A straightforward approach towards substituted morita-baylis-hillman products via hydrostannation of acetylenic ketones

Article abstract of DOI:10.1055/s-0029-1219196

Regioselective molybdenum-catalyzed hydrostannations of acetylenic ketones give rise to allenoxystannanes, which can be subjected to subsequent aldol reactions. Because aldehydes are not affected under the reaction conditions used, the hydrostannation-aldol addition can be performed as a one-pot reaction, providing easy access to substituted Morita-Baylis-Hillman-type products in a highly stereoselective fashion. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219196

LETTER
407
A Straightforward Approach towards Substituted Morita–Baylis–Hillman
Products via Hydrostannation of Acetylenic Ketones
Hydrostannation
.
of Acetyleni
V
c
K
etones asantha Lakshmi, Uli Kazmaier*
Institut für Organische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received 21 October 2009
Dedicated to Prof. M. Veith on the occasion of his 65th birthday
Hydrostannations of a,b-acetylenic ketones and esters are
also found to be highly regioselective, especially in tran-
sition-metal-catalyzed reactions.9 While the a-stannylated
a,b-unsaturated esters are relatively stable compounds,
Abstract: Regioselective molybdenum-catalyzed hydrostannations
of acetylenic ketones give rise to allenoxystannanes, which can be
subjected to subsequent aldol reactions. Because aldehydes are not
affected under the reaction conditions used, the hydrostannation–
aldol addition can be performed as a one-pot reaction, providing which can be separated, for example, by flash chromatog-
raphy,10 the corresponding ketones are much more trou-
easy access to substituted Morita–Baylis–Hillman-type products in
a highly stereoselective fashion.
blesome. Here, often mixtures of regio- and stereoisomers
Key words: aldol addition, alkynes, enolates, hydrostannation,
molybdenum, Morita–Baylis–Hillman
are obtained, and complete protodestannation during
workup is a severe problem.11 These difficulties can be
circumvented by using trineophyltin hydride, instead of
the usually applied tributyl or trimethyl analogues. As il-
During the last decades the Morita–Baylis–Hillman lustrated by Mitchell et al. good selectivities are obtained
(MBH) reaction has developed into a powerful tool in or- under Pd-catalyzed conditions, and these a-stannylated
ganic synthesis, giving rise to highly functionalized build- vinylketones can be purified by flash chromatography and
ing blocks.1 The reaction can be described as the coupling subjected to cross-coupling reactions or metal–iodine ex-
between the a-position of an activated double bond with change without problems.12
an electrophile, in general an aldehyde or an imine.2 A
O
XH
O
rich chemistry has been developed to convert the MBH
adducts into other valuable products, for example, via al-
lylic alkylations3 and other cross-coupling reactions.4 The
reaction is initiated by the addition of a nucleophilic cata-
lyst, in general a phosphine or an amine, towards the elec-
tron-poor double bond. Therefore, best results are
obtained with acylates or vinylketones giving rise to a-
methylene aldol products A (Scheme 1). Related struc-
tures with a b-substituted double bond, which might be
even more interesting building blocks, are not so easily
accessible by this protocol. Therefore, several other ap-
proaches have been developed during the last years.5
NR33 or PR3
X
3
+
Y
R1
Y
R1
H
X = O, NR2 Y = OR2, R2
A
O
OH
O
I
OH
O
R1
H
R3X
Pd0
TMSI
Cat.
R1
OR2
R1
OR2
+
COOR2
R3
B
HO R2
O
O
Cy2BH
Very recently, Ryu et al. reported on an enantioselective
Lewis acid catalyzed addition of alkynoates towards alde-
hydes giving rise to b-iodinated MBH esters B, which
could be subjected to further cross-coupling reactions.6
An alternative approach could be the hydrometalation of
alkynyl ketones or esters,7 if the a-metalated vinylic car-
bonyls are formed preferentially and if these undergo al-
dol additions. Kabalka et al. reported such an approach
using hydroborations.8 a,b-Acetylenic ketones could be
coupled via in situ formed allenoxyborinates to stereode-
fined substituted MBH-type products C. By using t-Bu-
ketones (R2 = t-Bu), these borinates could be trapped also
with several aldehydes.
R2
2
R2
R1
R1
R1
C
Scheme 1 Synthesis of MBH-type products
Our group is also involved in hydrostannation chemistry
for some time,13 and we developed a series of catalysts
based on molybdenum and tungsten.14 The most reliable
and generally applicable catalyst is Mo(CO)3(CNt-Bu)3
(MoBl3),15 which shows high a-selectivities in reactions
of functionalized electron-poor alkynes.16 Best results are
obtained under a CO atmosphere, while the CO can inter-
act as a ligand in the catalytic cycle.17 In analogy to the
Pd-catalyzed reactions, we received a-stannylated a,b-un-
saturated esters in a highly regio- and stereoselective fash-
ion, while the corresponding ketones could not be
isolated, although the conversion of the starting material
SYNLETT 2010, No. 3, pp 0407–0410
1
2.
0
2.
2
0
1
0
Advanced online publication: 14.01.2010
DOI: 10.1055/s-0029-1219196; Art ID: G35209ST
© Georg Thieme Verlag Stuttgart · New York

408
B. V. Lakshmi, U. Kazmaier
LETTER
was fast and complete. Trapping of the hydrostannation A similar result was obtained with 2-naphthaldehyde (en-
products with iodine gave the expected a-iodoketones try 2), while the introduction of electron-donating groups
with high regioselectivity.15a,b This clearly indicates that (entries 3 and 4) resulted in a significant drop of yield,
the expected hydrostannation product was formed, but whereas the Z/E-selectivity was nearly unchanged in the
probably not as the a-stannated product (as observed for range of 20:1. On the other hand, introduction of electron-
the corresponding esters), but as the allenoxystannane, withdrawing groups increased the yields to 70–75% (en-
comparable to the allenoxyborinates described by Kabal- tries 5–8). This differentiated reactivity allowed the selec-
ka.8
tive monoaddition towards terephthalaldehyde (entry 7).
Not unexpected the best result was obtained with the very
electron-poor dinitrobenzaldehyde (entry 9). Heterocyclic
aldehydes can be used with similar success. Electron-de-
manding aldehydes, such as pyridine carbaldehyde (entry
10), gave good yields, while no reaction was observed
with the five-membered heterocyclic aldehydes, such as
furan carbaldehyde. Unfortunately, aliphatic aldehydes
gave low yields of impure products.
In this case one should be able to trap the tin enolates with
electrophiles, such as aldehydes, to get directly b-substi-
tuted MBH products.
Therefore, we investigated the hydrostannation of ketone
1 in detail (Scheme 2). In principle, two isomeric hy-
drostannation products can be formed: the a-stannane 2
and the b-metalated ketone 3. But only 2 can form the tin
enolate 2¢, and therefore trapping the reaction mixture
with aldehyde should provide 4 and unconverted 3, which
can easily be separated by flash chromatography.
Table 1 MBH Products 4 via One-Pot Hydrostannation–Aldol
Reaction
O
O
OH
MoBI3 (3 mol%)
Bu3SnH (1.2 equiv)
R
O
O
O
THF, CO, 60 °C, 6 h
hydroquinone
Bu3SnH
MoBI3
+
1
SnBu3
+
SnBu3
(Z)-4
RCHO
3
2
1
Entry
R
Product
Yield (%) Ratio Z/E
1
2
Ph
4a
4b
4c
4d
4e
4f
40
45
15
10
69
73
75
75
95
72
92:8
96:4
95:5
96:4
97:3
95:5
94:6
97:3
98:2
94:6
OSnBu3
RCHO
O
2-Naph
OH
3
4-MeC6H4
4-MeOC6H4
3,4-Cl2C6H3
4-F3CC6H4
4-OHCC6H4
4-O2NC6H4
2,4-(O2N)2C6H3
2-Py
R
4
2'
4
MoBI3 = Mo(CO)3(CNt-Bu)3
5
Scheme 2 MBH products 4 via one-pot hydrostannation–aldol reac-
6
tion
7
4g
4h
4i
In principle, the hydrostannation occurs already at room
temperature, but the reaction is rather slow. Only 10–20%
conversion was observed after six hours, while at 60 °C
the ketone 1 was completely consumed. Therefore, we
used these conditions for the development of a one-pot
protocol. Hydroquinone was added to suppress possible
radical side reactions, and the reactions were investigated
under an atmosphere of CO to get good a-selectivities.17b
To prove if the aldehyde can be added directly at the be-
ginning of the reaction or if it has to be added after enolate
formation, we subjected it to the same reaction conditions.
Luckily, no reduction was observed. Therefore, we used
this combination to evaluate the one-pot protocol
(Table 1, entry 1).18 With benzaldehyde, the coupling
product 4a was obtained in 40% yield as a 8:92 E/Z-mix-
ture. The product ratio could easily be determined by
NMR using the very characteristic signal for the vinylic b-
H.19 For the preferentially formed Z-isomers this signal
appear typically around d = 6 ppm, while in the E-isomer
the signal shows a downfield shift of 1 ppm, (d = ca. 7
ppm).20
8
9
10
4k
To prove if this one-pot protocol can also be applied to
aliphatic ketones such as 5, or if isomerization of the tin
enolate provides regioisomeric products, we reacted 5
with the nitro-substituted aldehydes (Scheme 3). Al-
though no enolate isomerization was observed, with these
ketones the reactions were not as clean as with the aromat-
ic ketones, and always 20–30% of the ketone was recov-
ered, even when the tin hydride was used in threefold
excess.
In this case, the addition of the aldehyde after the hy-
drostannation was found to be more effective and the
yields could be increased to a preparative useful range.
Here, an interesting observation was made. In both cases
the Z-isomers were formed with excellent stereoselectivi-
Synlett 2010, No. 3, 407–410 © Thieme Stuttgart · New York

