The first air-stable and efficient nucleophilic trialkylphosphine organocatalyst for the Baylis-Hillman reaction

Article abstract of DOI:10.1002/adsc.200505403

1,3,5,-Triaza-7-phosphaadamantane (PTA) is first reported to be a convenient and efficient nucleophilic trialkylphosphine organocatalyst for the Baylis-Hillman reaction. Thus, under the mediation of 15-20 mol % of PTA and practical conditions, both aromat

Full text of DOI:10.1002/adsc.200505403

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DOI: 10.1002/adsc.200505403
The First Air-Stable and Efficient Nucleophilic Trialkylphosphine
Organocatalyst for the Baylis–Hillman Reaction
a, b
a
b
a,
Zhengrong He, Xiaofang Tang, Yaoming Chen, Zhengjie He *
a
Department of Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic of China
Fax: (þ86)-22-2350-2458, e-mail: zhengjiehe@nankai.edu.cn
b
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, Peopleꢀs Republic of China
Received: October 13, 2005; Accepted: January 12, 2006
[
3b, c]
Abstract: 1,3,5,-Triaza-7-phosphaadamantane (PTA)
is first reported to be a convenient and efficient nu-
cleophilic trialkylphosphine organocatalyst for the
Baylis–Hillman reaction. Thus, under the mediation
of 15–20 mol % of PTA and practical conditions,
both aromatic and aliphatic aldehydes react with
the activated alkenes like acrylates and methyl vinyl
ketone to afford the corresponding adducts in fair to
excellent yields.
organocatalytic reactions
such as the Rauhut–Curri-
er reaction. The nucleophilicity of trialkylphosphines is
the strongest among their amine analogues and triaryl-
phosphines. However, due to their extreme air-sensitiv-
ity, the potential utility of trialkylphosphines as nucleo-
philic organocatalysts with enhanced reactivity has been
limited. Contrarily, less reactive triarylphosphines, e.g.,
PPh , with relatively higher air stability have been
3
most often used. This situation may be claimed as a fac-
tor responsible for the lag in the development of nucle-
ophilic phosphine catalysts. Most recently, the superior-
ity of trialkylphosphines as nucleophilic catalysts over
their amine or triarylphosphine counterparts has at-
Keywords: activated alkenes; aldehydes; Baylis–Hill-
man reaction; nucleophilic organocatalyst; trialkyl-
phosphine
[
3b,4]
tracted increasing interest.
However, how to resolve
the issue of the air sensitivity of trialkylphosphines is still
a challenge for organic chemists in the field of organoca-
talysis. Pioneering work has been done by Fu and co-
[
5]
Organocatalysis is an increasingly hot research topic in workers, who suggested converting trialkylphosphines
[
1,2]
the field of organic chemistry. As the efficiency and into their air-stable conjugate acids such as tetrafluoro-
selectivity of many organocatalytic reactions have borate, and then releasing them in situ by treatment with
been continuously improved, organocatalytic reactions an appropriate base. This simple and practical method
are becoming powerful tools in modern organic syn- has been proven effective in a diverse set of reactions al-
thesis. In contrast to the transition metal catalysts in though it carries some obvious drawbacks such as in-
which the metal centers generally behave as good Lewis volving extra manipulations, not being atom economic,
acids, organocatalysts tend to act as heteroatom-cen- and still requiring inert atmosphere protection in the fi-
tered Lewis bases. These heteroatoms are most likely nal step. Up to date, there are no reports concerning the
N, P, and S, which have non-bonded lone pairs of elec- use of air-stable trialkylphosphines as a nucleophilic cat-
trons that often play an important role in organocataly- alyst.
sis.
A cage-like phosphine, 1,3,5-triaza-7-phosphaada-
Both tertiary amines and tertiary phosphines are pop- mantane (PTA), was first reported in 1974 by Daigle
[
3]
[6]
ular in nucleophilic catalysis. Due to their cheaper pri- and co-workers. It can be easily prepared in high yield
ces, better stability, and lower toxicity, tertiary amines from a commercially available material, tetrahydroxy-
[
7]
prevail over phosphines in organocatalysis. Only in last methylphosphonium chloride or sulfate. After its dis-
decade or so have phosphines as nucleophilic organoca- covery, related research activity had been quiet until re-
talysts attracted much attention, and remarkable ach- cently when it attracted renewed interest due to its prop-
[
3b, c,4]
ievements have been made in this area.
