Incorporation of phosphole moieties into the side chain of tyrosine and phenylalanine

Article abstract of DOI:10.1055/s-0030-1259066

A tyrosine derivative with a phosphole moiety covalently attached to the phenolic hydroxy group was successfully prepared through P-O bond-forming reaction, via a nucleophilic substitution reaction at the phosphorus, by slow addition of N-CBz-protected tyrosine methyl ester to a chlorophosphole adduct in the presence of triethylamine, albeit with a low yield. Furthermore, a phenylalanine derivative with a phosphole-containing side chain was conveniently synthesized by Stille cross-coupling reaction of a stannylphosphole reagent with N-Boc-protected 4-iodophenylalanine methyl ester, using Pd(dba)₂ as catalyst, in the absence of any additional ligand. These molecules must be seen as valuable building blocks for the preparation of metalloproteins of interest for chemical, biological, and medical applications

Full text of DOI:10.1055/s-0030-1259066

LETTER
3081
Incorporation of Phosphole Moieties into the Side Chain of Tyrosine and
Phenylalanine
P
hosphole Che
a
mistry brice Bisaro,* Pascal Le Floch1
Laboratoire ‘Hétéroéléments et Coordination’, Ecole Polytechnique, CNRS, 91128 Palaiseau Cedex, France
Fax +33(0)169334440; E-mail: fabrice.bisaro@wolfson.oxon.org
Received 7 October 2010
ments.13 In this context, our group is interested in devel-
oping a-amino acid derivatives with phosphole-
containing side chain.
Abstract: A tyrosine derivative with a phosphole moiety covalent-
ly attached to the phenolic hydroxy group was successfully pre-
pared through P–O bond-forming reaction, via a nucleophilic
substitution reaction at the phosphorus, by slow addition of N-CBz-
protected tyrosine methyl ester to a chlorophosphole adduct in the
presence of triethylamine, albeit with a low yield. Furthermore, a
phenylalanine derivative with a phosphole-containing side chain
was conveniently synthesized by Stille cross-coupling reaction of a
stannylphosphole reagent with N-Boc-protected 4-iodophenylala-
nine methyl ester, using Pd(dba)2 as catalyst, in the absence of any
additional ligand. These molecules must be seen as valuable build-
ing blocks for the preparation of metalloproteins of interest for
chemical, biological, and medical applications.
Phospholes, unsaturated phosphorus-containing five-
membered heterocycles, can bind a large variety of transi-
tion metals.14 They have extensively been used as ligands
in catalysis and for the production of electro-optical sub-
stances,15 and must be regarded as valuable building
blocks for other phosphorus heterocycles and new materi-
als.16 We recently proposed a viable route towards the
production of alanine derivatives with phosphole-contain-
ing side chain (phospholes of type I, Figure 1).17 Incorpo-
ration of phosphole moieties into the side chain of
tyrosine and phenylalanine derivatives was investigated
next. Herein, we disclose our results concerning the syn-
thesis of phospholes of type II and III depicted in
Figure 1.
