Palladium-catalyzed cross-coupling reactions between dihydropyranylindium reagents and aryl halides. Synthesis of C-aryl glycals

Article abstract of DOI:10.1021/ol0345428

(Matrix presented) Palladium(0)-catalyzed cross-coupling reactions between tris(dihydropyranyl)indium 1 and aryl halides 2 have been investigated. Aryl iodides and electron-deficient aryl bromides couple efficiently with the in situ-generated indium reage

Full text of DOI:10.1021/ol0345428

ORGANIC
LETTERS
2
003
Vol. 5, No. 14
405-2408
Palladium-Catalyzed Cross-Coupling
Reactions between
2
Dihydropyranylindium Reagents and
Aryl Halides. Synthesis of C-Aryl
Glycals
Ute Lehmann, Smita Awasthi, and Thomas Minehan*
Department of Chemistry, HarVey Mudd College, Claremont, California 91711
tom_minehan@hmc.edu
Received March 27, 2003
ABSTRACT
Palladium(0)-catalyzed cross-coupling reactions between tris(dihydropyranyl)indium 1 and aryl halides 2 have been investigated. Aryl iodides
3 2
and electron-deficient aryl bromides couple efficiently with the in situ-generated indium reagents in the presence of 1−5 mol % Cl Pd(PPh )
2
to produce substituted dihydropyrans 3 with minimal (<10%) dimer (4) formation. Organoindium reagents derived from D-glucal also undergo
cross couplings with aryl iodides to produce C-aryl glycals.
5
6
Transition metal-catalyzed cross-coupling reactions of or-
ganometallic reagents with organic electrophiles represent
one of the most powerful methods for the construction of
currently of great interest. Sarandeses has recently shown
that triorganoindium reagents can efficiently transfer all three
ligands in palladium- and nickel-catalyzed cross-coupling
1
7
carbon-carbon bonds. Linkages between unsaturated carbon
reactions. There is also evidence that organoindiums undergo
centers can efficiently be formed by palladium- or nickel-
similar cross couplings in aqueous media. This method has
the potential to provide a practical alternative to the problems
catalyzed cross-coupling reactions between aryl and alkenyl
2
(
pseudo)halides and organostannanes (Stille reaction), or-
3
ganoboranes (Suzuki coupling), and organozinc reagents
(
3) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki,
(
Negishi coupling).4
A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 2, p 49.
The development of environmentally friendly and atom-
economical reactions for forming carbon-carbon bonds is
(
4) Negishi, E. In Organozinc Reagents; Knochel, P., Jones, P., Eds.;
Oxford University Press: Oxford, U.K., 1999; Chapter 11.
5) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259. (b) Li,
(
(
1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
C.-J.; Chan, T. H. Organic Reactions in Aqueous Media; John Wiley &
Sons: New York, 1997. (c) Grieco, P. A. Organic Synthesis in Water;
Blackie Academic & Professional: London, 1998. (d) Li, C.-J.; Chan, T.-
H. Tetrahedron 1999, 55, 11149.
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Tsuji, J. Palladium Reagents
and Catalysts. InnoVations in Organic Synthesis; Wiley: Chichester, U.K.,
996. (c) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic
1
Press: New York, 1985.
2) (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction;
Wiley: New York, 1998. (b) Stille, J. K. Angew. Chem., Int. Ed. Engl.
986, 25, 508. (c) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771. (d) Pereye,
M.; Quintard, J.; Rahm, A. Tin in Organic Synthesis; Butterworth: London,
987.
(6) (a) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem. Soc. 2001,
123, 4155. (b) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 1999,
1, 1267. See also: Nomura, R.; Miyazaki, S.-I.; Matsuda, H. J. Am. Chem.
Soc. 1992, 114, 2738.
(7) Takami, K.; Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima,
K. Org. Lett. 2001, 3, 1997.
(
1
1
1
0.1021/ol0345428 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/11/2003

