Enantio- and regioselective heck-type reaction of arylboronic acids with 2,3-dihydrofuran

Article abstract of DOI:10.1021/jo070170v

(Figure Presented) Reported herein is a protocol for the enantioselective Pd(II)-catalyzed Heck-type reaction between arylboronic acids and 2,3-dihydrofuran. The highest chemical and optical yields were obtained when a Pd(OAc)₂/(R)-MeO(bipheny

Full text of DOI:10.1021/jo070170v

Enantio- and Regioselective Heck-Type Reaction of Arylboronic
Acids with 2,3-Dihydrofuran
Liza Penn, Alina Shpruhman, and Dmitri Gelman*
Department of Organic Chemistry, The Hebrew UniVersity of Jerusalem, Jerusalem, 91904 Israel
dgelman@chem.ch.huji.ac.il
ReceiVed January 31, 2007
Reported herein is a protocol for the enantioselective Pd(II)-catalyzed Heck-type reaction between
arylboronic acids and 2,3-dihydrofuran. The highest chemical and optical yields were obtained when a
Pd(OAc)2/(R)-MeO(biphenylphosphine) or a Pd(OAc)2/(R)-(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)
catalyst and a Cu(OAc)2 reoxidant were employed.
Introduction
extremely prolonged reaction times are normally required to
obtain satisfactory results (up to 9 days in some cases).6 Second,
enantioselectivity erosion is often observed when substrates
other than aryl/vinyl trifluoromethansulfonates (triflates) or
iodides are employed;7 when considering that efficient enan-
tiodifferentiation (at the olefin coordination and migratory
insertion steps) apparently requires a simultaneous coordination
of the palladium center to both the chiral diphosphine and the
prochiral olefin, a partial loss of enantioselectivity is the result
of the competition between cationic and neutral reaction
pathways (Scheme 1).8 As a consequence, the scope of
asymmetric MH reactions is mainly limited to aryl/vinyl triflates
and iodides, which tend to react according to the cationic
mechanism.7,9
Nowadays, the asymmetric palladium-catalyzed Mizoroki-
Heck (MH) reaction is a well-established and powerful method
for the construction of tertiary and quaternary chiral centers.1
Although both the intramolecular and intermolecular transfor-
mations are often used as key strategic steps in the syntheses
of complex polycyclic molecules2 and valuable synthetic
intermediates such as dihydrofurans,3 dihydropyrroles,4 and
cycloalkenes,5 there is still room for further improvements. First,
(1) (a) Shibasaki, M.; Miyazaki, F. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i. Ed., John Wiley & Sons:
New Jersey, 2002. (b) Palladium in Organic Synthesis; Tsuji, J. Ed.,
Springer: Heidelberg, Germany, 2005; Vol. 14. (c) Shibasaki, M.; Vogl,
E. M. J. Organomet. Chem. 1999, 1. (d) Dounay, A. B.; Overman, L. E.
Chem. ReV. 2003, 103, 2945.
(2) (a) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org.
Chem. 1993, 58, 6949. (b) Ashimori, A.; Bachand, B.; Overman, L. E.;
Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477. (c) Mizutani, T.; Honzawa,
S.; Tosaki, S.-Y.; Shibasaki, M. Angew. Chem., Int. Ed. 2002, 41, 4680.
(d) Enders, D.; Lenzen, A.; Backes, M.; Janeck, C.; Catlin, K.; Lannou,
M.-I.; Runsink, J.; Raabe, G. J. Org. Chem. 2005, 70, 10538. (e) Campos,
K. R.; Journet, M.; Lee, S.; Grabowski, E. J. J.; Tillyer, R. D. J. Org. Chem.
2005, 70, 268. (f) Enders, D.; Lenzen, A.; Raabe, G. Angew. Chem., Int.
Ed. 2005, 44, 3766.
(3) (a) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113,
1417. (b) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T. Organometallics
1993, 12, 4188. (c) Hennessy, A. J.; Connolly, D. J.; Malone, Y. M.; Guiry,
P. J. Tetrahedron Lett. 2000, 41, 7757. (d) Nilsson, P.; Gold, H.; Larhed,
M.; Hallberg, A. Synthesis 2002, 1611. (e) Kilroy, T. G.; Hennessy, A. J.;
Connolly, D. J.; Malone, Y. M.; Farrell, A.; Guiry, P. J. J. Mol. Catal. A
2003, 196, 65. (f) Tu, T.; Deng, W.-P.; Hou, X.-L.; Dai, L.-X.; Dong, X.-
C. Chem.sEur. J. 2003, 9, 3073. (g) Mata, Y.; Dieguez, M.; Pamies, O.;
Claver, C. Org. Lett. 2005, 7, 5597.
(5) (a) Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54,
4738. (b) De la Rosa, J. C.; Diaz, N.; Carretero, J. C. Tetrahedron Lett.
2000, 41, 4107. (c) Gilbertson, S. R.; Fu, Z. Org. Lett. 2001, 3, 161. (d)
Gilbertson, S. R.; Xie, D.; Fu, Z. J. Org. Chem. 2001, 66, 7240.
(6) (a) Ozawa, F.; Kubo, A.; Hayashi, T. Tetrahedron Lett. 1992, 33,
1485. (b) Trabesinger, G.; Albinati, A.; Feiken, N.; Kunz, R. W.; Pregosin,
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(b) Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571.
(8) (a) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 254. (b)
Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. (c) Only
several asymmetric Heck-type transformations that are catalyzed by
transition metal complexes bearing monodentate ligands are known. See
for example Imbos, R.; Minnaard, A. J.; Feringa B. L. J. Am. Chem. Soc.
2002, 124, 184.
(9) (a) Karabelas, K.; Westerlund, C.; Hallberg, A. J. Org. Chem. 1985,
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(4) Tu T.; Hou X.-L.; Dai L.-X. Org. Lett. 2003, 5, 3651.
10.1021/jo070170v CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/10/2007
J. Org. Chem. 2007, 72, 3875-3879
3875

Penn et al.
from an independent report by Mikami.15 Mikami and co-
workers demonstrated for the first time that an enantioselective
Pd(II)/Chiraphos-catalyzed organoboron-mediated Heck-type
reaction is, indeed, possible. Unfortunately, the reported trans-
formation was limited to 4-trifluorometyl-phenylboronic acid
and alkyl 1-cyclopentene-1-carboxylates.
SCHEME 1. Cationic vs Neutral Pathway in an
Asymmetric MH Reaction
Herein, we describe our catalytic system that demonstrates a
higher enantioselectivity and a wider reaction scope.
SCHEME 2. Electrophile-Mediated Pd(0)-Catalyzed vs
Nucleophile-Mediated Pd(II)-Catalyzed MH-Type Reaction
Results and Discussion
A set of optimization experiments was carried out to discover
suitable reaction conditions. Initially, we examined the arylation
of 2,3-dihydrofuran by phenylboronic acid in the presence of
Pd(OAc)2/rac-(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (rac-
BINAP) catalyst (eq 1). We found that the thermodynamically
more stable 2-phenyl-2,3-dihydrofuran could be obtained almost
exclusively at room temperature, in a THF medium, in the
presence of a stoichiometric amount of Cu(OAc)2 reoxidant,
and without a base applied. Remarkably, the regioselectivity
of the reaction was affected neither by the presence of inorganic
bases (K3PO4, K2CO3, and Na2CO3) nor by air as a re- or co-
oxidant, and comparable results in terms of regioselectivity were
obtained. In addition, the formation of biphenyl (a likely
byproduct) was negligible.
The related transformation, namely, the nucleophile-mediated
Pd(II)-catalyzed MH reaction, appears as an attractive alternative
to its classical counterpart (Scheme 2).
Performing transmetallation as the initial step (instead of
oxidative addition) and then performing reoxidation of the
palladium catalyst (following reductive elimination) as the final
step of the catalytic cycle distinguish between the two methods.
Indeed, a number of protocols utilizing silanols,10 organostan-
nates,11 and organoboron nucleophiles12 in the MH-type reaction
have been recently described. A priori, if a suitable catalytic
system for the asymmetric version of this transformation
(Scheme 3) is found, then one can expect the above-mentioned
limitations to be eliminated. First, because no halogen-
palladium species are involved in the catalytic cycle, the reaction
is likely to proceed via the cationic pathway, which improves
the optical yield. Second, the “bottleneck” oxidative addition
step (at least for catalysts bearing bidentate ligands)13 is replaced
by a simple transmetallation step.14 Therefore, the reaction times
may be reasonably shortened without making the reaction
conditions more harsh.
It is also noteworthy that phenylboronic acid had to be used
as a limiting reagent under our reaction conditions. When we
used an inverted phenylboronic acid/2,3-dihydrofuran (2,3-DHF)
ratio, we observed the formation of a significant amount of
4-hydroxy-1,4-diphenylbutan-1-one. Apparently, this product is
a result of the double arylation of 2,3-DHF that is followed by
isomerization and ring-opening of the intermediate (Scheme 4).16
A possible weak point of the initial protocol is the use of
oxidizable phosphine ligands under oxidative conditions. To our
surprise, the oxidation of BINAP was not extensive; the blank
experiment performed under similar reaction conditions, but in
the absence of 2,3-DHF, led to only ca. 10% BINAPO (based
on GC analysis). Unfortunately, this oxidation process was not
the only catalyst deactivation pathway. The formation of
triphenylphosphine was also observed, mainly, when the reaction
was carried out in the presence of air. This less expected
byproduct likely originates from a Pd-Phenyl/P-Phenyl2 ex-
change, which is a common and well-documented decomposi-
tion path for (PAr3)2Pd(Ar)X complexes (a Novak-type reac-
tion).17 However, this process was not extensive under airfree
conditions; thus, only a slight excess of the ligand (1.5:1) was
necessary for a successful transformation.
Some time ago, we initiated a research program that aimed
to explore the reaction. However, “the proof of concept” came
(10) (a) Hirabayashi, K.; Nishihara, Y.; Mori, A.; Hiyama, T. Tetrahedron
Lett. 1998, 39, 7893. (b) Hirabayashi, K.; Kondo, T.; Toriyama, F.;
Nishihara, Y.; Mori, A. Bull. Chem. Soc. Jpn. 2000, 73, 749. (c) Hirabayashi,
K.; Ando, J.; Kawashima, J.; Nishihara, Y.; Mori, A.; Hiyama, T. Bull.
Chem. Soc. Jpn. 2000, 73, 1409.
(11) (a) Oda, H.; Morishita, M.; Fugami, K.; Sano, H.; Kosugi, M. Chem.
Lett. 1996, 811. (b) Fugami, K.; Hagiwara, S.; Oda, H.; Kosugi, M. Synlett
1998, 477. (c) Hirabayashi, K.; Ando, J.; Nishihara, Y.; Mori, A.; Hiyama,
T. Synlett 1999, 99. (d) Parrish, J. P.; Jung, Y. C.; Shin, S. I.; Jung, K. W.
J. Org. Chem. 2002, 67, 7127.
(12) (a) Du, X.; Suguro, M.; Hirabayashi, K.; Mori, A. Org. Lett. 2001,
3, 3313. (b) Jung, Y. C.; Mishra, R. K.; Yoon, C. H.; Jung, K. W. Org.
Lett. 2003, 5, 2231. (c) Yoon, C. H.; Yoo, K. S.; Yi, S. W.; Mishra, R. K.;
Jung, K. W. Org. Lett. 2004, 6, 4037. (d) Andappan, M. M. S.; Nilsson, P.;
Larhed, M. Chem. Commun. 2004, 218. (e) Andappan, M. M. S.; Nilsson,
P.; von Schenck, H.; Larhed, M. J. Org. Chem. 2004, 69, 5212. (f) Yoo,
K. S.; Yoon, C. H.; Jung K. W. J. Am. Chem. Soc. 2006, 128, 16384.
(13) Although kinetics might change depending on the catalyst/reactants
combination (See for example Rosner, T.; Le Bars, J.; Pfaltz, A.; Blackmond,
D. G. J. Am. Chem. Soc. 2001, 123, 1848.), oxidative addition is very often
a rate-limiting step for catalysts bearing bidentate ligands. (a) Jutand, A.;
Mosleh, A. Organometallics 1995, 14, 1810. (b) Beletskaya, I. P.;
Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
Having these results in hand, experiments with the best
combinations of reagents were repeated in the presence of (R)-
BINAP. The representative results (Table 1) clearly show that
the presence of dioxygen either as a co-oxidant (entries 1-4,
Table 1) or as the only reoxidant (entry 5, Table 1) always led
to reduced chemical and optical yields; apparently, this is
(15) Akiyama, K.; Wakabayashi, K.; Mikami, K. AdV. Synth. Catal. 2005,
347, 1569.
(16) (a) Hedtmann, U.; Welzel, P. Tetrahedron Lett. 1985, 26, 2773. (b)
Takahashi, S.; Fujisawa, K.; Sakairi, N.; Nakata, T. Heterocycles 2000,
53, 1361.
(14) (a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 13978. (b) Navarro, O.; Kelly, R. A., III.; Nolan, S. P. J.
Am. Chem. Soc. 2003, 125, 16194. (c) Zhou, J.; Fu, G. C. J. Am. Chem.
Soc. 2003, 125, 14726.
