Palladium- and nickel-catalyzed coupling reactions of α- bromoalkenylphosphonates with arylboronic acids and lithium alkenylborates

Article abstract of DOI:10.1002/adsc.200404191

The coupling reaction of the α-bromoalkenylphosphonates with organoboranes was investigated. The palladium-catalyzed arylation took place successfully with arylboronic acids, while alkenylation proceeded with lithium alkenylborates and a nickel catalyst. In addition, an intramolecular Diels-Alder reaction of the diene prepared by the alkenylation afforded the corresponding adduct.

Full text of DOI:10.1002/adsc.200404191

FULL PAPERS
Palladium- and Nickel-Catalyzed Coupling Reactions of
a-Bromoalkenylphosphonates with Arylboronic Acids and
Lithium Alkenylborates
Yuichi Kobayashi,* Anthony D. William
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259-B52 Nagatsuta-cho, Midori-ku,
Yokohama 226-8501, Japan
Fax: (þ85)-45-924-5789, e-mail: ykobayas@bio.titech.ac.jp
Received: June 21, 2004; Accepted: October 29, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The coupling reaction of the a-bromoalke- reaction of the diene prepared by the alkenylation af-
nylphosphonates with organoboranes was investigat- forded the corresponding adduct.
ed. The palladium-catalyzed arylation took place suc-
cessfully with arylboronic acids, while alkenylation
proceeded with lithium alkenylborates and a nickel Keywords: boranes; borates; cross-coupling; nickel;
catalyst. In addition, an intramolecular Diels–Alder palladium; phosphonates
Introduction
These reactions allow the synthesis of the b-monoalk-
yl-substituted alkenylphosphonates, but are hardly suit-
Substitution of a carboxylic acid unit by a phosphonic able for more substituted alkenylphosphonates, which
acid moiety in biologically active organic compounds would be intermediates for advanced complex ana-
is a promising strategy for increasing the potency and/ logues. Methods for obtaining such phosphonates have
or selectivity of the original activity. The alkenylphos- recently appeared,[10] however, they suffer from low ef-
phonic acids listed in Figure 1 are successful examples ficiency in some cases and/or limited access to the specif-
of this strategy.[1] These alkenylphosphonic (or -ate) ic compounds or to the olefin stereoisomers. With the
groups can be constructed by several reactions[2] such fact that simple alkenylphosphonates are available easi-
as metal-catalyzed coupling reactions of alkenyl halides ly,[3–9] we envisioned the transformation presented in
with HP(O)(OR)2 and P(OR)3,[4] rhodium-catalyzed Scheme 1. The first stage is bromination and dehydro-
[3]
addition of HP(O)(OR)2 to acetylenes,[5] Heck reaction bromination of alkenylphosphonate A to afford a-bro-
of vinylphosphonates,[6] Wittig- and aldol-type reactions moalkenylphosphonate B, and the second stage is tran-
of aldehydes with methylphosphonates,[7] isomerization sition metal-catalyzed coupling reaction of B with aryl-
of allylphosphonates,[8] etc.[9]
or alkenylmetals. Since the influence of the phospho-
nate group on the coupling reaction has not been studied
except for reactions with the reverse combination
(a-metallic alkenylphosphonates with halides),[10d, e]
several coupling reagents such as organoboranes, -bo-
rates, and -zincs were chosen for our investigation. Suzu-
ki–Miyaura coupling[11,12] of B with arylboronic acid/Pd
catalyst proceeded efficiently to produce a-aryl-substi-
tuted alkenylphosphonate C. On the otherhand, alkeny-
lation was achieved with the lithium alkenylborate/Ni
catalyst, which was developed by us recently.[13,14] The
products C could be precursors of the phosphonic acid
versions of the a-arylalkanoic acids,[15] while dienes
D are advanced intermediates for further transfor-
mation.[10a, b,16] The intramolecular Diels–Alder reaction
of dienes D was also studied.[17]
Figure 1. Biologically active alkenylphosphonic acid deriva-
tives.
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Table 1. Preparation of alkenylphosphonates 3 and 4.[a]
Entry
Substrate
No.
Product
No.
X
R1
Yield [%]
1
2
3
4
5
6
1a
1b
1c
2a
2b
2c
Br
I
I
Br
I
I
Me
C5H11
Ph
Me
C5H11
Ph
3a
3b
3c
4a
4b
4c
90
73
80
92
91
87
[a]
Reactions between HP(O)(OEt)2 (1 equiv.) and alkenyl
halides (1.2 equivs.) were carried out with Pd(PPh3)4
(5 mol %) and Et3N (1 equiv.) at 608C for 12 h in THF.
