Palladium-Catalyzed Enantioselective Intermolecular Carboetherification of Dihydrofurans

Article abstract of DOI:10.1021/jacs.6b02158

A novel enantioselective Pd-catalyzed intermolecular carboetherification of dihydrofurans is reported. The in situ generation of chiral bis-phosphine mono-oxide ligands is crucial, and a general catalytic system has been identified based on this approach. It provides access to a variety of fused tetrahydrofurobenzofurans in consistently high yield and enantiomeric excess.

Full text of DOI:10.1021/jacs.6b02158

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Communication
Palladium-Catalyzed Enantioselective
Intermolecular Carboetherification of Dihydrofurans
Gustavo M. Borrajo Calleja, Vincent Bizet, and Clément Mazet
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02158 • Publication Date (Web): 15 Mar 2016
Downloaded from http://pubs.acs.org on March 15, 2016
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Palladium-Catalyzed Enantioselective Intermolecular
Carboetherification of Dihydrofurans
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Gustavo M. Borrajo-Calleja, Vincent Bizet, Clément Mazet*
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva, Switzerland.
Supporting Information Placeholder
In this communication, we describe the first examples of
enantioselective
carboetherifications
ABSTRACT:
intermolecular carboetherification of dihydrofurans is
reported. The in situ generation of chiral
A
novel enantioselective Pd-catalyzed
intermolecular
of olefins
Pd-catalyzed
affording
syn-
fused
tetrahydrofurobenzofurans in good yield and excellent level
of enantiomeric excess.
bisphosphinemonooxide (BPMO) ligands is crucial and a
general catalytic system has been identified based on this
Table 1. Reaction optimizationa
approach. It provides access to
a variety of fused
tetrahydrofurobenzofurans in consistently high yield and
enantiomeric excess.
The 2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran scaffold is
frequently found in biologically active compounds such as
Asperversin A or Aflatoxin B2, a potent mutagen (Figure 1,
A).1 Nonetheless, direct access to this synthetic motif
remains particularly challenging and only a handful of
enantioselective approaches has been disclosed.2 We
envisaged that the effective development of a Pd-catalyzed
enantioselective intermolecular carboetherification starting
from 2,3-dihydrofurans (dhf) and 2-halophenol derivatives
would provide direct access to this pattern (A on Figure 1, B).
Despite recent and remarkable advances in the field, such a
process is notably absent from the current portfolio of
carboetherification of alkenes.3 Importantly, most reported
examples proceed via intramolecular reactions and their
enantioselective variants are still scarce.4 Importantly, we
anticipated that the successful realization of this goal would
require circumventing the formation of the competing α-
etherification and Heck products B and C that may form
under typically basic cross-coupling reaction conditions.5,6
entry
ligand
t (h)
24
24
24
24
24
24
24
24
4
T (°C)
110
110
110
110
110
110
110
110
50
yield (%)b
1
L1 (CPhos)
56
2
3
L2 (DavePhos)
L3 (XPhos)
nr
nr
4
5
6
7
8
9
10
L4 (JohnPhos)
L5 (tBuDavePhos)
L6 (tBuXPhos)
L7 (TrixiePhos)
L8 (RuPhos)
L8 (RuPhos)
L8 (RuPhos)
L8 (RuPhos)
nr
45
68
36
73
traces
56c
73
6
110
80
11
4
a
b
c
Reaction conditions: 1 (1.0 mmol), 2a (0.2 mmol).
Determined after purification by column chromatography.
Using 2-chlorophenol.
In our exploratory experiments, we investigated the
coupling between 2,3-dihydrofuran 1a and 2-bromophenol 2a
Figure 1. Biologically active tetrahydrofurobenzofurans
(A) and proposed intermolecular carboetherification of
dihydrofuran (B).
using
CPhos
(L1),
a
prototypical
monodentate
biarylphosphine ligand (Table 1, Entry 1).7 After a rapid
survey of various reaction parameters, we were delighted to
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find that 3a could be formed exclusively and isolated in 56%
in situ generation of chiral bis-monophosphine oxide ligands
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8
yield after heating at 110°C a toluene solution for 24 h using
tBuONa (1.5 equiv.) and Pd2(dba)3 (2.5 mol%). In an attempt
to improve reactivity, additional Buchwald-type phosphine
ligands were evaluated next. Whereas L2 (DavePhos), L3
(XPhos) and L4 (JohnPhos) did not prove competent for this
transformation, the sterically demanding L5 (tBuDavePhos),
L6 (tBuXPhos) and L7 (TrixiePhos) all afforded 3a in
moderate to acceptable yield (45%, 68% and 36% yield
respectively; Table 1, Entry 2-7). Satisfactorily, with L8
(RuPhos), the yield was improved to 73%. This performance
could be maintained even when the reaction was performed
at lower temperature and in a much reduced time (80°C, 4 h;
Table 1, Entry 11). Of note, products 4a and 5a were only
detected when other bases or ligands were employed. Higher
yields were obtained using a 5:1 stoichiometry between 2,3-
dhf 1a and 2-bromophenol 2a (see Supporting Information
for details).
