Palladium-catalyzed oxidative tandem reaction of allylamines with aryl halides leading to α,β-unsaturated aldehydes

Article abstract of DOI:10.1039/b917782e

A novel tandem protocol involving a Heck reaction process for the synthesis of α,β-unsaturated aldehydes has been developed. In the presence of Pd(OAc), PPh₃, NaOAc, TBAB and air, N-allylbenzenamines underwent the reaction with various aryl hal

Full text of DOI:10.1039/b917782e

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Palladium-catalyzed oxidative tandem reaction of allylamines with
aryl halides leading to a,b-unsaturated aldehydesw
a
ab
Tao-Shan Jiang and Jin-Heng Li*
Received (in Cambridge, UK) 28th August 2009, Accepted 8th October 2009
First published as an Advance Article on the web 21st October 2009
DOI: 10.1039/b917782e
a
A novel tandem protocol involving a Heck reaction process for
Table 1 Screening optimal reaction conditions
the synthesis of a,b-unsaturated aldehydes has been developed.
3
In the presence of Pd(OAc), PPh , NaOAc, TBAB and air,
N-allylbenzenamines underwent the reaction with various aryl
halides to afford the corresponding a,b-unsaturated aldehydes
selectively in moderate to good yields. The protocol can also be
used as a valuable route for the deallylation of arylamines.
a,b-Unsaturated aldehydes, particularly cinnamaldehydes, are
an important class of chemical compounds that have a wide
Entry [Pd]
Ligand Base
Solvent
t/h Yield (%)
1
–5
use in the food, cosmetic and pharmaceutical industries
1
2
3
4
5
6
7
8
9
1
Pd(OAc)
Pd (dba)
Pd(PPh
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
—
—
—
L1
L2
L3
L4
L5
L1
L1
NaOAc DMF
NaOAc DMF
NaOAc DMF
NaOAc DMF
NaOAc DMF
NaOAc DMF
NaOAc DMF
NaOAc DMF
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
6
31
23
51
67
58
26
65
19
Trace
10
Trace
10
33
6
besides being valuable intermediates in organic synthesis.
Therefore, many practical methods, including oxidations of
2
3
3
)
4
7
allylic alcohols, Peterson olefinations, formylation, cross-
8
9
2
2
2
2
2
2
2
1
aldol condensations and Mannich reactions, and Saegusa
0
1
1
oxidations, have been developed for their preparation.
However, these methods are restricted to relatively harsh
reaction conditions, inaccessible substrates, expensive catalysts,
and/or unsatisfactory selectivity (regio- and chemoselectivity).
To overcome these drawbacks, a particularly attractive alternate
approach is palladium-catalyzed Heck reactions of acroleins
Cs CO
2
Et
3
DMF
DMF
0
3
N
11
12
Pd(OAc)2 L1
NaOAc DMSO
NaOAc Dioxane
NaOAc Toluene
NaOAc DMF
NaOAc DMF
NaOAc DMF
NaOAc DMF
NaOAc DMF
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)2 L1
Pd(OAc)
Pd(OAc)
2
2
2
2
L1
L1
L1
L1
1
1
1
3
4
5
b
60
o5
1
2
with aryl halides. Here, we report a novel tandem protocol
c
d
for the synthesis of a,b-unsaturated aldehydes involving a
16
75
73
de
df
1
Pd-catalyzed Heck process. In the presence of Pd(OAc)
3
1
1
7
8
2
L1
L1
2
,
2
10 Trace
PPh , NaOAc, TBAB and air, allylamines underwent the
3
a
Reaction conditions: 1a (0.25 mmol), 2a (0.2 mmol), [Pd] (5 mol%),
ligand (10 mol%), and base (0.4 mmol) in solvent (2 mL) at 120 1C
reaction with aryl halides selectively to afford the corresponding
a,b-unsaturated aldehydes in moderate to good yields
0
under air atmosphere. dppf = 1,1 -bis(diphenylphosphino)-ferrocene.
d
(
Scheme 1). To the best of our knowledge, it is the first example
b
c
4
Under oxygen atmosphere. Under argon atmosphere. n-Bu NBr
of palladium-catalyzed tandem reactions of allylamines with aryl
halides for the preparation of a,b-unsaturated aldehydes.
Our initial investigation focused on the reaction between
N-allyl-N-methylbenzenamine (1a) and iodobenzene (2a), and
the results are summarized in Table 1. We found that the
e
f
(
0.2 mmol) was added. At 100 1C. At 80 1C.
ligand has a fundamental influence on the reaction (entries 1–8).
In the absence of ligands, the reaction of N-allyl-N-methyl-
benzenamine (1a) with iodobenzene (2a) afforded the target
product 3 in low yields using either Pd(OAc)
2 2 3
or Pd (dba)
(
3 4
entries 1 and 2). To our delight, Pd(PPh ) enhanced the yield
to 51% (entry 3). Encouraged by these results, Pd(OAc)2
combined with ligands were evaluated, and it was found that
both PPh (L1) and 2-(di-tert-butylphosphino)biphenyl (L4)
3
provided the highest yields (entries 4–8). Subsequently, the
effect of bases and solvent were examined, respectively (entries
Scheme 1 A protocol involving an oxidative heck reaction process.
9
–13). The results demonstrated that NaOAc combined with
a
College of Chemistry and Materials Science, Wenzhou University,
DMF gave the best results. It is noteworthy that oxygen plays
an important role in the reaction (entries 14–16). While a
moderate yield of the desired product 3 was obtained under air
or oxygen atmosphere, argon reduced the yield to o5%. It
Wenzhou, 325035, China. E-mail: jhli@hunnu.edu.cn;
Fax: 0086731 8872 101; Tel: 0086731 8872 576
Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education), Hunan Normal
University, Changsha 410081, China
b
4
was interesting to observe that TBAB (n-Bu NBr) could
w Electronic supplementary information (ESI) available: Typical
experimental procedures, analytical data and spectra. See DOI:
1
1
4
improve the reaction (entry 17). Among the examination
of the reaction temperature, satisfactory results were still
0.1039/b917782e
7
236 | Chem. Commun., 2009, 7236–7238
This journal is ꢀc The Royal Society of Chemistry 2009

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achieved at 100 1C, but 80 1C did not favor the reaction
Table 2 Pd(OAc)
aldehydes
2
/PPh
3
(L1)-catalyzed synthesis of a,b-unsaturated
a
(
entries 18 and 19).
With the optimal reaction conditions in hand, we proceeded
to generate a number of a,b-unsaturated aldehydes (Table 2).
We found that the reaction conditions tolerated a variety of
functional groups on the aryl halide moiety, and the electronic
effect of these functional groups affected the reaction to some
Entry Substrate 1
1
Halide 2
t/h Yield (%)
2
extent (entries 1–13). In the presence of Pd(OAc) , L1, TBAB
and NaOAc, a number of electron-rich aryl iodides 2b–2e
underwent the reaction with N-allyl-N-methylbenzenamine
4
6
4
8
83 (4)
76 (5)
75 (6)
77 (7)
(
1a) smoothly in good yields (entries 1–4). Although the yields
were decreased to some extent, electron-deficient aryl iodides
2
3
4
2
1
f–2j were also suitable substrates for the reaction with amine
a at 100 1C (entries 5–10). 1-Iodo-4-nitrobenzene (2g), for
instance, provided only 35% yield of the target product 10 at
1
20 1C, whereas 100 1C increased the yield to 60% (entries 6
and 7). Gratifyingly, the standard conditions are compatible
with heteroaryl iodides 2k or 2l in moderate yields (entries 11
and 12). However, bromobenzene (2m) has no activity under
the same conditions (entry 13). It is noted that vinyl bromide
(
2n) is a suitable substrate to afford the corresponding 1,3-
5
6
6
75 (8)
dienal product 15 in 80% yield (entry 14). The suitable
allylamines were subsequently screened under the standard
conditions (entries 15–23). The results demonstrated that only
N-allylarylamines 1b–1g could undergo the reaction (entries
14 35 (9)
14 60 (9)
14 60 (10)
14 63 (11)
1
5–21), but the reaction of N-allylacetamide (1h) or 4-allyl-
morpholine (1i) with iodide 2b failed (entries 22 and 23). For
example, we were pleased to observe that N-allylbenzenamine
b
7
(
1b) could react with iodides 2b or 2h in moderate yields
entries 15 and 16). Substrate 1d bearing a N-(2-methylphenyl)
(
b
8
group also afforded the acceptable yield (entry 18). Both
substrates 1e and 1f with an electron-withdrawing N-aryl
group were suitable substrates in good yields (entries 19
and 20). It was interesting to disclose that the reaction of
N-allyl-N-phenylbenzenamine (1g) was also successful under
the standard conditions (entry 21).
b
9
d
0
1
6
72 (12)
A possible mechanism is proposed as outlined in Scheme 2 on
11–13,15
the basis of the reported mechanism.
The active Pd(0)
species, generated from the reaction of Pd(OAc) with ligand,
2
1
1
1
2
10 70 (13)
sequently undergoes the reaction with ArX and substrate 1 to
afford intermediates C and Dvia the Heck process. According to
Wang’s proposed mechanism, intermediate D can be converted
6
6
6
6
66 (14)
Trace (3)
80 (15)
52 (4)
1
1,15
to the Pd(II) intermediate E under air or oxygen atmosphere,
followed by addition to give the enamine intermediate F.
Reductive elimination of intermediate F occurs, leading to
intermediate G and the regeneration of the active Pd(0) species.
Finally, hydrolysis of intermediate G yields the desired product.
To elucidate the mechanism, a controlled reaction was carried
out (eqn (1) in Scheme 2). The results supported the intermediate
C to intermediate F process.
13
1
1
1
4
5
6
In summary, we have developed a new tandem approach
for the synthesis of a,b-unsaturated aldehydes. This novel
Pd-catalyzed tandem process allows the reaction between
N-allylbenzenamine and various aryl halides to provide useful
a,b-unsaturated aldehyde compounds in moderate to good
yields. It is noteworthy that the present protocol also provides
a new route for the deallylation of arylamines. Work to probe
the detailed mechanism and apply the present protocol in
organic synthesis is currently underway.
14 49 (10)
17
4
74 (4)
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Table 2 (continued )
This research was supported by the National Natural
Science Foundation of China (No 20872112), Zhejiang
Provincial Natural Science Foundation of China (No.
Y407116) and New Century Excellent Talents in University
Entry Substrate 1
Halide 2
t/h Yield (%)
(
No. NCET-06-0711),
1
8
4
4
51 (4)
93 (4)
Notes and references
1
(a) R. O. Wijesekera, Historical Overview of the Cinnamon
Industry, in CRC Critical Reviews in Food Science and Nutrition,
1
2
9
1978, vol. 10, p. 1; (b) J. M. Fang, S. A. Chen and Y. S. Cheng,
J. Agric. Food Chem., 1989, 37, 744.
2
3
M. Friedman, P. R. Henika and R. E. Mandrell, J. Food Protect.,
2
(a) S. Ishida, A. Matsuda, Y. Kawamura and K. Yamanaka,
Chemotherapy, 1960, 8, 157; (b) H. Ferhout, J. Bohatier,
J. Guillot and J. C. Chalchat, J. Essent. Oil Res., 1999, 11, 119.
M. Friedman, P. R. Henika and R. E. Mandrell, J. Food Protect.,
002, 65, 1545.
0
1
4
4
85 (4)
63 (4)
4
2
002, 65, 1545.
2
2
5
6
S.-T. Chang and S.-S. Cheng, J. Agric. Food Chem., 2002, 50, 1389.
