Insight into the copper-catalyzed borylation of strained alkenes

Article abstract of DOI:10.1055/s-0034-1379882

The copper-catalyzed hydro-and carboboration of strained alkenes is presented. The reaction is highly diastereoselective and affords boronic ester derivatives many of which are difficult to synthesize by known methods. Competition experiments with differe

Full text of DOI:10.1055/s-0034-1379882

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A. Parra et al.
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Insight into the Copper-Catalyzed Borylation of Strained Alkenes
Alejandro Parraa
Aurora Lópeza
Sergio Díaz-Tenderob
Laura Amenósa
José Luis García Ruanoa
Mariola Tortosa*a
O
Bpin
MeOH
H
O
O
hydroboration
B [Cu]
O
THF, r.t.
O
strained alkenes
Bpin
Me
carboboration
a
MeI
Departamento de Química Orgánica (módulo 01), Universidad
Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
mariola.tortosa@uam.es
Departamento de Química (módulo 13), Universidad Autónoma
de Madrid, Cantoblanco, 28049 Madrid, Spain
b
Received: 02.11.2014
Accepted: 26.11.2014
Published online: 09.01.2015
DOI: 10.1055/s-0034-1379882; Art ID: st-2014-d0915-l
orbital) of the alkene must be low enough in energy to in-
teract with the HOMO of the copper–boryl complex. In this
context, McQuade has recently shown that N-heterocyclic
carbene (NHC)–copper complexes are able to promote the
Abstract The copper-catalyzed hydro- and carboboration of strained
alkenes is presented. The reaction is highly diastereoselective and af-
fords boronic ester derivatives many of which are difficult to synthesize
by known methods. Competition experiments with different alkenes
show that high levels of chemoselectivity can be achieved. Density
functional theory calculations are in agreement with the observed che-
moselectivity.
5
hydroboration of norbornene derivatives A. In light of this
result, we were intrigued by the idea of extending the cop-
per-catalyzed hydroboration to alkenes with different de-
gree of strain and to establish, if possible, an order in reac-
tivity (Scheme 1). In particular, we focused our attention on
benzonorbornadienes derivatives C. These substrates were
particularly interesting for two reasons: First, boronic es-
ters E have not been previously synthesized by standard
borylation procedures. Second, the oxa- (X = O) and aza-
Key words bicyclic compounds, boron, catalysis, chemoselectivity,
copper
(X = NR) benzonorbornadiene derivatives present an addi-
The development of efficient and stereoselective cata-
tional challenge since copper-catalyzed additions of nucle-
ophiles are known to give ring-opened products.6 Herein,
we demonstrate that a readily available phosphine–copper
complex effectively catalyzes the hydroboration of benzo-
norbornadienes C. We have also extended our study to nor-
bornenes and norbornadienes with different degrees of
strain and have established an order in reactivity between
them. Additionally, we have shown that the bicyclic alkyl
copper intermediate D can react with MeI with excellent dia-
stereoselectivity.
,7
lytic methods to form carbon–boron bonds is a compelling
1
challenge in organic synthesis. In the last decade, copper-
catalyzed borylation reactions have emerged as a powerful
2
new tool for the synthesis of boronic ester derivatives. De-
spite the extensive efforts made in this field, there are some
challenges yet to be addressed, especially those related with
3
the hydroboration of nonactivated olefins. Theoretical
studies indicate that the olefin acts predominantly as a π-
4
Lewis acid in this class of transformations. The LUMO (π*
previous work
R1
R1
R2
Bpin
R2
NHC–Cu(I)
B2pin2
H
A
B
this work
X
X
X
Bpin
Bpin
Cu(I)–L
B2pin2
H+
H
CuL
RX
C
D
E
X = O, NR, CH2
order in reactivity?
X
alkene
carboboration
Bpin
R
F
Scheme 1 Copper-catalyzed hydroboration of strained alkenes
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Alejandro Parra (upper left) was born in 1980 in Toledo, Spain. He received his B.S. in Chemistry at the Universidad Autónoma of Madrid (Spain) in
2
2
004. In 2006 he spent four months in the laboratory of Prof. Andrew Myers at Harvard University (USA) working on the chemistry of tetracyclines. In
009, he earned his Ph.D. at the Universidad Autónoma de Madrid under the supervision of Prof. José Luis García Ruano. After that he carried out a post-
doctoral stay in Institute of Organic Chemistry, RWTH-Aachen (Germany), with Prof. Magnus Rueping (2009-2011). He came back to Spain and is cur-
rently working in Prof. José Luis García Ruano’s group. His research concerns asymmetric synthesis and boron chemistry.
