Dendralenes as a Platform for Selective Catalysis: Ligand-Controlled Cu-Catalyzed Chemo-, Regio-, and Enantioselective Borylations

Article abstract of DOI:10.1021/acs.orglett.0c01892

We report the development of two complementary methods for the Cu-catalyzed anti-Markovnikov borylation of one specific olefin in 2-substituted [n]dendralenes (n = 3-6). The first protocol operates with a bisphosphine ligand and occurs with high regio- A nd chemoselectivity for the terminal double bond, independently of the number of cross-conjugated alkenes. We show that the use of a chiral phosphanamine ligand enables the highly chemo-, regio-, and enantioselective borylation of the alkene cross-conjugated with the terminal olefin in [n]dendralenes.

Full text of DOI:10.1021/acs.orglett.0c01892

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Letter
[n]Dendralenes as a Platform for Selective Catalysis: Ligand-
Controlled Cu-Catalyzed Chemo‑, Regio‑, and Enantioselective
Borylations
́
́
Camille Desfeux, Celine Besnard, and Clement Mazet*
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ABSTRACT: We report the development of two complementary
methods for the Cu-catalyzed anti-Markovnikov borylation of one
specific olefin in 2-substituted [n]dendralenes (n = 3−6). The first
protocol operates with a bisphosphine ligand and occurs with high
regio- and chemoselectivity for the terminal double bond,
independently of the number of cross-conjugated alkenes. We
show that the use of a chiral phosphanamine ligand enables the
highly chemo-, regio-, and enantioselective borylation of the alkene
cross-conjugated with the terminal olefin in [n]dendralenes.
mong the various classes of polyunsaturated hydro-
functionalization of branched dienes using C-, Si-, B-, N-, P-,
Acarbons containing exclusively sp -hybridized carbon S-, or O-based reagents.11,12 In addition to excellent regio- and
2
chemoselectivity, in some cases high enantioselectivity has
been achieved. As a continuation of our interest in this area,13
we wondered whether 2-substituted [n]dendralenes could be
used as a platform for the development of chemo-, regio-, and
ultimately enantioselective hydrofunctionalizations. For the
simplest [3]dendralene derivatives, this would require the
identification of a catalytic system able to discriminate among
the 19 isomers that can be theoretically generated upon
monohydro-functionalization. This number follows the linear
equation displayed on Figure 1C and increases to 27, 35, and
43 for [4]-, [5]-, and [6]dendralenes, respectively. Realization
of this objective would undoubtedly expand knowledge in the
field of selective transition-metal catalysis whereby contrast
to enzymessite-specific modification of complex structures
remains a persistent challenge.10,14 Herein, we report our
progress in this endeavor with the identification of two
complementary Cu-catalyzed processes for the highly chemo-,
regio-, and enantioselective borylation of 2-subsituted [n]-
dendralenes (n = 3−6) (Figure 1D).
atoms, dendralenes occupy a singular position. Dendralenes
are acyclic cross-conjugated polyenes which have been much
less investigated than linear polyenes or annulenes, for instance
(Figure 1A).1,2 For a long time, these structures were difficult
to prepare and were believed to be unstable entities. Owing to
20 years of remarkable synthetic efforts, the Sherburn
laboratory has streamlined access to a great variety of
dendralenes on a practical scale, with derivatives containing
up to 12 olefinic units.3,4 The same group has investigated the
specific physicochemical properties of dendralenes as well as
their ability to engage into diene-transmissive Diels−Alder
cycloadditions (DTDA) (Figure 1B).3,5−7 Selective function-
alization of dendralenes is challenging. Ru-catalyzed cross-
metathesis of [3]dendralenes was realized by resorting to a
protection/deprotection strategy.3h,8 Lipshutz showed that
only judiciously designed [3]dendralenic Michael acceptors
undergo selective Cu-catalyzed 1,4- or 1,6-conjugate addition
(Figure 1B).9 The development of general catalytic and
selective protocols for the functionalization of one specific
alkene in minimally biased [n]dendralenes remains elusive.
