCN)3](SbF6)2 (4.5 mol %),
a-methylbenzylamine (0.36 mmol),
Ag2CO3 (0.6 mmol), acetone (3 mL), 120 °C, 24 h.
b
Isolated yield after column chromatography.
the product 2e-d8 was isolated in a slightly lower yield (Eq. 1).
Significantly, the aldehyde is not limited to benzaldehydes, and
heteroaryl aldehydes such as 2- and 3-furaldehydes and 2- and
3-thenaldehydes are well tolerated under the standard conditions,
with the yield of the products comparable to those for
benzaldehydes.
have independently studied the oxidation of cyclohexanones or
their imines to the corresponding phenols or anilines. In particu-
lar, Stahl applied palladium catalysis to the aerobic oxidation of
cyclohexanones to phenols under operationally simple condi-
tions,14 with cyclohexenone being an intermediate. Therefore,
we reasoned that these conditions could be viable for the
CD3
D
D
D
O
standard conditions
50%
CHO
MeO
+
ð1Þ
O
D3C
CD3
D
D
MeO
1e
2e
-d8 (> 95% D)
We felt that under suitable conditions, the cyclohexenone
product could be oxidized to a phenol, a highly useful building
block in synthesis. In fact, Stahl,14 Li,15 Deng,16 and Yoshikai17
oxidative derivatization of our cyclohexenone product. Indeed,
under Stahl’s conditions,14a enone 2a was smoothly oxidized to
phenol 4a in 72% yield (Eq. 2).

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F. Wang et al. / Tetrahedron Letters 55 (2014) 6399–6402
Table 3
by a Rh(III) complex and an amine. A broad scope of aldehyde sub-
Oxidative synthesis of phenolsa,b
strate has been defined. Importantly, the condensation products
can be readily converted to a disubstituted phenol under palla-
dium-catalyzed aerobic oxidation or in a one-pot fashion with
Cu(OAc)2 as an oxidant under rhodium catalysis. This method
may find applications in the synthesis of related complex
structures.
[RhCp*(MeCN)3](SbF6)2
(4.5 mol%)
CHO
O
+
R
Cu(OAc)2 (4 equiv)
PhCH(Me)NH2 (1.2 equiv)
120 oC, 24 h
Ar
OH
OH
1
4
Acknowledgments
This work was supported by the Dalian Institute of Chemical
Physics, Chinese Academy of Sciences and the National Natural
Science Foundation of China (Grant No. 21272231).
OH
OH
Cl
Br
4b
4c, 47%
4a, 62%
, 43%
a
Reaction conditions: aldehyde (0.3 mmol), [RhCp⁄(MeCN)3](SbF6)2 (4.5 mol %),
Supplementary data
a-methylbenzylamine (0.36 mmol), anhydrous Cu(OAc)2 (1.2 mmol), acetone (3 mL),
120 °C, 24 h.
b
Isolated yield after column chromatography.
Supplementary data (representative synthetic procedure,
analytical data of products, and NMR spectra) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2014.09.093.
Me
Me
Pd(TFA)2 (5 mol%)
2-DMAP (6 mol%)
TsOH (12 mol%)
DMSO, O2 (1 atm)
80 oC, 24 h
References and notes
ð2Þ
OH
O
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4a
72%
2a
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Although the oxidative derivatization of 2a provides an efficient
synthetic method to access disubstituted phenols, it would be
more step-economic to directly access such phenols via a single
step process. To achieve this goal, we replaced the Ag2CO3 additive
with Cu(OAc)2 (4 equiv) because it is widely used in oxidative cou-
pling reactions.12a,18 Under otherwise the same conditions, the
coupling of benzaldehydes with acetone did afford the desired
phenol as the major product (Table 3) although the reaction suf-
fered from limited selectivity and the yields of the phenols were
moderate (43–62%). To gain insight into this oxidation process,
enone 2a was allowed to react with Cu(OAc)2 in the absence of
any rhodium catalyst. However, essentially no desired phenol
was detected, indicating that the rhodium catalyst played an
important role in the oxidative aromatization of cyclohexanone.
Several experiments have been performed to probe the mecha-
nism. Subjection of the aldol condensation product 3a to the reac-
tion conditions led to formation of product 2a in 72% yield.
Therefore enone 3a is a likely intermediate leading to the forma-
tion of the final product. KIE experiments have been performed
to explore the cleavage of the C–H bond in acetone. The reaction
of 3a and an equimolar mixture of acetone and acetone-d6 gave a
mixture of 2a and its isotopomers. 1H NMR analysis of this product
mixture gave KIE = 0.92, and this small value indicates that the
cleavage of the C–H bonds is probably not involved in the rate-
limiting step.
3. (a) Pette, D.; Staudte, H. W.; Vrbová, G. Naturwissenschaften 1972, 59, 469; (b)
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13. Synthesis of 2a: Benzaldehyde (31.8 mg, 0.3 mmol), Ag2CO3 (165.5 mg,
0.6 mmol),
a
-methylbenzylamine
(43.6 mg,
0.36 mmol),
and
25 mL
[RhCp⁄(MeCN)3](SbF6)2 (11.2 mg, 4.5 mol %) were weighed into
a
pressure tube, to which acetone (3 mL) was added. The reaction tube was
sealed, and the mixture was stirred at 120 °C for 24 h. The mixture was filtered
through Celite, followed by removal of volatiles under reduced pressure.
Purification was performed by flash column chromatography on silica gel using
EtOAc and petroleum ether.
A proposed mechanism involves a non-metal-catalyzed aldol
reaction of aldehyde and acetone. Subsequent Robinson annulation
was catalyzed by rhodium, which acts as a Lewis acid that activates
enone 3a. In this process, acetone is likely activated to an enamine
via condensation with PhCH(Me)NH2. The role of Ag2CO3 is unclear
at this time, but it may also facilitate the activation of the enone
intermediate.
In summary, we have developed a catalytic method to access
3-methylcyclohexenones via the condensation between acetone
and simple aldehydes. This process was collaboratively catalyzed
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