P-C Bond formation via direct and three-component conjugate addition catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)

Article abstract of DOI:10.1016/j.tetlet.2006.11.019

The direct addition of P(O)-H bonds (dialkyl phosphites and diphenyl phosphonite) across various activated alkenes was catalyzed effectively by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). This is a mild, rapid and efficient protocol to generate P-C bonds.

Full text of DOI:10.1016/j.tetlet.2006.11.019

Tetrahedron Letters 48 (2007) 51–54
P–C Bond formation via direct and three-component conjugate
addition catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)
Zhiyong Jiang, Yan Zhang, Weiping Ye and Choon-Hong Tan*
Department of Chemistry, 3 Science Drive 3, National University of Singapore, Singapore 117543, Singapore
Received 25 September 2006; revised 25 October 2006; accepted 2 November 2006
Available online 21 November 2006
Abstract—The direct addition of P(O)–H bonds (dialkyl phosphites and diphenyl phosphonite) across various activated alkenes was
catalyzed effectively by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). This is a mild, rapid and efficient protocol to generate P–C bonds.
This simple procedure allows a series of dialkyl alkylphosphonates and trisubstituted phosphine oxides to be prepared in high yields.
Further investigation resulted in a convenient one-pot, three-component reaction containing diphenyl phosphonite, malononitrile
and an aldehyde.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
promote various reactions including the Wittig reac-
tion,14 the addition of azoles to a,b-unsaturated nitr-
iles15 and Knoevenagel reactions.16 We reported that
TBD can catalyze efficiently the Michael reaction
between 1,3-dicarbonyl donors and a range of alkenes.17
It has also been shown recently that TBD can catalyze
ring-opening polymerization of cyclic esters.18 Herein,
we describe mild and efficient protocols to construct
P–C bonds via the conjugate addition to activated
alkenes.
The versatile nature of phosphorus allows it to play a
major role in modern synthetic chemistry.1 Phospho-
nates and phosphorus ylides are important synthetic
intermediates used in Wittig and related reactions.2
Chiral phosphines have also found significant synthetic
utility as ligands in metal catalyzed reactions.3 Amino-
phosphonates and aminophosphinates, as isoteric ana-
logues of aminoacids, have been intensively studied as
stable transition state analogues and enzyme inhibitors.4
Natural products containing P–C bonds also show inter-
esting biological activities.5
We found that 20 mol % of TBD catalyzed the reaction
between diphenyl phosphite and phenylmaleimide 1a
(Fig. 1). The reaction was complete within 5 min and a
Amongst various methods to generate P–C bonds, the
addition of P(O)–H bonds across alkenes6 is one of
the most utilized. There are three general approaches:
(a) the phospha-Michael reaction of activated alkenes,
most commonly promoted by alkaline metal alk-
oxides,6,7 or the use of tetramethylguanidine (TMG),8
Lewis acids9 or microwaves;10 (b) addition to unacti-
vated olefins promoted by radical initiators such as
AIBN;11 (c) hydrophosphorylation of unactivated
alkenes catalyzed by transition metals.12
O
O
1a, R=Ph
5a, R=Ph
1b, R=4-MeC6H4
1c, R=4-MeOC6H4
1d, R=Bn
5b, R=4-MeC6H4
5c, R=4-MeOC6H4
5d, R=Bn
N
R
N
R
(PhO)2P
O
O
O
6a, R=Ph
6b, R=2-naphthyl
6c, R=1-furanyl
O
2a, R=Ph
2b, R=2-naphthyl
2c, R=1-furanyl
CN
(PhO)2P
R
R
R
CN
CN
CN
O
3a, R=Ph
7a, R=Ph
NO2
3b, R=4-BrC6H4
3c, R=4-ClC6H4
3d, R=4-MeOC6H4
7b, R=4-BrC6H4
7c, R=4-ClC6H4
7d, R=4-MeOC6H4
(PhO)2P
Bicyclic guanidine bases such as 1,5,7-triazabicyclo-
[4.4.0]dec-5-ene (TBD) are known as superbases due to
their high pKa values.13 They have been reported to
NO2
O
R
(PhO)2P
N
N
CO2Et
8
4
EtO2C
N
CO2Et
EtO2C
N
H
*
Corresponding author. Tel.: +65 6874 2845; fax: +65 6779 1691;
e-mail: chmtanch@nus.edu.sg
Figure 1. Reactants of diphenylphosphite addition across alkenes.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.019

