Comparison of amine-induced cyclization of 6-chloro-1-hexynylphosphonate and isobutyl 7-chlorohept-2-ynoate

Article abstract of DOI:10.1016/j.tet.2009.03.053

The reaction of 6-chloro-1-hexynylphosphonate with primary and secondary amines afforded exclusively 2-aminocyclohexenylphosphonates in 62-85% isolated yields. In contrast, reaction of various amines with isobutyl 7-chlorohept-2-ynoate in acetonitrile at

Full text of DOI:10.1016/j.tet.2009.03.053

Tetrahedron 65 (2009) 4389–4395
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Comparison of amine-induced cyclization of 6-chloro-1-hexynylphosphonate
and isobutyl 7-chlorohept-2-ynoate
,
,
c
,
a
a,
*
Hemant Kumar Srivastava a b, Abed Al Aziz Quntar a , Abdulatif Azab , Morris Srebnik
,
*
,b,
Avital Shurki a
*
a Department of Medicinal Chemistry and Natural Products, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel
b The Lise-Meitner Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel
c Department of Material Engineering, Faculty of Engineering, Al Quds University, East Jerusalem, Abu Dies, Palestinian Authority
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 6-chloro-1-hexynylphosphonate with primary and secondary amines afforded exclu-
sively 2-aminocyclohexenylphosphonates in 62–85% isolated yields. In contrast, reaction of various
amines with isobutyl 7-chlorohept-2-ynoate in acetonitrile at 70 ꢀC gave (E)-sec-butyl 2-(1-alkylpiper-
idin-2-ylidene)acetates in 65–78% isolated yields. Calculations offer an explanation for the difference in
the behavior of the two compounds classes. It is shown that C–C cyclization in the alkyne-phosphonate
group occurs via an initial formation of a zwitterionic intermediate, which is stabilized by both an in-
ductive effect of the phosphonate group and a newly formed hydrogen bond. The alkyne-carboxylate
group, on the other hand, proceeds via enamine formation as a result of the smaller inductive effect of
the carboxylate combined with involvement of an allene-like resonance form. This resonance form both
delocalizes the negative charge in the zwitterionic intermediate making it to be less available for attack,
and affects the geometry thus preventing formation of the stabilizing hydrogen bond. Hence, the
zwitterionic intermediate of the alkyne-carboxylates is less stable leading to formation of an enamine,
which is followed by N–C cyclization to give the azaheterocycles.
Received 8 January 2009
Received in revised form 5 March 2009
Accepted 19 March 2009
Available online 27 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Cyclic chiral
b-enamine esters have been prepared from u-halo-
geno
b
-keto esters with chiral amines.9,29,30,31
Cyclic
various other heterocycles.3–8 Various methods are known for
preparing cyclic -enamino esters, such as from unsaturated esters
b
-enamino esters1,2 are useful compounds for preparing
The addition of amines to 1-alkynylphosphonates32 leads to 2-
amino-1-alkenylphosphonates.33 The latter are useful intermediates
in organic synthesis for the preparation of other phosphorus-con-
taining compounds. They have been used to prepare various phos-
phorylated nitrogen heterocycles34 and the pharmacologically
b
possessing a pendent cyano moiety and B-Ar-9-BBNs in the pres-
ence of a rhodium(I) catalyst,9 by iodine-promoted cyclization of
enamino esters,10 from enol lactones, 4-keto amides, and 5-hydroxy
lactams,11 Knovenagel reactions on lactam-derived acetals,12,13 imino
ethers,14,15 iminium chloride,16 or (alkylthio) alkylidenium salts
followed by decarboxylation.17,18 Other routes include Eschen-
moser’s sulfide-contraction procedure via thiolactams19 and Wittig
reaction of N-sulfonyl lactams,20 application of the intramolecular
aza-Wittig reaction,21 from the formal ring transformation reaction
of lactones,22,23 by reaction of Meldrum’s acid with chloro-
imidates,24 from thiolactams with subsequent conversion to pyr-
important b
-aminophosphonates.35 (E)-2-Diethylaminophosphonate
was prepared in 1963 by Saunders and Simpson by addition of
diethylamine to ethynylphosphonate.36 Chatta and Aguiar reported
in 1973 that the addition of R2NH to 1-alkynylphosphonates pro-
ceeded in high yields to produce mixtures of (Z) and (E)-2-amino-
alkenylphosphonates, the latter presumably due to the high
temperatures employed and also possibly due to the use of a large
excess of amine.37 Acheson et al. in 1986 found that R2NH added to
ethynylphosphonate to form mixtures of (E) and (Z) products.38 In
1964, it was further reported that propynylphosphonate adds sec-
ondary amines to form 2-dialkylamino-1-propenylphosphonates
but in poor yield (10–15%) contaminated with 2,2-bis(dialkylami-
no)propylphosphonate.39 Ionin reported that addition of secondary
amines to 1-alkylnylphosphonates in the presence of Cu(I) salts in
polar solvents gave improved yields and with exclusive (E) selec-
tivity.40 Beletskaya used an Arbuzov reaction of the corresponding
roles,25 from
u-azido-b
-keto esters,26 from N-alkyl lactams.27,28
* Corresponding authors. Tel.: þ972 2 675 7301; fax: þ972 2 675 8201.
E-mail addresses: abedalaziza@ekmd.huji.ac.il (A.A. Aziz Quntar), morris.sreb-
nik@ekmd.huji.ac.il (M. Srebnik), avitalsh@ekmd.huji.ac.il (A. Shurki).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.053

4390
H.K. Srivastava et al. / Tetrahedron 65 (2009) 4389–4395
Table 1
bromo enamine to obtain 2-aminoalkenylphosphonates with
retention of stereochemistry.41 Palacios has prepared 2-amino-1-
alkenylphosphonates by the addition of primary amines to allenyl-
phosphonates.42 He has also prepared them bylithiation of phosphonates
and reaction with nitriles.43 They have also been prepared by re-
action of chloroimines with lithiated methylphosphonate; however,
mixtures of 2-iminophosphonates and 2-aminoalkynylphosphonates
were obtained.44
2-Aminocyclohexenylphosphonates, 2, from 6-chloro-1-hexynylphosphonates and
amines
Entry
Product
Amine
% Isolated
yield (conversion)
1
2
3
4
5
6
7
8
2aa
2bb
2ca
2da
2ec
2fc
Amyl
iso-Propyl
Propyl
Methyl
Benzyl
Pyrrolidine
Piperidine
Ethanolamine
83(>98)
78(>99)
82(>99)
85(>99)
85(>99)
62(>98)
68(>98)
70(>99)
We have recently reported that cyclization of diethyl 5-chloro-
1-pentynylphosphonate with various amines leads exclusively to
aminocyclopentenylphosphonates.45 The reaction proceeds by
unique mechanism involving zwitterionic intermediate.
Lhommet et al. reported in 2002 that mixtures of -amino-
b-
2ga
2ha
a
a
a
Obtained at 25 ꢀC in about 30 min.
Obtained at 0 ꢀC.
Obtained at 60 ꢀC in 4 h.
b
b
c
cyclohexenylcarboxylates and 2-(1-alkylpiperidin-2-ylidene)ace-
tates were always obtained from 7-chlorohept-2-ynoates and
amines.46 They interpreted the results on the basis of an in-
termediate b-enamino ester that either C or N ring closed. These
consistent with a cyclohexene ring. Further support for the cylo-
hexene ring was obtained from 13C NMR spectra, which showed
two doublets for C1 in the region 69.9–72.9 ppm and for C2 at
160.8–163.1 ppm due to splitting by phosphorus. GC/MS and
combustion analysis were consistent with the assigned structures.
In order to obtain an acid-stable product, we reduced the double
bond in compound 2a. The reagent of choice for the reduction was
NaBH4 in ethanol at 0 ꢀC, which proceeded to afford the product
trans-diethyl 2-(pentylamino)cyclohexylphosphate 3 in 95% yield
(Eq. 2).
results and our own results prompted us to compare cyclizations of
6-chloro-1-hexynylphosphonate and isobutyl 7-chlorohept-2-
ynoate with primary and secondary amines. We here report that
diethyl 2-(dialkylamino)cyclohex-1-enylphosphonates 2 (a pre-
viously unreported group of compounds) are exclusively obtained
from 6-chloro-1-hexynylphosphonate with primary and secondary
amines, and (E)-sec-butyl 2-(1-alkylpiperidin-2-ylidene)acetates 5
are the sole isolated products from the reaction of 7-chlorohept-2-
ynoate and primary amines. Calculations give insight into the
mechanisms of these cyclizations.
OEt
OEt
OEt
NaBH4
OEt
P
2. Results and discussion
2.1. Synthesis of 2
P
ð2Þ
O
NH
2a
O
NH
3
95%
Diethyl 6-chloro-1-hexynylphosphonate was prepared from 6-
chloro-1-hexyne by lithiation with n-BuLi followed by reaction
with diethyl chlorophosphate as previously described.45 When
diethyl 6-chlorohex-1-ynylphosphonate was reacted with amyl-
amine, one product 2a was isolated in 83% yield (Eq. 1). No trace of
the enamino vinylphosphonates could be detected by NMR spec-
troscopy or GC/MS.
In addition to its stability to acid, compound 3 is stable to air,
water, and was isolated by silica gel chromatography. The structure
of 3 and the trans stereochemistry were confirmed by the coupling
constant (10 Hz) between the neighboring hydrogens on C1 and C2,
which were identified by two-dimensional NMR techniques in-
cluding HSQC and COSY.
O
OEt
P
2.2. Synthesis of 5
+
n-C5H11NH2
Cl
P(O)(OEt)2
OEt
In contrast, when isobutyl 7-chlorohept-2-ynoate 5, which was
synthesized from isobutyl chloroforamate and lithiated 6-chloro-1-
hexyne was reacted with 2 equiv of an amine in acetonitrile at 70 ꢀC
for 8 h, (E)-sec-butyl 2-(1-alkylpiperidin-2-ylidene)acetates 5 were
produced (Scheme 1). When the reaction was carried out at 25 ꢀC
using 2 equiv of i-PrNH2, the enamine product 4a was formed and
isolated. Only traces of 5a were detected in the GC/MS, but were not
isolated.
Unlike compound 2, the presence of a singlet in the region
w4.6 ppm in compounds 5 corresponds to a vinylic hydrogen in the
1H NMR. The 13C NMR spectra and GC/MS are consistent with the
heterocycle structure of 5 rather than the cyclohexene ring (com-
pounds 2). As regards 4a, the singlet in the region 4.4 ppm in the 1H
NMR spectra together with the GC/MS data are indicative of its
enamine structure. Under the carboxylate reaction conditions
(acetonitrile, 70 ꢀC, 8 h), the chloroalkynylphosphonate also ex-
clusively gave compound 2a.
HN
1
n-C5H11
2a
X
O
P
OEt
OEt
83%
N
n-C5H11
ð1Þ
This reaction proved to be general for primary and secondary
amines (Table 1). It is carried out under mild conditions at 25 ꢀC
without inorganic additives or the need for metal catalysis. No
special or glove box techniques are required for this cyclization,
which is carried out in screw-capped vials fitted with a magnet. In
addition, this reaction tolerates on hydroxyl group (entry 8) and
water media (entry 4). Compounds 2 are air, water, and thermally
stable, but are sensitive to acid and quickly hydrolyze when ex-
posed to aqueous dilute acid. Thus, the reactions were worked up
with aqueous basic solutions. After extraction by CH2Cl2 the
products are stable to silica gel chromatography, which is the
preferred method of purification and isolation. The structures of 2
were confirmed by GC/MS, 31P, 13C, and 1H NMR spectroscopy, and
elemental analysis. In the 1H NMR spectra, the broad doublets of
triplets in the region 2.64–3.15 ppm, the two neighboring quintets
in the region 1.55–1.90 ppm and the triplets in the region 3.00–
3.32 ppm due to the hydrogens on C6 and C3, respectively, are
2.3. Calculations and mechanisms for formation of 2 and 5
To understand the different behavior of the alkynylphospho-
nates compared with alkynylcarboxylates, we decided to explore
the possible mechanisms of these reactions. Experimentally, an
enamine was observed for the isobutyl 7-chlorohept-2-ynoate

H.K. Srivastava et al. / Tetrahedron 65 (2009) 4389–4395
4391
O
Cl
Cl
O-iBu
O
2 RNH , acetonitrile,
2 i-PrNH2, acetonitrile,
O-iBu
2
O-iBu
N
O
70 °C, 8 h.
25 °C, 8 h.
iPrNH
R
5
4
2 RNH2, acetonitrile,
70 °C, 8 h.
X
O
O-iBu
NHR
Scheme 1. Conditions for the formation of either 4 or 5.
reaction but was not observed for the diethyl 6-chloro-1-hex-
ynylphosphonate reaction. Furthermore, our earlier study of the
ring closure reaction of diethyl 5-chloro-1-pentynylphosphonate
suggested that this system proceeds by an initial formation of
a zwitterion, which then prefers to cyclize rather than to protonate
to give an enamine.45 The additional CH2 group in our diethyl 6-
chloro-1-hexynylphosphonate is unlikely to cause major changes in
the mechanism. We therefore believe that diethyl 6-chloro-1-
hexynylphosphonate follows the same mechanism as suggested for
diethyl 6-chloro-1-hexynylphosphonate (Scheme 2 mechanism A).
Isobutyl 7-chlorohept-2-ynoate, on the other hand, is believed to
remain faithful to the traditional reaction course, which involves
enamine formation followed by N-cyclization in this case (Scheme
2 mechanism B).
