Synthesis of 5-Pyridyl-2-furaldehydes via palladium-catalyzed cross-coupling with triorganozincates

Article abstract of DOI:10.1021/ol0170612

(Equation Presented) 5-Pyridyl-and 5-aryl-2-furaldehydes are prepared from furaldehyde diethyl acetal in a four-step, one-pot procedure: (i) deprotonation; (2) Li to Zn transmetalation; (3) Pd-mediated cross-coupling; (4) aldehyde deprotection. Triorganozincate 7 was found to transfer all three groups in the Pd-catalyzed cross-coupling reaction with haloaromatics.

Full text of DOI:10.1021/ol0170612

ORGANIC
LETTERS
2002
Vol. 4, No. 3
375-378
Synthesis of 5-Pyridyl-2-furaldehydes via
Palladium-Catalyzed Cross-Coupling
with Triorganozincates
Donald R. Gauthier, Jr.,* Ronald H. Szumigala, Jr., Peter G. Dormer,
Joseph D. Armstrong, III, R. P. Volante, and Paul J. Reider
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065
donald_gauthier@merck.com
Received November 16, 2001
ABSTRACT
5-Pyridyl- and 5-aryl-2-furaldehydes are prepared from furaldehyde diethyl acetal in a four-step, one-pot procedure: (i) deprotonation; (2) Li
to Zn transmetalation; (3) Pd-mediated cross-coupling; (4) aldehyde deprotection. Triorganozincate 7 was found to transfer all three groups
in the Pd-catalyzed cross-coupling reaction with haloaromatics.
Substituted furans are ubiquitous structural units in natural
products and in pharmaceuticals1 and have often been used
as synthetic intermediates.2 We are interested in 5-pyridyl-
2-furaldehydes as synthetic intermediates for pharmaceuti-
cally active compounds. Herein we report a scaleable,
operationally simple procedure to prepare 5-aryl- and 5-pyr-
idyl-2-furaldehydes from inexpensive, commercially avail-
able 2-furaldehyde diethyl acetal.3 We also report that
triorgano- and tetraorganozincates transfers all organic
groups in the Pd-catalyzed cross-coupling reaction with aryl
halides.
Several transition metal catalyzed biaryl coupling ap-
proaches to 5-pyridyl-2-furaldehydes were considered. The
ease in which substitution can be incorporated at the 2- and
5-positions made this approach more attractive than cycliza-
tion of acyclic precursors.4 Although 2-halofurans are suitable
biaryl coupling partners,5 the prohibitive cost of the requisite
5-bromo-2-furaldehyde6 precluded its use on large scale.
Thus, we focused instead on using furaldehyde as the
nucleophilic component. In a recent report, this strategy was
employed using a Heck coupling to prepare 5-aryl-2-
furfurals; unfortunately, 2-halopyridines were poor sub-
strates.7 O’Doherty recently focused on Stille and Negishi
couplings to prepare 5-aryl-2-furfurals.5 A similar approach
to 5-pyridyl-2-furaldehydes using a one-pot, four-step se-
quence is illustrated in Scheme 1: (i) selective deprotonation
of furaldehyde diethyl acetal (1); (ii) transmetalation to an
organometallic nucleophile capable of undergoing transition
metal catalyzed cross-coupling;8 (iii) cross-coupling; (iv)
aldehyde deprotection.
(4) (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.;
Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955-2020. (b) Keay,
B. A. Chem. Soc. ReV. 1999, 28, 209-215. (c) Friedrichsen, W. In
ComprehensiVe Heterocyclic Chemistry II; Bird, C. W., Ed.; Elsevier: New
York, 1996; Vol. 2, Chapter 2.07, pp 352-368.
(1) Keay, B. A.; Dibble, P. W. In ComprehensiVe Heterocyclic Chemistry
II; Bird, C. W., Ed.; Elsevier: New York, 1996; Vol. 2, Chapter 2.08, pp
395-436.
(5) Balachari, D.; Quinn, L.; O’Doherty, G. A. Tetrahedron Lett. 1999,
40, 4769-4773.
(2) (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795-819. (b) Hou, X. L.;
Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H.
N. C. Tetrahedron 1998, 54, 1955-2020.
(6) Available from Aldrich Chemical Co. at $11/1 g. For selective
bromination of 2-furaldehyde, see: Nazarova, Z. N. J. Gen. Chem. (U.S.S.R.)
1954, 24, 589-592.
(3) Available from Aldrich Chemical Co. at $147/25 g, although the cost
of raw material 2-furaldehyde is comparable to common solvents.
(7) McClure, M.; Glover, B.; McSorley, E.; Millar, A.; Osterhout, M.;
Roschangar, F. Org. Lett. 2001, 3, 1677-1680.
10.1021/ol0170612 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/12/2002