52
Z. Jiang et al. / Tetrahedron Letters 48 (2007) 51–54
Table 1. Reactions between diphenyl phosphite and various alkenes
Table 2. Reactions between various phosphites and 2-benzylidenemalo-
nonitrile 2a
N
N
9a, R=Me; X=O
9b, R=Bn; X=O
9c, R=iPr; X=O
9d, R=tBu; X=O
9e, R=Me; X=S
N
N
X
O
H
(RO)2P
Ph
20 mol%
N
N
CN
+
substrate
product
Yielda (%)
(PhO)2P
H
H
Ph
CN
CN
20 mol%
phosphite
toluene, rt, 5 min
+
CN
2a
toluene, rt
Entry
Substrate
Product
Entry
Phosphite
Product
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
2a
2b
2c
3a
3b
3c
3d
4
5a
5b
5c
5d
6a
6b
6c
7a
7b
7c
7d
8
85
88
70
99
88
94
78
90b
87b
81b
80
O
1
2
9a
9b
2
82
99
(MeO)2P
H
O
0.5
(BnO)2P
H
H
O
3
4
5
9c
9d
9e
2
2
1
71
(iPrO)2P
O
65b
99
10
11
12
(tBuO)2P
H
86
S
a Isolated yield.
b THF as the solvent.
(MeO)2P
H
a Isolated yield.
b 40 mol % TBD.
high yield of the addition product 5a (Table 1, entry 1)
was obtained. Toluene, THF and dichloromethane were
found to be suitable solvents. Various arylmaleimides
1a–c and benzylmaleimide 1d (entries 1–4) were suitable
substrates, although alkylmaleimides gave lower yields.
2-Arylidene malononitriles 2a–c (entries 5–7) including
heteroaromatic types were also suitable substrates. a-
Nitrostyrenes 3a–d (entries 8–11), containing either elec-
tron withdrawing or electron donating substituents,
were also useful substrates. Interestingly, P–N bonds
can also be effectively constructed using diethyl azodi-
carboxylate 4 as a substrate (entry 12). Adduct 8 is
similar to the betaine intermediate of the Mitsunobu
reaction.19 A range of P(III) compounds containing
oxygen and nitrogen substituents was shown to add to
dialkyl azodicarboxylate, giving various penta- and
hexa-coordinated products.20
Table 3. Reactions between diphenylphosphine oxide and various
alkenes
N
N
N
O
H
10 mol%
+
H
substrate
product
Yielda (%)
Ph2P
toluene, rt, 5 min
Entry
Substrate
Product
1
2
3
4
5
6
7
8
9
1a
1d
12a
12b
12c
12d
13a
13b
13c
13d
13e
14
99
73
97
86
80
98
99
97
80
84
1e
1f
10a
10b
10c
10d
10e
11
With 2-benzylidenemalononitrile 2a as the acceptor, dif-
ferent phosphites were investigated (Table 2). Various
phosphites including dimethyl phosphite (entry 1), di-
benzyl phosphite (entry 2) and diisopropyl phosphite
(entry 3) added smoothly and the reactions were completed
between 30 and 120 min. However, di-tert-butyl phos-
phite (entry 4) was particularly slow and gave a poor
yield even when the amount of catalyst was increased.
Dimethyl thiophosphite (entry 5) was more active than
the corresponding dimethyl phosphite (entry 1); result-
ing in a faster reaction and gave a better yield.
10
a Isolated yield.
O
O
12a, R=Ph
1e, R=Et
1f, R=tBu
12b, R=Bn
12c, R=Et
12d, R=tBu
N
O
R
N
O
R
Ph2P
O
10a, R1=R2=CN
The P(O)–H protons are more acidic in alkylphosphine
oxides than in phosphites. This is reflected in the nucleo-
philicity of the corresponding anions and therefore the
rate of reaction. With 10 mol % of TBD, in toluene,
diphenylphosphine oxide was added smoothly to vari-
ous maleimides, including aliphatic ones, with high
yields (Table 3, entries 1–4). The reactions were
completed within 5 min. Linear alkenes such as
fumaronitrile 10a (Fig. 2), dimethyl fumarate 10b,
trans-1,2-dibenzoylethylene 10c, cinnamonitrile 10d,
13a, R1=R2=CN
O
10b, R1=R2=CO2Me
10c, R1=R2=COPh
10d, R1=Ph; R2=CN
10e, R1=Ph; R2=COPh
13b, R1=R2=CO2Me
13c, R1=R2=COPh
13d, R1=Ph; R2=CN
13e, R1=Ph; R2=COPh
Ph2P
R1
R2
R1
R2
O
O
14
PPh2
11
O
Figure 2. Diphenylphosphine oxide addition across alkenes.

