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Letter
Palladium-Catalyzed Cross-Coupling Reactions between
Dihydropyranylindium Reagents and Aryl Halides. Synthesis of C-Aryl Glycals
Ute Lehmann, Smita Awasthi, and Thomas Minehan
Org. Lett., 2003, 5 (14), 2405-2408 • DOI: 10.1021/ol0345428
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 ORGANIC
LETTERS

Palladium-Catalyzed Cross-Coupling 2003

Vol. 5, No. 14
Reactions between 2405-2408
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

[email protected]

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
and electron-deficient aryl bromides couple efficiently with the in situ-generated indium reagents in the presence of 1−5 mol % Cl2Pd(PPh3)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.

Transition metal-catalyzed cross-coupling reactions of or- currently of great interest.5 Sarandeses6 has recently shown
ganometallic reagents with organic electrophiles represent that triorganoindium reagents can efficiently transfer all three
one of the most powerful methods for the construction of ligands in palladium- and nickel-catalyzed cross-coupling
carbon-carbon bonds.1 Linkages between unsaturated carbon reactions. There is also evidence7 that organoindiums undergo
centers can efficiently be formed by palladium- or nickel- similar cross couplings in aqueous media. This method has
catalyzed cross-coupling reactions between aryl and alkenyl the potential to provide a practical alternative to the problems
(pseudo)halides and organostannanes (Stille reaction),2 or-
ganoboranes (Suzuki coupling),3 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.
The development of environmentally friendly and atom- J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 2, p 49.
(4) Negishi, E. In Organozinc Reagents; Knochel, P., Jones, P., Eds.;
economical reactions for forming carbon-carbon bonds is 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 &
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Tsuji, J. Palladium Reagents Sons: New York, 1997. (c) Grieco, P. A. Organic Synthesis in Water;
and Catalysts. InnoVations in Organic Synthesis; Wiley: Chichester, U.K., Blackie Academic & Professional: London, 1998. (d) Li, C.-J.; Chan, T.-
1996. (c) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic H. Tetrahedron 1999, 55, 11149.
Press: New York, 1985. (6) (a) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem. Soc. 2001,
(2) (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction; 123, 4155. (b) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 1999,
Wiley: New York, 1998. (b) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1, 1267. See also: Nomura, R.; Miyazaki, S.-I.; Matsuda, H. J. Am. Chem.
1986, 25, 508. (c) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771. (d) Pereye, Soc. 1992, 114, 2738.
M.; Quintard, J.; Rahm, A. Tin in Organic Synthesis; Butterworth: London, (7) Takami, K.; Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima,
1987. K. Org. Lett. 2001, 3, 1997.

10.1021/ol0345428 CCC: $25.00 © 2003 American Chemical Society

Published on Web 06/11/2003
of toxicity (tin) and handling (boron, zinc) associated with
other organometallic reagents.8 In this study, we report that Table 1. Coupling Reaction of Trisdihydropyranylindium 1
easily prepared tris-(dihydropyranyl)indium reagents cross- with Aryl Halides
couple with a variety of aryl halides in high yield under
palladium catalysis.9 The extension of this method to the
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-
man.10 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 entry 2 R X equiv 1 % yield of 3 (4)a
days without appreciable loss of reactivity (Scheme 1).
1 2a 4-COCH3 Br 0.33 72
2 2b 4-CO2Et Br 0.33 87
3 2c 3-CO2Et Br 1 85 (15)b
Scheme 1 4 2d 2-CO2Et Br 1 76
5 2e 4-Cl Br 0.33 95
6 2f 2-NO2 Br 1 69 (17)c
7 2g 2-CHO Br 1 44 (46)b
8 2h 1-naphthyl Br 1 87 (6)b
9 2i 4-CH3 Br 0.5 27 (5)c,d
10 2j 4-OCH3 Br 1 36 (6)
11 2k 2-OCH3 Br 1 23 (9)
We undertook our investigation of the palladium(0)- 12 2l 4-OAc Br 0.66 34 (14)
catalyzed cross-coupling reaction by adding one-third of an 13 2m H I 0.33 100e
14 2n 4-CH3 I 1 89 (7)c
equivalent of 1 to a boiling solution of iodobenzene and Pd-
15 2o 2-CH3 I 1 96 (4)b
(PPh3)2Cl2 (2 mol %). Within 1 h, consumption of starting 16 2p 4-OCH3 I 1 88b
material was complete as evidenced by TLC and GC-MS 17 2q 2-OCH3 I 1 89 (5)b
analysis. Dihydropyran 3m was obtained in 94% yield after a Because of product volatility/instability, reaction yields were determined
purification. As has been noted previously, the instability of by GC-MS analysis. b PdCl2(PPh3)2 (3 mol %) was used in the reaction.
the product to air and silica gel necessitated the use of rapid c PdCl (PPh ) (5 mol %) was used. d Yield determined by integration of
2 3 2
flash chromatography with short elution times.11 aromatic proton signals in 1H NMR. e PdCl2(PPh3)2 (2 mol %) was used.
Reactions of 1 with bromoarenes containing electron-
withdrawing groups gave moderate to high yields of the high yields of the desired substituted dihydropyrans were
desired substituted dihydropyrans (Table 1, entries 1-7) in obtained. However, the use of excess indium reagent (1
the presence of catalytic amounts of palladium salt. Interest- equiv) and 3-5 mol % catalyst were required in order to
ingly, both 1-bromo-2-nitrobenzene 2f and 2-bromobenzal- obtain optimal yields in these cases. Extended reaction times
dehyde 2g required more catalyst (5 and 3 mol %, respec- with either less 1 or lower catalyst loading led to decreased
tively) and 1 (1 equiv) to reach completion, and in each case overall yields.
4 (presumably arising from palladium(II)-mediated dimer- To investigate the hydrolytic stability of 1, we attempted
ization of the indium reagent) was obtained in competitive a reaction with 2a in a 10:1 THF/MeOH mixture at reflux
amounts. for 1 h, employing 3 mol % Pd(PPh3)2Cl2 as a catalyst.
Consistent with previous observations on the cross- Compound 3a was again obtained but in lower yield (46%).
coupling of glycal tin reagents with aryl halides,12 bromo- Interestingly, subjecting bis(dihydropyranyl)indium chloride
arenes containing electron-donating groups (Table 1, entries 1b13 to the same conditions (2a, 10:1 THF/MeOH, 3 mol %
9-12) gave poor yields of coupling product. These reactions Pd(PPh3)2Cl2) led to essentially no diminution in the yield
also gave rise to significant amounts (5-14%) of 4. Use of of 3a obtained (69%, Scheme 2). These results, in line with
Pd(PPh3)4 as a catalyst did not reduce the amount of dimer the observations of Oshima,7 suggest that protic solvents
formed and gave lower yields of the desired product. Cross- hydrolyze one ligand from triorganoindium reagents, leaving
coupling reactions of the corresponding aryl iodides with 1 the remaining groups to participate in the cross-coupling
were therefore tested. In all cases (Table 1, entries 13-17), reaction. Attempted cross coupling in 10:1 THF/H2O gave
none of the desired product, and indeed it was found in
(8) Anastas, P. T.; Warner, J. C. Green Chemistry; Oxford University general that anhydrous conditions were required to obtain
Press: Oxford, 1998; p 29.
(9) For previous examples of cross-coupling reactions of tetrahydro-
high yields of cross-coupled product and minimize dimer
pyranyl organometallics, see ref 11 and also: Mazal, C.; Vaultier, M. formation.
Tetrahedron Lett. 1994, 35, 3089. Chan et al. have demonstrated that the active intermediate
(10) (a) Boeckman, R. J.; Bruza, K. J. Tetrahedron Lett. 1977, 18, 4187.
(b) Boeckman, R. J.; Bruza, K. J. Tetrahedron 1981, 37, 3997. in indium-mediated aqueous Barbier reactions is an indium-
(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
1262. equiv of indium trichloride.

