Synthetic entry into 1-phosphono-3-azabicyclo[3.1.0]hexanes

Article abstract of DOI:10.1021/jo401185u

3-Azabicyclo[3.1.0]hex-2-en-1-yl phosphonates were prepared in a five-step reaction route from β-ketophosphonates. The key steps in this sequence are an atom-transfer radical cyclization and an unforeseen lithium-halogen exchange with n-BuLi. The cyclization reaction proceeds with excellent diastereoselectivity. The resulting cyclic imines were reduced, and 3-azabicyclo[3.1.0]hexan-1-yl phosphonates were obtained.

Full text of DOI:10.1021/jo401185u

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Synthetic Entry into 1‑Phosphono-3-azabicyclo[3.1.0]hexanes
Wouter Debrouwer,† Thomas S. A. Heugebaert,† Kristof Van Hecke,‡ and Christian V. Stevens*,†
†SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent
University, Coupure links 653, B-9000 Gent, Belgium
‡Department of Inorganic and Physical Chemistry, Faculty of Sciences, Ghent University, Krijgslaan 281-S3, B-9000 Gent, Belgium
S
* Supporting Information
ABSTRACT: 3-Azabicyclo[3.1.0]hex-2-en-1-yl phosphonates were
prepared in a five-step reaction route from β-ketophosphonates.
The key steps in this sequence are an atom-transfer radical cyclization
and an unforeseen lithium−halogen exchange with n-BuLi. The
cyclization reaction proceeds with excellent diastereoselectivity. The
resulting cyclic imines were reduced, and 3-azabicyclo[3.1.0]hexan-1-yl phosphonates were obtained.
However, these α-haloketones are prone to the Perkow
reaction, i.e., phosphite attack across the carbonyl function
yielding enol phosphate esters via a zwitterionic intermediate.
Electron-withdrawing substituents on the phenyl ring promote
the Perkow reaction. In order to avoid formation of these enol
phosphates, two literature procedures were applied. α-
Haloacetophenones were converted into the corresponding
hydrazones. This prevented phosphite attack across the
carbonyl function and favored the envisaged Michaelis−
Arbuzov reaction (route A).15 Consecutive hydrolysis delivered
the desired β-ketophosphonates 5 in good to excellent yields, as
depicted in Table 1.
INTRODUCTION
■
During our ongoing research on the use of heteroatom transfer
radical cyclization (HATRC) for the design of phosphonylated
heterocycles,1−4 an unexpected synthesis of diethyl (2-phenyl-
3-azabicyclo[3.1.0]hexan-1-yl)phosphonates 1 (Figure 1) has
been elaborated. Bicyclic β-aminophosphonates bearing a
phosphonate moiety at the bridgehead of the bicyclic structure
have only scarcely been reported in literature.5−8
For α-haloacetophenones with strong electron-withdrawing
groups on the phenyl ring (R = 4′-NO2, 4′-CN), formation of
the hydrazones appeared to be troublesome, leading to severe
degradation of the reaction products. Hence, a different
procedure using the MgCl2/Et3N system with diethyl
phosphonoacetic acid was evaluated and did cleanly yield the
desired electron poor β-ketophosphonates after decarboxyla-
tion (route B).16 Using two different methodologies, we
synthesized 10 substituted diethyl (2-oxo-2-phenylethyl)-
phosphonates (Table 1). When the purity of the crude reaction
product was unsatisfactory, column chromatography was
performed since even small impurities caused unproportionally
large amounts of side products in the following steps.
Next, diethyl (2-oxo-2-phenylethyl)phosphonates 5a−j were
reacted with allylamine under Dean−Stark conditions, yielding
an enamine/imine mixture 6/7a−j in ratios around 80/20 in
favor of the enamines (Scheme 1, Table 2). Only one isomer of
enamine 6a−j was formed, whereas the imines 7a−j were
obtained in both their E and Z forms, the E form prevailing (for
exact ratios, see Table 2). These β-enaminophosphonates 6 are
versatile building blocks and various syntheses of these
molecules have accordingly been reported, e.g., the addition
of amines to phosphonylated alkynes17−19 or addition of
metalated dialkyl phosphonates to nitriles.20−23 Furthermore,
Figure 1. New azabicyclic phosphonates 1.
In the class of 3-azabicyclo[3.1.0]hexane scaffolds, no
bicycles phosphonylated at the bridgehead have been reported.
The carboxylic acid derivatives, on the other hand, which are
bioisosters, have been reported in patent literature and exhibit a
wide range of therapeutic activities.9 Amino acid 2 is a bicyclic
GABA analogue,10 while 3 functions as a NK1 antagonist,
counteracting emesis in cancer patients receiving chemotherapy
(Figure 2).11 Coupling of the azabicyclic skeleton to larger
molecules furnishes antibacterial agents 4, antihistamines, and
S1P1 agonists.12−14 The synthesis of a library of diethyl (2-
phenyl-3-azabicyclo[3.1.0]hexan-1-yl)phosphonates was thus
pursued, in view of the interesting biological features of closely
related analogues and the lack of literature information
regarding this new class of compounds.
RESULTS AND DISCUSSION
■
Bicyclic β-aminophosphonates 1 were obtained from commer-
cially available substrates in a six-step synthethic pathway. Ten
derivatives were prepared starting from differently substituted
α-haloacetophenones. These substrates were evaluated for their
conversion into the corresponding β-ketophosphonates 5 by a
classic Michaelis−Arbuzov reaction with triethyl phosphite.
Received: May 30, 2013
Published: August 21, 2013
© 2013 American Chemical Society
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Figure 2. Biologically relevant carboxyl analogues.
Table 1. Yields of β-Ketophosphonates 5a−j
Table 2. Yields (%) and Conformational Ratios of
Enamines/Imines 6/7a−j and α,α-Dichlorinated Imines
8a−j
entry
R
route
5 (%)
a
b
c
d
e
f
4′-H
4′-F
4′-Cl
4′-Br
4′-OMe
4′-Me
4′-Ph
3′-OMe
4′-NO2
4′-CN
A
A
A
A
A
A
A
A
B
B
a
b
entry
R
yield 6 + 7 ratio 6/7 ratio E/Z yield of 8 (%)
50
b
51
a
b
c
d
e
f
4′-H
4′-F
4′-Cl
4′-Br
4′-OMe
4′-Me
4′-Ph
3′-OMe
4′-NO2
4′-CN
98
89
80
93
91
72
91
98
83
88
83/17
71/29
72/28
49/51
73/27
74/26
82/18
84/16
50/50
51/49
65/35
53/47
51/59
60/40
59/41
73/27
54/46
59/41
93/7
95
99
97
82
92
96
90
99
42
44
b
52
b
95
90
99
g
h
i
b
61
b
51
g
h
i
b
j
50
a
a
a
b
Commercially available product. After column chromatography.
j
78/22
a
After column chromatography.
they can be converted into a myriad of acyclic and cyclic
compounds, such as 1-aza-1,3-dienes,22,24,25 2-pyridones,23 and
pyrazoles.25 In this work, the enamine/imine mixture was α,α-
dihalogenated using 2 equiv of N-chlorosuccinimide (NCS)
furnishing the α,α-dichlorinated imines 8a−j in satisfactory
yields and with high purities. No column chromatography was
needed except for the derivatives with strong electron-
withdrawing groups on the phenyl ring (Table 2).
With a library of α,α-dichlorinated imines 8 in hand, a
HATRC was performed in order to acquire the 1-pyrrolines
11a−j.26 Usually, copper(I) complexes mediate this free-radical
ring closure, and their activity can be enhanced by adding
ligands that modify solubility and redox potential.27 The α,α-
dihalogenated imines 8a−j were stirred with Cu(I)Cl and
N,N,N′,N′,N″-pentamethyldiethylenetriamine (PMDTA) as a
ligand in CH2Cl2 at reflux temperature, and the reaction
progress was monitored using HPLC. After all starting material
8a−j had been consumed (ca. 5 h) and the crude reaction
mixture had been subjected to column chromatography, 1-
pyrrolines 11a−j were isolated in satisfactory yields (Scheme
2). Application of other ligating agents such as N,N,N′,N′-
tetramethylethyelenediamine (TMEDA) gave similar results.
Because of the molecular reorganization caused by the free-
radical cyclization process, two stereogenic centers have been
introduced into the molecule (Scheme 2, 11a−j). However, 31
P
NMR indicated a strong diastereoselectivity. Only one major
product peak was present, along with some small signals
accounting for the minor enantiomeric pair and a few minor
impurities. The diastereoisomeric ratios are all in the range of
90/10 and only the major pair of enantiomers could be
obtained in pure form (Table 3).
In order to determine the relative stereochemistry of the 1-
pyrrolines 11a−j, several NMR techniques were applied. A 2D-
NOESY experiment displayed no interaction between the
phosphonate ethoxy groups and H3, possibly indicating a trans
configuration (Figure 3). Furthermore, a heteronuclear 2D-
NOESY (HOESY) experiment was performed to determine if
any Overhauser effect between the phosphorus atom and H3
Scheme 1. Formation of α,α-Dichlorinated Imines 8a−j
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Scheme 2. Mechanism of the HATRC
Table 3. Yields (%) after Column Chromatography and
Diastereoisomeric Ratios of Crude Reaction Mixtures
(Based on 31P NMR)
entry
R
yield of 11 (%)
dr
a
a
b
c
d
e
f
4′-H
4′-F
4′-Cl
4′-Br
4′-OMe
4′-Me
4′-Ph
3′-OMe
4′-NO2
4′-CN
93
90/10
92/8
59
73
43
45
26
37
60
90/10
89/11
85/15
95/5
g
h
i
96/4
93/7
b
23
b
93/7
j
14
95/5
a
b
No column chromatography necessary. After first crystallization;
further crystallization proved difficult, so column chromatography was
used if necessary.
Figure 4. Asymmetric unit of the crystal structure of 11j showing
thermal ellipsoids at the 40% probability level. Both enantiomers are
present in the crystal structure. Disorder of the ethoxy groups is
omitted for clarity.
Formation of the five-membered ring proceeds through a
radical 5-exo-trig cyclization. In the transition state 9 the allylic
methylene carbon is preferentially oriented away from the
bulky phosphonate moiety (Scheme 2). In this manner, the
energetically most favorable five-membered ring is formed,
being the one with least steric hindrance.
With this five-membered ring in hand, the initial goal was to
perform a 1,4-dehydrohalogenation reaction in order to
produce phosphonylated pyrroles 13 (Scheme 3).29 Several
bases were evaluated. Not surprisingly, weak bases such as
triethylamine or potassium carbonate did not engender the
desired elimination. Bases of intermediate strength such as KO-
t-Bu and sodium hydride also failed to do so. The use of
LiHMDS yielded some pyrrole 13a, albeit in very small
amounts. In order to achieve complete conversion and to speed
up the reaction, n-BuLi was employed. However, this resulted
in the formation of an unexpected new compound instead of
the envisaged pyrrole 13a. After purification and careful NMR
studies, the structure of this new compound was assigned as
bicyclic product 14a (Scheme 3).
The alkyllithium reagent performed a Li−Cl exchange with
the tertiary chlorine atom to yield the most stable carbanion
15a−j (Scheme 4, only one enantiomer shown). This lithiated
anion subsequently underwent an intramolecular SN2 reaction
affording bicycle 14a−j. Conjugation with the imine bond as
well as the electron-withdrawing properties of the phosphonate
moiety ensure that only the tertiary chlorine is exchanged, and
the primary, more accessible one, is left untouched. This
hypothesis was proven by the fact that quenching the reaction
Figure 3. Absence of NOE (dashed arrows) and determination of 3JHP
(plain arrow).
could be detected. However, no interaction was observed in
this experiment, thereby supporting the result of the previous
1
experiment. Finally, several H-undecoupled 31P NMR spectra
were recorded with different intensities of decoupling
irradiation in order to obtain a clean signal (for details, see
the Supporting Information). These experiments proved the
3
coupling constant JHP to be 11.2 Hz (Figure 3). Literature
3
values for JHP in five-membered rings have been reported as
3JHP,trans = 5.4−6.0 Hz, while JHP,cis = 17.2−18.0 Hz.28 The
3
coupling constant observed in 11 lies in between these two
values, rendering the NMR observations inconclusive. In the
end, we were able to crystallize two derivatives (11i, R = 4′-
NO2 and 11j, R = 4′-CN). Opposed to the configuration
suspected from the NOE NMR experiments, single-crystal X-
ray diffraction indicated that the relative stereochemistry is cis,
with a torsion angle of −37.2(5)° and −33.1(3)° for 11i and
11j, respectively, between the phosphorus atom and H3 (Figure
4). As both compounds 11i and 11j crystallized in the
centrosymmetric space group P21/c, both enantiomers are
present in the crystal structures.
The origin of this diastereoselectivity most likely lies in steric
hindrance caused by the phosphonate’s bulky ethoxy
substituents, as no other obvious inducing factors are present.
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Scheme 3. Attempted Synthesis of Phosphonylated Pyrroles 13a through E2
Scheme 4. Mechanistic Proposal for the Formation of Bicyclic Phosphonates 14a−j (Only One Enantiomer Shown)
with methanol, 5 min after the addition of n-BuLi, yielded the
same bicyclic product 14a−j, whereas quenching with acetic
acid after the same time interval yielded a mixture of starting
material 11a−j, bicycle 14a−j, and some monochlorinated
compounds. After addition of methanol, lithiated product 15a−
j was quenched by the acidic alcohol proton, but the in situ
formed lithium methoxide was basic enough to deprotonate the
β-imino phosphonate and accomplish the intramolecular ring
closure, a process that could not be accomplished by the less
basic lithium acetate. If the primary chlorine atom had been
exchanged instead, lithium methoxide would not have been able
to deprotonate the resulting aliphatic methyl group. This
proves that the tertiary chlorine is exchanged after the addition
of n-BuLi.
In the 4′-Br derivative 11d, however, the bromine on the
phenyl ring was exchanged as well as a tertiary chlorine atom,
yielding inseparable mixtures of brominated, chlorinated, and
dehalogenated starting materials and cyclopropanated product.
Interestingly, lithium−halogen exchange in 11c (R = 4′-Cl)
occurs only on the tertiary chlorine atom and not on the
chlorine on the phenyl ring as no dehalogenated products were
detected. For 11j (R = 4′-CN), the simultaneous addition of n-
BuLi to the nitrile could not be prevented, resulting in a
mixture of starting material, cyclopropanated product with the
nitrile intact and cyclopropanated product with a pentanoyl
substituent 14j (Figure 5). Therefore, all of 11j was converted
into 14j by adding an excess of n-BuLi.
The other diastereoisomer of 11a−j, in which the tertiary
chlorine and the chloromethyl group are in a trans
configuration, is also converted into bicyclic product 14a−j.
In this case, the formation of the three-membered ring is
possible by inversion of the stereochemistry via the aza-enolate
in order to obtain the necessary configuration for the ring
closure. In this manner, we have achieved the unexpected
synthesis of diethyl (2-phenyl-3-azabicyclo[3.1.0]hex-2-en-1-
yl)phosphonates 14a−j (Table 4).
Figure 5. Product after addition of n-BuLi to 11j with loss of the
nitrile functional group.
To our surprise, further derivatization of the imine bond
proved to be extremely difficult. Hydrolysis in neutral, acidic, or
alkaline medium was unsuccessful as well as addition of
alkyllithium or Grignard reagents. N-Alkylation using methyl
iodide or trimethyloxonium tetrafluoroborate in order to
activate the imine bond was not successful, and reduction
with NaBH4 or LiAlH4 failed. However, application of
equimolar amounts of NaCNBH3 and acetic acid proved to
be effective for reduction to the bicyclic pyrrolidine 1a (Scheme
5, Table 4). Reaction progress was monitored by HPLC (Table
4). The lack of reactivity of 14a−j may be explained by steric
hindrance of the imine bond caused by the bulky ethoxy groups
of the phosphonate on one side and a cyclopropane proton on
the other side, blocking the antibonding π*-orbitals. Only the
smallest nucleophiles can add, given the imine bond is suitably
activated, i.e., by protonation.
Table 4. Yields of Cyclopropanation after Column
Chromatography and Reduction
entry
R
yield of 14 (%) reduction time (h) yield of 1 (%)
a
b
c
d
e
f
4′-H
4′-F
4′-Cl
4′-Br
4′-OMe
4′-Me
4′-Ph
3′-OMe
4′-NO2
4′-pentanoyl
76
49
33
40
51
54
30
72
20
36
1
2
1
84
74
85
a
b
16
16
24
24
4
92
63
91
30
81
60
g
h
i
c
c
c
j
24
a
b
Through this reduction, a third stereogenic center was
introduced into the molecule with high diastereoselectivity (dr
Inseparable mixture. Reduction was not performed because of
c
unpure starting material. After column chromatography.
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with 20 mL of 2 M HCl. The aqueous phase was extracted with
CH2Cl2 (3 × 20 mL) and was dried over MgSO4. The solvent was
removed in vacuo, and the product was purified using column
chromatography.
Scheme 5. Reduction of Imine 14a (Only One Enantiomer
Shown)
Diethyl (2-(4-Cyanophenyl)-2-oxoethyl)phosphonate 5j. A 3.00 g
(18.12 mmol) sample of commercially available 4-cyanobenzoyl
chloride was converted into 5j. After column chromatography, 2.55
1
g was obtained (9.06 mmol, 50% yield, yellow oil). H NMR (300
MHz, CDCl3) δ: 1.30 (6H, t, J = 7.1 Hz), 3.64 (2H, d, 2JHP = 23.1 Hz),
4.15 (4H, dq, 3JHP = 7.4 Hz, J = 7.1 Hz), 7.79 (2H, d, J = 8.0 Hz), 8.13
(2H, d, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.1 (d, 3JCP = 5.8
≥99/1 for all derivatives 1a−j based on 31P NMR). This
observation may again be explained by strong steric hindrance
at the imine bond, which forces the hydride to add from the
less hindered side of the five-membered ring. This results in a
racemic mixture of diethyl (2-phenyl-3-azabicyclo[3.1.0]hexan-
1-yl)phosphonates, with the phenyl ring and the phosphonate
moiety in a cis configuration.
1
2
Hz), 38.7 (d, JCP = 129.2 Hz), 62.7 (d, JCP = 5.8 Hz), 116.5, 117.8,
2
129.4, 132.4, 139.3, 190.9 (d, JCP = 5.8 Hz). 31P NMR (121 MHz,
CDCl3) δ: 19.18. IR (cm−1) νmax: 1019 (P−O), 1051 (P−O), 1248
(PO), 1685 (CO), 2232 (CN), 2984. MS (ESI, pos): m/z
282.3/283.0 (M + H+, 100/14). HRMS: m/z calcd for C13H17NO4P
(M + H)+ 282.0890, found 282.0899. Chromatography: hexanes/
EtOAc 2/3, Rf = 0.11.
Synthesis of Diethyl (2-(Allylamino)-2-phenylvinyl)-
phosphonates 6a−j and 7a−j. Diethyl (2-oxo-2-phenylethyl)-
phosphonates 5a−j were dissolved in toluene (1 mL/mmol) in a
round-bottom flask equipped with a Dean−Stark apparatus. Allylamine
(1.5 equiv) and p-TsOH (0.05 equiv) were added, and the reaction
mixture was heated to reflux temperature and left overnight. The
reaction progress was monitored using gas chromatography. After all
starting material had been consumed, the solvent was removed in
vacuo and the residue was redissolved in diethyl ether and washed with
aqueous NaHCO3. The organic phase was extracted with diethyl ether
(3 × 20 mL), dried over MgSO4, and concentrated in vacuo.
Synthesis of Diethyl (2-(Allylimino)-1,1-dichloro-2-
phenylethyl)phosphonates 8a−j. Diethyl (2-(allylamino)-2-
phenylvinyl)phosphonates 6a−j/7a−j were dissolved in CH2Cl2 (1
mL/mmol), and N-chlorosuccinimide was added (2 equiv). After 4 h,
the reaction mixture was poured into 2 M NaOH and extracted (3 ×
20 mL CH2Cl2). The combined organic layers were dried over MgSO4
and concentrated in vacuo. If necessary, the residue was purified using
column chromatography.
CONCLUSION
■
A library of 10 azabicyclic phosphonates with a manifold of
substituents on the phenyl ring was obtained in five steps. The
key steps are two ring-closure reactions of which the first, i.e.,
the HATRC, displays an excellent diastereoselectivity. The
relative stereochemistry of these compounds was confirmed by
X-ray analysis. The second ring closure is accomplished
through a lithium−chlorine exchange with n-BuLi, allowing
intramolecular cyclopropanation. The acquired cyclic β-imino
phosphonates proved very unreactive toward all kinds of
nucleophiles, only undergoing a diastereoselective reduction
with NaCNBH3 and acetic acid. This step furnishes diethyl (2-
phenyl-3-azabicyclo[3.1.0]hexan-1-yl)phosphonates in excellent
yields.
EXPERIMENTAL SECTION
■
Commercially available products were used as received without any
purification unless otherwise noted. Column chromatography was
performed in a glass column with silica gel (particle size 70−200 μm,
pore diameter 60 Å) using mixtures of ethyl acetate (EtOAc) and
hexanes. NMR spectra were recorded at 300 MHz (1H), 121 MHz
(31P), or 75 MHz (13C) in CDCl3 unless otherwise noted. 2D-NOESY
spectra were recorded using a 5 s relaxation delay and a 1.5 s mixing
time. Low-resolution mass spectra were obtained with a single
quadrupole mass spectrometer (ESI, 70 eV). High-resolution mass
spectra were obtained with a time of flight (TOF) mass spectrometer
(ESI or APCI). Melting points are uncorrected.
Synthesis of Diethyl (2-Oxo-2-phenylethyl)phosphonates
5a−h. A mixture of substituted 2-chloroacetophenone or 2-
bromoacetophenone (1 equiv) and methyl hydrazinecarboxylate
(1.05 equiv) was dissolved in toluene (2 mL/mmol) in a round-
bottom flask equipped with a Dean−Stark apparatus and heated to
reflux temperature for 5 h. Triethyl phosphite was added (1.1 equiv),
and the reaction mixture was refluxed for an additional 2 h. The
solvent was evaporated in vacuo before the residue was redissolved in a
mixture of 20 mL of acetone and 20 mL of 2 M HCl. After 3 h of
stirring, the acetone was evaporated in vacuo and the residue was
brought to pH 7 with 2 M NaOH before being extracted with CH2Cl2
(3 × 20 mL). The combined organic phases were dried over MgSO4
and concentrated in vacuo. If necessary, the product was purified using
column chromatography.
Diethyl (2-(allylimino)-1,1-dichloro-2-phenylethyl)phosphonate
8a. 3.08 g (10.43 mmol) of enamine/imine 6a/7a was converted
1
into 3.61 g of 8a (9.91 mmol, 95% yield, yellow oil). H NMR (300
MHz, CDCl3) δ: 1.37 (6H, t, J = 7.2 Hz), 3.86 (2H, d, J = 5.3 Hz),
4.27−4.48 (4H, m), 5.10 (1H, dd, JHH,Z = 10.6 Hz, J = 1.1 Hz), 5.21
(1H, dd, JHH,E = 17.1 Hz, J = 1.4 Hz), 5.90 (1H, ddt, JHH,E = 17.1 Hz,
JHH,Z = 10.6 Hz, J = 5.3 Hz), 7.31−7.33 (2H, m), 7.43−7.44 (3H, m).
13C NMR (75 MHz, CDCl3) δ: 16.5 (d, 3JCP = 5.8 Hz), 55.9, 65.4 (d,
1
2JCP = 6.9 Hz), 82.0 (d, JCP = 176.5 Hz), 116.3, 128.1, 128.9, 129.3,
131.7 (d, 3JCP = 5.8 Hz), 134.3, 166.0. 31P NMR (121 MHz, CDCl3) δ:
10.96. IR (cm−1) νmax: 1017 (P−O), 1054 (P−O), 1265 (PO),
1654, 2982. MS (ESI, pos): m/z 364.0/365.0/366.0 (M + H+, 100/
16/64). HRMS: m/z calcd for for C15H21Cl2NO3P (M + H)+
364.0631, found 364.0642.
Diethyl (2-(Allylimino)-1,1-dichloro-2-(4-fluorophenyl)ethyl)-
phosphonate 8b. 2.42 g (7.72 mmol) of enamine/imine 6b/7b was
1
converted into 2.92 g of 8b (7.64 mmol, 99% yield, yellow oil). H
NMR (300 MHz, CDCl3) δ: 1.38 (6H, t, J = 7.5 Hz), 3.87 (2H, dt, J =
5.3 Hz, J = 1.8 Hz), 4.26−4.48 (4H, m), 5.11 (1H, ddd, JHH,Z = 10.5
Hz, J = 3.4 Hz, J = 1.8 Hz), 5.20 (1H, ddd, JHH,E = 17.3 Hz, J = 3.4 Hz,
J = 1.8 Hz), 5.90 (1H, ddt, JHH,E = 17.3 Hz, JHH,Z = 10.5 Hz, J = 5.3
Hz), 7.13 (2H, dd, JHF = 8.5 Hz, J = 8.5 Hz), 7.28−7.35 (2H, m). 13
C
NMR (75 MHz, CDCl3) δ: 16.5 (d, 3JCP = 5.8 Hz), 55.9, 65.5 (d, 2JCP
= 6.9 Hz), 81.9 (d, 1JCP = 176.5 Hz), 115.3 (d, 2JCF = 20.8 Hz), 116.3,
3
1
127.6, 131.0 (d, JCF = 8.1 Hz), 134.0, 163.1 (d, JCF = 249.2 Hz),
Synthesis of Diethyl (2-Oxo-2-phenylethyl)phosphonates
5i,j. A mixture of diethyl phosphonoacetic acid (1 equiv) was dissolved
in CH3CN (2 mL/mmol), MgCl2 (1.2 equiv) and Et3N (2 equiv) were
added, and the reaction mixture was stirred for 2 h at room
temperature. Then the suspension was cooled to 0 °C, and the desired
acid chloride was dissolved in CH3CN (1 mL/mmol) and added
dropwise to the cooled solution. The reaction was allowed to slowly
warm to room temperature overnight. The solvent was removed in
vacuo, and the solids were redissolved in 20 mL of CH2Cl2 and washed
165.2. 19F NMR (282 MHz, CDCl3) δ: −110.98 to −110.87 (m). 31
P
NMR (121 MHz, CDCl3) δ: 10.76. IR (cm−1) νmax: 1019 (P−O),
1052 (P−O), 1229 (PO), 1507, 2983. MS (ESI, pos): m/z 382.0/
383.3/384.0 (M + H+, 100/16/64). HRMS: m/z calcd for
C15H20Cl2FNO3P (M + H)+ 382.0536, found 382.0540.
Diethyl (2-(Allylimino)-1,1-dichloro-2-(4-chlorophenyl)ethyl)-
phosphonate 8c. 0.63 g (1.91 mmol) of enamine/imine 6c/7c was
1
converted into 0.74 g of 8c (1.85 mmol, 97% yield, yellow oil). H
8236
dx.doi.org/10.1021/jo401185u | J. Org. Chem. 2013, 78, 8232−8241

The Journal of Organic Chemistry
Featured Article
NMR (300 MHz, CDCl3) δ: 1.38 (6H, t, J = 7.5 Hz), 3.85−3.88 (2H,
m), 4.26−4.48 (4H, m), 5.11 (1H, ddd, JHH,Z = 10.4 Hz, J = 3.4 Hz, 1.7
Hz), 5.20 (1H, JHH,E = 17.3 Hz, J = 3.4 Hz, J = 1.8 Hz), 5.89 (1H, ddt,
JHH,E = 17.3 Hz, JHH,Z = 10.4 Hz, J = 5.2 Hz), 7.26 (2H, d, J = 8.5 Hz),
7.42 (2H, d, J = 8.5 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.5 (d, 3JCP
Diethyl (2-(Allylimino)-1,1-dichloro-2-(3-methoxyphenyl)ethyl)-
phosphonate 8h. 2.01 g (6.18 mmol) of enamine/imine 6h/7h was
1
converted into 2.41 g of 8h (6.12 mmol, 99% yield, yellow oil). H
NMR (300 MHz, CDCl3) δ: 1.38 (6H, t, J = 7.2 Hz), 3.82 (3H, s),
3.88 (2H, dt, J = 5.3 Hz, J = 1.7 Hz), 4.27−4.49 (4H, m), 5.11 (1H,
dd, JHH,Z = 10.8 Hz, J = 1.7 Hz), 5.22 (1H, dd, JHH,E = 16.8 Hz, J = 1.7
Hz), 5.91 (1H, ddt, JHH,E = 16.8 Hz, JHH,Z = 10.8 Hz, J = 5.3 Hz),
6.85−6.91 (2H, m), 6.97 (1H, dd, J = 8.1 Hz, J = 2.2 Hz), 7.34 (1H,
dd, J = 8.1 Hz, J = 8.1 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.4 (d,
3JCP = 5.8 Hz), 55.2, 55.8, 65.3 (d, 2JCP = 6.9 Hz), 81.7 (d, 1JCP = 177.7
Hz), 114.5, 114.8, 116.1, 121.1, 129.2, 132.8 (d, 3JCP = 5.8 Hz), 134.3,
2
1
= 5.8 Hz), 56.0, 65.6 (d, JCP = 6.9 Hz), 81.8 (d, JCP = 177.0 Hz),
3
116.5, 128.5, 130.1 (d, JCP = 5.8 Hz), 130.4, 134.0, 135.7, 165.1. 31P
NMR (121 MHz, CDCl3) δ: 10.65. IR (cm−1) νmax: 1012 (P−O),
1054 (P−O), 1264 (PO), 1487, 2982. MS (ESI, pos): m/z 398.0/
400.0/402.0 (M + H+, 100/97/40). HRMS: m/z calcd for
C15H20Cl3NO3P (M + H)+ 398.0241, found 398.0246.
159.1, 165.7. 31P NMR (121 MHz, CDCl3) δ: 10.96. IR (cm−1) νmax
:
Diethyl (2-(Allylimino)-1,1-dichloro-2-(4-bromophenyl)ethyl)-
1019 (P−O), 1264 (PO), 1578, 2982. MS (ESI, pos): m/z 394.3/
395.3/396.3 (M + H+, 100/16/64). HRMS: m/z calcd for
C16H23Cl2NO4P (M + H)+ 394.0736, found 394.0743.
phosphonate 8d. 0.67 g (1.80 mmol) of enamine/imine 6d/7d was
1
converted into 0.65 g of 8d (1.48 mmol, 82% yield, yellow oil). H
NMR (300 MHz, CDCl3) δ: 1.38 (6H, t, J = 7.2 Hz), 3.86−3.87 (2H,
m), 4.24−4.48 (4H, m), 5.11 (1H, ddd, JHH,Z = 10.2 Hz, J = 3.3 Hz, J =
1.7 Hz), 5.20 (1H, ddd, JHH,E = 17.3 Hz, J = 3.3 Hz, J = 1.7 Hz), 5.90
(1H, ddt, JHH,E = 17.3 Hz, JHH,Z = 10.2 Hz, J = 5.2 Hz), 7.20 (2H, d, J =
8.3 Hz), 7.58 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.6
Diethyl (2-(Allylimino)-1,1-dichloro-2-(4-nitrophenyl)ethyl)-
phosphonate 8i. 1.78 g (5.23 mmol) of enamine/imine 6i/7i was
converted and purified by column chromatography into 0.90 g 8i (2.20
1
mmol, 42% yield, yellow oil). H NMR (300 MHz, CDCl3) δ: 1.39
2
1
(d, 3JCP = 5.8 Hz), 56.0, 65.7 (d, JCP = 6.9 Hz), 81.7 (d, JCP = 177.7
Hz), 116.5, 124.0, 130.5, 130.7, 131.5, 134.1, 165.1. 31P NMR (121
MHz, CDCl3) δ: 10.64. IR (cm−1) νmax: 1010 (P−O), 1054 (P−O),
1260 (PO), 1484, 2982. MS (ESI, pos): m/z 442.0/444.0/446.0 (M
+ H+, 62/100/45). HRMS: m/z calcd for C15H20BrCl2NO3P (M +
H)+ 441.9736, found 441.9743.
(6H, t, J = 7.2 Hz), 3.86 (2H, d, J = 5.4 Hz), 4.27−4.49 (4H, m), 5.15
(1H, d, JHH,Z = 11.2 Hz), 5.20 (1H, d, JHH,E = 17.8 Hz), 5.90 (1H, ddt,
JHH,E = 17.8 Hz, JHH,E = 11.2 Hz, J = 5.4 Hz), 7.54 (2H, d, J = 8.8 Hz),
8.31 (2H, d, J = 8.8 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.4 (d, 3JCP
2
1
= 5.8 Hz), 56.0, 65.7 (d, JCP = 6.9 Hz), 81.0 (d, JCP = 175.4 Hz),
116.6, 123.2, 130.2, 133.5, 138.2 (d, JCP = 5.8 Hz), 148.3, 163.9. 31P
3
NMR (121 MHz, CDCl3) δ: 10.12. IR (cm−1) νmax: 1013 (P−O),
1052 (P−O), 1263 (PO), 1347 (N−O), 1521 (N−O), 1600, 2980.
MS (ESI, pos): m/z 409.0/410.0/411.0 (M + H+, 100/16/64).
HRMS: m/z calcd for C15H20Cl2N2O5P (M + H)+ 409.0481, found
409.0492. Chromatography: hexanes/EtOAc 3/2, Rf = 0.11.
Diethyl (2-(Allylimino)-1,1-dichloro-2-(4-methoxyphenyl)ethyl)-
phosphonate 8e. 1.23 g (3.78 mmol) of enamine/imine 6e/7e was
converted into 1.37 g 8e (3.48 mmol, 92% yield, yellow oil). 1H NMR
(300 MHz, CDCl3) δ: 1.38 (6H, t, J = 7.4 Hz), 3.85 (3H, s), 3.89 (2H,
dt, J = 5.1 Hz, J = 1.7 Hz), 4.27−4.48 (4H, m), 5.10 (1H, ddd, JHH,Z
=
Diethyl (2-(Allylimino)-1,1-dichloro-2-(4-cyanophenyl)ethyl)-
phosphonate 8j. 1.60 g (5.00 mmol) of enamine/imine 6j/7j was
converted and purified by column chromatography into 0.86 g 8j (2.20
10.5 Hz, J = 3.6 Hz, J = 1.7 Hz), 5.21 (1H, ddd, JHH,E = 17.3 Hz, J =
3.6 Hz, J = 1.7 Hz), 5.91 (1H, ddt, JHH,E = 17.3 Hz, JHH,Z = 10.5 Hz, J =
5.1 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.8 Hz). 13C NMR
1
mmol, 44% yield, yellow oil). H NMR (300 MHz, CDCl3) δ: 1.38
(75 MHz, CDCl3) δ: 16.3 (d, 3JCP = 5.8 Hz), 55.0, 55.5, 65.0 (d, 2JCP
=
(6H, t, J = 7.2 Hz), 3.84 (2H, d, J = 5.0 Hz), 4.26−4.48 (4H, m), 5.14
1
3
5.8 Hz), 82.3 (d, JCP = 176.5 Hz), 113.3, 115.9, 123.5 (d, JCP = 5.8
Hz), 130.1, 134.2, 160.1, 165.9. 31P NMR (121 MHz, CDCl3) δ:
11.12. IR (cm−1) νmax: 1020 (P−O), 1055 (P−O), 1245 (PO),
1509, 2981. MS: m/z (ESI, pos) 394.3/395.3/396.3 (M + H+, 100/
17/64). HRMS: m/z calcd for C16H23Cl2NO4P (M + H)+ 394.0736,
found 394.0744.
(d, JHH,Z = 11.4 Hz), 5.19 (d, JHH,E = 18.0 Hz), 5.89 (1H, ddt, JHH,E
=
18.0 Hz, JHH,Z = 11.4 Hz, J = 5.0 Hz), 7.46 (2H, d, J = 8.3 Hz), 7.74
(2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.4 (d, 3JCP = 5.8
2
1
Hz), 55.8, 65.5 (d, JCP = 6.9 Hz), 81.0 (d, JCP = 176.5 Hz), 113.3,
116.5, 117.9, 129.8, 131.8, 133.6, 136.2 (d, JCP = 4.6 Hz), 164.0. 31P
3
NMR (121 MHz, CDCl3) δ: 9.96. IR (cm−1) νmax: 1016 (P−O), 1052
(P−O), 1264 (PO), 2232 (CN), 2984. MS (ESI, pos): m/z
389.0/390.0/391.0 (M + H+, 100/17/64). HRMS: m/z calcd for
C16H20Cl2N2O3P (M + H)+ 389.0583, found 389.0597. Chromatog-
raphy: hexanes/EtOAc 3/2, Rf = 0.10.
Diethyl (2-(Allylimino)-1,1-dichloro-2-(4-methylphenyl)ethyl)-
phosphonate 8f. 1.78 g (5.75 mmol) of enamine/imine 6f/7f was
converted into 2.09 g 8f (5.52 mmol, 96% yield, yellow oil). 1H NMR
(300 MHz, CDCl3) δ: 1.37 (6H, t, J = 6.9 Hz), 2.39 (3H, s), 3.87 (2H,
dt, J = 5.1 Hz, J = 1.7 Hz), 4.27−4.51 (4H, m), 5.10 (1H, ddd, JHH,Z
=
Synthesis of Diethyl (4-Chloro-3-(chloromethyl)-5-phenyl-
3,4-dihydro-2H-pyrrol-4-yl)phosphonates 11a−j. In a round-
bottom flame-dried flask and under a N2-atmosphere were dissolved
diethyl (2-(allylimino)-1,1-dichloro-2-phenylethyl)phosphonates 8a−j
in dry CH2Cl2 (1 mL/mmol). Cu(I)Cl (0.4 equiv) and N,N,N′,N′,N″-
pentamethyldiethylenetriamine (0.8 equiv) were added, and the
reaction mixture was heated to reflux. The reaction progress was
monitored using HPLC. After all starting material had been consumed,
the reaction mixture was poured into brine and extracted with CH2Cl2
(3 × 10 mL). The combined organic phases were washed with water
until no more Cu salts were present (blue color of the aqueous phase
disappears). The organic layer was dried over MgSO4 and
concentrated in vacuo, and the residue was purified by crystallization
or column chromatography. Only the major diastereoisomers could be
isolated in pure form.
10.4 Hz, J = 3.4 Hz, J = 1.7 Hz), 5.21 (1H, ddd, JHH,E = 17.1 Hz, J =
3.4 Hz, J = 1.7 Hz), 5.90 (1H, ddt, JHH,E = 17.1 Hz, JHH,Z = 10.4 Hz, J =
5.1 Hz), 7.22 (4H, d, J = 2.8 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.6
3
2
1
(d, JCP = 5.8 Hz), 21.5, 55.9, 65.5 (d, JCP = 6.9 Hz), 82.2 (d, JCP
=
2
176.5 Hz), 116.3, 128.8, 128.9, 134.5, 139.4, 166.3 (d, JCP = 2.3 Hz).
31P NMR (121 MHz, CDCl3) δ: 11.07. IR (cm−1) νmax: 1017 (P−O),
1052(P−O), 1262 (PO), 1654, 2982. MS (ESI, pos): m/z 378.3/
379.3/380.3 (M + H+, 100/18/64). HRMS: m/z calcd for
C16H23Cl2NO3P (M + H)+ 378.0787, found 378.0795.
Diethyl (2-([1,1′-Biphenyl]-4-yl)-2-(allylimino)-1,1-dichloroethyl)-
phosphonate 8g. 1.78 g (5.75 mmol) of enamine/imine 6g/7g was
1
converted into 2.09 g of 8g (5.52 mmol, 90% yield, yellow oil). H
NMR (300 MHz, CDCl3) δ: 1.38 (6H, t, J = 7.2 Hz), 3.92 (2H, dt, J =
5.1 Hz, J = 1.8 Hz), 4.28−4.50 (4H, m), 5.12 (1H, ddd, JHH,Z = 10.5
Hz, J = 3.4 Hz, J = 1.8 Hz), 5.24 (1H, ddd, JHH,E = 17.2 Hz, J = 3.4 Hz,
J = 1.8 Hz), 5.93 (1J, ddt, JHH,E = 17.2 Hz, JHH,Z = 10.5 Hz, J = 5.1 Hz),
7.35−7.49 (5H, m), 7.57−7.71 (4H, m). 13C NMR (75 MHz, CDCl3)
Diethyl (cis-4-Chloro-3-(chloromethyl)-5-phenyl-3,4-dihydro-2H-
pyrrol-4-yl)phosphonate 11a. 3.42 g (9.39 mmol) of 8a was
converted into 11a. 3.18 g of product was obtained in a dr of 90/10
1
δ: 16.6 (d, 3JCP = 5.8 Hz), 56.0, 65.6 (d, 2JCP = 6.9 Hz), 82.1 (d, 1JCP
=
(8.73 mmol, 93% yield, brown oil). H NMR (300 MHz, CDCl3) δ:
176.5 Hz), 116.4, 126.8, 127.2, 127.9, 129.0, 129.5, 130.7 (d, 3JCP = 5.8
1.20 (3H, t, J = 7.2 Hz), 1.28 (3H, t, J = 7.2 Hz), 3.22−3.38 (1H, m),
3.67 (1H, dd, J = 10.7 Hz, J = 10.7 Hz), 3.96−4.23 (6H, m), 4.45 (1H,
dd, J = 17.1 Hz, J = 6.6 Hz), 7.36−7.44 (3H, m), 8.02 (2H, d, J = 7.2
Hz). 13C NMR (75 MHz, CDCl3) δ: 16.3 (d, 3JCP = 5.8 Hz), 16.4 (d,
3JCP = 5.8 Hz), 44.2 (d, 3JCP = 2.3 Hz), 48.6, 63.2 (d, 3JCP = 10.4 Hz),
2
Hz), 134.4, 140.2, 142.2, 166.0 (d, JCP = 2.3 Hz). 31P NMR (121
MHz, CDCl3) δ: 10.93. IR (cm−1) νmax: 1019 (P−O), 1054 (P−O),
1262 (PO), 1712, 2982. MS (ESI, pos): m/z 440.3/441.3/442.3 (M
+ H+, 100/23/64). HRMS: m/z calcd for C21H25Cl2NO3P (M + H)+
440.0944, found 440.0947.
2
2
1
64.3 (d, JCP = 6.9 Hz), 64.7 (d, JCP = 8.1 Hz), 71.2 (d, JCP = 166.1
8237
dx.doi.org/10.1021/jo401185u | J. Org. Chem. 2013, 78, 8232−8241

The Journal of Organic Chemistry
Featured Article
2
Hz), 128.0, 129.3, 130.7, 132.8, 169.1 (d, JCP = 2.3 Hz). 31P NMR
(121 MHz, CDCl3) δ: 17.11. IR (cm−1) νmax: 1012 (P−O), 1043 (P−
O), 1263 (PO), 1606, 2981. MS (ESI, pos): m/z 364.0/365.0/366.0
(M + H+, 100/16/64). HRMS: m/z calcd for C15H21Cl2NO3P (M +
H)+ 364.0631, found 364.0636. Chromatography: hexanes/EtOAc 1/
1, Rf = 0.4.
394.0/395.0/396.0 (M + H+, 100/18/64). HRMS: m/z calcd for
C16H23Cl2NO4P (M + H)+ 394.0736, found 394.0740. Chromatog-
raphy: hexanes/EtOAc 3/2, Rf = 0.23.
Diethyl (cis-4-Chloro-3-(chloromethyl)-5-(4-methylphenyl)-3,4-
dihydro-2H-pyrrol-4-yl)phosphonate 11f. 1.82 g (4.81 mmol) of 8f
was converted into 11f. After column chromatography, 0.47 g of
product was obtained in a dr of 95/5 (1.25 mmol, 26% yield, brown
Diethyl (cis-4-Chloro-3-(chloromethyl)-5-(4-fluorophenyl)-3,4-di-
hydro-2H-pyrrol-4-yl)phosphonate 11b. 3.00 g (7.82 mmol) of 8b
was converted into 11b. After column chromatography, 1.77 g of
product was obtained in a dr of 92/8 (4.61 mmol, 59% yield, brown
1
oil). H NMR (300 MHz, CDCl3) δ: 1.20 (3H, t, J = 7.2 Hz), 1.30
(3H, t, J = 7.2 Hz), 2.37 (3H, s), 3.19−3.37 (1H, m), 3.65 (1H, dd, J =
10.5 Hz, J = 10.5 Hz), 3.94−4.23 (6H, m), 4.42 (1H, ddd, J = 17.1 Hz,
1
4
oil). H NMR (300 MHz, CDCl3) δ: 1.20 (3H, t, J = 7.2 Hz), 1.31
J = 7.2 Hz, JHP = 1.7 Hz), 7.19 (2H, d, J = 8.3 Hz), 7.95 (2H, d, J =
8.3 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.3 (d, 3JCP = 5.8 Hz), 16.5
(3H, t, J = 7.2 Hz), 3.23−3.36 (1H, m), 3.66 (1H, dd, J = 10.5 Hz, J =
10.5 Hz), 3.96−4.19 (6H, m), 4.43 (1H, ddd, J = 17.1 Hz, J = 7.2 Hz,
4JHP = 1.7 Hz), 7.07 (2H, dd, J = 8.8 Hz, 3JHF = 8.8 Hz), 8.10 (2H, dd,
3
3
3
(d, JCP = 5.8 Hz), 21.6, 44.3 (d, JCP = 2.3 Hz), 48.5, 63.0 (d, JCP
=
=
9.2 Hz), 64.4 (d, 2JCP = 6.9 Hz), 64.7 (d, 2JCP = 6.9 Hz), 71.2 (d, 1JCP
J = 8.8 Hz, JFH = 5.5 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.2 (d,
4
163.8 Hz), 128.7, 129.3, 129.7, 141.0, 168.8. 31P NMR (121 MHz,
CDCl3) δ: 17.36. IR (cm−1) νmax: 1014 (P−O), 1096 (P−O), 1264
(PO), 1606, 2359, 2981. MS (ESI, pos): m/z 378.3/379.3/380.3
(M + H+, 100/18/64). HRMS: m/z calcd for C16H23Cl2NO3P (M +
H)+ 378.0787, found 378.0782. Chromatography: hexanes/EtOAc 1/
1, Rf = 0.47.
3JCP = 5.8 Hz), 44.1 (d, JCP = 2.3 Hz), 48.4, 63.1 (d, JCP = 9.2 Hz),
64.5 (d, 2JCP = 12.1 Hz), 64.6 (d, 2JCP = 12.1 Hz), 71.1 (d, 2JCP = 165.0
Hz), 114.9 (d, 2JCF = 21.9 Hz), 128.7 (d, 4JCF = 3.5 Hz), 131.6 (d, 3JCF
3
3
= 8.1 Hz), 164.2 (d, JCF = 251.22 Hz), 167.7. 19F NMR (282 MHz,
1
CDCl3) δ: −109.43 to −109.32 (m). 31P NMR (121 MHz, CDCl3) δ:
17.08 IR (cm−1) νmax: 1012 (P−O), 1039 (P−O), 1263 (PO), 1509,
2980. MS (ESI, pos): m/z 382.0/383.0/384.0 (M + H+, 100/17/64).
HRMS: m/z calcd for C15H20Cl2FNO3P (M + H)+ 382.0536, found
382.0543. Chromatography: hexanes/EtOAc 4/1, Rf = 0.15.
Diethyl (cis-5-([1,1′-Biphenyl]-4-yl)-4-chloro-3-(chloromethyl)-
3,4-dihydro-2H-pyrrol-4-yl)phosphonate 11g. 1.15 g (2.61 mmol)
of 8g was converted into 11g. After column chromatography, 0.42 g of
product was obtained in a dr of 96/4 (0.97 mmol, 37% yield, brown
1
Diethyl (cis-4-Chloro-3-(chloromethyl)-5-(4-chlorophenyl)-3,4-di-
hydro-2H-pyrrol-4-yl)phosphonate 11c. 0.70 g (1.76 mmol) of 8c
was converted into 11c. After column chromatography, 0.51 g of
product was obtained in a dr of 90/10 (1.28 mmol, 73% yield, brown
oil). H NMR (300 MHz, CDCl3) δ: 1.22 (3H, t, J = 7.0 Hz), 1.31
(3H, t, J = 7.0 Hz), 3.25−3.40 (1H, m), 3.68 (1H, dd, J = 10.5 Hz, J =
10.5 Hz), 4.00−4.21 (6H, m), 4.47 (1H, ddd, J = 17.1 Hz, J = 6.9 Hz,
4JHP = 1.9 Hz), 7.35−7.47 (3H, m), 7.62−7.65 (4H, m), 8.14−8.18
(2H, m). 13C NMR (75 MHz, CDCl3) δ: 16.4 (d, 3JCP = 5.8 Hz), 16.5
1
oil). H NMR (300 MHz, CDCl3) δ: 1.21 (3H, t, J = 7.2 Hz), 1.31
(3H, t, J = 7.2 Hz), 3.22−3.36 (1H, m), 3.65 (1H, dd, J = 10.5 Hz, J =
(d, 3JCP = 5.8 Hz), 44.3, 48.5, 63.3 (d, 3JCP = 10.4 Hz), 64.5 (d, 2JCP
=
10.5 Hz), 3.94−4.23 (6H, m), 4.43 (1H, ddd, J = 17.1 Hz, J = 7.2 Hz,
2
1
6.9 Hz), 64.7 (d, JCP = 6.9 Hz), 71.3 (d, JCP = 165.0 Hz), 126.6,
4JHP = 1.7 Hz), 7.37 (2H, d, J = 8.8 Hz), 8.02 (2H, d, J = 8.8 Hz). 13
C
2
127.2, 127.9, 129.0, 129.9, 131.5, 140.3, 143.3, 168.5 (d, JCP = 2.3
NMR (75 MHz, CDCl3) δ: 16.3 (d, 3JCP = 5.8 Hz), 16.4 (d, 3JCP = 4.6
Hz), 44.1 (d, 3JCP = 3.5 Hz), 48.4, 63.2 (d, 3JCP1 = 9.2 Hz), 64.5 (d, 2JCP
Hz). 31P NMR (121 MHz, CDCl3) δ: 17.27. IR (cm−1) νmax: 1014
(P−O), 1043 (P−O), 1263 (PO), 1602, 2980. MS (ESI, pos): m/z
440.3/441.3/442.3 (M + H+, 100/23/64). HRMS: m/z calcd for
C21H25Cl2NO3P (M + H)+ 440.0944, found 440.0949. Chromatog-
raphy: hexanes/EtOAc 7/3, Rf = 0.29.
2
= 6.9 Hz), 64.7 (d, JCP = 6.9 Hz), 71.1 (d, JCP = 165.0 Hz), 128.2,
130.8, 131.0, 136.9, 167.8. 31P NMR (121 MHz, CDCl3) δ: 17.06. IR
(cm−1) νmax: 1012 (P−O), 1041 (P−O), 1263 (PO), 1491, 2982.
MS (ESI, pos): m/z 397.0/399.0/401.0 (M + H+, 100/96/31).
HRMS: m/z calcd for C15H20Cl3NO3P (M + H)+ 398.0241, found
398.0249. Chromatography: hexanes/EtOAc 7/3, Rf = 0.21.
Diethyl (cis-4-Chloro-3-(chloromethyl)-5-(3-methoxyphenyl)-3,4-
dihydro-2H-pyrrol-4-yl)phosphonate 11h. 2.11 g (5.35 mmol) of 8h
was converted into 11h. After column chromatography, 1.27 g of
product was obtained in a dr of 93/7 (3.21 mmol, 60% yield, brown
Diethyl (cis-4-Chloro-3-(chloromethyl)-5-(4-bromophenyl)-3,4-di-
hydro-2H-pyrrol-4-yl)phosphonate 11d. 0.65 g (1.47 mmol) of 8d
was converted into 11d. After column chromatography, 0.28 g of
product was obtained in a dr of 89/11 (0.63 mmol, 43% yield, brown
1
oil). H NMR (300 MHz, CDCl3) δ: 1.21 (3H, t, J = 7.2 Hz), 1.29
(3H, t, J = 7.2 Hz), 3.24−3.36 (1H, m), 3.66 (1H, dd, J = 10.5 Hz, J =
10.5 Hz), 3.84, 3.96−4.18 (6H, m), 4.45 (1H, dd, J = 17.1 Hz, J = 7.2
Hz), 6.99 (1H, d, J = 8.1 Hz), 7.30 (1H, dd, J = 8.1 Hz, J = 8.1 Hz),
7.63−7.66 (2H, m). 13C NMR (75 MHz, CDCl3) δ: 16.3 (d, 3JCP = 5.8
1
oil). H NMR (300 MHz, CDCl3) δ: 1.12 (3H, t, J = 7.2 Hz), 1.22
(3H, t, J = 7.2 Hz), 3.14−3.27 (1H, m), 3.56 (1H, dd, J = 10.5 Hz, J =
10.5 Hz), 3.88−4.13 (6H, m), 4.33 (1H, ddd, J = 17.2 Hz, J = 7.0 Hz,
3
3
Hz), 16.4 (d, JCP = 5.8 Hz), 44.2 (d, JCP = 2.3 Hz), 48.6, 55.4, 63.1
4JHP = 1.7 Hz), 7.44 (2H, d, J = 8.8 Hz), 7.88 (2H, d, J = 8.8 Hz). 13
C
(d, 3JCP = 10.4 Hz), 64.3 (d, 2JCP = 10.4 Hz), 64.7 (d, 2JCP = 10.4 Hz),
NMR (75 MHz, CDCl3) δ: 16.3 (d, 3JCP = 5.8 Hz), 16.4 (d, 3JCP = 5.8
Hz), 44.1 (d, 3JCP = 3.5 Hz), 48.4, 63.2 (d, 3JCP1 = 9.2 Hz), 64.5 (d, 2JCP
1
71.2 (d, JCP = 165.0 Hz), 114.1, 117.0, 121.7, 129.0, 133.8, 159.1,
168.8. 31P NMR (121 MHz, CDCl3) δ: 17.21. IR (cm−1) νmax: 1013
(P−O), 1263 (PO), 1578, 2981. MS (ESI, pos): m/z 394.3/395.3/
396.3 (M + H+, 100/16/64). HRMS: m/z calcd for C16H23Cl2NO4P
(M + H)+ 394.0736, found 394.0732. Chromatography: hexanes/
EtOAc 3/2, Rf = 0.29.
2
= 6.9 Hz), 64.7 (d, JCP = 6.9 Hz), 71.1 (d, JCP = 165.0 Hz), 125.4,
131.0, 131.1, 131.4, 167.8. 31P NMR (121 MHz, CDCl3) δ: 16.97. IR
(cm−1) νmax: 1010 (P−O), 1038 (P−O), 1266 (PO), 1394, 2978.
MS (ESI, pos): m/z 442.0/444.0/446.0(M + H+, 62/100/45). HRMS:
m/z calcd for C15H20BrCl2NO3P (M + H)+ 441.9736, found 441.9737.
Chromatography: hexanes/EtOAc 7/3, Rf = 0.19.
Diethyl (cis-4-Chloro-3-(chloromethyl)-5-(4-nitrophenyl)-3,4-di-
hydro-2H-pyrrol-4-yl)phosphonate 11i. 0.60 g (1.47 mmol) of 8i
was converted into 11i. After one crystallization, 0.14 g of product was
Diethyl (cis-4-Chloro-3-(chloromethyl)-5-(4-methoxyphenyl)-3,4-
dihydro-2H-pyrrol-4-yl)phosphonate 11e. 1.11 g (2.82 mmol) of 8e
was converted into 11e. After column chromatography, 0.50 g of
product was obtained in a dr of 85/15 (1.27 mmol, 45% yield, brown
1
obtained in a dr of 93/7 (0.34 mmol, 23% yield, orange needles). H
NMR (300 MHz, CDCl3) δ: 1.22 (3H, t, J = 7.2 Hz), 1.32 (3H, t, J =
7.2 Hz), 3.25−3.40 (1H, m), 3.67 (1H, dd, J = 10.5 Hz, J = 10.5 Hz),
3.97−4.25 (6H, m), 4.50 (1H, dd, J = 17.6 Hz, J = 7.2 Hz), 8.25 (4H,
1
oil). H NMR (300 MHz, CDCl3) δ: 1.19 (3H, t, J = 7.2 Hz), 1.31
(3H, t, J = 7.2 Hz), 3.21−3.35 (1H, m), 3.64 (1H, dd, J = 10.5 Hz, J =
10.5 Hz), 3.81 (3H, s), 3.91−4.22 (6H, m), 4.39 (1H, ddd, J = 17.1
Hz, J = 7.2 Hz, 4JHP = 1.7 Hz), 6.89 (2H, d, J = 9.4 Hz), 8.08 (2H, d, J
3
s). 13C NMR (75 MHz, CDCl3) δ: 16.3 (d, JCP = 5.8 Hz), 16.5 (d,
3
3
3JCP = 5.8 Hz), 43.9 (d, JCP = 2.3 Hz), 48.4, 63.6 (d, JCP = 9.2 Hz),
64.8 (d, 2JCP = 6.9 Hz), 71.1 (d, 1JCP = 163.8 Hz), 123.0, 130.5, 138.5,
= 9.4 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.2 (d, JCP = 5.8 Hz),
3
149.0, 167.4. 31P NMR (121 MHz, CDCl3) δ: 16.59. IR (cm−1) νmax
:
16.4 (d, 3JCP = 5.8 Hz), 44.3 (d, 3JCP = 3.5 Hz), 48.4, 55.2, 62.8 (d, 3JCP
= 9.2 Hz), 64.3 (d, 2JCP = 6.9 Hz), 64.5 (d, 2JCP = 6.9 Hz), 71.1 (d, 1JCP
1011 (P−O), 1041 (P−O), 1266 (PO), 1342 (N−O), 1518 (N−
O), 1594, 2980. MS (ESI, pos): m/z 409.0/410.0/411.0 (M + H+,
100/16/64). HRMS: m/z calcd for C15H20Cl2N2O5P (M + H)+
409.0481, found 409.0483. Melting point range: 108.0−109.0 °C.
= 163.8 Hz), 113.2, 124.8, 131.0, 161.5, 167.8 (d, JCP = 2.3 Hz). 31P
2
NMR (121 MHz, CDCl3) δ: 17.48. IR (cm−1) νmax: 1012 (P−O),
1177 (P−O), 1252 (PO), 1513, 1606, 2978. MS (ESI, pos): m/z
8238
dx.doi.org/10.1021/jo401185u | J. Org. Chem. 2013, 78, 8232−8241

The Journal of Organic Chemistry
Featured Article
3
3
3
Diethyl (cis-4-Chloro-3-(chloromethyl)-5-(4-cyanophenyl)-3,4-di-
hydro-2H-pyrrol-4-yl)phosphonate 11j. 0.85 g (2.18 mmol) of 8j was
converted into 11j. After one crystallization, 0.12 g of product was
obtained in a dr of 95/5 (0.31 mmol, 14% yield, transparent crystals).
1H NMR (300 MHz, CDCl3) δ: 1.21 (3H, t, J = 7.2 Hz), 1.32 (3H, t, J
= 6.9 Hz), 3.24−3.37 (1H, m), 3.66 (1H, dd, J = 10.5 Hz, J = 10.5
Hz), 3.96−4.24 (6H, m), 4.48 (1H, dd, J = 17.6 Hz, J = 7.2 Hz), 7.69
(2H, d, J = 8.3 Hz), 8.19 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz,
CDCl3) δ: 16.3 (d, 3JCP = 5.8 Hz), 16.5 (d, 3JCP = 4.6 Hz), 44.0 (d, 3JCP
(d, JCP = 3.5 Hz), 62.4 (d, JCP = 5.8 Hz), 62.6 (d, JCP = 5.8 Hz),
128.3, 130.2, 132.5, 136.7, 172.1 (d, JCP = 8.1 Hz). 31P NMR (121
2
MHz, CDCl3) δ: 22.74. IR (cm−1) νmax: 1020 (P−O), 1048 (P−O),
1247 (PO), 1596, 2984. MS (ESI, pos): m/z 328.3/330.3/329.3 (M
+ H+, 100/32/17). HRMS: m/z calcd for C15H20ClNO3P (M + H)+
328.0864, found 328.0868. Chromatography: EtOAc, Rf = 0.09.
Diethyl (2-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hex-2-en-1-yl)-
phosphonate 14e. 1.13 g (2.87 mmol) of 11e was converted into
14e. After column chromatography, 0.47 g of product was obtained
3
2
1
= 2.3 Hz), 48.4, 63.6 (d, JCP = 9.2 Hz), 64.8 (d, JCP = 6.9 Hz), 71.1
(1.46 mmol, 51% yield, brown oil). H NMR (300 MHz, CDCl3) δ:
0.81−0.87 (1H, m), 1.20 (6H, t, J = 7.5 Hz), 1.74 (1H, ddd, JHP
14.6 Hz, J = 8.5 Hz, J = 4.4 Hz), 2.56−2.66 (1H, m), 3.84 (3H, s),
3.93−4.03 (4H, m), 4.06 (2H, m), 6.91 (2H, d, J = 8.8 Hz), 7.91 (2H,
d, J = 8.8 Hz). 13C NMR (75 MHz, CDCl3) δ: 15.9 (d, J = 4.6 Hz),
(d, JCP = 166.1 Hz), 114.2, 118.5, 130.1, 131.7, 136.7, 167.6. 31P
1
3
=
NMR (121 MHz, CDCl3) δ: 16.67. IR (cm−1) νmax: 1011 (P−O),
1039 (P−O), 1266 (PO), 2230 (CN), 2984. MS (ESI, pos): m/z
389.0/390.0/391.0 (M + H+, 100/17/64). HRMS: m/z calcd for
C16H20Cl2N2O3P (M + H)+ 389.0583, found 389.0595. Melting point
range: 111.0−112.5 °C.
1
16.0 (d, J = 4.6 Hz), 18.7, 28.5, 33.4 (d, JCP = 199.6 Hz), 54.9, 60.5
3
2
2
(d, JCP = 3.5 Hz), 61.8 (d, JCP = 6.9 Hz), 62.1 (d, JCP = 6.9 Hz),
113.0, 126.5, 130.2, 161.2, 171.8 (d, JCP = 6.9 Hz). 31P NMR (121
2
Synthesis of Diethyl (2-Phenyl-3-azabicyclo[3.1.0]hex-2-en-
1-yl)phosphonates 14a−j. In a round-bottom flame-dried flask and
under a N2-atmosphere were dissolved diethyl (cis-4-chloro-3-
(chloromethyl)-5-phenyl-3,4-dihydro-2H-pyrrol-4-yl)phosphonates
11a−j in dry THF (1 mL/mmol). The solution was cooled to −78 °C,
and n-BuLi (1.2 equiv, however for 14j 2.2 equiv was used) was added
in a dropwise fashion. The reaction mixture was kept at −78 °C for 2 h
and was then slowly warmed to room temperature. Water was added,
and the solution was extracted with diethyl ether (3 × 10 mL). After
the combined organic layers were dried over MgSO4, the solvent was
removed in vacuo and the residue was purified using column
chromatography.
MHz, CDCl3) δ: 23.26. IR (cm−1) νmax: 1018 (P−O), 1174(P−O),
1249 (PO), 1514, 1607, 2918, 3429. MS (ESI, pos): m/z 324.3/
325.3(M + H+, 100/17). HRMS: m/z calcd for C16H23NO4P (M +
H)+ 324.1359, found 324.1359. Chromatography: EtOAc, Rf = 0.08.
Diethyl (2-(4-Methylphenyl)-3-azabicyclo[3.1.0]hex-2-en-1-yl)-
phosphonate 14f. 2.70 g (7.14 mmol) of 11f was converted into
14f. After column chromatography, 1.18 g of product was obtained
1
(3.86 mmol, 54% yield, brown oil). H NMR (300 MHz, CDCl3) δ:
0.83−0.88 (1H, m), 1.14−1.26 (6H, m), 1.74 (1H, ddd, JHP = 14.3
Hz, J = 8.3 Hz, J = 4.4 Hz), 2.38 (3H, s), 2.61 (1H, m), 3.92−4.04
(4H, m), 4.04−4.12 (2H, m), 7.20 (d, J = 8.0 Hz), 7.82 (d, J = 8.0
Hz). 13C NMR (75 MHz, CDCl3) δ: 16.2 (d, 3JCP = 5.8 Hz), 16.3 (d,
3JCP = 5.8 Hz), 19.2, 21.5, 28.7, 33.9 (d, 1JCP = 201.9 Hz), 61.1 (d, 3JCP
= 3.5 Hz), 62.2 (d, JCP = 5.8 Hz), 62.4 (d, JCP = 5.8 Hz), 128.7,
131.3, 140.7, 173.0 (d, 2JCP = 8.1 Hz). 31P NMR (121 MHz, CDCl3) δ:
23.18. IR (cm−1) νmax: 1024 (P−O), 1050(P−O), 1248 (PO), 1594,
2922. MS (ESI, pos): m/z 308.3/309.3 (M + H+, 100/18). HRMS: m/
z calcd for C16H23NO3P (M + H)+ 308.1410, found 308.1411.
Chromatography: EtOAc, Rf = 0.09.
Diethyl (2-([1,1′-Biphenyl]-4-yl)-3-azabicyclo[3.1.0]hex-2-en-1-
yl)phosphonate 14g. 1.84 g (4.18 mmol) of 11g was converted
into 14g. After column chromatography, 0.56 g of product was
3
Diethyl (2-Phenyl-3-azabicyclo[3.1.0]hex-2-en-1-yl)phosphonate
14a. 2.50 g (6.86 mmol) of 11a was converted into 14a. After column
chromatography, 1.53 g of product was obtained (5.21 mmol, 76%
2
2
1
yield, brown oil). H NMR (300 MHz, CDCl3) δ: 0.84−0.90 (1H,
∼q), 1.17 (3H, t, J = 7.2 Hz), 1.20 (3H, t, J = 7.2 Hz), 1.76 (1H, ddd,
3JHP = 14.6 Hz, J = 8.5 Hz, J = 4.7 Hz), 2.58−2.69 (1H, m), 3.91−4.03
(4H, m), 4.10 (2H, ∼t), 7.37−7.44 (3H, m), 7.91 (2H, d, J = 6.6 Hz).
13C NMR (75 MHz, CDCl3) δ: 16.2 (d, 3JCP = 4.6 Hz), 16.3 (d, 3JCP
=
5.8 Hz), 19.2, 28.7, 34.0 (d, 1JCP = 199.6 Hz), 61.3 (d, 3JCP = 3.5 Hz),
2
2
62.2 (d, JCP = 5.8 Hz), 62.4 (d, JCP = 6.9 Hz), 128.0, 128.7, 130.5,
134.1, 173.1 (d, 2JCP = 8.1 Hz). 31P NMR (121 MHz, CDCl3) δ: 22.91.
IR (cm−1) νmax: 1022 (P−O), 1049 (P−O), 1247 (PO), 1596, 2982.
MS (ESI, pos): m/z 294.3/295.3 (M + H+, 100/16). HRMS: m/z
calcd for C15H21NO3P (M + H)+ 294.1254, found 294.1264.
Chromatography: EtOAc, Rf = 0.06.
1
obtained (1.50 mmol, 30% yield, brown oil). H NMR (300 MHz,
CDCl3) δ: 0.85−0.92 (1H, ∼q), 1.21 (6H, t, J = 7.6 Hz), 1.78 (1H,
3
ddd, JHP = 14.2 Hz, J = 8.9 Hz, J = 4.8 Hz), 2.58−2.71 (1H, m),
3.95−4.07 (4H, m), 4.10−4.13 (2H, ∼t), 7.34−7.38 (1H, m), 7.45
(2H, dd, J = 7.3 Hz, J = 7.3 Hz), 7.64 (4H, d, J = 8.3 Hz), 8.01 (2H, d,
Diethyl (2-(4-Fluorophenyl)-3-azabicyclo[3.1.0]hex-2-en-1-yl)-
phosphonate 14b. 0.18 g (0.47 mmol) of 11b was converted into
14b. After column chromatography, 72 mg of product was obtained
J = 7.3 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.3 (d, JCP = 5.8 Hz),
3
16.4 (d, 3JCP = 5.8 Hz), 19.3, 28.8, 33.9 (d, JCP = 199.6 Hz), 61.3 (d,
1
1
(0.23 mmol, 49% yield, brown oil). H NMR (300 MHz, CDCl3) δ:
3JCP = 3.5 Hz), 62.3 (d, 2JCP = 5.8 Hz), 62.5 (d, 2JCP = 5.8 Hz), 126.7,
0.83−0.89 (1H, m), 1.18 (3H, t, J = 7.5 Hz) 1.21 (3H, t, J = 7.5 Hz),
1.75 (1H, ddd, 3JHP = 14.5 Hz, J = 8.4 Hz, J = 4.3 Hz), 2.54−2.69 (1H,
m), 3.93−4.05 (4H, m), 4.08 (2H, ∼t), 7.09 (2H, dd, J = 8.8 Hz, 3JFH
2
127.2, 127.8, 128.9, 129.3, 133.0, 140.5, 143.2, 172.8 (d, JCP = 8.1
Hz). 31P NMR (121 MHz, CDCl3) δ: 23.02. IR (cm−1) νmax:1021 (P−
O), 1045 (P−O), 1246 (PO), 1594, 2982. MS (ESI, pos): m/z
370.3/371.3 (M + H+, 100/23). HRMS: m/z calcd for C21H25NO3P
(M + H)+ 370.1567, found 370.1563. Chromatography: EtOAc, Rf =
0.10.
4
= 8.8 Hz), 7.94 (2H, dd, J = 8.8 Hz, JHF = 5.5 Hz). 13C NMR (75
MHz, CDCl3) δ: 16.3 (d, 3JCP = 5.2 Hz), 16.3 (d, 3JCP = 5.2 Hz), 19.2,
28.9, 33.9 (d, 1JCP = 200.8 Hz), 61.2 (d, 3JCP = 3.5 Hz), 62.3 (d, 2JCP
=
2
2
5.8 Hz), 62.5 (d, JCP = 5.8 Hz), 115.1 (d, JCF = 21.9 Hz), 130.3 (d,
3
1
4JCF = 2.3 Hz), 130.9 (d, JCF = 8.1 Hz), 164.3 (d, JCF = 250.4 Hz),
Diethyl (2-(3-Methoxyphenyl)-3-azabicyclo[3.1.0]hex-2-en-1-yl)-
phosphonate 14h. 1.72 g (4.36 mmol) of 11h was converted into
14h. After column chromatography, 1.01 g of product was obtained
172.0 (d, 2JCP = 8.1 Hz). 19F NMR (282 MHz, CDCl3) δ: −109.92 to
−109.82 (m). 31P NMR (121 MHz, CDCl3) δ: 22.83. IR (cm−1) νmax
:
1
(3.14 mmol, 72% yield, brown oil). H NMR (300 MHz, CDCl3) δ:
1019 (P−O), 1047 (P−O), 1229 (PO), 1510, 2984. MS (ESI, pos):
m/z 312.3/313.3 (M + H+, 100/17). HRMS: m/z calcd for
C15H20FNO3P (M + H)+ 312.1159, found 312.1165. Chromatog-
raphy: EtOAc, Rf = 0.09.
