Iron-catalyzed unexpected easy access to stereodefined trimethylsilyl vinyl ketenes

Article abstract of DOI:10.1021/ol3016176

Stereodefined trimethylsilyl vinyl ketenes with polysubstitution have been synthesized highly regio- and stereoselectively via an iron-catalyzed reaction of 2-trimethylsilyl-2,3-allenoates with Grignard reagents in good to excellent yields. The reaction w

Full text of DOI:10.1021/ol3016176

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iron-Catalyzed Unexpected Easy Access to
Stereodefined Trimethylsilyl Vinyl Ketenes
Guobi Chai, Chunling Fu, and Shengming Ma*
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang University, Hangzhou 310027, Zhejiang, P. R. China
masm@sioc.ac.cn
Received June 12, 2012
ABSTRACT
Stereodefined trimethylsilyl vinyl ketenes with polysubstitution have been synthesized highly regio- and stereoselectively via an iron-catalyzed
reaction of 2-trimethylsilyl-2,3-allenoates with Grignard reagents in good to excellent yields. The reaction was believed to proceed via a conjugate
addition and elimination mechanism. Applications of the products for the synthesis of stereodefined R-silyl-β,γ-unsaturated enones, a
stereodefined triene, and polysubstituted phenols have been carefully demonstrated.
The utility of ketenes in organic synthesis has been well
demonstrated in the past decades.1 For example, vinyl
ketenes could serve as both two- and four-carbon building
blocks for the assembly of a variety of carbocyclic
systems.2 However, they are highly unstable and often
generated as intermediates for in situ trapping, which
greatly restrict their application. In 1980, Danheiser et al.
reported the synthesis of trialkylsilyl vinyl ketenes by
the dehydrohalogenation of R-silyl-R,β-unsaturated acid
chlorides (Scheme 1, route a).3 The presence of the silyl
group could stabilize vinyl ketenes4 and allow them to
serve as enophiles in [4 þ 2] cycloadditions and reactive
carbonyl compounds;5 in 1998, Danheiser et al. reported
the photochemical Wolff rearrangement of R0-silyl-R0-
diazo-R,β-unsaturated ketones to afford trialkylsilyl vinyl
ketenes (Scheme 1, route b);6a in the same paper,6a thistype
of vinyl ketenes was also prepared by heating the R-silyl
cyclobutenone (Scheme 1, route c).6 Moreover, treatment
of the Fischer-type chromium carbene complexes with
silyl-substituted alkynes could also afford such vinyl
ketenes (Scheme 1, route d).7 Herein, we present our recent
unexpected observation for the synthesis of stereodefined
trimethylsilyl vinyl ketenes via an iron-catalyzed reaction
of 2-trimethylsilyl-2,3-allenoates with Grignard reagents
(Scheme 1, route e).
(1) Tidwell, T. T. Ketenes II; Wiley: Hoboken, NJ, 2006.
(2) For some representative examples, see: (a) Day, A. C.;
McDonald, A. N.; Anderson, B. F.; Bartczak, T. J.; R. Hodder,
O. J. J. Chem. Soc., Chem. Commun. 1973, 247. (b) Danheiser, R. L.;
Martinez-Davila, C.; Sard, H. Tetrahedron 1981, 37, 3943. (c) Danheiser,
R. L.; Gee, S. K.; Sard, H. J. Am. Chem. Soc. 1982, 104, 7670. (d) Berge,
J. M.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta 1982, 65, 2230. (e)
Jackson, D. A.; Rey, M.; Dreiding, A. S. Tetrahedron Lett. 1983, 24, 4817.
(f) Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49, 1672. (g)
Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller, R. F. J. Am.
Chem. Soc. 1990, 112, 3093. (h) Collomb, D.; Doutheau, A. Tetrahedron
Lett. 1997, 38, 1397.
(3) Danheiser, R. L.; Sard, H. J. Org. Chem. 1980, 45, 4810.
(4) For reviews of the chemistry of silylketenes, see ref 1 and (a)
Pommier, A.; Kocienski, P.; Pons, J.-M. J. Chem. Soc., Perkin Trans. 1
1998, 2105. (b) Pons, J.-M.; Kocienski, P. J. In Science of Synthesis;
Fleming, I., Ed.; Thieme: Stuttgart, 2001; Vol. 4, p 657. (c) George, D. M.;
Danheiser, R. L. In Science of Synthesis; Danheiser, R. L., Ed.; Thieme:
Stuttgart, 2006; Vol. 23, p 53.
