Regioselective Arylboration of Isoprene and Its Derivatives by Pd/Cu Cooperative Catalysis

Article abstract of DOI:10.1021/jacs.7b04024

A method for the regioselective arylboration of isoprene and its derivatives is presented. These reactions allow for the synthesis of useful building blocks from simple components. Through these studies, an unusual additive effect with DMAP has been uncovered that allows for altered reactivity and the formation of quaternary carbon centers. The utility of this method is demonstrated toward the formal synthesis of mesembrine.

Full text of DOI:10.1021/jacs.7b04024

Communication
pubs.acs.org/JACS
Regioselective Arylboration of Isoprene and Its Derivatives by Pd/Cu
Cooperative Catalysis
Kevin B. Smith and M. Kevin Brown*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
S
* Supporting Information
Scheme 1. Difunctionalization of Isoprene
ABSTRACT: A method for the regioselective aryl-
boration of isoprene and its derivatives is presented.
These reactions allow for the synthesis of useful building
blocks from simple components. Through these studies, an
unusual additive effect with DMAP has been uncovered
that allows for altered reactivity and the formation of
quaternary carbon centers. The utility of this method is
demonstrated toward the formal synthesis of mesembrine.
ue to the large-scale production (1 million tons produced/
Dyear) and low cost of isoprene, conversion to more
complex small molecules with additional functionality represents
an attractive process for chemical synthesis.1 In addition, due to
the presence of isoprene units in natural products (e.g., terpenes)
and biologically active molecules, isoprene-derived small
molecules constitute useful building blocks for the construction
of these targets. As such, numerous methods exist for the
functionalization of isoprene, the majority of which are
hydrofunctionalization processes.2 Difunctionalization of iso-
prene is less common but significant as the products incorporate
an additional group (compared to hydrofunctionalization).3−5 At
the outset of our studies, a recent report by Sigman et al.
represented the current state-of-the-art for three-component
couplings of isoprene (Scheme 1A).5e
Our group has taken an interest in carboboration processes
that operate by Pd/Cu cooperative catalysis.6−8 Accordingly, we
have developed methods for the arylboration of styrene
derivatives (note that Semba and Nakao independently
developed a closely related process).9,10 The reactions function
by addition of a Cu−Bpin complex across an alkene followed by
3
Pd-catalyzed cross-coupling of the generated Csp −Cu complex.
to the formation of up to four regioisomers. This event is
undoubtedly controlled by the nature of both the Pd catalyst and
Cu complex. Here we disclose a method for the regioselective
arylboration of isoprene in which, with different conditions,
either a 1,4-product or a 2,1-product can be generated (Scheme
1B). With respect to the latter process, we also have uncovered
an unusual additive effect with 4-(dimethylamino)pyridine
(DMAP).
Initial studies found that reaction of isoprene (1) under
conditions similar to those previously identified for arylboration
of styrenes led to the formation of 7, 8, and 9 in a 3:1:2 ratio
(Table 1, entry 1).6 It was reasoned that the formation of 7 and 8
We became interested in extending this process to the
arylboration of isoprene (Scheme 1B,C). Realization of such a
process would allow for the formation of synthetically versatile
products. It should be noted that during the final stages of this
study, two reports appeared for the carboboration of isoprene
with alkylidene malonates8a and imines.8e
It was reasoned that selective arylboration for the formation of
any regioisomer would be valuable; however, development of
such a transformation is challenging due to the potential
formation of up to four regioisomeric products (Scheme 1C).