Aurora López (upper middle) was born in Madrid in 1990. In 2012, she obtained her B.S. in Chemistry from the Universidad Autónoma de Madrid. In
2013, she received her master degree at the same university where she is currently working on the development of new borylation reactions under the
supervision of Dr. Mariola Tortosa.
Sergio Díaz-Tendero (upper right) was born in 1978 in Madrid (Spain). He received his B.S in Chemistry in 2000 from the Universidad Autónoma de
Madrid (Spain) and his Ph.D from the same university in 2005. He was a postdoc in the Institut de Minéralogie, de Physique des Matériaux et de Cosmo-
chimie (IMPMC) - Université Paris 6 (France) in 2005 and in the Laboratoire des Collisions Atomiques et Moléculaires (LCAM) - Université Paris-Sud
(
“
Orsay, France) from 2006 to 2009. In 2009 he joined the Departamento de Química in the Universidad Autónoma de Madrid, where he is currently
Ramon y Cajal” researcher. His research interests are theoretical study of the fragmentation dynamics of highly excited clusters and biomolecules,
modeling on charge transfer, electronic and vibrational excitation in molecules and nanostructures deposited on metal surfaces, and theoretical de-
scription of reactivity in organic chemistry.
Laura Amenós Núñez (down left) was born in 1989 in Tarragona, Spain. She obtained her B.S. in Chemistry from the Universitat Rovira i Virgili in 2008.
As an undergraduate, she spent 4 months at the University of Nottingham working in Robert Stockman’s group. In 2013, she obtained her master at
ICIQ (Institute of Chemical Research of Catalonia) under the supervision of Professor Antonio Echavarren. Currently, she is carrying out her graduate
work at the Universidad Autónoma de Madrid under the supervision of Dr. Mariola Tortosa.
José Luis García Ruano (down middle) received his Ph.D. at the Universidad Complutense (Madrid, 1973). He got a permanent position as Associate
Professor in Universidad Autónoma (Madrid, 1978) and was appointed to Full Professor in Organic Chemistry at Universidad Complutense (1982), re-
turning to Universidad Autónoma in 1983, where he was the Head of the Organic Chemistry Department for 12 years. He has held appointments as a
visiting Professor at the Florida State (1992), Emory (2003) and Florence (2010) Universities. From 1996 he is a Corresponding Member of the Academy
of the Scientific Research at Mexico. He served as Vice-president of the Spanish Royal Society of Chemistry for 4 years. In 2006 he was distinguished as
Fellow of the Japanese Chemical Society and he was awarded in 2011 with the Felix Serratosa’s medal by the Royal Spanish Society of Chemistry. His
research interests are centered in asymmetric synthesis of organic sulphur compounds, mainly those concerning sulfoxides and, more recently, in the
field of organocatalysis and alkynylation reactions. He has published around 350 papers and supervised forty Ph.D. theses.
Mariola Tortosa (down right) obtained her B.S. in Chemistry from the Universidad Autónoma de Madrid (UAM) in 1999. She then joined the group of
Dr. R. Fernández de la Pradilla at the Instituto de Química Orgánica General (Madrid, Spain) to carry out her graduate work on the development of new
asymmetric methods using chiral sulfoxides. In 2004, she received the Lilly Award for PhD students. In 2005, she moved to The Scripps Research Insti-
tute in Florida (USA) to work as a Postdoctoral Fellow with Prof. William Roush. Her research in Florida was directed toward completion of the total
synthesis of the antitumor agent Superstolide A using a transannular Diels–Alder strategy. In 2008 she returned to the Instituto de Química Orgánica
General (Madrid, Spain) as a Research Assistant. In 2011 she started her independent research at the Universidad Autónoma de Madrid as a Ramón y
Cajal Fellow. More recently, she received the ERC-Starting Grant awarded by the European Research Council to work on the project “Design and Applica-
tions of Unconventional Borylation Reactions”. Her research interests include boron chemistry, asymmetric catalysis and the synthesis of natural prod-
ucts. In 2014 she received the Young Investigator Award from the Royal Society of Chemistry of Spain and the Young Spanish Investigator Eli Lilly Award.