(5) (a) Bennett, D. M.; Okamoto, I.; Danheiser, R. L. Org. Lett. 1999,
1, 641. (b) Loebach, J. L.; Bennett, D. M.; Danheiser, R. L. J. Am. Chem.
Soc. 1998, 120, 9690. (c) Dalton, A. M.; Zhang, Y.; Davie, C. P.;
Danheiser, R. L. Org. Lett. 2002, 4, 2465. (d) Rigby, J. H.; Wang, Z.
Org. Lett. 2003, 5, 263. (e) Davie, C. P.; Danheiser, R. L. Angew. Chem.,
Int. Ed. 2005, 44, 5867. (f) Austin, W. F.; Zhang, Y.; Danheiser, R. L.
Tetrahedron Lett. 2008, 64, 915.
(6) (a) Loebach, J. L.; Bennett, D. M.; Danheiser, R. L. J. Org. Chem.
1998, 63, 8380. (b) Benda, K.; Knoth, T.; Danheiser, R. L.; Schaumann,
E. Tetrahedron Lett. 2011, 52, 46.
€
(7) (a) Dotz, K. H. Angew. Chem., Int. Ed. Engl. 1979, 18, 954. (b)
€
€
€
Dotz, K. H.; Fugen-Koster, B. Chem. Ber. 1980, 113, 1449. (c) Wulff,
W. D.; Tang, P.-C. J. Am. Chem. Soc. 1984, 106, 1132. (d) Wulff, W. D.;
Xu, Y.-C. J. Org. Chem. 1987, 52, 3263. (e) Moser, W. H.; Sun, L.;
Huffman, J. C. Org. Lett. 2001, 3, 3389. (f) Li, Z.; Moser, W. H.; Zhang,
W.; Hua, C.; Sun, L. J. Organomet. Chem. 2008, 693, 361.
(8) (a) Tsuji, J.; Sugiura, T.; Minami, I. Tetrahedron Lett. 1986, 27,
731. (b) Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997,
62, 367.
r
10.1021/ol3016176
XXXX American Chemical Society

Table 1. Optimization of the Reaction Conditions
Scheme 1. Synthesis of Trimethylsilyl Vinyl Ketenes
yielda (%)
entry
cat.
solvent
Z-2a (Z/E)a
Z-3a (Z/E)a
1b
2b
3c
Fe(acac)3
ꢀ
Et2O
Et2O
Et2O
Et2O
THF
48 (92/8)
30 (95/5)
88 (g99/1)
49 (92/8)
48 (86/14)
69 (95/5)
45 (94/6)
84 (g99/1)
65 (95/5)
75 (97/3)
11 (g98/2)
14 (90/10)
3 (g99/1)
4 (79/21)
Fe(acac)3
ꢀ
4c
5c
6c
Fe(acac)3
Fe(acac)3
Fe(acac)3
FeCl3
8 (g99/1)
14 (g98/2)
16 (g99/1)
4 (g99/1)
9 (g99/1)
10 (g99/1)
2-Trimethylsilyl-2,3-allenoates could be easily prepared
from the Pd-catalyzed methylcarboxylation of propargylic
mesylates by the reported procedure (Scheme 2).8
toluene
CH2Cl2
Et2O
Et2O
Et2O
7c,d
8c
9c
FeCl3 6H2O
3
10e
FeCl3 6H2O
3
Scheme 2. Synthesis of 2-Trimethylsilyl-2,3-allenoates
a Determined by NMR spectroscopy using dibromomethane as the
internal standard based on the integral area of vinyl hydrogen. b The
reaction was conducted at rt for 1 h. c The reaction was conducted at
ꢀ78 °C for 0.5 h, followed by warming up to rt for 2 h. d Substrate 1a was
recovered in 14% yield. e CH3MgBr (1.2 equiv) was used.
conjugate additionꢀprotonation product 3a due to the
presenceofH2O inFeCl3 6H2O (entries 9and 10, Table 1).
