Copper-catalyzed cross-coupling of boronic esters with aryl iodides and application to the carboboration of alkynes and allenes

Article abstract of DOI:10.1002/anie.201310275

Copper-catalyzed Suzuki-Miyaura-type cross-coupling and carboboration processes are reported. The cross-couplings function well with a variety of substituted aryl iodides and aryl boronic esters and allows for orthogonal reactivity compared to palladium-catalyzed processes. The carboboration method includes both alkynes and allenes and provides access to highly substituted and stereodefined vinyl boronic esters. The alkyne carboboration method is highlighted in the simple one-pot synthesis of Tamoxifen. Cross-Cu-pling: The title cross-couplings function well with a variety of substituted aryl iodides and aryl boronic esters and allows for reactivity orthogonal to that of the palladium-catalyzed processes. The title carboboration method includes both alkynes and allenes and provides access to highly substituted and stereodefined vinyl boronic esters. The alkyne carboboration method is highlighted in a simple one-pot synthesis of Tamoxifen.

Full text of DOI:10.1002/anie.201310275

Angewandte
Chemie
DOI: 10.1002/anie.201310275
Cross-Coupling
Copper-Catalyzed Cross-Coupling of Boronic Esters with Aryl Iodides
and Application to the Carboboration of Alkynes and Allenes**
Yiqing Zhou, Wei You, Kevin B. Smith, and M. Kevin Brown*
Abstract: Copper-catalyzed Suzuki–Miyaura-type cross-cou-
pling and carboboration processes are reported. The cross-
couplings function well with a variety of substituted aryl
iodides and aryl boronic esters and allows for orthogonal
reactivity compared to palladium-catalyzed processes. The
carboboration method includes both alkynes and allenes and
provides access to highly substituted and stereodefined vinyl
boronic esters. The alkyne carboboration method is high-
lighted in the simple one-pot synthesis of Tamoxifen.
To develop a copper-catalyzed Suzuki–Miyaura-type
cross-coupling, we envisioned an initial reaction between
ArB(OR)2 and CuX. We hypothesized that the resulting
nucleophilic Ar-CuI[16] species could react with an electro-
philic aryl halide, perhaps proceeding through a CuIII inter-
mediate (Scheme 1).[17] This type of cross-coupling, while not
unprecedented,[18] differs significantly from traditional pro-
cesses involving palladium complexes in which reaction with
the ArX precedes that with ArB(OR)2.[13]
C
opper-catalyzed cross-coupling reactions are valuable
reactions for chemical synthesis.[1,2] A variety of methods
[3–7]
[8]
[9,10]
À
À
À
are known for the preparation of C C,
C O, C N,
C S, and C X bonds.[12] Despite these advances, generally
effective and mild copper-catalyzed Suzuki–Miyaura-type
cross-couplings,[13,14] especially with C(sp2) electrophiles, are
lacking.[3]
[11]
À
À
Herein we disclose a method for mild copper-catalyzed
Suzuki–Miyaura-type cross-couplings. Introduction of this
method allows the identification of orthogonal reactivity
relative to palladium-catalyzed Suzuki–Miyaura cross-cou-
plings and has led to the development of novel carboboration
processes. Therefore, our interest in this area is driven both by
the low cost and low toxicity[15] associated with copper, as well
as by the discovery of new reactivity that will lead to the
synthesis of important molecules which were previously
difficult to access.
Scheme 1. Overall reaction scheme for copper-catalyzed cross-coupling
and generalized putative catalytic cycle.
Li and co-workers have developed copper-catalyzed
Suzuki–Miyaura-type processes, however high temperatures
(1258C in DMF) are needed and the reaction does not work
with sterically hindered or electron-poor aryl boronic
acids.[3c,d] Other systems involve the use of copper nano-
clusters[3a,b] or copper powder in polyethylene glycol sol-
vents.[3f] Recent studies by Liu and co-workers have demon-
strated that CuCl can promote the reaction of a variety of aryl
and alkyl boronic esters with unhindered C(sp3) electrophiles,
and is likely to proceed through an SN2-type pathway.[3f]
We initiated our studies by examination of the cross-
coupling reaction between the p-tolylphenyl boronic ester
1 and iodobenzene (2). Initial success was achieved with
IMes/CuCl in the presence of 1.2 equivalents of NaOtBu at
808C (Table 1, entry 1). Reaction optimization was achieved
primarily through the evaluation of the ligand. Xantphos was
identified to be the optimal ligand for this system in
combination with 2–3 equivalents NaOtBu (Table 1, entries 7
and 8). Reactions at lower temperature (608C versus 808C) or
with a reduced reaction time (8 h versus 15 h) provided the
product in diminished but acceptable yields (compare entry 8
with entries 9 and 10, Table 1).[19] Finally, it should be noted
that the coupling reaction in the absence of a ligand or copper
does not proceed (Table 1, entries 11 and 12).[20]
[*] W. You,[+] K. B. Smith, Prof. M. K. Brown
Department of Chemistry, Indiana University
800 E. Kirkwood Ave, Bloomington, IN 47401 (USA)
E-mail: brownmkb@indiana.edu
With an optimized set of reaction conditions in hand we
explored the scope and limitations of this process. Several
points learned from these studies are noteworthy (Table 2):
1) electron-deficient and electron-rich aryl boronic esters and
aryl iodides undergo cross-coupling in good yield. 2) Steri-
cally hindered aryl boronic esters undergo cross-coupling in
good yield, however [Cy3PCuCl] was necessary for this
process (Table 2, entries 4 and 16). For example, the reactions
Y. Zhou[+]
Department of Chemistry, Tsinghua University
Beijing, 100084 (China)
[+] These authors contributed equally to this work.
