Platinum-catalyzed reductive coupling of activated alkenes under hydrogenation conditions

Article abstract of DOI:10.1016/j.tetlet.2008.07.117

The Pt complex generated from PtCl₂, PR₃, and SnCl₂ catalyzes the reductive coupling of activated alkenes under environmentally benign hydrogenation conditions. Various bis-enones participated in the intramolecular cycliza

Full text of DOI:10.1016/j.tetlet.2008.07.117

Tetrahedron Letters 49 (2008) 5785–5788
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Platinum-catalyzed reductive coupling of activated
alkenes under hydrogenation conditions
*
Harim Lee, Min-Soo Jang, Jong-Tai Hong, Hye-Young Jang
Division of Energy Systems Research, Ajou University, Suwon 443-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The Pt complex generated from PtCl2, PR3, and SnCl2 catalyzes the reductive coupling of activated alkenes
under environmentally benign hydrogenation conditions. Various bis-enones participated in the intramo-
lecular cyclization, forming the desired cyclization products in moderate to good yield. Intermolecular
reductive coupling of the enone and the aldehyde provided the coupling product in good yield. This
methodology illustrates the first use of platinum complexes in hydrogen-mediated couplings of activated
alkenes.
Received 24 June 2008
Revised 14 July 2008
Accepted 22 July 2008
Available online 25 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Transition metal-catalyzed reductive couplings have been
widely investigated due to their versatile applications in the syn-
thesis of biologically active compounds.1 Among reductive cou-
pling protocols, Krische and co-workers have reported Rh- and
Ir-catalyzed reductive coupling involving hydrogen as a terminal
reductant.2,3 In contrast to commonly used reductants such as
silane, borane, and alane, hydrogen is a mild hydride source pro-
viding high selectivity of coupling products and functional group
tolerance. Moreover, due to the environmentally benign nature of
hydrogenation, the hydrogen-mediated reductive coupling has
received much interest.
reactivity of PtCl2 with phosphine ligands toward the reductive
cyclization of bis-enones was observed. In this account, we are
pleased to report the platinum complex-catalyzed reductive cycli-
zation of bis-enones, and the intermolecular reductive coupling of
the enone and the aldehyde under hydrogenation conditions.
Noticeably, this is the first account to present the hydrogen-medi-
ated cyclization of bis-enones.
Initially (2E,7E)-1,9-diphenylnona-2,7-diene-1,9-dione 1a was
subjected to reductive cyclization conditions using a platinum
complex generated in situ by mixing PtCl2 (5 mol %), PPh3
(5 mol%), and SnCl2 (25 mol %) in dichloroethane under 1 atm of
Despite the extensive studies regarding the hydrogen-mediated
reductive coupling of unsaturated systems containing alkenes,
alkynes, and carbonyls, the reductive cyclization of bis-enones
under hydrogenation conditions (Michael addition) remains chal-
lenging.1g,4,5 Considering the benefits of such cyclizations in the
synthesis of natural products and pharmaceutically useful building
blocks, investigations into new catalytic systems for the reductive
cyclization of bis-enones under mild and ecologically benign
hydrogenation conditions are vital.
H2 (Table 1, entry 1). The desired a,b-coupling product 1b was
observed in 76% yield as a mixture of cis and trans isomers (cis:
trans = 1:2.8). While most reductive cyclizations of bis-enones
have provided the b,b-coupling product in the presence of reduc-
tants such as SmI2, Bu3SnH, Mg, and R2Zn, the hydrogen-mediated
cyclization affords the
a,b-coupling product similar to Co- and
In-catalyzed reductive cyclizations of bis-enones using silane and
Among transition metal complexes, PtCl2 with SnCl2 has exhib-
ited excellent activity in hydrogen-mediated processes such as
hydroformylation.6 Recently, Pt-catalyzed hydrogen-mediated
reductive cyclizations of diynes and enynes have been reported.7
To conduct these cyclizations, platinum complexes possessing
Table 1
Optimization of hydrogen-mediated reductive cyclizations of 1a
Pt complex
SnCl2 (25 mol%)
COPh
COPh
PhOC
PhOC
H2 (1 atm)
80 ºC
the N-heterocyclic carbene (NHC) ligand, a well-known
r-donor
with SnCl2, are required. Despite the remarkable activity of Pt–
NHC complexes in these reductive cyclizations, Pt–NHC has shown
no activity toward bis-enones under the same hydrogenation
conditions. While we were screening Pt complexes with various
phosphine ligands for the reaction of activated alkenes, the novel
Dichloroethane (0.1M)
1a
Pt complex
1b
Entry
Ligand
Yield (%) (cis:trans)
1
2
3
4
5
PtCl2 (5 mol %)
PtCl2 (5 mol %)
PtCl2 (5 mol %)
PtCl2 (5 mol %)
PtCl2 (5 mol %)
PPh3 (5 mol %)
76 (1:2.8)
66 (1:2.6)
98 (1:2.0)
69 (1:3.5)
42 (1:4)
P(Ph-pOMe)3 (5 mol%)
P(Ph-pCF3)3 (5 mol %)
P(Ph-F5)3 (5 mol %)
P(Ph-pCF3)3 (10 mol%)
* Corresponding author. Tel.: +82 31 219 2555; fax: +82 31 219 1615.
E-mail address: hyjang2@ajou.ac.kr (H.-Y. Jang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.117