Key words: a-amino acids, phosphine-containing side chain, de-
sign, functional metalloproteins, phosphole chemistry, P–O bond-
forming reaction, Stille reaction
The development of powerful synthetic methodologies
for the incorporation of metal binding sites into the side
chain of a-amino acids has become a very important area
of research for the design of functional metalloproteins.2
Progress in this research field has allowed for the produc-
tion of valuable bioinorganic and bioorganometallic tran-
sition metal complexes for chemical,3 biological,4 and
medical applications.5 Incorporation of catalytically ac-
tive transition metal complexes into the side chain of a-
amino acids affords a simple and economical way of ac-
cessing chiral compounds with potential applications in
enantioselective catalysis.6 Amino acids bearing an orga-
nometallic substituent or a transition metal complex on
their side chain have also been used for the detection of
peptides by fluorescence spectroscopy,7 as molecular
probes for medical imaging applications,8 as synthetic in-
termediates,9 or as enzyme inhibitors.10 The versatile li-
gating capability of phosphines with transition metals and
their ability to stabilize catalytically active transition met-
als offer exciting prospects in these research fields.11 Re-
cently, some phosphine complexes have also been shown
to display a wide spectrum of anticancer activity in vivo,
especially in cisplatin-resistant cell lines.12 Incorporation
of phosphine complexes into the side chain of a-amino ac-
ids, which are key components of peptides and proteins
and are involved in numerous biological processes could
allow for the development of novel tumor-specific treat-
R
R
R
O
R
P
R
R
P
R
R
O
R
R
O
H2N
H
H2N
H
R
P
O
O
type I
type II
R
O
H2N
H
O
type III
Figure 1 Representative a-amino acid derivatives with phosphole-
containing side chain
Synthesis of a representative phosphole of type II (Figure
1) was considered first, through P–O bond-forming reac-
tion, by slow addition of N-CBz-protected tyrosine methyl
ester 118 to the chlorophosphole adduct 2, in the presence
of a base (Scheme 1). This type of nucleophilic substitu-
tion reaction, commonly used in phosphorus chemistry for
the incorporation of alkoxy moieties to the phosphorus at-
om,19 has never been applied to phosphole adducts. For
the phospholes, more sophisticated synthetic alternatives
have so far been developed, which often require quite
harsh reaction conditions to proceed.20 N-CBz-protected
tyrosine methyl ester 1 was readily prepared from Z-Tyr-
OH21 by selective protection of the acid with methyl
iodide.22 The starting chlorophosphole adduct 2 was syn-
thesized by metallacycle-transfer reaction from the corre-
SYNLETT 2010, No. 20, pp 3081–3085
x
x
.x
x
.2
0
1
0
Advanced online publication: 24.11.2010
DOI: 10.1055/s-0030-1259066; Art ID: G30610ST
© Georg Thieme Verlag Stuttgart · New York

3082
F. Bisaro, P. Le Floch
tetrasubstituted
LETTER
sponding
zircona-cyclopentadiene with trifluoromethanesulfonic anhydride in the presence
(prepared according to Negishi’s procedure)23 and PCl3.24 of pyridine in dichloromethane,30 and N-Boc-protected 4-
The nucleophilic substitution reaction was then examined iodophenylalanine methyl ester 5 was prepared from Boc-
by performing the reaction in THF at –78 °C and using tri- Phe(4-I)-OH31 by selective protection of the acid with me-
ethylamine as base. After removal of the triethylamine thyl iodide, in DMF,32 as for N-CBz-protected tyrosine
salts and protection of the phosphorus lone pair with sul- methyl ester 1 mentioned previously. Two differently sub-
fur, an aliquot was taken from the crude reaction mixture stituted stannylphosphole reagents were selected for this
for analysis. Complete conversion was observed, as deter- study: the 3,4-dimethyl-2-phenyl-1-tributylstannylphos-
mined by 31P{1H} NMR. The desired amino acid phosp- phole (6) and the 3,4-dimethyl-1-tributylstannylphosp-
hole adduct 3 could hardly be precipitated and extracted hole (7), both prepared from the corresponding
from the crude reaction mixture as a solid, but could be phospholide anions, by treatment with Bu3SnCl.33 The
isolated by column chromatography, albeit in a modest Stille reactions were carried out at 60 °C for 12 hours, in
20% yield due to product decomposition on silica gel either THF or MeCN, and a variety of reaction conditions
(Scheme 1).
were explored using Pd(dba)2 as precatalyst. Given that
phospholes can stabilize catalytically active palladium(0)
complexes,34 the reactions were performed in the absence
of any additional ligand. After 12 hours, an aliquot of each
crude reaction mixture was collected to determine the re-
action conversion by 31P{1H} NMR. Representative re-
sults are outlined in Table 1.