of toxicity (tin) and handling (boron, zinc) associated with
8
other organometallic reagents. In this study, we report that
Table 1. Coupling Reaction of Trisdihydropyranylindium 1
with Aryl Halides
easily prepared tris-(dihydropyranyl)indium reagents cross-
couple with a variety of aryl halides in high yield under
palladium catalysis. The extension of this method to the
9
preparation of C-aryl glycals is also detailed.
Metalation of dihydropyran was accomplished in THF by
treatment with t-BuLi according to the procedure of Boeck-
1
0
man. Addition of a 1.5 M lithiodihydropyran solution to
indium trichloride (33 mol %) in THF produced a cloudy
white suspension of tris(dihydropyranyl)indium 1 that could
be stored under argon with protection from light for several
days without appreciable loss of reactivity (Scheme 1).
entry
2
R
X
equiv 1
% yield of 3 (4)a
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
4-COCH3
4-CO2Et
3-CO2Et
2-CO2Et
4-Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
0.33
0.33
1
1
0.33
1
1
1
0.5
1
1
0.66
72
87
85 (15)b
76
Scheme 1
95
2-NO2
69 (17)c
44 (46)b
87 (6)b
27 (5)c,d
36 (6)
23 (9)
34 (14)
100e
2-CHO
1-naphthyl
4-CH3
4-OCH3
2-OCH3
4-OAc
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
We undertook our investigation of the palladium(0)-
catalyzed cross-coupling reaction by adding one-third of an
equivalent of 1 to a boiling solution of iodobenzene and Pd-
H
0.33
4-CH3
2-CH3
4-OCH3
2-OCH3
I
I
I
I
1
1
1
1
89 (7)c
96 (4)b
88b
89 (5)b
3 2 2
(PPh ) Cl (2 mol %). Within 1 h, consumption of starting
material was complete as evidenced by TLC and GC-MS
analysis. Dihydropyran 3m was obtained in 94% yield after
purification. As has been noted previously, the instability of
a
Because of product volatility/instability, reaction yields were determined
b
by GC-MS analysis. PdCl2(PPh3)2 (3 mol %) was used in the reaction.
PdCl2(PPh3)2 (5 mol %) was used. Yield determined by integration of
aromatic proton signals in H NMR. PdCl2(PPh3)2 (2 mol %) was used.
c
d
the product to air and silica gel necessitated the use of rapid
1
e
flash chromatography with short elution times.11
Reactions of 1 with bromoarenes containing electron-
withdrawing groups gave moderate to high yields of the
desired substituted dihydropyrans (Table 1, entries 1-7) in
the presence of catalytic amounts of palladium salt. Interest-
ingly, both 1-bromo-2-nitrobenzene 2f and 2-bromobenzal-
dehyde 2g required more catalyst (5 and 3 mol %, respec-
tively) and 1 (1 equiv) to reach completion, and in each case
high yields of the desired substituted dihydropyrans were
obtained. However, the use of excess indium reagent (1
equiv) and 3-5 mol % catalyst were required in order to
obtain optimal yields in these cases. Extended reaction times
with either less 1 or lower catalyst loading led to decreased
overall yields.
To investigate the hydrolytic stability of 1, we attempted
a reaction with 2a in a 10:1 THF/MeOH mixture at reflux
3 2 2
for 1 h, employing 3 mol % Pd(PPh ) Cl as a catalyst.
4
(presumably arising from palladium(II)-mediated dimer-
ization of the indium reagent) was obtained in competitive
amounts.
Compound 3a was again obtained but in lower yield (46%).
Consistent with previous observations on the cross-
1
2
Interestingly, subjecting bis(dihydropyranyl)indium chloride
coupling of glycal tin reagents with aryl halides, bromo-
arenes containing electron-donating groups (Table 1, entries
1
3
1
b to the same conditions (2a, 10:1 THF/MeOH, 3 mol %
Pd(PPh Cl ) led to essentially no diminution in the yield
3
)
2
2
9
-12) gave poor yields of coupling product. These reactions
also gave rise to significant amounts (5-14%) of 4. Use of
Pd(PPh as a catalyst did not reduce the amount of dimer
of 3a obtained (69%, Scheme 2). These results, in line with
7
the observations of Oshima, suggest that protic solvents
3 4
)
hydrolyze one ligand from triorganoindium reagents, leaving
the remaining groups to participate in the cross-coupling
reaction. Attempted cross coupling in 10:1 THF/H O gave
2
none of the desired product, and indeed it was found in
general that anhydrous conditions were required to obtain
high yields of cross-coupled product and minimize dimer
formation.
Chan et al. have demonstrated that the active intermediate
in indium-mediated aqueous Barbier reactions is an indium-
formed and gave lower yields of the desired product. Cross-
coupling reactions of the corresponding aryl iodides with 1
were therefore tested. In all cases (Table 1, entries 13-17),
(
8) Anastas, P. T.; Warner, J. C. Green Chemistry; Oxford University
Press: Oxford, 1998; p 29.
9) For previous examples of cross-coupling reactions of tetrahydro-
(
pyranyl organometallics, see ref 11 and also: Mazal, C.; Vaultier, M.
Tetrahedron Lett. 1994, 35, 3089.
(
10) (a) Boeckman, R. J.; Bruza, K. J. Tetrahedron Lett. 1977, 18, 4187.
(
b) Boeckman, R. J.; Bruza, K. J. Tetrahedron 1981, 37, 3997.
(
11) Denmark, S. E.; Neuville, L. Org. Lett. 2000, 2, 3221.
(12) Friesen, R. W.; Loo, R. W.; Sturino, C. F. Can. J. Chem. 1994, 74,
(13) Formed by addition of lithiodihydropyran to a THF solution of 0.5
equiv of indium trichloride.
1
262.
2406
Org. Lett., Vol. 5, No. 14, 2003

