Alkene carboboration enabled by synergistic catalysis

Article abstract of DOI:10.1002/chem.201404310

A synergistic Pd/Cu system for the coupling of alkenes, (Bpin)₂ (pin=pinacolate), and aryl/vinyl bromides is disclosed. This method allows for the catalytic generation of secondary Csp³-Cu nucleophiles in situ and subsequent Pd-catalyzed cross-coupling. A synergistic Pd/Cu system for the coupling of alkenes, (Bpin)₂ (pin=pinacolate), and aryl/vinyl bromides, was disclosed. This method allowed the catalytic generation of secondary Csp³-Cu nucleophiles in situ and subsequent Pd-catalyzed cross-coupling.

Full text of DOI:10.1002/chem.201404310

DOI: 10.1002/chem.201404310
Communication
&
Cross-Coupling
Alkene Carboboration Enabled by Synergistic Catalysis
Kevin B. Smith, Kaitlyn M. Logan, Wei You, and M. Kevin Brown*[a]
intercept the in situ generated Csp3- or Csp2ÀCu complexes
with various electrophiles (most commonly a proton) to turn-
over the catalyst.[9–14] Cross-coupling of in situ generated Csp3-
or Csp2-Cu-complexes with carbon-based electrophiles to for-
mally constitute a carboboration process[15] is significantly
more difficult.[8,13] These reactions are largely limited to cases
involving in situ generated Csp2ÀCu complexes or allyl–Cu
complexes.[8,13] The only examples describing capture of
Csp3ÀCu complexes utilize alkyl halides as the electrophilic
component.[13a–c,f,h,k]
Abstract: A synergistic Pd/Cu system for the coupling of
alkenes, (Bpin)2 (pin=pinacolate), and aryl/vinyl bromides
is disclosed. This method allows for the catalytic genera-
tion of secondary Csp3ÀCu nucleophiles in situ and subse-
quent Pd-catalyzed cross-coupling.
Palladium-catalyzed cross-coupling reactions have emerged as
an indispensable method for chemical synthesis.[1] The majority
of these methods rely on the pregeneration, and often isola-
tion, of the nucleophile component (Scheme 1). Synthesis of
the requisite nucleophile can often require tedious reaction se-
quences. Thus, catalytic generation of nucleophiles from
simple components and direct cross-coupling would represent
an attractive strategy for chemical synthesis.[2,3] Herein, we de-
scribe a synergistic Pd/Cu catalytic system that allows in situ
generation of Cu-based nucleophiles from simple alkenes and
diboron reagents followed by Pd-catalyzed cross-coupling
(Scheme 1).[4,5] As will be outlined below, this strategy offers
several advantages over traditional cross-coupling methods.
Our approach towards generating nucleophiles in situ was
inspired by the pioneering work of Sadighi and co-workers,
who demonstrated that Csp3ÀCu complexes could be generat-
ed by migratory insertion of NHCÀCu–Bpin (pin=pinacolate)
complexes across alkenes.[6,7] Subsequent studies by numerous
groups, including ours,[8] have developed catalytic variants that
We became interested in the cross-coupling of in situ gener-
ated Csp3- or Csp2ÀCu complexes with aryl halides, because
these processes would give rise to important and versatile
motifs for chemical synthesis (see below, for examples). Based
on these efforts, we recently reported a method for Cu-cata-
lyzed carboboration of alkynes and allenes.[8] This method en-
tails addition of a Cu–Bpin complex across an alkyne or allene
and direct capture of the resulting Csp2ÀCu complex or allyl-
Cu-complex, respectively, with aryl iodides. However, efforts to
extend this methodology to the coupling of simple alkenes
have been met with significant challenges. This is primarily
due to the slow reaction between the generated Csp3ÀCu
complex and the aryl halide. To circumvent this challenge, we
devised a form of synergistic catalysis that merges the Cu-cata-
lyzed migratory insertion of Cu–Bpin complexes across alkenes
with Pd-catalyzed cross-coupling reactions of aryl halides
(Scheme 1).[4,5,16]
Generally, we envisioned the catalytic cycle illustrated in
Scheme 2 would proceed as follows: The Csp3ÀCu complex III
would be generated by reaction of a Cu–Bpin complex (II)
with an alkene. Subsequent reaction with an [PdLnArX] com-
plex (VI) (generated by oxidative addition of [Pd0Ln] (V) to an
ArX) will provide a new Csp3ÀPd complex IV, as well as regen-
erate the starting Cu complex I. Reductive elimination of Pd
Scheme 1. Approaches towards cross-coupling.
[a] K. B. Smith, K. M. Logan, W. You, Prof. M. K. Brown
Department of Chemistry, Indiana University
800 E. Kirkwood Ave, Bloomington, IN 47401 (USA)
E-mail: brownmkb@indiana.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404310.
Scheme 2. Mechanistic idea to enable carboboration with synergistic
catalysis.
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complex IV would provide the product and regenerate Pd0Ln
(V).
