Ruthenium-catalyzed aldehyde functionality reshuffle: Selective synthesis of E-2-arylcinnamaldehydes from E-β-bromostyrenes and aryl aldehydes

Article abstract of DOI:10.1021/ja306025d

A new concept for highly selective synthesis of E-2-arylcinnamaldehydes has been developed via a formal arylformylation of E-β-bromostyrenes with readily available aryl aldehydes. This strategy involves an overall reshuffle of the aldehyde functionality with a loss of hydrogen bromide.

Full text of DOI:10.1021/ja306025d

Communication
pubs.acs.org/JACS
Ruthenium-Catalyzed Aldehyde Functionality Reshuffle: Selective
Synthesis of E‑2-Arylcinnamaldehydes from E-β‑Bromostyrenes and
Aryl Aldehydes
Ping Wang,†,‡ Honghua Rao,† Feng Zhou,† Ruimao Hua,‡ and Chao-Jun Li*,†
†Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada
‡Department of Chemistry, Tsinghua University, Beijing 100084, China
S
* Supporting Information
conjugated alkenones as well as the C−C triple bonds can also
be hydroacylated with aldehydes in different ways.5,6
ABSTRACT: A new concept for highly selective synthesis
of E-2-arylcinnamaldehydes has been developed via a
formal arylformylation of E-β-bromostyrenes with readily
available aryl aldehydes. This strategy involves an overall
reshuffle of the aldehyde functionality with a loss of
hydrogen bromide.
Recently, as a novel complement, we reported that aldehydes
could also undergo decarbonylative addition to unsaturated
bonds via a metal-aryl-CO-hydride complex intermediate
(Scheme 1b).7 During this process, the aryl and hydride parts
added to the unsaturated bonds to afford the corresponding
products while the carbonyl group was released as carbon
monoxide in the form of waste. We reasoned that the released
carbon monoxide could be reused in situ as a C1-building
block. In continuation of our previous research, we herein report
a formal arylformylation of E-β-bromostyrenes with readily
available aldehydes via a reshuffle of the aldehyde functionality
with a loss of hydrogen bromide, to give E-2-arylcinnamaldehydes
highly selectively (Scheme 1c).
To test our hypothesis, E-β-bromo-p-methoxystyrene (1a)
was reacted with benzaldehyde (2a) in the presence of 10 mol
% of [RuCl2Cp*]n. To our delight, the corresponding E-2-(4-
methoxyphenyl) cinnamaldehyde (3aa) was detected when
catalytic quantities of Cu-salts were added as a cocatalyst
(Table 1, entries 1−4). A trace amount of the corresponding
product was detected with [RuCl2Cp*]n together with small
amounts of products due to debromination and halogen
exchange; the combination of [RuCl2Cp*]n with CuI (possibly
activating the C−Br bond) showed the highest catalytic activity,
generating E-2-(4-methoxyphenyl) cinnamaldehyde (3aa) in
46% yield (Table 1, entry 4). Then, the introduction of a KI
additive slightly increased the yield possibly by converting some
of the vinyl bromide to the more active iodide in situ (Table 1,
entry 5). Encouraged by these initial results, we screened a
variety of other ruthenium or rhodium catalysts together with
different copper cocatalysts (Table 1, entries 6−11; Table S1,
entries 1−28). Unfortunately, none of them exhibited a better
effect than the combination of [RuCl2Cp*]n and CuI. Among
those additives examined, KI was better than other iodide salts
while AgBF4 nearly disabled the reaction completely (Table 1,
entry 12; Table S1, entries 29−32). In addition, an excess
amount of aldehyde decreased the yield drastically (Table 1,
entry 13). Subsequently, PPh3 and other nitrogen-containing
ligands such as proline, phenanthroline, tetramethylethylenedi-
amine, and N-monosubstituted glycines were examined, with
N,N-dimethylglycine providing the highest yield analogous to
n impressive number of classical textbook name reactions
A
rely on the unique reactivity of aldehydes, namely the
electrophilic character of the carbonyl group and the generation
of carbon nucleophiles by enolization.1 Recently, these
strategies have been complemented by transition-metal-
catalyzed functionalizations of the carbonyl C−H bond. In
general, these reactions are based on the oxidative addition of
the catalyst metal into the carbonyl C−H bond with the
formation of an acyl-metal hydride as a key intermediate, which
further reacts with olefins to afford the corresponding aliphatic
ketones (Scheme 1a). After early reports of catalytic hydro-
Scheme 1. Different Approaches for Addition of Aldehydes
to C−C Unsaturated Bonds
acylation of alkenes with aldehydes by Miller2 and Bosnich,3 the
scope of this type of reaction tremendously expanded both
intra- and intermolecularly, giving linear or branched hydro-
acylation ketone products with high regio- or stereoselectivity.4
For instance, Ryu’s group4j and Krische’s group4k independ-
ently realized intermolecular hydroacylation with the aldehyde’s
acyl group selectively added to the C3 position of the 2-
substituted 1,3-butadiene. Similarly, the C−C double bond of
Received: June 20, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja306025d | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
However, modification of the loading of each item in the
catalyst system influenced the reaction greatly: Reducing the
amount of [RuCl2Cp*]n to 5 mol %, CuI to 5 mol %, and KI
additive to 20 mol % afforded the highest yield (75%) of the
desired product (Table 1, entry 20), whereas reducing the
amount of ligand or the base resulted in a slightly lower yield or
only a trace amount of the product, respectively (Table 1,
entries 19, 21; Table S3).
Table 1. Arylformylation under Various Conditions
With the optimized reaction conditions in hand, the substrate
scope was explored at 120 °C under argon using 5 mol % of
[RuCl2Cp*]n as the catalyst, 5 mol % of CuI as the cocatalyst,
30 mol % of N,N-dimethylglycine as the ligand, 20 mol % of KI
as the additive, and 3 equiv of Cs2CO3 as the base in DMF for
24 h. As shown in Table 2, the reaction proceeded well with a
b
additive
(equiv)
% yield 3aa/
4aa/5/6/7
entry
mol % catalyst
solvent
1
2
10% [RuCl2Cp*]n
10% [RuCl2Cp*]n, 10%
CuCl
−
−
DMF
DMF
<10/−/16/14/−
<10/t / t/<10/−
c
a
Table 2. Scope of the Arylformylation
3
4
5
6
10% [RuCl2Cp*]n, 10%
CuBr
−
DMF
DMF
DMF
DMF
25/−/ 21/t/−
46/t/16/16/t
52/t/13/12/10
t/−/ 29/−/27
10% [RuCl2Cp*]n, 10%
CuI
−
10% [RuCl2Cp*]n, 10%
CuI
KI (2)
KI (2)
15% Ru3(CO)12, 10%
CuI
b
entry
R1
R2
product
% yield (E/Z)
7
8
10% RuCp2, 10% CuI
KI (2)
KI (2)
DMF
DMF
45/−/14/−/25
23/t/26/14/32
1
1a, p-MeO
2a, Ph
3aa+4aa
3ab+4ab
3ac+4ac
3ad+4ad
3ae+4ae
3af+4af
72 (94:6)
65 (95:5)
51 (94:6)
58 (93:7)
77 (95:5)
68 (95:5)
79 (95:5)
74 (95:5)
34 (50:50)
45 (83:17)
48 (96:4)
54 (95:5)
39 (97:3)
25 (97:3)
63 (97:3)
55 (97:3)
66 (95:5)
60 (96:4)
44 (96:4)
10% RuCl2(PPh3)3,
10% CuI
2
2b, p-MeO-C6H4
2c, p-Me-C6H4
2d, p-Ph-C6H4
2e, p-CF3-C6H4
2f, p-Cl-C6H4
2g, m-Cl-C6H4
2h, 3,4-Cl2-C6H3
2i, 4-quinoline
2j, 3-pyridine
2a, Ph
3
9
10% RuCl3·3H2O, 10%
CuI
KI (2)
−
DMF
DMF
DMF
DMF
DMF
14/t/14/27/18
19/t/17/16/−
21/t/t/14/−
t/−/32/17/t
22/t/26/14/11
4
5
10
11
12
10% [RuCl2Cp*]n, 10%
Cu dust
6
10% [RuCl2Cp*]n, 10%
Cu2O
−
7
3ag+4ag
3ah+4ah
3ai+4ai
8
10% [RuCl2Cp*]n, 10%
CuI
LiI (2)
KI (2)
KI (2)
KI (2)
KI (2)
KI (2)
KI (2)
KI (2)
KI (0.2)
KI (2)
9
10
11
12
13
14
15
16
17
18
19
3aj+4aj
d
13
10% [RuCl2Cp*]n, 10%
CuI
1b, H
3ba+4ba
3bb+4bb
3bc+4bc
3bd+4bd
3be+4be
3bf+4bf
3bg+4bg
3bh+4bh
3ca+4ca
2b, p-MeO-C6H4
2c, p-Me-C6H4
2d, p-Ph-C6H4
2e, p-CF3-C6H4
2f, p-Cl-C6H4
2g, m-Cl-C6H4
2h, 3,4-Cl2-C6H3
2a, Ph
14
15
16
10% [RuCl2Cp*]n, 10%
CuI
dioxane t/−/11/t/41
10% [RuCl2Cp*]n, 10%
CuI
PhCl
xylene
DMF
DMF
DMF
DMF
DMF
t/−/t/t/t
10% [RuCl2Cp*]n, 10%
CuI
32/−/10/t/10
24/t/14/17/16
47/t/25/10/10
66/t/14/t/13
75/t/ <10/t/t
−/−/18/15/35
e
17
10% [RuCl2Cp*]n, 10%
CuI
f
1c, m-F
18
10% [RuCl2Cp*]n, 10%
CuI
a
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), [RuCl2Cp*]n (5
mol %, based on Ru), CuI (5 mol %), N,N-dimethylglycine (30 mol
%), KI (20 mol %), Cs2CO3 (3 equiv), DMF (0.3 mL), 120 °C, 24 h,
under argon, unless otherwise noted. Total isolated yields of E- and
Z-isomers. The ratios of E- to Z-isomers are determined by H NMR
g
19
5% [RuCl2Cp*]n, 5%
CuI
20
5% [RuCl2Cp*]n, 5%
CuI
b
1
h
21
10% [RuCl2Cp*]n, 10%
CuI
analysis.
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), N,N-
dimethylglycine (30 mol %), Cs2CO3 (3 equiv), solvent (0.3 mL),
wide range of substrates, giving E-2-arylcinnamaldehydes
selectively. The ratio of E- to Z-isomer could reach up to
97:3 in several cases. Meanwhile, although the vinylic bromine
was removed during the reaction, halogen on the aryl aldehyde
could be tolerated, giving moderate to good yields of the
corresponding product (Table 2, entries 5−8, 15−19). The
electronic effect played an important role in this reaction.
Generally, E-β-bromostyrenes with the methoxy group gave
much better yields than those without any substituent, whereas
the latter performed relatively better than those with the fluoro-
substituent (Table 2, entries 1, 11, 19). In contrast, E-β-
bromostyrenes without a substituent displayed slightly higher
selectivity than those with the methoxy group to some extent.
Yet, aliphatic aldehydes could not undergo this reshuffle,
120 °C, 24 h under argon, unless otherwise noted. The loading of the
b
catalyst is based on the metal. 1H NMR yields with nitromethane as
c
d
e
the internal standard. A trace amount. 0.5 mmol of 2a was used. At
f
g
h
100 °C. At 140 °C. 20 mol % of N,N-dimethylglycine was used.
1
equiv of Cs2CO3 was used.
copper catalyzed Ullmann-type reactions of vinyl bromides with
amines8 (Table S2, entries 1−18).
Furthermore, a variety of bases and solvents were examined
and the results showed that Cs2CO3 as the base and DMF as
the solvent were most beneficial to this reaction (Table 1,
entries 14−16; Table S2, entries 19−22). A higher or lower
reaction temperature or a longer reaction time did not facilitate
the reaction (Table 1, entries 17−18; Table S2, entry 23).
