Coupling reactions of α-bromoalkenyl phosphonates with aryl boronic acids and alkenyl borates

Article abstract of DOI:10.1021/ol020167s

(equation presented) Transition metal-catalyzed arylation and alkenylation of the α-bromoalkenyl phosphonates were investigated with organoboranes and -borates. Arylation was successful with the aryl boronic acids and a palladium catalyst, while alkenylation was found to proceed with alkenyl borates 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:10.1021/ol020167s

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4241-4244
Coupling Reactions of r-Bromoalkenyl
Phosphonates with Aryl Boronic Acids
and Alkenyl Borates
Yuichi Kobayashi* and Anthony D. William
Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received August 20, 2002 (Revised Manuscript Received October 21, 2002)
ABSTRACT
Transition metal-catalyzed arylation and alkenylation of the r-bromoalkenyl phosphonates were investigated with organoboranes and -borates.
Arylation was successful with the aryl boronic acids and a palladium catalyst, while alkenylation was found to proceed with alkenyl borates
and a nickel catalyst. In addition, an intramolecular Diels−Alder reaction of the diene prepared by the alkenylation afforded the corresponding
adduct.
Organo phosphonates have been used as substitutes of the
corresponding esters and acids of high biological activity1
and as convenient probes for designing antibodies on the
basis of transition state models.2 These investigations have
been supported by organic synthesis; therefore, development
of protocols for obtaining phosphonates of complex structures
is inevitably important. However, investigation has been
concentrated rather on phosphorylation of organic com-
pounds such as alkynes, alkenes, and aldehydes, and hence
C-C bond formation on simple phosphonates seems left
behind. For example, alkenyl phosphonates with defined
stereochemistry have been prepared by several methods3 such
as palladium-catalyzed coupling reaction of alkenyl halides
and hydrogen phosphonates (HP(O)(OR)2),4 rhodium-cata-
lyzed addition of hydrogen phosphonates to acetylenes,5 and
a Wittig-type reaction with methylenebisphosphonates,6 etc.,7
whereas 1,4-addition8 and other reactions9 of alkenyl phos-
phonates are reactions that have been reported so far. Herein,
(5) Zhao, C.-Q.; Han, L.-B.; Goto, M.; Tanaka, M. Angew. Chem., Int.
Ed. 2001, 40, 1929-1932.
(6) (a) Waszluc, W.; Janecki, T.; Bodalski, R. Synthesis 1984, 1025-
1027. (b) Aboujaoude, E. E.; Lietje, S.; Collignon, N. Teulade, M. P.;
Savignac, P. Tetrahedron Lett. 1985, 26, 4435-4438. (c) Gupta, A.; Sacks,
K.; Khan, S.; Tropp, B. E.; Engel, R. Synth. Commun. 1980, 10, 299-304.
(7) (a) Quntar, A. A. A.; Melman, A.; Srebnik, M. Synlett 2002, 61-
64. (b) Quntar, A. A. A.; Srebnik, M. Org. Lett. 2001, 3, 1379-1381. (c)
Braga, A. L.; de Andrade, L. H.; Silveira, C. C.; Moro, A. V.; Zeni, G.
Tetrahedron Lett. 2001, 42, 8563-8565. (d) Pergament, I.; Srebnik, M.
Tetrahedron Lett. 2001, 42, 8059-8062. (e) Brunner, H.; Courcy, N. L.
C.; Genet, J.-P. Synlett 2000, 201-204. (f) Harnden, M. R.; Parkin, A.;
Parratt, M. J. Perkins, R. M. J. Med. Chem. 1993, 36, 1343-1355. (g) Zhu,
J.; Lu, X. Tetrahedron Lett. 1987, 28, 1897-1900. (h) Lu, X.; Zhu, J. J.
Organomet. Chem. 1986, 304, 239-243. (i) Koizumi, T.; Tanaka, N.; Iwata,
M.; Yoshii, E. Synthesis 1982, 917-918.
(1) (a) Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42, 8211-8213.
(b) Kim, D. Y.; Rhie, D. Y. Tetrahedron 1997, 53, 13603-13608 and
references therein.
(2) (a) Schultz, P.; Lerner, R. A. Acc. Chem. Res. 1993, 26, 391-395.
(b) Stewart, J. D.; Liotta, L. J.; Benkovic, S. J. Acc. Chem. Res. 1993, 26,
396-404. (c) Cox, R. J.; Hadfield, A. T.; Mayo-Mart´ın, M. B. Chem.