Scheme 1. Carbon-carbon bond formation at the a-position
of alkenylphosphonates.
Table 2. Preparation of a-bromoalkenylphosphonates 5 and
6.
Results and Discussion
Entry
R1
Alkenes
Product and yield [%][a, b]
Synthesis of a-Bromoalkenylphosphonates
5
6
[c]
[c]
1
2
3
4Me
5
6
Me
C5H11
Ph
3a
3b
3c
4a
4b
4c
5a, 61
5b, 73
5c, 4 5
5a, 12
5b, 17
5c, 31
–
–
(Z)- and (E)-alkenylphosphonates 3a–c and 4a–c with
Me, C5H11, and Ph groups as R1 were selected as com-
pounds A and were prepared from the corresponding
(Z)- and (E)-alkenyl halides 1 and 2 by the procedure
of Hirao[3] who originally carried out the phosphoryla-
tion of alkenyl halides with HP(O)(OEt)2 using
Pd(PPh3)4 as a catalyst at 908C in toluene. We modified
the conditions for coupling between HP(O)(OEt)2
(1 equiv.) and (Z)-propenyl bromide 1a (1.2 equivs.) in
order to prevent loss of the volatile bromide 1a
[Eq. (1)].[18] Thus, reaction at 608C in THF for 12 h pro-
duced the (Z)-propenylphosphonate 3a stereospecifi-
cally in 90% yield (Table 1, entry 1). The modified con-
ditions were also successful with (Z)- and (E)-alkenyl
bromides, thus furnishing the alkenylphosphonates 3b,
c and 4a–c in good to high yields (entries 2–6). Proba-
bly due to the steric reason, (E)-isomers 2a–c produced
higher yields of 4a–c than (Z)-isomers 1a–c. The olefin-
ic geometries of the products were established by the
coupling constants between the olefinic protons in the
1H NMR spectra: J¼13–14Hz and J¼ca. 17 Hz were
observed for (Z)-isomers 3a–c and (E)-isomers 4a–c,
6c, 30
6a, 58
6b, 60
6c, 4 7
C5H11
Ph
[a]
Separated by chromatography on silica gel.
Isolated yields.
[b]
[c]
1
Stereoisomer was not detected by H NMR spectroscopy
and TLC analysis.
À
respectively. The vicinal P H coupling constants also
Scheme 2. Preparation of a-bromoalkenylphosphonates. R1
for 3–6: a, Me; b, C5H11; c, Ph.
supported the stereochemistries of 3a, b and 4a, b. The
values, JP, H ¼53 Hz for 3a,b and JP, H ¼22 Hz for 4a, b,
are consistent with literature values for trans and cis re-
lationships of vicinal P and H atoms, respectively.[10f,19]
Bromination of these alkenylphosphonates 3a–c and
4a–c with Br2 proceeded at 108C to room temperature
to produce the crude bromine adducts, which underwent
dehydrobromination with Et3N at 4 08C in CH2Cl2 to af-
ford bromides 5a–c from 3a–c and 6a–c from 4a–c, re-
spectively, in good yields (Scheme 2, Table 2). Although
anti addition of Br2 followed by anti elimination of HBr
was the major stereochemical course, stereoselectivity
varied from quite high (entries 1 and 2) to moderate (en-
ð1Þ
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Pd- and Ni-Catalyzed Coupling Reactions of a-Bromoalkenylphosphonates
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tries 3–6) depending on the substituent R1 and the ole-
fin stereochemistry. Fortunately, differences in Rf values
of the products were large enough to allow easy separa-
tion of the stereoisomers by chromatography on silica
gel.[20]
The stereochemistries of the a-bromoalkenylphosph-
onates 5a–c and 6a–c were unambiguously determined
1
À
by the vicinal P H coupling constants in the H NMR
1
¼
spectra of the P-C(Br) CHR part. Coupling constants
J¼14–16 Hz observed for 5a–c and J¼38–40 Hz for
6a–c were decisive of the cis and trans relations between
the vicinal P and H atoms, respectively.[19]
Scheme 3. Arylation of a-bromoalkenylphosphonates. R1 for
5–8: a, Me; b, C5H11; c, Ph.
Arylation of a-Bromoalkenylphosphonates
Table 3. Arylation of a-bromoalkenylphosphonates 5 and 6.
Entry Substrate R1
Ar
Product,
The palladium-catalyzed coupling reaction of the a-bro-
moalkenylphosphonates 5a–c and 6a–c was investigat-
ed with arylboronic acids, which are reagents of high re-
activity as established by Suzuki and Miyaura
(Scheme 3).[11,12] The results are presented in Table 3.