E. F. Glorius, in Science of Synthesis, ed. R. Bruckner, Georg
Thieme Verlag, Stuttgart, 2007, vol. 25, p. 733.
7
(a) G. Tojo and M. Fernandez, in Oxidation of Alcohols to
´
2
3
12 Trace (4)
12 Trace (4)
Aldehydes and Ketones: A Guide to Current Common Practice, ed.
G. Tojo, Springer, Berlin, 2006, pp. 1–375; (b) M. Reid,
D. J. Roweb and R. J. Taylor, Chem. Commun., 2003, 2284.
2
8 D. J. Ager, Synthesis, 1984, 384.
9
(a) B. Breit, Acc. Chem. Res., 2003, 36, 264; (b) H. Neumann,
A. Sergeev and M. Beller, Angew. Chem., Int. Ed., 2008, 47, 4887.
a
Reaction conditions: 1 (0.25 mmol), 2 (0.2 mmol), Pd(OAc)
5 mol%), PPh (L1, 10 mol%), TBAB (0.2 mmol) and NaOAc
0.4 mmol) in DMF (2 mL) at 120 1C. At 100 1C.
2
1
0 (a) P. R. Mackie and C. E. Foster, in Comprehensive Organic Group
Transformations II, ed. A. R. Katritzky, R. J. K. Taylor and
K. Jones, Elsevier, Dordrecht, 2004, vol. 3, pp. 59–97;
(
(
3
b
(b) R. Brettle, in Comprehensive Organic Chemistry: The Synthesis
and Reactions of Organic Compounds, ed. D. Barton and
W. D. Ollis, Pergamon, Oxford, 1979, vol. 1, pp. 979–992;
(
c) R. C. Larock, Comprehensive Organic Transformations: A Guide
to Functional Group Preparations, Wiley-VCH, Weinheim, 1999,
pp. 317–340.
1 (a) Y. Ito, T. Hirao and T. Saegusa, J. Org. Chem., 1978, 43, 1011;
1
(
b) R. C. Larock, T. R. Hightower, G. A. Kraus, P. Hahn and
D. Zhang, Tetrahedron Lett., 1995, 36, 2423; (c) S. Porth,
J. W. Bats, D. Trauner, G. Giester and J. Mulzer, Angew. Chem.,
Int. Ed., 1999, 38, 2015.
1
2 (a) T. Jeffery, J. Chem. Soc., Chem. Commun., 1984, 1287;
(
(
b) M. R. Unroe and B. A. Reinhardt, Synthesis, 1987, 981;
c) G. Battistuzzi, S. Cacchi and G. Fabrizi, Org. Lett., 2003, 5,
7
1
3
2
77; (d) F. Berthiol, H. Doucet and M. Santelli, Catal. Lett., 2005,
02, 281; (e) E. Alacid and C. Najera, Eur. J. Org. Chem., 2008,
102; (f) S. Noel, L. Djakovitch and C. Pinel, Tetrahedron Lett.,
006, 47, 3839.
´
¨
1
3 For reviews of the Heck reaction, see: (a) I. P. Beletskaya and
A. V. Cheprakov, Chem. Rev., 2000, 100, 3009; (b) R. F. Heck, in
Comprehensive Organic Synthesis, ed. B. M. Trost, Pergamon,
New York, 1991, vol. 4, ch. 4.3; (c) W. Cabri and I. Candiani,
Acc. Chem. Res., 1995, 28, 2.
1
4 Another product, N-methylbenzenamine,was observed in >98%
GC yield based on 1a using the product 3 as the internal standard.
5 J. Zhu, J. Liu, R. Q. Ma, H. Xie, J. Li, H. Jiang and W. Wang,
Adv. Synth. Catal., 2009, 351, 1229.
1
Scheme 2 A possible mechanism.
7
238 | Chem. Commun., 2009, 7236–7238
This journal is ꢀc The Royal Society of Chemistry 2009