(BMPO) starting from their commercially available
bisphosphine precursors (Table 3). Our approach was
inspired by the seminal contributions of Ozawa and Hayashi
who demonstrated that Binap(O) could be generated in situ
under basic conditions using Pd(OAc)2 and controlled
amount of added water.13 Very recent reports from Li and
Belik, and Eastgate and Blackmond are also in line with this
approach.14-15
Table 3. Effect of added water and final evaluation of
chiral ligandsa
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Table 2. Chiral ligand surveya
ent ligand
ry
[Pd]
H2O
yield ee
(5 mol%)
(5 mol%)b (mol%) (%)c
(%)d
nd
92
90
83
1
DTBM-Segphos
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
-
-
-
nr
8
2
3
4
5
6
7
8
9
L14
DTBM-Segphos
16
31
DTBM-Segphos
Pd(OAc)2 20
Pd(OAc)2 40
Pd(OAc)2 60
Pd(OAc)2 40
Pd(OAc)2 40
Pd(OAc)2 40
Pd(OAc)2 40
DTBM-Segphos
40
35
76
66
31
85
81
DTBM-Segphos
L15
L16
L17
L18
90
90
65
92
a
Reaction conditions: 1a (1 mmol), 2a (0.2 mmol). Yields of
10
74
a
b
isolated products after purification. Enantioselectivity
determined by HPLC using a chiral column.
Reaction conditions: 1a (1 mmol), 2a (0.2 mmol).
Concentration in Pd. c After purification by chromatography.
d Determined by HPLC using a chiral column.
We next turned to the development of an enantioselective
version of this intermolecular carboetherification reaction
using the same model reaction between 1a and 2a (Table 2).
Reasoning that the MOP-type ligands originally designed by
Hayashi may constitute closely related structural analogues
of RuPhos, ligand L9 was evaluated first.8 After 24 h at 110°C,
3a was isolated in reasonable yield but in almost racemic
form (64% yield, 5% ee). The less basic Binol-based
phosphoramidite ligand (L10) and Taddol-based phosphite
ligand (L11) which were recently found to be suitable ligands
in a related intramolecular carboalkoxylation of alkenes only
generated traces of the carboetherification product 3a along
with minute amount of 5a.4g Interestingly, whereas Binap
(L12) was ineffective in the carboetherification reaction, its
corresponding monoxide Binap(O) (L13) delivered 3a in 15%
yield and 27% ee. These results are consistent with the notion
that Binap(O) is a hemilabile ligand that behaves temporarily
as a monodentate chiral phosphine ligand.9-11 With another
member of this ligand class, DTBM-Segphos(O) (L14), 3a was
still obtained in modest yield but in excellent enantiomeric
excess (92% ee).12
The model reaction between 1a and 2a was therefore
carried out using the bisphosphine ligand DTBM-Segphos (5
mol%), Pd(OAc)2 (5 mol%) and variable amounts of water
(0-60 mol%). Although reactivity was observed in the
absence of water, the optimal result was obtained when 40
mol% of water were added in the mixture (entry 3-6). The
yield in carboetherification product 3a was significantly
improved while the erosion in enantioselectivity remained
acceptable. Subsequently, a range of commercially available
bisphophines was evaluated (see SI for details). From this
screening, it clearly appeared that ligands of the Biphep
family (L15-18) with sterically demanding and electron-rich
aryl substituents were particularly well-suited candidates
(Table 3, entry 7-10).12 Gratifyingly, with L18 the
carboetherification product 3a was isolated in 74% yield and
92% ee.
The scope of the reaction was delineated with L18 using
the protocol for in situ mono-oxidation of the ligand (Table
4). Overall, both electron-rich and electron-deficient 2-
bromophenols participated efficiently in the syn-
carboetherification of 2,3-dihydrofuran 1a, delivering the
product in consistently good yield and high level of enantio-
To ensure rapid identification of a lead structure we next
focused on the development of a protocol that would enable
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without noticeable effect on the reaction outcome. However,
Table 4. Scope of the enantioselective intermolecular
carboetherification of 2,3-dihydrofurana
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2
3
when 2-bromo-3-methoxyphenol 2f was employed, both the
reactivity and the enantioselectivity were affected
significantly (3f: 42% yield, 57% ee).
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9
Substituted dihydrofurans are notoriously more difficult to
engage in cross-coupling reactions than their unsubstituted
counterparts.18 Therefore, the influence of substitution on
various positions of the dihydrofuran ring was investigated
next (Figure 2). When 5-methyl-2,3-dihydrofuran 1b was
subjected to the optimized reaction conditions, increasing
the catalyst loading to 10 mol% was required to maintain a
reasonable level of reactivity. The corresponding fused
tetrahydrofurobenzofurans 3l-m with a fully substituted
congested acetal carbon stereocenter were isolated in good
yields and excellent levels of enantioselectivity (Figure 2, A).
Interestingly, 2-(p-tolyl)-2,3-dihydrofuran 1 c – obtained from
an independent Heck cross-coupling reaction5,19 – also
proved a competent partner delivering 3n as a single
diastereoisomer in 67% yield and 91% ee (Figure 2, B). More
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remarkably,
trans-3-methyl-2-(p-tolyl)-2,3-dihydrofuran
1d19,20 afforded the corresponding carboetherification
product 3o with four contiguous stereocenters in 53% yield,
10:1 dr and 96% ee (Figure 2, C). Of note, an optically active
a Reaction conditions: 1a (1 mmol), 2a-k (0.2 mmol). Yields of
isolated products after purification. Enantioselectivity
determined by HPLC or GC using a chiral column. Absolute
configuration of all products is as shown and was assigned by
analogy with the X-ray crystallography analysis of (3S,8R)-
3h.16
tetrahydrofurobenzofurans with
such
a
level
of
stereochemical complexity would certainly be difficult to
prepare by conventional methods.21
In conclusion, we have developed a very general and
unprecedented enantioselective Pd-catalyzed intermolecular
syn-carboetherification of dihydrofurans using in situ
generated chiral bis-monophosphine oxide ligands. The
method gives readily access to synthetically relevant and
stereochemically complex fused tetrahydrofurobenzofurans
in high yield, diastereoselectivity and enantioselectivity.
Further mechanistic studies into the origin of the reactivity
and selectivity of this catalytic system are ongoing in our
laboratories.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization of all new com-
pounds, spectral data and X-ray data for compound 3h
(CCDC 1455966).This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Figure 2. Variation of the dihydrofuran structure. Reaction
conditions: 1b-d (1 mmol), 2a or 2g (0.2 mmol). Yields of
isolated product. Enantioselectivity determined by HPLC or
GC using a chiral column. Diastereomeric ratio measured by
1H NMR of the crude reaction mixture. A) Using 5-methyl-
2,3-dihydrofuran 1b. B) Using rac 2-(p-tolyl)-2,3-
dihydrofuran 1c. Recovered 1c: 37% yield, 12% ee, yield based
on rac-1c. C) Using rac trans-3-methyl-2-(p-tolyl)-2,3-
dihydrofuran 1d. Recovered 1d: 64% yield, 8% ee, yield based
on rac-1d.17
Prof. Clément Mazet. University of Geneva, Organic
Chemistry Department. Quai Ernest Ansermet 30, Geneva
1211 - Switzerland. clement.mazet@unige.ch
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the University of Geneva and the
Swiss National Science Foundation. S. Rosset is
acknowledged for technical assistance, Dr. C. Besnard for
assistance with X-ray analysis, crystallographic data
collection and refinement. Johnson-Matthey is acknowledged
for a generous gift of palladium precursors. This article is
-selectivity (10 examples: 3a-e,g-k 53-91% yield; 85-97% ee).
Interestingly, an electron-withdrawing or an electron-
donating group can be placed indifferently in para position
with respect to the bromine atom or the -OH functionality
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(12) Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N.; Saito, T.
dedicated to Prof. Andreas Pfaltz on the occasion of his
retirement.
Acc. Chem. Res. 2007, 40, 1385.
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(13) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 2177.
(14) (a) Ji, Y.; Plata, E.; Regens, C. S.; Hay, M.; Schmidt, M.;
Razler, T.; Qiu, Y.; Geng, P.; Hsiao, Y.; Rosner, T.; Eastgate,
M. D.; Blackmond, D. G. J. Am. Chem. Soc. 2015, 137, 13272;
(b) Li, H.; Belyk, K. M.; Yin, J.; Chen, Q.; Hyde, A.; Ji, Y.;
Oliver, S.; Tudge, M. T.; Campeau, L.-C.; Campos, K. R. J.
Am. Chem. Soc. 2015, 137, 13728.
(15) For other relevant contributions, see: (a) Fors, B. P.;
Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008, 10,
3505; (b) Boezio, A. A.; Pytkowicz, J.; Côté, A.; Charette, A. B.
J. Am. Chem. Soc. 2005 125, 14260; (c) Jian, H.; Hirao, H.; Li,
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Wu, C.; Zhou J. J. Am. Chem. Soc. 2014, 136, 650
(16) The molecular structure of 3h was generated using CYLview
(Legault, C. Y.: CYLview, version 1.0.561b; Université de
Sherbrooke: Sherbrooke, QC, 2009, http://www.cylview.org.
(17) Byproducts resulting from the isomerization of 1c or 1d were
detected in the 1H NMR analysis of the crude reaction
mixtures. These compounds decomposed upon attempt
purification by column chromatography.
(18) a) Tschoerner, M.; Pregosin, P. S.; Albinati, A.
Organometallics 1999, 18, 670; b) Borrajo-Calleja, G. M.;
Bizet, V.; Bürgi, T.; Mazet, C. Chem. Sci. 2015, 6, 4807; c)
Zhang, Q.-S.; Wan, S.-L.; Chen, D.; Ding, C.-H.; Hou, X.-L.
Chem. Commun. 2015, 51, 12235.
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