Borylation of propargylic substrates by bimetallic catalysis. Synthesis of allenyl, propargylic, and butadienyl bpin derivatives

Article abstract of DOI:10.1021/ja502792s

Bimetallic Pd/Cu and Pd/Ag catalytic systems were used for borylation of propargylic alcohol derivatives. The substrate scope includes even terminal alkynes. The reactions proceed stererospecifically with formal S _N2′ pathways to give allenyl boronates. Opening of propargyl epoxides leads to 1,2-diborylated butadienes probably via en allenylboronate intermediate.

Full text of DOI:10.1021/ja502792s

Communication
pubs.acs.org/JACS
Borylation of Propargylic Substrates by Bimetallic Catalysis.
Synthesis of Allenyl, Propargylic, and Butadienyl Bpin Derivatives
Tony S. N. Zhao, Yuzhu Yang, Timo Lessing, and Kalman J. Szabo*
́
́
́
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden
S
* Supporting Information
new catalytic procedures. Thus, we have decided to develop a
ABSTRACT: Bimetallic Pd/Cu and Pd/Ag catalytic
systems were used for borylation of propargylic alcohol
derivatives. The substrate scope includes even terminal
alkynes. The reactions proceed stererospecifically with
formal SN2′ pathways to give allenyl boronates. Opening of
propargyl epoxides leads to 1,2-diborylated butadienes
probably via en allenylboronate intermediate.
mild neutral approach for the synthesis of allenyl-Bpin
derivatives, which is based on Pd-catalysis (eq 2). To our
surprise using solely Pd as a catalyst proved to be inefficient for
the transformation of propargylic alcohol derivatives under the
reaction conditions that were optimal for the borylation of the
analogous allyl alcohol derivatives.3a−d Instead of borylation
only rearrangement and elimination reactions occurred usually
independently from the presence or absence of B2pin2 (1).
We have found that propargyl carbonates or other derivatives
of propargyl alcohol can be borylated with high yields, if a
bimetallic Pd/Cu catalyst system is employed (eq 2). The
optimized conditions involved a propargylic carbonate substrate
(such as 3a), B2pin2 (1) as the boronate source, and the use of
both Pd(PPh3)4 and CuI in catalytic amounts without any
addition of base (Table 1). Phosphonate as a leaving group can
llenyl and propargyl boronates are very useful reagents in
A
organic synthesis for the preparation of stereo- and
regiodefined allenes and propagylic compounds via C−C bond
formation.1 Yet, access to these reagents is severely limited by
the relatively few synthetic methods available.1i−l,2 In the past
decade a number of very useful transition-metal-catalyzed
procedures have been reported for the synthesis of the
structurally related allyl boronates,3 which fostered increased
activity in the field of carbonyl allylboration. However,
particularly few methods have been reported for the
transition-metal-catalyzed transformation of propargylic sub-
strates to allenyl and propargyl boronate derivatives.2a As far as
we know, the only catalytic transformation was reported by Ito
and Sawamura2a using B2pin2 (1) as a boronate source with
propargylic carbonates in the presence of the CuOt-Bu catalyst
(eq 1). This procedure has been one of the most important
Table 1. Variation of the Reaction Conditions
entry
deviation from the standard conditions
no change
yield (%)
1
2
3
4
5
6
7
8
92
−OPO(OEt)2 as LG instead of −OCO2Me
−OH or −OAc as LG instead of −OCO2Me
without Pd(PPh3)4 or without Cul
Pd2(dba)3 2b/30 mol % PPh3 instead of Pd(PPh3)4
under air
74
<5
<5
89
18
CuCl2 or CuCN instead of Cul
Ag2O instead of Cul
40−70
38
be used instead of carbonate (entry 2). When we used a
propargylic alcohol or acetate (entry 3) substrate under our
standard conditions, formation of 4a was not observed. We got
the same result, when the acetate substrate was reacted together
with NaOMe, which was slowly added to the reaction mixture.
The desired product 4a did not form, when either Pd(PPh3)4
or CuI was omitted (entry 4).
When Pd(PPh3)4 was replaced with Pd2(dba)3/PPh3 catalyst,
the yield was almost identical (entry 5). Interestingly, by
applying this catalyst system with toluene as solvent, 4a was
formed, even if CuI was omitted. However, in this case a
synthetic approaches to a large variety of allenyl boronates.1f,g,2b
This procedure (eq 1) usually requires use of freshly sublimated
CuOt-Bu to give high yields. In addition, terminal alkynes could
not be used as substrates, probably because of the easy
deprotonation by the CuOt-Bu catalyst.
Considering the increasing demand for these useful
Received: March 19, 2014
Published: May 13, 2014
reagents,1f−h,n,o there is a need for further development of
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
a
significant amount of byproducts were formed and the yield
dropped to 39%.