B
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Journal of the American Chemical Society
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indicating chemoselectivity between aromatic and aliphatic
aldehydes.
Scheme 3. Tentative Mechanism for the Arylformylation
To explore the mechanism of the reaction, some control
experiments were conducted under the optimized reaction
conditions. The reaction of phenylacetylene with benzaldehyde
gave neither E- nor Z-2-arylcinnamaldehyde product (Scheme
2a), suggesting that a potential in situ HBr elimination of E-β-
Scheme 2. Investigation of the Mechanism for the
Arylformylation
with aldehyde 2 immediately to give intermediate C and
regenerate water.12 Finally, reductive elimination of C gives the
final product 3 and regenerates the active ruthenium catalyst. It
is also possible that the reductive elimination occurred first or a
ruthenium-catalyzed direct conversion of the vinyl halide to
generate a phenylacetaldehyde, which undergoes the aldol
reaction to give the final product. However, phenylacetaldehyde
was not detected in a control experiment with only the vinyl
halide under the same reaction conditions. Furthermore,
replacing vinyl bromide 1 with phenylacetaldehyde did not
give any desired product under the same reaction conditions;
thus a mechanism involving an initial hydrolysis of styrene
bromide followed by an aldol reaction is unlikely. Another
alternative mechanism involves a Ru(III)/CuI-catalyzed [2 + 2]
cycloaddition of the two components to give 2-bromo-3,4-
diaryloxetanes, which may undergo ring opening to give
products directly. However, this is not consistent with the
16O and 18O isotope experiments. The exact mechanism of this
transformation is still not clear at this stage and is under further
investigation.
In summary, we have developed an unprecedented reshuffle
of the aldehyde functionality between the reaction of vinyl
bromide and aryl aldehydes. The reaction provides a selective
synthesis of E-2-arylcinnamaldehydes through a formal
arylformylation of E-β-bromostyrenes with aldehydes. A
broad range of substrates were examined, and an electronic
effect was observed in this reaction. Further efforts to increase
the reaction yield, to clarify the mechanism, and to expand the
application of such a reaction to aliphatic aldehydes are
underway in our laboratory.
bromostyrene was not involved in this reaction although the
involvement of an alkynyl-metal intermediate could not be
ruled out.9 However, if Z-β-bromostyrene was introduced
instead of the E- one, only trace amounts of E- and Z-products
were detected, demonstrating the importance of the config-
uration of β-bromostyrenes (Scheme 2b). When 13C-labeled
benzaldehyde was used, to our great surprise, the 13C was
incorporated exclusively into the CC bond (Scheme 2c). Yet,
when 18O-labeled water was added, both 16O and 18O products
were obtained as a mixture (16O:18O = 2:1 ratio in GC/MS:
note, the actual ratio may not be correct) (Scheme 2d). Similarly,
the addition of D2O also led to a mixture of both regular and
deuterated products (Scheme 2e).
With these experimental results, a tentative mechanism is
postulated in Scheme 3: Initially, vinyl bromide 1 reacts with
the active ruthenium catalyst together with a base to form the
vinylidene intermediate A. CuI might have catalyzed this
process (through the activation of the C−Br bond or through
the Fenkelstein iodo-bromo exchange reaction to generate the
more reactive vinyl iodide) and improved the yield. It should be
noted that a direct conversion of vinyl iodide to a vinyl-
ideneplatinum species via a vinylplatinum intermediate was
observed previously on the platinum surface during a gas-phase
reaction in 1994.10 However, we were unable to generate a
vinylidene product under stoichiometric conditions. Subse-
quently, nucleophilic addition of water to A generates
intermediate B,11 which undergoes an aldol-type reaction
ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectroscopic data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
cj.li@mcgill.ca
■
C
dx.doi.org/10.1021/ja306025d | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Canada Research Chair Foundation (to
C.J.L.), the CFI, FQRNT Center for Green Chemistry and
Catalysis, NSERC, and McGill University for support of our
research. P.W. also thanks the China Scholarship Council for
financial support. This paper is dedicated to Professor David N.
Harpp on the occasion of his 75th Birthday.
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