Table 1. Alkene carboboration: effect of changing reaction parameters.[a]
The approach outlined in Scheme 1 is particularly attractive,
because: 1) simple alkenes are used as the chemical input;
2) both positions of the alkene are functionalized, thus allow-
ing two new bonds to be generated in a single operation;
3) due to the presence of the Bpin substituent, further func-
tionalization is possible; and 4) this process would allow the
cross-coupling of secondary Csp3 nucleophiles, a recognized
challenge in the cross-coupling field.[1c,17,18]
Entry Change from optimized conditions
Yield [%][b]
1
none
>98
11
39
>98
10
73
<5
62[c]
91
<2
68
2
3
4
5
6
7
8
9
10
11
12
13
Cy3P CuCl instead of SIMesCuCl
tBu3P CuCl instead of SIMesCuCl
IMesCuCl instead of SIMesCuCl
SIPrCuCl instead of SIMesCuCl
IPrCuCl instead of SIMesCuCl
ICyCuCl instead of SIMesCuCl
PdÀPCy3 precatalyst instead of Pd-XPhos precatalyst
PdÀPtBu3 precatalyst instead of Pd-XPhos precatalyst
PhCl instead of PhBr
We initiated our studies by examining the carboboration of
styrenes, aryl bromides, and (Bpin)2. Our choice to begin our
studies herein was largely motivated by two factors: 1) the mi-
gratory insertion of Cu–Bpin complexes across styrenes is well
established;[6,12] and 2) this method would provide efficient
and, perhaps more importantly, modular access to the 1,1-dia-
rylalkane motif.[19] Numerous biologically relevant molecules
contain this structural pattern; two pertinent examples are il-
lustrated in Figure 1 (1–2).[20]
PhI instead of PhBr
no Pd-XPhos precatalyst
no SIMesCuCl
<2
<2
[a] See the Supporting Information for experimental details. [b] Yield de-
termined by GC analysis with a calibrated internal standard (dodecane).
[c] Regioisomeric product was formed in 23% yield, see the Supporting
Information for details.
7) Under the optimized set of conditions, <2% of products de-
rived from b-hydride elimination of either the putative Csp3À
Cu complex III or the Csp3ÀPd complex IV was observed.
8) The primary by-product from these reactions was Ph–Bpin
resulting from cross-coupling of PhBr and (Bpin)2. Under the
optimized set of conditions, the formation of this compound
was limited to ꢀ5%.
Figure 1. Representative 1,1-diarylalkanes.
After evaluation of numerous reaction parameters, we iden-
tified that 1,1-diarylalkane 4 could be generated in >98%
yield (GC) by treatment of styrene (3), PhBr, and (Bpin)2 in the
presence of 5 mol% SIMesCuCl and 1 mol% Pd-2-dicyclohexyl-
phosphino-2’,4’,6’-triisopropylbiphenyl (XPhos) precatalyst
(Table 1, entry 1).[21] Several points regarding our optimized re-
action conditions are noteworthy: 1) the reaction operates well
under mild conditions (228C) and short reaction time (6 h);
and 2) use of phosphine-based Cu complexes provided 4 in
low yield (Table 1, entries 2 and 3). Previous reports have de-
tailed that phosphine Cu–Bpin complexes undergo slower mi-
gratory insertion than NHCÀCu–Bpin complexes;[10a] and
3) Sterically hindered NHCÀCu complexes IPrCuCl and SIPrCuCl
are less efficient than SIMesCuCl (Table 1, entries 5 and 6) likely
due to slower rates of migratory insertion and transmetalation.
IMesCuCl performs with a similar level of efficiency to that of
SIMesCuCl. 4) Other Pd complexes gave 4, albeit in reduced
yield (Table 1, entries 8 and 9). The use of PdÀPCy3 pre-catalyst
led to the formation of a regioisomeric product.[22] Use of the
PdÀXPhos pre-catalyst (as opposed to in situ generated com-
plexes) is not necessary and was only employed for simplicity.
5) Reactions with PhI work in moderate yield (62%);[23] howev-
er, use of PhCl did not lead to formation of the desired prod-
uct (Table 1, entries 10–11). 6) Both the Cu and Pd complexes
are necessary for this process (Table 1, entries 12 and 13).
With an optimized set of conditions in hand, we explored
the scope and limitations of this process. Several points re-
garding the range of electrophiles are noteworthy (Scheme 3):
1) Electron-deficient (see products 6–7), electron-rich (see
products 5, 8), and sterically hindered (product 8) aryl bro-
mides undergo reaction in good yield. 2) Reaction with vinyl
bromides led to formation of 11 and 12 in 47 and 66% yields,
respectively. These examples are particularly noteworthy, be-
cause there is potential for migratory insertion of SIMesCu–
Bpin across the vinyl bromide. Reactions with less hindered
vinyl bromides (e.g., 1-bromo-1-propene) did not lead to prod-
uct formation, likely because of competitive migratory inser-
tion pathways. 3) Reactions with heterocyclic aryl bromides
also worked well (see products 9–10). These examples are es-
pecially relevant to the preparation of biologically active com-
pounds.[24] 4) Due to the mild reaction conditions, transesterifi-
cation of methyl esters with NaOtBu did not occur (7). 5) Ap-
proximately 10% of a product derived from b-hydride elimina-
tion was observed only in the cases of 2-bromotoluene and 3-
bromothiophene.[22] 6) Mesityl bromide did not work in this
process, likely due to severe steric interactions (not shown).
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Scheme 3. Reactions with aryl/vinyl bromides and styrene. Yields reported as
the average of two experiments. [a] Approximately 10% of products derived
from b-hydride elimination were observed. [b] Yield was determined by
1H NMR analysis with an internal standard.
Scheme 5. Reactions with disubstituted alkenes. Yields reported as the aver-
age of two experiments.
Scheme 4. Reactions with aryl bromides and alkenes. Yields reported as the
average of two experiments.
ed to the structure of biologically significant molecules after
oxidation or amination[27] of the resulting Bpin unit (Scheme 5,
26 and 27).[28]
The scope of this process has also been extended to other
classes of activated alkenes. As illustrated in Scheme 4, various
substituted styrene derivatives, including the sterically hin-
dered 2-methyl styrene, operated well in this reaction (see
products 6, 8, and 13). Dimethylphenyl vinylsilane is also
a competent substrate (Scheme 4).[13f] These products (14 and
15) are notable, because both the silyl and boron units can be
differentially functionalized. Preparation of 15 also represents
that ketones are tolerated under the reaction conditions.[25]
Reactions with cyclic 1,2-substituted styrene derivatives
were also investigated (Scheme 4). These substrates offer the
additional challenge, as well as opportunity, of diastereocon-
trol.[18,26] Furthermore, the products of these reactions are relat-
Under the optimized conditions, 1,2-dihydronaphthalene
(16) was converted to 17 in 20:1 diastereomeric ratio (d.r.) and
77% yield (Scheme 5). Reactions of 1,2-dihydronaphthalene
(16) with other sterically and electronically modified aryl bro-
mides also provided the products (18–21) in uniformly good
yields and diastereoselectivities. 2H-Chromene, as well as 6-
methoxy-1,2-dihydronaphthalene, led to formation of 23 and
22, respectively, in good yields and diastereoselectivities. Re-
markably, reaction of indene with PhBr provided 24 in low d.r.
(2.6:1 d.r.), but the same reaction with 2-bromotoluene gener-
ated 25 in high d.r. (15:1 d.r.).[29] In all cases, the stereochemical
relationship between the Ar and Bpin substituents was deter-
mined to be trans for the major diastereomer.[22]
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Keywords: carboboration
·
copper
·
cross-coupling
·
palladium · synergistic catalysis
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To provide evidence for the plausibility of the catalytic cycle
illustrated in Scheme 2, we have carried out the carboboration
reaction in a stepwise manner. (Scheme 6). Thus, treatment of
1,2-dihydronaphthalene
(1.0 equiv)
with
SIMesCuOt-Bu
(1.0 equiv), and (Bpin)2 (1.0 equiv) led to the formation of
a new complex in <5 min at 228C. Due to the low stability of
this new complex, full characterization was not possible.[22,30]
Based on literature precedent, the product is likely from a syn-
migratory insertion of SIMesCuBpin across 1,2-dihydronaphtha-
lene as illustrated by structure 28. After five minutes, treatment
of putative Cu complex 28 with 20 mol% Pd-Xphos precatalyst
(preactivated with 20 mol%NaOtBu) and PhBr (1.1 equiv) led
to the formation of 17 in 60% yield and >20:1 d.r. within
30 min at 228C. We expect that the transmetalation of the
Csp3ÀCu complex to generate the Csp3ÀPd complex likely pro-
ceeds with inversion of stereochemistry to ultimately provide
the trans-diastereomer after a stereoretentive reductive elimi-
nation.[31] This is largely due to the known configurational sta-
bility of related Csp3ÀCu complexes[6] and Csp3ÀPd com-
plexes,[32] especially given the time frame of the experiment (<
30 min). However, at the present time, a pathway that involves
epimerization of the alkyl metal intermediates as an explana-
tion for trans-diastereomer formation is still possible.[18a] Future
studies will be aimed at unravelling the subtle details of this
process.
In conclusion, we have developed a synergistic Pd/Cu cata-
lytic system that allows the cross-coupling of in situ generated
secondary Csp3ÀCu nucleophiles. The method functions well
with a variety of substrates and provides efficient access to
molecules that contain medicinally relevant scaffolds. We have
also demonstrated that high levels of diastereocontrol can be
achieved for many examples. We expect that due to the high
modularity of this method, a variety of useful processes can be
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Acknowledgement
We thank Indiana University for financial support.
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Received: May 15, 2014
Published online on August 11, 2014
Chem. Eur. J. 2014, 20, 12032 – 12036
www.chemeurj.org
12036
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim