The Directed Ortho Metalation-Ullmann Connection. A New Cu(I)-Catalyzed Variant for the Synthesis of Substituted Diaryl Ethers

Full text of DOI:10.1021/jo990114x

2986
J . Org. Chem. 1999, 64, 2986-2987
Sch em e 1
Th e Dir ected Or th o Meta la tion -Ullm a n n
Con n ection . A New Cu (I)-Ca ta lyzed Va r ia n t
for th e Syn th esis of Su bstitu ted Dia r yl
Eth er s
Alexey V. Kalinin, J ustin F. Bower,† Peter Riebel,† and
Victor Snieckus*,†
Guelph-Waterloo Centre for Graduate Work in Chemistry,
University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
Received J anuary 21, 1999
The recent reports by Buchwald, Hartwig, and others have
posited valuable new Pd-catalyzed C-N, C-O, and C-S
bond coupling methodology for aromatic substrates,1,2 which
is beginning to supplant the classical Ullmann reaction.3 The
utility of diaryl ethers as synthetic intermediates and their
structural presence in a variety of bioactive and natural
products4 provides a strong incentive for further method
development. In the course of work demonstrating a com-
bined Directed ortho and remote metalation (DoM and
DreM) method for the construction of thioxanthones,5a
xanthones,5b acridones,6 and dibenzo[b,e]phosphinones,7 from
the corresponding diaryl sulfones, ethers, amines, and
phosphine oxides, respectively, 2 f 1a ,b (Scheme 1), we
have uncovered a new variation of the Buchwald procedure1a
for systems 2 that augments the synthetic scope and
convenience for the construction of substituted diaryl ethers.
Herein, we disclose this methodology, which embodies the
following features: (a) it employs CuPF6(MeCN)4 (5 mol %)8
rather than the air-labile CuOTf(C6H6)0.5 complex in reflux-
Sch em e 2a
a
Conditions: 1.2-1.5 equiv of 4/0.05 equiv of CuPF6(MeCN)4/2 equiv
of Cs2CO3/toluene or xylenes/reflux/5-45 h.
* To whom correspondence should be addressed. E-mail: snieckus@
chem.queensu.ca.
ing toluene or xylenes in the presence of obligatory Cs2CO3
(2 equiv) as base;1a (b) it is successful for o-halo tertiary and
secondary benzamides and sulfonamides 3 (Scheme 2),
which are reported to be poorly behaved substrates;1a the
results obtained allow the DoM connection9,10 and hence
regiospecific access to 1,2,3-contiguous aromatic substitution
patterns; (c) iodo, bromo, and, in contrast to previous
Ullmann generalizations,1a,3 secondary chloro benzamides
serve as coupling partners; (d) thiophenol and benzylamine
undergo smooth coupling reactions; and (e) using double
Ullmann and Ullmann-Negishi protocols, it may be ex-
tended to the assemblage of Ar-O-Ar′-O-Ar′′ and Ar-Ar′-
O-Ar′′ motifs, 7 and 8, which are structural components of
biologically active and natural products.4
Selected results (Table 1) are illustrative of the scope of
the methodology. Treatment of N-ethyl 2-iodobenzamide
with m-cresol in the presence of CuPF6(MeCN)4 complex (5
mol %)8 and Cs2CO3 (2 equiv)1a in refluxing toluene for 24 h
indicated complete consumption of starting material (GC)
and formation of a 97:3 mixture of diaryl ether (5a ) and
deiodinated starting benzamide; normal workup and distil-
lation afforded pure product in 88% yield (entry 1). Cs2CO3
appears to be the base of choice, which is attributed to a
higher solubility of the formed ArOCs species.1a The effect
of catalyst solubility on the outcome of the reaction was
examined by experiments with the common, notably soluble,
Cu(I) sources, CuI and Cu2O. Both catalysts are as effective
as CuPF6 (Table 1, footnote c) but, similar to CuOTf, require
longer times compared to CuPF6 for completion of reaction
(GC monitoring). 2-Bromo benzamide (entry 2) was equally
effective to the iodo derivative; even N-ethyl 2-chloroben-
zamide (entry 3) led to satisfactory yields of diaryl ether
product but required higher reaction temperatures (xylenes,
† Current addresses: (J .F.B.) RiboTargets Ltd., c/o University Chemistry
Department, University of Cambridge, Lensfield Road, Cambridge, CB2
1EW, U.K.; (P.R.) R&D Centre Linz, DSM Fine Chemicals Austria GmbH,
St.-Peter-Strasse 25, P.O. Box 933, A-4021, Linz, Austria; (V.S.) Department
of Chemistry, Queen’s University, Kingston, ON K7L 3N6, Canada.
(1) C-O bond formation: (a) Marcoux, J .-F.; Doye, S.; Buchwald, S. L.
