Enantioselective rhodium-catalyzed conjugate alkynylation of 5-benzylidene Meldrum's acids with TMS-acetylene

Article abstract of DOI:10.1021/ja905336p

(Chemical Equation Presented) The enantioselective alkynylation of benzylidene Meldrum's acids has been successfully achieved through rhodium-catalyzed addition of TMS-acetylene in the presence of bisphosphine ligand 3,5-Xylyl-MeOBIPHEP. The resulting Mel

Full text of DOI:10.1021/ja905336p

Published on Web 09/28/2009
Enantioselective Rhodium-Catalyzed Conjugate Alkynylation of 5-Benzylidene
Meldrum’s Acids with TMS-acetylene
Eric Fillion* and Alexander K. Zorzitto
Department of Chemistry, UniVersity of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received June 29, 2009; E-mail: efillion@uwaterloo.ca
Catalytic enantioselective conjugate alkynylation of electron-
deficient olefins has recently attracted attention because of its
synthetic utility.1 To date, only four methods for carrying out this
C-C bond-forming transformation have been disclosed: two used
metalated terminal alkynes2 and two in situ-generated metal
alkynylides. From a practical point of view, the conjugate addition
of in situ-generated metal alkynylides is of great interest, as it is
accomplished in a single synthetic operation. In this context,
Carreira and co-workers described the PINAP-catalyzed conjugate
addition of in situ-generated copper aryl alkynylides to alkylidene
Meldrum’s acids.3,4 The method was optimal for the conjugate
addition of aryl acetylenes to alkylidene Meldrum’s acids derived
from aliphatic aldehydes.1 Subsequently, the Rh-catalyzed asym-
metric conjugate alkynylation of acyclic and cyclic enones using
sterically shielded (triisopropylsilyl)acetylene5 and analogous alky-
nylsilanols6 in the presence of the chiral bisphosphine DTBM-
SEGPHOS (3a) was reported by the Hayashi group.7
of 1a to (S)-2 were obtained with TMS-acetylene (entries 1, 4, 7,
and 10). In addition, DME was found to be optimal in regard to
conversion and enantioselectivity (entry 7).
With this promising lead in hand, we proceeded to optimize the
reaction conditions to improve the conversion and enantioselectivity.
For practical reasons and ease of purification of 2a, benzylidene
Meldrum’s acid 1a was used as the limiting reagent, with a 5-fold
excess of TMS-acetylene. Under these conditions, [RhOH(cod)]2
(10 mol % Rh)/3b (11 mol %) led to 62% conversion of 1a to
(S)-2a. The enantioselectivity was unaffected, as 2a was obtained
in 87% ee (Table 2, entry 1). Further optimization was realized by
varying the chiral phosphine ligand.9 (R)-3,5-Xylyl-BINAP (entry
2) provided similar results, while poor conversion was obtained
with (R)-BINAP (entry 3). No conversion was observed with
trialkylphosphine (entries 4-5) or monophosphine ligands (entries
6-8). (R)-DTBM-SEGPHOS (3a) furnished 85% conversion of 1a
to (S)-2a in 88% ee (entry 9). The series of (S)-MeO-BIPHEP
ligands 3j-m was then explored (entries 10-13); 3,5-Xylyl-
MeOBIPHEP (3m) provided superior results, yielding (R)-2a in
94% ee at 70% conversion of 1a.
Herein, we present a method for the enantioselective conjugate
addition of TMS-acetylene to benzylidene Meldrum’s acids 1
catalyzed by a Rh(I) complex. It was postulated that as an alternative
to the use of sterically shielded acetylenes to avoid competing
terminal alkyne dimerization, highly electrophilic acceptors8 would
modify the kinetics of the process and favor this unprecedented
conjugate alkynylation.
