Synthesis of allenic (α,α-difluoromethylene)phosphonates from propargylic tosylates and acetates

Article abstract of DOI:10.1055/s-2001-10795

Copper (I) bromide-promoted reactions of bromo[(diethoxyphosphoryl)difluoromethyl]zinc reagent 2 with propargylic tosylates and acetates were examined. The reaction proceeded in an S_N2′ manner to give allenic (α,α-difluoromethylene)phosphonates

Full text of DOI:10.1055/s-2001-10795

LETTER
287
Synthesis of Allenic ( , -Difluoromethylene)phosphonates from Propargylic
Tosylates and Acetates
Tsutomu Yokomatsu, Ai Ichimura, Junya Kato, Shiroshi Shibuya*
School of Pharmacy, Tokyo University of Pharmacy & Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax +81-426-76-3239; E-mail: shibuyas@ps.toyaku.ac.jp
Received 4 December 2000
R1
R2
M
CF2P(O)(OEt)2
R3
Abstract: Copper (I) bromide promoted reactions of
bromo[(diethoxyphosphoryl)difluoromethyl]zinc reagent 2 with
propargylic tosylates and acetates were examined. The reaction pro-
ceeded in an SN2’ manner to give allenic ( , -difluoromethyl-
ene)phosphonates in good to excellent yield.
1: M=Li
CF2PO3Et2
2: M=BrZn
3: M=CeCl
4: M=Br2Zn•Cu
5
Key words: allenes, addition reaction, organometallic reagents,
phosphate mimics, fluorine
and stoichiometric amounts of copper (I) bromide in THF,
DMF or DMA as usual,4,6 were treated with the represen-
tative propargylic substrates 6a-d at room temperature for
12 h. In either THF or DMF, propargyl bromide 6a react-
ed with 4 to give the allenic ( , -difluoromethylene)phos-
phonate 7 in moderate to good yield (entries 1 and 2). The
products from the reaction in THF were contaminated by
a trace amount of the acetylene derivative 8 (entry 1). The
choice of solvent was critical for the selective formation
of the allene, when propargyl tosylate 6b was used as a
substrate (entries 3 and 4). Upon treatment of 6b with 4 in
THF, an inseparable mixture of the allene 7 and the acet-
ylene 8 was produced in a ratio of 85:15.10 The allene/
acetylene distribution ratio was significantly improved
( , -Difluoromethylene)phosphonic acids (DFMPA) as
hydrolytically stable analogues of naturally occurring
phosphate esters have attracted much attention because
they mimic parental biophosphates more accurately than
analogous non-fluorinated phosphonates in their isosteric
and isopolar properties.1 Therefore, interest is growing in
the development of general methods that allow the synthe-
sis of compounds in which the DFMPA is borne within a
functionalized array of biological interest.2
Numerous literature citations involve the preparation of
DFMPA ester derivatives through carbon carbon bond
formation of metallated diethyl difluoromethylphospho-
nates 1-3.3-5 Our group’s contribution to this research field
resulted in the discovery of the novel reactivity of the zinc
reagent 2 in DMF or DMA in the presence of copper (I)
bromide.6 The presumed organocopper species 4, generat-
ed by the transmetalation of 2 with copper (I) bromide in
DMF and DMA, readily cross-coupled with a variety of
iodoalkenes and iodobenzene derivatives to give ( , -di-
fluoroallyl)- and ( , -difluorobenzyl)-phosphonate deriv-
atives in high yield.6 The methods have been recently ap-
plied to synthesize a number of biologically active
compounds on the basis of the DFMPA functional group
by ourselves and others.7,8
CF2PO3Et2
X
4
7
+
THF, DMFor DMA
6a-d
CF2PO3Et2
8
a: X=Br; b: X=OTs; c: X=OCOOMe; d: X=OAc
Scheme 1
In our continuous efforts to expand the utility of the orga-
nocopper species 4 derived from 2, we have pursued the
reaction with propargylic substrates in expectation of the
reaction giving allenic ( , -difluoromethylene)phospho-
nates 5.9 The structural novelty of 5 and the latent reactiv-
ity of the allenyl moiety would be potentially useful for
developing new DFMPA derivatives of biological inter-
est. Here, we describe the results of our studies.
Table 1 Reaction of 4 with propargylic substrates 6a-ca
Our initial experiments focused on finding suitable leav-
ing groups for the transformation of propargylic sub-
strates to the target allenic ( , -difluoromethyl-
ene)phosphonates 5 and the allene/acetylene product dis-
tribution for the reactions was verified (Table 1). The or-
ganocopper species 4, generated from the zinc reagent 2
a
All reactions were carried out at room temperature for 12 h in the
presence of 2.0 equiv of 4. b The ratio was determined by H NMR
1
(300 MHz) analysis. c The reaction was carried out under ultrasound-
irradiation.
Synlett 2001 No. 2, 287–289 ISSN 0936-5214 © Thieme Stuttgart · New York