Commun. 2001, 1710-1711.
(3) Reviews: (a) Minami, T.; Motoyoshiya, J. Synthesis 1992, 333-
349. (b) Minami, T.; Okauchi, T.; Kouno, R. Synthesis 2001, 349-357.
(4) Hirao, T.; Masunaga, T.; Yamada, N.; Ohshiro, Y.; Agawa, T. Bull.
Chem. Soc. Jpn. 1982, 55, 909-913.
(8) (a) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem.
Soc. 1999, 121, 11591-11592. (b) Nagaoka, Y.; Tomioka, K. Org. Lett.
1999, 1, 1467-1469. (c) Nagaoka, Y.; Tomioka, K. J. Org. Chem. 1998,
63, 6428-6429. (d) Afarinkia, K.; Binch, H. M.; Modi, C. Tetrahedron
Lett. 1998, 39, 7419-7422. (e) Junker, H.-D.; Fessner, W.-D. Tetrahedron
Lett. 1998, 39, 269-272.
(9) (a) Kouno, R.; Tsubota, T.; Okauchi, T.; Minami, T. J. Org. Chem.
2000, 65, 4326-4332. (b) Kouno, R.; Okauchi, T.; Nakamura, M.; Ichikawa,
J.; Minami, T. J. Org. Chem. 1998, 63, 6239-6246.
10.1021/ol020167s CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/01/2002

we report arylation and alkenylation of alkenyl phosphonates
by a method summarized in Scheme 1. Products C would
Table 1. Preparation of R-Bromoalkenyl Phosphonates 3 and 4
productsa and
yields (%)b
Scheme 1. Carbon-Carbon Bond Formation at the R-Position
entry
R1
Me
substrate
major
minor
of Alkenyl Phosphonates
1
2
3
4
5
6
1a
2a
1b
2b
1c
2c
3a (61)
4a (58)
3b (73)
4b (60)
3c (45)
4c (47)
Me
3a (12)
C5H11
C5H11
Ph
3b (17)
4c (30)
3c (31)
Ph
a Separated easily by routine chromatography on silica gel. b Isolated
yields.
anti elimination of HBr was the major stereochemical course,
stereoselectivity was varied from quite high (entries 1 and
3) to moderate (entries 5 and 6) depending on the substituent
R1 and the stereochemistry of the substrates.12 Fortunately,
large differences in Rf values13 of the products allowed easy
purification of the major products by routine chromatography
on silica gel.
be precursors of the phosphonic acid version of R-aryl
alkanoic acids,10 while dienes D are advanced intermediates
for further transformation.
The key reaction is a transition metal-catalyzed coupling
reaction of R-bromo compounds B, derived from alkenyl
phosphonates A, with organometallics. Since information
about the influence of the phosphonate group on the coupling
reaction is limited to the reverse combination (R-phospho-
noalkenyl boranes and stannanes with halides),7c,9b several
coupling reagents such as organoboranes, -borates, and -zincs
were chosen for the investigation. Aryl coupling proceeded
efficiently with the aryl boronic acids. On the other hand,
alkenylation was successful only with organoborates, which
were developed by us recently. In addition, an intramolecular
Diels-Alder reaction of compound D was studied.
Alkenyl phosphonates 1a-c and 2a-c with Me, C5H11,
and Ph groups were selected as compounds A of Scheme 1
and prepared in good yields without contamination of the
stereoisomers by the Hirao method4 with modification.11 As
summarized in Scheme 2, bromination of these alkenyl
Arylation of the R-bromoalkenyl phosphonates 3a-c and
4a-c was investigated with aryl boronic acids, which are
well-established reagents of high reactivity.14 The results are
presented in Table 2.12 Coupling was investigated first with
(Z)-isomer 3a (R1 ) Me), a sterically more congested isomer
than the corresponding (E)-isomer 4a due to the projection
of R1 () Me) toward the reaction site. The phenylation of
3a and PhB(OH)2 proceeded successfully under the condi-
tions reported15 with Pd(PPh3)4 (5 mol %) and Na2CO3 (1
equiv) at 90-95 °C for 5 h in DME to furnish product 5a in
93% yield (entry 1). No isomer of 5a (i.e., 6a) was detected
1
by TLC analysis and H NMR spectroscopy. Substrates 3b
and 3c with the more bulky C5H11 and Ph substituents as R1
also produced the phenylation products 5e and 5f, respec-
tively, in good yields with retention of the stereochemistry
(entries 5 and 6). As for boronic acids, p-Me-C6H4-B(OH)2
and p-MeO-C6H4-B(OH)2 showed reactivity similar to that
of PhB(OH)2 in the reaction with 3a to provide 5b and 5c
in good yields (entries 2 and 3). Likewise, p-(CH2dCH)-
Scheme 2a
(10) Goulioukina, N. S.; Dolgina, T. M.; Beletskaya, I. P.; Henry, J.-C.;
Lavergne, D.; Ratovelomanana-Vidal, V.; Genet, J.-P. Tetrahedron: Asym-
metry 2001, 12, 319-327 and references therein.