3
Finally, we defined the reaction of 2-trimethylsilyl-2,3-
allenoates with 1.1 equiv of Grignard reagents (solution
in Et2O) in Et2O at ꢀ78 °C in the presence of 2 mol %
of Fe(acac)3 followed by warming to rt as the standard
reaction conditions for the formation of trimethylsilyl
vinyl ketenes Z-2.
During further study on iron-catalyzed conjugate addi-
tion of 2,3-allenoates with Grignard reagents,9 we acciden-
tally found that the reaction of 2,3-allenoate 1a with
1.1 equiv of CH3MgBr (3 M solution in Et2O) in Et2O at
rt afforded an unknown new product 2a. Through careful
spectroscopic analysis (1H and 13C NMR, IR, and MS), 2a
was confirmed to have a trimethylsilyl vinyl ketene unit!
However, the Z/E selectivity (92:8) is poor. After extensive
screening of the reaction conditions, we were glad to
observe that when the reaction was conducted at ꢀ78 °C
in the presence of 2 mol % of Fe(acac)3 for 0.5 h followed
by warming up to rt, the yield of Z-2a could be improved
to 88% with excellent Z-stereoselectivity (g99/1) (entry 3,
Table 1). In the absence of catalyst the reaction afforded
Z-2a in a lower yield (entry 4, Table 1). Other solvents such
as THF, toluene, and CH2Cl2 also failed to afford better
results (entries 5ꢀ7, Table 1). It is worth noting that when
FeCl3 was used instead of Fe(acac)3, the ketene product
could also be obtained in a considerable although some-
The scope of this reaction was then investigated underthe
standard conditions (Table 2): the reaction is quite general
and proceeded very smoothly with a variety of 2-trimethyl-
silyl-2,3-allenoates and Grignard reagents: primary, sec-
ondary, and tertiary alkyl groups are all well tolerated,
affording corresponding trimethylsilyl vinyl ketenes
Z-2aꢀZ-2m in moderate to excellent yields under standard
conditions (entries 1ꢀ13, Table 2). However, it should be
noted that when primary alkyl Grignard reagents other
than CH3MgBr, i.e., EtMgBr and n-C5H11MgBr, were
used, slightly lower stereoselectivities and yields were
observed (entries 6 and 7, Table 2). A tert-butyl Grignard
reagent (1.3 equiv) was needed to complete the reaction
with 1a presumably due to the steric effect of the tert-butyl
group (entry 13, Table 2). In addition to alkyl Grignard
reagents, a phenyl Grignard reagent may also be used to
afford corresponding trimethylsilyl vinyl ketenes Z-2n and
Z-2o in slightly lower yields (entries 14ꢀ15, Table 2). When
vinyl magnesium bromide (1.0 M solution in THF) was
used, the reaction was conducted in toluene and warmed up
to 30 °C instead of rt, after 1 h at ꢀ78 °C, affording a 65%
yield (entry 16, Table 2). In addition, the reaction can be
easily conducted at a scale of 3.0 mmol of the substrate 1d
for a similar yield (entry 17, Table 2).
what lower yield (entry 8, Table 1). The use of FeCl3 6H2O
as the catalyst also led to a lower yield of Z-2a with more
3
(9) (a) Lu, Z.; Chai, G.; Ma, S. J. Am. Chem. Soc. 2007, 129, 14546.
(b) Lu, Z.; Chai, G.; Zhang, X.; Ma, S. Org. Lett. 2008, 10, 3517.