Z. Jiang et al. / Tetrahedron Letters 48 (2007) 51–54
53
trans-chalcone 10e and 2-cyclopenten-1-one 11 (entries
5–9) were useful substrates for this reaction. For all
substrates, parallel experiments were conducted in the
absence of a catalyst. In the time frame of the cata-
lyzed reaction, no product was observed for the control
reactions.
We then attempted a one-pot, three-component reaction
consisting of malononitrile, diphenylphosphine oxide
and propanal. The only product observed was adduct
15a (Table 4, entry 1). The reaction was completed with-
in 15 min, giving a high yield of 15a. It is interesting to
note that the possible side reaction leading to the aldol
product was not observed in this reaction. A range of
aliphatic and aromatic aldehydes were reacted which
gave the corresponding adducts 15b–i in high yields
within 1 h (entries 2–9). A high regioselectivity was ob-
served for a,b-unsaturated aldehydes such as trans-
cinnamaldehyde (entry 10). Another possible side
reaction, the Michael-type reaction between diphenyl-
phosphine oxide and trans-cinnamaldehyde was not
detected. Under the same reaction conditions, cyclic
ketones such as cyclopentanone and cyclohexanone gave
only Knoevenagel products. However, cyclobutanone
(entry 11) reacted smoothly to give adduct 16.
In multicomponent reactions (MCRs), a product is
assembled from three or more starting materials through
a series of bimolecular reactions.21 The ability to form
two or more C–C and/or C-heteroatom bonds in a sin-
gle operation is the main attraction of MCRs. In most
cases, almost all of the atoms in the starting materials
contribute to the newly formed product resulting in a
high atom economy. A typical challenge for MCRs is
to carry out the reaction in a manner in which only
the desired product is formed and the side products
are minimized.
We were interested in using 2-alkylidene malononitriles
and 2-arylidenemalononitriles as acceptors for the addi-
tion reaction with diphenylphosphine oxide. 2-Arylidene
malononitriles such as 2a–c were easily obtained
through the Knoevenagel reaction between malononit-
rile and aromatic aldehydes.22 However, we were unable
to obtain 2-alkylidenemalononitriles using such proto-
cols. While we were able to observe the 2-alkylidene-
malononitriles in the reaction mixture using NMR
(90% conversion after 40 min), we were not able to
purify them cleanly (Scheme 1). These products were
also not stable on storage.
The experiments have shown that this reaction is not
only suitable for malononitrile, but also for other Knoe-
venagel donors such as ethyl 2-cyanoacetate and ben-
zoylacetonitrile. This approach should allow a range
of useful P–C bond-containing compounds to be gener-
ated. Using our one-pot three-component protocol,
however, we were not successful preparing 6a–c by add-
ing diphenyl phosphite, malononitrile and aldehydes;
only the Knoevenagel products were observed.
In conclusion, we have developed a mild, rapid and effi-
cient protocol to generate P–C bonds. This simple pro-
cedure allows a series of dialkyl alkylphosphonates
and trisubstituted phosphine oxides to be prepared in
It is also well known that phosphonates can undergo
aldol-type reactions with aldehydes.23 We were able to
obtain a high yield of a-hydroxyphosphine oxides when
20 mol % of TBD was used to catalyze the addition of
diphenylphosphine oxide to propanal (Scheme 1). This
reaction is as fast as the Knoevenagel reaction used to
generate the 2-alkylidenemalononitriles. After 40 min,
100% conversion was observed and an isolated yield of
90% was obtained.
Table 4. Three-component reactions of diphenylphosphine oxide,
malononitrile and aldehydes or ketones
N
O
N
N
Ph2P
R
O
H
20 mol%
CN
+
CN
+
Ph2P
H
R
O
NC
15a-j
toluene, rt
CN
Entry Aldehyde/ketone Product
Time Yielda
(h) (%)
N
1
2
3
4
5
6
7
8
9
R = Et
15a
15b
15c
15d
15e
15f
15g
0.25 96
N
N
R = nPr
1.0
1.5
1.0
82
87
95
CN
CN
H
R = iPr
R = tert-Pentyl
R = c-Hexyl
R = tBu
R = Ph
R = 4-MeOC6H4 15h
R = 2-Naphthyl 15i
20 mol%
+
+
NC
CN
O
toluene, rt
N
0.25 86
(observed in NMR,
90% conversion)
48
76
0.25 97
1.0
1.5
80
97
N
N
O
H
O
20 mol%
Ph2P
Ph2P
H
H
O
O
toluene, rt,
90%, 40 min
Ph2P
OH
CN
CN
10
R = Cinnamyl
1.0
70
93
N
15j
O
N
N
NC
CN
H
20 mol%
Ph2P
O
no reaction
+
NC
CN
11
48
PPh2
O
toluene, rt
16
Scheme 1. Parallel reactions using malononitriles, propanal and
diphenylphosphine oxide.
a Isolated yield.