(11) Kobayashi, Y.; William, A. D.; Tokoro, Y. J. Org. Chem. 2001,
66, 7903-7906.
(12) Stereochemistry of the phosphonate group-attached olefin in com-
pounds 3a-c, 4a-c, 5a-f, 6a-c, 10a,b, 11a,b, 13, 16, and 17 was
1
determined by coupling counstants between vicinal H and P atoms in H
NMR spectra, which are given in Supporting Information. See ref 7a and
the following refs for general information about coupling constants: (a)
Kenyon, G. L.; Westheimer, F. H. J. Am. Chem. Soc. 1966, 88, 3557-
3561. (b) Borowitz, I. J.; Yee, K. C.; Crouch, R. K. J. Org. Chem. 1973,
38, 1713-1718. (c) Teulade, M.-P.; Savignac, P. J. Organomet. Chem. 1986,
304, 283-300.
a R1 for 1-4: a, Me; b, C5H11; c, Ph.
(13) Rf values of the products: 3a ) 0.26 and 4a ) 0.39 with 2:3 hexane/
EtOAc; 3b ) 0.53 and 4b ) 0.66 with 2: 3 hexane/EtOAc; 3c ) 0.21 and
4c ) 0.26 with 1:1 hexane/EtOAc.
phosphonates at 10 °C-rt followed by reaction of the crude
bromine adducts with Et3N at 40 °C in CH2Cl2 afforded
bromides 3a-c from 1a-c and 4a-c from 2a-c in good
yields (Table 1). Although anti addition of Br2 followed by
(14) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am. Chem. Soc.
1985, 107, 972-980.
(15) Enguehard, C.; Renou, J.-L.; Collot, V.; Hervet, M.; Rault, S.;
Gueiffier, A. J. Org. Chem. 2000, 65, 6572-6575.
4242
Org. Lett., Vol. 4, No. 24, 2002

These results recall the less reactive nature of R-iodo
enones to the coupling reaction.16 After several fruitless
reactions, borate 917 with a nickel catalyst, a reagent system
developed by us for coupling with sterically congested cis
alkenyl bromides,18 was found to furnish the coupling product
10a (R1 ) Me). Although <20% was recorded under the
original reaction conditions (NiCl2(dppf), rt, THF), a slightly
higher temperature of 40 °C raised the yield to 59% (Table
3, entry 1), though accompanied with stereoisomer 11a (R1
Table 2. Arylation of 3a-c and 4a-c
products
(yield, %)a
entry
substrate
R1
Me
Me
Me
Me
C5H11
Ph
Me
C5H11
Ph
Ar
Table 3. Coupling Reaction of 3a,b and 4a,b with Alkenyl
Reagent 9 and a Nickel Catalysta
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3b
3c
4a
4b
4c
Ph
5a (93)
5b (89)
5c (91)
5d (81)
5e (98)
5f (90)
6a (95)
6b (94)
6c (95)
p-MeC6H4
p-MeOC6H4
p-(CH2dCH)C6H4
productsc and
yields (%)d
entry
R1
Me
C5H11
Me
substrate
conditionsb
1
2
3
4
3a
3b
4a
4b
40 °C, 3 h
40 °C, 2 h
rt, 3 h
10a , 59
11a , 17
11b, 19
11a , 66
11b, 74
Ph
Ph
Ph
Ph
Ph
10b, 57
10a , 20
10b, 20
C5H11
rt, 3 h
a NiCl2(dppf) (5-10 mol %). b THF was used as a solvent. c Separated
easily by routine chromatography on silica gel. d Isolated yields.
a Isolated yield.
) Me) in 17% yield. Fortunately, 10a and 11a were easily
separated by routine chromatography on silica gel because
of the large difference in Rf values between 10a and 11a
(∆Rf ) 0.17 with 2:3 hexane/EtOAc). Similarly, 3b afforded
10b (R1 ) C5H11) and 11b in 57 and 19% yields, respec-
tively, with ∆Rf of 0.17 (entry 2). Reaction of less congested
(Z)-isomers 4a and 4b proceeded at room temperature to
afford 11a (R1 ) Me) and 11b (R1 ) C5H11) as the major
products (entries 3 and 4).19
The above protocol with a borate/Ni catalyst was extended
to the sterically more congested borate 12,17 which furnished
product 1312 in 59% yield with the isomer in 19% yield (∆Rf
) 0.15) (eq 1).
C6H4-B(OH)2 produced 5d in 81% yield (entry 4), which is
a new monomer in polymer science.
Next examined was phenylation of (E)-isomers 4a-c,
which under the same reaction conditions used for the (Z)-
isomers proceeded smoothly to furnish 6a-c in high yields
(entries 7-9).
Recently, synthesis of R-aryl compounds of type 6 has
been reported by Srebnik.7d This method is, however,
restricted to production of (Z)-isomers 6 and suffers from
moderate to low yields of 72-20%. On the contrary, the
present method covers production of both isomers in high
yields.
In contrast to the above arylation, alkenylation of 3a with
heptenylboronic acid (7) (Figure 1), which was selected as
Recently, dienes of type 11 have been synthesized through
zirconacycles.7a However, the present method is more flexible
in providing other stereoisomers such as 10 and 13, the latter
of which is the most congested diene.
Figure 1. Alkenyl reagents 7-9 we examined for coupling with
3 and 4; coupling products 10 and 11 were obtained from 9.
(16) Negishi, E.; Owczarczyk, Z. R.; Swanson, D. R. Tetrahedron Lett.
1991, 32, 4453-4456.
a representative alkenyl boronic acid, did not proceed under
the arylation conditions described above and resulted in
recovery of 3a. Use of zinc reagent 8 and Pd(PPh3)4 as a
catalyst at rt-50 °C in THF was also unsuccessful, producing
a complex mixture.
(17) Prepared from the corresponding boronate ester (structure not shown)
and MeLi (THF, 0 °C, 10-15 min).
(18) (a) Kobayashi, Y.; Nakayama, Y.; Mizojiri, R. Tetrahedron 1998,
54, 1053-1062. (b) Nakayama, Y.; Kumar, G. B.; Kobayashi, Y. J. Org.
Chem. 2000, 65, 707-715.
Org. Lett., Vol. 4, No. 24, 2002
4243

we investigated briefly the intramolecular Diels-Alder
reaction of 17, which was prepared by coupling reaction
between bromide 4a and borate 1517 followed by deprotection
of the TBS group and subsequent vinylation (Scheme 3).
Diels-Alder reaction of 17 proceeded successfully at 160-
170 °C in toluene for 15 h to produce adduct 18 in 55%
yield.
Scheme 3. Diels-Alder Reaction of Diene 18
In conclusion, we have shown arylation and alkenylation
of R-bromoalkenyl phosphonates. The products are a new
class of phosphonates with unique structures and function-
alities and will be useful in fields such as pharmacology and
polymer science.20
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports, and Culture, Japan.
Supporting Information Available: Typical experimen-
tal procedures, spectral data for all new compounds, and a
list of alkenyl phosphonates with coupling constants used
for determination of the olefin geometries. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Stereochemistry shown in the structure is that tentatively
assigned.
OL020167S
(19) Alkenylation of bormides 3c and 4c wtih 9 proceeded as well.
However, products from 3c and 4c were identical by 1H NMR spectroscopy
and TLC analysis. Unfortunately, the stereochemistry of the trisubstituted
olefin of the product could not be determined because of overlap of the
signals.
The multifunctional groups of the products are attractive
for further transformation to more complex compounds.
Asymmetric hydroxylation, asymmetric hydrogenation, Di-
els-Alder reaction, and 1,4-addition are such reactions. Thus,
(20) All new compounds were characterized by IR and 1H NMR spectra.
4244
Org. Lett., Vol. 4, No. 24, 2002