Copper catalyzed oxidation of organozinc halides

Article abstract of DOI:10.1039/b610218b

A wide range of organozinc substrates may be oxidized in the presence of catalytic copper to give carbon-carbon bonds in high yield. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b610218b

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Copper catalyzed oxidation of organozinc halides{
Xianbin Su, David J. Fox, David T. Blackwell, Kiyotaka Tanaka and David R. Spring*
Received (in Cambridge, UK) 25th July 2006, Accepted 21st August 2006
First published as an Advance Article on the web 1st September 2006
DOI: 10.1039/b610218b
A wide range of organozinc substrates may be oxidized in the
presence of catalytic copper to give carbon–carbon bonds in
high yield.
There is a need for efficient and functional group tolerant methods
for carbon–carbon bond formation, for example in biaryl
synthesis.1 Despite recent advances in palladium catalysis,2 only
copper-3 and nickel-mediated Ullmann reactions have proved
useful4 for the closure of medium rings by the formation of a biaryl
bond. A drawback of these methods is that they require the use of
excess metal reagent and optimization of conditions for each
substrate. Therefore, a general, efficient and functional group
tolerant method is required for the synthesis of the biaryl-
Scheme 1 Conventional methodology and our new methodology.
containing medium rings present in many ellagitannin, lignan and
alkaloid natural products.5
we discovered that on treating this aryl zinc reagent with copper(I)
bromide in DMA15 and subsequently oxidizing with dinitroarene 3
at room temperature (low temperatures were not required), an
excellent yield of the biaryl could be obtained (Table 1, Entry 1).{
The reaction can be catalyzed with copper, which has significant
economic, purification and waste disposal advantages (Table 1).
The diminution of the copper loading has not been possible
starting from organolithium intermediates. However, in this case it
proved feasible to reduce the amount of copper(I) salt used in these
Organocuprates, often used in conjugate addition, epoxide
opening, halide displacement and carbocupration,6 have
a
relatively high-lying HOMO, which means that carbon–carbon
bond synthesis by organocuprate oxidation is a relatively easy
process. The oxidation of lithium organocuprates7,8 has been
handicapped, however, by the poor functional group tolerance of
the organolithium precursors. We have recently shown that the
functional group tolerance can be improved somewhat by the use
of magnesium organocuprates9 made from organomagnesium
halides by transmetallation at low temperature.10 However, the
method still suffers from the limitations of requiring electronically-
activated aryl iodide precursors and a stoichiometric amount of
copper(I) salt.
Table 1 Initial optimization studies
In the hope of overcoming these difficulties the use of
organozinc halides in place of organomagnesium halides was
investigated, a method not previously reported.11 Organozinc
reagents were appealing substrates for this chemistry because (a)
they have improved functional group tolerance relative to aryl
Grignard reagents,12 (b) they undergo transmetallation readily
with copper(I) salts,13 and (c) there are a range of methods for their
synthesis under very mild conditions (Scheme 1).14 This last factor
is highly significant, because it allows the use of aryl bromides as
substrates, which are readily available and easier to synthesize than
aryl iodides. For example, the application of highly active Rieke
zinc (denoted Zn*),14a or cobalt-catalyzed insertion of zinc dust,14b
allowed aryl zinc reagents to be generated from electronically
activated and deactivated aryl bromides. Although there have been
no previous investigations of the oxidation of zinc organocuprates,
Cu(I)
[equiv.]a
Oxidant 3
[equiv.]
Isolated
yield [%]b
Entry
Atmosphere
1
0.5
0.1
0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
2.0
2.0
2.0
1.0
0.2
0
0.2
0
0
0.2
N2
N2
N2
N2
N2
N2
O2
O2
Ar
Ar
90
93
20
85
2
3c
4
5
68
, 20
95
6c
7
8d
9e
10e
a
81d
trace
, 20
Equivalents are based on the starting material 1a (0.5 mmol).
Yields obtained from chromatographic purification of the reaction
mixtures (SiO2; hexane : EtOAc, 8 : 1); average of two experiments.
