Synthesis of functionalized resorcinols by rhodium-catalyzed [5+1] cycloaddition reaction of 3-acyloxy-1,4-enynes with CO

Article abstract of DOI:10.1039/c0cc00747a

A novel [5+1] type carbonylative cycloaddition reaction has been developed using a Rh complex as catalyst. This reaction can convert readily available 3-acyloxy-1,4-enynes and CO to a wide range of functionalized resorcinols in good yields. A mechanism involving Rh-catalyzed cyclocarbonylation of 3-acyloxy-1,4-enynes accompanied by a 1,2-acyloxy shift is proposed for the present [5+1] type cycloaddition reaction. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c0cc00747a

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Synthesis of functionalized resorcinols by rhodium-catalyzed [5+1]
cycloaddition reaction of 3-acyloxy-1,4-enynes with COw
a
b
b
b
a
´
Celia Brancour, Takahide Fukuyama,* Yuko Ohta, Ilhyong Ryu,* Anne-Lise Dhimane,
Louis Fensterbank*a and Max Malacria*a
Received 3rd April 2010, Accepted 8th June 2010
First published as an Advance Article on the web 29th June 2010
DOI: 10.1039/c0cc00747a
A novel [5+1] type carbonylative cycloaddition reaction has
been developed using a Rh complex as catalyst. This reaction
can convert readily available 3-acyloxy-1,4-enynes and CO to a
wide range of functionalized resorcinols in good yields. A
mechanism involving Rh-catalyzed cyclocarbonylation of
3-acyloxy-1,4-enynes accompanied by a 1,2-acyloxy shift is
proposed for the present [5+1] type cycloaddition reaction.
(1)
[5+1] type cycloaddition reaction. By using gold and platinum
salts, 3-pivaloyloxy-1,4-enyne 1a was respectively recovered or
converted to cyclopentenone 4a.5,10–12 We were then pleased
to find that rhodium catalysis13 could lead to the desired
carbonylated compound 3a (Table 1). With [Rh(OAc)2]2 and
[RhCl2Cp*]2, conversion was insufficient and cyclopentenone
4a was formed as a byproduct (entries 1 and 2). The formation
of 4a was supressed by using [RhCl(CO)2]2 catalyst and the
yield of 3a was slightly increased (entry 3), whereas unidentified
polymeric materials were formed as byproducts. When the
reaction was carried out using dichloromethane as a solvent,
yield of 3a was further increased (entry 5). While the reaction
under 80 atm of CO gave 3a in 76% yield, 3a was obtained in
moderate yield under 20 atm of CO (entries 6 and 4). Other
rhodium complexes, such as Rh6(CO)16, Rh(acac)(CO)2, and
RhCl(PPh3)3, did not catalyze the present carbonylation
reaction.
For the past two decades, metal-catalyzed 1,n-enyne
rearrangements have proven to be an exquisite method for
access to a wide variety of carbo- and heterocyclic systems.1
While the parent cycloisomerization mode of reactivity has
thoroughly demonstrated its synthetic potential, the introduction
of intermolecular events such as carbonylation,2 and other
incorporations,3 in the process greatly expand the scope and
value of these reactions, as demonstrated by recent examples
of metal-catalyzed multi-component cycloaddition.4 In this
context, we focused our attention on the known Ohloff–
Rautenstrauch rearrangement,5 which originally consisted of
the Pd(II)- or the Pt(II)-catalyzed rearrangement of 1-ethynyl-
2-propenyl acetates 1 to give cyclopentadienyl acetates via
1,2-acyloxy migration.
We anticipated that under carbonylation conditions with
the proper metal complex, CO might be intercepted to give
transient 2, which would eventually lead to the aromatic
system of resorcinols 3, and found that [RhCl(CO)2]2 effectively
catalyzed a new [5+1] cycloaddition reaction leading to
resorcinols (eqn (1)). Resorcinols are valuable compounds
with important bioactivity,6 demonstrating, for instance,
efficient DNA cleavage properties under oxidative conditions,
as well as antibacterial activities.7 To the best of our knowledge,
transformation of 3-acetoxy-1,4-enynes into aromatics based
on a metal-catalyzed [5+1] carbonylative sequence has yet to
be achieved.8,9
With the optimal reaction conditions in hand, we set out to
define the scope of the present [5+1] type resorcinol synthesis
(Table 2). Cyclization was also successful when an ester group
was changed from pivalate to acetate (entry 2). The reaction
Table 1 Optimization of the Rh-catalyzed [5+1] cycloadditiona
We initiated our study with precursor 1a in the hope
of obtaining 4-phenyl substituted resorcinol derivative 3a.
