Tandem one-pot Wittig/reductive aldol reactions in which the waste from one process catalyzes a subsequent reaction

Article abstract of DOI:10.1002/asia.201100296

Putting waste to work: Tandem one-pot Wittig/reductive aldol reactions have been performed in which the byproduct of the Wittig reaction, Ph₃PO, catalyzes the reductive aldol reaction. This methodology is versatile and allows for three different building blocks to be combined in a simple, one-pot procedure. Copyright

Full text of DOI:10.1002/asia.201100296

DOI: 10.1002/asia.201100296
Tandem One-Pot Wittig/Reductive Aldol Reactions in which the Waste from
One Process Catalyzes a Subsequent Reaction
Jinni Lu and Patrick H. Toy*[a]
Tandem reactions, in which the product of one reaction
immediately serves as the starting material for a subsequent
transformation, have become attractive in organic synthesis
as they allow for the efficient build-up in structural com-
plexity from relatively simple starting materials in multistep,
one-pot procedures.[1] Usually, such processes are designed
so that only a single reagent or catalyst is required to per-
form all of the desired steps of the reaction sequence, and
thus issues regarding compatibility are sidestepped. Howev-
er, Zhou and co-workers have very recently described a con-
ceptual breakthrough in this context in which the byproduct
of one reaction serves as the catalyst for the second reaction
in one-pot reaction sequences.[2] Specifically they reported
tandem Wittig–conjugate-reduction reaction cascades in
which the Ph3PO generated as waste in the first process cat-
alytically activates HSiCl3 in the second step (Scheme 1a).
Furthermore, they also found that the Ph3PO formed in
Wittig reactions could work together with a chiral salen alu-
minium complex in catalytic asymmetric cyanosilylation re-
actions of enones formed in the first reaction (Scheme 1b).
While the Wittig reaction has been a workhorse for
alkene synthesis since its discovery over half a century
ago,[3,4] its deficiencies with regard to atom economy[5] and
product purification are well known.[6] In relation to the
latter point, we have been studying polymer-supported phos-
phines,[7–9] and have recently reported new phosphine-func-
tionalized polystyrenes that can be used in one-pot Wittig
reactions in which product isolation/purification is reduced
to simple filtration and solvent removal operations.[10,11] The
one-pot reactions studied involved in situ generation of the
required phosphorane by mixing the polymer-supported
phosphine reagent, an a-halo carbonyl compound, and an
amine base, followed by a reaction with an aldehyde sub-
strate.[12] As the methodology reported by Zhou and co-
workers used preformed phosphoranes, we were inspired to
see if it would be possible to couple one-pot Wittig reactions
with the phosphine oxide-catalyzed[13,14] reductive aldol reac-
tions reported by Suigura and Nakajima[15–18] in reaction se-
quences involving five distinct steps: 1) phosphorous alkyla-
tion, 2) phosphonium salt deprotonation, 3) Wittig reaction,
4) conjugate hydride addition, and 5) an aldol reaction
(Scheme 2). From the perspective of diversity-oriented syn-
thesis, such methodology would be highly attractive as it
Scheme 1. The “waste as catalyst/co-catalyst” strategy.
[a] J. Lu, Prof. Dr. P. H. Toy
Department of Chemistry
The University of Hong Kong
Pokfulam Road, Hong Kong (P. R. of China)
Fax : (+852)2857-1586
E-mail: phtoy@hku.hk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100296.
Scheme 2. The five-step one-pot Wittig/reductive aldol reaction cascade
concept.
Chem. Asian J. 2011, 6, 2251 – 2254
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COMMUNICATION
Table 1. Tandem one-pot Wittig/reductive aldol reactions using a single
aldehyde.
could allow for a large number of activated alkyl halides (1)
and nearly all aldehydes (2), or a combination of aldehydes
(when 2 is different in steps 3 and 5), to be combined in a
simple, one-pot procedure to generate products of the gen-
eral structure 3. Herein we report the realization of this con-
cept.
In the original report regarding asymmetric phosphine
oxide-catalyzed reductive aldol reactions, it was observed
that chalcone was a good substrate in such processes.[15b]
Thus, as we previously found that 2-bromoacetophenone
(1a) was a suitable activated alkyl halide for one-pot Wittig
reactions with benzaldehyde (2a),[10a] we chose this substrate
as a starting point to study the reaction involving these two
building blocks (Scheme 3). As one equivalent of 2a would
Entry
1
2
3
Yield [%][a] syn/anti
1
2
3
4
5
6
7
8
1a 2a 3a R1 =Ph, R2 =Ph
67
81
34:66
41:59
34:66
39:61
41:59
24:76
33:67
32:68
1a 2b 3b R1 =Ph, R2 =4-BrC6H4
1a 2c 3c R1 =Ph, R2 =4-MeC6H4
1a 2d 3d R1 =Ph, R2 =iPr
73
12[b]
82
1b 2a 3e R1 =4-BrC6H4, R2 =Ph
1c 2a 3 f R1 =4-MeOC6H4, R2 =Ph
1d 2a 3g R1 =Me, R2 =Ph
85
48
1d 2b 3h R1 =Me, R2 =4-BrC6H4
62
[a] Yield of the isolated product of reactions using 1a–d (0.5 mmol), 2a–
d (1.1 mmol), PPh3 (0.5 mmol), iPr2EtN (0.5 mmol), and 4 ꢁ molecular
sieves (0.1 g) in CHCl3 (1 mL) stirred at 608C for 2–24 h, followed by the
addition of HSiCl3 (1.0 mmol) and stirring at 08C for 1–4 h. The reaction
products were isolated as diastereomeric mixtures if not separable.
[b] The reductive aldol reaction was performed at room temperature.
Scheme 3. Tandem chalcone synthesis/reductive aldol reaction.
4’-methoxyacetophenone (1c), were used as the alkyl halide
with 2a, 3e and 3 f were obtained in excellent yield, respec-
tively (Table 1, entries 5 and 6). Additionally, chloroacetone
(1d) was also found to be a suitable alkyl halide, and when
used with 2a or 2b, products 3g or 3h were isolated in 48%
or 62% overall yield, respectively (Table 1, entries 7 and 8).
In these reactions, the general trend that the anti isomer of
the product was slightly favored was observed, as 1:1–1:3
ratios of syn/anti stereoisomers of 3a–h were obtained. As
already mentioned, such stereoselectivity mirrors what has
been reported in the literature.[15a]
As a strategy to increase the structural diversity of the
products 3, we next considered the possibility of using one
aldehyde in the one-pot Wittig reaction and a second, differ-
ent aldehyde as the electrophile in the reductive aldol pro-
cess. Thus, for the next set of experiments the aldehyde used
in the one-pot Wittig reaction, 2a or 3-phenylpropanal (2e),
was used as the limiting reagent, rather than in excess as
before (Table 2). For example, a mixture of 1a, 2a, Ph3P,
and iPr2EtN was heated to 608C until 2a was completely
consumed, and then the reaction was cooled to 08C and
HSiCl3 (2 equivalents) and 4-nitrobenzaldehyde (2 f; 1.2
equivalents) were added to eventually form 3i in 57% yield
(Table 2, entry 1). Other arylaldehydes, such as benzalde-
hydes 2g–i and heteroaromatic 2j, could also be used in the
reductive aldol step with in situ generated chalcone to
afford 3j–m in high overall yields (Table 2, entries 2–5).
When the initial one-pot Wittig reaction was performed
using 1a and aliphatic aldehyde 2e, and 2a was used in the
reductive aldol reaction, 3m was isolated in 71% overall
yield (Table 2, entry 6). Finally, using 1d in the first step
also afforded good results with various aldehyde combina-
tions (Table 2, entries 7 and 8). The stereoselectivity ob-
react with the phosphorane to form chalcone prior to the re-
ductive aldol reaction, we used a 1:1:1:2.2 molar ratio of 1a/
Ph3P/iPr2EtN/2a in our preliminary experiments. Gratifying-
ly, in chloroform at 608C, the initial Wittig reaction to form
chalcone was completed within 2 hours. The reaction mix-
ture was cooled to 08C and then HSiCl3 (2 equivalents) was
added. After one hour at this temperature, the in situ
formed chalcone was completely consumed, and 3a was iso-
lated in 67% yield as a 34:66 mixture of syn/anti diastereo-
mers (Table 1, entry 1). While at first glance the yield may
not appear to be overly impressive, it should be noted that
67% represents the overall yield of five sequential transfor-
mations (i.e. approximately 92% yield per step), and as
large excesses of reagents were not used, purification of the
desired product 3a was relatively straightforward. Further-
more, the observed stereoselectivity of the reductive aldol
step was similar to what was previously observed when
Ph3PO was used as the catalyst in similar reactions.[15a]
Encouraged by this positive result, we next examined the
substrate scope of the tandem one-pot Wittig/reductive
aldol condensation reaction procedure. Other aryl alde-
hydes, such as 4-bromobenzaldehyde (2b) and 4-methylben-
zaldehyde (2c), were found to work well with 1a, and af-
forded a high overall yield of 3b and 3c, respectively
(Table 1, entries 2 and 3). However, when branched isobu-
tyraldehyde (2d) was used with 1a, only a low yield of the
desired product 3d was obtained, even when the reductive
aldol reaction was performed at room temperature (Table 1,
entry 4). When acetophenones bearing aryl substituents,
such as 2-bromo-4’-bromoacetophenone (1b) and 2-bromo-
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Chem. Asian J. 2011, 6, 2251 – 2254