288
T. Yokomatsu et al.
LETTER
when the reaction was carried out in DMF in place of THF With these results in hand, we focused on the reaction
under similar conditions (entry 4). The reaction is com- with propargylic substrates 12a-g, derived from known
pletely regioselective, giving the allene as the sole product propargylic alcohols through the standard tosylation or
in high yield. Propargyl carbonate 6c showed modest re- acetylation,13,14 to examine the generality and scope of
activity toward 4; the allene was formed in low yield these reactions.16 As shown in Table 3, propargylic tosyl-
through the ultrasound assisted reaction in DMA (entry ates 12a-c reacted with 4 in DMF to give di-substituted
5).6b Propargyl acetate 6d was a poor substrate for this allenes 5a-c in good to excellent yield (entries 1 3). Pro-
transformation; only a traceable amount of 7 was con- pargylic acetates 12d-f, in which the acetoxy group is po-
firmed by 1H NMR.11
sitioned at either the quaternary or benzylic carbon, were
good substrates for this transformation (entries 4-6). From
these reactions, tri-substituted allenes 5d,e and the allene
5f conjugated to phenyl were isolated in good to excellent
yield. Endo-terminal propargylic acetate 12g did not react
with 4 under the conditions and was recovered (entry 7).
1
The structure of 7 was confirmed by means of H NMR
and IR spectroscopy.12 In the H NMR spectrum (400
1
MHz, CDCl3), diagnostic allene protons were observed
at 5.56-5.42 (1H, m) and 5.20 (2H, dddd, JHH = 5.3 Hz,
J
HP = 6.7 Hz, JFH = 6.8, 6.8 Hz), respectively, with the
characteristic H H, H P, and H F couplings. The anti-
symmetrical stretch band for the allene was observed at
1981 cm-1.
R3
R1
R2
XO
R1
4
R3
DMF
CF2PO3Et2
Terminal substituents on the acetylene are known to affect
greatly the regiochemical outcome of the addition of an
organocopper species to propargylic substrates.13,14 Then,
we next examined the steric effects of the terminal substit-
uents on the allene/acetylene distribution for these reac-
tions (Table 2). When the 1-bromo-2-butyne 9a was
treated with 4 in DMF; the reaction gave an inseparable
mixture of the allene 10 and the acetylene 11 in a ratio of
23:77 in 71% yield (entry 1).15 Under the same conditions,
the propargylic tosylate 9b gave an almost 1:1 mixture of
10 and 11 (entry 2). 1-Bromo-2-butyne 9a and the tosylate
9b showed different reactivity toward 4 in THF (entries 3
and 4). 1-Bromo-2-butyne 9a reacted with 4 in favor of
formation of the allene, whereas the tosylate 9b gave the
acetylene 11 in modest selectivity.
R2
12a-g
5a-g
X=Ts or Ac
Scheme 3
Table 3 Synthesis of allenic ( , -difluoromethylene)phosphonates
5a
CH3
CF2PO3Et2
10
X
a All reactions were carried out in DMF at room temperature for 12 h.
4
+
H3C
THF or DMF
CF2PO3Et2
9a,b
H3C
Deprotection of diethyl ester 5c under the conventional
conditions (i TMSBr, CH2Cl2; ii MeOH) gave the free
acid 13 in virtually quantitative yield without affecting the
11
a: X=Br; b: X=OTs
1
Scheme 2
allenic moiety. In the H NMR spectrum (300 MHz,
MeOH-d4), diagnostic allene protons were obserbed at
5.71-5.60 (1H, m) and 5.57-5.43 (1H, m) with the char-
acteristic H H, H P, and H F couplings. The structure
of 13 was also confirmed by FABMS analysis (m/z 213
(MH+)).
Table 2 Reaction of 4 with propargylic substrates 9a,ba
1) TMSBr
i-Pr
i-Pr
CH2Cl2
CF2PO3Et2 2)
CF2PO3H2
MeOH
a
All reactions were carried out at room temperature for 12 h in the
5c
13
b
1
presence of 2.0 equiv of 4. The ratio was determined by H NMR
(300 MHz) analysis.
Scheme 4
Synlett 2001, No. 2, 287–289 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Allenic (α,α-Difluoromethylene)phosphonates
289
(10) The propargylic methylene and terminal acetylenic protons of
8 were observed at 3.02 (tdd, J = 17.5, 5.8, 2.7 Hz) and 2.16
(t, J = 2.8 Hz), respectively, in the 1H NMR spectrum (300
MHz, CDCl3).
(11) The reaction between 4 and the aceteate 6d in DMF gave an
E/Z mixture (1:1) of ( , -difluoroallyl)phosphonates i as
major products:6a
In summary, a facile preparation of novel allenic ( , -di-
fluoromethylene)phosphonates is achieved by CuBr-pro-
moted reaction of BrZnCF2PO3Et2 with readily available