Reaction left stirring for 12 h; major product was debrominated
Phenolic products were also produced.
removed from the DMA solution of ArZnBr by ten freeze–pump–
thaw cycles backfilling with Ar. DMA = dimethylacetamide.
b
Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: drspring@ch.cam.ac.uk;
Fax: +44 (0)1223-336362; Tel: +44 (0)1223-336498
{ Electronic supplementary information (ESI) available: Full experimental
details, characterization and spectra of key compounds. See DOI: 10.1039/
b610218b
c
d
e
1a.
Residual gases
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Table 2 Intermolecular catalytic zinc organocuprate oxidationa
Table 3 Intramolecular catalytic zinc organocuprate oxidationa
Entry Substrate (1)
Product (2)
Isolated yield [%]
83
s
Isolated
yield
[%]
Entry X Product (2)
a
b
c
Br
Br
I
R9 = OMe
R9 = CO2Et
R9 = CO2Et
R9 = Br
95
90
82
92
t
81
d
I
e
f
g
h
Br
Br
Br
Br
R9 = CO2Et
R9 = COMe
R9 = CHLCH2
R9 =
86
87
84
76
a
Conditions: (i) Organozinc formation (1 equiv.); (ii) CuBr?SMe2
(0.2 equiv.), DMA, 22 uC, 5 min; (iii) Oxidant 3 (0.5 equiv.), DMA,
22 uC, 1 h.
OCH2CHLCH2
R9 = CN
slightly. The yield recovered if more oxidant was used,17 or if an
atmosphere of dry air or molecular oxygen was used above the
reaction mixture. When an oxygen atmosphere was used without
the arene oxidant present then significant quantities of phenolic
products were produced. If the reaction mixture was rigorously
degassed, then substoichiometric quantities of oxidant were
ineffective. These results suggest that the radical anion of 3 is
able to catalyze the reduction of molecular oxygen and avoid
undesired products in such reactions (Table 1, Entry 7).
i
j
Br
Br
90
92
k
Br
86
l
m
Br
Br
R9 = Br
R9 = CN
89
95
The scope of this reaction was investigated with other
organozinc reagents. A generic reaction procedure with substoi-
chiometric quantities of CuBr?SMe2 and oxidant 3 was employed
to generate a range of carbon–carbon bonds (Table 2). The
methodology was found to be applicable to a wide range of aryl,
heteroaryl, vinyl and benzyl bromides. Particularly noteworthy is
the dimerization in the presence of ketones (Table 2, Entries f,
p–q), a functional group that would not be compatible with
arylmagnesium halides, even at low temperature. The range of
substrates include mechanistic probes such as styrenes and ortho-
hydroxyallyl substituents (Table 2, Entries g–h, k), which provide
evidence against a simple radical termination mechanism. The
diastereoselectivity for the racemic over meso products (Table 2,
Entries p–r) was likely to be due to equilibration since the isolated
ratios were similar to the thermodynamic ratios.§
n
Cl
Br
85
ob
67
90
pc
qd
Cl
Br
R9 = H
R9 = Me
R0 = H
R0 = Cl 95
re
Br
92
The new methodology was used to forge biaryl bonds within a
medium ring in high yields (Table 3). It should be noted that in
these cases the acyclic substrates were aryl bromides rather than
iodides. These are valuable results as attempted cyclization of aryl
bromides in the presence of esters using the Ullmann reaction gave
polymeric material.18 The applicability of our methodology was
illustrated by the total synthesis of buflavine, an Amaryllidaceae
alkaloid with anti-serotonin properties (Scheme 2).19 Buflavine
a
Conditions: Organozinc (1 equiv.), CuBr?SMe2 (0.1 equiv.),
(0.25–0.5 equiv.). Major isomer shown, isolated from cinnamyl
3
b
c
bromide as a 16 : 5 : 1 mixture (92% combined yield). Major
diastereomer shown (10
determined by crystallography (. 20 : 1). Major diastereomer
d
:
1).
