The aza-Morita-Baylis-Hillman reaction of N-thiophosphoryl imines catalyzed by 1,3,5-triaza-7-phosphaadamantane (PTA) - Convenient synthesis of α-methylene-β-amino ketone or acid derivatives

Article abstract of DOI:10.1002/ejoc.200700572

In the presence of an effective air-stable nucleophilic trialkylphosphane orgaocatalyst, 1,3,5-triaza-7-phosphaadamantane, N-diethoxythiophosphorylimines 1 and N-diphenylthiophosphinoylimines 2 exhibited good reactivity in the methyl vinyl ketone or methy

Full text of DOI:10.1002/ejoc.200700572

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700572
The Aza-Morita–Baylis–Hillman Reaction of N-Thiophosphoryl Imines
Catalyzed by 1,3,5-Triaza-7-phosphaadamantane (PTA) –– Convenient
Synthesis of α-Methylene-β-Amino Ketone or Acid Derivatives
Xinyuan Xu,[a] Chungui Wang,[a] Zhenghong Zhou,*[a] Xiaofang Tang,[b] Zhengjie He,*[b]
and Chuchi Tang[a]
Keywords: Imines / Alkenes / Aza-Morita–Baylis–Hillman reaction / Ketones
In the presence of an effective air-stable nucleophilic trialkyl-
phosphane orgaocatalyst, 1,3,5-triaza-7-phosphaadaman-
tane, N-diethoxythiophosphorylimines 1 and N-diphenyl-
thiophosphinoylimines 2 exhibited good reactivity in the
methyl vinyl ketone or methyl acrylate based aza-Morita–
Baylis–Hillman reaction. The corresponding products were
obtained in fair-to-excellent chemical yields. Moreover, the
chiral-imine-induced diastereoselective aza-MBH reaction
was also realized with 90% de. This reaction provides a con-
venient method for the synthesis of synthetically valuable α-
methylene-β-amino ketone or acid derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
from an activated olefin, an aldehyde, and an N-protected
amine;[4c] Adolfsson used a Lewis base or a Lewis acid as
a cocatalyst to the aza-MBH reaction;[4g,4h] and Shi made
a significant contribution to this reaction by expanding the
scope of substrates to include activated olefins[4f,4l,4n,4p] and
by employing tertiary phosphanes[4i,4j,4m] as catalysts and
N-diphenylphosphinoylimines[4i] as alternative imine sub-
strates.
In the reported aza-MBH reactions, the tosyl and acyl
groups are most often used as protecting groups for the
imine moiety, probably because the protected imines have
better reactivities. In contrast, N-phosphinoyl imine was ra-
rely used owing to its troublesome preparation, poor sta-
bility, and low reactivity; however, the phosphinoyl group
could be easily deprotected by acidic hydrolysis from the
aza-MBH reaction adduct. Up to date, there is only one
report concerning the aza-MBH reaction of N-phosphinoyl
imines.[4i] The reported catalysts for aza-MBH reactions
mainly include the conventional MBH reaction catalysts
such as DABCO, triphenylphosphane, and DMAP.
Recently, we found that an easily prepared and air-stable
Introduction
The Morita–Baylis–Hillman reaction (MBH) is an effec-
tive carbon–carbon bond forming reaction that gives
densely multifunctional adducts under mild conditions.[1]
Because of its enormous potential in organic synthesis, it
has received much research interest.[2] As we know, most
recent efforts on this reaction have been directed towards
the following two aspects: the asymmetric MBH reaction
catalyzed by chiral catalysts[3] and the aza-MBH reac-
tion.[4,5] For the former, recent research has been focused
on the search of efficient chiral catalysts to accelerate the
reaction rates and promote efficiency (yields) and selectivity
(ee values), and for the latter, major efforts have been fo-
cused on the scope of the reaction and search for practical
catalysts[4] including chiral catalysts for the asymmetric ver-
sion of the aza-MBH reaction.[5] In 1984, Perlmutter re-
ported the first example of an aza-MBH reaction from N-
tosyl imines and ethyl acrylate catalyzed by DABCO.[4a]
However, this report did not attract much attention until
the last decade of the 20th century; the situation was turned
around and lots of new reports emerged.[4d–4p] For exam-
ples, Yamamoto first explored the aza-MBH reaction of N-
methoxycarbonyl protected imines;[4b] Bertendshaw estab-
lished a three-component version of the aza-MBH reaction
trialkylphosphane
1,3,5-triaza-7-phosphaadamantane
(PTA) was an efficient organocatalyst for the MBH reaction
of a variety of substrates, including aromatic and aliphatic
aldehydes, activated olefins acrylates, and methyl vinyl
ketone (MVK).[6] Because PTA has comparable nucleophi-
licity to pure trialkylphosphane and because it is air-stable,
it should be an alternative catalyst for important nucleo-
philic organocatalysis; for example it may serve as a catalyst
in the aza-MBH reaction. Herein, we report the PTA-cata-
lyzed aza-MBH reaction of N-thiophosphoryl or N-thio-
phosphinoyl imines. N-thiophosphoryl imines are chosen
[a] State Key Laboratory of Elemento-Organic Chemistry, Institute
of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China
[b] Department of Chemistry, Nankai University,
Tianjin 300071, P. R. China
Fax: +86-22-23508939
E-mail: z.h.zhou@nankai.edu.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 4487–4491
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X. Xu, C. Wang, Z. Zhou, X. Tang, Z. He, C. Tang
SHORT COMMUNICATION
because of their ease of preparation and better stability rel- MVK as a model (Table 1). The preliminary results shown
ative to N-diphenylphosphinoyl imines. Also, by introduc- in Table 1 revealed that PTA is to some extent a suitable
ing different substituents at the phosphorus center could catalyst in the present aza-MBH reaction. In addition, as
easily modulate its electronic properties. Therefore, this at- we expected, these N-thiophosphoryl imines display good
tempt provides a convenient and practical synthetic method stability. No decomposition towards the carbonyl com-
for versatile α-methylene-β-amino ketone or acid deriva- pound was observed under the reaction conditions.
tives.[4a,5a,5o,7]
On the basis of these results, the aza-MBH reaction of
N-thiophosphoryl imines 1 and 2 was thoroughly investi-
gated by employing PTA as the nucleophilic catalyst. The
aza-MBH reaction between N-thiophosphoryl imines 1 and
MVK in the presence of PTA at room temperature led to
promising results (Table 2).
Results and Discussion
N-Diethoxythiophosphorylimines 1 and N-diphenylthi-
ophosphinoylimines 2 were synthesized in excellent yields
through the thermal condensation of acetals and the corre-
sponding thiophosphoramides.[8] With these imines in
hand, their reactivity as electrophiles in the aza-MBH reac-
tion was investigated.
The reaction of imine 1a and MVK was chosen as a
model. As shown in Table 2, the evaluation of the solvents
revealed that the reaction performed best in acetonitrile
with a catalyst loading of 10 mol-% (Table 2, Entry 1). Ad-
justment of the catalyst loading to 5 mol-% made the reac-
tion very sluggish, as only 25% conversion of imine 1a was
achieved after stirring for 120 h (Table 2, Entry 6). An in-
crease in the catalyst loading to 30 mol-% resulted in a dra-
matic rate acceleration with a slight increase in yield
(Table 2, Entry 7). Under the optimal conditions (10 mol-%
catalyst loading, acetonitrile), this reaction was then ex-
tended to N-thiophosphoryl imines 1b–g. It was found that
the reaction displayed a high substrate generality. The aza-
MBH products were obtained in good yield no matter what
kind of imine was used. In addition, the electronic nature
of the imine had an obvious influence on the reaction. Rela-
tive to the imines containing electron-withdrawing groups
(1d–f; Table 2, Entries 10–12), those imines bearing an elec-
tron-donating group on the benzene ring (1b–c; Table 2, En-
tries 8, 9) or derived from electron-enriched 2-furylaldehyde
(1g; Table 2, Entry 13) exhibited much lower electrophilic
activities in terms of yield and reaction time.
Firstly, rough comparison of the catalytic activity of PTA
with the hitherto known catalysts, such as DABCO and
Ph3P, was performed by using the reaction of imine 1a and
Table 1. Different catalysts used in the aza-MBH reaction of imines
1a and 2a with MVK.[a]
Catalyst
Imine 1a
Imine 2a
[b]
Time [h]
Yield [%]
Time [h]
Yield [%][b]
PTA
DABCO
Ph3P
96
96
96
84
78
82
48
68
48
82
59
78
[a] All reactions were carried out in acetonitrile in the presence of
10 mol-% of catalyst with a 1:3 molar ratio of imine to activated
MVK. [b] Isolated yield.
Similarly, solvent evaluation proved that acetonitrile was
also the preferred solvent for the PTA-catalyzed aza-MBH
Table 2. The PTA-catalyzed aza-MBH reaction of imine 1 and MVK.
Entry
1 or 3
Ar
Solvent
PTA [mol-%]
Time [h]
Yield [%][a]
1
2
3
4
5
6
7
8
a
a
a
a
a
a
a
b
c
d
e
f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
MeCN
CH2Cl2
CHCl3
THF
10
10
10
10
10
5
30
10
10
10
10
10
10
96
96
96
96
96
120
5
108
96
84
60
84
96
84
63
61
77
MePh
76
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
57(25)[b]
86
4-MeC6H4
3-MeOC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
2-Furyl
67
81
84
92
86
79
9
10
11
12
13
g
[a] Isolated yield. [b] Data in parentheses is the conversion of the imine substrate.
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The Aza-Morita–Baylis–Hillman Reaction of N-Thiophosphoryl Imines
Table 3. The PTA-catalyzed aza-MBH reaction between imine 2 and MVK.
Entry
2 or 4
Ar
PTA [mol-%]
Time [h][a]
Yield [%][a,b]
1
2
3
4
5
6
7
8
a
a
a
a
b
c
d
e
f
Ph
Ph
Ph
Ph
10
5
60
120
36
4
72(5)
72(5)
60(4)
72(4)
72(4)
60(6)
48(2)
60(48)
82
73
85
88
52(89)
56(87)
78(90)
85(94)
88(93)
92(92)
57(97)
33(88)
20
30
10
10
10
10
10
10
10
10
4-MeC6H4
2-MeOC6H4
2-ClC6H4
3-F3CC6H4
4-BrC6H4
3-FC6H4
4-O2NC6H4
PhCH=CH
9
10
11
12
g
h
i
[a] Data in the parentheses were obtained for 30 mol-% catalyst loading. [b] Isolated yield.
reaction between N-diphenylthiophosphinoylimines 2 and vated alkene methyl acrylate (MA) was also carried out un-
MVK. Unlike the reaction of imine 1, the catalyst loading der identical conditions. The coupling of N-diphenylphos-
had a significant influence both on the reaction rate and phinoylimines 2 with MA afforded satisfactory results. The
the chemical yield. Generally, obvious rate accelerations corresponding adducts 5 were obtained in moderate yields
and yield improvements were observed with increasing with a PTA loading of 30 mol-% (Table 4). Under the same
amounts of catalyst loadings. However, in most cases, satis- conditions, no reaction was observed for imines 1. This can
factory results were also obtained in the presence of 10 probably be ascribed to the difference in the electrophilicit-
mol-% of catalyst at the expense of prolonged reaction ies of the two types of electrophiles in this reaction.
times. In all cases, the MBH reactions proceeded readily to
give the normal adducts in fair-to-excellent yields within
acceptable reaction times in the presence of 10–30 mol-%
PTA. The nature of the imine substrate was found to be an
essential factor to the reaction in the presence of 10 mol-%
of catalyst. For example, satisfactory results were obtained
for those imines with an electron-withdrawing group on the
benzene ring (Table 3, Entries 7–10; 78–92%). The nitro-
substituted imine is an exception. The reaction was quite
complicated because of its high reactivity (Table 3, Entry
11; 57%). Only moderate yields were obtained for less reac-
tive imines derived from aromatic aldehydes bearing an
electron-donating group (Table 3, Entries 5 and 6; 52 and
56%, respectively). The reaction was very sluggish for the
imine derived from aliphatic cinnamic aldehyde (Table 3,
Entry 12; 33%). Nevertheless, the reaction ran smoothly in
the presence of 30 mol-% catalyst (Table 3, Entry 12; 88%,
data in parentheses).
Table 4. The PTA-catalyzed aza-MBH reaction between imine 2
and MA.
Entry
Adduct 5
Ar
Time [h]
Yield [%][a]
1
2
3
4
5
a
c
c
d
e
Ph
2-ClC6H4
3-FC6H4
3-F3CC6H4 60
4-BrC6H4 60
72
84
72
66
57
60
63
72
[a] Isolated yield.
Moreover, under the otherwise same conditions, the dia-
To demonstrate the versatility of these N-thiophosphoryl stereoselective aza-MBH reaction of chiral thiophosphoryl-
imines, their aza-MBH reactions with the less reactive acti- imine 6 derived from (S)-1,1Ј-binaphthyl-2,2Ј-diol and
Eur. J. Org. Chem. 2007, 4487–4491
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4489