LETTER
Hydrostannation of Acetylenic Ketones
409
(3) (a) Trost, B. M.; Brennan, M. K. Org. Lett. 2007, 9, 3961.
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OSnBu3
Ph
O
OSnBu3
Ph
Bu3SnH
MoBI3
Ph
5
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CHO
O2N
R
O
OH
R
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Chem. 2009, 74, 6681.
Ph
NO2
98% (Z)
5 d
6a R = H
6b R = NO2 50%
42%
O
OH
R
Ph
NO2
98% (E)
Scheme 3 MBH products from aliphatic ketones and isomerization
ty (98%), as determined by NMR. But remeasuring the
NMR samples after a few days showed a complete
isomerization to the corresponding E-products (98%).20
Similar isomerizations were also reported previously, but
not completely as in our case.
(6) Senapati, B. K.; Hwang, G.-S.; Lee, S.; Ryu, D. H. Angew.
Chem. 2009, 121, 4462.
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M.; Ball, Z. T. Synthesis 2005, 853.
(8) (a) Kabalka, G. W.; Yu, S.; Li, N.-S.; Lipprandt, U.
Tetrahedron Lett. 1999, 40, 37. (b) Yu, S.; Li, N.-S.;
Kabalka, G. W. J. Org. Chem. 1999, 64, 5822.
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1990, 55, 1857. (b) Trost, B. M.; Li, C. J. Synthesis 1994,
1267.
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33, 4495. (b) Rossi, R.; Carpita, A.; Cossi, P. Synth.
Commun. 1993, 23, 143. (c) Sai, H.; Ogiku, T.; Nishitani,
T.; Hiramatsu, H.; Horikawa, H.; Iwasaki, T. Synthesis 1995,
582.
(11) (a) Cochran, J. C.; Bronk, B. S.; Terrence, K. M.; Phillips,
H. K. Tetrahedron Lett. 1990, 31, 6621. (b) Bellina, F.;
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J. C. J. Organomet. Chem. 2002, 650, 173. (b) Dodero, V.
I.; Koll, L. C.; Faraoni, M. B.; Mitchell, T. N.; Podesta, J. C.
J. Org. Chem. 2003, 68, 10087.
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(b) Deska, J.; Kazmaier, U. Angew. Chem. Int. Ed. 2007, 46,
4570; Angew. Chem. 2007, 119, 4654. (c) Kazmaier, U.;
Dörrenbächer, S.; Wesquet, A.; Lucas, S.; Kummeter, M.
Synthesis 2007, 320. (d) Wesquet, A. O.; Kazmaier, U.
Angew. Chem. Int. Ed. 2008, 47, 3050; Angew. Chem. 2008,
120, 3093.
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26.
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1, 1017. (b) Kazmaier, U.; Pohlman, M.; Schauß, D. Eur. J.
Org. Chem. 2000, 2761. (c) Braune, S.; Pohlman, M.;
In conclusion we could show that the hydrostannation of
acetylenic ketones can be used for the synthesis of MBH-
type adducts by trapping the in situ formed enolates with
aromatic aldehydes. Further attempts to improve the sub-
strate range and investigations concerning the isomeriza-
tion mechanisms are currently under way.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
and by the Fonds der Chemischen Industrie.
References and Notes
(1) For recent reviews, see: (a) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811.
(b) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev.
2007, 36, 1581. (c) Masson, G.; Housseman, C.; Zhu, J.
Angew. Chem. Int. Ed. 2007, 46, 4614; Angew. Chem. 2007,
119, 4698. (d) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007,
2905; and references cited therein.
(2) For a very recent review on aza-Morita–Baylis–Hillman
reactions, see: Declerck, V.; Martinez, M.; Lamaty, F.
Chem. Rev. 2009, 109, 1.
Synlett 2010, No. 3, 407–410 © Thieme Stuttgart · New York