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H. Lee et al. / Tetrahedron Letters 49 (2008) 5785–5788
organocatalyzed reductive cyclizations of enone–enal using the
Hantzsch ester.1g,4,5,8
PtCl2 (5 mol%)
P(Ph-pCF3)3 (5 mol%)
SnCl2 (25 mol%)
H
R
COPh
COPh
Generally, electronic properties of ligands are known to affect
the reaction yield as well as selectivity. Thus, electron rich phos-
phines such as P(Ph-pOMe)3, and electron deficient phosphines
such as P(Ph-pCF3)3 and P(Ph-F5)3 were utilized for the reductive
cyclization of 1a. Different electronic properties of the phosphine
ligands did affect the yield. The platinum catalyst involving P(Ph-
pOMe)3 afforded the reductive cyclized product 1b in 66% (Table
1, entry 2), a somewhat lower yield than that of the Pt complex
with PPh3. Employing P(Ph-pCF3)3 improved the catalytic activity
of the Pt complex to provide 1b in 98% (Table 1, entry 3). In the
presence of P(Ph–F5)3, which has more fluorides than P(Ph–
pCF3)3 and is expected to be more electron deficient, the product
yield is diminished to 69%. In terms of the diastereoselectivity,
the cis:trans ratio was observed from 1:2.0 to 1:3.5, depending
PhOC
D
PhOC
D2 (1 atm)
80 ºC
Dichloroethane (0.1M)
1a
1b
deuterio-
R = D (~ 74%)
H (~ 26%)
Scheme 2. Deuterium labeling experiment.
ketone out of the ring (74%). The extent of deuterium incorporation
at the b-position of the ketone in the ring was not determined by
NMR or Mass spectrometry.11 Based on the deuterium labeling
result, the following proposed mechanism which involves hydro-
metalation of the platinum-deuteride to the alkene can be
supported.
on the phosphine ligand. The strong
r-donor N-heterocyclic car-
bene (NHC) was examined for the reductive cyclization of 1a using
Pt(NHC)(allyl)Cl with SnCl2, which previously demonstrated an
excellent reactivity in the hydrogenative cyclization of diynes
and enynes.7 However, Pt(NHC)(allyl)Cl with SnCl2 did not afford
the reductive cyclization product under hydrogen, confirming that
the platinum complex, along with the electron deficient phosphine,
promoted the formation of 1a.
In addition to the electronic effects, the stoichiometry of the
phosphine ligands affects the catalytic activity of the Pt complex
in this transformation. As shown in entry 5 of Table 1, the Pt com-
plex with 10 mol % of P(Ph–pCF3)3 affords product 1b in 42% yield
with the 1:4 cis:trans ratio. Adding 10 mol % of phosphine to
5 mol % of PtCl2 might retard reactivity of the catalyst while favor-
ing trans product formation. As an optimal catalyst, the combina-
tion of 5 mol % of PtCl2, 5 mol % of P(Ph–pCF3)3, and 25 mol % of
SnCl2 was chosen for the hydrogen-mediated intra- and intermo-
lecular coupling of activated alkenes.
SnCl2 has been utilized not only as a co-catalyst in hydroformyl-
ation but also as a reductant.6,9 To identify the role of SnCl2, the fol-
lowing control experiments were performed. In the absence of
SnCl2, a mixture of PtCl2 and P(Ph–pCF3)3 was used for the hydro-
gen-mediated cyclization of bis-enone 1a to form product 1b in 6%
yield (Scheme 1). Under the optimized cyclization conditions
omitting hydrogen, compound 1a was not converted to product
1b, yet cycloisomerization product 1c was formed in 13% yield
(Scheme 1).10 Based on these results, SnCl2 acts not as a reductant
but as a co-catalyst to activate the Pt complex.
A plausible mechanism for the reductive cyclization is the fol-
lowing proposed catalytic cycle (Scheme 3). Based on a previously
reported mechanism of platinum catalyzed hydrogen-mediated
reductive cyclizations, the catalytic cycle begins with the forma-
tion of LnPtH(SnCl3) from PtCl2, phosphine, and SnCl2 in the pres-
ence of hydrogen.7,12 The Pt complex reacts with hydrogen to
form the dihydrido-platinum (IV) complex which undergoes facile
reductive elimination to afford LnPtH(SnCl3).13 The hydrido plati-
À
num complex possessing SnCl3 is catalytically competent in
hydrogenative processes such as hydroformylation.4b,12,14 Subse-
quent hydrometalation of the alkene by LnPtH(SnCl3) affords inter-
mediate I where the coordination of the platinum metal ion is not
strong enough toward the pendant alkene, resulting in cis and
trans mixture of cyclized intermediate II. Intermediate II under-
goes oxidative addition with the incoming hydrogen, followed by
reductive elimination, forming the cyclized product with the
concomitant generation of LnPtH(SnCl3).
To explore the scope of the substrates, a variety of bis-enones
(1a–5a) and enone 6a were evaluated under hydrogen-mediated
reductive coupling conditions (Table 2). Using the optimized
conditions from Table 1, aromatic bis-enone 2a derived from suc-
cinaldehyde underwent reductive cyclization, affording the
5-membered ring 2b as a mixture of cis and trans isomers (1:1)
in 71% yield (entry 2). Aromatic bis-enones 3a possessing elec-
tron-donating groups participated effectively to provide cyclized
product 3b in 91% yield (entry 2). In the case of bis-enone 4a, hy-
dride addition occurs at the b-position with respect to the phenyl
ketone as well as the b-position with respect to the methyl ketone
(4:1 ratio). The combined yields of 4b and 4c were 72% with a 1:1
cis:trans ratio, while the methyl-substituted bis-enone 5a gave a
59% yield with the 1:1 cis:trans ratio as well. In the case of the
bis-enoate containing the ethyl ester and oxygen tethered aro-
matic bis-enone, the alkene reduction occurred without cyclization
under the hydrogenation conditions. As an intermolecular coupling
example, enone 6a was tested. The Pt catalysts with various phos-
phine ligands did not promote reductive dimerization of 6a,
providing instead simple reduction products. However, in the
presence of aldehyde 6b, the optimized catalyst for the reductive
cyclization involving P(Ph-pCF3)3 afforded 6c in 50% yield. Under
these conditions, employing electron rich phosphine P(Ph–pOMe)3
can increase the yield of intermolecular coupling up to 83%.
In summation, the first hydrogen-mediated reductive cycliza-
tion of aromatic and aliphatic bis-enones has been presented.
The desired cyclized products were formed in good yield with
modest diastereoselectivity. In the case of the methyl substituted
Subsequent to the control experiments, a deuterium labeling
experiment using 1a was performed to provide deuterio-1b in
quantitative yield (Scheme 2). The structure and deuterium con-
tents of deuterio-1b were assigned by NMR. As indicated in
Scheme 2, deuteriums were incorporated at the
a-position of the
COPh
COPh
PtCl2 (5 mol%)
P(Ph-pCF3)3 (5 mol%)
COPh
PhOC
PhOC
PhOC
H2 (1atm)
80 ºC
Dichloroethane (0.1M)
1a
1a
1b
Yield = 6%
PtCl2 (5 mol%)
P(Ph-pCF3)3 (5 mol%)
SnCl2 (25 mol%)
COPh
PhOC
80 ºC
Dichloroethane(0.1M)
1c
Yield = 13%
bis-enone, a good conversion was observed. In particular,
a,b-cou-
Scheme 1. Control experiments.
pling of aliphatic enones has not been reported under other transi-

H. Lee et al. / Tetrahedron Letters 49 (2008) 5785–5788
5787
Ph
H
COPh
OPt(SnCl3)Ln
COPh
PhOC
H
I
OPt(SnCl3)Ln
Ph
SnCl2, H2
HCl
LnPtH(SnCl3)
PhOC
LnPtCl2
II
H2
COPh
PhOC
Scheme 3. A plausible mechanism for the reductive cyclization of 1a.
Table 2
Reductive coupling of various activated alkenes
Entry
Substrate
Product
Yield (%) (cis:trans)
98 (1:2.0)
COPh
COPh
PhOC
PhOC
1
1b
2b
1a
2a
COPh
COPh
PhOC
PhOC
2
3
71 (1:1)
COPh-pOMe
COPh-pOMe
MeOp-PhOC
MeOp-PhOC
91 (1:3.5)
3a
3b
COMe
COMe
MeOC
COPh
PhOC
PhOC
4
5
72 (1:1) 4b:4c=4:1
4a
4b
5b
4c
COMe
COMe
MeOC
MeOC
PhOC
59 (1:1)
5a
OH
OHC
PhOC
6
83a (1.3:1)
NO2
Me
NO2
6a
6b
6c
Hydrogen-mediated reductive cyclization conditions: To a premixed solution of PtCl2 (5 mol %), P(Ph-pCF3)3 (5 mol %), and SnCl2 (25 mol %), in dichloroethane (0.1 M) was
added each substrate under H2 (1 atm) at room temperature. The resulting mixture was allowed to run at 80 °C for 2 h or until the starting material was completely
consumed.
a
To the premixed solution of PtCl2 (5 mol %), P(Ph-pOMe)3 (5 mol %), and SnCl2 (25 mol %) in dichloroethane (0.1 M) were added 200 mol % of 6a and 100 mol % of 6b under
H2 (1 atm) at room temperature. The resulting mixture was allowed to run at 80 °C for 2 h.
tion metal-catalyzed reductive cyclization conditions.5,8 Inter-
molecular reaction of the enone proceeded in the presence of
aldehydes in good yield without dimerization of the enone. With
regard to the mechanism, the hydrometalation of the activated
alkenes with LnPtH(SnCl3) followed by cyclization was proposed
in the hydrogen-mediated cyclization, which was supported by a

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H. Lee et al. / Tetrahedron Letters 49 (2008) 5785–5788
3. Representative articles for hydrogen-mediated reductive couplings: (a) Jang,
H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 15156; (b)
Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 7875; (c) Kong, J.-R.; Cho,
C.-W.; Krische, M. J. J. Am. Chem. Soc. 2005, 127, 11269; (d) Barchuk, A.; Ngai,
M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 8432; (e) Skucas, E.; Bower, J.;
Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12678.
4. (a) Inanaga, J.; Handa, Y.; Tabuchi, T.; Otsubo, K. Tetrahedron Lett. 1991, 32,
6557; (b) Enholm, E. J.; Kinter, K. S. J. Am. Chem. Soc. 1991, 113, 7784; (c)
Chavan, S. P.; Ethiraj, K. S. Tetrahedron Lett. 1995, 36, 2281; (d) Lee, G. H.; Lee, H.
K.; Choi, E. B.; Pak, C. S. Bull. Korean Chem. Soc. 1995, 16, 1141; (e) Savchenko, A.
V.; Montgomery, J. J. Org. Chem. 1996, 61, 1562; (f) Montgomery, J.; Oblinger, E.;
Savchenko, A. V. J. Am. Chem. Soc. 1997, 119, 4911; (g) Handy, S. T.; Omune, D.
Tetrahedron 2007, 63, 1366.
5. (a) Baik, T.-G.; Luis, A. L.; Wang, L.-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123,
5112; (b) Wang, L.-C.; Jang, H.-Y.; Roh, Y.; Lynch, V.; Schultz, A. J.; Wang, X.;
Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448; (c) Miura, K.; Yamada, Y.;
Tomita, M.; Hosomi, A. Synlett 2004, 1985.
6. (a) Pittman, C. U., Jr.; Kawabata, Y.; Flowers, L. I. J. Chem. Soc., Chem. Commun.
1982, 473; (b) Holt, M. S.; Wilson, W. L.; Nelson, J. H. Chem. Rev. 1989, 89, 11;
(c) Stille, J. K.; Su, H.; Brechot, P.; Parrinello, G.; Hegedus, L. S. Organometallics
1991, 10, 1183.
7. Jung, I. G.; Seo, J.; Lee, S. I.; Choi, S. Y.; Chung, Y. K. Organometallics 2006, 25,
4240.
8. Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. J. Am. Chem. Soc. 2005, 127,
15036.
9. (a) Tan, X.-H.; Shen, B.; Deng, W.; Zhao, H.; Liu, L.; Guo, Q.-X. Org. Lett. 2003, 5,
1833; (b) Sawant, D.; Kumar, R.; Maulik, P. R.; Kundu, B. Org. Lett. 2006, 8, 1525.
10. Trost, B. M.; Krische, M. J. Synlett 1998, 1.
11. EI mass spectrometry results in the D/H scrambling of the product due to the
harsh conditions, thus deuterium contents of deuterio-1b could not be
determined. Using mild ESI mass spectrometry, no peak corresponding to
either monodeuterio-1b or dideuterio-1b was observed.
deuterium labeling experiment result. Using the powerful catalytic
system involving PtCl2, phosphine, and SnCl2, this methodology
would resolve limitations previously reported with hydrogenative
couplings. Further mechanistic studies to support the currently
proposed mechanism and modification of catalysts to improve
the activity are ongoing.
Acknowledgments
This work was supported by the Korea Science and Engineering
Foundation (Grant No. R01-2007-000-20223-0) and the Korea
Research Foundation (Grant No. KRF-2007-412-J04003).
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