propargylic substrates.
Acknowledgement
OAc
This work was supported in part by Grant-in-Aid for Scientific Re-
search (C) from the Ministry of Education, Science, Sports and Cul-
ture of Japan. We wish to thank Miss Yuka Hosokawa for her skilful
assistance.
OAc
4
+
7
DMF
H
CF2PO3Et2
6d
i
References and Notes
Scheme 5
(1) Blackburn, G. M. Chem. Ind. 1981, 134. Blackburn, G. M.;
Kent, D. E.; Kolmann, F. J. Chem. Soc. Perkin Trans. 1 1984,
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D. G. J. Org. Chem. 1993, 58, 6174. Berkowitz, D. B.; Shen,
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(b) Burton, D. J.; Yang, Z. -Y. Tetrahedron 1992, 48, 189 and
the references cited therein.
(12) All new compounds gave satisfactory spectroscopic (1H-,
19F-, 31P-, 13C NMR, MS and IR) and analytical data.
(13) Schuster, H. F.; Coppola, G. M., Allenes in Organic Synthesis;
A Wiley-Interscience: New York, 1984.
(14) Brandsma, L.; Verkruijsse, H. D. Synthesis of Acetylenes,
Allenes and Cumulenes; Elsevier: Amsterdam, 1981.
(15) The allenyl and methyl protons of 10 were observed at 5.10-
5.01 (m) and 1.87 (t with multiple small splits, J = 4.4 Hz); the
propargylic methylene and terminal methyl protons of 11
were observed at 2.96 (tdd, J = 17.7, 6.0, 2.6 Hz) and 1.81
(t, J = 2.6 Hz), respectively, in the 1H NMR spectrum (400
MHz, CDCl3) of a mixture of 10 and 11.
(5) Lequeux, T. P.; Percy, J. M. Synlett 1995, 361. Blades, K.;
Lapôtre, D.; Percy, J. M. Tetrahedron Lett. 1997, 38, 5895.
(6) (a) Yokomatsu, T.; Suemune, K.; Murano, T.; Shibuya. S. J.
Org. Chem. 1996, 61, 7207. (b) Yokomatsu, T.; Murano, T.;
Suemune, K.; Shibuya, S. Tetrahedron 1997, 53, 815.
(7) (a) Yokomatsu, T.; Abe, H.; Sato, M.; Suemune, K.; Kihara,
T.; Soeda, S.; Shimeno, H.; Shibuya, S. Bioorg. Med. Chem.
1998, 6, 2495. (b) Yokomatsu, T.; Murano, T.; Umesue, I.;
Soeda, S.; Shimeno, H.; Shibuya, S. Bioorg. Med. Chem. Lett.
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Kihara, T.; Soeda, S.; Shimeno, H.; Shibuya, S. Bioorg. Med.
Chem. Lett. 1999, 9, 2833 and references cited therein. (d)
Yokomatsu, T.; Yamagishi, T.; Suemune, K.; Abe, H.; Kihara,
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(8) (a) Shakespeare, W. C.; Bohacek, R. S.; Narula, S. S.;
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Botfield, M. C.; Holt, D. A. Bioorg. Med. Chem. Lett. 1999, 9,
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(9) Burton briefly described a reaction of propargyl chloride with
2 in THF in the presence of copper (I) bromide to give an
allene.4a However, the details of the reaction were not
disclosed.
(16) Typical experimental procedure for the synthesis of 5c:
Copper species 4 was generated in DMF (10 mL) from zinc
dust (650 mg, 10 mmol), diethyl bromodifluoromethyl-
phosphonate (2.67 g, 10 mmol), and copper (I) bromide
(1.43 g, 10 mmol) as described previously.6 To the solution of
4 thus generated in DMF was added a solution of 12c (1.0 g,
5 mmol) in DMF (10 mL) at room temperature. After being
stirred at room temperature for 12 h, water was added to
quench the reaction. The biphasic mixture was passed through
Celite, and extracted with Et2O. The extracts were washed
with brine, dried over MgSO4 and evaporated. The volatile
components of the residue were removed in vacuo (0.05
mmHg, 80 °C) to leave 5c (1.31 g, 98%) as an oil. 1H NMR
(400 MHz, CDCl3) 5.66-5.59 (1H, m), 5.51-5.43 (1H, m),
4.40-4.19 (4H, m), 2.51-2.35 (1H, m), 1.38 (6H, t, J = 7.0 Hz),
1.07 (6H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) 204.28
(m), 115.88 (td, JCP = 221.5 Hz, JCF = 258.6 Hz), 104.51,
88.45 (dt, JCP = 15.8 Hz, JCF = 26.1 Hz), 64.55 (d, JCP = 8.9
Hz), 64.47 (d, JCP = 8.9 Hz), 27.63, 22.00, 21.94, 16.33 (d,
J
J
CP = 5.27 Hz); 31P NMR (162 MHz, CDCl3) 6.89 (t,
PF = 115.1 Hz); 19F NMR (376 MHz, CDCl3, relative to BTF)
42.52 (2F, dddd, JPF = 115.1 Hz, JHF = 11.7, 5.6, 5.6 Hz),
IR (film) 1971, 1273 cm-1. MS (EI) m/z 269 (M++1), 268
(M+). HRMS (EI) calcd for C11H19F2O3P (M+): 268.1040.
Observed: 268.1041.
Article Identifier:
1437-2096,E;2001,0,02,0287,0289,ftx,en;Y20200ST.pdf
Synlett 2001, No. 2, 287–289 ISSN 0936-5214 © Thieme Stuttgart · New York