Tandem one pot asymmetric conjugate addition-vinyl inflate formation - Cross coupling methodology

Article abstract of DOI:10.1039/b418028c

Optically active vinyl triflate were obtained and employed in a series of one pot metal-catalyzed tandem asymmetric transformations. These vinyl triflates were used in Pd-catalyzed cross-coupling reactions with organometallic reagents to provide chiral ol

Full text of DOI:10.1039/b418028c

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C O M M U N I C A T I O N
Tandem one pot asymmetric conjugate addition–vinyl triflate
formation–cross coupling methodology
Rosa M. Sua´rez,† Diego Pen˜a,*‡ Adriaan J. Minnaard and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of
Groningen, Nijenborgh 4, 9747, AG Groningen, The Netherlands.
E-mail: b.l.feringa@chem.rug.nl; Fax: (+31) 50-3634296; Tel: (+31) 50-3634278
Received 30th November 2004, Accepted 14th January 2005
First published as an Advance Article on the web 2nd February 2005
Optically active vinyl triflates are obtained and employed
in a series of one pot metal-catalyzed tandem asymmetric
transformations.
enolates.7 The resulting silyl enol ethers were submitted to
subsequent transformations to show their synthetic utility, such
as in the formation of chiral vinyl triflates (4, Scheme 1).
According to these authors,7 the transformation of the zinc
enolate into the corresponding vinyl triflate could not be directly
accomplished.
Bearing in mind the vast amount of palladium-catalyzed
chemistry based on sp2 carbon–triflate bonds,8 vinyl triflates
are remarkably versatile synthons. Herein, we report a study
demonstrating that enantiomerically enriched cyclic vinyl tri-
flates can be obtained directly from cyclic enones in a tandem
asymmetric conjugate addition–enolate trapping reaction. In
addition, the synthetic utility of these chiral cyclic vinyl triflates
is demonstrated.
Reaction of 2-cyclohexenone (1) with diethylzinc (1.15 eq.)
in the presence of 1 mol% of Cu(OTf)2 and 2 mol% of ligand
(S,R,R)-5 in toluene at −30 ◦C, led to the quantitative formation
of the corresponding zinc enolate 2 (Scheme 2). Subsequent ad-
dition of triflic anhydride (Tf2O, 2.2 eq.) to the reaction mixture
at 0 ◦C, followed by aqueous work-up, afforded vinyl triflate 8a
in 83% yield and 97% ee (Table 1, entry 1).9 The application of
these conditions to enones 6 and 7 also led the corresponding
vinyl triflates in good yields and enantioselectivities ranging
from 94–99% (entries 3 and 5). Employing dibutylzinc as the
nucleophile we found lower yields of the vinyl triflates (55–58%)
and a decrease in the enantioselectivity (entries 2, 4 and 6),
compared to the use of diethylzinc. Remarkably, triflate 8d was
isolated in a modest 81% ee, while the enantioselectivity of the
corresponding 3-substituted cyclohexanone 3, resulting from the
acidic quenching of the enolate, turned out to be 95% ee (entry
4). The different level of enantioselection seems to be the result of
incomplete conversion in the conjugate addition step. Addition
of triflic anhydride in the presence of the enone promoted an
The enantioselective conjugate addition of organometallic
reagents to enones is one of the key methodologies for carbon–
carbon bond formation.1 In recent years, the discovery of
monodentate phosphoramidites as chiral ligands for the copper
catalyzed conjugate addition of dialkylzinc reagents,2 has stim-
ulated the development of numerous chiral ligands and catalysts
for this asymmetric transformation.3
In a typical example of our asymmetric Cu-catalyzed 1,4-
addition protocol, 2-cyclohexenone (1) reacts with a dialkylzinc
reagent in the presence of a chiral copper catalyst, leading to
an enantiomerically enriched zinc enolate 2 (Scheme 1). The
chiral Cu-catalyst is frequently prepared in situ from a copper
source (e.g. Cu(OTf)2) and a chiral ligand (e.g. phosphoramidite
5, Fig. 1). In the standard procedure, the intermediate zinc
enolate 2 is converted during the acidic work up into the
corresponding 3-substituted cyclohexanone 3. The reactivity of
this intermediate zinc enolate has been exploited in order to
enhance the synthetic scope of the conjugate addition. Although
the reactivity of a Zn enolate is lower than that of a Li, Na or
Mg enolate,4 this methodology has allowed the development of
tandem protocols to form additional C–C bonds, by trapping
the enolate with electrophiles such as allyl5 and alkyl6 derivatives
2a,5c
or aldehydes.