Phenylation of (Z)-alkenyl bromide 5a with PhB(OH)2
(1.2 equivs.) in a trial experiment under the conditions
reported by Gueiffier[21] with Pd(PPh3)4 (5 mol %) and
Na2CO3 (1 equiv.) at 90–958C for 5 h in DME proceed-
ed without any difficulty (entry 1). Product 7a isolated in
93% yield was free of the stereoisomer 8a by 1H NMR
spectroscopy and TLC analysis. Other boronic acids,
p-MeC6H4B(OH)2 and p-MeOC6H4B(OH)2, showed
similar reactivity to PhB(OH)2 to provide 7b and 7c in
Yield [%][a]
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5b
5c
6a
6b
6c
Me
Me
Me
Me
C5H11 Ph
Ph
Me
C5H11 Ph
Ph Ph
Ph
7a, 93
7b, 89
7c, 91
p-MeC6H4
p-MeOC6H4
¼
p-(CH2 CH)C6H4 7d, 81
7e, 98
7f, 90
8a, 95
8b, 94
8c, 93
Ph
Ph
[a]
Isolated yields by chromatography on silica gel.
good yields (entries 2 and 3). Likewise, p- pling with aryl halides.[10d] This method is, however, re-
(CH2 CH)C6H4B(OH)2 produced 7d in 81% yield (en- stricted to the production of (Z)-isomers 8 and suffers
try 4), which is a new monomer in polymer science. Oth- from low to moderate yields of 20–72%. In contrast,
er alkenyl bromides 5b and 5c with the more bulky C5H11 the present method covers the production of both iso-
and Ph substituents as R1 also produced the phenylation mers (7 and 8) in high yields.
products 7e and 7f, respectively, in good yields with re-
¼
tention of the olefin stereochemistry (entries 5 and 6).
Next, the (E)-isomers 6a–c, which are sterically less Alkenylation of a-Bromoalkenylphosphonates
congested than the (Z)-isomers 5a–c, were subjected
to the coupling reaction. Under the same reaction condi- We next studied alkenylation of (Z)-alkenylphospho-
tions used for the (Z)-isomers, phenylation with nate 5a (R1 ¼Me) with (E)-heptenylboronic acid (9),
PhB(OH)2 proceeded well with retention of the olefin which was selected as a representative alkenylboronic
geometry to afford 6a–c in high yields (Table 3, entries acid. Unfortunately, reaction did not proceed under
7–9).
the arylation conditions described above, and resulted
Olefin stereochemistry of the products 7a–f and 8a, b in recovery of 5a. An attempted reaction with zinc re-
À
was determined by the vicinalP H coupling constants in agent 10 and Pd(PPh3)4 as a catalyst at room tempera-
the 1H NMR spectra, which were 23–24Hz for 7a–f and ture to 508C in THF was also unsuccessful, producing
48 Hz for 8a, b, thus indicating (E)- and (Z)-stereoche- a complex mixture. These results are consistent with
mistries for the olefins, respectively.[19] In the case of the less reactive nature of a-iodoenones in the coupling
8c, the (Z)-geometry was determined on the basis of reaction.[22]
the different pattern of signals from that of 7f of (E)-ge-
ometry, which was assigned by the JP, H value, because
signals of the decisive proton overlapped with those of
other protons.
a-Aryl-substituted alkenylphosphonates have been
synthesized by Srebnik by hydroboration of alkynyl-
phosphonates followed by palladium-catalyzed cou-
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Table 4. Alkenylation of a-bromoalkenylphosphonates with
alkenylborate 11.[a]
Entry R1
Substrate Conditions Product and yield [%][b, c]
13
14
1
2
Me 5a
C5H11 5b
408C, 3 h 13a, 59
408C, 2 h 13b, 57
14a, 17
14b, 19
3
4Me
5
6
Ph
5c
6a
408C, 2 h 13c or 14c, 57
rt., 3 h
rt., 3 h
rt., 3 h
13a, 20
13b, 20
13c or 14c, 65
14a, 66
14b, 74
C5H11 6b
Ph 6c
[a]
Carried out with NiCl2(dppf) (10 mol %) in THF.
Separated by chromatography.
Isolated yields.
