Acyclic ene-carbamate. A useful tool for an original synthesis of phosphine-containing α-amino acids bearing a quaternary carbon

Article abstract of DOI:10.1016/j.tet.2009.11.046

A novel and efficient approach for the synthesis of phosphine-containing α-amino acids bearing quaternary carbon is described. The key step involves the original nucleophilic addition of lithiated phosphines onto acyclic ene-carbamates concomitant with a spontaneous internal (N→C) alkyloxycarbonyl migration.

Full text of DOI:10.1016/j.tet.2009.11.046

Tetrahedron 66 (2010) 498–503
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Acyclic ene-carbamate. A useful tool for an original synthesis of phosphine-
containing a-amino acids bearing a quaternary carbon
,
b
b
a
a,
*
Alexis Bouet a, Monika Cieslikiewicz a , Krzysztof Lewinski , Gerard Coudert , Isabelle Gillaizeau
´
a ICOA, UMR CNRS 6005, Universite´ d’Orle´ans, 45067 Orle´ans Cedex 2, France
b Faculty of Chemistry, Jagiellonian University, ul. R. Ingardena 3, 30-060 Krakow, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient approach for the synthesis of phosphine-containing a-amino acids bearing qua-
Received 22 September 2009
Received in revised form 7 November 2009
Accepted 10 November 2009
Available online 15 November 2009
ternary carbon is described. The key step involves the original nucleophilic addition of lithiated phos-
phines onto acyclic ene-carbamates concomitant with a spontaneous internal (N/C) alkyloxycarbonyl
migration.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
as a result of the original choice of the starting primary amine, the
phospholithium reagent or the palladium coupling agent. The first
The development of new synthetic approaches to non-natural
amino acids is a blossoming field of research since such compounds
have found applications in the synthesis of pharmacologically useful
molecules, analogues of bioactive peptides mimetics. Phosphine-
containing amino acids are of interest with respect to their biological
properties1 but are also useful building blocks for the synthesis of
amino-functional phosphines, P,N-heterocycles or hybrid ligands.2
As a consequence, developing new routes to highly functionalized
phosphine containing amino acids remains a great challenge. Most
phosphines are synthesized by addition of a Grignard or organo-
lithium reagent to a phosphine chloride, by reaction of phosphide
anions with an electrophile3 or by metal-catalyzed reaction.4,2e In
order to facilitate the synthesis of a phosphine-containing amino
acid core, we focused on a new approach that uses the nucleophilic
addition of lithiated phosphine onto the double bond of acyclic
ene-carbamates (cf. Scheme 1). Examples of nucleophilic addition
reactions of phosphane derivatives to a variety of functionalized al-
kenes have been reported in the literature.2c,2d,2g We have recently
described an original and efficient synthesis of precursors of
part of this work will concern the preparation of acyclic ene-carba-
mates from the corresponding vinylphosphates via a palladium
cross-coupling reaction. The nucleophilic addition of lithiated
phosphines onto the latter will be investigated in a second stage. The
method is significant in that it represents a potential general route to
enantiomerically pure phosphine- and/or phosphane oxides- con-
taining
a-amino acids.
Ar'
PRR'
Ar
N
H
*
COOtBu
O
P
M+P-RR'
or M+P-(O)RR'
Pd(0)
OPh
OPh
Ar
or
Ar
N
N
Boc
Ar'
O
PRR'
O
Ar'
Boc
Ar
N
H
*
COOtBu
Scheme 1. General route envisioned to phosphine- or phosphane oxides- containing
-amino-acids.
a
2. Results and discussion
Our previous results5 allowed us to realize the synthesis of the
original acyclic amide-derived vinylphosphates 3. Starting from
aromatic primary amines 1, after protection of the nitrogen, the
amide 2 was treated with LDA (1.2 equiv) at ꢀ78 ꢁC in THF pro-
viding the desired lithium enolate, that was quenched with
diphenylchlorophosphate (1.2 equiv) (cf. Table 1). After workup and
purification by silica gel chromatography, the required acyclic
amide-derived vinylphosphates 3a–c were isolated in good yields.
A Pd-catalyzed Suzuki–Miyaura coupling or Stille cross-coupling
reaction was then investigated. By using classical conditions and as
previously demonstrated, a range of acyclic ene-carbamates 4a–k,
substituted alpha to nitrogen by different aryl or heteroaryl groups,
was isolated in fair to good yields (cf. Table 2).
a-amino acids that was performed via an intermolecular carboli-
thiation reaction onto acyclic ene-carbamates. This key step was
concomitant with a spontaneous internal (N/C) alkyloxycarbonyl
migration which led to quaternary aminoesters.5 Accordingly, we
wondered if we could extend the scope of this reaction and so devise
a new route to phosphine-containing a-amino-acids (Scheme 1). The
strategy involved was expected to offer the potential advantage of
directly introducing further molecular diversity onto the molecules
* Corresponding author. Tel.: þ33 2 38 49 45 83.
E-mail address: Isabelle.Gillaizeau@univ-orleans.fr (I. Gillaizeau).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.046

A. Bouet et al. / Tetrahedron 66 (2010) 498–503
499
Table 1
Table 2
Preparation of acyclic amide-derived vinylphosphates 3a–c
Preparation of acyclic ene-carbamates 4a–k via Suzuki–Miyaura or Stille
cross-coupling reaction
1) aq. HCl, Ac2O, AcONa
Ar
2) Boc2O, DMAP, CH3CN
O
P
Ar NH2
N
Boc
O
OPh
Pd(0)
Ar
Ar
1
2
N
O
N
Ar'
OPh
Ar'B(OH)2
or Ar'SnBu3
Boc
Boc
3
4
O
P
1)LDA
OPh
OPh
Ar
N
Boc
O
3
2) ClP(O)(OPh)2
Entry Ar
Ar0B(OH)2
Or Ar0SnBu3
Products
Yield (%)
Entry
Ar
Amide 2a
(yield %)
2aa (82%)
2ba (61%)
2cb (82%)
Vinylphosphate
4a5
83%
3c (yield %)
1a
Ph
Ph
N
Boc
1
2
3
Ph
2-MeC6H4
Bn
3a 83%
3b 82%
3c 90%
B(OH)2
F
a
F
Conditions: (i) aqueous HCl, Ac2O, AcONa, rt, 15 min. (ii) Boc2O, DMAP, CH3CN,
4b
46%
2a
rt, 15 h.
N
Boc
b
The acetamide was synthetized from benzylamine by refluxing 30 min in acetic
B(OH)2
anhydride.
c
(i) 1.2 equiv LDA, THF, ꢀ78 ꢁC, 1h30. (ii) 1.2 equiv ClP(O)(OPh)2, ꢀ78 ꢁC, 2 h.
4c
88%
S
3a
Ph
Ph
N
Boc
Access to phosphine-containing amino acids was then consid-
ered, and acyclic ene-carbamates 4a–k were submitted to Ph2PLi (cf.
Table 3). Treatment of 4a, chosen as a model, with three equivalents
of Ph2PLi in THF at ꢀ78 ꢁC, followed by warming of the reaction
mixture to room temperature, led to the desired derivative 5a (see
entry 1, Table 3). As previously demonstrated, a spontaneous internal
(N/C)alkyloxycarbonylmigrationoccurred,which, afterhydrolysis,
S
B(OH)2
4d
74%
O
4a
N
Boc
O
B(OH)2
Sn(Bu)3
provided
a-aminoesters 5a–j, direct precursors of a-amino acids
bearing a quaternary carbon next to the nitrogen. Theoretical studies
reported by Hook and Bailey6 reveal that the initial step for the in-
termolecular carbometalation is an energetically favorable co-
4e
81%
5b
Ph
N
N
Boc
N
ordination of the lithium atom with the p-system. The p-chelation
was also promoted by a Complex Induced Proximity Effect (CIPE)7 of
the carbamate donor. By warming the reaction mixture to room
temperature, the benzylic organolithium type intermediate became
thermally labile and spontaneously underwent an internal Boc car-
bonyl migration from the nitrogen to the benzylic carbon via
Me
4f
90%
6a
2-MeC6H4
2-MeC6H4
N
Boc
B(OH)2
a strained three-membered ring8 to give
a-aminoesters 5 (Fig. 1).
It is worth noting that a spontaneous over-oxidation of phos-
phine-based derivatives could be observed during the hydrolysis
process, during the purification step on column chromatography or
while left standing in the air. However, the conversion of phosphine
oxides to phosphines could be performed with silanes or hydride
reducing agents. Structures 5e, 5f and 5k were unambiguously de-
termined by X-ray analyses (see Supplementary data).9 In the case of
benzodioxinic derivatives 4d or 4i, only decomposition products
were observed. For compounds 5b or 5g, no further fluoride sub-
stitution occurred. Additionally to the unavoidable over-oxidation,
and according to the quantity of lithiated phosphine present in the
reaction, a mixture of transferred or untransferred compounds
could also be observed in some cases. In the aim of rationalizing
these results, we decided to study the ratio of free and lithiated
phosphine, considering a possible effect on the path of the reaction
(Table 4). In the case of compound 4a (R1, R2¼Ph), it clearly appeared
thatthe presence ofnon lithiated phosphine improves theformation
of the untransferred products (see entries 1,2 and 3, Table 4). For
pyridinyl derivative 4e (R1¼Ph, R2¼Py) (entries 4 and 5, Table 4), the
presence of only one equivalent of free phosphine led to the com-
plete formation of untransferred product, allowing us to say that the
in situ reprotonation is considerably faster than the intramolecular
transfer of the Boc group. Finally, benzylic compound 4k (R1¼Bn,
R2¼Ph) (entry 6, Table 4), even in the absence of free phosphine, led
to the complete formation of the oxidized untransferred compound
owing to the slow rate of the nucleophilic addition of lithium
phosphide onto the double bond of the ene-carbamate.
Me
F
F
4g
64%
7a
N
Boc
B(OH)2
Me
4h
89%
8a
2-MeC6H4
S
N
S
B(OH)2
B(OH)2
Boc
Me
4i
94%
9a
2-MeC6H4
O
N
O
Boc
Me
4j
78%
10b
2-MeC6H4
N
N
Boc
N
Sn(Bu)3
B(OH)2
4k
81%
11a
Bn
N
Boc
a
Conditions: 2.5 equiv. ArB(OH)2, 10 mol % PdCl2(PPh3)2, 2 equiv aqueous Na2CO3
2 M, a few drops of EtOH, THF, reflux 30 min-1 h.
b
2.5 equiv. RSnBu3, 10 mol % PdCl2(PPh3)2, 2 equiv. LiCl, toluene, 18 h, reflux.

500
A. Bouet et al. / Tetrahedron 66 (2010) 498–503
Table 3
PPh2
Ar'
PPh2
Nucleophilic addition of Ph2PLi onto acyclic ene-carbamates 4a–ka
PPh2Li
Ar
Ar
5 + t-BuOLi
Ar'
N
Boc
4
Ar'
N
Ar
N
PPh2
Ar'
Li
O
PPh2Li
Ar
Ar
OLi
O
N
Ar'
N
COOtBu
O
H
5
Boc
4
Figure 1. Mechanistic proposal for the intramolecular (N/C) Boc migration.
Table 4
Entry
1
Ar
Ph
Ene-carbamates
Products
Ph2P
Yield (%)
5a
43%
4a
Influence of the ratio Ph2PH/Ph2PLi on the nucleophilic addition onto acyclic
ene-carbamates 4a, 4e and 4ka
N
H
Boc
F
O
PPh2
O
PPh2
PPh2
R2
PPh2
R
Ph2P
R1
O
Ph2PLi / Ph2PH
THF, -78°C to rt
R1
R1
R1
R1
N
R2
5b
41%
N
N
H
N
H
N
R
Boc 2
R2
2
Ph
4b
Boc 2
H
D
H
C
Boc
Boc
O
N
H
A
B
Boc
4a, 4e, 4k
Ph2P
5c
Entry Ratio Ph2PH/ SMb R1 R2 Products Ratio A/B/C/D (%)
Ph2PLi
3
4
Ph
Ph
4c
95%
N
H
S
Boc
Boc
A
B
C
D
0
1
2
3
4
5
6
0/3
2/2
2/1
0/3
1/2
0/3
4a
4a
4a
4e
4e
4k
Ph Ph 5a 100
Ph Ph 5a 39
Ph Ph 5a 30
Ph Py 5e 100
0
0
0
0
0
0
0
Ph2P
6a 35 6b 24
6a 62 6b
0
0
0
5d
0%
4d
9
N
H
0
O
Ph Py
Bn Ph
0
0
6c
100
5k 100
Ph2P
a
Conditions: 3 equiv (Ph2PLi/Ph2PH), THF, ꢀ78 ꢁC to rt, 15 min.
N
5e
47%
5
6
Ph
4e
4f
b
SM: starting material.
N
H
Boc
synthesized phosphide anion was first complexed with (ꢀ)-spar-
teine in order to induce stereoselectivity during the nucleophilic
attack onto the double bond of the ene-carbamate. Nevertheless, it
appeared that no stereoselectivity was induced on the substrate
even by conducting the reaction at low temperature.10 This
unfortunate result may be due to a racemization process which
occurred during the spontaneous Boc transfer.
Ph2P
5f
43%
2-MeC6H4
N
H
Boc
F
Me
Ph2P
5g
55%
Then, in accordance with the literature, we thought of per-
forming a nucleophilic addition of chiral phosphine11 or phos-
pholane oxide,12 onto acyclic ene-carbamate. We anticipated that,
as previously described, a spontaneous migration of the Boc group
could occur. Ene-carbamate 4e bearing a pyridine moiety was
chosen as a model. Unfortunately, despite experiments performed
in different conditions (n-BuLi, THF, ꢀ78 ꢁC to rt.13, or t-BuOK,
DMSO, 30–40 ꢁC14), the desired adduct could not be isolated
(Scheme 2).
7
8
2-MeC6H4
2-MeC6H4
4g
4h
N
H
Boc
Me
Ph2P
5h
54%
N
H
S
Boc
Me
Ph2P
HPPh(o-OMe-Ph)
5i
0%
or
9
2-MeC6H4
2-MeC6H4
4i
4j
O
P
Ph
H
N
H
O
Ph
Ph
O
Boc
PPh(o-OMe-Ph)
P
Me
Ph
N
N
N
or
*
Boc
*
N
X
N
Boc
4e
N
H
i
H
Boc
Ph2P
N
Boc
5j
0%
10
Scheme 2. Conditions: (i): n-BuLi, THF, ꢀ78 ꢁC to rt or t-BuOK, DMSO, 30–40 ꢁC.
N
H
Me
It is also noteworthy that preliminary experiments in this field
have shown that the nucleophilic addition of phosphide anion of
chiral phosphine borane15 onto the double of the ene-carbamate
was so far unsuccessful.
O
PPh2
5k
50%
11
Bn
4k
N
Boc
3. Conclusion
a
Conditions: 3 equiv. Ph2PLi, THF, ꢀ78 ꢁC to rt, 15 min.
To sum up, we extended the scope of the intermolecular car-
bolithiation reaction to the nucleophilic addition of phosphide
anions onto acyclic ene-carbamates. This methodology allowed
a convenient and efficient approach to phosphine-containing
However, considering the favorable conditions of the Boc
transfer process (see Table 3), attempts to trap, via an in-
termolecular way, the potential intermediate lithium anion by
various electrophiles were made but remained unsuccessful. Also,
a-amino acids bearing quaternary carbon. Unfortunately, so far it
in order to get enantiopure precursors of
a-amino-acids, the
has been impossible to induce stereoselectivity during the

A. Bouet et al. / Tetrahedron 66 (2010) 498–503
501
nucleophilic addition process by using (ꢀ)-sparteine. However,
4.4. General procedure (B) for the synthesis of the ene-
carbamates via a Stille cross-coupling (see Table 2)
synthesized phosphine-containing compounds could have differ-
ent relevant uses (phosphine ligands, peptides analogues, de-
velopment of metal binding group for medical imaging /) and
studies are currently being pursued in these fields.
Phosphate 3 (3.2 mmol) was dissolved in degassed toluene
(10 mL) under argon. The dichloro-bis(triphenylphosphine) palla-
dium (II) (0.32 mmol) was added and the mixture was degassed
and flushed under argon. 2-tributylstannylpyridine (8.0 mmol) and
lithium chloride (6.2 mmol) were added. The reaction mixture was
quickly degassed and flushed under argon. The mixture was then
heated at 90 ꢁC for a night. Brine (50 mL) and EtOAc (50 mL) were
added. The organic phase was separated and the aqueous phase
was extracted with 20 mL of EtOAc. Combined organic phases were
dried over MgSO4 and evaporated under vacuum. Flash chroma-
tography of the crude (silica gel, petroleum ether then petroleum
ether/EtOAc 9:1) provided pure product.
4. Experimental section
4.1. General methods
All non aqueous reactions were carried out in oven or flame-
dried glassware under an argon atmosphere, unless otherwise
noted. All solvents were reagent grade. THF was distilled from so-
dium/benzophenone ketyl immediately prior to use. NMR spectra
were recorded at 25 ꢁC on multinuclear FT-NMR spectrometer
Avance 400 (Bruker) at 400 (1H), 100 (13C), 376.5 (19F) and 162 (31P)
4.4.1. Tert-butyl 1-(2-fluorophenyl) vinyl(phenyl) carbamate (4b).
Colorless solid. Mp(ꢁC): 39–40 ꢁC. 1H NMR, 400 MHz, (CDCl3)
d
1.25
(9H, s), 5.16 (1H, s), 5.42 (1H, s), 7.03–7.20 (3H, m), 7.25–7.42 (6H,
m). 13C NMR, 100 MHz, (CDCl3)
27.0, 80.3, 113.7, 113.8, 114.9, 115.2,
MHz. Chemical shifts
d are given in parts per million, shift refer-
ences are tetramethylsilane for 1H and 13C. 13C and 31P spectra are
proton-decoupled. Compounds were visualized by UV irradiation
and/or spraying with a solution of potassium permanganate, fol-
lowed by charring at 150 ꢁC. Chromatography columns were per-
formed on silica gel 60 (230–400 mesh, 0.040–0.063 mm). Melting
points (mp [ꢁC]) were taken on samples in open capillary tubes and
are uncorrected. The infrared spectra of compounds were recorded
on an ATR-Infrared Fourier Transform spectrophotometer. Com-
pounds 3a, 3b and 4a were synthesized according to previously
published reports.
d
123.1, 123.2, 124.7, 125.2, 127.9, 128.0, 128.1, 128.5, 128.6, 142.3,
142.4, 142.4, 152.3, 157.9, 160.4. 19F NMR, 376.5 MHz (CDCl3)
d
ꢀ116.17. IR (neat) nmax cmꢀ1:. 1712, 1365, 1491, 1336, 1218. HRMS
(ESI) m/z [MþNa]þ calcd for C19H20NO223Na: 336.1375; found
336.1369.
4.4.2. Tert-butyl 1-(benzo[b]thiophen-2-yl) vinyl (phenyl) carbamate
(4c). Yellow solid. Mp(ꢁC): 117–118 ꢁC. 1H NMR, 400 MHz, (CDCl3)
d
1.36 (9H, s), 5.23 (1H, s), 5.69 (1H, s), 7.14–7.17 (1H, m), 7.25–
7.34 (5H, m), 7.42–7.45 (2H, m), 7.66–7.70 (1H, m), 7.71 (1H, m).
13C NMR, 100 MHz, (CDCl3)
28.1, 81.5, 114.5, 118.5, 121.5, 123.1,
124.8, 124.5, 124.7, 124.9, 125.3, 128.9, 139.4, 139.9, 142.5, 142.7,
142.9, 153.4. IR nmax cmꢀ1: 1711, 1503, 1317, 1288, 1251, 1150.
HRMS (ESI) m/z [M-tBu]þ calcd for [C17H12NO2]: 294.0589; found
294.0593.
4.2. General procedure for the preparation
of vinylphosphates (3a–c)
d
Starting amide 2 (3.7 mmol) was dissolved in dry THF (15 mL)
and the mixture was cooled down to ꢀ78 ꢁC under argon. A lithium
diisopropylamine solution (5.6 mmol, 2 M in THF/n-Heptane) was
then added dropwise and the mixture was stirred at ꢀ78 ꢁC for
90 min. Subsequently, diphenylchlorophosphate (5.6 mmol) was
added. After 2 h at ꢀ78 ꢁC, the mixture was quenched with water.
The aqueous phase was extracted with 20 mL of EtOAc. Combined
organic phases were dried over MgSO4 and evaporated under
vacuum. Flash chromatography (silica gel, petroleum ether/EtOAc
1:9) provided pure vinylphosphates 3a–c.
4.4.3. Tert-butyl 1-(benzofuran-2-yl) vinyl (phenyl) carbamate (4d).
Yellow solid. Mp(ꢁC): 120–121 ꢁC. 1H NMR, 400 MHz, (CDCl3)
d
1.39
(9H, s), 5.34 (1H, s), 6.00 (1H, s), 6.70 (1H, s), 7.14–7.55 (9H, m). 13C
NMR, 100 MHz, (CDCl3) 27.1, 80.4, 103.2, 110.1, 113.2, 120.3, 122.0,
d
123.9, 124.5, 127.6, 127.7, 137.8, 141.3, 152.4, 152.8, 153.9. IR nmax
cmꢀ1: 1705, 1118, 1063, 988, 711. HRMS (ESI) m/z [M-tBu]þ calcd for
[C17H12NO3]: 278.0817; found 278.0827.
4.2.1. Tert-butyl benzyl(1-(diphenoxyphosphoryloxy) vinyl)carba-
mate (3c). Colorless oil. 1H NMR, 400 MHz, (CDCl3)
d
1.42 (9H, s),
4.50 (1H, br s), 4.57 (2H, s), 4.97 (1H, br s), 7.19–7.36 (15H, m). 13C
NMR, 100 MHz, (CDCl3) 28.3, 51.7, 82.7, 98.2, 120.3, 125.8, 127.6,
4.4.4. Tert-butyl phenyl(1-(pyridin-2-yl) vinyl) carbamate (4e). Brown
oil. 1H NMR, 400 MHz, (CDCl3)
d 1.26 (9H, s), 5.23 (1H, s), 5.95 (1H, s),
7.11–7.20 (2H, m), 7.29 (2H, dd, J¼8.4 Hz), 7.43 (2H, dd, J¼0.8, 8.8 Hz),
d
7.49 (1H, d, J¼7.6 Hz), 7.65 (1H, dt, J¼1.6, 7.6 Hz), 8.60 (1H, m). 13C
128.0, 128.2, 130.0, 137.7, 146.4, 150.6, 153.8. 31P NMR, 162 MHz,
ꢀ18.7. IR nmax cmꢀ1: 1488, 1193, 1146, 944, 753, 689.
NMR, 100 MHz, (CDCl3)
d 27.9, 81.0, 114.4, 120.0, 122.7, 125.3, 125.5,
(CDCl3)
d
128.6,136.5143.3,148.2,149. 2,153.3,156.0. IR nmax cmꢀ1: 1707,1342,
1154, 1100, 746. HRMS (ESI) m/z [M-tBu]þ calcd for [C14H11N2O2]:
239.0821; found 239.0838.
4.3. General procedure (A) for the preparation of acyclic
ene-carbamates 4 via Suzuki coupling (see Table 2)
4.4.5. Tert-butyl 1-phenylvinyl(o-tolyl)carbamate (4f). Yellow oil. 1H
Phosphate 3 (3.2 mmol) was dissolved in degassed THF (10 mL)
under argon. Dichloro-bis(triphenylphosphine) palladium (II)
(0.32 mmol) was then added and the mixture was degassed and
flushed under argon. Boronic acid (8.0 mmol), aqueous sodium
carbonate solution (2 M, 3.2 mL), and EtOH (three drops) were
added at once. The reaction mixture was then rapidly degassed,
flushed under argon and heated at 60 ꢁC for 30 min. After cooling,
the reaction mixture was filtered through Celite, and was washed
with EtOAc (50 mL). The organic phase was washed with brine,
dried over anhydrous MgSO4 and concentrated. Flash chromatog-
raphy (silica gel, petroleum ether/EtOAc 9:1) afforded the desired
pure product.
NMR, 400 MHz, (CDCl3) d 1.16 (9H, s), 2.33 (3H, s), 4.57 (1H, s), 5.01
(1H, s), 7.11–7.32 (7H, m), 7.55 (2H, d, J¼7.0 Hz). 13C NMR, 100 MHz,
(CDCl3) d 18.2, 27.9, 80.9, 107.6, 126.0, 127.2, 127.6, 128.1, 128.4, 131.1,
135.7,139.9,142.5,149.5,153.2. IR nmax cmꢀ1: 1709,1345,1299,1163,
768. HRMS (ESI) m/z [MþNa]þ calcd for C20H23NO223Na: 332.1626;
found 332.1633.
4.4.6. Tert-butyl1-(2-fluorophenyl)vinyl(o-tolyl)carbamate(4g). Yellow
oil. 1H NMR, 400 MHz, (CDCl3)
d 1.18 (9H, s), 2.31 (3H, s), 4.61 (1H, s),
4.92 (1H, s), 7.01–7.31 (7H, m), 7.47 (1H, t, J¼7.7 Hz). 13C NMR,100 MHz,
(CDCl3)
d 27.8, 28.4, 80.9, 109.0, 109.1, 115.5, 115.7, 124.0, 127.1, 127.9,
130.8, 136.2, 141. 9, 143.7, 152.7, 158.5, 160.9. 19F NMR, 376.5 MHz

502
A. Bouet et al. / Tetrahedron 66 (2010) 498–503
(CDCl3)
d
ꢀ116.1. IR nmax cmꢀ1: 1709, 1307, 1218, 759. HRMS (ESI) m/z
(CDCl3)
d
ꢀ22.83. IR nmax cmꢀ1: 1713, 1504, 1288, 1148, 737. HRMS
[MþH]þ calcd for C20H23NO2F: 328.1699; found 328.1713.
(ESI) m/z [MþNa]þ calcd for C31H32NO223NaP: 504.2068; found
504.2063.
4.4.7. Tert-butyl 1-(benzo[b]thiophen-2-yl)vinyl(o-tolyl)carbamate
(4h). Yellow solid. Mp(ꢁC): 130 ꢁC. 1H NMR, 400 MHz, (CDCl3)
4.5.2. Tert-butyl 3-(diphenylphosphino)-2-(2-fluorophenyl)-2-(phe-
d
1.28 (9H, s), 2.37 (3H, s), 4.83 (1H, s), 5.35 (1H, s), 7.12–7.29 (6H,
nylamino)propanoate (5b). Colorless solid. Mp(ꢁC): 120–121 ꢁC. 1H
m), 7.42 (1H, s), 7.71 (2H, m). 13C NMR, 100 MHz, (DMSO)
d
18.2,
NMR, 400 MHz, (CDCl3)
d
1.24 (9H, s), 3.38 (2H, ddd, J¼4.0, 12.0,
28.1, 81.1, 111.3, 122.0, 122.7, 124.3, 125.1, 125.3, 127.2, 127.6, 131.4,
36.0 Hz), 5.13 (1H, s), 6.27 (2H, d, J¼8 Hz), 6.57 (1H, dd, J¼8 Hz),
6.89 (3H, m), 7.11–7.33 (6H, m), 7.48 (4H, m), 7.56 (3H, m). 13C
NMR, 100 MHz, (CDCl3) 27.5, (Unfortunately, coupling constant
with 19F precluded a nice description of the 13C NMR spectrum).
135.6, 139.0, 140.0, 142.0, 143.0, 143.3, 152.8. IR nmax cmꢀ1: 1707,
1102, 993, 728. HRMS (ESI) m/z [M]þ calcdd for C22H23NO2S:
ꢂ
365.1450; found 365.1470.
19F NMR, 376.5 MHz (CDCl3)
d
ꢀ109.9. 31P NMR, 162 MHz, (CDCl3)
4.4.8. Tert-butyl1-(benzofuran-2-yl)vinyl(o-tolyl)carbamate(4i). Yellow
d
ꢀ25.0. IR nmax cmꢀ1: 1720, 1602, 1503, 1281, 1146, 691. HRMS
1
solid. Mp(ꢁC): 110–111 ꢁC. H NMR, 400 MHz, (CDCl3)
d
1.30 (9H, s),
(ESI) m/z [MþH]þ calcd for C31H32FNO2P: 500.2155; found
2.38 (3H, s), 4.96 (1H, s), 5.63 (1H, s), 6.83 (1H, s), 7.12–7.31 (6H, m),
500.2153.
7.42–7.56 (2H, m). 13C NMR, 100 MHz, (DMSO)
d
18.1, 28.1, 81.0, 104.4,
111.0, 111.5, 121.8, 123.7, 125.4, 127.2, 127.7, 127.9, 128.9, 131.4, 135.8,
139.7, 141.9, 152.9, 154.3, 154.6. IR nmax cmꢀ1: 1709, 1324, 1108, 994.
HRMS (ESI) m/z [M-tBu]þ calcd for [C18H14NO3]: 292.0974; found
292.0953.
4.5.3. Tert-butyl 2-(benzo[b]thiophen-2-yl)-3-(diphenylphosphino)-
2-(phenylamino)propanoate (5c). Colorless solid. Mp(ꢁC): 178–
179 ꢁC. 1H NMR, 400 MHz, (CDCl3)
d 1.25 (9H, s), 3.28–3.53 (2H,
ddd, J¼2.6, 14.2, 80.6 Hz), 5.50 (1H, s), 6.30 (2H, d, J¼7.8 Hz),
6.54 (1H, m), 6.84 (m, 2H), 7.02 (5H, m), 7.25 (6H, m), 7.45 (1H,
s), 7.50 (2H, m), 7.68 (2H, dd, J¼7.6, 21.2 Hz). 13C NMR, 100 MHz,
4.4.9. Tert-butyl 1-(pyridin-2-yl)vinyl(o-tolyl)carbamate (4j). Yellow
oil. 1H NMR, 400 MHz, (CDCl3)
d
1.08 (9H, s), 2.27 (3H, s), 4.69 (1H,
(CDCl3)
d
27.5, (37.4, J¼10 Hz), (65.2, J¼20 Hz), 83.4, 115.4, 117.8,
s), 5.32 (1H, s), 7.06–7.25 (5H, m), 7.45 (1H, m), 7.57 (1H, t,
122.2, 123.7, 124.0, 128.0, 128.1, 128.4, 128.4, 128.5, 128.5,
(132.8, J¼10 Hz), (133.0, J¼10 Hz), 137.1, 138.5, 139.9, 140.4,
144.0, (148.2, J¼10 Hz), 170.7. 31P NMR, 162 MHz, (CDCl3)
J¼7.8 Hz), 8.50 (1H, d, J¼4.7 Hz). 13C NMR, 100 MHz, (CDCl3)
d 17.9,
27.8, 80.7, 109.9, 120.6, 122.5, 126.9, 127.1, 127.1, 130.8, 135.8, 136.2,
142.3, 148.9, 148.9, 152.9. IR nmax cmꢀ1: 1709, 1354, 1158 1082.
HRMS (ESI) m/z [MþH]þ calcd for C19H23N2O2: 311.1760; found
311.1754.
d
ꢀ23.4. IR nmax cmꢀ1:1715, 1602, 1501, 1433, 1288, 1149, 743.
HRMS (ESI) m/z [MþH]þ calcd for C33H33NO2PS: 538.1970;
found 538.1964.
4.4.10. Tert-butyl benzyl(1-phenylvinyl)carbamate (4k). Colorless
4.5.4. Tert-butyl 3-(diphenylphosphino)-2-(phenylamino)-2-(pyridin-
oil. 1H NMR, 400 MHz, (CDCl3)
d
1.13 (9H, s), 4.62 (2H, s), 4.85 (1H,
2-yl)propanoate (5e). Colorless solid. Mp(ꢁC): 146–147 ꢁC. 1H NMR,
s), 5.13 (1H, s), 7.11–7.22 (10H, m). 13C NMR, 100 MHz, (CDCl3)
400 MHz, (CDCl3)
d
1.27 (9H, s), 3.55 (2H, ddd, J¼2.4,16.0, 54.4 Hz),
d
27.9, 53.2, 80.4, 109.5, 125.8, 127.1, 127.5, 128.1, 128.2, 128.5, 128.6,
6.03 (1H, s), 6.21 (2H, d, J¼8.0 Hz), 6.51 (AH, dd, J¼7.2 Hz), 6.85
(2H, m), 6.99 (2H, m), 7.10 (4H, m), 7.21 (3H, m), 7.34 (2H, m), 7.42
(1H, m), 7.51 (1H, dt, J¼2.0, 8.0 Hz), 8.61 (1H, d, J¼4.8 Hz). 13C
138.7, 138.9, 147.8, 154.7. IR nmax cmꢀ1: 1695, 1366, 1153, 696.
HRMS (ESI) m/z [MþNa]þ calcd for C20H23NO223Na: 332.1627;
found 332.1626.
NMR, 100 MHz, (CDCl3)
d
27.7, (34.3, J¼10 Hz), (67.8, J¼20 Hz),
82.8, 114.7, 117.7, 121.4, 122.6, 128.0, 128.0, 128.1, 128.2, 128.2,
128.3, 128.7, 129.1, 129.3, 130.2, 132.8, 133.0, 133.2, 133.4, 134.4,
134.6, 136.7, 138.2, 139.4, 144.3, 148.6, 159.4, 172.2. 31P NMR,
4.5. General procedure for the nucleophilic addition
of lithiated phosphine onto acyclic ene-carbamates
162 MHz, (CDCl3)
d
ꢀ25.0. IR nmax cmꢀ1: 3329, 1729, 1600, 1280,
Ene-carbamate 4 (0.40 mmol) was dissolved in dry THF (2 mL)
and was degassed. The solution was cooled at ꢀ78 ꢁC. In a separate
1147, 740. HRMS (ESI) m/z [MþH]þ calcd for C30H31N2O2P:
483.2182; found 483.2201.
dry flask, to
a
degassed solution of diphenylphosphine
(1.20 mmol) in dry THF (2 mL) was added n-butyllithium
(1.20 mmol, 1.6 M solution in hexanes), which led to the appari-
tion of an intense red color. This red solution was slowly canulated
into the first flask cooled at ꢀ78 ꢁC. The cold bath was removed,
letting the reaction mixture warm up to room temperature for
15 min. The reaction mixture was then quenched with saturated
ammonium chloride (5 mL). EtOAc (5 mL) was added. The organic
phase was separated and the aqueous phase was extracted with
20 mL of EtOAc. Combined organic phases were dried over MgSO4
and evaporated under vacuum. Flash chromatography of the res-
idue (silica gel, petroleum ether then Petroleum ether/EtOAc 9/1)
provided the pure product.
4.5.5. Tert-butyl 3-(diphenylphosphino)-2-phenyl-2-(o-tolylamino)-
propanoate (5f). Clear yellow solid. Mp(ꢁC): 107–108 ꢁC. 1H NMR,
400 MHz, (CDCl3)
d
1.29 (9H, s), 2.03 (3H, s), 3.46 (2H, ddd, J¼2.7,
14.2, 73.3 Hz), 5.54 (1H, s), 5.87 (1H, d, J¼8.04 Hz), 6.45 (1H, t,
J¼7.3 Hz), 6.65 (1H, t, J¼7.9 Hz), 6.78 (1H, d, J¼7.9 Hz), 7.98 (2H, m),
7.07, (3H, m), 7.33 (7H, m), 7.42 (2H,), 7.59 (2H, d, J¼7.9 Hz). 13C
NMR,100 MHz, (CDCl3)
d
17.6, 27.6, 34.2 (J¼13 Hz), 66.4 (J¼21.2 Hz),
82.7, 112.8, 116.6, 123.2, 125.7, 126.8, 127.3, 127.6, 127.7, 128.1, 128.2,
128.4, 128.4, 128.5, 129.9, 132.6, 132.8, 132.8, 133.0, 136.3
(J¼11.0 Hz), 139.7 (J¼11.8 Hz), 141.2 (J¼7.0 Hz), 141.7, 172.3. 31P
NMR,162 MHz, (CDCl3)
d
ꢀ22.6. IR nmax cmꢀ1: 1719, 1280, 1150, 734.
HRMS (ESI) m/z [MþH]þ calcd for C32H35NO2P: 496.2413; found
496.2405.
4.5.1. Tert-butyl 3-(diphenylphosphino)-2-phenyl-2-(phenylamino)-
propanoate (5a). Colorless solid. Mp(ꢁC): 120–121 ꢁC. 1H NMR,
4.5.6. Tert-butyl 3-(diphenylphosphino)-2-(2-fluorophenyl)-2-(o-tolyl-
400 MHz, (CDCl3)
d
1.22 (9H, s), 3.42 (2H, ddd, J¼4.4, 14.1, 26.8 Hz),
amino)propanoate (5g). Colorless solid. Mp(ꢁC): 79–80 ꢁC. 1H NMR,
5.57 (1H, s), 6.08 (2H, d, J¼7.6 Hz), 6.47 (1H, dd, J¼7.2 Hz), 6.79 (2H,
dd, J¼7.2 Hz), 6.97 (2H, dd, J¼7.2 Hz), 7.07 (3H, m), 7.35 (7H, m), 7.43
(2H, dd, J¼12 Hz), 7.57 (2H, dd, J¼12 Hz). 13C NMR, 100 MHz,
400 MHz, (CDCl3)
d
1.26 (9H, s),1.95 (3H, s), 3.45 (2H, ddd, J¼2.1,14.4,
60.0 Hz), 5.18 (1H, s), 6.14 (1H, d, J¼8.1 Hz), 6.49 (1H, t, J¼7.3 Hz), 6.70
(1H, t, J¼7.6H), 6.83 (1H, d, J¼7.2 Hz), 7.08–7.35 (11H, m), 7.47 (2H, dt,
J¼1.4, 8.0 Hz), 7.57 (1H, t, J¼7.9 Hz). 13C NMR, 100 MHz, (CDCl3)
(Unfortunately, coupling constant with 19F precluded a nice de-
scription of the 13C NMR spectrum). 31P NMR, 162 MHz, (CDCl3)
(CDCl3)
d
27.7, (34.9, J¼10 Hz), 66.6, 82.8, 115.1, 116.9, 127.0,
127.5, 128.0, 128.1, 128.3, 128.4, 128.5, 128.6, 132.9, 133.0, 133.1,
133.3, 137.3, 139.6, (141.2, 141.3), 144.1, 172.2. 31P NMR, 162 MHz,

A. Bouet et al. / Tetrahedron 66 (2010) 498–503
503
d
ꢀ24.3. 19F NMR, 376.5 MHz (CDCl3)
d
ꢀ109.7. IR nmax cmꢀ1: 1731,
132.0, 140.9, 148.5, 154.5. 31P NMR, 162 MHz, (CDCl3)
d
29.3. MS
1279, 1150, 741, 695. HRMS (ESI) m/z [MþH]þ calcd for C32H34FNO2P:
(ESI) m/z [MþH]þ C30H32N2O3P: 499.
514.2296; found 514.2311.
Acknowledgements
4.5.7. Tert-butyl 1-(benzo[b]thiophen-2-yl)-2-(diphenylphosphino)-
ethyl(o-tolyl)carbamate (5h). Brown oil. 1H NMR, 250 MHz, (CDCl3)
Financial support of this study by grant from ANR is gratefully
acknowledged. X-ray data of 5k and 5e were collected at Oxford
Diffraction Ltd, Yarnton, U.K. Authors thank Dr.. Zoltan Gal and
Oxford Diffraction staff for all their help and advice.
d
1.29 (9H, s), 2.02 (3H, s), 3.25–3.65 (2H, ddd, J¼4.5, 14.3, 82.8 Hz),
5.49 (1H, s), 6.2 (1H, d, J¼8.0 Hz), 6.50 (1H, dt, J¼1.0, 7.5 Hz), 6.67
(1H, t, J¼7.5 Hz), 6.81 (1H, m), 7.00–7.39 (13H, m), 7.69 (2H, m). 13C
NMR, 100 MHz, (CDCl3)
d
17.5, 28.3, 36.5 (J¼10 Hz), 65.2 (J¼20 Hz),
83.4, 113.2, 117.6, 122.1, 122.3, 123.6, 123.7, 124.0, 126.0, 127.5, 127.8,
127.9, 128.3, 128.5, 128.6, 130.1, 132.7, 132.9, 136.4, 138.6, 139.9,
Supplementary data
140.4,141.9,148.5.,170.9. 31P NMR,162 MHz, (CDCl3)
d
ꢀ23.1. IR nmax
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2009.11.046.
cmꢀ1: 1729, 1243, 1045, 694. MS (ESI) m/z [MþH]þ C34H34NO2PS:
552.
References and notes
4.5.8. Tert-butyl benzyl 3-(diphenylphosphino)-2-phenyl-2-(o-tolyl-
amino)propanoate (5k). Colorless solid. Mp(ꢁC): 150–151 ꢁC. NMR,
1. Aminophosphonic and Aminophosphonic Acids; Kuhkar, V. P., Hudson, H. R., Eds.;
Wiley: Chichester, UK, 2000.
400 MHz, (CDCl3)
br s), 4.46 (1H, br s), 5.37 (m, 1H), 7.12–7.30 (8H, m), 7.40–7.50 (8H,
m). 13C NMR, 100 MHz, (CDCl3)
28.3, 32.7, 33.4, 55.1, 59.0, 61.9,
d 1.27 (9H, s), 2.95 (1H, dt, 5.0, 12.5 Hz), 4.05 (1H,
2. (a) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988–10989; (b) Miller,
S. J. Acc. Chem. Res. 2004, 37, 601–610; (c) Holz, J.; Gensow, M.-N.; Zayas, O.;
Bo¨rner, A. Curr. Org. Chem. 2007, 11, 61–106; (d) Bunlaksananusorn, T.; Polborn,
K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 3941–3943; (e) Agarkov, A.;
Greenfield, S.; Xie, D.; Pawlick, R.; Starkey, G.; Gilbertson, S. R. Biopolymers
(Peptide Science) 2006, 84, 48–73; (f) Guiry, P. J.; Saunders, C. P. Adv. Synth. Catal.
