Cross-coupling reactions of two different activated alkenes through tetrabutylammonium fluoride (TBAF) promoted deprotonation/activation strategy: A regioselective construction of quaternary carbon centers

Article abstract of DOI:10.1021/ol1028332

A novel TBAF-promoted intermolecular crossed-conjugate addition has been developed. For a range of cyclic β-halo-α,β-unsaturated carbonyl compounds, the vinylogous enolates generated by deprotonation at the γ-position preferentially reacted with Michael a

Full text of DOI:10.1021/ol1028332

ORGANIC
LETTERS
2011
Vol. 13, No. 2
176-179
Cross-Coupling Reactions of Two
Different Activated Alkenes through
Tetrabutylammonium Fluoride (TBAF)
Promoted Deprotonation/Activation
Strategy: A Regioselective Construction
of Quaternary Carbon Centers
Jing-Li Zhang and Yue-Fa Gong*
Department of Chemistry, Huazhong UniVersity of Science and Technology, 1037
Luoyu Road, Wuhan, 430074, China
gongyf@mail.hust.edu.cn
Received September 8, 2010
ABSTRACT
A novel TBAF-promoted intermolecular crossed-conjugate addition has been developed. For a range of cyclic ꢀ-halo-r,ꢀ-unsaturated carbonyl
compounds, the vinylogous enolates generated by deprotonation at the γ-position preferentially reacted with Michael acceptors at the r-position
to deliver cross-coupling products in good yields.
Carbon-carbon bond formation is of significant importance
in organic synthesis, with much research focused on dis-
covering new, high efficiency, and selective reactions.
Among many synthons for the formation of new C-C bonds,
the electron-withdrawing group (EWG) activated alkene is
considered one of the most fundamental building blocks in
the construction of organic molecules. Its great reaction mode
is the long-known conjugate 1,4-addition (Michael addition).
Another important reaction of EWG-activated alkenes is the
Lewis base promoted Morita-Baylis-Hillman (MBH) reac-
tion, which merges the concepts of conjugate addition and
carbanionic nucleophilic addition.1 In addition to the MBH
reaction, any coupling of one active alkene/latent enolate to
a second Michael acceptor, creating a new C-C bond
between the R-position of one activated alkene and the
ꢀ-position of a second alkene under the influence of a
nucleophilic catalyst is referred to as the Rauhut-Currier
(RC) reaction (Scheme 1, Option 1).2 The MBH or RC
reaction, as a simple, efficient, and atom-economical process,
which rapidly combines organic functionalities within a
single manipulation, provides the densely functionalized
products that serve as substrates for various attractive
transformations.
In comparison to the MBH reaction, the RC reaction has
received much less attention due to the low reactivity of
substrates and difficulty in controlling the selectivity of a
cross-coupling reaction. The main problem is that homo-
couplings compete under the reaction conditions, and the
products which are electron-deficient alkenes as well are
(2) (a) Rauhut, M. M.; Currier, H. U.S. Patent 3,074,999, 1963; Chem.
Abstr. 1963,58,11224a. . (b) Aroyan, C. E.; Dermenci, A.; Miller, S. J.
Tetrahedron 2009, 65, 4069–4084.
(1) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. ReV. 2007, 36,
1581–1588.
10.1021/ol1028332  2011 American Chemical Society
Published on Web 12/10/2010