The metal-catalyzed selective intermolecular hydrofunction-
alization of conjugated 1,3-dienes has emerged as an
enthralling approach to elaborate complex multifunctional
small molecules from readily available starting materials. It
represents a formidable challenge for fundamental study in
selective catalysis because the number of theoretical isomers
depends on the substitution pattern of the diene.10 For acyclic
2-substituted dienes, up to 11 chemo-, regio-, and stereo-
isomers can be obtained. In recent years, several groups have
disclosed complementary selective processes for the hydro-
We began our investigations by evaluating several ligands
under prototypical reaction conditions for the Cu-catalyzed
borylation of dienes using the known 2-phenyl[3]dendralene
1a as the model substrate (Table 1).12e,13a,15 Whereas no
Received: June 5, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01892
© XXXX American Chemical Society
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A

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Analysis of the crude reaction mixture revealed a
1:5.3:8.7:10 ratio between the products of formal 4,5-, 3,3′-,
3′,5-, and 1,3′-addition denoted as 2a, 3a, 4a, and 5a,
respectively. Although 4a and 5a appeared to be generated as
single stereoisomers, the geometry of the CC bond could
not be unequivocally determined. The use of tricyclohexyl
phosphine (L2) or of a (P,N) ligand (L3) led to complex
mixtures of inseparable isomers (entries 3 and 4). With the
imidazolium salt L4, 3a was obtained as major product, and
with bisphophine L5, 2a was the most abundant isomer
(entries 5 and 6). The substantial amount of remaining
substrate and of other chemo- and regioisomers present in
these experiments hampered efficient purification in both
cases. With L6, 2a, the product of formal 4,5-addition with anti-
Markovnikov selectivity, was obtained as major isomer
together with reduced amount of 3a. No traces of 4a and 5a
were detected (entry 7). This result was significantly improved
using L7, and 2a was obtained as a single chemo- and
regioisomer (rr > 20:1) in 81% yield. The catalyst loading
could be reduced to 5 mol % (entries 8 and 9). Of note, the
influence of the supporting ligand associated with copper on
selectivity appears clearly from the results disclosed in Table 1
(entries 1−9). Formation of 5a (entries 2−5) highlights the
fact that even the less exposed internal diene units in 1a is
reactive.
We next set out to develop a modular synthetic route to
readily access related 2-substituted [n]dendralenes; a task
which remains challenging despite the development of several
successful strategies. Our approach takes inspiration from
previous tactics developed by the Sherburn group and builds
upon our Ni-catalyzed Kumada cross-coupling protocol for the
synthesis of 2-substituted 1,3-dienes (Figure 2).3,17 Dienol
phosphate 7a was prepared in high yield by treatment of 3-
phenylbut-3-en-2-one 6a with LDA at −78 °C, followed by
addition of 1.5 equiv of diethyl chlorophosphate.
Figure 1. (A) Prototypical classes of polyenes. (B) Functionalization
of [n]dendralenes and selective functionalizations. (C) Selectivity
challenges in the hydrofunctionalization of 2-substituted 1,3-dienes
and 2-substituted [n]dendralenes (n = 3−6).
a
Table 1. Reaction Optimization
With [(dmpe)NiCl2] as catalyst, 7a was cross-coupled with
vinyl magnesium bromide Mg-1, affording 1a in 78% yield. 2-
b
b
entry
ligand
conv (%)
2a:3a:4a:5a
c
1
2
3
4
none
L1
L2
L3
L4
nr
>99
>99
96
1:5.3:8.7:10
1:1.8:3.2:3.1
2.2:1: 1.9:1.8
7.8:17.5:1:3.2
11:1.8:−:1
d
5
63
6
7
8
L5
L6
L7
L7
88
76
99
97 (81)
5.3:1:−:−
>20:1:−:−
e
f
9
>20:1:−:−
a
b
1
Reaction conditions: 1a (0.15 mmol). Determined by H NMR
c
d
using an internal standard. No reaction. Using 50 mol % of KOtBu.
e
f
Using 5 mol % of CuCl, 5 mol % of L7, and 5 mol % of KOtBu. The
yield after purification is shown in parentheses.
reaction occurred in the absence of ligand, complete
conversion into a mixture of four distinguishable regioisomers
was obtained using triphenylphosphine (L1) (entries 1 and
2).16
Figure 2. Syntheses of 2-aryl- and 2-alkyl[n]dendralenes (n = 3−6).
aYield after purification.
