A novel reductive coupling reaction between diphenylphosphine sulfide and formamides

Article abstract of DOI:10.1016/j.tetlet.2006.03.073

The coupling reaction of diphenylphosphine sulfide with N,N-disubstituted formamides in the presence of an excess amount of sodium hydride proceeded smoothly to give the corresponding aminomethyldiphenylphosphine sulfides in good yields. This method is ex

Full text of DOI:10.1016/j.tetlet.2006.03.073

Tetrahedron Letters 47 (2006) 3467–3469
A novel reductive coupling reaction between
diphenylphosphine sulfide and formamides
Peng Yan and Yukihiko Hashimoto*
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-8656, Japan
Received 21 December 2005; revised 2 March 2006; accepted 5 March 2006
Abstract—The coupling reaction of diphenylphosphine sulfide with N,N-disubstituted formamides in the presence of an excess
amount of sodium hydride proceeded smoothly to give the corresponding aminomethyldiphenylphosphine sulfides in good yields.
This method is expected to provide a useful synthesis of P,N-containing ligands.
Ó 2006 Elsevier Ltd. All rights reserved.
Phosphine sulfides are used as an effective protective
group of phosphines due to their air stability.1 However,
the other properties of phosphine sulfides have received
much less attention so far. We have reported that some
phosphine sulfide ligands play a significant role in tran-
sition metal catalyzed reactions.2 Since the use of phos-
phine sulfides has increased in the field of organic
synthesis, the investigation of their properties and reac-
tivity has become more necessary.
tion could be characteristic for phosphine sulfide
compounds.
NaH (excess)
DMF, rt, 4 h
H
NMe2
+
Ph2P(S)H
NMe2
Ph2(S)P
ð1Þ
O
2
1
3
81%
We initially investigated whether the reaction could also
proceed in other solvents. Treatment of 1 with an equi-
molar amount of DMF in the presence of excess NaH in
toluene gave a similar product in 25% yield, however,
the major product was a hydroxymethyl-derivative 4.
After having tested other solvents, it was concluded that
the use of polar solvents minimized the formation of
byproduct 4 and when the reaction was run in dimethyl-
imidazolidinone (DMI), 3 was obtained in 67% yield
(Eq. 2).
In this letter, we present a novel reaction which is useful
in the synthesis of phosphorus containing ligands. We
believe that the studies of the nature, scope, and mech-
anistic aspects of this reaction will provide valuable
insights into the properties of phosphine sulfides.
The reaction comprises treatment of diphenylphosphine
sulfide 13 with excess NaH in dimethylformamide
(DMF) 2, resulting in the formation of (dimethylamino-
methyl)diphenylphosphine sulfide 34 as the main prod-
uct (Eq. 1). A reductive coupling process between 1
and 2 proceeded to form a new carbon–phosphine bond.
We also tested the corresponding reaction of diphenyl-
phosphine oxide under the same conditions as Eq. 1,
but the reaction gave no valuable compounds including
the same type of coupling adduct. Therefore, this reac-
NaH (5 eq.)
NMe2
+ Ph2(S)P
OH
1 + 2
Ph2(S)P
100 ºC, 4 h
4
3
ð2Þ
Toluene
DMSO
DMI
25%
4%
67%
41%
0%
trace
Next, we turned our attention to the mechanistic aspects
of the reductive step. It seems that neither phosphine
sulfide nor DMF is the reductant in view of the fact that
the yield of 3 exceeded 50% in the equimolar reaction
(Eq. 2). Further evidence is the result that 3 was ob-
tained in 80% yield when DMF was replaced by tetra-
methylurea, which has no reducing ability (Eq. 3). On
Keywords: Diphenylphosphine sulfide; Formamide; Sodium hydride;
Reductive coupling.
*
Corresponding author. Tel.: +81 03 58417209; fax: +81 03
58417269; e-mail: hashimoto@chiral.t.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.073