Table 2. Survey of Chiral Phosphine Ligands
This hypothesis was verified by initially studying the addition
of a series of silylated acetylenes to benzylidene Meldrum’s acid
1a. As depicted in Table 1, with [RhOH(cod)]2 (10 mol % Rh),
and (R)-p-Tol-BINAP (3b) (11 mol %), the silylacetylene addition
proceeded at room temperature; the highest levels of conversion
conversion (%)a b
ee (%)
,
entry
ligand 3
1
2
3
4
5
6
7
8
(R)-p-Tol-BINAP (3b)
(R)-3,5-Xylyl-BINAP (3c)
(R)-BINAP (3d)
62
71
25
none
none
none
none
none
85
87
86
N/A
-
Table 1. Influence of the Solvent and Silylacetylene
(R,R)-Me-BPE (3e)
(S,S,R,R)-TangPHOS (3f)
(R,R)-BozPHOS (3g)
-
-
(S)-MOP (3h)
-
(R)-iPr-PHOX (3i)
-
9
(R)-DTBM-SEGPHOS (3a)
(S)-3,5-tBu-4-MeO-MeOBIPHEP (3j)
(S)-MeOBIPHEP (3k)
(S)-p-Tol-MeOBIPHEP (3l)
(S)-3,5-Xylyl-MeOBIPHEP (3m)
88
-
10
11
12
13
none
50c
83
88
94
entry
solventa
SiR3
conversion (%)b
ee (%)
66c
70c
1
2
3
4
5
6
7
8
PhMe
PhMe
PhMe
THF
THF
THF
DME
DME
SiMe3t
SiMe2 Bu
SiiPr3
SiMe3t
SiMe2 Bu
SiiPr3
SiMe3t
SiMe2 Bu
SiiPr3
39 (2a)
23 (2a′)
15 (2a′′)
41(2a)
26 (2a′)
23 (2a′′)
54 (2a)
23 (2a′)
NR
78
69
14
66
62
3
87
73
-
67
66
38
a The final concentration of Meldrum’s acid 1a was 0.6 M.
b Determined by analysis of the 1H NMR spectra of the crude reaction
mixtures. c (R)-2a was obtained.
The alkynylation proceeded to completion when the catalyst
loading was increased to 15 mol % Rh, which also benefited
enantioselection. In the presence of 3m (16 mol %) and [RhOH-
(cod)]2 (15 mol % Rh), addition of TMS-acetylene to 1a gave (R)-
2a in 98% ee and 91% isolated yield after 66 h at room temperature
(Table 3, entry 1).10
9
DME
10
11
12
1,4-dioxane
1,4-dioxane
1,4-dioxane
SiMe3t
SiMe2 Bu
SiiPr3
30 (2a)
23 (2a′)
20 (2a′′)
a The final concentration of silylacetylene was 0.6 M. b Determined
1
The scope of the catalytic conjugate alkynylation reaction was then
explored, and the results are summarized in Table 3. 2-Naphthyl
by analysis of the H NMR spectra of the crude reaction mixtures using
mesitylene as internal standard.
9
14608 J. AM. CHEM. SOC. 2009, 131, 14608–14609
10.1021/ja905336p CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Synthetic Transformations of 2aa
substrate 1b provided 2b in 99% ee (entry 2). Alkylidene 1c reacted
smoothly with TMS-acetylene, but a lower enantioselectivity was
observed (entry 3). Substrate 1d bearing a methyl group at the
2-position of the aromatic moiety withstood alkynylation (entry 4).
The lower conversion of 1b and the lack of reactivity of 1d are likely
the results of increased steric hindrance around the electrophilic carbon
center. Methyl substitution at the 3- and 4-positions of the phenyl
moiety had no impact on the enantioselectivity of the alkynylation
(entries 5 and 6), but lower conversion was observed for para-
substituted substrate 1f. However, introduction of a larger alkyl group
at the para position restored the reactivity: 1g yielded 2g in 94% ee
(entry 7). A similar trend was observed with methoxy-substituted
substrates 1h and 1i, as the 4-methoxy substrate was less reactive
(entries 8 and 9). Replacing the methyl protecting group on the phenol
with a pivalate group solved this reactivity issue. As a result, 1j and
1k furnished 2j and 2k, respectively, in good yields and ee’s (entries
10 and 11). Methyl esters at the 3- and 4-positions of the arene also
furnished the corresponding alkynylated products (entries 12 and 13).
It was further shown that a range of functional groups, including
triisopropylsilyl ether and free phenol (entries 14 and 15), was
compatible with the conjugate alkynylation method. Furthermore, the
mildness of the reaction conditions was clearly illustrated with boronic
ester-substituted 1p, which was stable and yielded 2p in good yield
and enantioselectivity (entry 16).
a Reagents and Conditions: (a) TBAF, THF, rt, 2 h, 83%; (b) PhI, CuI
(29 mol %), Pd2(dba)3 (2.4 mol %), PhOH (2 equiv), nBu4NI (2 equiv),
DMF/iPr2NEt (20:1), -5 °C, 1 h, 64%; (c) H2O/pyridine (3:1), 95 °C, 4 h,
96%; (d) Ag2CO3 (10 mol %), PhH/MeOH (4:1), 85 °C, 2 h, 72%.
conditions are compatible with an array of functional groups. Further
efforts to expand the scope of the enantioselective conjugate
alkynylation of highly electrophilic acceptors with TMS-acetylene
and to synthesize medicinally relevant compounds are underway.
Acknowledgment. This work was supported by the Government
of Ontario (Early Researcher Award to E.F.), the Merck Frosst
Center for Therapeutic Research, NSERC, CFI, OIT, and the
University of Waterloo. Aaron M. Dumas, University of Waterloo,
is acknowledged for generously sharing benzylidene Meldrum’s
acids. Ashraf Wilsily, University of Waterloo, is thanked for help
with the derivatization experiments.
Table 3. TMS-acetylene Addition to Benzylidene Meldrum’s Acids 1
Supporting Information Available: Experimental procedures and
NMR spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) For a review, see: Fujimori, S.; Kno¨pfel, T. F.; Zarotti, P.; Ichikawa, T.;
Boyall, D.; Carreira, E. M. Bull. Chem. Soc. Jpn. 2007, 80, 1635.
(2) Conjugate addition of alkynyl boronates to ꢀ-aryl enones catalyzed by 3,3′-
diiodobinaphthol: (a) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005,
127, 3244. Stoichiometric conjugate addition of alkynyl boronates: (b)
Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc. 2000, 122, 1822.
Chiral nickel-bisoxazoline complex-catalyzed conjugate addition of dime-
thylaluminum TMS-acetylide to 2-cyclohexenone: (c) Kwak, Y.-S.; Corey,
E. J. Org. Lett. 2004, 6, 3385. Me2Zn- and chiral amino alcohol-mediated
addition of aryl alkynes to nitro olefins under stoichiometric conditions: (d)
Yamashita, M.; Yamada, K.; Tomioka, K. Org. Lett. 2005, 7, 2369.
Organocatalytic formal alkynylation of R,ꢀ-unsaturated aldehydes: (e)
Nielsen, M.; Jacobsen, C. B.; Paixa˜o, M. W.; Holub, N.; Jørgensen, K. A.
