One-pot aza-Baylis-Hillman reactions of arylaldehydes and diphenylphosphinamide with methyl vinyl ketone in the presence of TiCl4, PPh3, and Et3N

Article abstract of DOI:10.1016/S0040-4039(02)02263-3

We found that one-pot, three-component, aza-Baylis-Hillman reactions of arylaldehydes, diphenylphosphinamide, and methyl vinyl ketone (MVK) can be realized in the presence of TiCl₄ (0.8 equiv.), PPh₃ (0.1 equiv.), and Et₃N

Full text of DOI:10.1016/S0040-4039(02)02263-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9171–9174
One-pot aza-Baylis–Hillman reactions of arylaldehydes and
diphenylphosphinamide with methyl vinyl ketone in the presence
of TiCl4, PPh3, and Et3N
Min Shi* and Gui-Ling Zhao
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Received 19 August 2002; revised 23 September 2002; accepted 4 October 2002
Abstract—We found that one-pot, three-component, aza-Baylis–Hillman reactions of arylaldehydes, diphenylphosphinamide, and
methyl vinyl ketone (MVK) can be realized in the presence of TiCl4 (0.8 equiv.), PPh3 (0.1 equiv.), and Et3N (12 equiv.) in
dichloromethane to give the corresponding aza-Baylis–Hillman adducts 2 in good yields. © 2002 Elsevier Science Ltd. All rights
reserved.
Since Baylis and Hillman first reported reactions of
acetaldehyde with ethyl acrylate and acrylonitrile in the
presence of catalytic amounts of a strong Lewis base
such as 1,4-diazabicyclo[2.2.2]octane (DABCO) in
1972,1 the Baylis–Hillman reaction has made great pro-
gress,2 and now includes a catalytic asymmetric ver-
sion.3 However, in this very simple and useful reaction,
(MVK), methyl acrylate, and acrylonitrile in the pres-
ence of various Lewis bases such as PPh3, PPh2Me or
DABCO (Scheme 1).5 In this case, we used N-aryli-
denediphenylphosphinamides 1, which were prepared in
moderate yields from the reaction of diphenylphosphi-
namide with arylaldehyde in the presence of TiCl4 (0.55
equiv.) and triethylamine (Et3N, 3.0 equiv.) according
to the literature, in this Baylis–Hillman reaction
(Scheme 1).6 Recently, an efficient and selective one-
pot, three-component, procedure for the formation of
a-methylene-b-amino acid derivatives using the aza-
Baylis–Hillman protocol has been disclosed using
DABCO (Lewis base) and La(OTf)3 or Ti(OPri)4 (Lewis
only
aldehydes1–3
and
N-benzylidene-4-
methylbenzenesulfonamides4 are generally used as the
substrates for reactions with a,b-unsaturated ketones,
nitriles or esters. Previously, we reported an unprece-
dented aza-Baylis–Hillman reaction of N-arylid-
enediphenylphosphinamides 1 with methyl vinyl ketone
Scheme 1.
Keywords: diphenylphosphinamide; Lewis base; Baylis–Hillman reactions; methyl vinyl ketone (MVK); titanium(IV) chloride (TiCl4); triethyl-
amine (Et3N).
* Corresponding author. Fax: 86-21-64166128; e-mail: mshi@pub.sioc.ac.cn
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02263-3

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M. Shi, G.-L. Zhao / Tetrahedron Letters 43 (2002) 9171–9174
acid) in which methyl acrylate is often utilized as the
substrate (Scheme 2).7 Thus, we attempted to simplify
the reaction procedure of the aza-Baylis–Hillman reac-
tion of 1 with MVK in a one-pot manner. Herein, we
wish to report an unprecedented one-pot, three compo-
nent, aza-Baylis–Hillman reaction between arylalde-
hydes, diphenylphosphinamide, and MVK.
because 3 or 20 equiv. of Et3N can completely stop the
reaction under the same conditions (Table 1, entries 1,
2 and 4). Dichloromethane is the best solvent for this
reaction (Table 1, entries 3 and 5–7). During further
optimizing the reaction conditions, we found that the
best reaction conditions for this one-pot aza-Baylis–
Hillman reaction involve using PPh3 (0.1 equiv.) as the
Lewis base and TiCl4 (0.8 equiv.) as the Lewis acid in
the presence of Et3N (12 equiv.) (Table 1, entry 8).8 The
First of all, we examined this one-pot reaction using the
reported methods shown in Scheme 2. However, we
found that no reactions occurred under these condi-
tions. We selected TiCl4 as the Lewis acid and PPh3 as
the Lewis base to examine this one-pot reaction of an
arylaldehyde (2.0 equiv.), diphenylphosphinamide (1.0
equiv.), and MVK (2.0 equiv.) because N-aryli-
denediphenylphosphinamides 1 have been synthesized
in the presence of TiCl4 (Scheme 1) and PPh3 is the best
Lewis base for promoting the Baylis–Hillman reaction
of arylaldehydes with 1.5 As a result, it was found that
when the reaction was carried out in the presence of
TiCl4 (0.55 equiv.), PPh3 (1.0 equiv.) and triethylamine
(Et3N) (9.0 equiv.) in dichloromethane, the correspond-
ing aza-Baylis–Hillman adduct 2a was formed in 58%
yield (Table 1, entry 3). Triethylamine (Et3N) itself
cannot promote the Baylis–Hillman reaction of 1 with
MVK, but it was employed to quench the HCl formed
during the reaction. TiCl4 acted as a Lewis acid in the
condensation of an arylaldehyde with diphenylphosphi-
namide to produce 1 in situ; we were able to observe
the formation of 1 on a TLC plate during the reaction.
The amount of Et3N is crucial for this one-pot reaction
,
results are summarized in Table 1. The presence of 4 A
molecular sieves did not improve the yield of 2a (Table
1, entry 10).
Under the optimized reaction conditions, we next car-
ried out this novel one-pot reaction using various aryl-
aldehydes as the substrates (Table 2). In general, the
corresponding Baylis–Hillman adducts were obtained in
40–86% yields. The results are summarized in Table 2.
For the arylaldehydes having strongly electron-with-
drawing substituents such as p-nitrobenzaldehyde and
p-fluorobenzaldehyde (active arylaldehydes), we found
that some by-products were formed and the yields of 2
decreased. This is because these active arylaldehydes
can undergo a TiCl4 and amine promoted Baylis–Hill-
man reaction to give the chlorinated adducts and rear-
ranged Z-olefins in addition to the normal
Baylis–Hillman products.2t–y Therefore, in these cases
(Table 2, entries 4, 6 and 7), 1.0 equiv. of arylaldehyde
was employed and the corresponding aza-Baylis–Hill-
man adducts were obtained in moderate yields.
Scheme 2.
Table 1. One-pot three component aza-Baylis–Hillman reaction of benzaldehyde (2.0 equiv.), diphenylphosphinamide (1.0
equiv.), with MVK (2.0 equiv.) in the presence of TiCl4, Et3N and PPh3 at room temperature
Entry
TiCl4 (equiv.)
Et3N (equiv.)
Lewis base PPh3 (equiv.)
Solvent
Time (h)
Yield (%)a 2a
1
2
3
4
5
6
7
8
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.8
3.0
3.0
9.0
20.0
9.0
9.0
0.2
1.0
1.0
1.0
1.0
1.0
0.1
0.1
0.1
0.1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
72
72
72
72
72
72
72
72
72
72
No reaction
No reaction
58
Trace
11
Trace
57
64
34
30
DMF
9.0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
12.0
15.0
9.0
9
1.0
0.55
10b
a Isolated yields.
b
,
In the presence of 4 A molecular sieves.