J . Am. Chem. Soc. 1997, 119, 10539-10540 and references therein. C-N
bond formation: (b) Old, D. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem.
Soc. 1998, 120, 9722-9723 and references therein. (c) Mann, G.; Hartwig,
J . F.; Driver, M. S.; Fernandez-Rivas, C. J . Am. Chem. Soc. 1998, 120, 827-
828. (d) For a recent review on transition metal catalyzed synthesis of
arylamines/ethers, see: Hartwig, J . F. Angew. Chem., Int. Ed. Engl. 1998,
37, 2046-2067. Hartwig, J . F. Synlett 1997, 329-340. (e) Ma, D.; Zhang,
Y.; Yao, J .; Wu, S.; Tao, F. J . Am. Chem. Soc. 1998, 120, 12459-12467.
C-S bond formation: (f) Pinchart, A.; Dallaire, C.; Gingras, M. Tetrahedron
Lett. 1998, 39, 543-546. (g) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara,
J .-i.; Kato, Y.; Kosugi, M. Bull. Chem. Soc. J pn. 1980, 53, 1385-1389.
(2) For a promising new methodology of diaryl ether/amine synthesis
using copper-mediated coupling of aryl boronic acids with phenols and
amines, see: (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M.
P. Tetrahedron Lett. 1998, 39, 2933-2936. (b) Evans, D. A.; Katz, J . L.;
West, T. R. Tetrahedron Lett. 1998, 39, 2937-2940. (c) Lam, P. Y. S.; Clark,
C. G.; Saubern, S.; Adams, J .; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941-2944. (d) Cundy, D. J .; Forsyth, S. A.
Tetrahedron Lett. 1998, 39, 7979-7982.
(3) Review: Lindley, J . Tetrahedron 1984, 40, 1433-1456. For an
Ullmann reaction under ultrasound, see: Hanoun, J .-P.; Galy, J .-P.;
Tenaglia, A. Synth. Commun. 1995, 25, 2443-2448. For a non-Ullmann
diaryl ether synthesis, see: J ung, M. E.; Starkey, L. S. Tetrahedron 1997,
53, 8815-8824.
(4) See, inter alia: Evans, D. A.; Dinsmore, C. J .; Watson, P. S.; Wood,
M. R.; Richardson, T. I.; Trotter, B. W.; Katz, J . L. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2704-2708. Nicolaou, K. C.; Takayanagi, M.; J ain, N. F.;
Natarajan, S.; Koumbis, A. E.; Bando, T.; Ramanjulu, J . M. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2717-2719. Sawyer, J . S.; Schmittling, E. A.;
Palkowitz, J . A.; Smith, W. J ., III. J . Org. Chem. 1998, 63, 6338-6343 and
references therein. Boger, D. L.; Miyazaki, O. L.; Beresis, R. T.; Castle, S.
L.; Wu, J . H.; J in, Q. J . Am. Chem. Soc. 1998, 120, 8920-8926.
(5) (a) Beaulieu, F.; Snieckus, V. J . Org. Chem. 1994, 59, 9, 6508-6509.
(b) Familoni, O. B.; Ionica, I.; Bower, J . F.; Snieckus, V. Synlett 1997, 1081-
1083.
(6) MacNeil, S. L.; Gray, M.; Briggs, L. E.; Li, J . J .; Snieckus, V. Synlett
1998, 419-421.
(7) Gray, M.; Chapell, B. J .; Taylor, N. J .; Snieckus, V. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1558-1560.
(9) Snieckus, V. Chem. Rev. 1990, 90, 879-933.
(10) Maillet, M.; Snieckus, V. Unpublished results.
(8) Kubas, G. J . Inorg. Synth. 1979, 19, 90-92.
10.1021/jo990114x CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/15/1999

Communications
J . Org. Chem., Vol. 64, No. 9, 1999 2987
Ta ble 1. Cu (I)-Ca ta lyzed Ullm a n n Syn th esis of 5a
Sch em e 3a
a
Conditions: (a) 1.1 equiv of s-BuLi/THF/-78 °C/1 h/then ZnCl2/
1.4 equiv of PhI/0.1 equiv of PdCl2(PPh3)2/0.2 equiv of DIBALH/rt/16
h; (b) 1.2 equiv of 4-(MeO)C6H4OH/0.05 equiv of CuPF6(MeCN)4/2 equiv
of Cs2CO3/xylenes/reflux/24 h.