B
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Letter
Phenyl[4]dendralene 8a and 2-phenyl[6]dendralene 10a were
prepared similarly using Mg-2 and Mg-3. While 8a was isolated
in 77% yield on a 7 mmol scale, 10a was obtained in only 16%
yield. Variation of the starting α,β-unsaturated methyl ketone
provided expedient access to a collection of 2-substituted
[3]dendralenes (1b−g) in usually high yields (average: 72%).
The cyclohexyl derivative 1h was prepared in 37% yield from
diethylphosphate 7b and 1-cyclohexylvinylmagnesium bromide
Mg-4 using [(dppe)NiCl2] as catalyst. A similar protocol was
employed for the synthesis of 2-phenyl[5]dendralene 9a using
11 and Mg-5 as cross-coupling partners (40% yield).
18a in 87% yield.19 The nonsymmetrically substituted
[3]dendralene 12a was treated with an excess of N-
methylmaleimide at 50 °C and yielded products of
monocycloaddition 19a and 20a exclusively. The reaction
occurred with a marked preference for the electron-rich alkyl
substituted diene unit over the aryl substituted diene fragment
(rr 7:1) (Figure 4). This results complements observations
The scope of the Cu-catalyzed 4,5-borylation of 2-
substituted [3]dendralenes was investigated next (Figure 3).
Figure 4. Postcatalytic functionalizations.
made by the Sherburn group on cycloadditions with 2-
substituted [3]dendralenes, which typically generate mixtures
of diastereomeric bisadducts.3c
Encouraged by results obtained during our first optimization
campaign (Table 1), we questioned whether a complementary
catalytic system that would target isomer 3a could be
developed. Two chiral N-heterocyclic carbene ligands were
evaluated initially (Table 2, entries 1 and 2).20 With L8, the
reactivity was moderate, and only 2a, 4a, and 5a were formed.
With L9, 2a and 3a were generated as major isomers in nearly
equimolar amounts. A low but measurable er was obtained for
the latter. The three chiral (P,N) ligands surveyed produced
preferentially 3a in low enantiomeric ratio and together with
hardly tractable mixtures of isomers (entries 3−5). Phosphan-
amine L13 developed by Alexakis and which gave excellent
results in the Cu-catalyzed enantioselective anti-Markovnikov
1,2-borylation of 2-aryl-1,3-dienes, was tested next (entry
6).13a,21 The increased er prompted us to vary additional
reaction parameters and to evaluate other structures of the
same family. When the reaction was performed in pentane, 2a
and 3a were the only detectable borylation products, and we
found that the regioisomeric ratio and enantiomeric ratio were
improved by conducting the reaction at low temperature
(entries 7−9). Evaluation of other members of this ligand class
led to the identification of L16 as the best candidate (entries
10−12). Finally, when 2 equiv of B2pin2 was employed, 3a was
generated in a 10.7:1 ratio and could be isolated in 80% yield
and 93:7 er (entry 13).
The scope of this second Cu-catalyzed borylation reaction
was evaluated using the same set of 2-substituted [n]-
dendralenes (Figure 5). Electron-rich, electron-neutral, and
electron-deficient 2-aryl[3]dendralenes delivered the 3,3′-
addition products 3a−e in high yield, excellent regioselectivity,
and high enantiomeric ratio (average: 91:9). Lower levels of
enantiocontrol were obtained for 2-aliphatic[3]dendralenes,
but the chemo- and regioselectivity remained very high both
for primary and secondary alkyl derivatives (3f−h). This
borylation protocol could be applied to [4]-, [5]-, and even
[6]dendralenes affording the products of 4,4′-, 5,5′-, and 6,6′-
addition with anti-Markovnikov selectivity as major isomers
Figure 3. Cu-catalyzed borylation of the remote alkene unit in
[n]dendralenes (n = 3−6) (0.15−5.2 mmol). Selectivity determined
by 1H NMR of the crude reaction mixture. The regioisomeric ratio rr
is expressed as the major isomer over the sum of all other detectable
a
b
isomers. Yield after purification. 20 h. 42 h.
Preferential borylation of the terminal alkene with perfect anti-
Markovnikov selectivity occurred in all cases. The 3,3′-addition
products 3a−h were the only other detectable borylated
isomers. Consistently high yield and excellent chemo- and
regioselectivity were achieved with 2-aryl[3]dendralenes 2a−e.