Incorporation of carbon monoxide was examined in the
presence of a variety of transition metal catalysts for the envisaged
Entry Rh cat.
Solvent CO (atm) Yield of 3ab
1
2
3
4
5
6
[Rh(OAc)2]2 (2.5 mol%) PhMe
50
50
50
20
50
80
30%c
40%d
45%
41%
66%
76%
[RhCl2Cp*]2 (2.5 mol%) PhMe
[RhCl(CO)2]2 (2.5 mol%) PhMe
[RhCl(CO)2]2 (2.5 mol%) DCM
[RhCl(CO)2]2 (2.5 mol%) DCM
[RhCl(CO)2]2 (2.5 mol%) DCM
a
´
Institut Parisien de Chimie Moleculaire (UMR CNRS 7201) - FR
2769 UPMC univ Paris 06, C. 229, 4 place Jussieu, 75005 Paris,
France
b Department of Chemistry, Graduate School of Science,
Osaka Prefecture University, Sakai, Osaka 599-8531, Japan.
E-mail: fukuyama@c.s.osakafu-u.ac.jp; Fax: +82-72-254-9695;
Tel: +82-72-254-9743
a
Reactions were performed on a 0.5 mmol scale with 0.05 M of
b
substrate concentration for 5 h at 80 1C. Isolated yields after flash
chromatography on SiO2. Recovery of 1a: 53%. 4a was formed in
30% yield.
c
d
w Electronic supplementary information (ESI) available: Experimental
details, spectral data and NMR spectra. See DOI: 10.1039/c0cc00747a
ꢀc
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was compatible with the varying electronic effects of substituents
on the aromatic ring; thus, functional groups such as trifluoro-
methyl (entry 3) and methoxy groups (entry 4) could be
implemented. Enyne 1e, having a 4-methyl group, also worked
well to give 3-methyl-4-phenyl substituted resorcinol derivative
3e (entry 5). Enyne 1f, having a tertiary acetoxy unit, gave 3f
(entry 6). In this case we used 1f as a mixture of E/Z (1 : 0.22).
However, it turned out that the Z isomer was not reactive
towards the carbonylative cyclization.
Table 2 [RhCl(CO)2]2-catalyzed synthesis of functionalized resorcinol
derivatives by [5+1] cycloadditiona
Entry Substrate 1
Product 3
Yield (%)b
We then investigated the reaction of alkylated enynes. The
present catalytic system was tolerant and comparable in
reactivity of 1-ethynyl-2-propenyl pivalates bearing alkyl
chains. Me, n-Bu, and i-Pr substitution of alkene allowed
the formation of the desired products in 58 to 74% yield
(entries 7–9).
1
1a
1b
3a 76
2
3
3b 67
Saponification of the products to the corresponding
resorcinols was simple to achieve. For example, 3h was
saponified by 2 M NaOH to provide the corresponding
resorcinol that had been reported to inhibit tyrosinase activity14
(see Electronic Supplementary Informationw). The reaction of
an enyne 1k gave 3k in moderate yield, which can lead to the
natural product olivetol15 (entry 11). In this case, however,
formation of non-carbonylated product competed to give
cyclopentenone 4k in 19% yield.
1c
1d
3c 56
4
3d 56
While a detailed mechanism awaits further study, based on
our results, we suggest plausible reaction pathways in
Scheme 1. We postulate that the reaction is initiated by
electrophilic activation of the alkyne moiety of 1 by the
rhodium catalyst leading to p-complex A.16 The nucleophilic
5
6
1e
1f
3e 53
attack by the carboxylate would occur to generate
a
zwitterionic vinyl-rhodium species B, which would undergo
ring-closure accompanied by 1,2-acyloxy migration to give
rhodacyclohexadiene C (path a). Carbonyl insertion to give
D,17 followed by reductive elimination would give the transient
intermediate 2, which would undergo aromatization leading to
3. An alternative path for resorcinols 3 would include the
formation of ketene F18 and subsequent 6p-electrocyclization
(path b).19
3f 68c
7
8
1g
1h
3g 58
3h 64
9
1i
3i 74
10
1j
lk
3j 58
3k 37
11d
4k 19
Scheme 1 Proposed mechanistic pathway.
a
Reactions were performed on a 0.5 mmol scale in 0.05–0.016 M of
dichloromethane at 80 atm of CO except for entry 6 (50 atm).