Table 2. Synthesis of Allenyl and Propargylic Boronates
The yield was strongly reduced, when the reaction was not
conducted under inert conditions (entry 6). Other Cu-salts,
such as CuCl2 or CuCN, could also be used albeit with a lower
yield of 4a (entry 7). The reaction could also be conducted
using Ag2O as a cocatalyst (entry 8). However, when CuI was
replaced by Ag2O, large amounts of byproducts were formed
and, thus, the yield dropped substantially. Crudden and co-
workers4 reported that Ag2O can be employed in Suzuki−
Miyaura5 type couplings to accelerate the transmetalation of the
organoboronate substrate. It can apparently be used as a
cocatalyst for the activation of B2pin2, as well. This observation
helped us to solve the problems related to borylation of
terminal propagylic substrates (see below).
The synthetic scope of the borylation for internal propargylic
substrates is broad (Table 2, entries 1−8). The yields are
usually high, when aliphatic moieties are attached to the alkyne,
such as for the borylation of 3a, 3c−d, 3f−h. In the case of
phenyl substitution (3b) the yield was lower due to the lower
reactivity of the substrate (entry 2). Terminal Bpin allenes, such
as 4e−f can also be efficiently prepared. The fair isolated yield
for 4e is due to the volatility of the product. Interestingly, when
3a and 3d reacted in the presence of CuCl instead of CuI the
isomeric propargylic products 6a and 6b were formed (cf.
entries 1, 9 and entries 4, 10). In this reaction, a formal SN2
type displacement of the carbonate occurred. However,
formation of products 6a−b was not observed, when CuCl
was replaced with other chloride salts, such as KCl (in the
presence of CuI). Unfortunately, the effect of CuCl was not
general and we could not change the allenyl vs propargyl
selectivity for the rest of the reactions.
Synthesis of monosubstituted allenyl boronates (such as 4i−
k) is particularly challenging. Using transition-metal-catalyzed
borylation methods, monosubstituted allenyl boronates are
expected to form by transformation of terminal alkynes (such as
5a−c). We have found a single multistep synthesis of such a
species in the literature by Roush and co-workers.1g
A
transition-metal-catalyzed procedure using a propargylic
substrate and B2pin2 is not available at all. By the procedure
described in the seminal paper of Ito and Sawamura2a (eq 1)
only traces of these type of monosubstituted allenyl boronates
are formed. A possible reason is that the precursors of such
allenyl-Bpin compounds are terminal alkynes, such as 5a−c,
which readily undergo Glaser homocoupling6 particularly under
basic conditions. Therefore, a Cu-catalyst (or cocatalyst)
cannot be used in these borylation reactions. The Glaser
coupling of propargyl acetates is more difficult6 than that for
propargyl carbonates; therefore, we employed 5a−c as
substrates. We have found that Cu can be replaced by Ag as
the cocatalyst in the borylation process. Although Ag2O (Table
1, entry 8) is effective, the best results could be achieved by
AgOAc and AgOPiv (entries 11−13). In these reactions,
Pd2(dba)3 2b with PPh3 gave better results for 5a−b (entries
11−12) than Pd(PPh3)4 as a catalyst and we changed the
solvent to toluene. The relatively low yields (31−45%) are due
to the instability of allenyl-Bpin derivatives 4i−k. These
compounds easily undergo protodeborylation under the
reaction and purification.
a
General procedure: 3 (0.30 mmol), 2a (0.015 mmol), cocatalyst
(0.015 mmol), 1 (0.60 mmol) was stirred in THF (1.2 mL) at 50 °C
for 16 h. Isolated yields. Reaction conditions: 5 (0.3 mmol), 2b
(0.015 mmol), cocatalyst (0.03 mmol), 1 (0.60 mmol), PPh3 (0.06
mmol), in toluene (0.3 mL). At 40 °C for 12 h. At 45 °C for 8 h.
Reaction conditions: 5 (0.3 mmol), 2a (0.03 mmol), cocatalyst (0.03
mmol), 1 (0.60 mmol), in toluene (0.6 mL) at 35 °C for 16 h.
b
c
d
e
f
Using the same conditions (method A) as those for the
borylation of propargylic carbonates, diborylated butadienes
(8a−e) were obtained. The intermediate product of the
reaction is probably the expected allenyl-Bpin species. Since
this intermediate product has an allyl alcohol character a
subsequent borylation step may occur3i to give a diborylated
butadienyl derivative (8a−e) as the final product (see eq 5 and
a brief discussion in the mechanistic part). The reaction of the
propargyl epoxides was faster than that for the allenyl
carbonates, and thus the temperature could be reduced from
50 °C to room temperature. The reaction proceeds with high
selectivity providing mainly (entries 1,3) or exclusively (entries
7,9) one stereoisomer. The reaction with method A occurred
with a low yield for 7c and 7e. It was found that by using the
CuCl/PCy3 catalyst and substoichiometric amounts of KOt-Bu
Inspired by our previously published results for Pd-catalyzed
silylation and stannylation of propargylic substrates to obtain
functionalized allenyl silanes and stannanes,7 we considered
propargyl epoxide substrates 7a−e as well (eq 3, Table 3).
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Communication
Table 3. Synthesis of Borylated Butadienes by
Transformation of Propargylic Epoxides
Figure 1. Plausible mechanism for the borylation.
3b and the relatively poor yield for the formation of 4b (Table
2, entry 2).
Complex 9 is supposed to undergo transmetalation with Cu-
Bpin complex 10. Formation of 10 occurs by transmetalation of
the CuI catalyst with B2pin2. Such type of transmetalation
reactions were first described by Sadighi9 and co-workers, and
similar reactions have been suggested as the key step for many
Cu-catalyzed borylation reactions.2a,3g,10 This B2pin2 → Cu-
Bpin transmetalation is probably favored in the presence of
KOt-Bu, as the driving force of the process is formation of
stable t-BuO-Bpin. However, under neutral conditions using
CuI as catalyst the reaction is slower and probably reversible.
Therefore, the subsequent Cu-Bpin → Pd-Bpin transmetalation
should proceed with close proximity to quickly consume Cu-
Bpin complex 10. Thus, Cu serves as a transmetalation
cocatalyst in the process. The iodide and the methoxy
counterions can be exchanged between Cu, Pd, and Bpin.
When small amounts of CuOMe are formed the efficiency of
the Cu cocatalyst to facilitate the transmetalation is
substantially improved.
a
General procedure; Method A: 7 (0.30 mmol), 1 (0.90 mmol), 2a
(0.03 mmol), CuI (0.03 mmol), in THF (1.2 mL) stirred at 22 °C for
16 h under Ar. Method B: 7 (0.30 mmol), 1 (0.90 mmol), CuCl (0.03
mmol), KOt-Bu (0.09 mmol), PCy3 (0.09 mmol) in THF (1.2 mL)
b
c
stirred at 22 °C for 16 h under Ar. Isolated yields. E/Z isomer ratios
d
determined from crude 1H NMR. Reactions were performed in
MeOH (1.2 mL) at 50 °C.
(method B) the yields can be substantially improved (cf. entries
5,6 and entries 9,10). The rest of the epoxide opening reactions
also gave better yields with method B than with method A.
We have briefly studied the stereochemistry of the reaction.
It was found that the displacement of the carbonate leaving
group of 3 proceeds with a very high level of chirality transfer
(eq 4). When compound 3c8 was reacted with B2pin2 using
The reductive elimination of Bpin in complex 11 is probably
fast11 to give product 4. When CuCl is used as a cocatalyst
instead of CuI the carbonate of 3 is displaced by a formal SN2
mechanism instead of an SN2′ pathway, and therefore propargyl
boronate is formed instead of the allenyl product (Table 2,
entries 9, 10). A similar change of allenyl vs propargyl
selectivity was reported for the Pd-catalyzed stannylation of
propargylic substrates.7 The SN2-type of displacement of the
carbonate was not observed in the Cu-catalyzed borylation of
propargyl carbonates (eq 1).2a The exact reason for the SN2-
type stereochemistry using CuCl (instead of CuI) is still
unclear. Kurosawa and co-workers12 studied the structure and
isomerization possibilities of η1 and η3 propargyl and allenyl
palladium complexes. These authors found that halide ligands
(iodide, bromide, and chloride) have a strong effect on the
equilibrium of the different forms. It was concluded that
chloride ligands in particular strongly stabilize the η1-propargyl
palladium complexes. Exploration of the mechanistic relevance
of these observations on the propargyl vs allenyl boronate
Pd(PPh3)4 and CuI catalysts at room temperature, chiral
allenyl-Bpin 4c was obtained. The stereochemical outcome of
this reaction and the procedure by Ito and Sawamura (eq 1)2a
are identical.
A plausible mechanism for the reaction is given in Figure 1.
The first step of the process is oxidative displacement of the
carbonate group of 3 with an SN2′ mechanism (eq 4) to give 9.
The oxidative addition probably requires precoordination of the
substrate to Pd. This precoordination may be hindered by
bulky substituents. For example steric interaction between
palladium and the phenyl substituent in 3b may be unfavorable
for the π-coordination. This may explain the low reactivity of
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Journal of the American Chemical Society
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selectivity of the above process is the subject of ongoing studies
in our laboratory.
As mentioned above the epoxide opening reactions (Table 3)
probably give the expected allenyl boronates 12 with an allyl-
OBpin moiety. This allyl-OBpin species undergoes a second
Cu-catalyzed borylation with an SN2′-type mechanism to give
the corresponding butadiene product 8 (eq 5).
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mild neutral conditions allow even borylation of terminal
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preparing 1,2-diborylated butadiene derivatives by opening of
propargyl epoxides. The borylation of propargylic carbonates
with a Pd/Cu bimetallic system proceeds stereospecifically via
an SN2′ mechanism. We propose that the Cu cocatalyst assists
in the activation of B2pin2 and facilitates the transmetalation
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ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and compound character-
ization data are given. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
kalman@organ.su.se.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the financial support of the Swedish
Research Council (VR) and the Knut och Alice Wallenbergs
Foundation. Y.Y. thanks the Olle Engkvist Foundation for a
postdoctoral fellowship.
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