Compared erties of water solubility and strong coordinating ability
[8]
to their nitrogen analogues, tertiary phosphines have with a wide range of transition metals. In most of the
better nucleophilicity and weaker basicity, which are recent reports, PTA has been used as a unique water-
most likely attributed to the greater polarizability and soluble phosphine ligand. To the best of our knowledge,
lower electron density of the phosphorus atom. These there have been no reports concerning its utility as a
unique characteristics may render phosphines some ad- phosphine organocatalyst before. In addition to its coor-
vantages over amines as evidenced in some nucleophilic dinating ability, the overall reactivity, including nucleo-
Adv. Synth. Catal. 2006, 348, 413 – 417ꢁ Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
413

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Zhengrong He et al.
philicity, of PTA is comparable to other pure trialkyl- lis–Hillman reactions readily proceed giving the normal
phosphines except that PTA is air stable. Its air stability adducts in fair to excellent yields and within acceptable
is even much higher than triphenylphosphine with re- reaction times (Tables 1 and 2). In the case of acrylate,
[
9]
spect to the kinetic constants of oxidation. This kind only aromatic aldehydes can substantially give the ex-
of unique property of PTA prompted us to explore its pected products in a relatively short reaction time, as
potential utility as an air-stable trialkylphosphine alter- shown in Table 1. The availability of previous experi-
native organocatalyst. Herein, we report that PTA is a mental data on similar Baylis–Hillman reactions cata-
convenient and efficient phosphine catalyst for the Bay- lyzed by tertiary amines allows us to make a rough com-
lis–Hillman reaction of both aromatic and aliphatic al- parison of PTAꢀs catalytic efficiency with those of amine
dehydes with activated alkenes.
catalysts. Based on the results reported by Hu and co-
[
11]
The Baylis–Hillman reaction, also known as the Mor- workers, PTA shows a comparable catalytic activity
ita–BaylisÀHillman reaction, is an attractive method for to the most often used tertiary amine catalyst DABCO
forming carbon-carbon bonds and yields highly func- with respects to catalyst loading, reaction time and yield
tionalized products. It can be broadly defined as a cou- of product (Table 1, entries 1–3, 6–8). In 2004, Vascon-
[
12]
pling reaction between an alkene activated by an elec- cellos et al. reported that hexamethylenetetramine
tron-withdrawing group and an aldehyde under the me- (HMT) could be used as an alternative catalyst in the
diation of a nucleophilic catalyst, usually a tertiary Baylis–Hillman reaction of aromatic aldehydes. Re-
amine such as 1,4-diazabicyclo[2.2.2]octane (DABCO) garding its structural similarity to PTA, HMT should
and a tertiary phosphine. Since its discovery, it has be a perfect catalyst candidate for the purpose of com-
been associated with a number of problems, most nota- parison, which structurally differentiates itself with
bly, its sluggish reaction rate, especially for the substrate PTA only by the displacement of one nitrogen atom
acrylate. In the last decade, much research effort has with phosphorus (Figure 1). On the basis of the reported
been directed toward its efficiency and selectivity, and results for HMTand those for PTA (Table 1, entries 3, 6,
[
10]
significant advances have been made.
8), it may be concluded that PTA is overall much supe-
rior over HMT in the Baylis–Hillman reaction of aro-
matic aldehydes with acrylate. For the precise compari-
son, two reactions of 4-nitrobenzaldehyde with ethyl
acrylate were run under otherwise identical conditions,
except for the catalysts, and results confirm the superior-
ity of PTA over HMT, again. This superiority does not
only indicate that PTA is a better catalyst than HMT in
the Baylis–Hillman reaction of aromatic aldehydes, but
also implies that the phosphorus makes a vital contribu-
tion to the catalysis, and PTA acts as an efficient nucle-
[
13]
Figure 1. Catalysts in the Baylis–Hillman reaction.
