Pd-catalyzed cascade Heck-Saegusa: Direct synthesis of enals from aryl iodides and allyl alcohol

Article abstract of DOI:10.1039/b922351g

A new efficient Pd-catalyzed cascade Heck-Saegusa protocol for the synthesis of synthetically useful α,β-unsaturated aldehydes in high yields from readily available aryl iodides and allyl alcohol has been developed.

Full text of DOI:10.1039/b922351g

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Pd-catalyzed cascade Heck–Saegusa: direct synthesis of enals
from aryl iodides and allyl alcoholw
Jie Liu,a Jin Zhu,a Hualiang Jiang,ac Wei Wang*abc and Jian Li*a
Received (in College Park, MD, USA) 26th October 2009, Accepted 23rd November 2009
First published as an Advance Article on the web 1st December 2009
DOI: 10.1039/b922351g
A new efficient Pd-catalyzed cascade Heck–Saegusa protocol
for the synthesis of synthetically useful a,b-unsaturated
aldehydes in high yields from readily available aryl iodides and
allyl alcohol has been developed.
blocks, we questioned whether it might be possible to merge
the widely used Heck reaction with the direct Saegusa
oxidation process to create a new one-pot approach to these
substances (Scheme 1, eqn (2)). We envisioned that a
Pd-catalyzed Heck reaction14,15 of aryl iodides and allyl
alcohol would produce b-aryl aldehydes, which would serve
as starting materials for the subsequent Saegusa reaction to
directly produce enals. Despite the significant challenges
regarding reagent/reaction condition compatibility and their
potential interference, it may be feasible to develop such a
cascade process since the same Pd(OAc)2 is used as a promoter
in both reactions.
a,b-Unsaturated aldehydes (enals) as versatile synthetic building
blocks, are widely used in the cosmetic,1 pharmaceutical2 and
agrochemical3 industries. Moreover, notably, they have
embraced recent dramatic growing interest as a result of their
broad applications in organocatalysis.4 In the past, a variety
of synthetic strategies toward their synthesis have been
developed. These are the palladium-catalyzed arylation of
acrolein diethyl acetal,5 the oxidation of allylic alcohols,6
Peterson olefinations,7 or formylation,8 cross-metathesis
reactions of acrolein,9 cross-aldol condensations,10 Wittig
olefinations,11 and oxidation–eliminations of a-selenoaldehydes.12
However, these methods are flawed due to low synthetic
efficiency such as extensive polymerization, harsh reaction
conditions, multiple step synthesis, use of not readily available
substances, or the generation of a large amounts of chemical
waste and hazards. A practical synthesis of enals would
employ commercially available and inexpensive reagents, use
a catalytic approach under mild reaction conditions, and be
atom economical. Furthermore, the transformation should be
amenable to a one-pot procedure to enable rapid generation of
an array of enals. Driven by the ever-growing demand
for enals and environmentally benign technologies in fine
chemical synthesis, new, direct, and more efficient approaches
are urgently needed. Herein we disclose a direct, yet broadly
applicable, one-pot catalytic approach to give a,b-unsaturated
aldehydes in high yields from simple aryl iodides and allyl
alcohol.
To prove the working hypothesis, we performed a reaction
of iodobenzene 1a with allyl alcohol 2 by combining a typical
Heck reaction protocol with the direct Saegusa reaction
procedures we have developed at 60 1C (Table 1, entries 1
and 2). Under the conditions, the desired enal product 4a was
observed in 18% and 39% yield with (S)-diphenylprolinol
and o-anisidine as co-catalysts, respectively. In addition, a
considerable amount of 3-phenylpropionaldehyde 3a was also
produced in respective 27% and 9% yields. Gratifyingly, the
yields (46% and 39%, entries 3 and 4) were improved
significantly for the desired 4a whereas those of by-product
3a were reduced to 1% and 2% when DMF was employed as
the solvent. Further optimization led to the use of a 1 : 1
mixture of DMSO and DMF and the yield dramatically
increased to 67% and 61% (entries 5 and 10). Probing the
reaction temperature using (S)-diphenylprolinol as catalyst
revealed that 60 1C was optimal (entries 5–9). Unexpectedly,
even higher yield (79%) was obtained in the absence of the
amine catalyst (entry 11). Moreover, it was found that the
NaHCO3 base and the phase transfer reagent (Bu4N+ClÀ)
were both essential for the reaction and without either sub-
stance, no product 4a was observed (entries 12 and 13).