O
O
H
H
MeI, KHCO3, r.t.
DMF, 96%
OH
OMe
CbzHN
CbzHN
O
O
1
N-CBz-protected tyrosine triflate methyl ester 4 was
found reluctant to cross-couple with both the stannylphos-
pholes 6 and 7, in the presence of 2 mol% of Pd(dba)2, in
THF or MeCN at 60 °C (entries 1–3). Attempts to activate
the reaction through Sn/Cu transmetalation reactions35 by
addition of catalytic amount of copper(I) halides failed
(entries 4–6). In particular, complete decomposition of the
starting phospholes was observed in MeCN when using 8
mol% of copper(I) chloride, as co-catalyst (entry 6). The
use of N-Boc-protected 4-iodophenylalanine methyl ester
5 was thus considered to facilitate the oxidative addition
step (entries 7–9). Stille cross-coupling reaction of N-
Boc-protected 4-iodophenylalanine methyl ester 5 was
found successful with the 3,4-dimethyl-2-phenyl-1-tribu-
tylstannylphosphole (6), in THF at 60 °C, using 2 mol%
of Pd(dba)2 in the absence of any additives (entry 7). Total
conversion was observed in this case and isolation of the
end product was achieved by column chromatography on
silica gel after protection of the phosphorus lone pair with
sulfur in 78% yield (Scheme 2).
Ph
Ph
Ph
Ph
1. BuLi, –78 °C
2. PhCCPh
PCl3, 0 °C
Cp2ZrCl2
Ph
Ph
Ph
Ph
THF, 100%
CH2Cl2, 100%
P
Zr
Cp
Cp
Cl
2
Ph
S
P
O
1. Et3N, –78 °C, 12 h
2. S8, r.t., 48 h
Ph
1
+
2
Ph
THF, 20%
Ph
OMe
O
CbzHN
3
Scheme 1 Preparation of a representative phosphole of type II
through P–O bond–forming reaction
In view of synthesizing more robust substrates, attention
was then turned towards the synthesis of phenylalanine
derivatives with phosphole-containing side chain (phosp-
holes of Type III, Figure 1), through P–C bond-forming
reactions, and the Stille cross-coupling reaction25 was
considered. Palladium-catalyzed cross-coupling reaction
of stannylphosphine reagents with aryl halides has already
been proven to be an effective method for the production
of a wide variety of arylphosphines under mild reaction
conditions.26 However, to date, this strategy has scarcely
been exploited,27 and to the best of our knowledge, never
successfully applied to the incorporation of phosphorus
moieties into the side chain of a-amino acids derived from
tyrosine or phenylalanine.11 A study of the viability of the
Stille cross-coupling reaction for the synthesis of pheny-
lalanine derivatives with phosphole-containing side chain
was thus undertaken, starting from N-CBz-protected ty-
rosine triflate methyl ester 428 and N-Boc-protected 4-
iodophenylalanine methyl ester 5.29 N-CBz-protected ty-
rosine triflate methyl ester 4 was readily synthesized from
N-CBz-protected tyrosine methyl ester 1 by treatment
No such result was obtained with the 3,4-dimethyl-1-
tributylstannylphosphole (7), with which only trace
amounts of product formed under the same reaction con-
I
OMe
Ph
S
BocHN
O
5
1. Pd(dba)2 (2 mol%), 60 °C, 12 h
2. S8, r.t., 24 h
P
+
THF, 78%
OMe
BocHN
Ph
P
O
8
SnBu3
6
Scheme 2 Preparation of a representative phosphole of type III by
Stille cross-coupling reaction.
