Ambient Temperature, Ullmann-like Reductive Coupling of Aryl, Heteroaryl, and Alkenyl Halides

Full text of DOI:10.1021/jo9700078

2
312
J . Org. Chem. 1997, 62, 2312-2313
Am bien t Tem p er a tu r e, Ullm a n n -lik e
Red u ctive Cou p lin g of Ar yl, Heter oa r yl,
a n d Alk en yl Ha lid es
Shijie Zhang, Dawei Zhang, and
Lanny S. Liebeskind*
F igu r e 1.
Sanford S. Atwood Chemistry Center, Emory University,
ligating substituent, while 2-iodoheteroaromatic and
alkenyl substrates do not. The latter substrates couple
with retention of alkene stereochemistry. A synthetically
versatile range of substrates participate in the reductive
coupling, including aromatics bearing both electron-
withdrawing and electron-donating ortho-substituents.
The most noticeable limitation of the process is the lack
of reaction of aromatic halide substrates not possessing
a coordinating ortho-substituent. The reductive coupling
requires a polar, coordinating solvent such as N-meth-
ylpyrrolidinone, perhaps to generate reactive Cu(I) mono-
mers from the insoluble Cu(I) carboxylate polymer. The
intramolecular reductive coupling example depicted in
eq 1 suggests that CuTC might be useful in other
intramolecular reductive-coupling reactions.
1
515 Pierce Drive, Altanta, Georgia 30322
Received J anuary 6, 1997
The Ullmann synthesis of biaryls by the copper-
induced reductive coupling of aromatic halides is of broad
synthetic use.1
-7
Typically, the reaction is conducted
above 200 °C, although certain specific substrates un-
dergo Ullmann reductive coupling under much milder
conditions.8 Cohen demonstrated that CuOSO
CF in
2 3
acetone in the presence of ammonia could induce the
reductive coupling of a few selective aryl and vinyl
halides at much lower temperature,9
,10
and Ziegler de-
scribed an ambient-temperature cross-coupling of pre-
formed arylcopper reagents with aryl iodides.11 Although
not a reductive coupling, Lipshutz has developed a
synthesis of unsymmetrically-substituted biaryls by the
oxidative degradation of kinetic higher-order cuprates
generated at -125 °C from aryllithium reagents.12 Zero-
valent nickel-based protocols have also been described.1
It was recently shown that copper(I) thiophene-2-
carboxylate (CuTC) promotes a very rapid Stille cross-
coupling of aryl-, heteroaryl-, and alkenylstannanes with
alkenyl iodides and some aryl iodides between 0 °C and
room temperature, suggesting the possibility of a facile
oxidative addition of CuTC to alkenyl iodides at ambient
temperatures. That mechanistic possibility led to con-
sideration of a CuTC-mediated Ullmann reductive cou-
pling at or near room temperature, which if suitably
general and versatile could be of significant synthetic
utility. Herein, we report that copper(I) thiophene-2-
carboxylate induces the reductive coupling of substituted
aromatic iodides and bromides, 2-iodoheteroaromatics,
and the stereospecific reductive coupling of alkenyl
iodides efficiently and in many cases rapidly at room
temperature.
(1)
3,14
Although radical intermediates are possible in the
classical high-temperature Ullmann coupling of aryl
halides, they are not required. In the present ambient-
temperature Ullmann-like reductive coupling, retention
of stereochemistry for the alkenyl substrates precludes
the presence of radical intermediates and strongly im-
plicates the existence of organocopper intermediates
formed by oxidative addition to the Cu(I) reagent, as first
1
5
17
9,10,18
suggested by Cohen over 20 years ago.
What then is the unique attribute that Cu(I) thiophene-
-carboxylate brings to this Ullmann-like reductive cou-
pling? It is probably not internal coordination as depicted
2
in structure 7 (Figure 1), since certain other Cu(I)
1
9
carboxylates also induce the reductive coupling reaction.
Depicted in Table 1 are representative examples of the
CuTC-mediated reductive coupling of aryl iodides and
bromides, heteroaryl iodides, and alkenyl iodides.16 The
CuTC-mediated reaction is quite general and tolerant of
functionality. Efficient reductive coupling of the aromatic
substrates minimally requires the presence of an ortho-
If, as suggested,10 the oxidative addition of CuX reagents
to aryl iodides is reversible (eq 2), the efficacy of CuTC
may be due to an inherent ability of carboxylate as a
(
16) Rep r esen ta tive Exp er im en ta l P r oced u r e. CuTC (1.14 g,
.0 mmol, 3.00 equiv) was added in one portion to N-acetyl-2-iodo-
,4,5-trimethoxyaniline (0.70 g, 2.0 mmol, 1.00 equiv) in 8 mL of NMP
6
3
(
(
(
(
1) Fanta, P. E. Chem. Rev. 1964, 64, 613.
2) Fanta, P. E. Synthesis 1974, 9.
3) Sainsbury, M. Tetrahedron 1980, 36, 3327.
4) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed.
under N
with 15 mL of EtOAc, and the resulting slurry was passed through a
plug of SiO using EtOAc as eluent (150 mL). Solvents were removed
by rotary evaporation and then vacuum distillation. Residual NMP
was removed under vacuum overnight at rt. The crude product was
2
. After being stirred at rt for 1 h, the mixture was diluted
2
Engl. 1990, 29, 977.