Fig. 1 Privileged monodentate phosphoramidite ligand.
Scheme 2 Synthesis of chiral vinyl triflates in one pot.
Table 1 Yields and ee’s obtained for triflates 8a–fa
Entry Enone
n
R1 R2 Compound 8 Yield(%)b Ee(%)c
Scheme 1 Cu-catalyzed asymmetric conjugate addition.
1
2
3
4
5
6
1
1
6
6
7
7
1
1
2
2
1
1
H
H
H
H
Et 8a
Bu 8b
Et 8c
Bu 8d
83
55
65
55
74
58
97
93
94
Recently, Alexakis and Knopff reported a tandem asymmetric
conjugate addition–silylation of enantiomerically enriched zinc
81 (95)d
99
Me Et 8e
Me Bu 8f
95
† Current address: Dept. de Qu´ımica Fundamental, Universidade da
Corun˜a, 15071 A Corun˜a, Spain.
‡ Current address: Dept. de Qu´ımica Orga´nica, Facultad de Qu´ımica,
Universidad de Santiago de Compostela, 15782, Santiago de Com-
postela, Spain.
a See Scheme 2. b Isolated yields. c Determined by chiral GC. See ref.
10 for details. d Ee of the corresponding cyclohexanone 3 is given in
brackets.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 2 9 – 7 3 1
7 2 9
©

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uncatalyzed 1,4-addition and therefore resulted in a decrease of
the enantiomeric excess.
The Pd-catalyzed coupling between the vinyl triflate and
RZnOTf, both formed in situ by the addition of Tf2O to the zinc
enolate, is by itself an interesting transformation. Preliminary
results show that the addition of catalytic amounts of Pd(PPh3)4
to the reaction mixture, obtained from the first two steps shown
in Scheme 5, lead to the formation of the chiral olefin 10 with
more than 80% conversion.15 Therefore, the appropriate com-
bination of two metal-catalyzed transformations (1,4-addition
and cross-coupling) can lead to the transfer of both alkyl groups
from the diorganozinc reagent to the enone.
In conclusion, cyclic enantiomerically enriched vinyl triflates
can be easily obtained directly from cyclic enones in a tandem
Cu-catalyzed asymmetric conjugate addition–enolate trapping
reaction, without recourse to a separately isolated silyl ether as
previously reported. In addition, these vinyl triflates can be used
in Pd-catalyzed cross-coupling reactions with organometallic
reagents to provide chiral olefins from enones in one pot,
expanding the utility of the Cu-catalyzed asymmetric conjugate
addition of dialkylzinc reagents.
Optically active vinyl triflates are interesting building blocks,
which can easily be transformed by palladium-catalyzed cou-
pling reactions.8 Among those reactions, we decided to test the
palladium-catalyzed coupling with organozinc reagents. Indeed,
reaction of triflate 8a with PhZnCl (1.5 eq.) in the presence
of 4 mol% of Pd(PPh3)4 in THF at 50 ◦C afforded the chiral
hydrocarbon 9a in 86% yield (Scheme 3). Notably, chiral olefins
are not only of fundamental interest but have recently been used
as ligands in Rh-catalyzed asymmetric addition of arylboronic
acids.11
Scheme 3 Pd-catalyzed coupling reaction of vinyl triflate 8a.