2004, 346, 497–537; (g) Knuhl, G.; Sennhenn, P.; Helmchen, G. J. Chem. Soc.,
Chem. Commun. 1995, 1845–1846; (h) Meyer, F.; Laaziri, A.; Papini, A.-M.; Uziel,
J.; Juge, S. Tetrahedron 2004, 60, 3593–3597.
3. (a) Organophosphorous Chemistry; The Royal Chemical Society: London, 1969–
1983; Vols. 1–15; (b) Organic Phosphorous Compounds, 2nd ed.; Kosolapoff, G.
M., Maier, L., Eds.; Wiley-Interscience: New York, NY, 1972; Vol. 1.
4. Gilbertson, S. R.; Starkey, G. W. J. Org. Chem. 1996, 61, 2922–2923.
5. Cottineau, B.; Gillaizeau, I.; Farard, J.; Auclair, M.-L.; Coudert, G. Synlett 2007,
1925–1929.
6. (a) Houk, K. N.; Rondan, N. G.; Schleyer, P. V. R.; Kaufman, E.; Clark, T. J. Am.
Chem. Soc. 1985, 107, 2821–2822; (b) Bailey, W. F.; Khnaolkar, A. D.; Gavaskar, K.;
Ovaska, T. V.; Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc.1991,113, 5720–5727.
7. Klein, S.; Mareck, I.; Normant, J.-F. J. Org. Chem. 1994, 59, 2925–2926.
8. N–C acyl migration Rouden, J.; Ragot, A.; Gouault, S.; Cahard, D.; Plaquevent,
J.-C.; Lasne, M.-C. Tetrahedron: Assymmetry 2002, 13, 1299–1305.
9. Structures of 5e, 5f and 5k have been deposited with the Cambridge Crystal-
lographic Data Centre (entries CCDC 748011, 748012 and 748216).
10. The enantiomeric excess of phosphine-containing aminoesters was studied by
supercritical fluid chromatography on chiral columns. See West, C.; Bouet, A.;
Gillaizeau, I.; Coudert, G.; Lafosse, M.; Lesellier, E. Chirality 2009. doi:10.1002/
chir.20735
d
64.7, 127.9, 128.2, 128.5, 128.6, 130.4, 130.5, 130.7, 130.8, 131.6, 138.9,
154.9, 182.4, 209.9. 31P NMR, 162 MHz, (CDCl3)
d 28.5. MS (ESI) m/z
[MþNa]þ C33H34NO2PNa: 518.
¨
4.5.9. Tert-butyl2-(diphenylphosphino)-1-phenylethyl(phenyl)carbamate
(6a). Colorless oil. 1H NMR, 400 MHz, (CDCl3)
1.34 (9H, s), 2.62 (2H,
m), 5.55 (1H, m), 6.87 (2H, m), 7.17–7.49 (18H, m). 13C NMR, 100 MHz,
(CDCl3)
28.4, 32.4 (J¼13.7 Hz), 57.5 (18.1 Hz), 127.1, 127.7, 128.3, 128.4,
d
d
128.5,128,128.7,128.8,128.9,129.1,130.2,130.3,132.5,133.4,139.4,141.4
(J¼5.8 Hz), 155.1. 31P NMR, 162 MHz, (CDCl3)
d
ꢀ22.8. MS (ESI) m/z
[MþH]þ C31H33NO2P: 482.
4.5.10. Tert-butyl
2-(diphenylphosphoryl)-1-phenylethyl(phenyl)-
1.22 (9H,
carbamate (6b). Colorless oil. 1H NMR, 400 MHz, (CDCl3)
d
s), 2.78–2.86 (1H, m), 3.36 (1H, m), 5.65 (1H, m), 6.76–6.79 (2H,
m), 7.10 (8H, m), 7.3–7.5 (6H, m), 7.5–7.7 (4H, m). 13C NMR,100 MHz,
(CDCl3)
d
28.2, 33.4 (J¼69 Hz), 57.1 80.3, 114.3, 126.6, 128.3,
128.5, 129.1, 130.7, 131.5, 133.8, 140.6 (J¼8 Hz), 154.4, 171.1. 31P
NMR, 162 MHz, (CDCl3)
498.
d
28.6. MS (ESI) m/z [MþH]þ C31H33NO3P:
11. Togni, A.; Breutel, C.; Soares, M. C.; Zanetti, N.; Gerfin, T. Inorg. Chim. Acta 1994,
222, 213–224.
12. Toffano, M.; Dobrota, C.; Fiaud, J.-C. Eur. J. Org. Chem. 2006, 650–656.
13. Bunlaksananusorn, T.; Knochel, P. J. Org. Chem. 2004, 69, 4595–4601.
14. Haynes, R. K.; Lam, W. W.-L.; Yeung, L.-L. Tetrahedron Lett. 1996, 37, 4729–4732.
15. (a) Bauduin, C.; Moulin, D.; Kaloun, E. B.; Darcel, C.; Juge´, S. J. Org. Chem. 2003,
11, 4293–4301; (b) Jackson, M.; Lennon, I. C. Tetrahedron Lett. 2007, 48, 1831–
1834; (c) Pilkington, C. P.; Zanotti-Gerosa, A. Org. Lett. 2003, 5, 1273–1275; (d)
Oisaki, K.; Zhao, D.; Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2005, 46,
4325–4329.
4.5.11. Tert-butyl 2-(diphenylphosphoryl)-1-(pyridin-2-yl)ethyl(phe-
nyl)carbamate (6c). Colorless oil. 1H NMR, 400 MHz, (CDCl3)
1.32
d
(9H, s), 3.08 (1H, br s), 3.49–3.57 (1H, m), 5.86–5.93 (1H, m), 6.94
(m, 2H), 7.20–7.70 (16H, m), 8.37 (m, 1H). 13C NMR, 100 MHz,
(CDCl3)
d 28.4, 31.3, 32.0, 57.9, 80.9, 122.3, 122.9, 126.5, 128.7, 131.0,