3468
P. Yan, Y. Hashimoto / Tetrahedron Letters 47 (2006) 3467–3469
Table 1. Scope of the reductive coupling reaction in DMIa
the other hand, product 3 could not be obtained on
replacement of NaH with other bases such as t-BuOK,
NaOH, NaNH2, or when the amount of NaH was de-
creased to less than 3 M equiv. In these reactions, the
product became a complicated mixture with no detect-
able amount of the desired compound, and furthermore
the material balance between the crude mixture and
starting material could not be established. From all
the data in hand, it was concluded that NaH plays the
role of reducing agent in the coupling reaction.
Although it is known that NaH can be used in the cleav-
age of halogen–carbon bonds,5 there are few reports on
the use of NaH to cleave carbon–oxygen bonds. We
then focused on anchimeric assistance from phosphine
sulfide group.
NaH (5 eq.)
H
NRR'
+
Ph2P(S)H
NRR'
Ph2(S)P
DMI, 100 °C,
O
2
4 h
1
Entry
Formamide
Yield (%)
1
2
Me2NCHO
Et2NCHO
67
63
3b
4b
79
72
NCHO
NCHO
OMec
5
52
N
CHO
NaH (10 eq.)
NMe2
Me2N
NMe2
a General reaction conditions unless otherwise stated: Ph2P(S)H
(1 equiv), formamide (1 equiv).
b 3 equiv of formamide was used.
+
Ph2(S)P
Ph2P(S)H
100 °C, 4 h
O
ð3Þ
1
3
c Prepared according to Ref. 7.
80%
Now, on the basis of these results and taking into
account the formation of byproduct 4, the mechanism
as shown is proposed (Scheme 1). Following the nucleo-
philic attack on the formamide by the thiophosphinoyl
anion, which is formed via deprotonation of the phos-
phine sulfide, tetrahedral intermediates 5, and 6 are
formed. 3 is produced from 5 via reductive carbon–oxy-
gen bond cleavage by NaH.
a
b
NMe2
NMe2
Ph2(O)P
Ph2P
3
7
8
ð4Þ
61%
a. Raney Ni, EtOH, 40 °C, 90min; b. air, rt.
N,N-Disubstituted aminomethylphosphine sulfide can be
synthesized by sulfurizing the corresponding phosphine8
or by condensation of secondary phosphine sulfides with
N-hydroxymethyldialkylamines.9 The reductive coupling
reaction, that we present here, is also expected to be a
new method to prepare these compounds.
Our exploration of the scope of this coupling reaction is
shown in Table 1.6 Formamides were successfully con-
verted to the desired products. In entry 5, the product,
a thiophosphorus derivative of L-proline, contains an
asymmetric center,7 and can be expected to be a useful
ligand in transition metal catalyzed asymmetric synthe-
sis. N-Monosubstituted formamides (such as BnNH-
CHO, t-BuNHCHO) were not suitable for this
reaction due to their acidic protons.
In conclusion, our results indicate that this coupling
reaction between diphenylphosphine sulfide and forma-
mides is promoted by excess sodium hydride, and that
the carbon–oxygen bond is cleaved by sodium hydride.
Furthermore, we hope that this reaction will be a useful
methodology in the synthesis of phosphorus containing
compounds.
Finally, the product 3 was converted to the correspond-
ing phosphine 7 via desulfurization with Raney Ni (Eq.
4).1 Moreover phosphine oxide 8 was also obtained via
air oxidation of 7 (Eq. 4). Both are known as effective
ligands for a variety of hydroformylation catalysts.8
References and notes
1. For example, see: Gilbertson, S. R.; Genov, D. G.;
Rheingold, A. L. Org. Lett. 2000, 2, 2885.
2. Hayashi, M.; Hashimoto, Y.; Yamamoto, Y.; Usuki, J.;
Saigo, K. Angew. Chem., Int. Ed. 2000, 39, 631; Hayashi,
M.; Takezaki, H.; Hashimoto, Y.; Takaoki, K.; Saigo, K.
Tetrahedron Lett. 1998, 39, 7529.
3. Diphenylphosphine sulfide was synthesized by sulfurizing
diphenylphosphine in benzene solvent. The crude products
were then purified with recrystallization from MeCN and
filtration through a CH2Cl2–alumina column, according to
a modified procedure reported by Semenzin, D.; Etemad-
Moghadam, G.; Albouy, D.; Diallo, O.; Koenig, M. J. Org.
Chem. 1997, 62, 2414.
H
NMe2
Ph2P(S)
NMe2
O
2
Ph2(S)P
Ph2(S)P
Ph2(S)P
H
+
NMe2
O
5
O
6
Reduction
NaH
4. An authentic sample synthesized with sulfurating (dimeth-
ylaminomethyl)diphenylphosphine was proven identical
with 3 with data of GCMS, NMR, and elemental analysis.
The phosphine was obtained according to Aguiar, A. M.;
Hansen, A. M. J. Org. Chem. 1967, 32, 2383. (Dimethyl-
NMe2
Ph2(S)P
OH
3
4
Scheme 1. Proposed reaction mechanism.