Synlett 2010, No. 20, 3081–3085 © Thieme Stuttgart · New York

LETTER
Phosphole Chemistry
3083
Table 1 Optimization Study for the Stille Cross–Coupling Reaction
Ph
Y
P
P
Pd(dba)2 (2 mol%)
or
or
+
Ph
P
P
60 °C, 12 h
X
OMe
N
0.2M
SnBu3
6
SnBu3
7
X
OMe
X
OMe
O
H
N
N
O
H
H
O
Entry
6 or 7
X
Y
Solvent
THF
Additives
None
Conversion (%)a
1
2
3
4
5
6
7
8
9
6
7
7
6
7
7
6
7
7
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Boc
Boc
Boc
OTf
OTf
OTf
OTf
OTf
OTf
I
0
THF
None
0
MeCN
THF
None
0
CuI (8 mol%)
CuI (8 mol%)
CuCl (8 mol%)
None
0
THF
0
MeCN
THF
Decompositionb
100c
I
THF
None
Tracesd
I
THF
CuI (8 mol%)
Tracesd
a Conversion determined by 31P{1H} NMR of the crude reaction mixtures.
b No more signal detected (31P{1H} NMR in MeCN).
c One single signal detected at d = 5.2 ppm (s) (31P{1H} NMR in THF).
d One new signal detected at d = –2.5 ppm (s) integrating for less than 5% (31P{1H} NMR in THF).
ditions, with or without co-catalytic copper(I) halides (en- Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
tries 8 and 9). It was assumed that the palladium(0)
1H NMR, 13C NMR, 31P{1H} NMR spectra of compounds 3 and 8.
catalyst was poisoned by the starting phosphole adduct in
this case. The electron-rich character of the 3,4-dimethyl-
1-tributylstannylphosphole (7) could account for this re-
sult.
Acknowledgment
We thank the NEST Adventure STREP Project artizymes (contract
no. FP6-2003-NEST-B3 15471) for funding.
In conclusion, two novel synthetic strategies have been in-
vestigated and were found successful, for the incorpora-
tion of phosphole moieties into the side chain of a-amino
acids derived from tyrosine and phenylalanine.36 Simple
nucleophilic substitution reaction at the phosphorus, by
slow addition of N-CBz-protected tyrosine methyl ester to
a chlorophosphole adduct in the presence of triethylamine
as base, was shown to allow easy access to a phosphole of
type II (Figure 1) through P–O bond formation, albeit
with a low yield. Furthermore, Stille cross-coupling reac-
tion of a stannylphosphole reagent with N-Boc-protected
4-iodophenylalanine methyl ester was successfully ap-
plied to the preparation of a phenylalanine derivative with
phosphole-containing side chain (phosphole of type III,
Figure 1), using Pd(dba)2 as precatalyst and performing
the reaction in the absence of any additional ligand. Phos-
pholes of type II and III must be seen as valuable building
blocks for the preparation of metalloproteins of interest
for a wide range of applications. Efforts currently directed
towards application of these molecules in catalysis and in
medicine will be reported in due course.
References and Notes
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Synlett 2010, No. 20, 3081–3085 © Thieme Stuttgart · New York

3084
F. Bisaro, P. Le Floch
LETTER
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tetraphenylphosphole (2): The synthetic procedure was
adapted from ref 34a. The Schlenk technique was used.
n-BuLi (8.6 mL, c = 1.6 M, 1.37 × 10–2 mol) was added to a
solution of zirconocene dichloride (Cp2ZrCl2, 2.0 g, 6.84 ×
10–3 mol) in THF (27.3 mL → c = 0.25 M) at –78 °C. The
resulting reaction mixture was stirred for 1 h at –78 °C. After
treatment of (n-Bu)2ZrCp2 generated in THF with
diphenylacetylene (2 equiv, 2.44 g, 1.37 × 10–2 mol), the
temperature of the reaction mixture was allowed to rise to r.t.
overnight. After evaporation of THF, CH2Cl2 was added and
the reaction mixture was filtered. The solvents were
evaporated and CH2Cl2 was added (22.8 mL → c = 0.3 M).
Phosphorus trichloride (597 mL, 6.84 × 10–3 mol) was
subsequently added at 0 °C. The temperature of the reaction
mixture was allowed to rise to r.t. After 30 min, the solvents
were removed in vacuo. A solution of hexane–THF (1:1)
was added and the reaction mixture was filtered. The
solvents were evaporated to produce the desired compound
quantitatively. 31P{1H} NMR of the crude reaction mixture
in CDCl3 showed one major signal at d = 76.4 ppm (s). No
purification was attempted on this substrate.
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(31) Boc-Phe(4-I)-OH [ 99.0% (TLC)] was purchased from
Sigma-Aldrich Co.
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(32) Experimental Procedure for N-Boc-Protected L-4-
Iodophenylalanine Methyl Ester (5): The Schlenk
technique was used. To a solution of Boc-Phe(4-I)-OH (3.0
g, 7.67 × 10–3 mol) in DMF (19.2 mL → c = 0.4 M) at 0 °C
were added subsequently KHCO3 (845 mg, 8.44 × 10–3 mol)
and MeI (0.955 mL, 1.53 × 10–2 mol). The reaction mixture
was stirred overnight at r.t. The reaction was quenched with
a sat. aq solution of NaHCO3. The mixture was extracted
with EtOAc, dried over MgSO4 and concentrated in vacuo.
Purification of the residue by silica gel chromatography
(EtOAc–hexane, 1:3) allowed isolation of the desired
compound (3.0 g, 7.41 × 10–3 mol, yield: 96%) as a white
solid. The analytical data were consistent with the previously
reported data for this compound (Cf. ref. 29).
(33) (a) Experimental Procedure for 3,4-Dimethyl-2-phenyl-
1-tributylstannylphosphole (6): The synthetic procedure
was adapted from ref. 27b. The Schlenk technique was used.
To potassium 3,4-dimethyl-2-phenylphospholidediglyme
adduct (prepared according to ref. 33b; 1.0 g, 2.77 × 10–3
mol) in THF (4.62 mL → c = 0.6 M), at 0 °C, tributyltin
chloride (752 mL, 2.77 × 10–3 mol) was added. After stirring
at r.t. for 5 min, the solvent was distilled off. Degassed
hexane was added. The mixture was filtered into another
Schlenk flask via a cannula. The solid residue was washed
with degassed hexane (2 ×). The hexane was distilled off to
give the desired product as a yellow oil (conversion: 100%).
31P{1H} NMR of the crude reaction mixture in CDCl3
showed one single signal at d = –50.1 ppm (s). This product
was dissolved in THF (13.8 mL) to produce a 0.2 M solution
of 3,4-dimethyl-2-phenyl-1-tributylstannylphosphole.
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(21) Z-Tyr-OH (97%) was purchased from Sigma-Aldrich Co.
(22) Experimental Procedure for N-CBz-Protected
L-Tyrosine Methyl Ester (1): The Schlenk technique was
used. To a solution of Z-Tyr-OH (3.0 g, 9.51 × 10–3 mol)
in DMF (23.8 mL → c = 0.4 M) at 0 °C were added
subsequently KHCO3 (1.05 g, 1.05 × 10–2 mol) and MeI
(1.18 mL, 1.90 × 10–2 mol). The reaction mixture was stirred
overnight at r.t. The reaction was quenched with a sat. aq
solution of NaHCO3. The mixture was extracted with
EtOAc, dried over MgSO4 and concentrated in vacuo.
Purification of the residue by silica gel chromatography
(EtOAc–hexane, 1:2; deposit in CH2Cl2) allowed isolation
of the desired compound (3.0 g, 9.12 × 10–3 mol, yield: 96%)
as a white solid. The analytical data were consistent with the
previously reported data for this compound (Cf. ref. 18).
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Synlett 2010, No. 20, 3081–3085 © Thieme Stuttgart · New York

LETTER
Phosphole Chemistry
3085
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(36) General Procedures: All reactions were routinely
performed under an inert atmosphere of argon or nitrogen by
using Schlenk and glovebox techniques and anhyd
1H NMR (300.131 MHz, CDCl3): d = 2.86–3.04 (2 H, m),
3.58 (3 H, s), 4.47–4.56 [1 H, 2 × t overlapping (2nd order
signal), 3J = 6.3 Hz], 4.99 (2 H, s), 5.06 (1 H, 2 × br s
overlapping), 6.60–7.40 (29 H, m). 13C NMR (75.468 MHz,
CDCl3): d = 39.3 (s), 54.2 (s), 56.5 (s), 68.9 (s), 123.9 (d,
JP = 4.0 Hz), 129.9–130.1 (m), 130.4 (s), 131.4 (s), 131.8 (d,
JP = 1.6 Hz), 131.9 (d, JP = 6.1 Hz), 133.1 (d, JP = 95.4 Hz),
133.9 (d, JP = 10.7 Hz), 134.6 (s), 136.3 (d, JP = 18.9 Hz),
138.0 (s), 150.5 (d, JP = 30.5 Hz), 151.2 (d, JP = 11.8 Hz),
157.4 (s), 173.5 (s). 31P{1H} NMR (121.497 MHz, CDCl3):
d = 99.4 (s). HRMS (EI+): m/z [M+] calcd for C46H38O5NSP:
747.2208; found: 747.2237.
deoxygenated solvents. Anhyd THF and hexane were
obtained by distillation from Na/benzophenone. Anhyd
CH2Cl2 was distilled over P2O5. NMR spectra were recorded
at r.t. on a Bruker AC-300 SY spectrometer operating at
300.0 MHz for 1H NMR, 75.5 MHz for 13C NMR, and 121.5
MHz for 31P NMR. Solvent peaks are used as internal
reference relative to Me4Si for 1H NMR and 13C NMR
chemical shifts (ppm). 31P chemical shifts are relative to an
85% H3PO4 external reference. Coupling constants are given
in Hz. The following abbreviations are used: s, singlet; d,
doublet; t, triplet; m, multiplet. All reagents and chemicals
were obtained commercially and used as received.
Experimental Procedure for (S)-2-tert-Butoxy-
carbonylamino-3-[4-(3,4-dimethyl-2-phenyl-1-
thioxophosphol-1-yl)phenyl]propionic Acid Methyl
Ester (8): The Schlenk technique was used. N-Boc-
protected L-4-iodophenylalanine methyl ester (849 mg, 2.10
× 10–3 mol) was dissolved in a solution of 3,4-dimethyl-2-
phenyl-1-tributylstannylphosphole (10.5 mL, 0.2 M, 2.10 ×
10–3 mol) in THF. Pd(dba)2 (24 mg, 4.19 × 10–5 mol, 2
mol%) was added and the reaction mixture was stirred for 12
h at 60 °C. After cooling off the reaction mixture to r.t., an
aliquot was taken (conversion: 100%). 31P{1H} NMR of the
aliquot (in THF) showed one signal at d = 5.2 ppm (s).