Scheme 2
Table 2. Cross-Coupling Reactions of Per-TIPS-glucal 5 with
Aryl Iodides
2a
R
% yield of 6 (7)
b
entry
1
2
3
4
5
6
2a
2d
2h
2o
2q
2p
4-COCH3
2-CO2CH3
1-naphthl
2-CH3
2-OCH3
4-OCH3
55% (<5%)
54% (<5%)
59% (9%)
60% (5%)
60% (<5%)
40% (19%)
I) species;14 furthermore, organoindium (I) reagents have
(
been successfully employed in carbon-carbon bond-forming
reactions in organic solvents.15 However, attempted trans-
metalation of lithiodihydropyran with 1 equiv of InBr led to
the production of indium metal as a grayish-silver precipitate,
and minimal amounts (∼10%) of cross coupling were
a
Used 1.5 equiv of 2. b Yields are of purified material.
2 to 6 equivalents), along with up to 1 equiv of InCl . In all
cases, little or no product formation was observed, likely
3
observed in the presence of 1 mol % Pd(PPh
3
)
2
Cl
2
and
4
-bromoacetophenone after 1 h at reflux.
We next turned our attention to the possibility of using
indicating that the excess base consumes InCl3 before
transmetalation of lithioglucal can occur.
this method to form C-aryl glycals, which have been
employed in the preparation of a variety of biologically
important C-aryl glycosides.16 1-Lithio-3,4,6-tri-O-(triiso-
propylsilyl)-D-glucal, prepared by treatment of per-TIPS
glucal 5 with 1.5 equiv of t-BuLi at -78 °C followed by
stirring at 0 °C for 1.5 h, was added to a solution of 0.5
3
Since 0.5 equiv of InCl and 1.5 equiv of t-BuLi are
employed in the optimized procedure, it is possible that
mono- and/or diglucal indium species are formed during the
2 2
transmetalation (i.e., (glucal)In(t-Bu) or (glucal) In(t-Bu))
1
7
and that these intermediates preferentially transfer their
carbohydrate ligands in the palladium-mediated cross-
coupling reaction.
equiv of InCl
presence of 3 mol % Pd(PPh
3
at -78 °C. Subsequent cross coupling in the
Cl and 2-iodotoluene 2o (1.5
)
3 2
2
The reactions above were also tested in the presence of
protic solvents. Addition of methanol (10 equiv) prior to
addition of the aryl iodide 2o and Pd(PPh ) Cl lowered the
equiv, 24 h, reflux) gave 60% yield of the C-aryl glycal 6o,
along with ∼5% dimer 7 and 35% recovered starting material
3
2
2
(Table 2). Reactions with both electron-deficient (entries
yield of C-aryl glycal 6o obtained (32%). One possible
1-2) and electron-rich (entries 3-6) aryl iodides proceed
explanation is that preferential hydrolysis of one of the glucal
in good yields, and negligible amounts of 7 were detected
in the reaction mixtures (assayed by HNMR of the crude
ligands from an intermediate such as (glucal) In(t-Bu) leads
to an organometallic species that can transfer only one
2
1
material) except for entry 6. Starting material 5 was also
cleanly recovered from these reactions and reused in
subsequent couplings. The use of aryl bromides instead of
aryl iodides uniformly resulted in low yields.18
carbohydrate moiety, giving the observed yield of product.
Addition of water (5-10 equiv) instead of methanol resulted
in formation of an insoluble white precipitate that failed to
Incomplete lithiation of 5 may account for the moderate
yields of C-aryl glycals obtained. To address this issue, the
same reactions were performed with longer deprotonation
times (1.5-3 h) and using a greater excess of t-BuLi (from
Scheme 3
(
(
14) Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228.
15) (a) Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 2000, 122, 402. (b)
Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64, 8214.
16) (a) Parker, K. A.; Georges, A. T. Org. Lett. 2000, 2, 491. (b) Parker,
(
K. A.; Coburn, C. A. J. Org. Chem. 1992, 57, 5547. (c) Friesen, R. W.;
Sturino, C. F. J. Org. Chem. 1990, 55, 5808. (d) Friesen, R. W.; Daljeet,
A. K. Tetrahedron Lett. 1990, 31, 6133. (e) Dubois, E.; Beau, J. M.
Tetrahedron Lett. 1990, 31, 5165. (d) Dubois, E.; Beau, J. M. Carbohydr.
Res. 1992, 223, 157.
(
17) Friesen, R. W. Sturino, C. F.; Daljeet, A. K.; Kolaczewska, A. J.
Org. Chem. 1991, 56, 1944.
18) We have also employed bulky phosphines as ligands for palladium
Pd2dba3/P(t-Bu)3 and Pd2dba3/P(o-tolyl)3) in an attempt to improve yields
(
(
in this process; although these reactions in some cases proceed to completion
in shorter times (4 vs 24 h), the overall yields did not change significantly
from those reported in Table 2.
Org. Lett., Vol. 5, No. 14, 2003
2407