This result prompted us to develop a tandem version of
this reaction, in which the Cu-catalyzed asymmetric conju-
gate addition, the formation of the vinyl triflate and its Pd-
catalyzed coupling with an organometallic reagent were carried
out in one pot. This procedure would avoid the isolation of
vinyl triflates, directly transforming enones to enantiomerically
enriched hydrocarbons. In our first attempts, a solution of
PhZnCl and a catalytic amount of Pd(PPh3)4 were added to
the reaction mixture obtained after the tandem Cu-catalyzed
conjugate addition of Et2Zn to cyclohexenone and subsequent
enolate trapping reaction with Tf2O. We were pleased to see the
formation of olefin 9a, although we also detected the formation
of olefin 10 (Scheme 5). Apparently, there is competition in the
Pd-catalyzed coupling reaction of the vinyl triflate between the
external (PhZnCl) and the internal (EtZnOTf) organometallic
reagents.12 To avoid this side reaction we employed PhMgBr
as an external organometallic reagent. As expected, the higher
reactivity of the Grignard reagent allowed the isolation of
the chiral olefin 9a in good yield and high enantioselectivity
(Scheme 4), in a one pot procedure from cyclohexenone over
three consecutive steps (Table 2, entry 1).13 The use of other
enones, 6 and 7, also led to the formation of the corresponding
chiral hydrocarbons 9b,c in moderate to good yields (entries 2
and 3).14
Acknowledgements
R. M. S. thanks the Spanish Ministry of Education for the
award of a research grant (FPU). D. P. thanks the European
Community (IHP Program) for the award of a Marie Curie
Fellowship (Contract HPMF-CT-2002-01612).
References
1 K. Tamioka and Y. Nagaoka, in Comprehensive Asymmetric Cataly-
sis, ed. E. N. Jacobsen, A. Pfaltz, and H. Yamamoto, Springer-Verlag,
Berlin/Heidelberg, 1999, vol. 3, ch. 31.1.
2 (a) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos and A. H. M.
de Vries, Angew. Chem., Int. Ed., 1997, 36, 2620; (b) B. L. Feringa,
Acc. Chem. Res., 2000, 33, 346; (c) A. Duursma, A. J. Minnaard and
B. L. Feringa, J. Am. Chem. Soc., 2003, 125, 3700; (d) D. Pen˜a, F.
Lo´pez, S. R. Harutyunyan, A. J. Minnaard and B. L. Feringa, Chem.
Commun., 2004, 1836; (e) J. Schuppan, A. J. Minnaard and B. L.
Feringa, Chem. Commun., 2004, 792; (f) M. Pineschi, F. del Moro,
F. Gini, A. J. Minnaard and B. L. Feringa, Chem. Commun., 2004,
1244.
3 Reviews: (a) N. Krause and A. Hoffmann-Ro¨der, Synthesis, 2001,
171; (b) B. L. Feringa, R. Naasz, R. Imbos and L. A. Arnold,
in Modern Organocopper Chemistry, ed. N. Krause, Wiley-VCH,
Weinheim, 2002, ch. 7, p. 224; (c) A. Alexakis and C. Benhaim,
Eur. J. Org. Chem., 2002, 3221.
4 M. J. Chapdelaine and M. Hulce, Org. React., 1990, 38, 225.
5 (a) M. Kitamura, T. Miki, K. Nakano and R. Noyori, Tetrahedron
Lett., 1996, 37, 5141; (b) R. Naasz, L. A. Arnold, A. J. Minnaard
and B. L. Feringa, Chem. Commun., 2001, 735; (c) L. A. Arnold,
R. Naasz, A. J. Minnaard and B. L. Feringa, J. Am. Chem. Soc.,
2001, 123, 5841; (d) E. W. Dijk, L. Panella, P. Pinho, R. Naasz, A.
Meetsma, A. J. Minnaard and B. L. Feringa, Tetrahedron, 2004, 60,
9687.
6 S. J. Degrado, H. Mizutani and A. M. Hoveyda, J. Am. Chem. Soc.,
Scheme 4 Synthesis of chiral olefins 9a–e in one pot.
2001, 123, 755.
7 O. Knopff and A. Alexakis, Org. Lett., 2002, 4, 3835.
8 (a) K. Ritter, Synthesis, 1993, 735; (b) L. F. Tietze, H. Ila and H. P.
Bell, Chem. Rev., 2004, 104, 3453.