[b]
[c]
We have recently developed a highly reactive system
of borates and a Ni catalyst for coupling reactions[13]
with sterically congested 1-bromo-1-alkenes[14] and
with secondary allylic esters.[23] This reagent system
was applied to the alkenylation with 5a. Thus, MeLi
(1.5 equivs.) was added to a mixture of boronate ester
12[14a] (1.5 equivs.) and NiCl2(dppf) (10 mol %) in THF
to generate lithium borate 11 and an active Ni(0) cata-
lyst. Reaction of 5a (1 equiv.) with the mixture was
slow at room temperature, but proceeded at 408C effi-
ciently to afford diene 13a (R1 ¼Me) in 59% yield ac-
companied by stereoisomer 14a (R1 ¼Me) in 17% yield
(Scheme 4; Table 4, entry 1). The dienes were easily sep-
arated by chromatography on silica gel because of the
large difference in Rf values between 13a and 14a
[DRf ¼0.17, hexane/EtOAc (2:3)].
Scheme 4. Alkenylation of bromides 5 and 6 with (E)-alke-
nylborate 11. R1 for 5, 6, 13, 14: a, Me; b, C5H11; c, Ph.
Similarly, reaction of alkenyl bromide 5b (R1 ¼C5H11)
with borate 11 under the above conditions afforded 13b
and 14b in 57% and 19% yields, respectively, after chro-
matography (DRf ¼0.17) (entry 2). In contrast to the
(Z)-bromides 5a and 5b, the less congested (E)-isomers
6a and 6b underwent coupling with 11 at room temper-
ature giving 14a (R1 ¼Me) and 14b (R1 ¼C5H11) as the
major products (entries 4and 5).
In contrast to the above bromides 5a,b and 6a,b, the
coupling reaction of (Z)-alkenyl bromide 5c (R1 ¼Ph)
with borate 11 afforded a single product of the unidenti-
¼
Scheme 5. Alkenylation of a more congested combination.
fied olefin geometry at the PC C(H)Ph unit in 57% 1H NMR spectra, which are consistent with literature
yield (entry 3). The same product was produced as a values for the olefin isomers (Figure 2).[19] However,
sole product from (E)-isomer 6c as well (entry 6).
overlap of proton Ha and the aromatic protons in 13c
With the protocol for the alkenyl coupling in hand, we or 14c (derived from 5c and 6c) prevented determina-
next studied the reaction of (Z)-olefin 5a (R1 ¼Me) with tion of the JP,Ha
.
(Z)-borate 16[14a] (Scheme 5). Both olefin 5a and borate
16 are sterically more congested than the corresponding
stereoisomers. Nevertheless, the coupling did proceed Diels–Alder Reaction of the Dienes
cleanly at 408C to produce diene 17 in 59% yield along
with the isomer 18 in 19% yield after chromatography The alkenyl coupling products are electron-poor dienes
(DRf ¼0.15) (Scheme 5).
and Diels–Alder reaction of these dienes attracts much
The olefin stereochemistry in the coupling products attention. We synthesized diene 21 and examined the in-
13a, b, 14a, b, 17, and 18 was determined unambiguously tramolecular Diels–Alder reaction of 25 derived from
on the basis of the vicinal coupling constants in the 21 through alcohol 22 (Scheme 6).
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Figure 2. Coupling constants of dienes. R1: a, Me; b, C5H11, c,
Ph.
The requisite boronate ester 19 was prepared from
acetylene 29, which was first converted into iodide 30
by hydrozirconation[24] followed by iodination in 80%
yield (Scheme 7). Lithiation and subsequent reaction
of the alkenyl anion with B(O-i-Pr)3, according to the
procedure of Brown,[25] afforded boronic acid 31 after
hydrolysis. Finally, esterification with Me2C(CH2OH)2
furnished 19 in 74% yield.
Scheme 6. Synthesis of dienes and their Diels–Alder reaction.
Coupling of the (E)-bromide 6a with borate 20 de-
rived from 19 and MeLi proceeded at room temperature
to afford 21 and the stereoisomer 23 in 64% and 20%
yields, respectively (Scheme 6). After separation of the
Scheme 7. Synthesis of boronate ester 19. (a) Cp2ZrCl2,
LiBHEt3 then I2; (b) (i) n-BuLi, (ii) B(O-i-Pr)3, (iii) H2O;
products by chromatography, 21 was converted into vi- (c) Me2C(CH2OH)2, MgSO4.
nyl ether 25 in good yield through 22. The Diels–Alder
reaction was carried out at 160–1708C for 17 h to afford
26 in 55% yield. The stereochemistry of the product was structures and functionalities which we hope will be use-
tentatively assigned on the basis of the literature prece- ful in the pharmaceutical field as well as in the field of
dents for similar full-carbon structures.[26] On the other polymer science as building blocks for complex phos-
hand, the vinyl ether 27 derived from the stereoisomer phonates.
23 decomposed totally upon heating.