Although a slightly diminished selectivity was noticed for
[3]dendralenes with a primary alkyl substituent (1f−g), the
cyclohexyl derivative 1h led to results comparable to those
obtained with the aryl-containing substrates. A methoxy (2b),
a chloro (2c), a fluoro (2d), a trifluoromethyl (2e), and an
isolated alkene (2g) were found to be compatible. No traces of
overborylated product were detected. Quite remarkably, the
anti-Markovnikov borylation could be extended to [4]-, [5]-,
and [6]dendralenes, leading to products of 5,6-, 6,7-, and 7,8-
addition with excellent chemo- and regioselectivity (58−83%
yield). To demonstrate the robustness of the protocol, the
borylation of [4]dendralene 8a was conducted on a gram scale
to afford 12a in 80% yield and 8.6:1 rr. Our current hypothesis
for the observed selectivity relies on the formation of a
sterically less demanding σ-allyl copper species resulting from
the addition of the putative [Cu-Bpin] intermediate to the
most reactive terminal alkene.11c,18
[3]Dendralene 12a was cross-coupled with 4-bromoanisole
using conditions for a Pd-catalyzed Suzuki reaction to afford
C
https://dx.doi.org/10.1021/acs.orglett.0c01892
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Letter
a
Table 2. Reaction Optimization
b
T
(°C)
conv
(%)
b
entry
L
solvent
2a:3a:4a:5a
er of 3a
c
d
1
L8
L9
23
23
23
23
23
23
23
0
−40
−40
−40
−40
−40
THF
THF
THF
THF
THF
THF
pentane
pentane
pentane
pentane
pentane
pentane
pentane
53
2.1:−:1:1.4
6.4:7:1:1
nd
e
2
89
30
80
75
51
89
98
93
85
88
90
(80)
64.5:35.5
58:42
60.5:39.5
54:46
3
4
5
6
7
8
9
10
11
12
L10
L11
L12
L13
L13
L13
L13
L14
L15
L16
L16
1:2.9:1.3:2.6
2.1:4.5:−:1
1.1:3.2:−:1.1
2.8:4.4:1.4:1
1:6.5:−:−
1:5.3:−:−
1:7.7:−:−
6.6:2.4:1.4:1
1:9.9:−:−
73:27
85.5:14.5
88.5:11.5
92:8
78:22
85:15
1:10.2:−:−
1:10.7:−:−
91.5:8.5
93:7
f
g
13
Figure 5. Scope of the enantioselective borylation of [n]dendralenes
1
a
b
Reaction conditions: 1a (0.1−0.3 mmol). Determined by 1H NMR
using an internal standard. The imidazolium iodide was employed
with 50 mol % of KOtBu. Not determined. The CuCl complex was
used. 3 h. In parentheses, yield after purification.
(n = 3−6) (0.14−0.3 mmol scale). rr determined by H NMR. er
c
determined by HPLC or SFC after oxidation to the alcohol. (i) H2O2
(30% aq), NaOH (4.0 M), THF, 23 °C, 30 min. (ii) 4-bromobenzoyl
chloride (1.2 equiv), DMAP (0.2 equiv), Et3N (1.5 equiv), CH2Cl2,
23 °C, 12 h. aThe minor isomer is 5g. b17 h. c6 h. The stereochemistry
of 3b−h, 13a, 15a, and 17a was assigned by analogy with 3a based on
the X-ray crystallographic analysis of its benzoyl derivative (S)-21a.22
d
e
f
g
(13a, 15a, 17a). In contrast to the first catalytic system,
inspection of the crude reaction mixture revealed the formation
of other borylated products, most of them being present in
negligible amounts. Therefore, the values expressed as rr in
Figure 5 reflect the ratio of the major isomer over the sum of
all other detectable isomers. To appreciate the effectiveness of
the catalytic system, these results must be analyzed in light of
the theoretical number of structures that can be generated
upon hydrofunctionalization. Indeed, the regioisomeric ratio
(rr) indicates that, for [3]−[6]dendralenes, the catalytic
system is able to generate predominantly 2 isomers out of
19, 27, 35, and 43 isomers, respectively, while the enantiomeric
ratio (er) underscores the ability of the chiral catalyst to
further impart appreciable levels of stereodifferentiation
between the two main isomers remaining (∼90:10).