natural products.9 One versatile access to all-carbon quater-
nary centers relies on the conjugated addition of enolates to
acceptor-activated olefins. In this paper, we present an
unprecedented tetrabutylammonium fluoride (TBAF) pro-
moted tandem deprotonation/crossed-conjugate addition be-
tween cyclic ꢀ-halo-R,ꢀ-unsaturated carbonyl compounds
and Michael acceptors, which affords a wide variety of 1,5-
difunctional compounds containing an all-carbon quaternary
center (Scheme 1, Option 2). This process is operationally
simple as well as atom economic and minimizes the reaction
time.
Scheme 1
.
Intermolecular Cross-Coupling Strategies of
Electron-Deficient Alkenes
Based on our previous research, we speculated that TBAF
would abstract a proton from cyclic ꢀ-chloro-enal at the
γ-carbon to generate a carbanion intermediate or enolate and
envisioned the carbanion intermediate could be intercepted
by a Michael acceptor. With this hypothesis in mind, we
initiated our investigation of cyclic ꢀ-chloro-enal 1a with
acrylonitrile 2a in the presence of TBAF in THF. To our
delight, such an intermolecular crossed-conjugate addition
could indeed be accomplished. The reaction at room tem-
perature proceeded smoothly within 3 min and gave a cross-
coupling product 3 in 71% yield possessing an all-carbon
quaternary center (Table 1, entry 1). However, no reaction
susceptible to polymerizations. In the past decade, significant
progress has been made in the intramolecular RC reactions
as well as in the enantioselective variants.3
Despite these advances in the intramolecular RC reactions,
currently available synthetic applications of intermolecular
RC reactions are sporadically documented in the literature.4
For example, Scheidt made progress in the intermolecular
RC reaction using silyloxyallenes catalyzed by a Lewis acid.5
Ma reported an efficient, tertiary amine mediated cross-RC/
acetalization of cyclic ꢀ-haloenals and ꢀ,γ-unsaturated
R-ketoesters.6 Recently, enantioselective intermolecular
crossed-conjugate additions between nitroalkenes and R,ꢀ-
enals through a dual activation were achieved by Shi’s
group.7 Moreover, there was also a report of crossed
intramolecular RC-type processes in the synthesis of the
iridoid framework.8 These notable works represent an
attractive strategy in C-C bond construction. However, to
date, there is still a lack of effective methodology for the
intermolecular crossed-conjugate addition of different acti-
vated alkenes, which will produce highly functionalized
products. On the other hand, the construction of a quaternary
center is a significant challenge in the total synthesis of
Table 1. Optimization of the Reaction Conditionsa
entry base (mol %) solvent temp (°C) timeb yield (%)c
1
2
3
4
5
6
7
8
TBAF(100)
KF(100)
THF
DMSO
THF
THF
THF
THF
THF
DMF
DMSO
CH3CN
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
20
15
3 min
48 h
48 h
71
-
-
DBU(100)
TBAF(25)
TBAF(50)
TBAF(75)
TBAF(125)
TBAF(100)
TBAF(100)
TBAF(100)
TBAF(100)
TBAF(100)
24 h
26
43
65
61
27
42
22
69
70
12 min
6 min
2 min
7 h
30 s
48 h
9
(3) For recent intramolecular RC reaction, see: (a) Mergott, D. J.; Frank,
S. A.; Roush, W. R. Org. Lett. 2002, 4, 3157–3160. (b) Agapiou, K.;
Krische, M. J. Org. Lett. 2003, 5, 1737–1740. (c) Methot, J. L.; Roush,
W. R. Org. Lett. 2003, 5, 4223–4226. (d) Jellerichs, B. G.; Kong, J. R.;
Krische, M. J. J. Am. Chem. Soc. 2003, 125, 7758–7759. (e) Mergott, D. J.;
Frank, S. A.; Roush, W. R. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11955–
11959. (f) Wang, L. C.; Luis, A. L.; Agapiou, K.; Jang, H. Y.; Krische,
M. J. J. Am. Chem. Soc. 2002, 124, 2402–2403. (g) Frank, S. A.; Mergott,
D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404–2405. (h) Aroyan,
C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 256–257. (i) Seidel, F.;
Gladysz, J. A. Synlett 2007, 986–988.
10
11
12
5 min
10 min
THF
a 1a (0.5 mmol), acrylonitrile (1.0 mmol), and Brønsted base in solvent
(3.0 mL). b Reaction time was determined by TLC. c Isolated yields.
occurred with KF due to its poor solubility in the solvent
(entry 2). Examination of other bases such as DBU (entry
3), Et3N, DABCO, DMAP, imidazole, and PPh3 revealed
that none of them displays activities in this reaction. When
25 mol % of TBAF was employed in THF, the reaction
proceeded slowly and afforded 3 in 26% yield after 24 h
(entry 4). Upon changing the amount of TBAF to 50 mol %
(4) (a) Hwu, J. R.; Hakimelahi, G. H.; Chou, C. T. Tetrahedron Lett.
1992, 33, 6469–6472. (b) Yin, Y. B.; Zhang, Q.; Li, J.; Sun, S. G.; Liu, Q.
Tetrahedron Lett. 2006, 47, 6071–6074. (c) Dadwal, M.; Mohan, R.; Panda,
D.; Mobin, S. M.; Namboothiri, I. N. N. Chem. Commun. 2006, 338–340.
(d) Sun, X. H.; Sengupta, S.; Petersen, J. L.; Wang, H.; Lewis, J. P.; Shi,
X. D. Org. Lett. 2007, 9, 4495–4498.
(5) Reynolds, T. E.; Binkley, M. S.; Scheidt, K. A. Org. Lett. 2008, 10,
2449–2452.
(6) Yao, W. J.; Wu, Y. H.; Wang, G.; Zhang, Y. P.; Ma, C. Angew.
Chem., Int. Ed. 2009, 48, 9713–9716.
(7) Zhong, C.; Chen, Y. F.; Petersen, J. L.; Akhmedov, N. G.; Shi, X. D.
Angew. Chem., Int. Ed. 2009, 48, 1279–1282.
(9) For reviews, see: (a) Christoffers, J.; Baro, A. Angew. Chem., Int.
Ed. 2001, 40, 4591–4597. (b) Douglas, C. J.; Overman, L. E. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5363–5367. (c) Trost, B. M.; Jiang, C. H.
Synthesis 2006, 369–396. (d) Cozzi, P. G.; Hilgarf, R.; Zimmermann, N.
Eur. J. Org. Chem. 2007, 5969–5994.
(8) Marque´s-Lo´pez, E.; Herrera, R. P.; Marks, T.; Jacobs, W. C.;
Ko¨nning, D.; de Figueiredo, R. M.; Christmann, M. Org. Lett. 2009, 11,
4116–4119.
Org. Lett., Vol. 13, No. 2, 2011
177