volume and the amount of transition metal reagents,18 we
aimed to minimize the amount of ZnCl2. Thus, diorganozinc
6 was initially prepared by simply adjusting the ratio of
reagents (Figure 1). Using the appropriate furyllithium
2/ZnCl2 stoichiometry, organozincate 7 (3:1) and higher order
zincate 8 (4:1) were also prepared.
Scheme 1. Four-Step, One-Pot Synthesis of
5-Pyridylfuraldehydesa
a Reagents and conditions: (a) n-BuLi, THF, TMEDA, -25 °C;
(b) ZnCl2, -25 °C to rt; (c) 2-chloropyridine (9a), Pd(dppf)Cl2, 6
h, 50 °C; (d) 5 N HCl.
Figure 1.
The deprotonation of furaldehyde diethyl acetal 1 in THF
with n-BuLi is selective at -78 °C, providing furyllithium
2 (Scheme 1).9,10 The extreme cryogenics of the deprotona-
tion could be avoided with the addition of N,N,N′,N′-
tetramethylethylenediamine (TMEDA).11 Using TMEDA, the
deprotonation and subsequent transmetalation steps could be
conducted at -20 to -30 °C.12,13
Diorganozincs are more reactive than organozinc halides
toward electrophiles and sometimes transfer only one of the
two groups.19 In cross-coupling reactions, diorganozincs
generally transfer both organic groups.20 Mixed aryl-
dialkyl zincates have been shown to selectively transfer an
aryl group to an electrophile.21,22 We report here that
triorganozincate 7 transfers all three organic groups in the
cross-coupling reaction with 2-chloropyridine (9a) and is
equally efficient as mono and bis organozincs 3 and 6
(Table 1, entries 1 and 4). However, slightly lower yields
were typically obtained with higher order zincate 8 (Table
1, entry 5). We ascribe the lower yields with higher order
zincate 8 to its lower thermal stability compared to that of 6
and 7.23
Organozinc reagents have seen widespread use due to
exceptional functional group tolerance, ease of preparation,
and removal of zinc byproducts.14 Treatment of 2 with ZnCl2
(1.1 equiv) provided organozinc chloride 3. Several catalysts
derived from Ni and Pd were screened to optimize the
15
reaction of 3 with 2-chloropyridine (9a). Pd(dppf)Cl2 (2
mol %) gave the best results, providing 5a in 90% yield after
deprotection. For kilogram-scale runs, catalyst loading was
reduced to 0.25 mol % without adverse effects on yield or
reaction time.
The optimized coupling procedure was applied using
organozinc reagents 6 and 7 with chloropyridines 9a-g
(Table 1). Since we mainly were interested in chloropyri-
dines, the coupling reaction was also conducted using the
Commercial bulk sources of “anhydrous” ZnCl2 solid
typically contain no less than 1% H2O.16 Dissolution in THF
and extensive molecular sieve drying was therefore neces-
sary.17 For this reason, as well as reducing the overall reaction
(18) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
(b) Anastas, P. T.; Warner, J. C. Green Chemistry; Oxford University Press
Inc.: New York, 1998, Chapter 4.
(19) (a) Knochel, P. Synlet 1995, 393-403. (b) Soai, K.; Niwa, S. Chem.
ReV. 1992, 92, 833-856. (c) Knochel, P.; Singer, R. D. Chem. ReV. 1993,
93, 2117-2188.
(8) For synthetic routes to biaryls, see: (a) Stanforth, S. P. Tetrahedron
1999, 54, 263-303. (b) Knight, D. W. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3,
pp 481-516.
(20) This distinction is sometimes overlooked. See, for example:
Perez, I.; Sestelo, J.; Sarandeses, L. J. Am. Chem. Soc. 2001, 123, 4155-
4160.
(9) (a) Thames, S.; Odom, H. J. Heterocycl. Chem. 1966, 3, 490-
494. (b) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1987, 52, 104-
109.
(21) (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem.
Soc. 1999, 121, 3539-3540. (b) Kondo, Y.; Komine, T.; Fujinami, M.;
Uchiyama, M.; Sakamoto, T. J. Comb. Chem. 1999, 1, 123-126. (c) Kondo,
Y.; Takazawa, N.; Yamazaki, C.; Sakamoto, T. J. Org. Chem. 1994, 59,
4717-4718.
(10) The deprotonation step was monitored by HPLC by the following
method: an aliquot of solution 2 was quenched with MeI. HPLC typically
showed 95% conversion to 2 compared to authentic standards of furaldehyde
and 5-methyl-2-furaldehyde.
(11) Collum, D. B. Acc. Chem. Res. 1992, 25, 448-454.
(12) Furyllithium 2 was stable in THF with TMEDA at -20 °C for
several hours. Aging at higher temperatures (e.g., -10 °C, 1 h) resulted in
diminished yields of coupled product 5a (54%).
(13) Without TMEDA, unidentifiable decomposition occurs upon aging
the solution of 2 above -40 °C.
(14) (a) Knochel, P.; Jones, P. Organozinc Reagents, A Practical
Approach; Oxford University Press Inc.: New York, 1999. (b) Erdik, E.
Organozinc Reagents in Organic Synthesis; CRC Press: Boston, 1996.
(15) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158-163.
(22) For interesting applications of zincates and higher order zincates,
see: (a) Harada, T.; Kaneko, T.; Fujiwara, T.; Oku, A. J. Org. Chem. 1997,
62, 8966-8967. (b) Harada, T.; Katsuhira, T.; Osada, A.; Iwazaki, K.;
Maejima, K.; Oku, A. J. Am. Chem. Soc. 1996, 118, 11377-11390. (c)
Harada, T.; Otani, T.; Oku, A. Tetrahedron Lett. 1997, 38, 2855-2858.
(d) Harada, T.; Katsuhira, T.; Hara, D.; Kotani, Y.; Maejima, K.; Kaji, R.;
Oku, A. J. Org. Chem. 1993, 58, 4897-4907. (e) Katsuhira, T.; Harada,
T.; Maejima, K.; Osada, A.; Oku, A. J. Org. Chem. 1993, 58, 6166-6168.
(f) Harada, T.; Hara, D.; Hattori, K.; Oku, A. Tetrahedron Lett. 1988, 29,
3821-3824. (g) Oku, A.; Harada, T.; Hattori, K.; Nozaki, Y.; Yamaura,
Y. J. Org. Chem. 1988, 53, 3089-3098. (h) McWilliams, J. C.; Armstrong,
J. D., III; Zheng, N.; Bhupathy, M.; Volante, R. P.; Reider, P. J. J. Am.
Chem. Soc. 1996, 118, 11970-11971. (i) Uchiyama, M.; Kameda, M.;
Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto, T. J. Am.
Chem. Soc. 1998, 120, 4934-4946.
(16) Kilogram quantities of solid ZnCl2 can be oven dried at 120 °C, 23
in. Hg with an N2 purge for 3-5 days. However, handling of a THF solution
on scale is preferred to the hygroscopic solid.
(17) Commercial ZnCl2 solution (0.5 M in THF, Aldrich Chemical Co.)
contains 0.5% H2O (∼0.3 M) as determined by Karl Fisher titration.
(23) Yield of coupled product 5a was significantly lower after aging 8
at 25 °C for 1 h.
376
Org. Lett., Vol. 4, No. 3, 2002