(c) Chai, G.; Lu, Z.; Fu, C.; Ma, S. Adv. Synth. Catal. 2009, 351, 1946.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Scope of the Reactiona
Scheme 3. Rationale for the Formation of Trimethylsilyl Vinyl
Ketene Z-2a
entry
R1
R2
CH3
Z-2, yieldb (%)
1
n-C4H9 (1a)
Z-2a, 77
Z-2b, 81
Z-2c, 78c
Z-2d, 82
Z-2e, 82
Z-2f, 63d
Z-2g, 50e
Z-2h, 80
Z-2i, 83
Z-2j, 80c
Z-2k, 85
Z-2l, 91
Z-2m, 90
Z-2n, 60
Z-2o, 59
Z-2p, 65
Z-2d, 74
2
n-C9H19 (1b)
c-C6H11 (1c)
CH3
3
CH3
4
CH2dCH(CH2)8 (1d)
Ph(CH2)2 (1e)
n-C4H9 (1a)
CH3
5
CH3
6
Et
addition product Z-3b was afforded in 29% yield (entry 1,
Table 3). No ketene or its related product was formed even
when 2.4 equiv of CH3MgBr were used9 (entry 2, Table 3;
see also Scheme 3) or the temperature was raised up
(entry 4, Table 3): the conjugate additionꢀprotonation
product Z-3b was formed in 49% or 51% yields, respec-
tively, indicating the importanceofthe trimethylsilylgroup
in the current transformation.10
7
n-C4H9 (1a)
n-C5H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
t-C4H9
Ph
8
n-C4H9 (1a)
9
n-C9H19 (1b)
c-C6H11 (1c)
10
11
12
13f
14
15
16g
17h
CH2dCH(CH2)8 (1d)
t-C4H9 (1f)
n-C4H9 (1a)
n-C9H19 (1b)
c-C6H11 (1c)
Ph
Since the trimethylsilyl vinyl ketenes are now easily
available, in addition to what is already known,5 synthetic
potentials have been further extensively explored:
n-C4H9 (1a)
Vinyl
CH3
CH2dCH(CH2)8 (1d)
a The reaction was conducted with 0.6 mmol of 2,3-allenoates, 5 mL
of Et2O, and 1.1 equiv of RMgX in Et2O (3.0 M solution for CH3MgBr,
3.0 M solution for EtMgBr, 2.0 M solution for n-C5H11MgBr, 2.0 M
solution for c-C6H11MgCl, 3.0 M solution for PhMgBr, and 1.7 M
(1) The resulting trimethylsilyl vinyl ketenes Z-2a and
Z-2d could further react with primary, secondary,
and tertiary alkyl organolithium reagents affording
R-silyl-β,γ-unsaturated enones Z-4, which are
synthetically very useful because of the allylic silane
moiety,12 yet difficult to prepare due to the pre-
sence of the nonconjugated CdC bond, ketone,
and the silyl group (Scheme 4).
t
solution for BuMgCl) or vinyl magnesium bromide (1.0 M solution
in THF). Z/E g 99/1 unless other noted. b Isolated yield. c Z/E g 98/2.
d Z/E = 96/4. e Z/E = 93/7. f t-BuMgCl (1.3 equiv) was used. g The
reaction was conducted in toluene and warmed up to 30 °C instead of
rt after 1 h at ꢀ78 °C. h The reaction was conducted with a 3.0 mmol scale
(0.9261 g) of 1d.
In addition, it was observed that the reaction bet-
ween trimethylsilyl vinyl ketenes Z-2 and Grignard
reagents is very slow; thus, the one-pot synthesis
of product Z-4e from 2,3-allenoate 1c could be
realized in a 50% yield by sequential addition of
CH3MgBr and t-BuLi, although the yield of the
three-step synthesis of Z-4e without purification
of the ketene intermediate is much higher (76%)
(Scheme 5). Accordingly, the starting 2,3-allenoate
1 may be viewed as synthon A.
After careful study, it was observed that the reaction of
1a with 1.1 equiv of CH3MgBr (3 M solution in Et2O) in
Et2O at rt also afforded the conjugate addition product
allylsilane Z-3a in 11% yield, together with trimethylsilyl
vinyl ketene Z-2a (entry 1, Table 1). Thus, we believed that
after the formation of the magnesium 1,3-dienolate inter-
mediate generated from the conjugate addition of 2-tri-
methylsilyl-2,3-allenoate 1a with the Grignard reagent,9
elimination of the methoxy group would afford the tri-
methylsilyl vinyl ketene product Z-2a (Scheme 3).10,11
Due to fact that such an elimination of ROLi from
lithium ester enolates forming ketenes is known,9 reac-
tions of 2-butyl-4-cyclohexyl-2,3-butadienoate 1g with
CH3MgBr under different conditions were conducted
(Table 3). Under the standard conditions, the conjugate
(2) Further in situ trapping of the reaction inter-
mediate with acyl chloride would afford polysub-
stituted triene 5(Z),7(Z)-5 highly stereoselectively
(Scheme 6).