To test these proposed mechanisms and understand the
grounds for the difference in the behavior of the two systems, we
turned to calculations (see Experimental section for details).
Compounds 2d and 5b obtained from diethyl 6-chloro-1-hexynyl-
phosphonate and methylamine or isobutyl 7-chlorohept-2-ynoate
and methylamine, respectively, were considered as model systems.
Figure 1 depicts reaction profiles obtained for the two systems
when mechanism A is assumed, namely formation of a zwitterion
intermediate followed by direct cyclization. Figure 1a and b corre-
sponds to the reaction with diethyl 6-chloro-1-hexynyl-
phosphonate and isobutyl 7-chlorohept-2-ynoate, respectively.
Additional results at various calculation levels are given as Sup-
plementary data.
alkylation step. The phosphonate group is a better electron with-
drawing group than the carboxylate (e.g., sm (phosphonate)¼0.55
whereas sm (carboxylate)¼0.37).47 Thus, part of the stabilization
of the zwitterion intermediate in the phosphonate system compared
to that of the carboxylate system may result from the differential
inductive effect caused by these groups. Yet, while certainly being
responsible for part of the stabilization, it is unlikely to account for all
the effect.
To gain more insight and understand the root cause for the
difference, Figure 2 compares the respective geometries of the
zwitterionic intermediates (Int-A1 in Fig. 1) for the two systems.
Figure 2a and b present the intermediate obtained from the al-
kyne-phosphonate and the alkyne-carboxylate groups, re-
spectively. Only parts of the molecule, where major differences
have been observed, are illustrated. Two major differences are
apparent when looking at Figure 2. The first difference relates to
the distance between the amine hydrogen and the oxygen of ei-
ther the P]O and the carbonyl groups, being 1.84 Å and 2.68 Å,
respectively. This distance indicates that the zwitterionic in-
termediate in the phosphonate system enjoys additional stabili-
zation of a hydrogen bonding, which is absent in the case of the
carboxylate system. Together with the larger inductive effect of
the phosphonate group, the relative stability of the zwitterionic
intermediates is clear.
The second difference observed in Figure 2 and further high-
lighted in Scheme 3a relates to the dihedral angles :CCPO com-
pared with :CCCO, which describe the angles between the plain of
the alkene-anion group and the plain of the P]O or carbonyl
groups, respectively. This angle, which is around 0ꢀ in the case of
the alkene-phosphonate becomes around 80ꢀ in the case of alkene-
carboxylate. We note that this large difference does not appear in
the reactants implying that it is a consequence of the zwitterion
formation. In fact, this dihedral angle in the case of the carboxylate
Looking at the results it is clearly seen that the overall barrier for
diethyl 6-chloro-1-hexynylphosphonate cyclization is lower than
that for isobutyl 7-chlorohept-2-ynoate. This trend is consistent and
does not depend on the calculation level. The stabilization of the
phosphonate system is apparent in both steps of the reaction.
Namely, both in the formation of the zwitterion and in the following
EWG
EWG
R1R2NH
R1R2N
Cl
Cl
EWG
EWG
R1R2NH
R1R2NH
H
H
Cl
H
EWG
EWG
EWG=P(O)(OEt)2; C(O)O-iBu
NR1
N
R2
R1
EWG
R1R2N
Scheme 2. Two possible mechanisms of amine-induced ring closure.

4392
H.K. Srivastava et al. / Tetrahedron 65 (2009) 4389–4395
Cl
Cl
(a)
(b)
O-iBu
OEt
C
ClC4H8
O-iBu
CH3HNH
OEt
P
O
TS-A2
ClC4H8
HC
C
C
O
OEt
OEt
CH3HNH
O
TS-A2
C
C
P
30.7
H2NCH3
O
22.6
CH3HNH
TS-A1
19.6
TS-A1
15.6
Int-A1
Int-A1
14.2
Cl
Cl
7.9
OEt
React
ClC4H8
React
O-iBu
OEt
C
O
ClC4H8
P
OEt
OEt
O-iBu
CH3HNH
CH3HNH
C
C
O
C
C
C
P
O
O
Int-A2
CH3HNH
CH3HNH
Cl
-40.5
Int-A2
-50.2
O-iBu
Cl
P
C
OEt
CH3HNH
O
OEt
CH3HNH
O
Figure 1. Calculated energy profile of methylamine addition to (a) diethyl 6-chloro-1-hexynylphosphonate and (b) isobutyl 7-chlorohept-2-ynoate, followed by alkylation according
to mechanism. A. Energies (in kcal/mol) are obtained at the MP4(SDQ)/6-311G
*
//HF/6-31G
*
level of calculation with PCM.
system can be explained if one considers resonance between the
two forms 6 and 7 as depicted in Scheme 3b.
Intermediate 7 contains an allene group. It is well known that
since the p-bonds of allenes are orthogonal, the planes defined by
7-chlorohept-2-ynoate. This path may lead to either N- or C-cy-
clization. Hence, we calculated both C- and N-cyclization of the
corresponding enamine (Fig. 3). Additional results at various levels
of calculations are given in Supplementary data.
their end substituents are also orthogonal. Hence, contribution of 7
to the overall wavefunction of the system is expected to affect the
angle around these carbons. Hence, the angle being w80ꢀ suggests
that the carbon system involves some allene character, which re-
sults from a resonance with 7. On the other hand, the fact that the
corresponding angle in the phosphonate system is around zero
implies that this resonance form does not play an important role in
this case. This in turn leads to an additional explanation for the
higher barrier for the reaction with alkyne-carboxylate compared
to that of the alkyne-phosphonate via mechanism A. In the phos-
phonate system, the negative charge on the alkene-anion remains
relatively localized and ready to complete alkylation. In the car-
boxylate system, on the other hand, this lone pair undergoes de-
localization as a result of the resonance with 7. Therefore, its
availability for the C–Cl attack is reduced resulting in an increased
barrier for the alkylation within mechanism A.
The reaction barrier for N-cyclization is found to be slightly
lower than that for the C-cyclization suggesting agreement with
the experimental results that this will be the preferred product.
These results are consistent at most of the computational levels
tested. Yet, the difference in the calculated barriers is usually very
small. Thus, in contrast to the experimental observation, being
100% azaheterocycle, based on the calculations one would expect
a mixture of both C- and N-cyclization with a strong preference
toward the azaheterocycle product. In fact, Lhommet et al. per-
formed this reaction in the presence of different solvents and ob-
served mixtures of the corresponding azaheterocycle and
cyclohexenylcarboxylate. Their results suggest that the products
largely depend on the system’s environment.46 Thus, in general,
one would expect small differences in the barrier of the two
mechanisms. It is important to note that still, although Lhommet
et al. used the acetylenic methyl esters, azaheterocycles were the
major products when the reaction was carried out in acetonitrile,46
which is consistent with our results. We believe, therefore, that our
results are satisfactory, and in this specific case the too small dif-
ferences are merely an outcome of deficiency in the description of
the solvent effect.
Finally, in order to complete the description one has to consider
the enamine path, which appears to be the choice of isobutyl
O
(a)
O
C
C
P
C
(b)
ClC4H8
ClC4H8
O-iBu
O-iBu
C C
C
O
C
C C
R2R1HN
R2R
1HN
O
7
6
Figure 2. Calculated structures of the zwitterionic intermediates resulting from me-
thylamine addition to (a) diethyl 6-chloro-1-hexynylphosphonate and (b) isobutyl 7-
chlorohept-2-ynoate. Only key atoms are shown.
Scheme 3. (a) Comparison of the dihedral angles :CCPO and :CCCO in the zwit-
terionic form of the phosphonate versus the carboxylate systems, respectively. (b) Two
possible resonance forms of the zwitterionic intermediate of the carboxylate system.

H.K. Srivastava et al. / Tetrahedron 65 (2009) 4389–4395
4393
Cl
(a)
(b)
H
C
H
C
O-iBu
O-iBu
TS
C
CH3NH
NH
O
O
TS
CH3
31.4
Cl
30.6
Int
Cl
2.8
React
H
H
C
Cl
Int
React
O-iBu
H
C
-4.3
O-iBu
H
C
NH
O
O-iBu
O-iBu
C
O
CH3NH
O
C
O
CH3
CH3NH
CH3NH
Cl
Cl
Figure 3. Calculated energy profiles of (a) C-cyclization and (b) N-cyclization of enamine that resulted from methylamine addition to isobutyl 7-chlorohept-2-ynoate. Energies (in
kcal/mol) are obtained at the MP4(SDQ)/6-311G
*
//HF/6-31G level of calculation with PCM.
*
3. Conclusion
2JPC¼21.5 Hz); MS (EI): m/z (%) 303 (10.3), 274 (10.2), 260 (13.0), 246
(34.1), 166 (70.1), 97 (95.4), 95 (100), 82 (19.2), 55 (26.1), 41 (35.5),
29 (48.6). Anal. Calcd for C15H30NO3P: C, 59.38; H, 9.97; N, 4.62; P,
10.21. Found: C, 59.45; H, 10.07; N, 4.53; P, 10.13.
We have developed a simple but effective procedure for pre-
paring 2-aminocyclohexenylphosphonates, 2, from amines (pri-
mary and secondary) and diethyl 6-chloro-1-hexynylphosphonate.
In one case, 2a was reduced to the corresponding trans-2-amino-
cyclohexylphosphonate, 3, a previously unreported class of com-
pounds. In contrast, azaheterocycles 5 are the only compounds
obtained by cyclization of 7-chlorohept-2-ynoate with primary
amines. Calculations suggest formation of 2 directly via a zwitter-
ionic intermediate while the formation of 5 is through enamines 4,
which can be isolated. It is shown that a combination of induction
effects, hydrogen bonding and resonance, leads the systems to
choose the mechanism.
4.2.2. Diethyl 2-(iso-propylamino)cyclohex-1-enylphosphonate 2b
(Table 1, entry 2)
Yield 0.22 g, 78%, yellow oily liquid; 1H NMR (300 MHz, CDCl3):
d
¼1.11, (d, 6H, JHH¼6.3 Hz), 1.30 (t, 6H, JHH¼7.2 Hz), 1.63 (qn, 2H,
JHH¼6.6 Hz), 1.71 (qn, 2H, JHH¼6.3 Hz), 2.76 (dt, 2H, JHH¼6.3 Hz,
3JPH¼1.5 Hz), 3.05 (t, 2H, JHH¼6.3 Hz), 3.62 (m, 1H), 4.02 (qn, 4H,
JHH¼7.2 Hz); 31P NMR (121.4 MHz, CDCl3):
d
¼30.06; 13C NMR
3
(75.5 MHz, CDCl3): 16.2 (d, JPC¼6.9 Hz), 18.7, 19.4, 23.3, 27.6 (d,
2JPC¼5.6 Hz), 39.4, 47.6, 60.5 (d, 2JPC¼5.4 Hz), 70.4 (d,
1JPC¼216.6 Hz), 162.1 (d, JPC¼21.5 Hz); MS (EI): m/z (%) 275 (10.0),
2
4. Experimental
4.1. General
260 (8.7), 232 (12.1), 138 (100), 97 (48.7), 96 (25.8), 82 (17.1), 55
(21.4), 41 (26.6). Anal. Calcd for C13H26NO3P: C, 56.71; H, 9.52; N,
5.09; P, 11.25. Found: C, 56.68; H, 9.58; N, 5.05; P, 11.35.
All reactions were carried out under N2 unless otherwise noted.
All solvents were purified according to standard methods prior to
use. 1H NMR and 13C NMR spectra were recorded in chloroform-d3
on a Bruker 300 MHz.
4.2.3. Diethyl 2-(propylamino)cyclohex-1-enylphosphonate 2c
(Table 1, entry 3)
Yield 0.23 g, 82%, yellow oily liquid; 1H NMR (300 MHz, CDCl3):
d
¼0.87 (t, 3H, JHH¼7.5 Hz), 1.58 (t, 6H, JHH¼7.2 Hz), 1.64 (qn, 2H,
JHH¼6.9 Hz), 1.75 (qn, 2H, JHH¼6.9 Hz), 1.96 (m, 2H), 2.83 (dt, 2H,
3
4.2. Representative procedure for the synthesis of 2
JHH¼7.5 Hz, JPH¼2.1 Hz), 3.16 (t, 2H, JHH¼7.2 Hz), 3.82 (t, 2H,
JHH¼6.6 Hz), 3.95 (qn, 4H, JHH¼7.2 Hz); 31P NMR (121.4 MHz,
4.2.1. Preparation of 4 diethyl 2-(pentylamino)cyclohex-1-
enylphosphonate 2a (Table 1, entry 1)
CDCl3):
d
¼31.78; 13C NMR (75.5 MHz, CDCl3): 13.8, 15.1 (d,
3JPC¼6.8 Hz), 20.1, 21.0, 22.3, 23.4, 27.0, 39.0, 51.0, 60.2 (d,
1
2
To 0.252 g (1 mmol) of diethyl 6-chlorohex-1-ynylphosphonate
was added to 2 mmol of the amine in a 9 mL vial. After stirring for
3 h at ambient temperature, the reaction mixture was washed with
0.1 N NaOH solution, extracted with (2ꢁ20 mL CH2Cl2), and sepa-
rated on silica gel column (10% methanol/90% ethyl acetate), and
was analyzed by GC/MS, elemental analysis, and NMR spectroscopy.
Yield 0.25 g, 83%, yellow oily liquid; 1H NMR (300 MHz, CDCl3):
2JPC¼5.4 Hz), 72.2 (d, JPC¼215.1 Hz), 161.8 (d, JPC¼20.9 Hz); MS
(EI): m/z (%) 275 (14.7), 244 (27.7), 230 (8.7), 218 (8.7), 160 (17.6),
138 (100), 110 (42.2), 97 (68.6), 83 (68.6), 55 (29.9), 41 (55.9). Anal.
Calcd for C13H26NO3P: C, C, 56.71; H, 9.52; N, 5.09; P, 11.25. Found:
C, 56.63; H, 9.61; N, 4.97; P, 11.36.
4.2.4. Diethyl 2-(methylamino)cyclohex-1-enylphosphonate 2d
(Table 1, entry 4)
d
¼0.90 (t, 3H, JHH¼7.2 Hz), 1.31 (t, 6H, JHH¼7.2 Hz), 1.20–1.38
(overlap, 4H), 1.52–1.66 (overlap, 4H), 1.74 (qn, 2H, JHH¼6.3 Hz),
2.75 (dt, 2H, JHH¼6.3 Hz, 3JPH¼1.8 Hz), 3.10 (t, 2H, JHH¼8.1 Hz), 3.16
(t, 2H, JHH¼6.0 Hz), 4.02 (qn, 4H, JHH¼7.2 Hz); 31P NMR (121.4 MHz,
Yield 0.21 g, 85%, yellow oily liquid; 1H NMR (300 MHz, CDCl3):
d
¼1.30 (t, 6H, JHH¼7.2 Hz), 1.62 (qn, 2H, JHH¼6.3 Hz), 1.77 (qn, 2H,
JHH¼6.3 Hz), 2.75 (s, 3H), 2.74 (dt, 2H, JHH¼7.8 Hz, 3JPH¼2.1 Hz), 3.14
CDCl3):
d
¼29.49; 13C NMR (75.5 MHz, CDCl3): 13.7, 16.1 (d,
(t, 2H, JHH¼6.0 Hz), 4.02 (qn, 4H, JHH¼7.2 Hz); 31P NMR (121.4 MHz,
3JPC¼6.9 Hz), 19.5, 22.1, 23.3, 24.5, 27.1 (d, JPC¼4.5 Hz), 29.0, 49.0,
CDCl3):
d
¼29.48; 13C NMR (75.5 MHz, CDCl3): 15.8 (d, 3JPC¼7.2 Hz),
2
2
1
51.7, 60.3 (d, JPC¼5.1 Hz), 69.9 (d, JPC¼216.4 Hz), 160.8 (d,
19.9, 23.3, 26.9 (d, 2JPC¼4.6 Hz), 39.1, 51.0, 60.1 (d, 2JPC¼5.4 Hz), 72.0

4394
H.K. Srivastava et al. / Tetrahedron 65 (2009) 4389–4395
1
2
(d, JPC¼214.9 Hz), 161.5 (d, JPC¼21.2 Hz); MS (EI): m/z (%) 247
(19.3), 232 (3.9), 218 (4.0), 202 (5.2),172 (6.9),126 (4.9),112 (7.7),111
(100), 110 (81.4), 109 (89.2), 108 (18.3), 96 (10.1), 82 (21.4), 68 (12.6),
55 (21.1), 42 (30.1), 28 (40.6). Anal. Calcd for C11H22NO3P: C, 53.43;
H, 8.97; N, 5.66; P, 12.53. Found: C, 53.51; H, 9.04; N, 5.57; P, 12.59.
stirred for 1 h at 0 ꢀC and then it was heated gradually to room
temperature and stirred for additional 2 h. The product was
extracted with (2ꢁ20 mL CH2Cl2), and separated on silica gel col-
umn (10% methanol/90% ethyl acetate), and was analyzed by GC/
MS, elemental analysis, and NMR spectroscopy.
Yield 0.29 g, 95%, yellow oily liquid; 1H NMR (300 MHz, CDCl3):
4.2.5. Diethyl 2-(benzylamino)cyclohex-1-enylphosphonate 2e
(Table 1, entry 5)
d
¼0.88 (t, 3H, JHH¼7.2 Hz), 1.34 (t, 6H, JHH¼6.9 Hz), 1.20–1.38
(overlap, 4H), 1.39–1.66 (overlap, 6H), 1.76–2.04 (overlap, 3H),
Yield 0.28 g, 85%, yellow oily liquid; 1H NMR (300 MHz, CDCl3):
2.28–2.53 (overlap, 2H), 2.90–3.10 (m, 1H, JHH¼10.1 Hz), 4.11 (m,
d
¼1.26 (t, 6H, JHH¼6.9 Hz), 1.71 (qn, 2H, JHH¼6.0 Hz), 1.81 (qn, 2H,
4H); 31P NMR (121.4 MHz, CDCl3):
d
¼32.38; 13C NMR (75.5 MHz,
3
JHH¼6.6 Hz), 2.88 (dt, 2H, JHH¼6.6 Hz, JPH¼2.4 Hz), 3.24 (t, 2H,
JHH¼6.0 Hz), 3.94 (qn, 4H, JHH¼6.0 Hz), 4.35 (s, 2H), 7.15–7.38
CDCl3): 13.6, 16.0 (d, 3JPC¼6.3 Hz), 20.6, 22.2, 23.4 (d, 1JPC¼161.4 Hz),
2
24.7, 25.7, 29.3, 30.1 (d, JPC¼1.7 Hz), 49.0, 53.5, 53.7, 61.1 (d,
(overlap, 5H); 31P NMR (121.4 MHz, CDCl3):
d
¼28.40; 13C NMR
2JPC¼6.9 Hz), MS (EI): m/z (%) 305 (4.9), 276 (2.8), 248 (40.6), 234
(19.2), 168 (11.8), 154 (100), 97 (14.3), 84 (10.6), 41 (8.1). Anal. Calcd
for C15H32NO3P: C, 58.99; H, 10.56; N, 4.59; P, 10.14. Found: C, 59.08;
H, 10.64; N, 4.49; P, 10.07.
3
(75.5 MHz, CDCl3): 16.2 (d, JPC¼6.9 Hz), 19.9, 23.5, 27.5 (d,
2JPC¼4.6 Hz), 49.6, 55.0, 60.5 (d, 2JPC¼5.4 Hz), 72.9 (d,
1JPC¼214.3 Hz),126.5, 126.9, 128.4, 136.2, 161.5 (d, 2JPC¼21.5 Hz); MS
(EI): m/z (%) 323 (14.1), 294 (1.2), 278 (2.8), 232 (14.7), 207 (1.6), 186
(87.1), 104 (8.2), 91 (77.9), 82 (29.0), 65 (23.0), 55 (15.4), 28 (67.1).
Anal. Calcd for C17H26NO3P: C, 63.14; H, 8.10; N, 4.33; P, 9.58. Found:
C, 63.08; H, 8.05; N, 4.25; P, 9.55.
4.4. (E)-Isobutyl 7-chloro-3-(iso-propylamino)hept-2-
enoate 4a
To 0.216 g (1 mmol) of isobutyl 7-chlorohept-2-ynoate dis-
solved in 5 mL of dry acetonitrile was added 2 equiv of iso-propyl
amine in a screw-capped vial at room temperature. The mixture
was stirred for 8 h at room temperature and then the product was
separated on silica gel column (90% petroleum ether/10% ethyl
acetate), and analyzed by GC/MS, elemental analysis, and NMR
spectroscopy.
4.2.6. Diethyl 2-(pyrrolidin-1-yl)cyclohex-1-enylphosphonate 2f
(Table 1, entry 6)
Yield 0.18 g, 62%, yellow oily liquid; 1H NMR (300 MHz, CDCl3):
d
¼1.30 (t, 6H, JHH¼7.2 Hz),1.55–1.72 (overlap, 2H),1.90 (m, 4H), 2.63
(overlap, 4H), 3.05 (br t, 2H, JHH¼7.2 Hz), 3.25 (br t, 2H, JHH¼5.4 Hz),
4.00 (qn, 4H, JHH¼6.9 Hz); 31P NMR (121.4 MHz, CDCl3):
d¼28.92;
13C NMR (75.5 MHz, CDCl3): 16.3 (d, JPC¼6.9 Hz), 23.2, 26.6, 28.0,
3
Yield 0.24 g, 87%, yellow oily liquid; 1H NMR: (CDCl3, 300 MHz)
2
2
31.3 (d, JPC¼4.3 Hz), 53.8, 55.5, 60.5 (d, JPC¼5.5 Hz), 71.9 (d,
1JPC¼216.9 Hz), 162.8 (d, JPC¼21.1 Hz); MS (EI): m/z (%) 287 (1.5),
2
d
¼0.90 (d, 6H, JHH¼6.6 Hz), 1.18 (d, 6H, JHH¼6.3 Hz), 1.64–1.76 (m,
2H), 1.80–1.92 (overlap, 3H), 2.19 (t, 2H, JHH¼7.5 Hz), 3.54 (t, 2H,
235 (2.5),168 (3.4), 152 (1.8),110 (4.1), 84 (100), 70 (6.6), 55 (5.9), 42
(10.6). Anal. Calcd for C14H26NO3P: C, 58.52; H, 9.12; N, 4.87; P,10.78.
Found: C, 58.41; H, 9.20; N, 4.95; P, 10.72.
JHH¼6.3 Hz), 3.77 (d, 2H, JHH¼6.9 Hz), 4.40 (s, 1H); 13C NMR: (CDCl3,
75.5 MHz)
d
¼19.2, 24.3, 25.6, 27.9, 31.4, 31.9, 44.2, 44.5, 68.7, 81.1,
163.8, 170.9; MS (EI): m/z (%) 277 (3.8), 275 (6.8), 260 (2.0), 240
(100), 220 (5.7), 202 (32.2), 184 (38.0), 166 (12.2), 160 (29.5), 138
(18.5), 124 (20.5), 96 (27.0), 82 (29.9), 68 (15.5), 57 (24.7). Anal.
Calcd for C14H26ClNO2: C, 60.96; H, 9.50; Cl, 12.85; N, 5.08. Found: C,
61.06; H, 9.57; Cl, 12.69; N, 4.97.
4.2.7. Diethyl 2-(piperidin-1-yl)cyclohex-1-enylphosphonate 2g
(Table 1, entry 7)
Yield 0.21 g, 68%, yellow oily liquid; 1H NMR (300 MHz, CDCl3):
d
¼1.30 (t, 6H, JHH¼6.9 Hz), 1.27–1.62 (overlap, 10H), 2.25–2.40
(overlap, 4H), 2.64 (br t, 2H, JHH¼7.5 Hz), 3.16 (br t, 2H, JHH¼5.4 Hz),
4.02 (qn, 4H, JHH¼7.2 Hz); 31P NMR (121.4 MHZ, CDCl3):
d¼29.55;
4.4.1. (E)-Isobutyl 2-(1-iso-propylpiperidin-2-ylidene)acetate 5a
(Table 2, entry 1)
13C NMR (75.5 MHz, CDCl3): 15.8 (d, JPC¼6.9 Hz), 22.3, 22.8, 27.8,
3
2
2
To 0.216 g (1 mmol) of isobutyl 7-chlorohept-2-ynoate dis-
solved in 5 mL of dry acetonitrile was added 2 equiv of an amine in
a screw-capped vial at room temperature. The mixture was heated
at 70 ꢀC for 8 h, then it was cooled to room temperature and the
product was separated on silica gel column (90% petroleum ether/
10% ethyl acetate), and analyzed by GC/MS, elemental analysis, and
NMR spectroscopy.
29.3 (d, JPC¼4.3 Hz), 53.5, 54.7, 60.0 (d, JPC¼5.4 Hz), 71.7 (d,
1JPC¼217.4 Hz), 162.3 (d, JPC¼20.9 Hz); MS (EI): m/z (%) 301 (1.2),
2
154 (2.6), 136 (2.2), 123 (2.8), 97 (24.5), 84 (100), 70 (9.4), 42 (13.5).
Anal. Calcd for C15H28NO3P: C, 59.78; H, 9.36; N, 4.65; P, 10.28.
Found: C, 59.91; H, 9.27; N, 4.70; P, 10.19.
4.2.8. Diethyl 2-(2-hydroxyethylamino)cyclohex-1-
enylphosphonate 2h (Table 1, entry 8)
Yield 0.19 g, 78%, yellow oily liquid; 1H NMR: (CDCl3, 300 MHz)
Yield 0.19 g, 70%, yellow oily liquid; 1H NMR (300 MHz, CDCl3):
d
¼0.91 (d, 6H, JHH¼6.6 Hz), 1.20 (d, 6H, JHH¼6.9 Hz), 1.59–1.78
(overlap, 4H), 1.83–1.96 (m, 1H), 3.08 (t, 2H, JHH¼6.3 Hz), 3.12 (t, 2H,
JHH¼6.9 Hz), 3.77 (d, 2H, JHH¼6.6 Hz), 3.98–4.08 (m, 1H), 4.68 (s,
d
¼1.31 (d, 6H, JHH¼7.2 Hz), 1.71 (qn, 2H, JHH¼7.2 Hz), 1.83 (qn, 2H,
3
JHH¼7.2 Hz), 2.92 (dt, 2H, JHH¼7.5 Hz, JPH¼1.8 Hz), 3.30 (t, 2H,
JHH¼7.2 Hz), 3.47 (t, 2H, JHH¼7.2 Hz), 3.76 (t, 2H, JHH¼5.7 Hz), 3.98
1H); 13C NMR: (CDCl3, 75.5 MHz)
d¼18.9, 19.2, 19.3, 23.1, 26.4, 28.1,
(qn, 4H, JHH¼7.2 Hz); 31P NMR (121.4 MHz, CDCl3):
d
¼28.44; 13C
39.9, 48.1, 68.6, 81.0, 163.0, 169.6; MS (EI): m/z (%) 239 (30.0), 224
NMR (75.5 MHz, CDCl3): 15.7 (d, 3JPC¼6.9 Hz), 21.1, 22.5, 32.1, 43.3,
58.6, 61.0 (d, 2JPC¼5.5 Hz), 62.4, 165.9 (d, 2JPC¼21.6 Hz); MS (EI): m/z
(%) 277 (12.7), 260 (3.9), 246 (13.7), 234 (94.0), 206 (25.9), 164
(40.2), 146 (46.1), 108 (100), 97 (45.1), 83 (27.5), 65 (14.7), 41 (17.6).