Major diastereomer shown,
e
shown, determined by crystallography (5 : 1).
reactions to 0.1 equivalents (with respect to 1a) with no decrease in
isolated yield or apparent reaction rate.16 We have previously
found that substoichiometric oxidant can be successfully used to
oxidise magnesium organocuprates.9 Pleasingly, it was found that
this was also possible in conjunction with aryl zinc halides in the
catalytic copper system (0.2 equiv.), although the yield suffered
Scheme 2 Total synthesis of buflavine.
3884 | Chem. Commun., 2006, 3883–3885
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1 J. Hassan, M. Se´vignon, C. Gozzi, E. Sculz and M. Lemaire, Chem.
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A. I. Meyers, T. D. Nelson, H. Moorlag, D. J. Rawson and A. Meier,
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Scheme 3 Proposed catalytic cycle for oxidation of zinc diarylcuprates.
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Thieme, Stuttgart, 2004, vol. 3, p. 305; (b) Modern Organocopper
Chemistry, ed. N. Krause, Wiley-VCH, Weinheim, 2002; (c)
Organocopper Reagents—A Practical Approach, ed. R. J. K. Taylor,
Series ed. L. M. Harwood and C. J. Moody, Oxford University Press,
Oxford, 1994.
7 (a) G. M. Whitesides, J. SanFilippo, Jr., C. P. Casey and E. P. Panek,
J. Am. Chem. Soc., 1967, 89, 5302; (b) For low temperature cross-
coupling, see B. H. Lipshutz, K. Siegmann, E. Garcia and F. Kayser,
J. Am. Chem. Soc., 1993, 115, 9276; (c) For intramolecular coupling, see:
B. H. Lipshutz, F. Kayser and Z.-P. Liu, Angew. Chem., Int. Ed. Engl.,
1994, 33, 1842; (d) For cross-coupling of lithium dialkylcuprates, see:
R. K. Dieter, S. Li and H. Chen, J. Org. Chem., 2004, 69, 2867. For
selected applications see: (e) R. S. Coleman and S. R. Gurrala, Org.
Lett., 2005, 7, 1849; (f) D. R. Spring, S. Krishnan, H. E. Blackwell and
S. L. Schreiber, J. Am. Chem. Soc., 2002, 124, 1354; (g) R. W. Baker,
R. V. Kyasnoor, M. V. Sargent, B. W. Skelton and A. H. White, Aust.
J. Chem., 2000, 53, 487; (h) M. B. Andrus, D. Asgari and J. A. Sclafani,
J. Org. Chem., 1997, 62, 9365.
8 For a recent review see: D. S. Surry and D. R. Spring, Chem. Soc. Rev.,
2006, 35, 218.
9 D. S. Surry, X. Su, D. J. Fox, V. Franckevicius, S. J. F. Macdonald and
D. R. Spring, Angew. Chem., Int. Ed., 2005, 44, 1870.
10 I. Hiriyakkanavar, O. Baron, A. J. Wagner and P. Knochel, Chem.
Commun., 2006, 583 and references therein.
11 For the oxidation of zinc amidocuprates in the formation of carbon–
nitrogen bonds, see: F. Cane`, D. Brancaleoni, P. Dembech, A. Ricci and
G. Seconi, Synthesis, 1997, 545.
features a rare 5,6,7,8-tetrahydrobenzo[c,e]azocine skeleton con-
sisting of a biaryl encompassed within an eight-membered
N-heterocyclic ring and constitutes a challenging synthetic target.
It has been synthesized previously by several groups,20 but not by
the most direct strategy of medium ring and biaryl formation in
one step. Treatment of the acyclic aryl bromide with Rieke zinc
under the standard conditions, followed by transmetallation to the
intramolecular cuprate and oxidation provided an excellent yield
of buflavine, the spectroscopic data of which matched that
reported for the natural material.19
There have been several discussions on the mechanism of the
stoichiometric organocuprate oxidation reaction.7a,d In order to
account for the use of substoichiometric amounts of copper(I) and
oxidant the catalytic cycle in Scheme 3 is proposed. Consistent
with this mechanism is the finding that aryl zinc halides are not
oxidised at an appreciable rate under the reaction conditions. Also,
the inorganic residue that remained after catalytic organocuprate
oxidation could be used successfully in subsequent reactions,
suggesting that the copper salt is acting in a truly catalytic manner.