3876 J. Org. Chem., Vol. 72, No. 10, 2007

SelectiVe Heck-Type Reaction of Arylboronic Acids
TABLE 1. Representative Optimization Results
TABLE 2. Chiral Ligands for Enantioselective Heck-Type
Reaction
entry
conditions
yield, %a
ee, %b
1
2
3
4
5
6
7
8d
Cu(OAc)2, K2CO3, air, RT
Cu(OAc)2, Na2CO3, air, RT
Cu(OAc)2, K3PO4, air, RT
Cu(OAc)2, no base, air, RT
K2CO3, air, RT
Cu(OAc)2, K2CO3, no air, RT
Cu(OAc)2, no base, no air, RT
Cu(OAc)2, no base, no air, 15 °C
34
29
31
33
17
46
69
63
41
45
41
43
n/dc
57
57
61
entry
ligand
yield, %a
ee, %b
1
2
3
4
5
6
(R)-BINAP
69
36
63
trace
trace
trace
57
28
(R)-3,5-xyl-BINAP
(R)-MeOBiphep
(S,S)-chiraphos
83
n/dc
n/dc
n/dc
(R,R)-DIOP
2,2′-Bis[(4S)-4-benzyl-2-oxazoline]
a Yield based on 1H NMR. b The ee was determined by chiral GC-
chromatography (Chiraldex G-TA). c None detected.
a Yield based on 1H NMR. b The ee was determined by chiral GC
chromatography (Chiraldex G-TA). c None detected. d The reaction was
carried out at 5 °C.
may be achieved only when para- or meta- substituted arylbo-
ronic acids are used (with one exception). At the same time,
the electronic nature of the substituent does not appear to affect
the reaction outcome. Thus, both electron-rich (entries 1, 7, and
8, Table 3) and electron-poor (entries 3-5 and 10, Table 3)
starting materials result in the formation of enantioenriched
2-aryl-2,3-dihydrofurans in comparable yields and with 63-
85% ee. In all of these cases, (R)-MeOBiphep demonstrates a
clear superiority over the (R)-BINAP ligand (42-57% ee for
the last).
because of the enhanced ligand destruction. However, the use
of inorganic bases did not affect the enantioselectivity but only
affected the efficacy of the reaction (entry 6 vs 7, Table 1). It
is possible that excessive acetate ions can efficiently facilitate
the initial transmetallation step.18 Thus, strong basic and airfree
conditions were beneficial in terms of chemical and optical
yields (entry 7, Table 1). Further, a very slight improvement
can be achieved by performing the reaction at a lower temper-
ature; the desired product was obtained in 63% yield and 61%
enantiomeric excess (ee, entry 8, Table 1).
Unfortunately, enantioselectivity drops significantly when an
ortho substituent is present. For instance, o-tolylboronic and
1-naphthylboronic acids led to the formation of essentially
racemic products in the presence of (R)-MeOBiphep. Remark-
ably, the previously less efficient (R)-BINAP was slightly
superior in these cases (entries 2 and 9, Table 3). However, the
reaction of 2-chlorophenylboronic acid (entry 6, Table 3) was
again enantioselective, but it demonstrated an inconsiderable
superiority of BINAP for ortho-substituted starting materials
(86 vs 82%). The last result appears to indicate that electronic
factors may also play a role in some cases.
Other chiral ligands were examined as well (Table 2). It is
noteworthy that only the use of biphenyl-based diphosphines
was advantageous (entries 1-3, Table 2). The best result was
obtained with commercially available (R)-MeO(biphenylphos-
phine) (biphenylphosphine ) Biphep), which showed a superior
enantioselectivity without a notable difference in chemical yield.
Nonoxidizable nitrogen-based ligands such as oxazolines (entry
6, Table 2) and flexible diphosphines (DIOP and Chiraphos)
did not work well under our reaction conditions.
The scope and limitations of the suggested transformation
were studied at this point. The results of the study are tabulated
in Table 3. All of the reactions were performed using both (R)-
BINAP and (R)-MeOBiphep/Pd(OAc)2 catalysts.
It is not yet clear if relatively high enantioselectivities under
our reaction conditions are achieved because of the efficient
enantiodifferentiation at the migratory-insertion step or because
of a possible kinetic resolution that may take place during the
In general, we found that the reaction is highly sensitive to
the steric properties of the starting materials and that high ee
SCHEME 3. Nucleophile-Mediated Pd(II)-Catalyzed Pathway (blue) vs Nucleophile-Mediated Pd(0)-Catalyzed Pathway (red)
in the Asymmetric MH-Type Reaction
J. Org. Chem, Vol. 72, No. 10, 2007 3877

Penn et al.