in THF, the reaction rate increased remarkably and the yield
was improved to 43% (entry 5). When 75 mol % or 125
mol % of TBAF was used in THF, the yield of 3 increased
to 65% after 6 min and 61% after 2 min, respectively (entries
6-7). Solvent screening gave THF as the most suitable
solvent (entries 1, 8-10). Lowering the reaction temperature
to 20 or 15 °C only led to a slightly extended reaction time
without a decline in the yield (entries 11-12). The formation
of cross-coupling product 3 indicated that the base directly
abstracted a proton at the γ-position from 1a, whereas the
resulting vinylogous enolate preferentially reacted with 2a
at the R-position.
Table 3. Substrate Scope of the Cross-Coupling Reactiona
To study the reaction intensively, tetramethylammonium
hydroxide pentahydrate (TMAH) and tetramethylammonium
fluoride (TMAF), a “naked” fluoride of high basicity, were
also employed as a Brønsted base in this reaction. Because
of their poor solubility in THF, the same reaction was
performed in DMSO. In the presence of 5 mol % of TMAH,
3 was obtained in 4% yield at a very slow rate (Table 2,
Table 2. Examination of TMAH and TMAF in the Reactiona
entry base (mol %) solvent temp (°C)
timeb
yield (%)c
1
2
3
4
5
6
7
8
TMAH(5)
TMAH(10)
TMAH(15)
TMAH(25)
TMAF(15)
TMAF(25)
TMAF(50)
TMAF(75)
TBAF(25)
TBAF(50)
TBAF(75)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
48 h
24 h
10 min
30 s
13 h
5 min
1 min
30 s
11 h
7 min
2 min
4
22
34
25
18
28
35
18
20
37
46
9
10
11
a 1a (0.5 mmol), acrylonitrile (1.0 mmol), and Brønsted base in solvent
(3.0 mL). b Reaction time was determined by TLC. c Isolated yields.
a Unless otherwise indicated, reactions were carried out at room
temperature, 1/olefin ) 1:2, and Brønsted base in solvent (3.0 mL). b Time
for consuming 1. c Isolated yields. d Reaction performed at 10 °C. e Reaction
performed at 35 °C.
entry 1). When the loading of TMAH was enhanced to 10
mol %, the reaction rate increased and the yield was
improved (entry 2). Using 15 mol % of TMAH led to a
considerable increase in the reaction rate and gave the
product in a better yield (entry 3). However, upon employing
25 mol % of TMAH in this reaction, the yield of 3 fell to
25% (entry 4). Similar to TMAH, with the increase of TMAF
concentration, the substrate consumption rate increased
consistently, while the yield climbed and then declined
(entries 5-8). The parallel experiments for TBAF in DMSO
were also carried out, and the yield of 3 was much lower in
DMSO than in THF (Table 2, entries 9-11). The results
revealed that not only fluoride ion but also hydroxide ion
are capable of deprotonating 1a, but among the three bases,
TBAF provides the best yield.
The ratio of the two diastereomers of 4 was determined by
1H NMR analysis to be 10:1 (entry 1). Reaction of 1a with
methyl vinyl ketone (MVK) proceeded smoothly, and the
corresponding cross-coupling product 5 was furnished in 67%
yield (entry 2). In addition, methyl acrylate (MA), a less
reactive Michael acceptor than MVK, could also react with
1a at 35 °C, affording a moderate yield of the product 6
(entry 3). ꢀ-Nitrostyrene, however, failed to give the desired
product due to its polymerization under the reaction condi-
tions.
On the other hand, various cyclic ꢀ-halo-enals 1b-1g were
also investigated. The substituted variant 2-chloro-5-meth-
ylcyclohex-1-enecarbaldehyde 1b was effective in furnishing
the mixture of both diastereomers in a very short time, and
the diastereoselective ratio of 7 was 1.9:1 (entry 4). The
reactivity of the five-membered enal 1c was comparative to
that of 1a, whereas the seven-membered enal 1d was inactive
The substrate scope of the TBAF-promoted cross-coupling
reaction was then explored under the optimized conditions
(Table 3). Interestingly, an unexpected spiro-3,4-dihydro-
2H-pyran derivative was achieved by a tandem deprotona-
tion/Michael addition/acetalization reaction process when
2-benzylacrylaldehyde 2b was used as a Michael acceptor.
178
Org. Lett., Vol. 13, No. 2, 2011