We began by examining the reactivity of oxabenzonor-
bornadiene 1a under copper-catalyzed borylation condi-
tions using pinacol borane (pinBH).3 Unfortunately, using
CuCl (10 mol%), Xantphos (11 mol%), pinBH (1.1 equiv), and
NaOt-Bu (0.5 equiv) in THF, we obtained a mixture of the
desired compound 2a and the ring-opened product 3a
(Scheme 2). We then searched for conditions using bispina-
colatodiboron (B pin ) as the boron source. Gratifyingly, in
c,d
2
2
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OH
O
O
CuCl/Xantphos
10 mol%)
Bpin
(
+
NaOt-Bu (0.5 equiv)
pinBH (1.1 equiv)
THF, r.t.
1a
2a
3a
O
O
CuCl/Xantphos
Bpin
(10 mol%)
O
PPh2
Xantphos
1a
NaOt-Bu (0.5 equiv)
B2pin2 (1.1 equiv)
THF, r.t.
2a
50% yield
(>98% conversion)
PPh2
O
O
Bpin =
B
Scheme 2 Copper-catalyzed hydroboration of 1a
the presence of CuCl (10 mol%), Xantphos (11 mol%), B pin2
This result led us to explore the possibility of using an
an alkyl halide, such as MeI, instead of MeOH to form a C–B
and a C–C bond in a single catalytic cycle (Scheme 4). After
2
(1.1 equiv), NaOt-Bu (0.5 equiv), and MeOH (4 equiv) in
9
THF, we observed the formation of boronic ester 2a with
excellent diastereoselectivity and without observing ring-
opened products. The conversion was high but the yield
was only moderate due to partial decomposition of the
product during the purification process.
several experimentation, we were pleased to find that the
use of CuCl (10 mol%), Xantphos (11 mol%), B pin (1.1
2
2
equiv), NaOt-Bu (1 equiv), and MeI (4 equiv) in THF afford-
ed bicyclic alkenes 4a and 4b in good yields as single diaste-
reomers (Scheme 4). As we and others previously observed
for the carboboration of alkynes,10 the use of one equivalent
of NaOt-Bu was crucial in this transformation as it regener-
ates the copper alkoxide species involved in the catalytic
cycle. The use of less than one equivalent of base resulted in
lower conversions. In all cases, the diastereomer resulting
from the syn addition of the methyl and boron groups was
formed with complete selectivity. As above, we did not ob-
With these conditions in hand, we decided to study the
influence of the bridgehead atom as well as the strain of the
alkene in the borylation reaction (Table 1). Aza- and carbo-
bicyclic alkenes 1b and 1c showed similar behavior afford-
ing 2b and 2c as single compounds. Less strained oxanor-
bornene 1d also gave boronic ester 2d in good yield. Nor-
bornadiene (1e) selectively afforded the monoborylated
product 2e when using one equivalent of bis(pinacolato)di-
boron. Similarly, with two equivalents of B pin the bisbor-
1
serve any traces of ring-opened products in the H NMR
2
2
ylated product was obtained. This approach notably im-
proves the reported synthesis of 2e, previously prepared as
an endo/exo mixture of diastereomers through a Diels–
Alder cycloaddition. Norbornene (1f) reacted smoothly un-
der the conditions described above to give boronic ester 2f
spectra of the crude mixtures.
Next, we decided to run competition experiments to see
what level of chemoselectivity could be achieved in the
copper-catalyzed borylation of strained alkenes (Figure 1).
To do so, an equimolecular mixture of two strained alkenes
was subjected to copper-catalyzed hydroboration condi-
tions [CuCl (10 mol%), Xantphos (11 mol%), NaOt-Bu (0.5
equiv), and MeOH (4 equiv)] with a deficiency of B pin (0.5
8
in excellent yield. Additionally, from cyclopentadiene dimer
1g, we observed exclusive borylation of the more strained
alkene. Finally, when we moved to less strained alkenes, we
observed a noticeable decrease in reactivity (Table 1, en-
tries 3–5). Cyclopentene (1h) afforded boronic ester 2h in
only 16% yield while cyclohexene (1i) did not react under
the conditions described above.
2
2
equiv). After 12 hours, the borylated product ratio was
1
measured in the H NMR spectra of the crude mixture. First,
we selected alkenes 1a and 1c to study the effect of the
bridgehead atom in the copper-catalyzed hydroboration.
Surprisingly, we did not see any signals corresponding to 2c
In the presence of MeOD, oxabicycle 1d afforded com-
pound 2j in 65% yield as a single diastereomer (Scheme
1
in the H NMR spectra of the crude product, and boronic es-
3
,>98% D incorporation). The diastereoselective formation
ter 2a was the only product obtained. This result reveals the
profound influence of the oxygen atom in the reactivity of
these bicycles. Starting from an equimolecular mixture of
alkenes 1a and 1d, with the same bridgehead atom but dif-
ferent degree of strain, we observed exclusive formation of
of the C–D bond reveals the potential to capture the inter-
mediate alkyl copper species D (Scheme 1) with electro-
philes other than proton.
O
CuCl/Xantphos (10 mol%)
NaOt-Bu (0.5 equiv)
B2pin2 (1.1 equiv)
O
2a. Therefore, the ring strain is also playing an important
Bpin
MeO
MeO
MeO
MeO
role in the reactivity. Bicycles 1c and 1e, with the same
bridgehead and similar degree of strain, afforded a 62:38
mixture of 2c and 2e. The strong influence of the oxygen
atom was further shown in competition 4. A mixture of
D
MeOD (4 equiv)
THF, r.t., 16 h, 65%
1d
2j
Scheme 3 Deuteration experiment with bicycle 1d
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O
O
Bpin
Me
CuCl/Xantphos (10 mol%)
NaOt-Bu (1 equiv), B2pin2 (1.1 equiv)
MeI (4 equiv)
1a
4a (55%)
Ts
N
Ts
N
THF, r.t., 16 h
Bpin
Me
4b (78%)
1b
Scheme 4 Copper-catalyzed carboboration of strained alkenes
alkenes 1d and 1e afforded oxygenated bicycle 2d with high
chemoselectivity. Finally, competition 5 confirmed that
norbornadiene (1e) is more reactive than the nonstrained
styrene derivative 1k. With these results and those ob-
tained in Table 1 we have established the order in reactivity
shown in Figure 1 with the oxa derivatives 1a and 1d being
the most reactive. The complete chemoselectivity ob-
served in most cases is striking and could be useful for site-
selective functionalizations.
7
pinB
84c
1g
2g
Bpin
Bpin
16d
8
9
11
1
h
2h
<2d
Table 1 Copper-Catalyzed Hydroboration of Strained Alkenes
1i
2i
a
b
c
Yield of isolated products; unoptimized reaction times.
Conversion determined by analysis of H NMR spectra of crude products.
Obtained as a 69:31 mixture of regioisomers.
1
CuCl/Xantphos (10 mol%)
NaOt-Bu (0.5 equiv)
R1
R2
R1
R2
H
d
Conversion determined by GC using an internal standard.
B2pin2 (1.1 equiv)
MeOH (4 equiv)
THF, r.t., 12 h
Bpin
To gain further insight into the role of the bridgehead
Entry Alkene
Product
Yield (%)a
atom, we analyzed by density functional theory (DFT) cal-
culations the frontier molecular orbitals for benzonorborn-
adienes 1a and 1c (Figure 2). As mentioned above, previous
theoretical studies indicate that the olefin acts predomi-
nantly as a π-Lewis acid in the copper-catalyzed hydrobora-
tion of alkenes.4 Therefore, the LUMO (π* orbital) of the
alkene interacts with the HOMO (σ orbital) of the copper–
boryl species. The lower-lying LUMO of the oxabenzonor-
bornadiene (1a) derivative makes it a better electrophile
than 1c which is in agreement with the higher reactivity
observed for 1a (Figure 1, competition 1).