To summarize, we developed two complementary methods
for the Cu-catalyzed selective borylation of 2-substituted
[n]dendralenes. Using a bisphosphine ligand, the first protocol
enables precise functionalization of the terminal olefin with
excellent anti-Markovnikov selectivity. The system is applicable
to various [n]dendralenes (n = 3−6). When n > 3, the
possibility to engage the new dendralenes generated into
postcatalytic cross-coupling and cycloaddition reactions has
been established. With the second protocol, the alkene cross-
conjugated with the terminal olefin is borylated preferentially
with excellent anti-Markovnikov selectivity. Selectivity was
modulated by changing the nature of the supporting ligand
from a bisphosphine to a monosphosphine. Identification of a
chiral phosphanamine afforded the borylated polyolefins with
high levels of enantiocontrol for various lengths of [n]-
dendralenes (n = 3−6). Our efforts are currently directed
toward understanding the origin of the high levels of chemo-,
regio-, and enantioselectivity obtained and at developing other
catalytic transformations for the site-specific functionalization
of [n]dendralenes.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
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General procedures, experimental details, and character-
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Accession Codes
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data for this paper. These data can be obtained free of charge
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Letter
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AUTHOR INFORMATION
Corresponding Author
■
́
Clement Mazet − Department of Organic Chemistry, University
of Geneva, 1211 Geneva, Switzerland; orcid.org/0000-
0002-2385-280X; Email: clement.mazet@unige.ch
Authors
Camille Desfeux − Department of Organic Chemistry,
University of Geneva, 1211 Geneva, Switzerland
́
Celine Besnard − Laboratory of Crystallography, University of
Geneva, 1211 Geneva, Switzerland; orcid.org/0000-0001-
5699-9675
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01892
Notes
The authors declare no competing financial interest.
(4) For selected examples, see: (a) Arisawa, M.; Sugihara, T.;
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of allenes with palladium-phenol catalyst. Chem. Commun. 1998,
2615. (b) Woo, S.; Squires, N.; Fallis, A. G. Indium-Mediated γ-
Pentadienylation of Aldehydes and Ketones: Cross-Conjugated
Trienes for Diene-Transmissive Cycloadditions. Org. Lett. 1999, 1,
573. (c) Brummond, K. M.; Chen, H.; Sill, P.; You, L. A Rhodium(I)-
Catalyzed Formal Allenic Alder Ene Reaction for the Rapid and
Stereoselective Assembly of Cross-Conjugated Trienes. J. Am. Chem.
Soc. 2002, 124, 15186. (d) Chin, S.; Lee, H.; Park, H.; Kim, M.
Synthesis of Cross-Conjugated Olefins from Alkynes: Regioselective
C-C Bond Formation between Alkynes. Organometallics 2002, 21,
3889. (e) Shimizu, M.; Nakamaki, C.; Shimono, K.; Schelper, M.;
Kurahashi, T.; Hiyama, T. Stereoselective Cross-Coupling Reaction of
1,1-Diboryl-1-alkenes with Electrophiles: A Highly Stereocontrolled
Approach to 1,1,2-Triaryl-1-alkenes. J. Am. Chem. Soc. 2005, 127,
12506. (f) Shimizu, M.; Kurahashi, T.; Shimono, K.; Tanaka, K.;
Nagao, I.; Kiyomoto, S.-I.; Hiyama, T. Facile Synthesis and
Palladium-Catalyzed Cross-Coupling Reactions of 2,3-Bis-
(pinacolatoboryl)-1,3-butadiene. Chem. - Asian J. 2007, 2, 1400.
(g) Miura, T.; Biyajima, T.; Toyoshima, T.; Murakami, M. Synthesis
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[3]Dendralene Synthesis: Rhodium(III)-Catalyzed Alkenyl C-H
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Catalyzed Cross-Cyclotrimerization and Dimerization of Allenes with
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ACKNOWLEDGMENTS
■
Financial support was provided by the University of Geneva
and the Swiss National Foundation (Grant Nos.
200020_175489 and 200021_188490). We thank S. Rosset,
A. Adam, and L. Avondo (University of Geneva) for technical
assistance.
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■
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G
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