Reducing the concentration of O2 led to lower yield (29%)
of the desired 4a (entry 14). Finally, the use of other Pd
Recently, we have developed a novel amine–Pd(OAc)2
co-catalyzed direct Saegusa oxidation reaction of unmodified
b-aryl aldehydes to a,b-unsaturated aldehydes (Scheme 1,
eqn (1)).13 In our continuing efforts aimed at developing more
efficient synthetic tools toward the highly valuable building
a School of Pharmacy, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, China.
E-mail: jianli@ecust.edu.cn; Fax: (+86) 21-64252584;
Tel: (+86) 21-64252584
b Department of Chemistry and Chemical Biology, University of
New Mexico, MSC03 2060, Albuquerque, NM 87131-0001, USA.
E-mail: wwang@unm.edu; Fax: (+1) 505-277-2609
c Drug Discovery and Design Center, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data for the compounds 4a–4s. See DOI:
10.1039/b922351g
Scheme 1 Design of Pd(OAc)2 catalyzed cascade Heck–Saegusa
reactions.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 415–417 | 415

View Online
Table 2 Synthesis of enols from aryl iodides and allyl alcohol in one pota
Table 1 Exploration of the catalytic Heck–Saegusa cascade reactiona
Entry
Aryl iodides
t/h
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1a, PhI
1b, 2-Me-C6H4I
1c, 2-Cl-C6H4I
1d, 2-MeO2C-C6H4I
1e, 4-CN-C6H4I
1f, 4-NO2-C6H4I
1g, 4-Et-C6H4I
1h, 4-Me-C6H4I
1i, 4-Cl-C6H4I
1j, 4-MeCO-C6H4I
1k, 4-MeO2C-C6H4I
1l, 4-Ph-C6H4I
1m, 3-Me-C6H4I
1n, 3-F-C6H4I
1o, 2,4-di-Cl-C6H3I
1p, 2-Me-4-NO2-C6H3I
1q, 2-F-4-Me-C6H3I
1r, 3-I-pyridine
15
24
9
7
4
5
30
6
20
3
8
19
6
12
12.5
5
5.5
20
16
3a : 4a 1 : 79
3b : 4b 0 : 81
3c : 4c 0 : 81
3d : 4d 0 : 80
3e : 4e 3 : 68
3f : 4f 5 : 60
3g : 4g 0 : 72
3h : 4h 0 : 81
3j : 4j 0 : 62
3j : 4j 0 : 67
3k : 4k 0 : 80
3l : 4l 0 : 80
3m : 4m 0 : 78
3n : 4n 0 : 59
3o : 4o 0 : 77
3p : 4p 0 : 58
3q : 4q 0 : 67
3r : 4r 0 : 57
3s : 4s 0 : 82
Yield
Catalyst T/1C t/h 3a : 4a (%)b
Entry Solvent
1c
2c
3c
4c
5
DMSO
DMSO
DMF
DMF
DMSO : DMF (1 : 1)
DMSO : DMF (1 : 1)
DMSO : DMF (1 : 1)
DMSO : DMF (1 : 1)
DMSO : DMF (1 : 1)
I
II
I
II
I
I
I
I
I
60
60
60
60
60
45
90
110
110
60
60
60
4
4
4
27 : 18
9 : 39
1 : 46
2 : 39
2 : 67
25 : 42
1 : 52
2 : 59
1 : 41
6 : 61
1 : 79
0 : 0
4
10
10
10
10
10
10
15
15
15
15
6
7
8
9d
10
DMSO : DMF (1 : 1) II
11
DMSO : DMF (1 : 1)
DMSO : DMF (1 : 1)
DMSO : DMF (1 : 1)
DMSO : DMF (1 : 1)
—
—
—
—
12e
13f
14g
60
60
0 : 0
17 : 29
1s, 1-I-naphthalene
a
Unless stated otherwise, the reaction was carried out with 1a
(0.49 mmol) and 2 (0.74 mmol) under standard conditions: [Pd(OAc)2
(0.2 equiv.), aminocatalysis (0.2 equiv.), O2 (1 atm), NaHCO3 (2.5 equiv.)
a
Unless specified, all reactions were carried out with 1 (0.49 mmol)
with 2 (0.74 mmol), Pd(OAc)2 (0.2 equiv.), O2 (1 atm), NaHCO3
(2.5 equiv.) and Bu4N+ClÀ (1.0 equiv.) at 60 1C in DMSO : DMF =
b
c
and Bu4N+ClÀ (1.0 equiv.)]. Isolated yield. 0.1 equiv. Pd(OAc)2
b
1 : 1. Isolated yields.
d
e
f
used. 0.4 equiv. Pd(OAc)2 used. NaHCO3 was removed. In the
absence of Bu4N+ClÀ. Air (1 atm) used.
g
cinnamaldehydes is proposed (Fig. 1). Alternatively, the
oxidation may happen first to give cinnamaldehydes 4,
followed by the Heck reaction. A typical Heck pathway is
involved and results in the formation of enol 8 or allylic
alcohol 9 from b-elimination reaction.14 Enol 8 as substrate
engages in the subsequent Saegusa process with a similar
mechanism to that of a classic Saegusa process,13,16 which
sources, such as palladium chloride, bis(acetonitrile)dichloro-
palladium(II), tris(dibenzylideneacetone)dipalladium and,
tetrakis(triphenylphosphine) palladium(0), resulted in 6%,
18%, 45% and 0% yields, respectively, indicative of the
sensitive nature of the Pd catalyst for the cascade process.
Having established the optimal reaction conditions, we next
explored the scope and generality of the methodology. The
powerful cascade served as a general approach to enals with
significant structural variation of aryl iodides (Table 2). The
desired enal products 4 were generated dominantly in good
yields. A variety of substituents on the aryl ring including
halogens, alkyl groups, CN, CO2Me, NO2, carbonyls, etc.
were tolerated well. This indicated that the electronic effects
were limited. It appeared that the aryl iodides bearing
electron-neutral (entry 1) and -rich substituents (entries 2, 7,
8 and 13) gave higher yields. The same observation was seen
for the moderately electron-withdrawing groups (entries 4 and 11).
Nevertheless, relatively lower yields were obtained with
strongly electron-withdrawing substituents such as cyano,
nitro, acetyl, fluoro (entries 5, 6, 10 and 14). We also investi-
gated the steric effect of the aryl iodides on the cascade
processes. All para-, meta-, and ortho-substituted substrates were
smoothly transformed into the desired products, indicating that
the steric effect had little impact on the reaction (Table 2, entries
2–4 and 16–17). Finally, heterocyclic (entry 18) and conjugated
aromatic substrates (entries 12 and 19) could efficiently partici-
pate in the cascade transformations as well.
was validated by
a control reaction (bottom section,
Scheme 2). It is noteworthy that the proposed cycle also
explains why no amine catalyst is needed since the
resulting enol 8 or allylic alcohol 9 are able to directly
participate in the Saegusa reaction under the developed
reaction conditions. Our preliminary control studies
prove the hypothesis (Scheme 2). Under the standard
conditions [Pd(OAc)2, Bu4N+ClÀ, NaHCO3, O2 (1 atm),
DMSO : DMF = 1 : 1 (1 mL), 60 1C], allylic alcohol 9a
was smoothly transformed to cinnamaldehyde 4a in a
good yield (87%) (eqn (3)). Moreover, 3-phenylpropion-
aldehyde 10a underwent tautomerization to form enol 8a
under the basic conditions (eqn (4)). The in situ formed enol
8a was oxidized via a classic Saegusa process to afford
cinnamaldehydes 4 in 71% yield.
In conclusion, we have developed a new and practical
Pd-catalyzed cascade Heck–Saegusa reaction for one-pot
synthesis of useful cinnamaldehydes using readily available
aryl iodides and allyl alcohol under mild reaction conditions.
The cascade reactions are compatible with a variety of
functional groups on the aryl ring and even with heterocycles
in good yields. The detailed mechanistic aspects and
application of the cascade reaction in the preparation
A plausible reaction mechanism of the Pd(II) catalyzed
cascade Heck–Saegusa process for the formation of
ꢀc
This journal is The Royal Society of Chemistry 2010
416 | Chem. Commun., 2010, 46, 415–417

View Online
We are grateful for financial support from the National
Natural Science Foundation of China (Grants 90813005
and 20902022, J. Li), the 863 Hi-Tech Program of China
(Grant 2006AA020404, J. Li), and the China 111 Project
(Grant B07023, J. Li and W. Wang).
Notes and references
1 (a) M. Friedman, N. Kozukue and L. A. Harden, J. Agric. Food
Chem., 2000, 48, 5702; (b) J. Cocchiara, C. S. Letizia, J. Lalko,
A. Lapczynski and A. M. Api, Food Chem. Toxicol., 2005, 43, 867.
2 For recent selected examples, see: (a) G. Brackman, T. Defoirdt,
C. Miyamoto, P. Bossier, S. Van Calenbergh, H. Nelis and
T. Coenye, BMC Microbiol., 2008, 8, 149; (b) L. K. Chao,
K. F. Hua, H. Y. Hsu, S. S. Cheng, I. F. Lin, C. J. Chen,
S. T. Chen and S. T. Chang, Food Chem. Toxicol., 2008, 46, 220;
(c) C. W. Lee, S. H. Lee, J. W. Lee, J. O. Ban, S. Y. Lee, H. S. Yoo,
J. K. Jung, D. C. Moon, K. W. Oh and J. T. Hong, J. Pharmacol.
Sci., 2007, 104, 19; (d) K. Sato, S. Krist and G. Buchbauer, Biol.
Pharm. Bull., 2006, 29, 2292.
3 For selected examples, see: (a) E. J. Lee, J. R. Kim, D. R. Choi and
´
Y. J. Ahn, J. Econ. Entomol., 2008, 101, 1960; (b) A. Rodrıguez,
C. Nerın and R. Batlle, J. Agric. Food Chem., 2008, 56, 6364;
´
(c) S. T. Chang and S. S. Cheng, J. Agric. Food Chem., 2002, 50,
1389; (d) I. K. Park, H. S. Lee, S. G. Lee, J. D. Park and Y. J. Ahn,
J. Agric. Food Chem., 2000, 48, 2528.
4 (a) D. Almasi, D. A. Alonso and C. Najera,
Tetrahedron: Asymmetry, 2007, 18, 299; (b) S. B. Tsogoeva, Eur.
´
J. Org. Chem., 2007, 1701; (c) J. L. Vicario, D. Badıa and
L. Carrillo, Synthesis, 2007, 2065; (d) D. Enders, C. Grondal and
M. R. M. Huttl, Angew. Chem., Int. Ed., 2007, 46, 1570;
(e) X.-H. Yu and W. Wang, Org. Biomol. Chem., 2008, 6, 2037.
5 G. Battistuzzi, S. Cacchi and G. Fabrizi, Org. Lett., 2003, 5, 777.
6 G. Tojo and M. Fernandes, in Oxidation of Alcohols to Aldehydes
´
and Ketones: A Guide to Current Common Practice, ed. G. Tojo,
Springer, Berlin, 2006, p. 1.
7 D. J. Ager, Synthesis, 1984, 384.
Fig. 1 Proposed mechanism for Pd-catalyzed cascade Heck–Saegusa
reactions.
8 (a) B. Breit, Acc. Chem. Res., 2003, 36, 264; (b) H. Neumann,
A. Sergeev and M. Beller, Angew. Chem., Int. Ed., 2008, 47, 4887.
9 M. T. Crimmins and B. W. King, J. Am. Chem. Soc., 1998, 120,
9084.
10 P. R. Mackie and C. E. Foster, in Comprehensive Organic Group
Transformations II, ed. A. R. Katritzky, R. J. K. Taylor and
S. Jone, Elsevier, Dordrecht, 2004, vol. 3, p. 59.
11 B. E. Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863.
12 R. C. Larock, Comprehensive Organic Transformations, John
Wiley & Sons, New York, 1999.
13 (a) J. Zhu, J. Liu, R.-Q. Ma, H.-X. Xie, J. Li, H.-L. Jiang and
W. Wang, Adv. Synth. Catal., 2009, 351, 1229; (b) J. Liu, J. Zhu,
H.-L. Jiang, W. Wang and J. Li, Chem.–Asian J., 2009, 4, 1712.
14 (a) J. B. Melpolder and R. F. Heck, J. Org. Chem., 1976, 41, 265;
(b) A. J. Chalk and S. A. Magennis, J. Org. Chem., 1976, 41, 273;
(c) A. J. Chalk and S. A. Magennis, J. Org. Chem., 1976, 41,
1206; (d) G. Dyker and P. Grundt, Tetrahedron Lett., 1996, 37,
619; (e) J. T. Li, A. W. Mau and C. R. Strauss, Chem. Commun.,
1997, 1275.
Scheme 2 Conversion of respective 9a and 10a to cinnamaldehyde 4a.
15 K. E. Torraca, S. Kuwabe and S. L. Buchwald, J. Am. Chem. Soc.,
2000, 122, 12907.
16 S. Porth, J. W. Bats, D. Trauner, G. Giester and J. Mulzer,
Angew. Chem., Int. Ed., 1999, 38, 2015.
of bioactive molecules are currently being pursued in our
laboratory.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 415–417 | 417