410
B. V. Lakshmi, U. Kazmaier
LETTER
Kazmaier, U. J. Org. Chem. 2004, 69, 468. (d) Wesquet,
A. O.; Dörrenbächer, S.; Kazmaier, U. Synlett 2006, 1105.
7.26 (m, 2 H), 7.23–7.19 (m, 1 H), 5.91 (td, J = 7.6, 1.2 Hz,
1 H), 5.55 (s, 1 H), 3.24 (br s, 1 H, OH), 1.79 (q, J = 7.6 Hz,
2 H), 1.31 (sext, J = 7.6 Hz, 2 H), 0.75 (t, J = 7.6 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): d = 200.1, 141.5, 141.4,
137.7, 134.7, 133.3, 129.2, 128.4, 128.3, 127.6, 126.3, 76.5,
31.7, 22.2, 13.5 ppm. HRMS (CI): m/z calcd for C19H20O2
[M]+: 280.1463; found: 280.1461.
(16) (a) Kazmaier, U.; Schauß, D.; Pohlman, M.; Raddatz, S.
Synthesis 2000, 914. (b) Kazmaier, U.; Schauß, D.; Raddatz,
S.; Pohlman, M. Chem. Eur. J. 2001, 7, 456. (c) Kazmaier,
U.; Wesquet, A. O. Synlett 2005, 8, 1271. (d) Jena, N.;
Kazmaier, U. Eur. J. Org. Chem. 2008, 3852.
(17) (a) Lin, H.; Kazmaier, U. Eur. J. Org. Chem. 2009, 1221.
(b) Wesquet, A. O.; Kazmaier, U. Adv. Synth. Catal. 2009,
1395.
Aldol Product (Z)-6a
1H NMR (400 MHz, CDCl3): d = 8.13 (d, J = 8.4 Hz, 2 H),
7.45 (d, J = 8.4 Hz, 2 H), 7.25–7.03 (m, 3 H), 7.06 (dd,
J = 8.4, 1.6 Hz, 2 H), 5.92 (t, J = 7.6 Hz, 1 H), 5.42 (s, 1 H),
3.27 (br s, 1 H, OH), 2.90–2.70 (m, 4 H), 2.18 (q, J = 7.6 Hz,
2 H), 1.45 (sext, J = 7.6 Hz, 2 H), 0.91 (t, J = 7.6 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): d = 203.0, 150.6, 147.0,
146.9, 140.6, 140.5, 128.5, 128.3, 126.2, 126.0, 123.5, 69.8,
39.5, 30.8, 30.1, 22.0, 14.0 ppm.
(18) General Procedure for One-Pot Hydrostannation–Aldol
Additions
The acetylenic ketone (1.0 mmol), hydroquinone (10 mol%),
and Mo(CO)3 (CNt-Bu)3 (MoBI3) (3 mol%) were dissolved
in THF (3 mL) in a Schlenk tube under N2. Then Bu3SnH
(1.2 mmol) and the corresponding aldehyde (1.2 mmol) were
added, the flask was evacuated and flushed with CO. The
mixture was warmed to 60 °C for 6 h. After cooling to r.t.,
the solvent was removed in vacuo, and the reaction mixture
was subjected to column chromatography (silica, EtOAc–
hexanes).
Aldol Product (E)-6a
1H NMR (400 MHz, CDCl3): d = 8.14 (d, J = 8.8 Hz, 2 H),
7.47 (d, J = 8.8 Hz, 2 H), 7.29–7.18 (m, 3 H), 7.11 (dd,
J = 8.4, 1.6 Hz, 2 H), 6.87 (t, J = 7.6 Hz, 1 H), 5.69 (s, 1 H),
3.08–2.91 (m, 2 H), 2.85 (t, J = 7.6 Hz, 2 H), 2.43 (sext,
J = 7.6 Hz, 1 H), 2.34 (sext, J = 7.6 Hz, 1 H), 1.56 (sext d,
J = 7.6, 2.0 Hz, 2 H), 1.00 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): d = 203.0, 150.6, 147.0, 146.9, 140.6,
140.5, 128.5, 128.3, 126.3, 126.0, 123.5, 69.9, 39.5, 30.8,
30.1, 22.0, 14.0 ppm. HRMS (CI): m/z calcd for C21H23NO4
[M]+: 353.1627; found: 353.1647.
(19) Leonard, W. R.; Livinghouse, T. J. Org. Chem. 1985, 50,
730.
(20) Analytical Data of Selected Products
Aldol Product 4a
1H NMR (400 MHz, CDCl3): d = 7.73 (dd, J = 8.4, 1.6 Hz, 2
H), 7.50 (tt, J = 7.6, 1.6 Hz, 1 H), 7.40–7.34 (m, 4 H), 7.32–
Synlett 2010, No. 3, 407–410 © Thieme Stuttgart · New York

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