Tandem One-Pot Wittig/Reductive Aldol Reactions
Table 2. Tandem one-pot Wittig/reductive aldol reactions using two aldehydes.
Experimental Section
General Procedure A for Tandem One-Pot Wittig/Reductive
Aldol Reactions using a Single Aldehyde (Table 1)
A mixture of alkyl halide 1a–d (0.5 mmol), aldehyde 2a–d
(1.1 mmol), PPh3 (0.5 mmol), iPr2EtN (0.5 mmol), and 4 ꢁ mo-
lecular sieves (0.1 g) in CHCl3 (1 mL) was stirred at 608C for
2–24 h. Then HSiCl3 (1.0 mmol) was added at 08C and the re-
action mixture was stirred for 1–4 h more. The reaction was
quenched with sat. NaHCO3, filtered through Celite, and
washed with ethyl acetate. The organic layer was dried over
MgSO4 and concentrated in vacuo. The crude product was pu-
rified by silica-gel column chromatography (ethyl acetate/
hexane=1:15 then 1:3) to afford syn- and anti-3a–h as pure
stereoisomers, or as a mixture of diastereomers.
Entry
1
1st alde-
hyde
2nd alde-
hyde
3
Yield
[%][a]
syn/
anti
1
2
3
4
5
6
1a 2a
1a 2a
1a 2a
1a 2a
1a 2a
1a 2e
2 f
2g
2h
2i
3i R1 =R2 =Ph,
R3 =4-NO2C6H4
3j R1 =R2 =Ph,
R3 =4-FC6H4
57
68
78
68
67
71
51:49
45:55
37:63
29:71
50:50
25:75
General Procedure B for Tandem One-Pot Wittig/Reductive
Aldol Reactions using Two Different Aldehydes (Table 2)
3k R1 =R2 =Ph,
R3 =4-ClC6H4
3l R1 =R2 =Ph,
R3 =4-MeOC6H4
3m R1 =R2 =Ph,
R3 =2-furyl
A mixture of alkyl halide 1a or 1d (0.65 mmol), aldehyde 2a
or 2e (0.5 mmol), PPh3 (0.65 mmol), iPr2EtN (0.65 mmol), and
4 ꢁ molecular sieves (0.1 g) in CHCl3 (1 mL) was stirred at
608C for 16–24 h until complete consumption of the aldehyde
was observed by TLC analysis. Aldehydes 2 f–j (0.6 mmol) and
HSiCl3 (1.0 mmol) were then added at 08C. After stirring for
1–2.5 h more, the reaction was quenched and worked-up as de-
scribed in general procedure A. The crude product was puri-
fied by silica-gel column chromatography (ethyl acetate/
hexane=1:15 then 1:3) to afford syn- and anti-3i–p as pure ste-
reoisomers, or as a mixture of diastereomers.
2j
2a
3n R1 =Ph,
R2 =PhCH2CH2,
R3 =Ph
7
8
1d 2a
1d 2e
2h
2a
3o R1 =Me,
R2 =Ph,
49
60
34:66
31:69
R3 =4-ClC6H4
3p R1 =Me,
R2 =PhCH2CH2,
R3 =Ph
[a] Yield of the isolated product of reactions using 1a or 1d (0.65 mmol), 2a or 2e
(0.5 mmol), PPh3 (0.65 mmol), iPr2EtN (0.65 mmol), and 4 ꢁ molecular sieves (0.1 g)
in CHCl3 (1 mL) stirring at 608C for 16–24 h, followed by the addition of 2a, 2 f–j
(0.6 mmol) and HSiCl3 (2.0 mmol) stirring at 08C for 1–2.5 h. The reaction products
were isolated as diastereomeric mixtures if not separable.
Acknowledgements
This research was supported financially by the University of
Hong Kong and the Research Grants Council of the Hong
Kong S. A. R., P. R. of China (Project No. 704108P).
served in this set of reactions involving two aldehydes was
Keywords: aldol reaction
organocatalysis · tandem reaction · Wittig reactions
·
conjugate reduction
·
similar to what was found before when one aldehyde was
used, and products 3i–p were formed as approximately 1:1–
1:3 mixtures of syn/anti stereoisomers.
In summary, we have developed a tandem one-pot Wittig/
reductive aldol reaction procedure that allows for the rapid
synthesis of complex molecules that are composed of three
building blocks. This protocol is noteworthy in that the by-
product of the one-pot Wittig reaction, Ph3PO, catalyzes the
subsequent reductive aldol process. Furthermore, the flexi-
bility of this strategy is exhibited by the fact that different
aldehydes can be used in the one-pot Wittig and reductive
aldol reactions. Thus, it appears to have potential in the con-
text of diversity-oriented synthesis.
As Ph3PO is a byproduct of several reactions, including
the Mitsunobu reaction,[19] and is a good Lewis base catalyst
for numerous processes,[14] this general strategy for perform-
ing tandem reaction sequences could have many applica-
tions in organic synthesis. We are currently investigating
such synthetic procedures, which include chiral phosphines
and enantioselective phosphine oxide catalysis, and will
report our findings in due course.
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COMMUNICATION
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Received: March 23, 2011
Published online: July 6, 2011
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Chem. Asian J. 2011, 6, 2251 – 2254