2406 Org. Lett., Vol. 5, No. 14, 2003

 Scheme 2 Table 2. Cross-Coupling Reactions of Per-TIPS-glucal 5 with
Aryl Iodides

entry 2a R % yieldb of 6 (7)

1 2a 4-COCH3 55% (<5%)
2 2d 2-CO2CH3 54% (<5%)
3 2h 1-naphthl 59% (9%)
4 2o 2-CH3 60% (5%)
(I) species;14 furthermore, organoindium (I) reagents have 5 2q 2-OCH3 60% (<5%)
been successfully employed in carbon-carbon bond-forming 6 2p 4-OCH3 40% (19%)
reactions in organic solvents.15 However, attempted trans- a Used 1.5 equiv of 2. b Yields are of purified material.
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 2 to 6 equivalents), along with up to 1 equiv of InCl3. In all
observed in the presence of 1 mol % Pd(PPh3)2Cl2 and cases, little or no product formation was observed, likely
4-bromoacetophenone after 1 h at reflux. indicating that the excess base consumes InCl3 before
We next turned our attention to the possibility of using transmetalation of lithioglucal can occur.
this method to form C-aryl glycals, which have been Since 0.5 equiv of InCl3 and 1.5 equiv of t-BuLi are
employed in the preparation of a variety of biologically employed in the optimized procedure, it is possible that
important C-aryl glycosides.16 1-Lithio-3,4,6-tri-O-(triiso- mono- and/or diglucal indium species are formed during the
propylsilyl)-D-glucal, prepared by treatment of per-TIPS transmetalation (i.e., (glucal)In(t-Bu)2 or (glucal)2In(t-Bu))
glucal 517 with 1.5 equiv of t-BuLi at -78 °C followed by and that these intermediates preferentially transfer their
stirring at 0 °C for 1.5 h, was added to a solution of 0.5 carbohydrate ligands in the palladium-mediated cross-
equiv of InCl3 at -78 °C. Subsequent cross coupling in the coupling reaction.
presence of 3 mol % Pd(PPh3)2Cl2 and 2-iodotoluene 2o (1.5 The reactions above were also tested in the presence of
equiv, 24 h, reflux) gave 60% yield of the C-aryl glycal 6o, protic solvents. Addition of methanol (10 equiv) prior to
along with ∼5% dimer 7 and 35% recovered starting material addition of the aryl iodide 2o and Pd(PPh3)2Cl2 lowered the
(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 ligands from an intermediate such as (glucal)2In(t-Bu) leads
in the reaction mixtures (assayed by 1HNMR of the crude to an organometallic species that can transfer only one
material) except for entry 6. Starting material 5 was also carbohydrate moiety, giving the observed yield of product.
cleanly recovered from these reactions and reused in Addition of water (5-10 equiv) instead of methanol resulted
subsequent couplings. The use of aryl bromides instead of in formation of an insoluble white precipitate that failed to
aryl iodides uniformly resulted in low yields.18
Incomplete lithiation of 5 may account for the moderate
yields of C-aryl glycals obtained. To address this issue, the Scheme 3
same reactions were performed with longer deprotonation
times (1.5-3 h) and using a greater excess of t-BuLi (from

(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, reagents typically employed in C-aryl glycal synthesis and
and only starting material was recovered from the reaction can be performed in the presence of protic solvents.
mixture.
The C-aryl glycals obtained in this study can be easily Acknowledgment. We are grateful for the generous
transformed into C-aryl glycosides by established procedures financial support of this work by the National Science
(Scheme 3). Catalytic hydrogenation of compound 6o in the Foundation (Grant No. 0097262) and the donors of the
presence of PtO2 furnishes the corresponding 2-deoxy-β-C- Petroleum Research Fund, administered by the American
aryl glycoside 8 in 90% yield; hydroboration/oxidation of Chemical Society (PRF # 38271-GB1). The authors also wish
6p employing the protocol of Friesen19 produces glycoside to thank Cole Witham for assisting with the reactions shown
9 in 40% yield. in Scheme 2.
In summary, palladium-mediated cross-coupling reactions
Supporting Information Available: Complete experi-
of glycalindium (III) compounds offer a practical and
mental details for all compounds prepared in Tables 1 and
environmentally friendly alternative for obtaining C-aryl
2, including spectroscopic data. This material is available
glycals. This one-pot method avoids the use of toxic tin
free of charge via the Internet at http://pubs.acs.org.
(19) Friesen, R. W.; Daljeet, A. K. Tetrahedron Lett. 1990, 31, 6133. OL0345428

2408 Org. Lett., Vol. 5, No. 14, 2003