54
Z. Jiang et al. / Tetrahedron Letters 48 (2007) 51–54
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high yields. A convenient one pot, three-component
reaction, containing diphenyl phosphonite, malono-
nitrile and an aldehyde was catalyzed effectively by
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). Possible side
reactions leading to aldol products were not observed.
A high regioselectivity for a,b-unsaturated aldehydes
was observed.
2. Experimental
A typical experimental procedure of the three-compo-
nent addition is described. Propionaldehyde (0.05 mmol,
1.0 equiv 4 ll) and malononitrile (0.05 mmol, 1.0 equiv,
3.3 mg) were added into a glass vial containing 90 ll of
toluene. This is followed by TBD (0.01 mmol, 0.2 equiv,
1.4 mg in 10 ll tol). After 1 min, diphenylphosphine
oxide (0.06 mmol, 1.2 equiv, 12 mg in 100 ll tol) was
added dropwise into the stirring reaction mixture. The
reaction was completed in 15 min. 2-[1-(Diphenylphos-
phoryl)propyl]malononitrile 15a was obtained as a white
solid (15.6 mg, 96%) after flash chromatographic
purification.
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Acknowledgements
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This work was supported by a grant from the National
University of Singapore (R-143-000-222-112). We thank
the Medicinal Chemistry Program for their financial
support. We also thank Dr. Martin J. Lear for helpful
discussions.
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Supplementary data
Experimental procedures and spectral data of the prod-
ucts are presented. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.11.019.
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References and notes
1. (a) New Aspects in Phosphorus Chemistry I; Majoral, J.-P.,
Ed.; Springer: Berlin Heidelberg, 2002; (b) New Aspects in
Phosphorus Chemistry II; Majoral, J.-P., Ed.; Springer:
Berlin Heidelberg, 2002.