(
(
(
(
5) Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 3061.
6) Nelson, T. D.; Meyers, A. I. J . Org. Chem. 1994, 59, 2655.
7) Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 3259.
8) Grigg, R.; J ohnson, A. W.; Wasley, J . F. W. J . Chem. Soc. 1963,
2 2 2
dissolved in 4 mL of CH Cl and 10 mL of Et O, the volume of solvents
was reduced by half, and then 2 mL of hexane was added. On standing
in a freezer, N,N′-diacetyl-6,6′-diamino-2,2′,3,3′,4,4′-hexamethoxybi-
phenyl was formed as an off-white solid (0.380 g, 0.85 mmol, 85%):
1
3
59.
mp 149-151 °C (Et
2
O/hexane); IR (CH
2
Cl
2
, KCl, cm- ) 3410 (br, m),
1
(
(
(
9) Cohen, T.; Cristea, I. J . Org. Chem. 1975, 40, 3649.
10) Cohen, T.; Cristea, I. J . Am. Chem. Soc. 1976, 98, 748.
11) Ziegler, F. E.; Chliwner, I.; Fowler, K. W.; Kanfer, S. J .; Kuo,
1691 (s), 1601 (s); H NMR (CDCl
(s, 6 H), 3.84 (s, 6 H), 3.62 (s, 6 H), 1.91 (s, 6 H); C NMR (CDCl
168.8, 153.5, 151.2, 139.1, 132.4, 111.5, 103.2, 61.0, 60.9, 55.9, 24.2.
Anal. Calcd for C22 : C, 58.91; H, 6.29; N, 6.25. Found: C,
59.00; H, 6.29; N, 6.23.
3
) δ 7.49 (s, 2 H), 7.08 (s, 2 H), 3.88
13
3
) δ
S. J .; Sinha, N. D. J . Am. Chem. Soc. 1980, 102, 790.
12) Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser, F. J . Am.
Chem. Soc. 1993, 115, 9276.
13) Semmelhack, M. F.; Helquist, P. M.; J ones, L. D. J . Am. Chem.
Soc. 1971, 93, 5908.
14) Semmelhack, M. F.; Ryono, L. S. J . Am. Chem. Soc. 1975, 97,
873.
28 2 8
H N O
(
(17) Xi, M.; Bent, B. E. J . Am. Chem. Soc. 1993, 115, 7426.
(18) Cohen, T.; Wood, J .; Dietz, J r., A. G. Tetrahedron Lett. 1974,
3555.
(19) Dramatic differences in the ease of synthesis, stability to air,
and rate of reaction with aryl halides have been noted for a variety of
Cu(I) carboxylates. The results of these studies will be reported in
due course.
(
(
3
2
(
15) Allred, G. D.; Liebeskind, L. S. J . Am. Chem. Soc. 1996, 118,
748.
S0022-3263(97)00007-8 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 8, 1997 2313
Ta ble 1. Cu (I) Th iop h en e-2-ca r boxyla te-In d u ced Red u ctive Cou p lin g Rea ction s
ligand to stabilize the oxidative addition product, as
implied by the position of the equilibrium depicted in eq
halides, the heteroatom of the 2-iodoheteroaromatics, and
the alkene of the alkenyl substrates all provide the
necessary site for coordination to copper. The easy and
economical preparation of CuTC, its handling in air, and
the high yields of reductively coupled products achieved
under mild reaction conditions could make CuTC or other
Cu(I) carboxylates19 the reagents of choice for many
Ullmann-like reductive coupling reactions. Further stud-
ies of copper-mediated reductive and cross-coupling reac-
tions are in progress and will be reported in due course.
3
.
(2)
(3)
Ack n ow led gm en t . This investigation was sup-
ported by Grant No. CA40157, awarded by the National
Cancer Institute, DHHS, and by partial funding from
Bristol-Myers Squibb. We acknowledge the use of a VG
Control experiments demonstrated that both CuCl and
CuBr, but not CuI, can induce the reductive coupling of
methyl 2-iodobenzoate at room temperature in N-meth-
ylpyrrolidinone. However, the yields are low and com-
promised by halide exchange between the substrate and
CuX, the latter observation a further indication of the
reversible oxidative addition of aryl iodides to copper(I)
halides. In order to probe the unique aspect of the
carboxylate ligand in this chemistry, a survey of the
reactivity of additional Cu(I) carboxylates is underway.19
The results collected here strongly implicate a neces-
sary precoordination of the substrate to copper prior to
oxidative addition and restrict the choice of copper
reagent to one that is coordinatively unsaturated or one
easily made so. The ortho-substituent on the aromatic
7
0-S mass spectrometer purchased through funding
from the National Institutes of Health, S10-RR-02478,
and a 300 MHz NMR and 360 MHz NMR purchased
through funding from the National Science Foundation,
NSF CHE-85-16614 and NSF CHE-8206103, respec-
tively. We thank Professor Theodore Cohen (Pitts-
burgh) for sharing with us his perspective and some
relevant references on the role of organocopper inter-
mediates in the Ullmann coupling reaction.
Su p p or tin g In for m a tion Ava ila ble: A complete descrip-
tion of the synthesis and characterization of all compounds in
the manuscript (21 pages).
J O9700078