In summary, we have shown that zinc organocuprates may be
oxidized to give a wide range of carbon–carbon bonds in high yield
in the presence of electrophilic functional groups such as esters,
nitriles and ketones. We have disclosed for the first time the use of
copper and organic oxidant loadings well below the level of one
equivalent for each carbon–carbon bond made and have presented
a tentative catalytic cycle to explain these results. The new
methodology was applied in the total synthesis of the
Amaryllidaceae alkaloid buflavine, by concomitant biaryl bond
(from aryl bromides) and medium ring formation. Taken together,
these findings represent a significant advance and should herald
greater use of organocuprate oxidation in synthesis. Ongoing
studies in our laboratories are concerned with the expansion of the
substrate scope beyond organic halides and with further applica-
tion in the synthesis of natural products.
12 P. Knochel and R. D. Singer, Chem. Rev., 1993, 93, 2117.
13 P. Wipf, Synthesis, 1993, 537.
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1445; (b) H. Fillon, C. Gosmini and J. Pe´richon, J. Am. Chem. Soc.,
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1990, 31, 4413; (d) R. Ikegami, A. Koresawa, T. Shibata and K. Takagi,
J. Org. Chem., 2003, 68, 2195.
15 Other solvents can be used, such as THF, MeCN; however, yields were
highest using DMA.
16 Further decreases in the amount of copper reduced the yield marginally.
17 Electron-rich systems, for example 4-bromoanisole, required 0.25 equiva-
lents of oxidant per aryl zinc; whereas electron-poor systems, for
example ethyl 4-bromobenzoate, required 0.5 equivalents of oxidant per
aryl zinc. This disparity may reflect the differences in the energy of the
HOMO of the respective zinc organocuprates.
18 M. Takahashi, T. Ogiku, T. Okamura, T. Da-te, H. Ohmizu, K. Kondo
and T. Iwasaki, J. Chem. Soc., Perkin Trans. 1, 1993, 1473.
19 F. Viladomat, J. Bastida, C. Codina, W. E. Campbell and S. Mathee,
Phytochemistry, 1995, 40, 307.
Notes and references
{ General procedure: Aryl bromide (1.0 mmol) in THF (2 mL) was added
to Rieke zinc (4 mL, 5 g/100 mL suspension in THF). After addition the
reaction mixture was heated at reflux and then concentrated in vacuo. The
aryl zinc was dissolved in DMA (4 mL) and transferred via cannula onto
solid copper(I) bromide–dimethyl sulfide complex (20 mg, 0.1 mmol).
Oxidant 3 (147 mg, 0.5 mmol) in DMA (2 mL) was then added and the
solution was kept stirring for 1 h at room temperature. The reaction
mixture was filtered through a plug of silica eluting with hexane and
EtOAc. The filtrate was concentrated in vacuo and the residue purified by
flash column chromatography on silica gel.
20 For syntheses of buflavine, see: (a) S. Kodama, H. Takita, T. Kajimoto,
K. Nishide and M. Node, Tetrahedron, 2004, 60, 4901; (b)
P. Sahakitpichan and S. Ruchirawat, Tetrahedron Lett., 2003, 44, 5239;
(c) C. Hoarau, A. Couture, E. Deniau and P. Grandclaudon, J. Org.
Chem., 2002, 67, 5846; (d) P. A. Patil and V. Snieckus, Tetrahedron Lett.,
1998, 39, 1325; (e) S. Kobayashi, S. Kihara, S. Shizu, S. Katayama,
H. Ikeda, K. Kitahiro and H. Matsumoto, Chem. Pharm. Bull., 1977, 25,
3312 (synthesis coincidentally predates the isolation and structural
elucidation of buflavine); (f) For the synthesis of buflavine analogues, see:
P. Appukkuttan, W. Dehaen and E. V. Eycken, Org. Lett., 2005, 7, 2723.
§ CCDC 609161–609164. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b610218b
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Chem. Commun., 2006, 3883–3885 | 3885