9 General procedure for the synthesis of vinyl triflates 8a–f in one
pot: In a Schlenk tube equipped with a septum and stirring bar, a
mixture of Cu(OTf)2 (3.6 mg, 0.01 mmol) and (S,R,R)-5 (10.8 mg,
0.02 mmol) was dissolved in toluene (5 mL). After stirring under
argon at room temperature for 30 min, the enone (1, 6 or 7, 1
mmol) was added. The resulting mixture was cooled to −30 ◦C
and the corresponding dialkylzinc reagent (solution in toluene, 1.15
mmol) was added dropwise. After stirring under argon for 2 h,
Tf2O (350 lL, 2 mmol) was added at 0 ◦C. The resulting mixture
was allowed to reach room temperature overnight. Standard work-
up with saturated aqueous NaHCO3 and purification by column
chromatography (SiO2; pentane) afforded vinyl triflates 8a–f. All the
products gave satisfactory NMR (1H, 13C) and HRMS. Selected data
Scheme 5 Formation of chiral olefin 10 in one pot.
Table 2 Yields and ee’s obtained for olefins 9a–ca
Entry
Enone
n
R1
Compound 9
Yield(%)b
ee(%)c
1
2
3
1
6
7
1
2
1
H
H
Me
9a
9b
9c
46
27
59
96
N.d.d
N.d.d
1
for 8a (see ref. 7): H-NMR (300 MHz, CDCl3): d = 5.63 (s, 1H),
2.30–2.22 (m, 2H), 2.16 (m, 1H), 1.85 (m, 1H), 1.73 (m, 1H), 1.63 (m,
1H), 1.43–1.29 (m, 2H), 1.17 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H) ppm.
13C-NMR (75.5 MHz, CDCl3): d = 149.4 (C), 122.6 (CH), 118.6
(q, J = 320 Hz, C), 36.6 (CH), 28.2 (CH2), 27.7 (CH2), 27.1 (CH2),
a See Scheme 4. b Isolated yields. c Determined by chiral GC. See ref. 10
for details. d Not determined.
7 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 2 9 – 7 3 1

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21.4 (CH2), 11.0 (CH3) ppm. HRMS for C9H13F3O3S, cal: 258.0537,
found: 258.0526.
Et2O, 500 mL, 1.5 mmol) at −78 ◦C. The resulting mixture was
allowed to reach room temperature overnight. Standard work-
up with saturated aqueous NaHCO3 and purification by column
chromatography (SiO2; pentane) afforded olefins 9a–c. All the
products gave satisfactory NMR (1H, 13C) and MS. Selected data
for 9a: 1H-NMR (300 MHz, CDCl3): d = 7.36 (d, J = 7.0 Hz, 2H),
7.27 (t, J = 7.7 Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 5.98 (s, 1H),
2.37–2.34 (m, 2H), 2.11 (m, 1H), 1.91–1.77 (m, 2H), 1.61 (m, 1H),
1.49–1.29 (m, 2H), 1.21 (m, 1H), 0.94 (t, J = 7.7 Hz, 3H) ppm. 13C-
NMR (50.3 MHz, CDCl3): d = 142.6 (C), 136.2 (C), 129.7 (CH),
128.2 (2 CH), 126.5 (CH), 125.0 (2 CH), 37.6 (CH), 29.2 (CH2), 28.3
(CH2), 27.7 (CH2), 22.1 (CH2), 11.6 (CH3) ppm. MS (EI) m/z (%):
186 (15), 157 (100).
10 Enantiomeric excesses were determined by capillary GC analysis
with a Chiraldex G-TA column for 8a, 8c–e and 9a; a Chiraldex
B-TA column for 8b or a Chiraldex B-PM column for 8f. Absolute
configurations were determined by comparison of the configuration
of the corresponding cyclohexanones 3 with those reported (see ref.
2a) .
11 T. Hayashi, K. Ueyama, N. Tokunaga and K. Yoshida, J. Am. Chem.
Soc., 2003, 125, 11508.
12 The internal organometallic reagent EtZnOTf is presumed to be
formed in addition to the vinyl triflate from the reaction of the zinc
enolate with Tf2O.
13 General procedure for the synthesis of olefins 9a–c in one pot:
Following the procedure in ref. 9, the reaction mixture of the
corresponding vinyl triflate 8 was sequentially treated with Pd(PPh3)4
(46.2 mg, 0.04 mmol) in THF (0.6 mL) and PhMgBr (3 M in
14 The ee of 9b and 9c could not be determined but are assumed to be
the same as for the corresponding triflates 8c and 8e, respectively.
15 The volatility of this hydrocarbon has prevented the determination
of an accurate isolated yield.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 2 9 – 7 3 1
7 3 1