A set of aromatic and aliphatic aldehydes was selected ophilic phosphine catalyst.
to react with two kinds of activated alkenes, acrylate and
Under very friendly conditions (room temperature
methyl vinyl ketone (MVK). Preliminary results show and ambient atmosphere), the Baylis–Hillman reaction
that in the presence of PTA (15–20 mol %), the Bay- of both aromatic and aliphatic aldehydes with MVK
Table 1. The PTA-catalyzed Baylis–Hillman reaction of aromatic aldehydes with ethyl (n-butyl) acrylates.
[a]
[b]
Entry
Ar
R
Reaction time [h]
Product
Yield [%]
1
2
3
4
5
6
2-NO C H
Et
Et
Et
Et
Et
Et
n-Bu
n-Bu
9
7
5
15
7
7
1a
1b
1c
1d
1e
1f
84
72
91
80
60
59
93
79
2
6
4
4
4
3-NO C H
2
6
4-NO C H
2
6
2,4-Cl C H
2
6
3
2-F-4-ClC H
6
3
2-pyridyl
C H
7
8
2-NO
19
15
1g
1h
2
6
4
4
4-NO C H
2
6
[
[
a]
1
13
Identified by H and C NMR, and satisfactory microanalysis obtained for new compounds 1d and 1e.
b]
Isolated yield based on the aldehyde.
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Adv. Synth. Catal. 2006, 348, 413 – 417

Air-Stable and Efficient Nucleophilic Trialkylphosphine Organocatalyst
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Table 2. The PTA-catalyzed Baylis–Hillman reaction of aldehydes with methyl vinyl ketone.
[a]
[b]
Entry
R
Reaction time [h]
Product
Yield [%]
1
2
3
4
5
6
2-NO C H
4
2.5
1
20
4
2a
2b
2c
2d
2e
2f
2g
2h
2i
91
95
82
57
86
96
63
80
66
93
2
6
4
4
4
3-NO C H
2
6
4-NO C H
2
6
3-FC H
6
4
2,4-Cl C H
2
6
3
2-Cl-4-FC H
3.5
6
3
7
8
9
0
2-pyridyl
6
C H
H
C H
2
9
24
5
6
5
5
1
2j
[
[
a]
1
13
Identified by H and C NMR, and satisfactory microanalysis obtained for new compound 2f.
b]
Isolated yield based on the aldehyde.
readily proceeds under the mediation of a catalytic
amount of PTA (15 mol %). Most of reactions can be
complete in a couple of hours to give the normal adducts
in 57–96% yields (Table 2).
In the course of this study, we observed that the reac-
tion of 4-nitrobenzaldehyde with ethyl acrylate in THF-
H O (4:1, v/v) under the mediation of PTA (20 mol %)
2
completely subsided within 6 h after an initially rapid
31
conversion (TLC monitored). P NMR analysis of the
Scheme 1. Formation of the zwitterions 3 of PTA.
reaction mixture showed that the catalyst PTA (d ¼
P
À98.3 ppm in D O) had disappeared and a new species
2
(
d ¼ À37.6 ppm in D O) had emerged. Subsequent in- ported data for tertiary amine-catalyzed Baylis–Hill-
P
2
vestigation disclosed that this species is the zwitterion 3 man reactions and of the formation of the zwitterionic
resulting from the Michael addition of PTA with ethyl adduct 3, we concluded that the phosphorus in PTA
acrylate followed by protonation and hydrolysis of the plays a critical role in the catalysis. As trialkylphos-
intermediate ester (Scheme 1). Species 3 can be readily phines are emerging as important nucleophilic catalysts
prepared by the reaction of PTA with ethyl acrylate in in an array of new organic reactions as a result of their
aqueous THF. The Baylis–Hillman reaction with acryl- unique nucleophilicity, we anticipate that PTA will be
ate takes place smoothly under anhydrous condition, widely used as a convenient alternative organocatalyst
even in a protic solvent like alcohol, although the results for air-sensitive trialkylphosphines. PTA-promoted nu-
listed in Table 1 were all obtained from solvent-free re- cleophilic reactions of aldehydes with electron-deficient
actions. The formation of 3 unanimously confirms the alkynes and allenes are currently under investigation in
occurrence of the Michael addition between the phos- our laboratory.
phorus and acrylate. It also provides solid evidence for
the Michael addition step in the catalytic cycle, and
proves that PTA acts as a tertiary trialkylphosphine,
not a tertiary amine, in the catalysis. An analogous zwit-
terion from the reaction of DABCO with methyl acryl-
Experimental Section
Commercially available chemicals were used as received. PTA
was prepared from tetrahydroxymethylphosphonium sulfate
ate in aqueous 1,4-dioxane was isolated and character-
[11]
ized by Hu.
In conclusion, we have demonstrated that 1,3,5-triaza-
-phosphaadamantane, as the first air-stable, nucleo-
[7]
according to a previously reported procedure. Nuclear mag-
7
1
13
31
netic resonances ( H, C, and P) were recorded on a Bruker
00 MHz NMR spectrometer using TMS as internal standard
philic trialkylphosphine organocatalyst, is efficient for
the Baylis–Hillman reaction of both aromatic and ali-
3
(
1
13
31
H, C) and 85% phosphoric acid as external standard ( P),
phatic aldehydes with activated alkenes including ethyl unless otherwise mentioned. Elemental analyses were per-
acrylate and methyl vinyl ketone. On the basis of the re- formed on a Yanaco CHN Corder MT-3 automatic analyzer.
Adv. Synth. Catal. 2006, 348, 413 – 417ꢁ Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Zhengrong He et al.
1
3
PTA-Catalyzed Baylis–Hillman Reaction of Aromatic 2.39 (dt, J¼17.1, 6.3 Hz, 2H), 2.15 (m, 2H); C NMR (D
O,
2
DMSO as internal reference): d¼179.1 (s), 71.4 (d, J¼
Aldehydes with Ethyl (n-Butyl) Acrylates; General
3
1
6
.8 Hz), 39.4 (s), 28.9 (s), 18.5 (d, J¼27.8 Hz); P NMR
Procedure
(
D O): d¼ À37.6; anal. calcd. For C H N O P·2 H O:
2
9
16
3
2
2
A mixture of aromatic aldehyde (1.0 mmol) and PTA
C 40.75, H 7.60, N 15.84; found: C 40.69, H 7.96, N 15.97.
(
0.2 mmol) in 1.0 mL of ethyl acrylate or butyl acrylate (in ex-
cess) was stirred at room temperature for the time specified in
Table 1. Then the volatile components were removed on a ro-
tary evaporator, and the residue was mixed with 20 mL of di-
chloromethane, washed twice with water (2ꢀ5 mL), and dried
over anhydrous sodium sulfate. After filtration and evapora-
tion of solvent, the crude product was purified by column chro-
matography on silica gel (petroleum ether-ethyl acetate, gradi-
Acknowledgements
This work was supported by National Natural Science Founda-
tion ofChina (Grant No. 20421202) and Research Starting Fund
from Nankai University. We also thank Professor Chuchi Tang
of Nankai University for the generous gifting of some chemical
reagents.
ent elution) to afford pure product 1.
1
1
d: viscous oil; H NMR (CDCl ): d¼7.50 (d, J¼8.1 Hz,
3
1
6
2
(
1
H), 7.37 (d, J¼0.5 Hz, 1H), 7.28 (dd, J¼8.1, 0.5 Hz, 1H),
.34 (s, 1H), 5.91 (br s, 1H), 5.57(s, 1H), 4.22 (q, J¼7.2 Hz,
1
3
References and Notes
H), 3.41 (br s, 1H), 1.28 (t, J¼7.2 Hz, 3H); C NMR
CDCl ): d¼166.3, 140.7, 137.2, 134.0, 133.4, 129.2, 129.1,
3
[
1] For reviews, see: a) P. I. Dalko, L. Moisan, Angew. Chem.
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27.2, 126.6, 68.7, 61.1, 14.0; anal. calcd. for C H Cl O : C
12 12 2 3
5
2.39, H 4.40; found: C 52.28, H 4.41.
1
1
e: viscous oil; H NMR (CDCl ): d¼7.21 (m, 2H), 7.10 (dd,
3
J¼9.6, 1.2 Hz, 1H), 6.24 (s, 1H), 5.68 (d, J¼5.4 Hz, 1H), 5.56 (s,
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1H), 4.07(q, J¼7.2 Hz, 2H), 3.52 (d, J¼5.4 Hz, 1H), 1.15 (t, J¼
7
1
1
3
.2 Hz, 3H); C NMR (CDCl ): d¼166.1, 140.5, 137.0, 133.8,
3
33.3, 128.9, 128.8, 127.0, 126.4, 68.5, 60.9, 13.7; anal. calcd.
for C H ClFO : C 55.72, H 4.68; found: C 55.36, H 4.65.
12
12
3
8
1
948–8949; e) Y. Du, J. Feng, X. Lu, Org. Lett. 2005, 7,
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Aldehydes with Methyl Vinyl Ketone; General
Procedure
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A mixture of aldehyde (1.0 mmol), methyl vinyl ketone
(
3.0 mmol), and PTA(0.15 mmol) in 2.0 mL of THF was stirred
at room temperature for time specified in Table 2. Then the re-
action mixture was concentrated on a rotary evaporator, and
the crude product was subjected to similar work-up and purifi-
cation by silica gel column chromatography as described in the
[
general procedure for compounds 1 to give pure product 2.
1
2
f: viscous oil; H NMR (CDCl ): d¼7.33 (m, 2H), 7.20 (dd,
3
J¼9.9, 1.8 Hz, 1H), 6.19 (s, 1H), 5.88 (br s, 1H), 5.80 (d, J¼
1
3
5
(
1
6
.7Hz, 1H), 3.52 (d, J¼5.4 Hz, 1H), 2.36 (s, 3H); C NMR
[
[
CDCl ): d¼200.2, 161.7(d, J¼83.2 Hz), 157.8, 148.2, 129.4,
3
4
298.
27.5, 127.3 (d, J¼27.0 Hz), 121.6, 118.8 (d, J¼27.0 Hz),
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6.6, 26.2; anal. calcd. for C H ClFO : C 57.78, H 4.41; Found:
1
1
10
2
C 57.62, H 4.56.
[
[
Formation of the Zwitterionic Adduct 3 of PTA with
Ethyl Acrylate
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1995, 117, 272–280.
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PTA (0.32 g, 2.0 mmol) was added in one portion into a solu-
tion of ethyl acrylate (0.60 g, 6.0 mmol) in 5 mL of a THF-H O
2
(
4:1, v/v) mixture. The resulting mixture was stirred at room
temperature for 6 h. Then the solvent was removed under re-
duced pressure and the crude product was dissolved in 5 mL
of distilled water. The aqueous solution was extracted twice
with ether (2ꢀ5 mL) and the ethereal layer was discarded.
The aqueous layer was evaporated to dryness under vacuum
to give a pale yellow crystalline solid 3; yield: 0.53 g (100%);
1
mp 2388C (dec.); H NMR (D O): d¼4.45–4.28 (m, 12H),
2
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Air-Stable and Efficient Nucleophilic Trialkylphosphine Organocatalyst
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Synthesis 2004, 1595–1600.
lyst (0.2 mmol) in ethyl acrylate (2.0 mL) was stirred for
6 h. After removal of volatile components on a rotary
evaporator, the residue was subjected to silica gel col-
umn chromatography (petroleum ether-ethyl acetate,
6:1, v/v) to afford the product. The average yields for
HMT and PTA were 8% and 86%, respectively, for 3
runs.
[
[
[13] Reactions were run as follows: at room temperature, a
mixture of 4-nitrobenzaldehyde (1.0 mmol) and the cata-
Adv. Synth. Catal. 2006, 348, 413 – 417ꢁ Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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