We attempted to trap the ketene intermediate by MeOH.
When the carbonylation of enyne 1d was carried out in the
presence of MeOH (20 equiv.), the envisaged methyl ester 5
was obtained in 16% yield together with resorcinol derivative
b
c
Isolated yields by silica gel chromatography. NMR yield from E
d
isomer. Reaction time: 15 h.
ꢀc
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3d and non-carbonylated cyclopentenone (eqn (2)). The
methyl ester 5 is likely to be formed by nucleophilic trapping
of ketene intermediate F by MeOH, thus this might support
the above mechanism.20
8 For Pd-catalyzed cyclocarbonylation of enynols leading to 6-mem-
bered ring lactones, see: H. Cao, W. J. Xiao and H. Alper, J. Org.
Chem., 2007, 72, 8562.
9 Recent examples of transition metal-catalyzed carbonylative [5+1]
cycloaddition of cyclopropane derivatives. (a) M. Murakami,
K. Itami, M. Ubukata, I. Tsuji and Y. Ito, J. Org. Chem., 1998,
63, 4; (b) A. Kamitani, N. Chatani, T. Morimoto and S. Murai,
J. Org. Chem., 2000, 65, 9230; (c) T. Kurahashi and A. de Meijere,
Synlett, 2005, 2619.
(2)
10 Insertion of CO in Pt–alkyl bonds has been reported:
(a) A. Sivaramakrishna, B. C. E. Makhubela, F. Zheng, H. Su,
G. S. Smith and J. R. Moss, Polyhedron, 2008, 27, 44. It has also
been proposed as a ligand of PtCl2 that increases the electrophilic
In summary, we have developed a Rh-catalyzed [5+1] type
synthetic procedure for the efficient preparation of functionalized
resorcinols, including biaryl derivatives from readily available
3-acyloxy-1,4-enynes and CO. Further elaborations of the
reaction toward target-oriented synthesis and asymmetric
synthesis of biaryl derivatives are underway in our labs.
This work was supported by CNRS, IUF (LF, MM),
UPMC and OPU. CB gratefully acknowledges MRES,
UPMC, le college doctoral France-Japon and OPU. IR and
TF thank JSPS/MEXT for funding.
character of the metal center, see: (b) A. Furstner, P. W. Davies
¨
and T. Gress, J. Am. Chem. Soc., 2005, 127, 8244.
11 For Pd(II)-catalyzed oxidative carbonylation, see: (a) A. Bacchi,
M. Costa, B. Gabriele, G. Pelizzi and G. Salerno, J. Org. Chem.,
2002, 67, 4450; (b) K. Kato, R. Teraguchi, S. Yamamura,
T. Mochida, H. Akita, T. A. Peganova, N. V. Vologdin and
O. V. Gusev, Synlett, 2007, 638.
12 Cyclopentenone 4a results from an isomerized cyclopentadienyl
pivaloate already observed by Toste and co-workers, see ref. 5d.
13 (a) Modern Rhodium-Catalyzed Organic Reactions, ed. P. A.
Evans, Wiley-VCH, Weinheim, 2005. For a recent review on
rhodium-catalyzed carbonylative cyclization, see: (b) M. P. Croatt
and P. A. Wender, Eur. J. Org. Chem., 2010, 19. For a recent report
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Y. Fukumoto and N. Chatani, Chem. Commun., 2010, 46, 3345.
14 D.-S. Kim, S.-Y. Kim, S.-H. Park, Y.-G. Choi, S.-B. Kwon,
M.-K. Kim, J.-I. Na, S.-W. Youn and K.-C. Park, Biol. Pharm.
Bull., 2005, 28, 2216.
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´
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16 In the case of (Z)-1f, a p-coordinated intermediate might have
difficulty in being formed because the phenyl group blocks the
rhodium catalyst approach to the alkyne moiety. Probably for this
reason, Z-isomer of 1f would not be reactive towards the present
carbonylative cyclization.
17 Carbonyl insertion into Rh–C(sp3) is also possible.
18 Examples of stoichiometric reactions of metal carbenoids with CO
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19 This mechanism is similar to the one proposed in the Dotz
¨
reaction. For reviews, see: (a) K. H. Dotz and P. Tomuschat,
¨
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¨
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20 E/Z isomerization of the vinylcarbenoid E and/or the vinylketene
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Pennington, Organometallics, 1992, 11, 255.
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This journal is The Royal Society of Chemistry 2010
5472 | Chem. Commun., 2010, 46, 5470–5472