0.86 (1H, ∼q), 1.18 (3H, t, J = 7.3 Hz), 1.20 (3H, t, J = 7.3 Hz), 1.75
(1H, ddd, 3JHP = 14.7 Hz, J = 8.4 Hz, J = 4.3 Hz), 2.57−2.69 (1H, m),
3.86 (3H, s), 3.93−4.04 (4H, m), 4.08 (2H, ∼t), 6.99 (1H, dd, J = 8.1
Hz, J = 2.8 Hz), 7.31 (1H, dd, J = 8.1 Hz, J = 8.1 Hz), 7.48−7.54 (2H,
m). 13C NMR (75 MHz, CDCl3) δ: 16.3 (d, 3JCP = 5.8 Hz), 19.2, 28.9,
Diethyl (2-(4-Chlorophenyl)-3-azabicyclo[3.1.0]hex-2-en-1-yl)-
phosphonate 14c. 0.15 g (0.38 mmol) of 11c was converted into
14c. After column chromatography, 41 mg of product was obtained
34.0 (d, 1JCP = 200.8 Hz), 55.4, 61.3 (d, 3JCP = 3.5 Hz), 62.2 (d, 2JCP
=
2
1
6.9 Hz), 62.5 (d, JCP = 6.9 Hz), 113.3, 117.1, 121.3, 129.0, 135.3,
152.3, 173.0 (d, 2JCP = 6.9 Hz). 31P NMR (121 MHz, CDCl3) δ: 22.97.
IR (cm−1) νmax: 1018 (P−O), 1238 (PO), 1327, 1575, 2981. MS
(ESI, pos): m/z 324.3/325.3 (M + H+, 100/16). HRMS: m/z calcd for
C16H23NO4P (M + H)+ 324.1359, found 324.1361. Chromatography:
EtOAc, Rf = 0.18.
(0.13 mmol, 33% yield, brown oil). H NMR (300 MHz, CDCl3) δ:
0.81−0.88 (1H, m), 1.18 (3H, t, J = 7.2 Hz), 1.22 (3H, t, J = 7.2 Hz),
1.75 (1H, ddd, 3JHP = 14.5 Hz, J = 8.4 Hz, J = 4.4 Hz), 2.58−2.69 (1H,
m), 3.93−4.05 (4H, m), 4.09 (2H, ∼t), 7.38 (2H, d, J = 8.5 Hz), 7.87
(2H, d, J = 8.5 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.3 (d, 3JCP = 5.8
Hz), 16.4 (d, 3JCP = 5.8 Hz), 19.2, 28.9, 33.9 (d, 1JCP = 199.6 Hz), 61.3
8239
dx.doi.org/10.1021/jo401185u | J. Org. Chem. 2013, 78, 8232−8241

The Journal of Organic Chemistry
Featured Article
Diethyl (2-(4-Nitrophenyl)-3-azabicyclo[3.1.0]hex-2-en-1-yl)-
phosphonate 14i. 0.38 g (0.94 mmol) of 11i was converted into
14i. After column chromatography, 64 mg of product was obtained
Diethyl ((1S*,2S*,5R*)-2-(4-Chlorophenyl)-3-azabicyclo[3.1.0]-
hexan-1-yl)phosphonate 1c. 0.20 g (0.61 mmol) of 14c was
converted into 1c. 0.17 g of product was obtained (0.52 mmol, 85%
yield, yellow oil). 1H NMR (300 MHz, CDCl3) δ: 1.05 (3H, d, J = 7.2
Hz), 1.11−1.29 (3H, m, 2H, m), 2.00 (1H, m), 2.53 (1H, br s), 3.15
(2H, br s), 3.72−4.05 (4H, m), 4.49 (1H, d, 3JHP = 3.9 Hz), 7.27−7.31
(2H, m), 7.41−7.44 (2H, m). 13C NMR (75 MHz, CDCl3) δ: 8.4, 16.1
1
(0.19 mmol, 20% yield, brown oil). H NMR (300 MHz, CDCl3) δ:
0.87−0.93 (1H, m), 1.19 (3H, t, J = 6.9 Hz), 1.23 (3H, t, J = 7.2 Hz),
1.80 (1H, ddd, 3JHP = 13.9 Hz, J = 8.1 Hz, J = 4.3 Hz), 2.69 (1H, m),
3.95−4.08 (4H, m), 4.16 (2H, ∼t), 8.10 (2H, d, J = 8.5 Hz), 8.27 (2H,
d, J = 8.5 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.3 (d, 3JCP = 5.8 Hz),
16.4 (d, 3JCP = 6.9 Hz), 19.3, 29.0, 34.1 (d, 1JCP = 201.9 Hz), 61.9, 62.5
1
(d, 3JCP = 5.8 Hz), 16.5 (d, 3JCP = 5.8 Hz), 24.8, 25.7 (d, JCP = 198.5
Hz), 47.5, 61.8 (d, 3JCP = 5.8 Hz), 62.0 (d, 3JCP = 5.8 Hz), 62.1 (d, 2JCP
= 11.5 Hz), 128.2, 129.4, 133.4, 138.3. 31P NMR (121 MHz, CDCl3)
δ: 28.32. IR (cm−1) νmax: 1014 (P−O), 1021 (P−O), 1232 (PO),
1491, 2924, 3423. MS (ESI, pos): m/z 330.3/331.3/332.3(M + H+,
100/17/32). HRMS: m/z calcd for C15H22ClNO3P (M + H)+
330.1021, found 330.1024.
2
(d, 2JCP = 5.8 Hz), 62.7 (d, JCP = 5.8 Hz), 123.3, 129.8, 139.9, 150.0,
2
171.5 (d, JCP = 9.2 Hz). 31P NMR (121 MHz, CDCl3) δ: 22.17. IR
(cm−1) νmax: 1018 (P−O), 1047 (P−O), 1248 (PO), 1325 (N−O),
1519 (N−O), 1586, 2983. MS (ESI, pos): m/z 339.3/340.3 (M + H+,
100/16). HRMS: m/z calcd for C15H20N2O5P (M + H)+ 339.1104,
found 339.1114. Chromatography: EtOAc, Rf = 0.21.
Diethyl ((1S*,2S*,5R*)-2-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]-
hexan-1-yl)phosphonate 1e. 87 mg (0.27 mmol) of 14e was
converted into 1e. 81 mg of product was obtained (0.25 mmol, 92%
yield, yellow oil). 1H NMR (300 MHz, CDCl3) δ: 1.03 (3H, t, J = 7.2
Hz), 1.19−1.33 (3H, t, J = 7.2 Hz, 2H, m), 1.96−2.04 (1H, m), 3.15,
Diethyl (2-(4-Pentanoylphenyl)-3-azabicyclo[3.1.0]hex-2-en-1-
yl)phosphonate 14j. 0.44 g (1.13 mmol) of 11j was converted into
14j. After column chromatography, 0.15 g of product was obtained
1
(0.41 mmol, 36% yield, brown oil). H NMR (300 MHz, CDCl3) δ:
3
3.71−4.09 (4H, m), 3.80 (3H, s), 4.52 (1H, d, JHP = 4.4 Hz), 6.86
0.86−0.92 (1H, m), 0.96 (3H, t, J = 7.4 Hz), 1.17 (3H, t, J = 7.3 Hz),
1.21 (3H, t, J = 7.3 Hz), 1.41 (2H, sext, J = 7.4 Hz), 1.73 (2H, quint, J
= 7.4 Hz), 1.78−1.83 (1H, m), 2.61−2.71 (1H, m), 2.99 (2H, t, J = 7.4
Hz), 3.92−4.05 (4H, m), 4.14 (2H, d, J = 3.9 Hz), 7.99 (4H, s). 13C
NMR (75 MHz, CDCl3) δ: 14.0, 16.3 (d, 3JCP = 6.9 Hz), 16.4 (d, 3JCP
(2H, d, J = 8.3 Hz), 7.41 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz,
3
3
CDCl3) δ: 8.6, 16.1 (d, JCP = 6.9 Hz), 16.5 (d, JCP = 6.9 Hz), 24.3,
25.5 (d, 1JCP = 198.5 Hz), 47.3, 55.3, 61.8 (d, JCP = 5.8 Hz), 62.1 (d,
2
2JCP = 5.8 Hz), 62.5 (d, 2JCP = 11.5 Hz), 113.6, 129.2, 130.6, 159.4. 31
P
1
NMR (121 MHz, CDCl3) δ: 27.95. IR (cm−1) νmax: 1019 (P−O),
1177(P−O), 1249 (PO), 1514, 1607, 2918, 3429. MS (ESI, pos):
m/z 326.3/327.3 (M + H+, 100/18). HRMS: m/z calcd for
C16H25NO4P (M + H)+ 326.1516, found 326.1521.
= 6.9 Hz), 19.2, 22.5, 26.4, 28.9, 34.1 (d, JCP = 200.8 Hz), 38.6, 61.7
3
2
2
(d, JCP = 3.5 Hz), 62.4 (d, JCP = 5.8 Hz), 62.6 (d, JCP = 5.8 Hz),
127.8, 129.0, 138.1, 138.3, 172.5 (d, JCP = 9.2 Hz), 200.3. 31P NMR
2
(121 MHz, CDCl3) δ: 22.56. IR (cm−1) νmax: 1024 (P−O), 1249 (P
O), 1684 (CO), 2931. MS (ESI, pos): m/z 378.3/379.3 (M + H+,
100/16). HRMS: m/z calcd for C20H29NO4P (M + H)+ 378.1829,
found 378.1835. Chromatography: EtOAc, Rf = 0.16.
Diethyl ((1S*,2S*,5R*)-2-(4-Methylphenyl)-3-azabicyclo[3.1.0]-
hexan-1-yl)phosphonate 1f. 75 mg (0.24 mmol) of 14f was
converted into 1f. 47 mg of product was obtained (0.15 mmol, 63%
yield, yellow oil). 1H NMR (300 MHz, CDCl3) δ: 1.03 (3H, t, J = 6.9
Hz), 1.21−1.30 (3H, t, J = 7.2 Hz, 2H, m), 1.91−2.21 (2H, m), 2.33
Synthesis of Diethyl (2-Phenyl-3-azabicyclo[3.1.0]hexan-1-
yl)phosphonates 1a−j. Diethyl (2-phenyl-3-azabicyclo[3.1.0]hex-2-
en-1-yl)phosphonates 14a−j were dissolved in MeOH (1 mL/mmol).
Then NaCNBH3 (1.05 equiv) and HOAc (1.05 equiv) were added.
The reaction progress was monitored using HPLC. After all starting
material had been consumed, the reaction mixture was poured into
aqueous NaHCO3 and extracted with diethyl ether (3 × 10 mL). The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. All compounds were obtained in a dr of ≥99/1.
3
(3H, s), 3.15 (2H, br s), 3.67−4.05 (4H, m), 4.50 (1H, d, JHP = 3.9
Hz), 7.12 (2H, d, J = 8.0 Hz), 7.36 (2H, d, J = 8.0 Hz). 13C NMR (75
3
MHz, CDCl3) δ: 8.5, 16.1 (d, 3JCP = 6.9 Hz), 16.5 (d, JCP = 6.9 Hz),
3
21.2, 24.9, 25.7 (d, 1JCP = 197.3 Hz), 47.7 (d, JCP = 3.5 Hz), 61.7 (d,
2JCP = 6.9 Hz), 61.9 (d, 2JCP = 5.8 Hz), 62.8 (d, 2JCP = 10.4 Hz), 127.8,
128.9, 136.4, 137.5. 31P NMR (121 MHz, CDCl3) δ: 28.62. IR (cm−1)
νmax: 1020 (P−O), 1177(P−O), 1236 (PO), 1443, 2978. MS (ESI,
pos): m/z 310.3/311.3 (M + H+, 100/18). HRMS: m/z calcd for
C16H25NO3P (M + H)+ 310.1567, found 310.1569.
Diethyl ((1S*,2S*,5R*)-2-Phenyl-3-azabicyclo[3.1.0]hexan-1-yl)-
phosphonate 1a. 87 mg (0.32 mmol) of 14a was converted into
1a. 79 mg of product was obtained (0.27 mmol, 84% yield, yellow oil).
