Heck reactions of crotonaldehyde

Article abstract of DOI:10.1055/s-2008-1032095

A direct method for the synthesis of β,β-disubstituted-α, β-unsaturated aldehydes via Heck reaction of aryl halides with crotonaldehyde and related substrates has been developed. The reaction provides rapid access to products usually prepared via multistep sequences. The power of the method in combination with an organocatalytic transfer hydrogenation is illustrated with a short asymmetric synthesis of (S)-Florhydral. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032095

LETTER
597
Heck Reactions of Crotonaldehyde
Heck
R
eactions of Cro
i
tonalde
c
hyde hael Stadler, Benjamin List*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062999; E-mail: list@mpi-muelheim.mpg.de
Received 19 December 2007
Abstract: A direct method for the synthesis of b,b-disubstituted-
[Pd]
CHO
CHO
+
ArX
Ar
a,b-unsaturated aldehydes via Heck reaction of aryl halides with
crotonaldehyde and related substrates has been developed. The re-
action provides rapid access to products usually prepared via multi-
step sequences. The power of the method in combination with an
organocatalytic transfer hydrogenation is illustrated with a short
asymmetric synthesis of (S)-Florhydral®.
Scheme 1 Proposed route to a,b-unsaturated aldehydes via Heck re-
action of crotonaldehyde
90 °C, (c) using N-methyl pyrrolidinone (NMP) as the
solvent, (d) with 2 mol% of Pd(OAc)2 as the catalyst, and
(e) with tetrabutylammonium chloride as the phase-trans-
fer catalyst, greatly enhanced reaction rates and yields of
the desired cinnamaldehyde derivatives were obtained.
Key words: Heck reaction, unsaturated aldehydes, palladium, ary-
lations, cross-coupling, crotonaldehyde
With our optimal conditions in hand,11 we set out to probe
the scope and limitations of the reaction of both aryl and
vinyl bromides and iodides with crotonaldehyde
(Table 1). We first investigated the influence of steric hin-
drance (entries 1–6). Both para and meta substitution are
well tolerated and the corresponding products 1 are ob-
tained in good yields. Slightly reduced yields are obtained
when a substituent in ortho position is introduced (entry
4). Almost no conversion is observed when both ortho po-
sitions are occupied (entry 5).
During our studies on organocatalytic transfer hydrogena-
tions of enals1 we needed a practical synthetic approach to
b-methyl- or alkyl-substituted cinnamaldehydes. Report-
ed methods involve multistep sequences such as Wittig
olefination of an acetophenone derivative to the a,b-un-
saturated ester followed by reduction to the allylic alcohol
and re-oxidation to the aldehyde.2 Other methods, such as
the palladium-catalyzed reaction of 1,2-dien-4-ols with
aryl or alkenyl halides,3 the Vilsmeyer–Haack formyla-
tion of olefins,4 the oxidative rearrangement of tertiary al-
lylic alcohols via PCC,5 or the Meyer–Schuster
rearrangement of acetylenic alcohols,6 lack generality, re-
quire tedious substrate syntheses, or require drastic reac-
tion conditions.
Varying the electronic nature of the aromatic ring led to
the surprising finding that electron-rich substituents allow
the product formation in very good yields (entries 8 and
9), while a mildly electron-deficient substituent gave only
moderate yields (entry 10). The desired reaction is barely
observed at all with a strongly electron-deficient arene
(entry 11). In this case the competing homocoupling reac-
tion of the aryl halide becomes the predominant reaction
pathway. The same homocoupling is also observed with
2-iodothiophene (entry 12), which did not yield the prod-
uct of the desired Heck reaction in synthetically useful
quantities. Vinyl halides can also be employed as sub-
strates (entries 13 and 14), yielding a,b,g,d-unsaturated al-
dehydes in moderate to good yields.12
A simple and elegant approach would be the direct substi-
tution of the vinylic hydrogen in b-position of crotonalde-
hyde or a related aldehyde. One interesting but little
investigated approach is the direct, oxidative coupling of
crotonaldehyde with benzene under palladium catalysis as
described by Tsuji.7 The Heck reaction of aryl halides
with crotonaldehyde appeared to be a potentially more
general alternative (Scheme 1).
However, while acrolein has been used by several groups
already,8 only a single example of a low yielding (20%)
Heck coupling of crotonaldehyde with bromobenzene has
been reported.9 In addition, subjecting 1-iodo-4-methyl-
benzene and crotonaldehyde to Heck reaction conditions
resembling those previously employed in the reaction of
cinnamaldehyde with iodobenzene10 gave the desired
product in only 35% yield.
As commonly observed, the reactivity of bromides is gen-
erally lower compared to the corresponding iodides, and
slightly lower yields were accordingly obtained from bro-
mides. In general, mixtures of E- and Z-isomers were ob-
tained, although Heck reactions are normally trans-
selective. The E/Z-ratio of the products seems to be ther-
modynamically controlled. When we subjected pure (E)-
3-(p-tolyl)-2-butenal to isomerization conditions, the
equilibrium ratio corresponds to that obtained in the Heck
reaction of entry 2. We suspect the isomerization to occur
during the reaction, possibly via a nucleophilic pathway.
Separation of the isomers was possible during chromato-
graphic purification.
We have now developed efficient and practical conditions
for Heck couplings with crotonaldehyde. By (a) using two
equivalents of crotonaldehyde, (b) running the reactions at
SYNLETT 2008, No. 4, pp 0597–0599
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032095; Art ID: G41307ST
© Georg Thieme Verlag Stuttgart · New York