J. Am. Chem. Soc. 2009, 131, 10581.
entry
Ra
conversion (%)b
yield (%)
ee (%)
1
2
3
4
5
6
7
8
Ph (1a)
>95
80
>95
NR
90
91 (2a)
70 (2b)
85 (2c)
-
72 (2e)
65 (2f)
73 (2g)
83 (2h)
N/A
83 (2j)
86 (2k)
74 (2l)
80 (2m)
77 (2n)
85 (2o)
84 (2p)
98
99
74
-
2-naphthyl (1b)
iPr (1c)
2-MeC6H4 (1d)
3-MeC6H4 (1e)
98
98
94
95
N/A
94
93
84
85
89
97
92
4-MeC6H4 (1f)
73
4-tBuC6H4 (1g)
>95
>98
40
>98
>98
>95
>95
>98
>98
>98
3-MeOC6H4 (1h)
4-MeOC6H4 (1i)
3-(OCOtBu)C6H4 (1j)
4-(OCOtBu)C6H4 (1k)
3-(CO2CH3)C6H4 (1l)
4-(CO2CH3)C6H4 (1m)
3-(TiPSO)C6H4 (1n)
3-(HO)C6H4 (1o)
3-[B(O2C6H12)]C6H4 (1p)
9
(3) Kno¨pfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. J. Am. Chem.
Soc. 2005, 127, 9682.
10
11
12
13
14
15
16
(4) (a) Fujimori, S.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 4964.
(b) Kno¨pfel, T. F.; Boyall, D.; Carreira, E. M. Org. Lett. 2004, 6, 2281.
(c) Kno¨pfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003, 125, 6054.
(5) Nishimura, T.; Guo, X.-X.; Uchiyama, N.; Katoh, T.; Hayashi, T. J. Am.
Chem. Soc. 2008, 130, 1576.
(6) Nishimura, T.; Tokuji, S.; Sawano, T.; Hayashi, T. Org. Lett. 2009, 11, 3222.
(7) Rh-catalyzed asymmetric rearrangement of alkynyl alkenyl carbinols, the
synthetic equivalent of asymmetric conjugate alkynylation of enones, has
been reported. See: Nishimura, T.; Katoh, T.; Takatsu, K.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2007, 129, 14158.
a The final concentration of Meldrum’s acid 1 was 0.6 M. b Determined
by analysis of the 1H NMR spectra of the crude reaction mixtures.
(8) Highly electrophilic alkylidene Meldrum’s acids have been shown to
participate in various conjugate additions under mild reaction conditions.
See: (a) Wilsily, A.; Lou, T.; Fillion, E. Synthesis 2009, 2066. (b) Dumas,
A. M.; Fillion, E. Org. Lett. 2009, 11, 1919. (c) Wilsily, A.; Fillion, E.
Org. Lett. 2008, 10, 2801. (d) Fillion, E.; Carret, S.; Mercier, L. G.;
Starting from orthogonally functionalized 2a, subsequent trans-
formations generated diverse chiral structures without loss of enan-
tiopurity. Deprotection of 2a followed by Sonogashira coupling of
the resulting terminal alkyne 2q with iodobenzene provided 2r.11
Selective hydrolysis of the Meldrum’s acid moiety of 2a furnished
carboxylic acid 2s.12 Lactone 2t was formed by Ag2CO3-catalyzed
heterocyclization of 2q.
In conclusion, we have described a novel method for the
enantioselective conjugate alkynylation of benzylidene Meldrum’s
acids using TMS-acetylene. This method employs the commercially
available ligand 3,5-Xylyl-MeOBIPHEP (3m), and the mild reaction
´
Tre´panier, V. E. Org. Lett. 2008, 10, 437. (e) Fillion, E.; Wilsily, A.; Liao,
E-T. Tetrahedron: Asymmetry 2006, 17, 2957. (f) Fillion, E.; Wilsily, A.
J. Am. Chem. Soc. 2006, 128, 2774.
(9) For a complete survey of ligands, see the Supporting Information.
(10) The addition of 4 Å molecular sieves provided consistent yields and ee’s.
(11) The absolute stereochemistry of the addition products was determined by
comparison with known compound 2r (see ref 3).
(12) 3-Substituted phenylpropionic acid is a salient structural motif in medicinal
chemistry. See: Bharate, S. B.; Nemmani, K. V. S.; Vishwakarma, R. A.
Expert Opin. Ther. Pat. 2009, 19, 237.
JA905336P
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