by regioselective metalation/iodination,10 with representative
phenol partners (entries 14-17, Table 1). As observed for
benzamides, coupling was incomplete with p-anisidine.11
To provide additional synthetic scope, sequential DoM-
Ullmann coupling and DoM-transition metal catalyzed
cross coupling reactions were investigated (Scheme 3). Thus,
diaryl ether 5i (Table 1, entry 11) was selectively trans-
formed into the corresponding 2-iodo derivative 6 in high
yield using the standard DoM protocol for the powerful
amide DMG.9 CuPF6-catalyzed coupling of 6 with p-meth-
oxyphenol provided the bis-diaryl ether 8 in 38% yield
(isolated).14 On the other hand, one-pot lithiation of 5i,
transmetalation with ZnCl2, and cross coupling with iodo-
benzene under Negishi conditions15 led to the triaryl diether
7 in 36% yield. Despite the modest yields, these results
illustrate new routes to regiospecifically designed products
of mixed aryl-aryl and aryl-O-aryl structural motifs.16
In summary, we have established a new variant of the
Buchwald catalytic Ullmann diaryl ether synthesis,1a 3 + 4
f 5, using CuPF6 as a more convenient, air insensitive
copper source compared to the CuOTf-benzene complex.
Synthetic scope has been established in coupling of o-iodo
and -bromo benzamides and the corresponding sulfonamides
with phenols, thiophenols, and benzylamine.16 In contrast
to the previous study,1a secondary and tertiary benzamides
have been shown to be well tolerated in the coupling process.
Connections between DoM and Negishi cross coupling and
the Ullmann process, 5i f 7, 8, indicate further reaction
links from which diverse synthetic application may be
anticipated.
a
Unless otherwise noted, CuPF6(MeCN)4 was used as catalyst.
b
Yields are of purified materials. Solvent: xylenes (entries 3,
6-12, and 17) and toluene (entries 1, 2, 4, 5, and 14-16) at 0.5
M. For entry 13, the reaction was performed in a sealed tube at
140 °C using toluene as solvent. GC analysis of crude reaction
mixture inducated 1-5% formation of dehalogenated starting
material for entries 1, 2, 4, and 5 and 7-17% for entries 3 and
6-12. c Using 3b, yields of 5a with CuI (84%) and Cu2O (83%),
respectively. Using 3e, yields of 5e with CuI (71%) and Cu2O
Ack n ow led gm en t. We gratefully acknowledge the sup-
port of NSERC Canada and Monsanto under the Industrial
Research Chair and Research Grant Programs. A.V.K.
thanks NSERC and NATO for a Science Fellowship,and
P.R. thanks the DFG for a Postdoktorandenstipendium.
d
(75%), respectively. 1.1 equiv of 4 and 3 equiv of Cs2CO3 were
used.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures with spectral data (NMR, IR, MS) for all new compounds.
140 °C). High yields were achieved in coupling with thiophe-
nol (entry 4) and benzylamine (entry 5); on the other hand,
p-anisidine showed incomplete reaction.11,12
J O990114X
In contrast to secondary amides, tertiary 2-iodo and
2-bromo benzamides were less reactive, requiring refluxing
xylenes (140 °C) conditions (entries 6-12). Reaction of 3d
with 2,6-dimethylphenol produced primarily deiodinated
product, undoubtedly reflecting a steric effect. Even a
multifunctional benzamide provided a highly substituted
diaryl ether in preparatively useful yield (entry 13). N,N-
Diethyl 2-chlorobenzamide failed to produce synthetically
meaningful amounts of diaryl ether. The higher reactivity
of secondary compared to tertiary benzamides may be due
to formation of soluble and therefore more reactive Cu-
amide complexes of the former under the slightly basic
reaction conditions.13
(11) Reactions of 3a and 3g with p-anisidine resulted in low conversions
into the corresponding diarylamines (<40% yields). Polymerization of
anilines in the presence of CuPF6 has been reported: Suzuki, T.; Hasegawa,
K.; Ando, O. J P 63243130 1988; Chem. Abstr. 1988, 110, 86797q.
(12) In the reaction of N-(2-bromophenyl)pivaloylamide with m-cresol and
2,6-dimethylphenol 2-t-butylbenzoxazole was obtained as the major product.
Se also: Perry, R. J .; Wilson, B. D. J . Org. Chem. 1992, 57, 6351-6354 (for
details, see the Supporting Information).
(13) For studies of CuI-benzamide complex formation and thermal
reactions, see: Broadbelt, L. J .; Klein, M. T.; Dean, B. D.; Andrewa, S. M.
J . Polymer. Sci. A: Polymer Chem. 1997, 35, 3305-3322.
(14) Formation of a 75:23:5 mixture of 8:5i:6 was observed (GC analysis).
(15) Negishi, E.-I.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller, J . A.;
Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181-5184.
(16) Phenolic diaryl ethers are of current interest in polymer synthesis;
see: Higashimura, H.; Fujisawa, K.; Moro-oka, Y.; Kubota, M.; Shiga, A.;
Terahara, A.; Uyama, H.; Kobayashi, S. J . Am. Chem. Soc. 1998, 120, 8529-
8530.
The CuPF6/Cs2CO3 conditions were also successful for the
Ullmann reaction of o-iodo-p-toluenesulfonamides, available