[**] We thank Indiana University and Tsinghua University for financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310275.
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Table 1: Optimization studies.[a]
Table 2: Copper-catalyzed cross-coupling: Substrate scope.[a]
Entry
Ar
ArI
Product
Yield [%][b]
1
2
3
4
5
6
7
C6H5
4-ClC6H4I
4-ClC6H4I
4-ClC6H4I
4-ClC6H4I
4-ClC6H4I
4-ClC6H4I
4-ClC6H4I
4
5
6
7
8
94
90
92
82c
89
96
76
Entry
Ligand
T [8C]
X equiv NaOtBu
Yield [%][b]
4-MeC6H4
3,4-Cl2C6H3
1-napht
2-napht
4-OMeC6H4
4-CF3C6H4
1
2
3
4
5
6
7
8
IMes
DPEPhos
dppb
dppf
PCy3
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
none
80
80
80
80
80
80
80
80
60
80
80
80
1.2
1.2
1.2
1.2
1.2
1.2
2.0
3.0
3.0
3.0
3.0
3.0
28
6
8
9
10
29
56
82
96
99
72
88[c]
<2
<2
8
4-ClC6H4I
11
70
9
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-CF3C6H4
1-napht
C6H5I
3
12
13
14
15
16
17
18
90
70
90
76
10
11
12
13
14
15
16
4-MeC6H4I
4-CF3C6H4I
4-OMeC6H4I
2-MeC6H4I
4-iodopyridine
2,6-Me2C6H3I
2,6-Me2C6H3I
9
10
11
12
71
Xantphos
(no CuCl)
80
71[d]
75[c]
[a] See the Supporting Information for experimental details. [b] Yield
determined by GC analysis using n-dodecane as an internal standard.
[c] Reaction run for 8 h. dppb=1,4-bis(diphenylphosphino)butane,
dppf=1,1’-bis(diphenylphosphino)ferrocene.
[a] See the Supporting Information for experimental details. [b] Yield of
the isolated product after silica gel column chromatography. [c] Reac-
tions run with 10 mol% Cy3PCuCl at 1208C. [d] Reaction carried out at
1208C.
presented in entries 4 and 16 of Table 2, promoted by
Xantphos/CuCl provided the product in 55 and 65% yield,
respectively. 3) Reactions with aryl bromides resulted in
complete recovery of the starting materials. 4) Boronic acids
are not suitable substrates for the process because of rapid
protodemetallation of the putative aryl copper intermediate.
5) Boronic esters derived from pinacol can be used in this
process, however reduced yields were observed. For example,
cross-coupling of PhBpin with 4-iodochlorobenzene pro-
moted by 10 mol% Xantphos/CuCl at 808C provided the
desired product in 44% yield (compare with Table 2, entry 1).
The alkene-substituted aryl iodides 19 and 20 were
investigated to probe the mechanistic question of whether
or not radical intermediates are generated [Eq. (1)].[21] Under
the optimized reaction conditions, cross-coupling of 19 and 20
with 1, catalyzed by Xantphos/CuCl, proceeded smoothly to
generate 21 (64%) and 22 (89%), respectively, without the
formation of any cyclized products (< 2%). This data suggests
that radical intermediates are not involved in the cross-
coupling.[21] In addition, these reactions also demonstrate that
orthogonal reactivity compared to that of palladium-cata-
lyzed reactions may be achieved. For example, the analogous
reaction between 1 and 19 promoted by palladium catalysts
leads not to the formation of 21 but rather to the formation of
Heck-type products.[22]
The cross-coupling reactions presented above likely
involve the intermediacy of RCuI (R = aryl or vinyl), which
is generated by a transmetalation process. We hypothesized
that if RCuI intermediates could be generated through
À
a migratory insertion across C C p bonds and then subjected
to reaction with aryl halides, useful three-component reac-
tions could be developed.
The addition of CuI/Bpin complexes across alkynes and
allenes has been established to be an efficient process for the
generation of vinyl– and allyl–copper bonds, respectively
(Scheme 2).[23] Typically, the organocopper bond is subject to
protonation and thus constitutes a hydroboration proces-
s.[24,25a–d,26] Much less developed are examples where the
organocopper bond is intercepted with a carbon-based
electrophile.[25e,27–29] Furthermore, trapping of the organo-
copper with aryl halides is unknown and development of such
a process would establish a straightforward and useful method
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Scheme 2. Overall reaction scheme for carboboration and potential
catalytic cycle. pin=pinacol.
for carboboration. Described below is the development of
carboboration reactions with alkynes and allenes.
We have discovered that the vinyl–copper bond generated
through a migratory insertion of a Cu/Bpin complex across an
alkyne could be subjected to cross-coupling with an aryl
iodide (Scheme 3). This method is important because it
provides access to highly substituted alkenes, which is
a challenging problem in chemical synthesis.[30,31] The optimal
catalyst for these reactions was determined to be the readily
available and inexpensive [Cy3PCuCl], and the reaction
proceeded under relatively mild reaction conditions (808C).
Premature reaction of an in situ generated Cu/B intermediate
with the aryl iodide was slow relative to reactions with an
alkyne.[32] The process was tolerant of a variety of aryl iodide
substitution patterns and provided the product as a single
alkene isomer (23–32 and 39; Scheme 3). With unsymmetrical
alkynes, regioisomers were often generated (33–38). For
example, reactions with aryl/alkyl alkynes led to formation of
33–35 with high levels of regioselectivity (ꢀ 8:1) while
reactions with unsymmetrical alkynes bearing two different
C(sp2)-derived substituents resulted in formation of the
desired products in low regioselectivity (ꢁ 2:1; 36–38).
Reactions with terminal alkynes led to low yields of the
desired product, with formation of the disubstituted vinyl-
borane as the major product. This product likely arises by
protonation of the vinyl copper intermediate with the
Scheme 3. Copper-catalyzed carboboration of alkynes. See the Support-
ing Information for experimental details. Yield refers to yield of
isolated product after silica gel column chromatography. A >20:1 d.r.
1
is observed in all cases as determined by H NMR analysis of the
unpurified reaction mixture. Regioisomeric ratios (r.r.) determined by
1H NMR analysis of the unpurified reaction mixture. [a] Reaction
carried out at 1208C [b] Reactions run with 10 mol% [IMesCuCl] at
1208C.
terminal alkyne hydrogen.[33]
.
The utility of the carboboration process was highlighted in
the rapid synthesis of the estrogen receptor antagonist
Tamoxifen [Eq. (2)]. Copper-catalyzed carboboration of the
commercially available alkyne 41 with the aryl iodide 40
(prepared in one step) resulted in the formation of 42 (which
can be isolated if necessary in 80% yield and 10:1 r.r.).
Iodobenzene and additional NaOtBu and [Cy3PCuCl] were
then added and the reaction mixture heated for an additional
24 hours to provide Tamoxifen, after isolation, in 36% yield
(> 10:1 d.r.). This strategy constitutes a simple two-step
synthesis of Tamoxifen.[34]
Thus, treatment of in situ generated [Cy3PCuCl] with
NaOtBu, (Bpin)2, and 41 leads to the formation of the vinyl
copper intermediate 44. The selectivity of the migratory
insertion of the putative intermediate, pinB–CuPCy3, is in
complete agreement with previous reports.[24,27] The reaction
of 44 with 4-ClC6H4I led to formation of 34 in 76% yield with
10:1 d.r., thus confirming that vinyl copper intermediates are
capable of reaction with an aryl iodide.[35]
Similarly, the carboboration of allenes functions well
when [IMesCuCl] is employed as the catalyst, and leads to the
formation of stereodefined vinyl boronic esters (47–51,
We have investigated the mechanism of the carboboration
of alkynes by preparation of a putative intermediate [Eq. (3)].
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In conclusion, we have developed a copper-catalyzed
Suzuki–Miyaura-type cross-coupling reaction. The process is
notable for the wide substrate scope relative to known
copper-catalyzed Suzuki–Miyaura-type cross-couplings.[3]
Furthermore, because of the likely difference in reaction
mechanism relative to related palladium-catalyzed reactions,
unique reactivity can be achieved. These observations have
led to the development of carboboration processes. Future
efforts in this area will be directed toward expanding the
scope to include less reactive aryl halides, elucidation of
reaction mechanism, and development of enantioselective
variants.
Received: November 26, 2013
Revised: January 7, 2014
Published online: February 14, 2014
Keywords: alkenes · carboboration · copper · cross-coupling ·
.
synthetic methods
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Scheme 4. Copper-catalyzed carboboration of allenes. See the Support-
ing Information for experimental details. Yield refers to yield of
isolated product after silica gel column chromatography. A >98:2 d.r.
and >98:2 r.r. observed in all cases as determined by 1H NMR analysis
of the unpurified reaction mixture. [a] Contaminated with ca. 7% of
a protonated product. See the Supporting Information for details.
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.
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for details.
[20] CuCl (Alfa, 99.999%) or CuCl (Strem, 99.99%) was used for all
reactions. Reactions with CuBr (Aldrich, 99.999%) and CuI,
(Strem, 99.999%) provided the desired product in similar yield
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Angew. Chem. Int. Ed. 2014, 53, 3475 –3479
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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