Experimental Section
Conclusion
We have synthesized functionalized a-bromoalkenyl-
phosphonates in good yields and utilized them success-
fully in the Suzuki–Miyaura coupling reaction with aryl-
boronic acids/Pd catalyst. We have also studied the alke-
nylation of a-bromoalkenylphoshonates, which pro-
ceeded with (E)- as well as (Z)-alkenylborates/Ni cata-
lyst. The products obtained from these coupling
General Remarks
The 1H NMR spectra were taken in CDCl3 at 300 MHz other-
wise unless noted. The 31P MR spectra were measured in
CDCl3 at 121.5 MHz. Infrared (IR) spectra are reported in
wave numbers (cmÀ1). The following solvents were distilled
before use: THF (from Na/benzophenone), Et2O (from Na/
benzophenone), and CH2Cl2 (from CaH2). An ethereal solu-
reactions are a new class of phosphonates with unique tion of MeLi (1.0 M) was prepared from MeI and Li metal in
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Et2O, titrated, and stocked under argon atmosphere. Et2O and
THF were distilled from sodium benzophenone ketyl. All reac-
tions sensitive to O2 or moisture were conducted under argon
atmosphere in dried flasks. Routinely, the products were ex-
tracted with appropriate solvents. The combined extracts
were dried over MgSO4 and, after concentration under vac-
uum, the crude products were purified by chromatography
on silica gel using a mixture of hexane and EtOAc as eluent.
Typical Procedure for Arylation: Synthesis of Diethyl
(E)-1-Phenyl-1-propenylphosphonate (7a)
To a solution of 5a (100 mg, 0.389 mmol) and Pd(PPh3)4
(22 mg, 0.019 mmol) in DME (5 mL) were added PhB(OH)2
(57 mg, 0.47 mmol) and aqueous Na2CO3 (41 mg, 0.39 mmol)
in H2O (1 mL). The mixture was stirred at 90–958C for 5 h
and cooled to room temperature. Brine and EtOAc were add-
ed to the mixture and the organic layer was separated. The
aqueous layer was extracted with EtOAc twice. The combined
extracts were dried and concentrated to afford an oil, which
was purified by chromatography (hexane/EtOAc) to furnish
Typical Procedure for Phosphorylation: Synthesis of
Diethyl (Z)-1-Propenylphosphonate (3a)
7a; yield: 92 mg (93%). IR (neat): n¼1250, 1025, 963 cmÀ1
;
1H NMR: d¼1.25 (t, J¼7 Hz, 6H), 1.73 (dd, J¼7, 3.5 Hz,
3H), 3.98–4.14 (m, 4H), 6.98 (dq, J¼23, 7 Hz, 1H), 7.18–
7.40 (m, 5H); 31P NMR: d¼17.7; anal. calcd. for C13H19O3P:
C 61.41, H 7.53; found: C 61.22, H 7.65.
To a solution of cis bromide 1a (1.12 mL, 13.0 mmol),
HP(O)(OEt)2 (1.40 mL, 10.9 mmol), and Et3N (1.51 mL,
10.9 mmol) in THF (20 mL) was added Pd(PPh3)4 (627 mg,
0.543 mmol). The mixture was stirred at 60 8C for 12 h. After
being cooled to 08C, the mixture was diluted with EtOAc
and saturated NaHCO3 (1:1, 30 mL). The organic layer was
separated and the aqueous layer was extracted with EtOAc
twice. The combined extracts were dried and concentrated to
give an oil, which was purified by chromatography to furnish
3a; yield: 1.74g (90%); IR (neat): n¼1628, 1250, 1027,
Brief experimental procedures for and the spectral data of
7b–f and 8a–c are presented in the Supporting Information.
Typical Procedure for Alkenylation: Synthesis of
Diethyl (E)-1-[(E)-1-Heptenyl]-1-
propenylphosphonate (13a) and Diethyl (Z)-1-[(E)-1-
1
962 cmÀ1; H NMR d¼1.33 (t, J¼7 Hz, 6H), 2.09 (dq, J¼7,
1.5 Hz, 3H), 4.09 (dq, J¼7.5, 7 Hz, 4H), 5.61 (ddq, J¼20, 13, Heptenyl]-1-propenylphosphonate (14a)
1.5 Hz, 1H), 6.58 (ddq, J¼53, 13, 7 Hz, 1H); 31P NMR: d¼
To an ice-cold solution of NiCl2(dppf) (27 mg, 0.039 mmol) and
17.0; anal. calcd. for C12H17O3P: C 59.99, H 7.13; found: C
60.21, H 7.43.
trans-boronate ester 12 (122 mg, 0.58 mmol) in THF (5 mL)
was added MeLi (0.58 mL, 1.0 M in Et2O, 0.58 mmol), and
the resulting dark brown solution was stirred at 08C for
10 min to prepare the solution of borate 11 and active nickel
species. To this was added cis-bromide 5a (100 mg,
0.389 mmol). The resulting solution was stirred at 408C for
3 h, cooled to 08C, and diluted with saturated NaHCO3 and
EtOAc. The organic layer was separated and the aqueous layer
was extracted with EtOAc twice. The combined organic layers
were washed with brine, dried, and concentrated to afford an
oil, which was purified by chromatography tofurnish 13a; yield:
63 mg (59%) and its isomer 14a; yield: 18 mg (17%).
Brief experimental procedures for and the spectral data of
3b, c and 4a–c are presented in the Supporting Information.
Typical Procedure for the a-Bromoalkenylphosponates:
Synthesis of Diethyl (Z)-1-Bromo-1-
propenylphosphonate (5a)
To an ice-cold solution of 3a (1.93 g, 10.84mmol) in CCl 4
(25 mL) was added dropwise bromine (0.62 mL, 12 mmol).
The resulting solution was stirred at room temperature for
1.5 h. After being cooled to 08C, the reaction was quenched
with aqueous Na2S2O3. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 twice. The com-
bined extracts were dried and concentrated to afford the bro-
mine adduct, which was used as such for the next reaction.
1H NMR: d¼1.38 (t, J¼7 Hz, 6H), 1.87 (d, J¼7 Hz, 3H),
4.13 (dd, J¼13, 4 Hz, 1H), 4.18–4.34 (m, 4H), 4.51–4.64 (m,
1H).
trans Phosphonate 13a: IR (neat): n¼1252, 1025, 969 cmÀ1
;
1H NMR: d¼0.86 (t, J¼7 Hz, 3H), 1.19–1.45 (m, 12H), 1.86
(dd, J¼7, 3.5 Hz, 3H), 2.11 (q, J¼7 Hz, 2H), 3.90–4.12 (m,
4H), 6.02–6.15 (m, 1H), 6.15 (dd, J¼24, 16 Hz, 1H), 6.62
(dq, J¼23, 7 Hz, 1H); 31P NMR: d¼19.8.
The spectral data of the minor isomer 14a are presented in
the Supporting Information.
Brief experimental procedures for and the spectral data of
13b, diene (13c or 14c), and 14a, b are presented in the Support-
ing Information.
To an ice-cold solution of the above bromine adduct (3.64g)
in CH2Cl2 (25 mL) was added dropwise Et3N (3.02 mL,
21.7 mmol). The resulting solution was stirred at 408C for
3 h. After being cooled to 08C, the solution was poured into
1 N HCl with CH2Cl2. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 twice. The com-
bined organic layers were washed with brine, dried, and con-
centrated to afford an oil, which was purified by chromatogra-
phy to furnish cis bromide 5a; yield: 1.70 g (61%). IR (neat): n¼
Reaction of 5a with 16
According to the typical procedure for the alkenylation, a mix-
ture of cis-bromide 5a (100 mg, 0.389 mmol), boronate ester 15
(122 mg, 0.58 mmol), MeLi (0.58 mL, 1.0 M in Et2O,
0.58 mmol), and NiCl2(dppf) (27 mg, 0.039 mmol) in THF
(5 mL) was stirred at 408C for 3 h to furnish 17; yield: 62 mg
(59%) and its isomer 18; yield: 20 mg (19%).
1
1623, 1252, 1022, 973 cmÀ1; H NMR d 1.36 (dt, J¼1, 7 Hz,
6H), 1.95 (dd, J¼6.5, 3 Hz, 3H), 4.00–4.23 (m, 4H), 7.24 (dq,
J¼14, 6.5 Hz, 1H); 31P NMR: d¼9.3.
trans Phosphonate 17: IR (neat): n¼1624, 1251, 1028,
1
Brief experimental procedures for and the spectral data of
5b, c and 6a–c are presented in the Supporting Information.
962 cmÀ1; H NMR (300 MHz, CDCl3): d¼0.85 (t, J¼7 Hz,
3H), 1.22–1.39 (m, 12H), 1.71 (ddd, J¼7, 3.5, 1.5 Hz, 3H),
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Pd- and Ni-Catalyzed Coupling Reactions of a-Bromoalkenylphosphonates
FULL PAPERS
1.82–1.93 (m, 2H), 3.92–4.12 (m, 4H), 5.62–5.78 (m, 2H), 6.69
(dq, J¼24, 7 Hz, 1H); 31P NMR: d¼18.6. The multiplet at dH ¼
5.62–5.78 was resolved at 500 MHz (CDCl3) into d¼5.70 (ddt,
J¼11, 1, 6.5 Hz, 1H) and 5.76 (dm, J¼11 Hz, 1H).
