Mo(CO)6-mediated intramolecular pauson-Khand reaction of substituted Diethyl 3-Allyloxy-1-Propynylphosphonates

Article abstract of DOI:10.1021/jo801988k

Cyclisation of diethyl 3-allyloxy-1-propynylphosphonates with Mo(CO) ₆ under PK conditions to give 3-substituted-5-oxo-3,5,6,6a- tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonate, 2a-h,in45-88% isolated yields was done. The R groups are always syn with H_b (where applicable). The stereochemistry was determined via both NMR and crystal X-ray analysis.

Full text of DOI:10.1021/jo801988k

Mo(CO)6-Mediated Intramolecular Pauson-Khand Reaction of
Substituted Diethyl 3-Allyloxy-1-Propynylphosphonates
Dorit Moradov,†,‡ Abed Al Aziz Al Quntar,†,§ Manar Youssef, Reem Smoum,†
Abraham Rubinstein,‡ and Morris Srebnik*,†
Department of Medicinal Chemistry and Natural Products and Department of Pharmaceutics, School of
Pharmacy, Hebrew UniVersity in Jerusalem, Jerusalem 91120, Israel, and Department of Material
Engineering, Faculty of Engineering, Al Quds UniVersity, Abu Dies, Jerusalem, Palestinian Authority
morris.srebnik@ekmd.huji.ac.il
ReceiVed September 16, 2008
Cyclisation of diethyl 3-allyloxy-1-propynylphosphonates with Mo(CO)6 under PK conditions to give
3-substituted-5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonate, 2a-h, in 45-88% isolated
yields was done. The R groups are always syn with Hb (where applicable). The stereochemistry was
determined via both NMR and crystal X-ray analysis.
Introduction
Ti(II) reagents.7-16 The Pauson-Khand reaction (PKR)17-21
is compatible with many functional groups and enables the
construction of relatively complex fused bicyclic structures. The
use of phosphonate partners in the PKR has not been extensively
explored. Thus, vinyl phosphonates using octacarbonyldicobalt
have been reported to undergo intramolecular PKR to give
selective formation of exocyclic 1,3-dienes versus PK cyclo-
pentenone products depending on the reaction conditions.22
Furthermore, Rivero and Carretero showed that under thermal
conditions in acetonitrile there is mainly PK cyclopentenone
product from the vinyl phosphonate starting material.22 Kerr
and co-workers have divulged that an intermolecular PKR using
allylphosphonate led to two phosphorylated cyclopentenones
products with moderate regioselectivity in the presence of
DodSMe as promoter.23Having stated this, the same research
team showed that modified PKR conditions with allylphospho-
nates in intermolecular processes led to elevated levels of
regioselectivity between the two PK cyclopentenone products,
hence establishing a normally less readily achieved regioselec-
tive intermolecular PK processes.24 In contrast, the successful
use of 1-alkynylphosphonates in the PK reaction has not been
Not only are vinylphosphonates important organic inter-
mediates,1-3 but we and others have shown that they possess
considerable pharmacological activity.4-6 In a series of papers,
we have demonstrated that highly substituted vinylphosphonates
can be prepared from 1-alkynylphosphonates and Zr(II) and
† Department of Medicinal Chemistry and Natural Products, Hebrew Uni-
versity in Jerusalem.
‡ Department of Pharmaceutics, School of Pharmacy, Hebrew University in
Jerusalem.
§ Department of Material Engineering, Faculty of Engineering, Al Quds
University.
(1) Minami, T.; Okauchi, T.; Kouno, R. Synthesis 2001, 349–357.
(2) Dembitsky, V. M.; Al Quntar, A. A. A.; Haj-Yehia, A.; Srebnik, M. Mini-
ReV. Org. Chem. 2005, 2, 91–109.
(3) Maffei, M. Curr. Org. Synth. 2004, 1, 355–375.
(4) Quntar, A. A.; Baum, O.; Reich, R.; Srebnik, M. Arch. Pharm. 2004,
337, 76–80.
(5) Quntar, A. A.; Gallily, R.; Katzavian, G.; Srebnik, M. Eur. J. Pharmacol.
2007, 556, 9–13.
(6) Cristau, H. J.; Gasc, M. B.; Mbianda, X. Y.; Geze, A. Phosphorus Sulfur
Silicon Relat. Elem. 1996, 111, 759–759.
(7) Baum, O.; Quntar, A. A.; Demitsky, V. M.; Srebnik, M. Tetrahedron
2004, 60, 1359–1364.
(8) Ben-Valid, S.; Quntar, A. A.; Srebnik, M. J. Org. Chem. 2005, 70, 3554–
3559.
(9) Quntar, A. A.; Baum, O.; Shibli, A.; Dembitsky, V. M.; Srebnik, M.
Angew. Chem., Int. Ed. 2003, 42, 4777–4779.
(10) Quntar, A. A.; Melman, A.; Srebnik, M. J. Org. Chem. 2002, 67, 3769–
3772.
(16) Quntar, A. A. A.; Rosenthal, D.; Srebnik, M. Tetrahedron 2006, 62,
5995–5999.
(17) Blanco-Urgoiti, J.; An˜orbe, L.; Pe´rez-Serrano, L.; Dominguez, G.; Pe´rez-
Castells, J. Chem. Soc. ReV. 2004, 33, 32–42.
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(15) Quntar, A. A. A.; Melman, A.; Srebnik, M. Synlett 2002, 61–64.
(18) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263–3283.
(19) Chung, Y. K. Coord. Chem. ReV. 1999, 188, 297–341.
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10.1021/jo801988k CCC: $40.75
Published on Web 12/24/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1029–1033 1029

Moradov et al.
SCHEME 1. Synthesis of Diethyl 3-Allyloxy-1-propynyl-
reported. However, in 1999, Spicer and co-workers reported
the preparation of 1-alkynylphosphonate hexacarbonyldicobalt
complexes.25 Surprisingly, the authors found these complexes
to be highly stable and totally inert to carbon-carbon bond
formation. This was explained on the basis of the electron
deficiency of the triple bond due to the electron-withdrawing
character of the phosphonate group, which in turn deactivated
the cobalt core of the complex preventing alkene coordination
necessary for subsequent carbon-carbon bond formation ac-
cording to the accepted mechanism of the PKR.26 These
observations intrigued us, and we reasoned that an intramo-
lecular PKR should overcome the inertness of the 1-alky-
nylphosphonate cobalt complexes and lead to novel and
interesting fused PK 2-phosphonocyclopentenones 2a-h. Sev-
eral approaches to monocyclic substituted 2-phosphonocyclo-
pentenones have been reported in the literature. For instance,
as byproduct in low yield from ꢀ-tert-butyldimethylsilyloxy-R-
diazo-ꢀ-ketophosphonates via a rhodium(II)-catalyzed C-H
insertion reaction,27-29 by ozonolysis/intramolecular aldol con-
densation of ꢀ-keto-ω-alkenylphosphonates requiring a multistep
reaction,30 from diethyl-2(5-methyl)furyl-hydroxymethylphos-
phonate via diethyl hex-3-en-2,5-dione-1-ylphosphonate fol-
lowed by reduction and condensation,31 by conversion of cyclic
vinyl sulfones to vinylphosphonates,32 and by Arbuzov reaction
of cyclohexenylbromide (one example)33 and as mixtures in low
yield from enallenic phosphonates and R,ꢀ-unsaturated phos-
phoryl ketones with chromyl chloride.34,35 This being the case,
we decided to explore the possible use of 1-alkynylphosphonates
in an intramolecular PKR, and in this paper, we describe our
results for the general synthesis of the novel diethyl 3-substituted-
5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-ylphospho-
nates 2 from diethyl 3-allyloxy-1-propynylphosphonates 1. The
preparation of 2 has not been previously reported.
phosphonates 1
SCHEME 2. Intramolecular PKR of 2a Mediated by
Mo(CO)6
After unsuccessful efforts to react alkynyl alcohols with allyl
bromide using n-BuLi, we found that metalation with KH
preceded smoothly.37 The resultant 3-(allyloxy)-1-yne was
lithiated with n-BuLi and phosphorylated with diethyl chloro-
phosphate to give yellowish oily products, diethyl 3-allyloxy-
1-propynylphosphonates 1, in 35-65% isolated yield after
column chromatography (Table 1). The structures of 1 were
1
confirmed by H, 13C, and 31P NMR. The hydrogens in the
double-bond region ∼5.2 and ∼ 5.9 ppm, the double-bond
carbons ∼130 and ∼120 ppm, together with the triple-bond
carbons at ∼100 and ∼70 ppm coupled to phosphorus are
consistent with structure 1. Also, the peak at ∼-6 ppm in the
31P NMR is evidence that the phosphonate group coupled to
sp-hybridized carbon.