X. Xu, C. Wang, Z. Zhou, X. Tang, Z. He, C. Tang
SHORT COMMUNICATION
MVK was realized with 90% de (determined by 31P and 1H
NMR spectroscopic analysis, see Supporting Information).
Finally, to exemplify that the above-mentioned method-
ology is a convenient and practical method for the synthesis
of synthetically valuable α-methylene-β-amino ketone or
acid derivatives, adducts 4a and 5a were readily converted
to α-methylene-β-amino ketone hydrochloride 8 and acid
ester hydrochloride 9, respectively, in excellent yields upon
acidic methanolysis with 3.75  HCl/MeOH at room tem-
perature within several hours. In addition, the byproduct
O-methyl diphenylphosphinothioate can be conveniently
transformed into diphenylphosphinothioic chloride through
basic hydrolysis and chlorination in excellent yield accord-
ing to the literature,[9,10] and it can be reused in the prepara-
tion of the starting diphenylphosphinothioic amide.
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Conclusions
We developed a novel N-thiophosphoryl imine based
aza-MBH reaction. The corresponding aza-MBH adducts
were obtained in fair-to-excellent yields in the presence of
an efficient air-stable nucleophilic trialkylphosphane orgao-
catalyst – PTA. On the basis of these results, the chiral-
imine-induced diastereoselective aza-MBH reaction was re-
alized with good diastereoselectivity (90% de). Because the
N-thiophosphoryl moiety can be readily deprotected
through acidic methanolysis in excellent yields, this proto-
col provides a convenient method for the synthesis of syn-
thetically valuable α-methylene-β-amino ketone or acid de-
rivatives.
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and characteristic data of aza-MBH ad-
ducts 3a–h, 4a–g, and 5 and the corresponding α-methylene-β-
amino ketone hydrochloride 8 and acid ester hydrochloride 9.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 20472033) for generous financial support of our pro-
grams.
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Received: June 21, 2007
Published Online: August 8, 2007
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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