P. Yan, Y. Hashimoto / Tetrahedron Letters 47 (2006) 3467–3469
3469
aminomethyl)diphenylphosphine sulfide 3:8 1H NMR 2.29
(6H, s, Me); 3.45 (2H, d, PCHN); 7.26–7.49 (6H, m, Ph);
7.92–7.99 (4H, m, Ph); 31P NMR 35.44. Anal. Calcd for
C15H18NPS: C, 65.43; H, 6.59; N, 5.09; S, 11.65. Found: C,
65.43; H, 6.67; N, 5.10; S, 11.93.
8.05 (4H, m, Ph); 31P NMR 36.04. Diphenyl(pyrrolidino-
methyl)phosphine sulfide:9 1H NMR 1.66 (4H, m, CH); 2.55
(4H, m, NCH); 3.67 (2H, d, PCHN); 7.41–7.50 (6H, m, Ph);
7.91–7.98 (4H, m, Ph); 31P NMR 36.60. Diphenyl(piperidi-
nomethyl)phosphine sulfide:9 1H NMR 1.35 (2H, m, CH2);
1.44 (4H, m, CH2); 2.39 (4H, m, NCH); 3.42 (2H, d,
PCHN); 7.43–7.51 (6H, m, Ph); 7.98–8.05 (4H, m, Ph); 31P
NMR 35.09. ((S)-2-Methoxymethylpyrrolidinomethyl)-
diphenylphosphine sulfide: 1H NMR 1.37–1.43 (1H, m);
1.61–1.70 (2H, m); 1.80–1.86 (1H, m); 2.42 (1H, dd); 2.90–
3.05 (1H, m); 3.10–3.30 (3H, m); 3.19 (3H, s, Me); 3.60 (1H,
d); 4.40 (1H, dd); 7.44–7.50 (6H, m, Ph); 7.90–8.00 (4H, m,
Ph); 31P NMR 37.20.
5. Nelson, R. B.; Gribble, G. W. J. Org. Chem. 1974, 39,
1425.
6. General procedure for the coupling reaction in DMI: a
mixture of diphenylphosphine sulfide (0.5 mmol) and
formamide (0.5 mmol) was dissolved in DMI (1 mL), then
sodium hydride, 60% dispension in mineral oil (5 equiv) was
added in one portion. After heating at 100 °C, brine was
added at rt. Then the mixture was extracted with diethyl
ether. The organic layer was dried (MgSO4), filtered, and
evaporated. The residue was purified by column chroma-
tography on silica gel. (Diethylaminomethyl)diphenylphos-
phine sulfide:9 1H NMR 0.85 (6H, t, Me); 2.59 (4H, q,
CHMe); 3.59 (2H, d, PCHN); 7.41–7.51 (6H, m, Ph); 7.98–
7. Enders, D.; Fey, P.; Kipphardt, H. Org. Synth. 1987, 65,
173.
8. Chalil, A.-G.; Ibrahim, A. J. Organomet. Chem. 1996, 516,
235.
9. Maier, L. Helv. Chim. Acta 1966, 49, 1249.