Anal. Calcd for C12H24NO4P: C, 51.98; H, 8.72; N, 5.05; P, 11.17.
Found: C, 52.07; H, 8.81; N, 4.95; P, 11.09.
(20.6), 210 (4.8), 197 (6.2), 182 (14.4), 166 (77.5), 138 (100), 124
Table 2
(E)-sec-Butyl 2-(1-alkylpiperidin-2-ylidene)acetates 5
Entry
Product
Amine
% Isolated
yielda (conversionb)
1
2
3
4
5a
5b
5c
5d
iso-Propyl
Methyl
Benzyl
78(>98)
73(>98)
75(>98)
65(>98)
4.3. (rac) Diethyl trans-2-(pentylamino)cyclohexyl-
phosphonate 3
Ethanolamine
a
To the reaction mixture of 2a, 4 mL of ethanol and 2 equiv of
NaBH4 were added to the reaction mixture at 0 ꢀC. The mixture was
After silica gel chromatography.
Estimated by GC/MS.
b

H.K. Srivastava et al. / Tetrahedron 65 (2009) 4389–4395
4395
(69.6), 97 (76.5), 82 (34.3), 55 (37.3). Anal. Calcd for C14H25NO2: C,
References and notes
70.25; H, 10.53; N, 5.85. Found: C, 70.13; H, 10.49; N, 5.98.
1. Elassar, A. Z. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463–8480.
2. Ferraz, H. M. C.; Pereira, F. L. C. Quim. Nova 2004, 27, 89–95.
3. Cheng, Y.; Yang, H. B.; Huang, Z.-T.; Mei-Xiang Wang, M.-X. Tetrahedron Lett.
2001, 42, 1757–1759.
4. Wang,M.-X.;Miao, W.S.;Cheng,Y.;Huang,Z.-T. Tetrahedron1999, 55,14611–14622.
5. Bacos, D.; Celerier, J.-P.; Lhommet, G. Tetrahedron Lett. 1987, 28, 2353–2354.
6. Augusti, R.; Eberlin, M. N.; Kascheres, C. J. Heterocycl. Chem. 1995, 32, 1355–1357.
7. David, O.; Blot, J.; Bellec, C.; Fargeau-Bellassoued, M. C.; Haviari, G.; Celerier, J.
P.; Lhommet, G.; Gramain, J. C.; Gardette, D. J. Org. Chem. 1999, 64, 3122–3131.
8. Wang, Z.; Neidlein, R.; Krieger, C. Synthesis 2000, 255–258.
9. Miura, T.; Harumashi, T.; Murakami, M. Org. Lett. 2007, 9, 741–743.
10. Ferraz, H. M. C.; Deoliveira, E. O.; Payretarrua, M. E.; Brandt, C. A. J. Org. Chem.
1995, 60, 7357–7359.
4.4.2. (E)-Isobutyl 2-(1-methylpiperidin-2-ylidene)acetate 5b
(Table 2, entry 2)
Yield 0.15 g, 73%, yellow oily liquid; 1H NMR: (CDCl3, 300 MHz)
d
¼0.92 (d, 6H, JHH¼6.9 Hz), 1.57–1.63 (m, 2H), 1.70–1.73 (m, 2H),
1.85–1.90 (m, 1H), 2.80 (s, 3H), 3.06 (t, 2H, JHH¼6.6 Hz), 3.20 (t, 2H,
JHH¼5.7 Hz), 3.79 (d, 2H, JHH¼6.6 Hz), 4.53 (s, 1H); 13C NMR: (CDCl3,
75.5 MHz)
d¼19.3, 19.9, 23.5, 26.7, 28.1, 39.9, 51.8, 68.7, 82.5, 162.6,
169.0; MS (EI): m/z (%) 211 (17.0), 169 (4.5), 156 (15.0), 138 (100), 111
(99.9), 96 (6.0), 82 (13.0), 68 (9.0), 55 (9.9). Anal. Calcd for
C12H21NO2: C, 68.21; H, 10.02; N, 6.63. Found: C, 68.33; H, 9.97; N,
6.70.
11. Abell, A. D.; Oldham, M. D.; Taylor, J. M. J. Org. Chem. 1995, 60, 1214–1220.
12. Meerwein, H.; Florian, W.; Scho¨n, N.; Stopp, G. Justus Liebigs Ann. Chem. 1961,
641, 1–39.
13. Shvo, Y.; Shanan-Atidi, H. J. Am. Chem. Soc. 1969, 91, 6689–6696.
14. Horii, Z.; Morikawa, K.; Ninomiya, I. Chem. Pharm. Bull. 1969, 17, 2230–2239.
4.4.3. (E)-Isobutyl 2-(1-benzylpiperidin-2-ylidene)acetate 5c (Table
2, entry 3)
´ ´
15. Celerier, J. P.; Deloisy, E.; Lhommet, G.; Maitte, P. J. Org. Chem. 1979, 44, 3089.
16. Bredereck, H.; Bredereck, K. Chem. Ber. 1961, 94, 2278–2295.
17. Gugelchuk, M. M.; Hart, D. J.; Tsai, Y. M. J. Org. Chem. 1981, 46, 3671–3675.
18. Restle, S.; Wermuth, C. G. Tetrahedron Lett. 1979, 4837–4840.
19. Roth, M.; Dubs, P.; Gotschi, E.; Eschenmo, A. Helv. Chim. Acta 1971, 54, 710–734.
20. Natsume, M.; Takahash, M.; Kiuchi, K.; Sugaya, H. Chem. Pharm. Bull. 1971, 19,
2648–2651.
21. Lambert, P. H.; Vaultier, M.; Carrig, R. J. Org. Chem. 1985, 50.
22. Wang, M.-X.; Liu, Y.; Gao, H. Y.; Zhang, Y.; Yu, C.-Y.; Huang, Z.-T.; Fleet, G. W. J.
J. Org. Chem. 2003, 68, 3281–3286.
Yield 0.22 g, 75%, yellow oily liquid; 1H NMR: (CDCl3, 300 MHz)
d
¼0.89 (d, 6H, JHH¼6.6 Hz), 1.60–1.89 (overlap, 4H), 1.87–1.93 (m,
5H), 3.20 (t, 2H, JHH¼6.6 Hz), 3.25 (t, 2H, JHH¼6.0 Hz), 3.76 (d, 2H,
JHH¼6.6 Hz), 4.41 (s, 2H), 4.70 (s, 1H), 7.16–7.37 (m, 5H); 13C NMR:
(CDCl3, 75.5 MHz)
d¼19.3, 19.7, 23.3, 26.8, 28.0, 49.7, 55.1, 68.7, 82.7,
126.6, 127.1, 128.7, 136.2, 162.5, 169.3; MS (EI): m/z (%) 287 (35.6),
272 (1.5), 232 (8.5), 214 (42.3), 186 (92.2), 171 (23.2), 91 (100), 82
(22.9). Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found:
C, 75.35; H, 8.90; N, 4.68.
23. Zhao, M.-X.; Wang, M.-X.; Yu, C.-Y.; Fleet, G. W. J. J. Org. Chem. 2004, 69, 997–
1000.
24. Kapron, P.; Lhommet, G.; Maitte, P. Tetrahedron Lett. 1981, 22, 2255–2258.
25. Robinson, R. S.; Dovey, M. C.; Gravestock, D. Eur. J. Org. Chem. 2005, 505–511.
26. Khoukhi, N.; Vauitier, M.; Carrie´, R. Tetrahedron 1987, 43, 1811–1822.
27. Yamaguchi, M.; Hirao, I. J. Org. Chem. 1985, 50, 1975–1977.
28. David, O.; Vanucci-Bacque, C.; Fargeau-Bellassoued, M. C.; Lhommet, G. Hetero-
cycles 2004, 62, 839–846.
4.4.4. (E)-Isobutyl 2-(1-(2-hydroxyethyl)piperidin-2-
ylidene)acetate 5d (Table 2, entry 4)
Yield 0.16 g, 65%, yellow oily liquid; 1H NMR: (CDCl3, 300 MHz)
29. Calvet, S.; David, O.; Vanucci-Bacque´, C.; Fargeau-Bellassoued, M. C.; Lhommet,
G. Tetrahedron 2003, 59, 6333–6339.
30. Calvet-Vitale, S.; Vanucci-Bacque, C.; Fargeau-Bellassoued, M. C.; Lhommet, G.
J. Org. Chem. 2006, 71, 2071–2077.
d
¼0.92 (d, 6H, JHH¼6.6 Hz), 1.57–1.74 (overlap, 4H), 1.85–1.90 (m,
1H), 2.45 (t, 2H, JHH¼7.2 Hz), 3.12 (t, 2H, JHH¼6.6 Hz), 3.33 (t, 2H,
JHH¼6.6 Hz), 3.56 (t, 2H, JHH¼6.6 Hz), 3.87 (d, 2H, JHH¼6.6 Hz), 4.52
´ ´
31. Celerier, J.-P.; Deloisy-Marchalant, E.; Lhommet, G. J. Heterocycl. Chem. 1984, 21,
(s, 1H); 13C NMR: (CDCl3, 75.5 MHz)
d
¼19.1, 19.2, 20.2, 23.4, 26.5,
1633–1635.
32. Yatsumonji, Y.; Ogata, A.; Tsubouchi, A.; Takeda, T. Tetrahedron Lett. 2008, 49,
2265–2267.
33. Iorga, B.; Eymery, F.; Carmichael, D.; Savignac, P. Eur. J. Org. Chem. 2000, 3103–3115.
34. Palacios, F.; de Retana, A. M. O.; Pascual, S.; de Munain, R. L.; Oyarzabal, J.;
Ezpeleta, J. M. Tetrahedron 2005, 61, 1087–1094.
35. Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899–931.
36. Saunders, B. C.; Simpson, P. J. Chem. Soc., Perkin Trans. 1 1963, 3351–3357.
37. Chattha, M. S.; Aguiar, A. M. J. Org. Chem. 1975, 58, 820–822.
38. Acheson, R. M.; Ansell, P. J.; Murray, J. R. J. Chem. Res., Synop. 1986, 378–379.
39. Pudovik, A. N.; Khusainova, N. G.; Ageeva, A. G. Zh. Obshch. Khim. 1964, 34,
3938–3942.
31.8, 61.7, 70.6, 95.0, 164.8, 170.9; MS (EI): m/z (%) 241 (6.8), 226
(3.5), 210 (16.5), 198 (41.2), 168 (53.5), 142 (45.1), 127 (87.5), 126
(100), 111 (42.3), 97 (59.2), 82 (54.6), 55 (69.5). Anal. Calcd for
C13H23NO3: C, 64.70; H, 9.61; N, 5.80. Found: C, 64.83; H, 9.67; N,
5.65.
4.5. Computational details
40. Panarina, A. E.; Dogadina, A. V.; Zakharov, V. I.; Ionin, B. I. Tetrahedron Lett. 2001,
42, 4365–4368.
41. Kazankova, M. A.; Trostyanskaya, I. G.; Lutsenko, S. V.; Beletskaya, I. P. Tetra-
hedron Lett. 1999, 40, 569–572.
All calculations were perfomed with the Gaussian 03 program
package.48 Geometries were gradient-optimized and characterized
by frequency analysis at the HF/6-31G level. Profiles were ascer-
*
42. Palacios, F.; Aparicio, D.; Garcia, J. Tetrahedron 1996, 52, 9609–9628.
43. Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J. Tetrahedron Lett. 1996, 37,
4577–4580.
44. Xiao, J.; Yuan, C. Heteroat. Chem. 2000, 11, 541–545.
45. Al Quntar, A. A.; Srivastava, H. K.; Srebnik, M.; Melman, A.; Ta-Shma, R.; Shurki, A.
J. Org. Chem. 2007, 72, 4932–4935.
tained by following the reaction path using the intrinsic reaction
coordinate (IRC) technique with mass weighted coordinates.49 The
effect of the solvent on the reaction profiles was calculated with the
use of the PCM Model.50,51 Profiles for the reactions with diethyl 6-
chloro-1-hexynylphosphonate were calculated assuming a water
environment whereas those of isobutyl 7-chlorohept-2-ynoate
were calculated in an acetonitrile environment, in agreement with
the experimental conditions.
46. David, O.; Fargeau-Bellassoued, M. C.; Lhommet, G. Tetrahedron Lett. 2002, 43,
3471–3474.
47. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.
48. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz,
J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision B.04; Gaussian: Pittsburgh, PA, 2003.
Acknowledgements
The research in AS Lab was partially supported by The Israel
Science Foundation (grants No. 1317/05 and 1320/05), Applied
Funds of the Hebrew University and the David R. Bloom Foundation
for Pharmacy.
Supplementary data
49. Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154–2161.
50. Miertus, S.; Scrocco, E.; Tomasi, J. J. Chem. Phys. 1981, 55, 117–129.
51. Tomasi, J.; Persico, M. Chem. Rev. 1994, 94, 2027–2094.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.03.053.