Additionally, in order to investigate the energetics relat-
ed to the insertion of the alkene into the Cu–B bond, we
carried out DFT calculations using alkene 1a and the model
copper–boryl complex G (Figure 3). We simplified the cal-
culations by substituting the methyl groups in the phos-
phine ligand and in the Bpin ligand with hydrogen. We
found a two-step mechanism with a first transition state
TSI-1a corresponding to the complexation of the copper–
boryl complex to the alkene and a second transition state
TSII-1a corresponding to the insertion of the alkene into
the Cu–B bond.12
O
O
Bpin
50 (>98)b
1
2
1
a
2a
Ts
N
Ts
N
Bpin
Bpin
54 (>98)b
1
1
b
c
2b
3
4
50 (>98)b
65 (>98)b
2c
O
O
Bpin
MeO
MeO
MeO
MeO
2d
1
1
1
d
e
f
Bpin
Bpin
5
6
75
75
2e
2f
Finally, we compared the energetic profile for the com-
plexation and insertion in alkenes 1a, 1c, 1e, and 1l (Figure
4). In all cases, the complexation transition state TSI
showed lower energy than the insertion transition state
TSII. In the oxa derivatives 1a and 1l, the transition states
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competition 1 (1a + 1c)
competition 2 (1a + 1d)
competition 3 (1c + 1e)
O
O
2a
2d
O
2c
2e
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
MeO
MeO
2a
2c
2a/2c ≥ 98:2
2a/2d ≥ 98:2
2c/2e = 62:38
competition 4 (1d + 1e)
competition 5 (1e + 1k)
O
Me
Bpin
Bpin
Bpin
Bpin
Ph
MeO
MeO
2e
2k
2d
2e
2
d/2e = 93:7
2e/2k ≥ 98:2
order in reactivity
O
O
R1
R , R = alkyl
Me
MeO
MeO
R2
1
>
>
~
>
>
~
Ph
2
1a
1d
1c
1e
1k
Figure 1 Competition experiments
for insertion TSII and the intermediates IN-B are at lower
energies than in the corresponding nonoxa cases 1c and 1e.
This is consistent with the LUMO energies and with the
competition experiments.
tivity of different strained olefins. These experiments are
also supported by computational studies. We believe this
study could be useful in other metal-catalyzed reactions in-
volving the π* orbital of the alkene. The development of en-
antioselective versions of the transformations described
above is under way.
Acknowledgment
We thank the European Research Council (ERC-337776) and MINECO
(CTQ2012-35957 and CTQ2013-43698-P) for financial support. M. T.
and S. D.-T thank MINECO for RyC contracts. A. P. thanks MINECO for
JyC contract. We acknowledge the generous allocation of computer
time at the Centro de Computación Científica at the Universidad
Autónoma de Madrid (CCC-UAM).
Supporting Information
Supporting information for this article is available online at
Figure 2 Frontier molecular orbitals and energies (in eV) for alkenes 1a
and 1c computed at the B3LYP/6-311++G(d,p) level of theory including
solvent effects over the geometry obtained at the B3LYP/6-31G(d) lev-
el.
http://dx.doi.org/10.1055/s-0034-1379882.
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References and Notes
In summary, we have demonstrated that bicyclic
alkenes with different degrees of strain can undergo
copper-catalyzed hydroborations. Some of the examples
described above represent boronic esters that have not
been previously prepared using standard hydroboration
conditions. We have also demonstrated that alkylcopper in-
termediate species, formed in this transformation, can react
with electrophiles other than a proton. Interestingly, we
have carried out experiments to establish the order of reac-
(
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Figure 3 Energetic profile for the reaction of 1a with copper–boryl complex G. Gibbs free energies are referred to the reactants and are given in kcal mol .
They have been computed at the B3LYP/6-311++G(d,p) level of theory including solvent effects over the geometry obtained at the B3LYP/6-31G(d)
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Figure 4 Energetic profile for the reaction of 1a, 1c, 1e, and 1l with copper–boryl complex G. Gibbs free energies are referred to the reactants and are
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ence of the ring strain and the bridgehead atom in the copper–
boryl complex insertion. We did not include azabenzonorborn-
adiene 1b in the competition study because additional steric
effects from the tosyl group, not present in the other bicycles,
could also affect the reactivity.
(12) Complexation followed by insertion has been previously pro-
posed for similar reactions. See ref. 4a and: Jang, H.; Zhugralin,
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 494–500