Table 1. Synthesis of 5-Substituted Pyridylfurals via Pd-Catalyzed Coupling of Pyridylhalide 9a-g and Organozinc Reagents 6, 7
and 8
a Organozinc reagents were used in the following stoichiometry: 6 (0.6 equiv), 7 (0.35 equiv), and 8 (0.27 equiv). b “1:1 Pd/(t-Bu)3P” was prepared from
a 0.5:1 ratio of Pd2(dba)3 to (t-Bu)3P.
catalyst system derived from (t-Bu)3P/Pd2(dba)3.24 As dis-
covered by Fu, the (t-Bu)3P:Pd ratio is an important
parameter.25 For diorganozinc 6, a 1:1 ratio gave significantly
better yields than commercially available Pd(P(t-Bu)3)2.26 Use
of Pd2(dba)3 with monodentate phosphine ligands such as
P(t-Bu)3, P(c-Hx)3, PPh3, P(2-furyl)3, and P(o-tolyl)3 failed
to promote the reaction of halopyridines or haloaromatics
with zincates 7 or 8 (Table 1, entries 3 and 21). Bidentate
ligands, such as dppf, dppe, dppp, and dppb, promoted the
Pd-catalyzed reaction with zincates 7 and 8, but dppf was
superior.
We also examined a series of aryl bromides in the
Pd(dppf)Cl2-catalyzed cross-coupling with organozinc re-
(24) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-2724.
(25) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028.
(26) Coupling of 6 and 9g with (t-Bu)3P/Pd2(dba)3 (2 mol % Pd) at
0.5:1, 1:1, 2:1, and 3:1 (ligand: Pd) gave 70%, 76%, 20%, and 20% yields,
respectively.
Org. Lett., Vol. 4, No. 3, 2002
377

Table 2. Pd(dppf)Cl2-Catalyzed Preparation of 5-Substituted
Arylfurfurals from Aryl Halides 12a-f and Organozinc
Reagents 6, 7, and 8
Table 3. Synthesis of 2-Phenylpyridine (13a) via
Pd(dppf)Cl2-Catalyzed Coupling of Ph-M with 2-Chloropyridine
(1.2 equiv)
entry
δPh (ppm)a
Ph-M (equiv)
yield (%)
1
2
3
4
5
187.4
159.4
161.8
168.9
170.5
PhLi (1.0)b
PhZnCl (1.0)
Ph2Zn (0.6)
Ph3ZnLi (0.35)
Ph4ZnLi2 (0.27)
<5%
98
95
100
99
organozinc
reagenta
a Ipso Ph carbon (M-C) 13C data in THF-d8, with reference to C-2 THF
signal at 67.57 ppm. b PhLi was prepared from bromobenzene and s-BuLi.
entry
substrate (R)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
12a (H)
6
7
8
6
7
8
6
7
8
6
7
8
6
7
8
6
7
8
77
76
71
88
78
76
85
79
75
75
62
41
84
81
61
84
63
56
in nearly quantitative yield. To address whether the reaction
is catalytic in Zn(II), ZnCl2 (10 mol %) was added to PhLi,
followed by 2-chloropyridine and Pd(dppf)Cl2 (2 mol %).
Only a 37% yield was attained, indicating the initial
formation of Ph4ZnLi2 followed by transfer of all four
groups.28 Interestingly, slow addition of PhLi to a THF
solution of ZnCl2 (10 mol %), 2-chloropyridine, and Pd-
(dppf)Cl2 (2 mol %) produced an 82% yield of 13a.29
12b (Me)
12c (OMe)
12d (NO2)
12e (CN)
An extremely efficient process for the synthesis of 5-aryl-
and 5-pyridyl-2-furaldehydes has been demonstrated. The
four-step, one-pot procedure takes advantage of using sub-
stoichiometric quantities of ZnCl2. A triorganozincate inter-
mediate successfully transfers all three groups in the cross-
coupling reaction. Thermally stable higher order zincates
(e.g., Ph4ZnLi2) transfer all four groups. Efforts to under-
stand and find further application of this chemistry are
ongoing.
12f (CO2Et)
a Organozinc reagents were used in the following stoichiometry: 6 (0.6
equiv), 7 (0.35 equiv), and 8 (0.27 equiv). b HPLC assay yields base on an
authentic standard of each product.
agents 6, 7, and 8 (Table 2). Making optimal use of the
transition metal reagent ZnCl2 via complex 8 is more efficient
than standard Negishi couplings; however, it suffers from
less functional group tolerance (Table 2, entries 12, 15, and
18).
Acknowledgment. The authors thank Dr. Phil Pye, Dr.
Chris McWilliams, and Dr. Anthony O. King and for
insightful discussions. We also thank Dr. Ziqiang Guan for
HRMS data.
Spectroscopic evidence for zincate and higher order zincate
formation was relayed to a simpler system generated from
PhLi. 13C NMR data indicates a clear trend (Table 3) in that
a low-field shift in the ipso Ph-M carbon occurs with
increasing electron density in the aromatic ring.27 In the cross-
coupling reaction with 2-chloropyridine, Ph3ZnLi (0.35
equiv) and Ph4ZnLi2 (0.27 equiv) transferred all aryl groups
Supporting Information Available: Experimental pro-
cedures and characterizations for all new compounds. This
information is available free of charge via the Internet at
http://pubs.acs.org.
OL0170612
(28) The reaction appears to stall, and added Pd catalyst failed to produce
more product.
(27) This trend is opposite for aliphatic protons, see: Uchiyama, M.;
Koike, M.; Kameda, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1996,
118, 8733-8734.
(29) The PhLi (1 equiv) was added over 1 h at room temperature to 35
°C. The reaction was then aged at 60 °C for 2 h. Biphenyl (9%) was the
only byproduct.
378
Org. Lett., Vol. 4, No. 3, 2002