TABLE 3. Scope of the Enantioselective Heck-Type Reaction
1
a Isolated yield (average of two runs). b The ee was determined by HPLC using a Chiralpack AD column. c The ee was determined by H NMR using
(+)-Pr(hfc)3 as a reagent.
SCHEME 4
In conclusion, we demonstrated for the first time that the
Mizoroki-Heck type reaction of arylboronic acids with isomer-
izable olefins can be performed in a highly enantio- and
regioselective fashion. Further investigation of this reaction with
other olefins and attempts to improve the chemical yield and
to possibly apply the method to the synthesis of more complex
molecules are in progress.
isomerization of the kinetic 2-phenyl-2,5-dihydrofuran into the
thermodynamic 2-phenyl-2,3-dihydrofuran (Scheme 3).3b On the
basis of the fact that we do not observe the accumulation of the
kinetic product at any stage of the reaction, we can speculate
that the isomerization is fast and, therefore, has little effect if
any on enantioselectivity. However, a deeper insight into the
mechanism of the enantioselection process might be obtained
after detailed kinetic studies.
Experimental Section
Representative Procedure for the Enantioselective Orga-
noboron-Mediated Heck-Type Reaction. Both (R)-MeOBiphep
(29 mg, 0.05 mmol) and Cu(OAc)2 (120 mg, 0.66 mmol) were
added to a solution of Pd(OAc)2 (7.4 mg, 0.033 mmol) in a single-
use screw-capped tube that was equipped with a stir bar. Air was
replaced with 99.999% N2 by means of three evacuation/refill
cycles. A solution of 2,3-DHF (100 µL, 1.32 mmol) in THF (1
mL) was added to the mixture, and the blue suspension was stirred
for 20 min. Phenylboronic acid (80 mg, 0.66 mmol) in 3 mL of
(17) On Pd-mediated P-C cleavage see (a) Herrmann, W. A.; Brossmer,
C.; Ofele, K.; Beller, M.; Fischer, H. J. Organomet. Chem. 1995, 491, C1.
(b) Kong, K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113, 6313. (c)
Baranano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 2937. (d)
Goodson, F. E.; Wallow, T. I.; Novak, B. M. J. Am. Chem. Soc. 1997, 119,
12441. (e) Mann, G.; Baranano, D.; Hartwig, J. F.; Rheingold, A. L.; Guzei,
I. A. J. Am. Chem. Soc. 1998, 120, 9205. (f) Grushin, V. V. Organomeallics
2000, 19, 1888.
(18) van Berkel, S. S.; van den Hoogenband, A.; Terpstra, J. W.; Tromp,
M.; van Leeuwen, P. W. N. M.; van Strijdonck, G. P. F. Tetrahedron Lett.
2004, 45, 7659.
3878 J. Org. Chem., Vol. 72, No. 10, 2007

SelectiVe Heck-Type Reaction of Arylboronic Acids
THF was injected, and the reaction mixture was allowed to stir for
12 h at room temperature. Following the end of the mixing time,
the mixture was diluted with EtOAc, filtered through a pad of Celite,
washed with water and brine, and dried with MgSO4. The solution
was evaporated under reduced pressure, and the residue was purified
by column chromatography to give (S)-2,3-dihydro-2-phenylfuran
(64 mg, 67%). HPLC (Chiralpack AD, hexane: i-PrOH 99.9:0.1,
1.0 mL/min): (S)-isomer tR ) 9.06 min, (R)-isomer tR ) 7.8 min;
MHz, CDCl3): δ 145.3, 143.0, 128,5, 127.6, 125.6, 99.0, 82.3, 37.8;
MS (70 eV, EL) m/z: 145 [M+], 117, 115, 91.
Acknowledgment. We thank the German-Israeli Foundation
for Scientific Research and Development (Grant No. I-2096-
1393.5/2004) for financial support.
Supporting Information Available: 1H and 13C NMR spectra
and enantiomeric purity determination for all compounds listed in
Table 3. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
82% ee; H NMR (300 MHz, CDCl3): δ ) 7.41-7.29 (5H, m),
6.51-6.48 (1H, m), 5.53 (1H, dd, J ) 10.7, 8.4 Hz), 5.01-4.98
(1H, m), 3.17-3.06 (1H, m), 2.69-2.60 (1H, m); 13C NMR (75
JO070170V
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