and no desired product was detected (entries 5-6). With
respect to the halogen atom, not only chlorides but also
bromides (entries 7-9) could be employed to give cross-
coupling products 9-11 with a slower rate. Similarly, the
diastereoselective ratio of the product 10 was 2.2:1. The
compound 1h gave the desired product in a modest yield
(entry 10). Furthermore, cyclic ꢀ-haloenone 1i also went
well, albeit with lower yields and a longer time (entry 11).
A plausible pathway A for this Brønsted base promoted
crossed-Michael addition is illustrated in Scheme 2. We
lecular aldol reaction. The cycloaldolization reaction readily
rendered the spiro cyclic enone 14 in 82% yield in an acidic
medium (Scheme 3). In contrast, a DBU-mediated intramo-
Scheme 3
Scheme 2. Possible Reaction Pathways
lecular aldol reaction of 5 led to spiro compound 15 as a
single diastereomer in 80% yield. This transformation
provided an effective and concise method to obtain the useful
molecules containing a spiro structure. In addition, the
lactone 16 was also easily achieved by oxidation of hemi-
acetal 4 with pyridinium chlorochromate (PCC) in 85% yield.
In summary, we have developed a new Brønsted base
promoted method for the intermolecular crossed-conjugate
addition between two different activated alkenes under mild
conditions. This method facilitates the construction of all-
carbon quaternary centers and synthesis of spirocyclic
compounds. Specifically, a functionalized spiro-2H-pyran
derivative involving a quaternary carbon center and adjacent
vinyl halogen group in the skeleton is readily synthesized
from enal and an enal through a highly selective crossed-
Michael addition. Moreover, the products with 1,5-difunc-
tional groups are synthetically attractive and can be easily
transformed into many other complex building blocks. Efforts
are currently directed at further innovations in reaction scope
and the development of enantioselective variants, and the
results will be reported in due course.
propose that the base abstracts a hydrogen atom directly from
ꢀ-haloenal 1a at the γ-position, and the vinylogous enolate
I produced in situ preferentially reacts with a Michael
acceptor at its R-position to afford another carbanion
intermediate II. Subsequent protonation gives the cross-
coupling product 3. As for the formation of spiro-3,4-
dihydro-2H-pyran 4, an alternative pathway B for the tandem
deprotonation/Michael addition/acetalization reaction is il-
lustrated in Scheme 2. Deprotonation of enal 1a provides
vinylogous enolate I, subsequent intermocular Michael
addition onto 2-benzylacrylaldehyde 2b affords another
enolate III, and the newly formed enolate proceeds intramo-
lecular acetalization with the tethered aldehyde giving
spirocyclic alkoxide IV. Finally, the protonation of inter-
mediate IV generates hemiacetal 4. Another conjugate
addition of compound 1h to the Michael acceptor is also
shown in Scheme 2. The nonconjugated alkenyl ketone is
easily deprotonated at the R-position to produce the viny-
logous enolate V, the carbanionic intermediate adds to
Michael acceptor yields intermediate VI, and the protonation
of VI gives product 12.
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (20872041).
The Center of Analysis and Testing of HUST is thanked for
characterization of new compounds.
Note Added after ASAP Publication. Scheme 2 con-
tained errors in the version published ASAP December 10,
2010; the correct version reposted December 16, 2010.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Gratifyingly, the cross-coupling product 5 could be
converted into a spirocyclic compound by a direct intramo-
OL1028332
Org. Lett., Vol. 13, No. 2, 2011
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