(3) It could also be utilized as a four-carbon building
block in the construction of polysubstituted phenol
6 by a DielsꢀAlder reaction with highly electron-
deficient DMAD.3 It is worth noting that the
reaction may also proceed with ethyl propionate
(10) For a report on the formation of a ketene facilitated by the
presence of two silyl groups via such an elimination of LiOBut, see:
Sullivan, D. F.; Woodbury, R. P.; Rathke, M. W. J. Org. Chem. 1977, 42,
2038.
(11) For the generation of normal ketene intermediates from such an
elimination of a lithium anion generated from the treatment of carbox-
(12) Allylsilanes are important intermediates for carbonꢀcarbon and
carbonꢀheteroatom bond formation in organic synthesis because of
their easy handling, unique reactivity, and high regiocontrollability. For
reviews, see: (a) Hosomi, A. Acc. Chem. Res. 1988, 21, 200. (b)
Langkopf, E.; Schinzer., D. Chem. Rev. 1995, 95, 1375. (c) Chabaud,
L.; James, P.; Landais., Y. Eur. J. Org. Chem. 2004, 3173. (d) Hosomi,
A.; Miura., K. Bull. Chem. Soc. Jpn. 2004, 77, 835.
€
ylates with a lithium base followed by in situ trapping, see: (a) Haner, R.;
Laube, T.; Seebach, D. J. Am. Chem. Soc. 1985, 107, 5396. (b) Seebach,
D.; Amstutz, R.; Laube, T.; Schweizer, W. B.; Dunitz, J. D. J. Am.
Chem. Soc. 1985, 107, 5403. (c) Tomioka, K.; Shindo, M.; Koga, K. J.
Org. Chem. 1990, 55, 2276. (d) Tanaka, T.; Otsubo, K.; Fuji, K. Synlett
1995, 933. (e) Barbero, A.; Pulido, F. J. Synlett 2001, 827.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Reactions of 2-Butyl-4-cyclohexyl-2,3-butadienoate 1g
with CH3MgBr under Different Conditions
Scheme 5. Synthesis of Z-4e from 1c
entry
n
yielda of Z-3b (%) (Z/E)a
1
1.1
2.4
1.2
1.2
29 (g98/2)
51 (g99/1)
90c (g96/4)
49 (g98/2)
2
3b
4d
a Determined by NMR spectroscopy using dibromomethane as the
internal standard. b The reaction was quenched directly at ꢀ78 °C
instead of warming up to rt, and the conversion was 98%. c Isolated
yield. d The reaction was conducted at ꢀ78 °C for 1 h, then warmed up to
ꢀ20 °C by gradient heating (ꢀ60 °C, 1 h; then ꢀ40 °C, 2 h; then ꢀ20 °C,
2 h), and quenched at ꢀ20 °C.
Scheme 4. Synthesis of R-Silyl-β,γ-unsaturated Enones Z-4
from Z-2
Scheme 6. Tandem Reaction of Trimethylsilyl Vinyl Ketene
Z-2d, n-BuLi, and Acyl Chloride
Scheme 7. Synthesis of Phenols 6 and 7
to afford phenol 7 regiospecifically (Scheme 7).5a
It should be noted that the [1,5]-shift reaction of
Z-2a was not observed probably due to the presence
of an excess amount of the electron-deficient
alkynes.13
In conclusion, we disclose here a convenient synthesis of
trimethylsilyl vinyl ketenes by elimination of MeOMgX
from the magnesium 1,3-dienolate intermediate generated
in situ from the conjugate addition of Grignard reagents
with the readily available 2-trimethylsilyl-2,3-allenoates.6
In addition, the resulting products could be easily con-
verted to polysubstituted stereodefined R-silyl-β,γ-unsatu-
rated enones, stereodefined triene, and phenols with
high stereoselectivity. Considering the diversity of both
starting materials and broad applications of the products,
especially the presence of the silyl group, this protocol will
be of high interest in organic chemistry and related
disciplines.
Acknowledgment. Financial support from the National
Basic Research Program of China (2011CB808700) is
greatly appreciated. S.M. is a Qiu Shi Adjunct Professor
at Zhejiang University. We thank Mr. J. Cheng in our
group for reproducing the results presented in entries 4, 7,
and 15 of Table 2 and 4b in Scheme 4.
Supporting Information Available. General procedure
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) For the [1,5]-H shift of ketenes affording aldehydes, see: Pirkle,
W. H.; Seto, W. H.; Turner, W. V. J. Am. Chem. Soc. 1970, 92, 6984.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX