A New One-pot Synthesis of Alkynylphosphonates

Article abstract of DOI:10.1021/ol0066173

equation presented A method for the palladium-catalyzed synthesis of alkynylphosphonates from 1,1-dibromo-1-alkenes has been developed. In general, the best catalyst system for this transformation was found to be Pd(OAc)₂, dppf, H-phosphonate, propylene oxide, DMF, 80°C. The reaction appears tolerant of a range of functional groups in both the 1,1-dibromo-1-alkene and H-phosphonate coupling partners. The synthesis of a backbone-modified thymidine dimer is used to illustrate the application of this methodology in the synthesis of complex target molecules.

Full text of DOI:10.1021/ol0066173

ORGANIC
LETTERS
2
000
Vol. 2, No. 24
873-3875
A New One-Pot Synthesis of
Alkynylphosphonates
3
Manuel Lera and Christopher J. Hayes*
The School of Chemistry, The UniVersity of Nottingham, UniVersity Park,
Nottingham, NG7 2RD, UK
chris.hayes@nottingham.ac.uk
Received September 19, 2000
ABSTRACT
A method for the palladium-catalyzed synthesis of alkynylphosphonates from 1,1-dibromo-1-alkenes has been developed. In general, the best
catalyst system for this transformation was found to be Pd(OAc) , dppf, H-phosphonate, propylene oxide, DMF, 80 °C. The reaction appears
2
tolerant of a range of functional groups in both the 1,1-dibromo-1-alkene and H-phosphonate coupling partners. The synthesis of a backbone-
modified thymidine dimer is used to illustrate the application of this methodology in the synthesis of complex target molecules.
Recent work has shown that 1,1-dibromo-1-alkenes are useful
electrophiles in palladium-catalyzed cross-coupling reactions.
The ability of a palladium(0) catalyst to undergo stereo-
selective oxidative insertion into the trans-carbon-bromine
bond has led to a new method for the stereoselective
alkenes to that reported by Zapata and Shen and have used
this to develop a one-pot synthesis of substituted alkyn-
ylphosphonates. This methodology provides a convenient
route to a range of alkynylphosphonates, which themselves
may be used as precursors to a range of other useful
1
5
synthesis of a range of substituted olefins. During the course
functionality such as â-ketophosphonates, vinylogous phos-
6
7
of their work studying the stereoselective Stille coupling
phonamides and 2,2-disubstituted vinylphosphonates. Our
interest in this transformation arose from a chance discovery
made during work examining the synthesis of backbone-
modified nucleic acids via a palladium-catalyzed coupling
2
reactions of 1,1-dibromo-1-alkenes, Zapata et. al., and more
3
recently Shen et. al., observed that under certain conditions
the major products of this reaction were substituted enynes
rather than the expected bromodienes. In an extension to this
8
of vinyl bromides and H-phosphonates. While attempting
4
work, Shen et. al. have shown that 1,1-dibromo-1-alkenes
to synthesize the bromovinylphosphonate 2 via a stereo-
can also be used as precursors to diynes in a process related
to the Sonagashira coupling.
selective palladium-catalyzed monocoupling between dibro-
mide 1 and dimethyl phosphite, we found that the major
9
As part of a project examining the use of transition metal-
catalyzed carbon-phosphorus cross-coupling reactions in
synthesis, we noticed a similar reactivity of 1,1-dibromo-1-
product was in fact the alkynylphosphonate 3 (63%) (Scheme
1).
To explore the generality of this transformation, we
synthesized a range of 1,1-dibromo-1-alkenes (see Table 1)
1
0
(
1) (a) Shen, W. Synlett 2000, 737. (b) Xu, C.; Negishi, E. Tetrahedron
Lett. 1999, 40, 431. (c) Shen, W.; Wang, L. Tetrahedron Lett. 1998, 39,
625. (d) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912. (e) Baldwin,
J. E.; Chesworth, R.; Parker, J. S.; Russell, A. T. Tetrahedron Lett. 1995,
6, 9551. (f) Minato, A. J. Org. Chem. 1991, 56, 4052. (g) Roush, W. R.;
(5) (a) Poss, A. J.; Belter, R. K. J. Org. Chem. 1987, 52, 4810. (b)
Chattha, M. S.; Aguiar, A. M. J. Org. Chem. 1973, 38, 2908. For use in
synthesis, see: Corey, E. J.; Virgil, S. C. J. Am. Chem. Soc. 1990, 112,
6429.
7
3
Moriarty, K. J.; Brown, B. B. Tetrahedron Lett. 1990, 31, 6509. (h) Uenishi,
J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O. Tetrahedron Lett. 1996, 37,
(6) Chattha, M. S.; Aguiar, A. M. J. Org. Chem. 1973, 38, 820.
(7) Gil, J. M.; Oh, D. Y. J. Org. Chem. 1999, 64, 2950.
(8) (a) Abbas, S.; Hayes, C. J. Tetrahedron Lett. 2000, 41, 4513. (b)
Abbas, S.; Hayes, C. J., Synlett 1999, 1124.
6
759. (i) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem.
998, 63, 8965.
1
(2) Zapata, A. J.; Ruiz, J. J. Organomet. Chem. 1994, 479, C6.
(3) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873.
(4) Shen, W.; Thomas, S. A. Org. Lett. 2000, 2, 2857.
(9) For an example of a Nickel-catalyzed monocoupling, see: Kazankova,
M. A.; Trostyanskaya, I. G.; Lutsenko, S. V.; Beletskaya, I. P. Tetrahedron
Lett. 1999, 40, 569.
1
0.1021/ol0066173 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/10/2000

Scheme 1
Table 1. Preparation of Alkynylphosphonates
using standard methodology11 and studied their cross-
coupling reactions. The first substrate to be examined was
the cyclohexyl-substituted 1,1-dibromo-1-alkene 4 (Scheme
2). We were pleased to find that under conditions identical
Scheme 2
solventa
catalyst
yield of 5 (%)
yield of 18 (%)
DMF
DMF
THF
Pd(OAc)2, dppf
Pd2(dba)3, dppf
Pd(OAc)2, dppf
Pd(OAc)2, dppf
76
43
41
48
0
trace
24
15
toluene
a
All reactions were heated using an oil bath at 80 °C.
to those used for the formation of 3 from 1 (i.e., Pd(OAc)
2
1
2
a
(0.2 equiv), dppf (0.4 equiv), dimethyl phosphite (2.0
Reaction conditions: Pd(OAc)2 (0.2 equiv), dppf (0.4 equiv), H-
phosphonate (2.0 equiv), propylene oxide (3.0 equiv), DMF, 80 °C, 14 h.
The yields in parentheses were obtained when dppf was replaced with
TFP as ligand; all other conditions were identical.
equiv), propylene oxide (3.0 equiv), DMF, 80 °C, 14 h), 4
was cleanly converted into the corresponding alkynylphos-
phonate 5 in 76% yield. Because of its partial water solubility
and subsequent difficulties with extraction, the isolated yield
of the desired product 5 was substantially reduced if we
performed an aqueous workup at the end of the reaction.
We found that the product was best isolated by removing
the solvent in vacuo followed by silica gel chromatography
of the resulting residue.
b
solvents. When the DMF was replaced by toluene, the
acetylene 5 was still formed as the major product, albeit in
a reduced yield of 48%. In addition to 5 we were also able
to isolate the corresponding monocoupling product 18 in 15%
yield. A similar result was obtained using THF as solvent,
with both 5 (41%) and 18 (24%) being produced. These
results showed that there is a solvent effect on the yield and
product ratio and that DMF is the best solvent to use for the
selective formation of the alkynyl phosphonate. We briefly
In an attempt to eliminate the need to remove DMF in
vacuo, we examined the coupling reaction in lower-boiling
(
10) When triethylamine was used in place of propylene oxide for this
coupling, reduction of the 1,1-dibromo-1-alkene to the corresponding
-bromo-1-alkene was observed. See: Abbas, S.; Hayes, C. J.; Worden, S.
Tetrahedron Lett. 2000, 41, 3215 and references therein.
11) For preparation of 1,1-dibromo-1-alkenes see: Ramirez, F.; Desai,
N. B.; McKelvie, N. J. Am. Chem. Soc. 1962, 84, 1745.
12) dppf ) 1, 1′-Bis(diphenyl-phosphino)ferrocene.
1
3
examined the use of Pd
2
(dba)
3
as the source of palladium,
1
and while we were able to isolate the desired product 5 in
(
(13) No reaction of 4 was observed using the optimized monocoupling
3
(
conditions of Shen (Pd2(dba)3, TFP, toluene, 100 °C).
3874
Org. Lett., Vol. 2, No. 24, 2000

moderate yield (43%), higher yields and cleaner reaction
mixtures were obtained with the use of Pd(OAc)
2
.
Scheme 3
With these results in hand we next performed the coupling
reaction with a more extensive range of 1,1-dibromo-1-
alkenes using the original “DMF” conditions (vide supra).
As shown in Table 1, the coupling reaction appears to be
tolerant of a range of functionality with the corresponding
alkynylphosphonates being isolated in modest to good
1
4
yields. In the case of the furan-containing 1,1-dibromo-1-
alkene 14, the yield of the desired product 15 could be
improved dramatically if the ligand was changed from dppf
1
5
2
to TFP. Under these modified conditions (Pd(OAc) (0.2
equiv), TFP (0.8 equiv), dimethyl phosphite (2.0 equiv),
propylene oxide (3.0 equiv)), DMF, 80 °C, 14 h), the isolated
yield of 15 increased from 16% to 60%. The use of TFP as
ligand in the coupling reactions of other substrates in Table
1
was examined, but this led to a reduction in yield in most
cases. It is worth noting that, in their work, Shen et. al.
observed ligand effects on the product distribution (i.e.,
alkyne formation vs monocoupling) when certain orga-
nostannanes were used as nucleophiles, but in their case TFP
access to highly functionalized targets. We are currently
examining the use of this coupling reaction for the synthesis
of a range of other backbone-modified nucleic acids, and
these results will be published in due course.
16
tended to favor monocoupling rather than alkyne formation.
In summary, we have developed a convenient method for
the one-pot preparation of a range of alkynylphosphonates
It is not immediately apparent to us why the yield of the
alkyne 15 is improved by the use of TFP while the yields of
other couplings are reduced. Work is currently underway to
explain this observation and provide a better mechanistic
understanding of this process.17
20
from the corresponding 1,1-dibromo-1-alkenes, which is
2
1
complementary to existing methodology. In general, the
best catalyst system for this transformation was found to be
Pd(OAc)
appears tolerant of a range of functional groups in both the
,1-dibromo-1-alkene and H-phosphonate coupling partners,
2
, dppf, propylene oxide, DMF, 80 °C. The reaction
Having shown that the thymidine-derived dibromide 1 was
relatively well tolerated in the coupling with dimethyl
phosphite, we next wondered if this methodology could be
used to prepare the modified nucleotide dimer 20 by coupling
1
which should allow this methodology to find use in the
synthesis of complex target molecules.
1
8
with the more highly functionalized H-phosphonate 19.
Pleasingly, the desired alkyne-containing thymidine dimer
Acknowledgment. The authors thank the Nuffield Foun-
dation (NUF-NAL) and the School of Chemistry, University
of Nottingham, for financial support and The University of
Nottingham for the provision of a Ph.D. studentship (M.L.).
1
9
20 was formed in 51% isolated yield (+12% recovered 1)
when a mixture of 1 (1.0 equiv) and 19 (1.4 equiv) was
exposed to the “DMF/dppf” coupling conditions (vide supra)
(Scheme 3). Considering the complexity of this product, we
believe that this result is particularly impressive and it clearly
demonstrates the potential of this methodology to allow
Supporting Information Available: Characterization
data for all alkynylphosphonate products. This material is
available free of charge via the Internet at http://pubs.acs.org.
14) All new compounds showed satisfactory H, 13C, 31P, IR, MS, and/
1
(
or elemental analytical data.
OL0066173
(
15) TFP ) tris(2-furyl)phosphine.
(
16) One exception to this was when trimethyl(phenyl)tin was used as
the coupling partner. In this case alkyne formation was observed with a
range of ligands, including TFP (see ref 3). The rate of transmetalation of
the organostannane was proposed as the determining factor controling
product selectivity in this process.
(20) Typical Procedure for the Preparation of Alkynylphosphonates:
A mixture of Pd(OAc)2 (7 mg, 0.033 mmol) and dppf (36 mg, 0.066 mmol)
in DMF (1 mL) was flushed with dry nitrogen and stirred at room
temperature for 20 min. A solution of 1 (104 mg, 0.165 mmol) in DMF
(1.5 mL), propylene oxide (35 µL, 0.50 mmol), and dimethyl phosphite
(30 µL, 0.33 mmol) were added and the mixture was heated at 80 °C (bath
temperature) for 14 h and then cooled to room temperature. Removal of
the solvent in vacuo left a residue which was purified by column
chromatography (SiO2, EtOAc/pentane (3:1)) to afford 3 as a white solid
(60 mg, 63%).
(
17) We believe the mechanism of this reaction to be similar to that
proposed by Shen (see ref 3).
18) For synthesis, see ref 8b. The material was used as a 1:1 mixture
of diastereoisomers at phosphorus.
19) The product 20 was produced as a 1:1 mixture of diasteroisomers
(
(
at phosphorus, which were readily separable by column chromatography
using silica gel and ethyl acetate/pentane/methanol (10:10:1) as eluant.
(21) See refs 5, 6, and 7 for alternative methodology.
Org. Lett., Vol. 2, No. 24, 2000
3875