M. Shi, G.-L. Zhao / Tetrahedron Letters 43 (2002) 9171–9174
9173
Table 2. One-pot three component aza-Baylis–Hillman reaction of arylaldehydes (2.0 equiv.), diphenylphosphinamide (1.0
equiv.), with MVK (2.0 equiv.) in the presence of TiCl4, Et3N and PPh3 at room temperature
Entry
Ar
Product
Time (h)
Yield (%)a
2
1
2
p-MeC6H4
p-EtC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
p-FC6H4
2b
2c
2d
2e
2f
2g
2h
2i
120
120
120
72
72
48
51
86
52
56
60
40
48
42
3
4b
5
6b
7b
8
p-NO2C6H4
C6H5CHꢀCH
12
120
9
2j
120
120
70
52
10
m-C6H5OC6H4
2k
a Isolated yields.
b 1.0 equiv. of arylaldehyde was employed.
It should be emphasized here that when methyl acrylate
or acrylonitrile is used as the Michael acceptor under
the above, one-pot, reaction conditions, no reaction
takes place.
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In conclusion, we have found that a novel one-pot three
component aza-Baylis–Hillman reaction of arylalde-
hydes, diphenylphosphinamide, and MVK can be
achieved using TiCl4 (0.8 equiv.) and PPh3 (0.1 equiv.)
in dichloromethane in the presence of Et3N (12 equiv.).
The reaction proceeds via the reaction of 1 formed in
situ with MVK promoted by the Lewis base PPh3.
Efforts are underway to elucidate the mechanistic
details of this reaction and the key properties required
of the Lewis bases for the different substrates in this
novel, one-pot, aza-Baylis–Hillman reaction. Work
along these lines is currently in progress.
Acknowledgements
We thank the State Key Project of Basic Research
(Project 973) (No. G2000048007) and the National
Natural Science Foundation of China for financial sup-
port (20025206).
References
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9174
M. Shi, G.-L. Zhao / Tetrahedron Letters 43 (2002) 9171–9174
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diphenylphosphinamide (113.5 mg, 0.5 mmol), and
triphenylphosphine (13.1 mg, 0.050 mmol) in CH2Cl2 (2.0
mL) was added methyl vinyl ketone (MVK) (70 mg, 81
mL, 1.0 mmol) under an argon atmosphere and the reac-
tion mixture was stirred for 72 h at room temperature
(20°C). The solvent was removed under reduced pressure
and the residue was purified by a silica gel column chro-
matography (eluent: EtOAc/petroleum=1/1) to give 2e
(117 mg, 56%) as a colorless solid.
The spectral data of 2e: mp 161–164°C; IR (KBr) w 1674
cm−1 (CꢀO); 1H NMR (CDCl3, 300 MHz, TMS) l 2.28
(3H, s, CH3), 3.37 (1H, dd, JCH-NH=11.1 Hz, JP-N-H=8.4
Hz, NH), 4.87 (1H, t, JCH-NH=11.1 Hz, JP-N-CH=11.1 Hz,
CH), 6.11 (1H, s, ꢀCH), 6.21 (1H, s, ꢀCH), 7.20–7.31 (4H,
m, Ar), 7.37–7.56 (6H, m, Ar), 7.80–7.90 (4H, m, Ar); MS
(EI) m/e 409 (M+, 4.82), 340 (M+−69, 12.31), 208 (M+−
201, 100); [found: C, 67.44; H, 5.36; N, 3.38.
C23H21NClO2P requires C, 67.40; H, 5.17; N, 3.42%].
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8. Typical reaction procedure for the one-pot aza-Baylis–
Hillman reaction of p-chlorobenzaldehyde, diphenylphos-
phinamide, methyl vinyl ketone (MVK): To a Schlenk
tube with p-chlorobenzaldehyde (70 mg, 0.50 mmol),