1H NMR (300 MHz, CDCl3): d¼0.87 (t, J¼7 Hz, 3H), 1.22–
1.38 (m, 12H), 2.06–2.17 (m, 5H), 3.98–4.13 (m, 4H), 5.56
(dt, J¼11, 7 Hz, 1H), 5.92 (dm, J¼11 Hz, 1H), 6.31 (dq, J¼
51, 7 Hz, 1H); 31P NMR: d¼16.9.
both of which were independently subjected to deprotection
with Bu4NF as follows.
To an ice-cold solution of 21 (90 mg, 0.248 mmol) in THF
(5 mL) was added Bu4NF (0.37 mL, 1.0 M in THF,
0.37 mmol). After being stirred at room temperature for 1 h,
the solution was cooled to 08C and diluted with saturated
NaHCO3. The mixture was extracted with CH2Cl2 twice to af-
ford an oily product, which was purified by chromatography to
furnish cis-phosphonate 22; yield: 60 mg (98%). IR (neat): n¼
3411, 1233, 1024, 969 cmÀ1; 1H NMR: d¼1.33 (t, J¼7 Hz, 6H),
2.12 (dd, J¼7.5, 3.5 Hz, 3H), 2.10–2.22 (m, 1H), 2.35 (q, J¼
6.5 Hz, 2H), 3.67 (t, J¼6.5 Hz, 2H), 3.98–4.18 (m, 4H), 5.95
(dt, J¼16, 7 Hz, 1H), 6.12 (t, J¼16 Hz, 1H), 6.52 (dq, J¼48,
7 Hz, 1H); 31P NMR: d¼15.0.
cis Phosphonate 18: IR (neat): n¼1249, 1026, 963 cmÀ1
;
(E)-{4-[(tert-Butyldimethylsilyl)oxy]-1-butenyl}-1,3,2-
dioxaborolane (19)
Similarly, olefin isomer 23 was converted into alcohol 24 in
To a flask containing Cp2ZrCl2 (3.49 g, 11.9 mmol) was added
super hydride (11.9 mL, 1.0 M in THF, 11.9 mmol). After being
stirred at room temperature in the dark for 2 h, acetylene 29
(1.0 g, 5.43 mmol) in THF (10 mL) was added. The mixture
was stirred for additional 30 min and cooled to 08C. To this
was added I2 (1.65 g, 6.50 mmol). After 10 min of stirring, the
reaction was quenched by addition of saturated NaHCO3 and
EtOAc (1:1, 10 mL). The organic layer was separated and
the aqueous layer was extracted with EtOAc twice. The com-
bined organic layers were washed with brine, dried, and con-
centrated to afford an oil, which was purified by chromatogra-
phy to furnish iodide 30; yield: 1.35 g (80%).
99% yield. IR (neat): n¼3400, 1235, 1025, 970, 794 cmÀ1
;
1H NMR: d¼1.32 (t, J¼7 Hz, 6H), 1.91 (dd, J¼7, 3.5 Hz,
3H), 1.95–2.15 (m, 1H), 2.42 (q, J¼6.5 Hz, 2H), 3.71 (t, J¼
6.5 Hz, 2H), 3.96–4.19 (m, 4H), 6.13 (dt, J¼16, 7 Hz, 1H),
6.31 (dd, J¼27, 16 Hz, 1H), 6.67 (dq, J¼23, 7 Hz, 1H).
Diethyl (Z)-1-[(E)-4-Vinyloxy-1-butenyl]-1-
propenylphosphonate (25)
A solution of 22 (200 mg, 0.805 mmol) and Hg(OAc)2 (52 mg,
0.081 mmol) in ethyl vinyl ether (2 mL) was refluxed for 24h,
cooled to 08C, and diluted with aqueous K2CO3. The product
was extracted with EtOAc twice to afford an oil, which was pu-
rified bychromatography to furnish 25;yield: 143 mg (65%). IR
(neat): n¼1618, 1245, 1199, 1024, 968 cmÀ1; 1H NMR: d¼1.29
(t, J¼7 Hz, 6H), 2.10 (dd, J¼7.5, 3.5 Hz, 3H), 2.42 (q, J¼7 Hz,
2H), 3.70 (t, J¼7 Hz, 2H), 3.94–4.18 (m, 6H), 5.93 (dt, J¼16,
6.5 Hz, 1H), 6.08 (t, J¼16 Hz, 1H), 6.42 (dd, J¼14, 7 Hz, 1H),
6.49 (dq, J¼48, 7.5 Hz, 1H).
To a solution of 30 (900 mg, 2.88 mmol) in THF (10 mL) at
À788C was added n-BuLi (1.45 mL, 2.37 M in hexane,
3.44 mmol). After being stirred at À788C for 1 h, B(O-i-Pr)3
(0.66 mL, 2.86 mmol) was added to the solution. The reaction
was carried out for 2 h and quenched by pouring into saturated
NH4Cl. The mixture was extracted with EtOAc twice. The
combined solutions of the crude boronic acid 31 were used
for the next reaction without concentration.
To the solution of the crude boronic acid 31 were added
MgSO4 (0.35 g, 2.88 mmol) and 2,2-dimethyl-1,3-propanediol
(329 mg, 3.16 mmol). After being stirred at room temperature
for 12 h, the reaction mixture was filtered through a pad of Cel-
ite and the filtrate was concentrated to afford an oil, which was
purified by chromatography to furnish 19; yield: 636 mg (74%).
Diels–Alder Reaction of 25
IR (neat): n¼1640, 1476, 1415, 1256, 1093, 836, 776 cmÀ1
;
A solution of 25 (60 mg, 0.219 mmol) in toluene (5 mL) in a
sealed tube was heated at 160–1708C for 15 h. The solvent
was removed under vacuum to afford an oil, which was purified
by chromatography to furnish 26; yield: 33 mg (55%). IR
1H NMR: d¼0.04(s, 6H), 0.88 (s, 9H), 0.96 (s, 6H), 2.31–2.44
(m, 2H), 3.62 (s, 4H), 3.68 (t, J¼7 Hz, 2H), 5.40 (dt, J¼18,
1.5 Hz, 1H), 6.50 (dt, J¼18, 7 Hz, 1H).
(neat): n¼1243, 1025, 963 cmÀ1
;
1H NMR: d¼1.25 (d, J¼
7 Hz, 3H), 1.32 (t, J¼7 Hz, 6H), 1.67–2.32 (m, 4H), 2.43–
2.56 (m, 1H), 2.78–2.94(m, 1H), 3.65–4.25 (m, 7H), 6.68 (dd,
J¼23, 2.5 Hz, 1H); 31P NMR: d¼20.1.
Diethyl (Z)-1-[(E)-4-Hydroxy-1-butenyl]-1-
propenylphosphonate (22) and Diethyl (E)-1-[(E)-4-
Hydroxy-1-butenyl)-1-propenylphosphonate (24)
To an ice-cold solution of NiCl2(dppf) (27 mg, 0.039 mmol) and
trans-boronate ester 19 (174mg, 0.583 mmol) in THF (5 mL)
was added MeLi (0.58 mL, 1.0 M in Et2O, 0.583 mmol). The
solution was stirred at 08C for 10 min to prepare borate 20.
To this was added trans-bromide 6a (100 mg, 0.389 mmol)
and the reaction was carried out at room temperature for 3 h.
The mixture was cooled to 08C and diluted with saturated
NaHCO3. The organic layer was separated and the aqueous
layer was extracted with EtOAc twice. The combined organic
layers were washed with brine, dried, and concentrated to af-
ford an oil, which was purified by chromatography to furnish
21; yield: 90 mg (64%) and its isomer 23; yield: 28 mg (20%),
Diethyl (E)-1-[(E)-4-Vinyloxy-1-butenyl]-1-
propenylphosphonate (27)
A solution of 24 (250 mg, 1.00 mmol) and Hg(OAc)2 (65 mg,
0.101 mmol) in ethyl vinyl ether (2 mL) was refluxed for 24h
to furnish 27; yield: 198 mg (72%). IR (neat): n¼1617, 1249,
1199, 1025, 968 cmÀ1
;
1H NMR: d¼1.25 (t, J¼7 Hz, 6H),
1.85 (dd, J¼7, 3.5 Hz, 3H), 2.46 (q, J¼7 Hz, 2H), 3.70 (t, J¼
7 Hz, 2H), 3.91–4.15 (m, 6H), 6.09 (dt, J¼16, 7 Hz, 1H), 6.25
(dd, J¼26, 16 Hz, 1H), 6.40 (dd, J¼14, 7 Hz, 1H), 6.65 (dq,
J¼23, 7 Hz, 1H).
Adv. Synth. Catal. 2004, 346, 1749–1757
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ꢀ 2004WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Yuichi Kobayashi, Anthony D .William
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Acknowledgements
This workwas supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Cul-
ture, Government of Japan.
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