598
M. Stadler, B. List
LETTER
Table 1 Heck Reaction of Crotonaldehyde with Different Aryl and
Vinyl Halides
Table 2 Heck Reaction of Various a,b-Unsaturated Aldehydes with
4-Iodoanisole
I
Pd(OAc)2 (2 mol%)
Bu4NCl, NaOAc
CHO
CHO
RX
+
R
MeO
NMP, 90 °C, 45–75 min
R
1
Pd(OAc)2 (2 mol%)
CHO
Bu4NCl, NaOAc
Entry
R
Yield (%)
X = Br
Yield (%)
X = I
E/Za
CHO
R
NMP, 90 °C, 75 min
MeO
1
Ph
50
70
70
46
–
68
2.8:1
2.8:1
3.0:1
1:2.9
n.d.b
2.5:1
1:2.1
4:1c
Entry
R
Yield (%)
E/Z ratioa
3.3:1
2
4-MeC6H4
3-MeC6H4
2-MeC6H4
2,2¢-Me2C6H3
3-i-PrC6H4
naphth-2-yl
4-Me2NC6H4
4-MeOC6H4
4-FC6H4
77
1
2
3
4
5
6
Me
Et
92
61
80
65
<5
52
3
70
1.4:1
4
55
n-Pr
n-Hex
i-Pr
Ph
1.6:1
5
trace
–
1.4:1
6
65
71
76
73
40
<10
trace
74
n.d.b
7
43
1.7:1
8
87
a Determined by GC analysis of the crude reaction mixture.
b Not determined.
9
92
3.3:1
3.0:1
n.d.b
n.d.b
1.7:1
10
11
12
13
44
4-O2NC6H4
thiophen-2-yl
< 10
n.d.b
60
i-Pr
CO2Et
O
2 steps
2
i-Pr
(a)
2 steps
14
44
–
6.7:1
i-Pr
CHO
i-Pr
CHO
1. yeast reduction
2. oxidation
3
a Determined by GC analysis of the crude reaction mixture.
b Not determined.
(S)-Florhydral® (4)
c Determined by 1H NMR after column chromatography.
er = 98.5:1.5
Our reaction conditions can be readily extended to other
a,b-unsaturated aldehydes as probed with the reaction of
4-iodoanisole (Table 2). The reaction works well with dif-
ferent enals but with increasing steric bulk and chain
length the yields are decreasing. For example, an isopro-
pyl group at the enal is not tolerated (entry 5).
Pd(OAc)2 (2 mol%),
Bu4NCl, NaOAc
Br
+
CHO
3
NMP, 90 °C, 75 min
65%
i-Pr
5
i-Pr
i-Pr
To illustrate the utility of our Heck approach for the syn-
thesis of chiral b-branched aldehydes, we have developed
a short synthesis of (S)-Florhydral®, the more intense
smelling enantiomer of a chiral fragrance marketed by
Givaudan.13 A route for the preparation of enantiomerical-
ly pure Florhydral® has been described.14 It requires seven
steps with an overall yield of less than 3% starting from
commercially available diene 2 and relies on a yeast-me-
diated reduction of a,b-unsaturated aldehyde 3 (used as a
5:1 E/Z-mixture) to the corresponding saturated alcohol as
the key step (Scheme 2, route a).
i-Pr
O
N
O
O
MeO2C
CO2Me
O
(b)
P
O
N
i-Pr
H2
i-Pr
H
(1.1 equiv)
i-Pr
i-Pr
(20 mol%)
4
dioxane, 50 °C, 27 h, 60%
er = 99:1
Our approach requires only two steps (Scheme 2, route b).
The synthesis of aldehyde 3 was achieved employing the
standard conditions developed for the Heck reaction of
Scheme 2 Previous synthesis (a) and our approach (b) to (S)-Flor-
hydral®
Synlett 2008, No. 4, 597–599 © Thieme Stuttgart · New York