The regioselectivity of the reaction is established at two distinct
stages. First, the initial addition of Cu−Bpin across isoprene can
generate two possible adducts, 5 and 6.11 Even if this process can
be controlled with judicious choice of ligand and reaction
conditions, the subsequent Pd-catalyzed cross coupling can lead
Received: April 20, 2017
Published: June 5, 2017
© 2017 American Chemical Society
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DOI: 10.1021/jacs.7b04024
J. Am. Chem. Soc. 2017, 139, 7721−7724

Journal of the American Chemical Society
Communication
Table 1. Optimization of Reactions Conditions
Scheme 2. Substrate Scope
a
entry Cu catalyst
Pd catalyst
Pd-Pt-Bu3-G3
7:8:9
yield of 7 (%)
b
1
2
3
4
5
6
IMesCuCl
It-BuCuBr
It-BuCuBr
It-BuCuBr
It-BuCuBr
It-BuCuBr
3:1:2
24
42
57
47
77
58
b
Pd-Pt-Bu3-G3
11:1:<0.1
11:1:<0.1
3:1:< 0.1
15:1:<0.1
10:1:<0.1
Pd-Pt-Bu3-G3
Pd-Pt-Bu2CH2t-Bu-G3
Pd-QPhos-G3
c
Pd-QPhos-G3
a
1
Yield and product ratios determined by H NMR analysis of the
b
crude reaction mixture with an internal standard. Reaction run with
1.5 equiv of KOt-Bu instead of 2 equiv. Reaction run with NaOt-Bu
c
instead of KOt-Bu.
a
Yield and selectivity of the allylboronate determined by analysis of the
b
1
crude H NMR with an internal standard. Yield (two steps from
R2Br) of isolated alcohol after oxidation (only a mixture of alkene
c
d
isomers). 9:1 product:other isomers. 8:1 product:other isomers.
e
resulted from Cu complex 5 whereas the remaining product 9 is
formed from the regioisomeric complex 6. It was reasoned that
the regioselectivity could be increased if a more sterically
encumbered NHC was used such that reaction at the less
substituted alkene of isoprene would be favored. This ultimately
led to the identification of It-BuCuBr as a catalyst, which allowed
for formation of only 7 and 8 suggesting that the borylcupration
step could be controlled (Table 1, entry 2). Since the
regioselectivity of borylcupration had been overcome, Pd
catalysts were evaluated to increase the selectivity of the
transmetalation. This initiative led to the discovery that Pd-
QPhos-G312 allowed for highly selective synthesis of 7 (vs 8 or 9)
as a 9:1 mixture of Z- and E-isomers (Table 1, entry 5).
4.4:1 product:other isomers.
Scheme 3. Formation of 2,1-Arylboration Product with
Bromopyridine
With an optimized set of conditions in hand, the scope of this
process was evaluated. Several points are noteworthy (Scheme
2): (1) Electron-rich and electron-poor aryl bromides can be
used (products 11, 12 and 10, 13, respectively). (2) Sterically
hindered aryl bromides functioned less well in this process, likely
due to adverse steric interactions during the putative trans-
metalation (product 15). (3) Vinyl bromides were found to be
competent; however, slightly lower diastereoselectivities (Z:E)
are observed relative to those achieved with aryl bromides
(product 16). (4) In all cases, while good yields of the
allylboronic ester were observed, the reaction products were
typically oxidized to allow for more facile purification. (5) The
related terpene, myrcene, also functioned well under the reaction
conditions (products 17 and 18).
During the course of our investigations, the observation was
made that reactions involving pyridine derivatives, such as 19,
gave rise to small quantities of the 2,1-adduct 22 (Scheme 3).
The formation of the 2,1-arylboration product 9 was observed
previously with reactions promoted by IMesCuCl (Table 1, entry
1). However, optimization of the reaction for selective formation
of 9 was unsuccessful. Since pyridine derivatives were clearly
affecting the selectivity of these reactions, further studies were
carried out based on the result outlined in Scheme 3.
reactions with isoprene and PhBr were carried out under
standard conditions shown in Scheme 2, except that various
pyridine derivatives were added. Initially, when pyridine was used
as an additive, the formation of 9 was observed, albeit in low yield
as the minor isomer (Table 2, entry 1). Further evaluation of
pyridine derivatives led to the finding that DMAP allowed for
generation of 9 as the major product. Standard optimization of
conditions and assessment of other sterically large phosphine
ligands led to improved reaction yields (Table 2, entry 6). Finally,
it was found that increased equivalents of DMAP (2.0 vs 1.0)
allowed for formation of 9 as the exclusive product in 61% yield
1
as judged by H NMR analysis (Table 2, entry 8). Control
experiments were also carried out that suggested DMAP is not
simply replacing It-Bu or Pt-Bu2CH2t-Bu from either Cu or Pd,
respectively (Table 2, entries 9 and 10).
The scope of the 2,1-arylboration reactions was investigated
and found to accommodate electron-rich (products 24, 25, 28),
electron-poor (products 26 and 27), and sterically hindered aryl
bromides (products 23, 24) (Scheme 4). In addition, myrcene
could also be substituted for isoprene with little loss in efficiency
(products 30 and 31). In general, the 2,1-arylboration products
were formed in high selectivity (>10:1 product:other isomers);
they can also be converted to other structures due to the
We reasoned that the Lewis basic nitrogen of the pyridine was
allowing for the altered reactivity. To test this hypothesis,
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DOI: 10.1021/jacs.7b04024
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Journal of the American Chemical Society
Communication
Table 2. Evaluation of Pyridine Derivatives as Additives
Scheme 5. Representative Functionalizations
yield of 9
a
a
entry additive/equiv
Pd catalyst
7:8:9
(%)
b
1
2
3
4
5
6
7
8
9
10
pyridine/1.0
Pd-QPhos-G3
6:1:1
1:1:4
2:1:3
4:1:2
1:1:5
1:1:11
2:1:13
1:1:>20
n.d.
5
17
34
14
27
68
67
61
<2
<2
b
DMAP/1.0
Pd-QPhos-G3
Scheme 6. Stereoselective Arylboration
DMAP/1.0
DMAP/1.0
DMAP/1.0
DMAP/1.0
Pd-QPhos-G3
Pd-Pt-Bu3-G3
Pd-APhos-G3
Pd-Pt-Bu2CH2t-Bu-G3
Pd-Pt-Bu2CH2t-Bu-G3
Pd-Pt-Bu2CH2t-Bu-G3
[Pd-G3]2
c
DMAP/1.0
c
DMAP/2.0
c
DMAP/2.0
cd
,
DMAP/2.0
Pd-Pt-Bu2CH2t-Bu-G3
n.d.
a
1
Yield and (1,2):(1,4) determined by H NMR analysis using 1,3,5-
b
trimethoxybenzene as an internal standard. Reaction run with 1.5
equiv of (Bpin)2 and 2.0 equiv of KOt-Bu. Reaction run at 45 °C
instead of 22 °C. Reaction run with 5 mol% CuBr instead of 5 mol%
It-BuCuBr. n.d. = not determined
c
d
Scheme 4. Substrate Scope
Preliminary mechanistic investigations of the reaction have
been carried out. To probe the regioselectivity of the migratory
insertion, isoprene was treated with equimolar quantities of It-
BuCuBr, KOt-Bu and (Bpin)2 (Scheme 7A). This reaction led to
the formation of 43 and 44 in a 3:1 ratio in 98% yield. It should be
noted that 43 and 44 are formed at roughly the same rate.17
Treatment of this mixture with Pd-QPhos-G3 and PhBr gave rise
to 7 and 45 in a 3:1 ratio and 75% yield (also note that 7 and 45
are produced at approximately the same rate).17 This result is
surprising as under the optimized catalytic reaction conditions,
<2% of isomer 45 is formed. The above data suggests that either
43 and 44 undergo interconversion, or 43 is formed selectively
under the catalytic reaction conditions. With respect to the
former we have not been able to provide evidence of this
interconversion through crossover experiments (this scenario is
also unlikely as qualitative rate measurements for formation and
consumption of 43 and 44 are nearly the same, as mentioned
previously).17 Regarding the latter, we probed the transient
formation of 43 and 44 by running the catalytic reaction in the
presence of t-BuOH, as protonation of allylcopper intermediates
is known to be rapid.18 In this case only the expected arylboration
product 7 and the protoboration adduct (46) derived from 43
were observed. This suggests that 44 was not generated under
the catalytic reaction conditions. The apparent divergence in
selectivity for the stoichiometric and catalytic reactions is unclear
at this time.
a
Yield of isolated product (>20:1 product:other isomers) after silica
b
1
gel column chromatography. Yield determined by H NMR analysis
of the crude reaction mixture with an internal standard. 8:1
product:other isomers. 9:1 product:other isomers. 2:1 product:other
isomers. Yield reported for two steps after oxidation to alcohol, 16:1
c
d
e
f
product:other isomers, see the SI for details.
versatility of the C−B bond.13 Illustrated in Scheme 5 are two
representative examples of C−C bond formation.
Cyclic 1,2-disubstituted diene 34 was also tolerated (Scheme
6). In this example, 36 was generated in high selectivity with
formation of the anti-diastereomer. Boronic ester 36 could be
easily converted to 37 through a hydroboration−oxidation
sequence,14 which can be transformed to mesembrine (38)
through established protocols.15,16 Several additional examples
of arylboration (products 40 and 42) are also shown in Scheme 6.
Highly stereoselective synthesis of 40 demonstrates the effect of
an existing stereocenter, while preparation of 42 showcases
heterocycle functionalization.
With respect to the mechanism of the 2,1-arylboration
reaction, DMAP was found to not inhibit or alter in any way
the stoichiometric formation of 43 and 44. Furthermore, the
mixture of 43 and 44 could not be converted to the 2,1-
arylboration products, despite numerous attempts (Scheme
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Journal of the American Chemical Society
Communication
Scheme 7. Mechanistic Studies
ACKNOWLEDGMENTS
We thank Indiana University and the NIH (5R01GM114443)
for generous financial support.
■
REFERENCES
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7A).17 In addition, a protoboration experiment in the presence of
DMAP (Scheme 7B) also resulted in the exclusive formation of
46. This data suggests that 43 was generated under the 2,1-
arylboration reaction conditions; however, its potential role as a
catalytic intermediate on the pathway to product 9 remains
unclear. Altogether, it is evident that the mechanisms of the both
1,4- and 2,1-arylboration reactions are quite complex and further
investigations are in progress.
Finally, for formation of Z-crotyl metal Cu complexes 43 and
44, two possibilities are proposed: (1) it has been established that
Z-crotyl metal complexes are more stable relative to the E-crotyl
metal complexes,19 and (2) insertion of 1,3-dienes into organo-
metal bonds occurs preferentially in the s-cis conformation to
give rise to Z-crotyl metal complexes.20
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Tetrahedron Lett. 2002, 43, 2297. (b) Wu, X.; Chen, Z.; Bai, Y.-B.; Dong,
V. M. J. Am. Chem. Soc. 2016, 138, 12013.
In conclusion, a process for the regioselective arylboration of
isoprene and its derivatives is presented. DMAP has been shown
to alter the normal reactivity of the system. Future efforts aim to
further investigate the role of DMAP and develop enantiose-
lective variants.
(16) Diene 34 did not lead to arylboration products under conditions
outlined in Scheme 2.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b04024.
(17) See the Supporting Information for details.
(18) Semba, K.; Shinomiya, M.; Fujihara, T.; Terao, J.; Tsuji, Y. Chem. -
Eur. J. 2013, 19, 7125.
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Organomet. Chem. 1992, 426, 143. (c) Liepins, V.; Backvall, J. E. Eur. J.
■
S
Experimental procedures and analytical data (PDF)
̈
Org. Chem. 2002, 2002, 3527.
(20) For a seminal report, see: Ojima, I.; Kumagai, M. J. Organomet.
Chem. 1978, 157, 359.
AUTHOR INFORMATION
Corresponding Author
*brownmkb@indiana.edu
■
ORCID
M. Kevin Brown: 0000-0002-4993-0917
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/jacs.7b04024
J. Am. Chem. Soc. 2017, 139, 7721−7724