Synthesis of Diethyl 3-Substituted 5-Oxo-3,5,6,6a-tetrahy-
dro-1H-cyclopenta[c]furan-4-ylphosphonates 2. After the
successful completion of the synthesis of the starting materials,
diethyl 3-allyloxy-1-propynylphosphonates 1, we started to
explore the appropriate Pauson-Khand reaction (PKR) condi-
tions in order to obtain the corresponding diethyl 3-substituted
5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-ylphospho-
nate 2. Various conditions were initially tried and the results
are summarized in Table 2.
Results and Discussion
Synthesis of Diethyl 3-Allyloxy-1-propynylphosphonates
1. The diethyl 3-allyloxy-1-propynylphosphonates 1a-h were
synthesized by reacting allyl bromide with either the com-
mercially available alkynyl alcohols (1a-c) or with alkynyl
alcohols prepared by treatment of ethynylmagnesium bromide
with aldehydes (1d,e) or ketones36 (1f-h) as shown in
Scheme 1.
Under conditions A or B, only ∼50% of the diethyl 3-(allyl-
oxy)but-1-ynylphosphonate, 1a, reacted with octacarbonyldi-
cobalt complex to form the alkynylphosphonate hexacarbonyl-
dicobalt complex 1a′ (Figure 1), but 1a′ was extremely stable,
and the Co complex did not further react by coordination to
the double bond of the allyloxy group to form the desired diethyl
3-methyl-5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-
ylphosphonate, 2a, in agreement with the observations of Spicer
et al.25 The reaction could be followed by 31P NMR in which
the deep red color of alkynylphosphonate hexacarbonyldicobalt
complex 1a′ has a chemical shift of ∼20 ppm compared to 1a,
which has a chemical shift of ∼-6 ppm.
(23) Brown, J. A.; Irvine, S.; Kerr, W. J.; Pearson, C. M. Org. Biomol. Chem.
2005, 3, 2396–2398.
(24) Brown, J. A.; Janecki, T.; Kerr, W. J. Synlett 2005, 2023–2026.
(25) Baxter, R. J.; Knox, G. R.; McLaughlin, M.; Pauson, P. L.; Spicer, M. D.
J. Organomet. Chem. 1999, 579, 83–89.
(26) Christoph, B.; Reinhardt, K. HelV. Chim. Acta 1996, 79, 2164–2171.
(27) Boukraa, M.; Dayoub, W.; Doutheau, A. Lett. Org. Chem. 2006, 3, 204–
206.
(28) Dayoub, W.; Diabb, Y.; Doutheaua, A. Tetrahedron Lett. 2002, 43,
4131–4132.
(29) Dayoub, W.; Diab, Y.; Doutheaua, A. Tetrahedron Lett. 2001, 42, 8455–
8457.
(30) Gil, J. M.; Hah, J. H.; Park, K. Y.; Oh, D. Y. Tetrahedron Lett. 1998,
39, 3205–3208.
(31) Castagnino, E.; Corsano, S.; Strappaveccia, G. P. Tetrahedron Lett. 1985,
26, 93–96.
(32) Noshi, M. N.; El-awa, A.; Torres, E.; Fuchs, P. L. J. Am. Chem. Soc.
2007, 129, 11242–11247.
When working under catalytic conditions C or D, the starting
material 1a was recovered and no traces of PK product 2a were
(33) Eirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Tetrahedron Lett. 1980,
21, 3595–3598.
(37) Verdaguer, X.; Moyano, A.; Pericas, M. A.; Riera, A.; Greene, A. E.;
Piniella, J. F.; Alvarez-Larena, A. J. Organomet. Chem. 1992, 433, 305–310.
(38) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org. Lett.
2005, 7, 593–595.
(39) Jeong, N.; Jo Lee, S. Tetrahedron Lett. 1993, 34, 4027–4030.
(40) SMART-NT V5.6; BRUKER AXS GMBH: Karlsruhe, 2002.
(41) SAINT-NT V5.0; BRUKER AXS GMBH: Karlsruhe, 2002.
(42) SHELXTL-NT V6.1, D-76181; BRUKER AXS GMBH: Karlsruhe, 2002.
(34) Dangyan, Y. M.; Tirakyan, M. R.; Panosyan, G. A.; Badanyan, S. O.
Zh. Obsh. Khim. 1985, 55, 1631–1632 (CAN 104:149005).
(35) Dangyan, Y. M.; Tirakyan, M. R.; Panosyan, G. A.; Denisenko, V. I.;
Badanyan, S. O. Zh. Obsh. Khim. 1988, 58, 1240–1247 (CAN 110:135363).
(36) Renzulli, M. L.; Rocheblave, L.; Avramova, S. I.; Galletti, E.; Castag-
nolo, D.; Tafi, A.; Corelli, F.; Botta, M. Tetrahedron 2007, 63, 297–509.
1030 J. Org. Chem. Vol. 74, No. 3, 2009

Pauson-Khand Reaction of Diethyl 3-Allyloxy-1-Propynylphosphonates
TABLE 1. Structures and Yields of Diethyl 3-Allyloxy-1-propynyl-
phosphonates 1
TABLE 4. Structures and Yields of 2 Obtained by PKR under
Conditions F
conversiona/
entry
1
R1
R2
yield (%)
entry
2
R1
R2
time (h)
isolated yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
H
H
H
methyl
butyl
pentyl
nonyl
phenyl
56
51
52
41
35
65
48
53
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
H
H
H
H
H
methyl
butyl
pentyl
nonyl
phenyl
2
2
8
6
5
4
3
3
>98/78
90/67
95/65
>98/58
96/45
97/81
>98/88
95/83
H
pentamethylene
hexamethylene
cyclopropyl
pentamethylene
hexamethylene
1g
1h
2g
2h
phenyl
phenyl
cyclopropyl
a Based on 31P NMR. b After silica gel chromatography.
TABLE 2. Different Conditions for Intramolecular PKR of 1a
metal
T
condition metal equiv solvent
promoter
(°C) time (h) 2a (%)
Aa
Ba
C
Co (CO)
2
1.3
1.3
CH CN
3
80
25
80
70
100
100
20
1.5
48
6
24
2
0
0
0
0
0
8
8
8
8
Co (CO)
CH Cl
2
7 equiv of CH NO
3
2
2
Co (CO)
2
0.06 CH CN
0.05 THF
1.2
1.2
3
Db
Ed
Fd
Co (CO)
TMTUc, CO balloon
5 equiv of DMSO
5 equiv of DMSO
2
Cr(CO)
6
toluene
toluene
FIGURE 1. Structure of alkynylphosphonate hexacarbonyldicobalt
complex 1a′.
Mo(CO)
78
6
a According to ref 22. b According to ref 38. c TMTU:
tetramethylthiourea. d According to ref 39.
TABLE 3. Optimization of PKR of 1a under Mo(CO)6
entry
solvent
T (°C)
time (h)
2a (%)
1
2
3
4
5
6
toluene
CH3CN
DCE
petroleum ether
DMF
THF
100
82
83
50
150
60
2
8
24
24
1
78
69
0a
0a
0b
0b
FIGURE 2. Structure and stereochemistry of 2a.
24
a Starting material recovered. b Complex reaction mixture obtained.
detected. Similar results were obtained when Cr(CO)6 complex
under conditions E was used, and only 1a was detected in the
reaction mixture. Interestingly, Mo(CO)6, conditions F, gave the
desired diethyl 3-methyl-5-oxo-3,5,6,6a-tetrahydro-1H-cyclo-
penta[c]furan-4-ylphosphonate product, 2a, in 78% isolated yield
and in a relatively short reaction time (Scheme 2).
We found that the reaction is solvent dependent, and the
highest yield was obtained in toluene, though acetonitrile
afforded satisfactory yields. In the case of dichloroethane (DCE)
or petroleum ether, the diethyl 3-(allyloxy)but-1-propynylphos-
phonate 1a remained intact, and no traces of 2a were observed.
On the other hand, when the reactions were carried out in DMF
or THF, a mixture of many unidentified products was obtained
as shown in Table 3.
The novel products 3-substituted 5-oxo-3,5,6,6a-tetrahydro-
1H-cyclopenta[c]furan-4-ylphosphonates 2a-h are stable and
isolated by silica gel column chromatography in good yields
(45-88%). Unlike 2f and 2h, which were obtained as
yellowish solids, the other products are oils. The reaction
was general for various R1 and R2 substituents including alkyl
(2a-d), aryl (2e, 2h), and cyclic (2f,g) as shown in Table 4.
In certain cases, 2b-d,f, in addition to the major PK product
which has a chemical shift of ∼10 ppm in 31P NMR, a
unidentified side product at ∼7 ppm was observed in ∼6%
yield.
FIGURE 3. Structure of 2h.
1H NMR of the fused cyclopentenones showed that the two
hydrogens on the same carbon (a or c) have different chemical
shifts, which is indicative of diastereoisotopic hydrogens. Two-
dimensional NMR including HSQC and NOESY techniques
were essential to identify the structure and the stereochemistry
of these compounds. The doublets in the regions ∼125 ppm
and ∼198 ppm in 13C NMR correspond to vinylic carbons split
by phosphorus. Also, the doublet at ∼204 ppm and the sharp
peak at ∼1700 cm-1 in IR are evidence of a carbonyl carbon.
Concerning the stereochemistry determination, the NOESY
NMR showed that there was an interaction between the
hydrogen on carbon (b) and the hydrogens of the methyl group
of 2a, but no interaction was seen with the allylic hydrogen on
carbon (d), which is indicative that the methyl group and the
hydrogen on carbon (b) are cis and the two allylic hydrogens
are trans.
Solving the stereochemistry of compound 2h was more
problematic (Figure 3). Protons Hb and Hc have the same
chemical shift ∼3.4 ppm (both on 300 and 500 MHz instru-
ments). Thus, the relative stereochemistry of Hb and the phenyl
or the cyclopropyl groups could not be determined from 2D
NOESY NMR since both protons Hb and Hc show interactions
with the phenyl and cyclopropyl groups.
The structure and relative stereochemistry of product 2a
(Figure 2) was determined by NMR, GC/MS, and IR data. The
J. Org. Chem. Vol. 74, No. 3, 2009 1031

Moradov et al.
TABLE 5. Crystal and Structure Refinement for Compound 2h
In the absence of hydrogen on carbon (d), 2f-h, two different
chemical shifts for the OCH2 carbons of the phosphonate ethoxy
groups were seen at ∼62.1 ppm and ∼62.5 ppm in 13C NMR.
Initially we thought that this is due to hindered rotation around
P-C bond. Interestingly, variable-temperature 13C NMR for 2f
in DMSO-d from 25 to 130 °C did not show any coalescence
of the OCH2 groups, which is indicative that these carbons are
diastereotopic rather than the result of hindered rotation around
the P-C bond.
The stereochemistry of compound 2h was determined by
X-ray analysis. The phenyl group is cis to Hb, while the
cyclopropyl group is in the trans position. In addition, there
are several interesting aspects of the structure of 2h. The dihedral
angle (H14-C14-C6-O1) is 170.5° and therefore nearly
bisects the plane of the cyclopropyl ring (C15-16). Also, the
phenyl ring is essentially periplanar with the O1-C6 bond
(O1-C6-C8-C13 ) 7.43°), while O1 tilts toward the cyclo-
propyl group and imparts significant nonplanarity between the
two fused five-membered rings (C1-C2-C4-C5 ) 137.07°).
The distances between O3/H14, O3/H9, and O1/H13 (2.320,
2.471, and 2.391 Å, respectively) rule out any intramolecular
hydrogen bonding. In addition, it can be seen from the values
of R1 and wR2 that the X-ray structure is of relatively poor
quality. This result is probably a consequence of one of the
ethoxy groups on the phosphorus which seems to be disordered.
The crystal data and structure with the refinement are sum-
marized in Table 5 and Figure 4.
Regarding the mechanism, the PKR proceeds by initial
complexation to the triple bond.19,20 Subsequently, complexation
of the initially formed alkynyl complex with a C-C double
bond is necessary. Co is a first-row transition metal. Mo is a
second-row transition metal. Second-row dp electrons are more
basic and available than first row dp electrons, and back-bonding
is facilitated (i.e., CO stretching frequencies-Co2(CO)8, ν(CO)
) 2044, Mo(CO)6, ν(CO) ) 2004). Thus, in the case of the Co
complexes of 1, the electron-withdrawing phosphonate group
diminished the ability of Co to form alkene complexes. But,
back-bonding of second- and third-row metal carbonyls is
greater than for the first row, and Mo complexes of 1 could
complex the alkene as illustrated in Scheme 3. DMSO facilitates
the displacement of CO’s.
formula
C20H25O5P
Fw
376.37
plates
colorless
173(1)
habit
color
T, K
radiation
cryst size, mm
cryst syst
space group
Mo ΚR
0.29 × 0.22 × 0.16
monoclinic
P21/c
a, Å
b, Å
c, Å
13.581(1)
7.2664(6)
20.337(2)
90.00
109.45
90.00
1892.5(3)
4
1.321
800
0.173
R, deg
ꢀ, deg
γ, deg
V, Å3
Z
dcalcd, g cm-3
F(000)
µ, mm-1
θ range, deg
no. of unique reflns
no. of restraints
hkl limits
no. of variables
no. of reflns with [I > 2σ(I)]
finala R indices [I > 2σ(I)]
wR2
2.12-27.00
20053
0
-17, 17/-9, 9/-25, 25
227
4122
0.1301
0.2867
R1 indices (all data)
wR2
0.1359
0.2903
1.207 and -0.817
1.308
max and min peak, e Å-3
GOF
a
2
2
R1 ) Σ|Fo - Fc|/Fo. wR2 ) {Σ[w(Fo - Fc2)2]/Σw(Fo )2]}1/2
.
FIGURE 4. Molecular structure and stereochemistry of compound 2h.
View of the molecular structure of 2h showing the atom-numbering
scheme. Ellipsoid represents thermal displacement parameters at the
50% probability level. Selected bond distances (Å) and angles (deg)
are as follows: C1-C7 ) 1.337(6), C1-C2 ) 1.495(7), C2-O2 )
1.210(6), C3-C4 ) 1.517(7), C4-C7 ) 1.506(6), C4-C5 ) 1.507(7),
C5-O1 ) 1.435(7), C6-O1 ) 1.451(5), C6-C7 ) 1.505(7), C6-C14
) 1.519(7), C6-C8 ) 1.539(6), O3-P1 ) 1.454(4), O4-P1 )
1.565(4), O5-P1 ) 1.557(5), C7-C1-C3 ) 108.1(4), C1-C2-C3
) 107.7(4), C7-C4-C5 ) 99.9(4), C7-C4-C3 ) 104.2(4),
C5-C4-C3 ) 122.4(4), O1-C5-C4 ) 105.2(4), O1-C6-C14 )
109.1(4),C7-C6-C14)114.1(4),O1-C6-C8)109.8(3),C14-C6-C8
) 111.1(4), C1-C7-C6 ) 139.0(4), C4-C7-C6 ) 107.0(4),
C17-O4-P1 ) 123.1(4), C19-O5-P1 ) 118.3(7), O3-P1-O5 )
114.7(3), O3-P1-O4 ) 115.9(3), O5-P1-O4 ) 101.7(3), O3-P1-C1
) 116.8(2), O5-P1-C1 ) 104.0(3), O4-P1-C1 ) 101.7(2).
Conclusion
A facile synthesis of novel 3-substituted 5-oxo-3,5,6,6a-
tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonates 2a-h start-
ing from diethyl 3-allyloxy-1-propynylphosphonates 1a-h
utilizing PK conditions has been discussed. This reaction was
successful using Mo(CO)6, but with other metals like Co2(CO)8
and Cr(CO)6 no traces of 2 were observed. The structure and
the stereochemistry of the products and the reactants were
confirmed by NMR, GC/MS, IR, X-ray and elemental analysis.
Experimental Section
Typical Procedure for the Synthesis of Diethyl
3-(Allyloxy)but-1-ynylphosphonate (1a). To KH (0.802 g, 20
mmol) suspended in dry THF (10 mL) was added 1-butyn-3-ol
(1.402 g, 20 mmol) at -78 °C. After the mixture was stirred for
2 h at -78 °C, allyl bromide (2.419 g, 20 mmol) was added. The
reaction mixture was gradually warmed to room temperature and
was stirred overnight. Then the reaction mixture was quenched with
1 M HCl solution, the product was extracted with ether (3 × 50
mL), and the solvent was removed by rotavaporator after drying
over Na2SO4.
Then, without further purification, 2.5 M n-BuLi (7.84 mL, 19.6
mmol) was added to the freshly prepared 3-(allyloxy)but-1-yne
(2.156 g, 19.6 mmol) dissolved in dry ether (100 mL) at -78 °C.
The reaction was gradually warmed to -20 °C and was stirred for
1032 J. Org. Chem. Vol. 74, No. 3, 2009

Pauson-Khand Reaction of Diethyl 3-Allyloxy-1-Propynylphosphonates
SCHEME 3. Proposed Mechanism for the Formation of 2
from 1 and Mo(CO)6
(2.775 g, 12.5 mmol) dissolved in dry ether (70 mL) at -78 °C.
The reaction was gradually warmed to -20 °C and was stirred for
2 h. Then the mixture was cooled to -78 °C, and diethyl
chlorophosphate (2.157 g, 12.5 mmol) was added. Again, the
mixture was gradually warmed to rt and stirred overnight. After
the reaction was quenched with 1 M HCl, the product, diethyl
3-(allyloxy)dodec-1-ynylphosphonate (1d), was extracted with ether
(3 × 50 mL). Then, after drying over Na2SO4 and removal of the
solvents by rotavaporator, the product was separated on silica gel
column chromatography using a gradient eluent of ethyl acetate/
petroleum ether to yield 3.670 g (41%) of 1d.
1H NMR (300 MHz): δ 0.87 (t, 3H, JHH ) 7.2 Hz), 1.20-1.32
(m, 12H), 1.36 (t, 6H, JHH ) 7.2 Hz), 1.41-1.50 (m, 2H),
1.71-1.86 (m, 2H), 3.95 (dd, 1H, JHH ) 6.3 Hz, JHH ) 12.6 Hz),
4.07-4.22 (m, 5H), 4.24 (m, 1H), 5.21 (d, 1H, JHH ) 10.5 Hz),
5.29 (d, 1H, JHH ) 15.6 Hz), 5.88 (m, 1H). 31P NMR (121 MHz):
2
δ -6.03. 13C NMR (75.5 MHz): δ 133.9, 118.1, 99.9 (d, JPC
)
1
3
48.7 Hz), 74.8, 74.3 (d, JPC ) 85.1 Hz), 68.9 (d, JPC ) 4.0 Hz),
2
63.4 (d, JPC ) 5.4 Hz), 36.1, 32.0, 29.6, 29.6, 29.4, 29.4, 29.2,
2 h. Then the mixture was cooled to -78 °C, and diethyl
chlorophosphate (3.382 g, 19.6 mmol) was added. Again, the
mixture was gradually warmed to rt and stirred overnight. After
the reaction was quenched by 1 M HCl, the product, diethyl
3-(allyloxy)but-1-ynylphosphonate (1a), was extracted with ether
(3 × 50 mL). Then, after drying over Na2SO4, and removal of the
solvents by rotavaporator, the product was separated by silica gel
column chromatography using a gradient eluent of ethyl acetate/
petroleum ether yielding 2.755 g (56%) of 1a.
22.8, 16.3 (d, 3JPC ) 6.9 Hz), 14.3. Anal. Calcd for C19H35O4P: C,
63.66; H, 9.84; P, 8.64. Found: C, 63.08; H, 9.45; P, 8.84.
Synthetic Procedure for Diethyl 3-Methyl-5-oxo-3,5,6,6a-
tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonate (2a). To Mo-
(CO)6 (1.584 g, 6 mmol) in dry toluene (20 mL) was added diethyl
3-(allyloxy)but-1-ynylphosphonate, 1a (1.230 g, 5 mmol), followed
by addition of dry DMSO (1.952 g, 25 mmol). After being refluxed
for 2 h at 100 °C, the reaction mixture was cooled, and ethyl acetate
(20 mL) was added. The mixture was filtered through silica gel,
and the product was separated on silica gel column chromatography
using a gradient eluent of metanol/dichloromethane to yield 1.068
g (78%) of 2a.
1H NMR (300 MHz): δ 1.36 (t, 6H, JHH ) 7.2 Hz), 1.47 (d, 3H,
JHH ) 6.9 Hz), 3.95 (dd, 1H, JHH ) 6.3 Hz, JHH ) 12.3 Hz),
4.08-4.21 (m, 5H), 4.27 (dd, 1H, JHH ) 3.3 Hz, JHH ) 6.6 Hz),
5.20 (d, 1H, JHH ) 10.5 Hz), 5.29 (d, 1H, JHH ) 16.8 Hz), 5.88
(m, 1H). 31P NMR (121 MHz): δ -6.06. 13C NMR (75.5 MHz): δ
133.50, 117.8, 99.9 (d, 2JPC ) 48.7 Hz), 73.3 (d, 1JPC ) 83.1 Hz),
1H NMR (300 MHz): δ 1.33 (t, 6H, JHH ) 6.9 Hz), 1.52 (d, 3H,
JHH ) 6.6 Hz), 2.22 (dd, 1H, JHH ) 4.2 Hz, JHH ) 17.7 Hz), 2.7
(dd, 1H, JHH ) 6.6 Hz, JHH )17.7 Hz), 3.29 (dd, 1H, JHH ) 7.5
Hz, JHH ) 11.1 Hz), 3.38 (m, 1H), 4.08-4.25 (m, 4H), 4.35 (t,
1H, JHH ) 7.5 Hz), 4.99 (q, 1H, JHH ) 6.6 Hz). 31P NMR (121
3
2
69.9, 64.2 (d, JPC ) 4.0 Hz), 63.0 (d, JPC ) 5.4 Hz), 21.0, 15.9
(d, 3JPC ) 6.9 Hz). Anal. Calcd for C11H19O4P: C, 53.65; H, 7.78;
P, 12.58. Found: C, 53.72; H, 7.61; P, 12.68.
Typical Procedure for the Synthesis of Diethyl 3-(Allyloxy)-
dodec-1-ynylphosphonate (1d). To decanal (3.906 g, 25 mmol)
in dry THF (100 mL) was added dropwise over 5 min under N2
atmosphere 0.5 M ethynylmagnesium bromide in THF (150 mL,
75 mmol) at 0 °C. The reaction was stirred for 45 min at 0 °C, and
then it was warmed to rt and stirred for an additional 2 h. After
being cooled to 0 °C, the reaction was quenched with 1 M NH4Cl
solution. Then the product was extracted with ether (3 × 50 mL)
and dried over Na2SO4, and the solvent was removed by
rotavaporator.
Without further purification, to KH (0.562 g, 14 mmol) suspended
in dry THF (7 mL) was added the freshly prepared dodec-1-yn-3-
ol (2.548 g, 14 mmol) at -78 °C. After being stirred for 2 h at
-78 °C, allyl bromide (1.694 g, 14 mmol) was added. The reaction
mixture was gradually warmed to room temperature and was stirred
overnight. Then the reaction mixture was quenched with 1 M HCl
solution, the product was extracted with ether (3 × 50 mL), and
the solvent was removed by rotavaporator after drying over Na2SO4.
Then, without further purification, 2.5 M n-BuLi (5.0 mL, 12.5
mmol) was added to the freshly prepared 3-(allyloxy)dodec-1-yne
2
MHz): δ 9.924. 13C NMR (75.5 MHz): δ 204.7 (d, JPC ) 13.7
2
1
Hz), 198.6 (d, JPC ) 12.6 Hz), 125.8 (d, JPC ) 194.9 Hz), 73.4,
2
3
70.7, 62.5 (d, JPC ) 5.7 Hz), 44.9 (d, JPC ) 15.4 Hz), 39.9 (d,
3JPC ) 9.7 Hz), 19.7 (d, JPC ) 1.1 Hz), 16.2 (d, JPC ) 6.6 Hz).
MS(EI): m/z 274 (15.8), 246 (11.5), 228 (46.7), 218 (16.5), 200
(100), 188 (19.7), 172 (21.6), 147 (14.1), 138 (11.5), 120 (13.4),
91 (18), 77 (21.8). Anal. Calcd for C12H19O5P: C, 52.55; H, 6.98;
P, 11.29. Found: C, 52.43; H, 7.05; P, 11.35.
3
3
Acknowledgment. The study was supported by a research
grant (no. 1358/05) from the Israeli Science Foundation. A.R.
and M.S. are affiliated with the David R. Bloom Center for
Pharmacy.
1
Supporting Information Available: H and 13C NMR for
compounds 2a-h and 1a-h; details (CIF) of 2 h. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO801988K
J. Org. Chem. Vol. 74, No. 3, 2009 1033