LETTER
Heck Reactions of Crotonaldehyde
599
(2) See, for example: Fuganti, C.; Serra, S. J. Chem. Soc., Perkin
Trans. 1 2000, 3758.
(3) Shimizu, I.; Sugiura, T.; Tsuji, J. J. Org. Chem. 1985, 50,
537.
(4) (a) Lorenz, H.; Wizinger, R. Helv. Chim. Acta 1945, 28,
600. (b) Schmidle, C. J.; Barnett, P. G. J. Am. Chem. Soc.
1956, 78, 3209.
(5) (a) Wietzerbin, K.; Bernadou, J.; Meunier, B. Eur. J. Inorg.
Chem. 2000, 1391. (b) Srikrishna, A.; Satyanarayana, G.
Tetrahedron Lett. 2003, 44, 1027.
(6) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71,
429.
(7) Tsuji, J.; Nagashima, H. Tetrahedron 1984, 40, 2699.
(8) See, for example: Jeffery, T. J. Chem. Soc., Chem. Commun.
1984, 1287.
(9) Nejjar, A.; Pinel, C.; Djakovitch, L. Adv. Synth. Catal. 2003,
345, 612.
(10) Aggarwal, V. K.; Staubitz, A. C.; Owen, M. Org. Process
Res. Dev. 2006, 10, 64.
(11) Representative Experimental Procedure for the Heck
Reaction of Crotonaldehyde (Table 1, Entry 2)
4-Bromotoluene (256.4 mg, 1.5 mmol), TBACl (438 mg,
1.57 mmol), and NaOAc (148 mg, 1.80 mmol) were
suspended in NMP (8 mL). Palladium acetate (6.8 mg, 0.03
mmol) in NMP (4 mL) was added, followed by croton-
aldehyde (250 mL, 3 mmol). Oxygen was removed by two
cycles of freeze-pump-thaw. The mixture was then heated at
an oil-bath temperature of 90 °C for 75 min. After being
cooled, the reaction mixture was poured into a half-
concentrated aqueous solution of NaHCO3 (80 mL) and
extracted three times with CH2Cl2 (120 mL in total). The
combined organic fractions were washed with brine once,
dried over MgSO4, and concentrated under reduced pressure.
The resulting solution in NMP was directly loaded onto a
column packed with silica gel and eluted with Et2O–pentane
(15:85, v/v) to yield the product in fractions of pure E- and
Z-isomers (70% combined yield).
crotonaldehyde, starting from commercially available 1-
bromo-3-isopropylbenzene 5, in 65% yield (Table 1, en-
try 6). The resulting E/Z-mixture (2.5:1) was directly em-
ployed in the asymmetric counteranion-directed (ACDC)
organocatalytic transfer hydrogenation under the standard
conditions developed in our lab.15 As this reaction is ste-
reoconvergent, both olefin geometric isomers were trans-
formed into the same enantiomer in 60% yield and with an
excellent er of 99:1. With no optimization studies under-
taken on either reaction we obtained a 39% yield of the es-
sentially enantiopure target compound over two steps.
In conclusion, we have developed a protocol that allows
for the rapid access of a,b-unsaturated, b-disubstituted al-
dehydes via the Heck reaction of crotonaldehyde and re-
lated aldehydes. Our method relies on a simple and
relatively inexpensive reaction system, employing palla-
dium(II)acetate as the catalyst and sodium acetate as the
stoichiometric base. The reactions are generally finished
in approximately one hour, rendering them highly practi-
cal. Furthermore, we were able to utilize our protocol in
shortening a formerly lengthy synthesis of the odorant
Florhydral®.
Acknowledgment
Generous support by the Max-Planck-Society, the DFG (Priority
Program Organocatalysis SPP1179), Novartis (Young Investigator
Award to B.L.), and by the Fonds der Chemischen Industrie (Silver
Award to B.L.) is gratefully acknowledged. We also thank Merck,
Saltigo, Sanofi-Aventis, and Wacker for general support, Degussa
and BASF for donating chemicals; Hendrik van Thienen for techni-
cal support and Sonja Mayer for providing the required ACDC ca-
talyst and Hantzsch ester.
(12) Also see: Li, X.; Zeng, X. Tetrahedron Lett. 2006, 47, 6839.
(13) (a) Chalk, A. J. EP 0368156, 1989. (b) Chalk, A. J. US
4910346, 1990.
References and Notes
(14) Abate, A.; Brenna, E.; Dei Negri, C.; Fuganti, C.; Serra, S.
Tetrahedron: Asymmetry 2002, 13, 899.
(15) Mayer, S.; List, B. Angew. Chem. Int. Ed. 2006, 45, 4193.
(1) (a) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. Angew.
Chem. Int. Ed. 2004, 43, 6660. (b) Yang, J. W.; Hechavarria
Fonseca, M. T.; Vignola, N.; List, B. Angew. Chem. Int. Ed.
2005, 44, 108. (c) Also see: Ouellet, S. G.; Tuttle, J. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32.
Synlett 2008, No. 4, 597–599 © Thieme Stuttgart · New York

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