Elemental sulfur (135 mg, 4.19 × 10–3 mol) was added and
the reaction mixture was stirred at r.t. for 24 h. An aliquot
was then taken from the crude reaction mixture for analysis
(conversion: 100%). 31P{1H} NMR of the aliquot (in THF)
showed no more signal at d = 5.2 ppm, one new signal at d =
49.8 ppm (s). The solvents were removed under reduced
pressure. Purification of the residue by silica gel chroma-
tography (hexane–EtOAc, 3:1) allowed isolation of the
desired compound (814 mg, 1.64 × 10–3 mol, yield: 78%) as
a 1:1 mixture of its two diastereoisomers, as a white solid. 1H
NMR (300.131 MHz, CDCl3): d = 1.33 (9 H, s), 2.02 (3 H,
d, JP = 2.3 Hz), 2.12–2.16 (3 H, m), 2.90–3.10 [2 H, 2 × dd
(2nd order signals), 3J = 6.1 Hz, 2J = 13.8 Hz], 3.55–3.59 (3
H, 2 × br s overlapping, 1:1 ratio), 4.40–4.55 [1 H, 2 × t
overlapping (2nd order signal), 3J = 6.3 Hz], 4.90 (1 H, 2 × br
s overlapping), 6.11 (1 H, d, JP = 31.0 Hz), 7.08 (2 H, dd,
JP = 2.3 Hz, 3J = 8.0 Hz), 7.12–7.24 (5 H, m), 7.64 (2 H, dd,
3J = 8.2 Hz, JP = 13.7 Hz). 13C NMR (75.468 MHz, CDCl3):
d = 13.6 (d, JP = 14.1 Hz), 17.2 (d, JP = 17.2 Hz), 27.3 (s),
37.4 (m), 51.3 (s), 53.2 (m), 79.1 (s), 122.6 (d, JP = 83.3 Hz),
125.4 (dm, JP = 77.3 Hz), 126.9 (d, JP = 1.4 Hz), 127.3 (s),
127.9 (d, JP = 4.6 Hz), 128.7 (d, JP = 12.9 Hz), 129.9 (d,
JP = 12.1 Hz), 131.8 (d, JP = 11.8 Hz), 136.5 (dm, JP = 80.5
Hz), 139.7 (d, JP = 2.9 Hz), 145.3 (dm, JP = 24.4 Hz), 153.7
(d, JP = 16.9 Hz), 153.9 (m), 170.87, 170.92 (2 × s). 31P{1H}
NMR (121.497 MHz, CDCl3): d = 54.9 (s). HRMS (EI+):
m/z [M+] calcd for C27H32O4NSP: 497.1790; found:
497.1779.
Experimental Procedure for (S)-2-Benzyloxy-
carbonylamino-3-[4-(2,3,4,5-tetraphenyl-1-thioxo-
phosphol-1-yloxy)phenyl]propionic Acid Methyl Ester (3):
The Schlenk technique was used. A solution of N-CBz-
protected L-tyrosine methyl ester (1.125g, 3.42 × 10–3 mol)
and Et3N (477 mL, 3.42 × 10–3 mol) in THF (68.4 mL → c =
0.05 M) was added dropwise (over 4–5 h) to the starting 1-
chloro-2,3,4,5-tetraphenylphosphole (2.89 g, 6.84 × 10–3
mol) in THF (68.4 mL → c = 0.1 M) at –78 °C. The
temperature of the reaction mixture was allowed to rise to r.t.
for 12 h. The white solid was filtered off and washed with
Et2O. The filtrates and washings were combined and the
solvent was removed under reduced pressure. 31P{1H} NMR
of the crude reaction mixture in CDCl3 showed one major
signal at d = 120.0 ppm (s) and a small side product at d =
–12.0 ppm (s). The crude product was dissolved in THF
(22.8 mL → c = 0.15 M) and elemental sulfur (438 mg,
1.37 × 10–2 mol) was added. The reaction mixture was stirred
for 48 h at r.t. An aliquot was taken from the crude reaction
mixture for analysis (conversion: 100%). 31P{1H} NMR of
the aliquot (in THF) showed no more signal at d = 120.0
ppm, one new signal at d = 93.8 ppm (s), and a minor signal
(less than 5% conversion) at d = 78.3 ppm (s). The solvents
were removed under reduced pressure. Purification of the
residue by silica gel chromatography (hexane–EtOAc, 3:1;
deposit CH2Cl2) allowed isolation of the desired compound
(515 mg, 6.89 × 10–4 mol, yield: 20%) as a yellow oil, which
slowly solidified under vacuum to give a light yellow glass.
Synlett 2010, No. 20, 3081–3085 © Thieme Stuttgart · New York

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