1H NMR (300 MHz, CDCl3) δ: 1.00 (3H, t, J = 7.2 Hz), 1.19−1.32
Diethyl ((1S*,2S*,5R*)-2-([1,1′-Biphenyl]-4-yl)-3-azabicyclo-
[3.1.0]hexan-1-yl)phosphonate 1g. 0.12 g (0.32 mmol) of 14g was
converted into 1g. 0.11 g of product was obtained (0.30 mmol, 91%
yield, pale yellow solid). 1H NMR (300 MHz, CDCl3) δ: 1.03 (3H, t, J
= 7.2 Hz), 1.28 (3H, t, J = 7.2 Hz, 2H, m), 1.99−2.09 (1H, m), 3.19
(2H, d, J = 1.7 Hz), 3.73−4.14 (4H, m), 4.58 (1H, d, 3JHP = 4.4 Hz),
7.21−7.26 (1H, m), 7.32−7.37 (1H, m), 7.42−7.47 (2H, m), 7.56
(2H, s), 7.56−7.60 (3H, m). 13C NMR (75 MHz, CDCl3) δ: 8.5, 16.1
(3H, t, J = 7.2 Hz, 2H, m), 1.97−2.06 (1H, m), 2.09 (1H, br s), 3.16
3
(2H, s), 3.64−4.05 (4H, m), 4.52 (d, JHP = 3.9 Hz), 7.27−7.34 (3H,
m), 7.48 (2H, d, J = 6.6 Hz). 13C NMR (75 MHz, CDCl3) δ: 8.6, 16.1
3
1
(d, 3JCP = 5.8 Hz), 16.5 (d, JCP = 5.8 Hz), 24.8, 25.8 (d, JCP = 198.5
Hz), 47.7 (d, 3JCP = 3.5 Hz), 61.7 (d, 2JCP = 5.8 Hz), 61.9 (d, 2JCP = 6.9
Hz), 63.0 (d, JCP = 10.4 Hz), 127.9, 128.0, 128.2, 139.6. 31P NMR
2
(121 MHz, CDCl3) δ: 28.51. IR (cm−1) νmax: 1019 (P−O), 1056 (P−
O), 1234 (PO), 1366, 2981, 3310. MS (ESI, pos): m/z 296.3/297.3
(M + H+, 100/16). HRMS: m/z calcd for C15H23NO3P (M + H)+
296.1410, found 296.1416.
1
(d, 3JCP = 6.9 Hz), 16.5 (d, 3JCP = 5.8 Hz), 24.9, 25.9 (d, JCP = 198.5
Hz), 47.7 (d, 3JCP = 3.5 Hz), 61.8 (d, 2JCP = 5.8 Hz), 62.0 (d, 2JCP = 5.8
Hz), 62.7 (d, 2JCP = 10.4 Hz), 126.9, 127.1, 127.4, 128.4, 128.9, 138.9,
140.7, 141.0. 31P NMR (121 MHz, CDCl3) δ: 28.59. IR (cm−1)
νmax:1017 (P−O), 1052 (P−O), 1233 (PO), 1484, 2982. MS (ESI,
pos): m/z 372.3/373.3 (M + H+, 100/23). HRMS: m/z calcd for
C21H27NO3P (M + H)+ 372.1723, found 372.1718.
Diethyl ((1S*,2S*,5R*)-2-(4-Fluorophenyl)-3-azabicyclo[3.1.0]-
hexan-1-yl)phosphonate 1b. 0.48 g (1.53 mmol) of 14b was
converted into 1b. 0.36 g of product was obtained (1.13 mmol, 74%
yield, yellow oil). 1H NMR (300 MHz, CDCl3) δ: 1.02 (3H, t, J = 7.2
Hz), 1.25 (3H, t, J = 7.2 Hz, 2H, m), 1.89−2.01 (1H, m), 2.43 (1H, br
Diethyl ((1S*,2S*,5R*)-2-(3-Methoxyphenyl)-3-azabicyclo[3.1.0]-
hexan-1-yl)phosphonate 1h. 88 mg (0.27 mmol) of 14h was
converted into 1h. After column chromtography 26 mg of product was
3
s), 3.11 (2H, br s), 3.66−4.04 (4H, m), 4.47 (1H, d, JHP = 4.4 Hz),
6.98 (2H, dd, J = 8.6 Hz, 3JHF = 8.6 Hz), 7.45 (2H, dd, J = 8.6 Hz, 4JHF
1
obtained (0.08 mmol, 30% yield, yellow oil). H NMR (300 MHz,
3
= 5.5). 13C NMR (75 MHz, CDCl3) δ: 8.0, 15.9 (d, JCP = 6.9 Hz),
CDCl3) δ: 1.04 (3H, t, J = 7.3 Hz), 1.19−1.29 (3H, t, J = 7.3 Hz, 2H,
m), 1.96−2.02 (1H, m), 2.04 (1H, br s), 3.16 (2H, s), 3.69−4.16 (4H,
m), 3.81 (3H, s), 4.51 (d, 3JCP = 4.4 Hz), 6.82 (1H, dd, J = 7.8 Hz, J =
4.5 Hz), 7.05−7.09 (2H, m), 7.23 (1H, dd, J = 7.3 Hz, J = 7.3 Hz). 13C
16.3 (d, 3JCP = 6.9 Hz), 24.6, 25.7 (d, J = 198.5 Hz), 47.3 (d, 3JCP = 3.5
2
Hz), 61.5 (d, J = 6.9 Hz), 61.7 (d, J = 6.9 Hz), 61.9 (d, JCP = 10.4
Hz), 114.6 (d, 2JCF = 21.9 Hz), 129.4 (d, 3JCF = 8.1 Hz), 135.6 (d, 4JCF
= 2.3 Hz), 162.2 (d, 1JCF = 245.8 Hz). 19F NMR (282 MHz, CDCl3) δ:
−115.20 to −115.11. 31P NMR (121 MHz, CDCl3) δ: 28.42. IR
(cm−1) νmax: 1021 (P−O), 1058 (P−O), 1231 (PO), 1508, 2982.
MS (ESI, pos): m/z 314.3/315.3 (M + H+, 100/17). HRMS: m/z
calcd for C15H22FNO3P (M + H)+ 314.1316, found 314.1325
NMR (75 MHz, CDCl3) δ: 8.6, 16.1 (d, 3JCP = 6.9 Hz), 16.5 (d, 3JCP
=
5.8 Hz), 25.0, 25.7 (d, 1JCP = 197.3 Hz), 47.7 (d, 3JCP = 3.5 Hz), 55.3,
2
2
2
61.7 (d, JCP = 6.9 Hz), 61.9 (d, JCP = 5.8 Hz), 62.9 (d, JCP = 10.4
Hz), 113.2, 113.7, 120.2, 129.1, 141.3, 159.5. 31P NMR (121 MHz,
CDCl3) δ: 28.53. IR (cm−1) νmax: 1020 (P−O), 1232 (PO), 1438,
8240
dx.doi.org/10.1021/jo401185u | J. Org. Chem. 2013, 78, 8232−8241

The Journal of Organic Chemistry
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1602, 2981, 3308. MS (ESI, pos): m/z 326.3/327.3 (M + H+, 100/17).
HRMS: m/z calcd for C16H25NO4P (M + H)+ 326.1516, found
326.1512. Chromatography: EtOAc, Rf = 0.08.
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Diethyl ((1S*,2S*,5R*)-2-(4-Nitrophenyl)-3-azabicyclo[3.1.0]-
hexan-1-yl)phosphonate 1i. 70 mg (0.21 mmol) of 14i was
converted into 1i. After column chromtography 58 mg of product
was obtained (0.17 mmol, 81% yield, yellow oil). 1H NMR (300 MHz,
CDCl3) δ: 1.06 (3H, t, J = 7.2 Hz), 1.13−1.21 (2H, m), 1.28 (3H, t, J
= 7.2 Hz), 1.85 (1H, br s), 2.03−2.11 (1H, m), 3.22 (2H, br s), 3.74−
3
4.09 (4H, m), 4.63 (1H, d, JHP = 4.4 Hz), 7.69 (2H, d, J = 8.8 Hz),
8.18 (2H, d, J = 8.8 Hz). 13C NMR (75 MHz, CDCl3) δ: 8.5, 16.2 (d,
3JCP = 6.9 Hz), 16.5 (d, 3JCP = 6.9 Hz), 25.0, 26.1 (d, 1JCP = 200.8 Hz),
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2653251 A1 19770608.
3
2
2
47.4 (d, JCP = 3.5 Hz), 61.9 (d, JCP = 6.9 Hz), 62.0, 62.1 (d, JCP
=
(11) Alvaro, G.; Cardullo, F.; Castiglioni, E. PCT Int. Appl. 2010, WO
2010007032 A1 20100121.
6.9 Hz), 123.3, 129.0, 147.6, 147.9. 31P NMR (121 MHz, CDCl3) δ:
27.72. IR (cm−1) νmax: 1023 (P−O), 1238 (PO), 1347 (N−O),
1520 (N−O), 2982, 3303. MS (ESI, pos): m/z 341.3/342.3 (M + H+,
100/17). HRMS: m/z calcd for C15H22N2O5P (M + H)+ 341.1261,
found 341.1265. Chromatography: EtOAc, Rf = 0.07.
(12) Brighty, K. E. US Patent 1992, US 5164402 A 19921117.
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I.; Stevens, C. V. Eur. J. Org. Chem. 2010, 5444.
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Diethyl ((1S*,2S*,5R*)-2-(4-Pentanoylphenyl)-3-azabicyclo-
[3.1.0]hexan-1-yl)phosphonate 1j. 51 mg (0.14 mmol) of 14j was
converted into 1j. After column chromtography 32 mg of product was
1
obtained (0.08 mmol, 60% yield, yellow oil). H NMR (300 MHz,
CDCl3) δ: 0.95 (3H, t, J = 7.5 Hz), 1.02 (3H, t, J = 7.0 Hz), 1.17−1.29
(3H, t, J = 7.0 Hz, 2H, m), 1.41 (2H, sext, J = 7.5 Hz), 1.71 (2H, quint,
J = 7.5 Hz), 1.85 (1H, br s), 1.99−2.09 (1H, m), 2.95 (2H, t, J = 7.5
3
Hz), 3.19 (2H, s), 3.69−4.07 (4H, m), 4.57 (d, JHP = 4.4 Hz), 7.58
(2H, d, J = 8.0 Hz), 7.91 (2H, d, J = 8.0 Hz). 13C NMR (75 MHz,
3
3
CDCl3) δ: 8.5, 14.0, 16.1 (d, JCP = 5.8 Hz), 16.5 (d, JCP = 6.9 Hz),
1
3
22.6, 24.9, 25.9 (d, JCP = 199.6 Hz), 26.7, 38.5, 47.6 (d, JCP = 3.5
2
2
2
Hz), 61.8 (d, JCP = 5.8 Hz), 62.0 (d, JCP = 5.8 Hz), 62.5 (d, JCP
=
11.5 Hz), 128.0, 128.2, 136.6, 145.2, 200.5. 31P NMR (121 MHz,
CDCl3) δ: 28.14. IR (cm−1) νmax: 1025 (P−O), 1238 (PO), 1681
(CO), 2931, 3308. MS (ESI, pos): m/z 380.3/381.3 (M + H+, 100/
17). HRMS: m/z calcd for C20H31NO4P (M + H)+ 380.1985, found
380.1978. Chromatography: EtOAc, Rf = 0.06.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of new compounds as well as H-
1
undecoupled 31P NMR spectra of 11j; crystallographic data for
11i and 11j (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chris.stevens@ugent.be.
■
(29) Masschelein, K. G. R.; Stevens, C. V. Tetrahedron Lett. 2008, 49,
4336.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Research Foundation Flanders (FWO) for
financial support. K.V.H. thanks the Hercules Foundation
(project AUGE/11/029 “3D-SPACE: 3D Structural Platform
Aiming for Chemical Excellence”) for funding. Professor Kristof
Demeestere and Patrick De Wispelaere are gratefully acknowl-
edged for some urgent analyses.
REFERENCES
■
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dx.doi.org/10.1021/jo401185u | J. Org. Chem. 2013, 78, 8232−8241