redissolve even at reflux; no C-aryl glycals were formed,
and only starting material was recovered from the reaction
mixture.
The C-aryl glycals obtained in this study can be easily
transformed into C-aryl glycosides by established procedures
reagents typically employed in C-aryl glycal synthesis and
can be performed in the presence of protic solvents.
Acknowledgment. We are grateful for the generous
financial support of this work by the National Science
Foundation (Grant No. 0097262) and the donors of the
Petroleum Research Fund, administered by the American
Chemical Society (PRF # 38271-GB1). The authors also wish
to thank Cole Witham for assisting with the reactions shown
in Scheme 2.
(Scheme 3). Catalytic hydrogenation of compound 6o in the
presence of PtO furnishes the corresponding 2-deoxy-â-C-
2
aryl glycoside 8 in 90% yield; hydroboration/oxidation of
p employing the protocol of Friesen19 produces glycoside
in 40% yield.
6
9
In summary, palladium-mediated cross-coupling reactions
Supporting Information Available: Complete experi-
mental details for all compounds prepared in Tables 1 and
, including spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
of glycalindium (III) compounds offer a practical and
environmentally friendly alternative for obtaining C-aryl
glycals. This one-pot method avoids the use of toxic tin
2
(19) Friesen, R. W.; Daljeet, A. K. Tetrahedron Lett. 1990, 31, 6133.
OL0345428
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Org. Lett., Vol. 5, No. 14, 2003