Multigram Synthesis and C?C/C?N Couplings of Functionalized 1,2-Disubstituted Cyclopropyltrifluoroborates

Article abstract of DOI:10.1002/adsc.201900879

A convenient approach to the multigram synthesis of functionalized 1,2-disubstituted cyclopropyltrifluoroborates was developed, based on Pd(II)- or Cu(I)-catalyzed reaction of vinyltrifluoroborate and diazo compounds. Optimized protocols allowed for the preparation of the target products as pure diastereomers on multigram scale. It was shown that the title compounds were good coupling partners for the Suzuki-Miyaura and Chan-Lam reactions, which provide medicinally relevant (het)arylcyclopropanes with high diastereoselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201900879

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Title: Multigram synthesis and C–C/C–N couplings of functionalized
1,2-disubstituted cyclopropyltrifluoroborates
Authors: Oleksandr Hryshchuk, Yevhen Yurov, Andriy Tymtsunik,
Volodymyr Kovtunenko, Igor Komarov, and Oleksandr
Grygorenko
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900879
Link to VoR: http://dx.doi.org/10.1002/adsc.201900879

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10.1002/adsc.201900879
FULL PAPER
Advanced Synthesis & Catalysis
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Multigram Synthesis and C–C/C–N Couplings of
Functionalized 1,2-Disubstituted Cyclopropyltrifluoroborates
Oleksandr V. Hryschuk,a, b Yevhen Yurov,a, b Andriy V. Tymtsunik,a Volodymyr O.
Kovtunenko,b Igor V. Komarov,a, b and Oleksandr O. Grygorenkoa, b*
a
Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
b
Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
[Tel.: +38-044-239-3315; fax: +38-044-531-9497; e-mail: gregor@univ.kiev.ua]
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A convenient approach to the multigram synthesis for the Suzuki–Miyaura and Chan–Lam reactions, which
of
functionalized
1,2-disubstituted provide medicinally relevant (het)arylcyclopropanes with
cyclopropyltrifluoroborates was developed, based on Pd(II)- high diastereoselectivity.
or Cu(I)-catalyzed reaction of vinyltrifluoroborate and diazo
Keywords: Organoboron compounds; Diazoalkanes;
Cyclopropanes; Suzuki–Miyaura reaction; Chan–Lam
reaction
compounds. Optimized protocols allowed for the preparation
of the target products as pure diastereomers on multigram
scale. It was shown that the title compounds were good
coupling partners
CH2I2–Et2Zn (Scheme 1, A).[2–10] Other methods
included the use of ,-dihalogenoboronic esters
(B),[11,12] copper-catalyzed reaction of allyl carbonates
with a diboron derivative (C),[13] C–H borylation of
Introduction
1,2-Disubstituted cyclopropanes have proven their
beneficial role as structural motifs for drug
discovery–from
tranylcypromine and cyprolidol to recently approved
tasimelteon, a drug for non-24-hour sleep–wake
disorder, or ticagrelor, platelet aggregation inhibitor
(Figure 1).[1] It is not surprising therefore that mono-
1960s’
antidepressants
cyclopropanes
(D),[14–16]
sulfoxide–magnesium
exchange/functionalization (E),[17] and transformation
of existing functional groups in 1,2-disubstituted
cyclopropyl boronic acid derivatives (F).[9,18–22]
Recently, Duncton and co-workers reported synthesis
of 2-(trifluoromethyl)cyclopropylboronic derivatives
by Pd(OAc)2-catalyzed reaction of dibutyl
vinylboronic ester or MIDA vinylboronate with
2,2,2-trifluorodiazoetane (Scheme 1, G).[23,24] Other
recent methods which were mostly used for the
preparation of polysubstituted cyclopropyl boronates
included copper-catalyzed desymmetrization of
cyclopropenes,[25,26] directed remote metalation–
and
bifunctional
reagents
enabling
direct
modification at one of the cyclopropane ring carbon
atoms are of significant interest. Functionalized
boryl-substituted cyclopropanes are especially
promising in this view since they allow for wide
variation of the substituent through the well-
established carbon–carbon and carbon–heteroatom
coupling reactions.
borylation
of
N-cyclopropylamides,[27]
To date, a number of functionalized 1,2-disubstituted
cyclopropane boronic derivatives were described in
the literature. In most cases, cyclic boronic esters or
MIDA boronates were obtained via cyclopropanation
of appropriate vinyl derivatives with diazomethane or
enantioselective transfer of redox-active carbenes to
alkenylboronates,[28,29]
and
stereoselective
cyclopropanation thereof.[30]
Figure 1. 1,2-Disubstituted cyclopropanes–marketed and investigational drugs.
1
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10.1002/adsc.201900879
Advanced Synthesis & Catalysis
Scheme 1. Known methods for the preparation of functionalized 1,2-disubstituted cyclopropane boron reagents
Unlike the literature examples described in the
Scheme 1, our approach aimed at the direct synthesis
of functionalized cyclopropyl trifluoroborates. It
should be noted that trifluoroborates attracted much
interest in the last two decades,[31,32] being more
nucleophilic and typically more stable than more
classical boronic acid derivatives.[33] To date,
65% yield (dr 4:1); nevertheless, removal of the
Cu (I) catalyst from the crude products appeared to be
not feasible. Therefore, we switched back to
Pd(OAc)2; it was found that with this catalyst, the
reaction could be launched when the temperature was
increased to 40 C. The products 2a and 2b were
obtained in 71% total yield (dr 4:1), however, their
isolation in pure form was not fruitful. With
Rh2(OAc)4, no significant conversion of 1 could be
achieved even at elevated temperatures.
functionalized
1,2-disubstituted
cyclopropyl
trifluoroborates were reported in the literature, but
they were prepared via the corresponding boronic
esters.[8,14,15,19–21,27]
Further optimization of the reaction conditions
included variation of the solvent. It was found that at
40–45 C, the conversion of 1, yield of the products
2a and 2b, as well as their diastereomeric ratio were
not affected significantly upon replacing acetone with
THF. In the case of MeCN, conversion of 1 under
analogous conditions was not complete. Nevertheless,
the crude mixture of diastereomers 2a and 2b
obtained from the THF solution could be successfully
separated by fractional crystallization, so that 2a and
2b were obtained in 53% and 23% yields,
respectively.
Results and Discussion
In a search for the short and efficient synthetic
sequence for the preparation of functionalized 1,2-
disubstituted cyclopropyl trifluoroborates, we have
turned our attention to the above-mentioned method
of Duncton and co-workers (Scheme 1, G)[23,24] since
it would allow preparation of various functionalized
1,2-disubstituted cyclopropanes using
a
single
organoboron derivative as the starting material.
Potassium vinyltrifluoroborate (1), which have
recently become available from commercial sources
in large quantities, could be such starting material. To
check if this statement is true, we have performed
reaction of 1 with ethyl diazoacetate under various
reaction conditions (Table 1, Entries 1–7). A series of
works by the Pietruszka group describing reactions of
1,2-disubstituted alkenes with diazomethane are
appropriate to mention here since similar conditions
were described therein.[2–7]
It should be noted that the developed procedure was
used for the multigram cyclopropanation of 1 without
significant change in the reaction outcome.
We have also tried reaction of ethyl diazoacetate and
vinylboronic acid pinacol ester under the optimized
conditions described above. In this case, the starting
alkene and the products of carbene dimerization were
found in the crude reaction mixture.
It was found that in acetone at 25 C, the reaction of 1
with ethyl diazoacetate did not occur in the presence
of Pd(OAc)2, and only traces of the target products
were detected when Rh2(OAc)4 was used as a catalyst.
With CuCl, the complete conversion of 1 could not
be achieved. Using CuPF6 under the same conditions
led to the formation of cyclopropanes 2a and 2b in
Reaction of 1 and benzyl diazoacetate followed
trends similar to those described above for the ethyl
counterpart, although the yield of the products 3a and
3b were somewhat lower (Table 1, Entries 9–15).
The optimized conditions (1, BnO2CCHN2 (5 eq),
Pd(OAc)2 (2% mol.), THF, 45 C, overnight) gave 3a
2
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10.1002/adsc.201900879
Advanced Synthesis & Catalysis
Table 1. Reaction of 1 and diazoalkanes
#
R
Catalyst
Solvent
Conversion of 1 (%)
Yield (%)b)
trans:cis
Temperature, C
1
CO2Et
Pd(OAc)2
Rh2(OAc)4
CuCl
25
25
25
25
40
65
65
45
25
25
25
25
40
45
45
25
25
25
25
25
25
25
25
25
acetone
acetone
acetone
acetone
acetone
CH3CN
THF
<5
–
–
2
<5
traces
59
65
71
60
60
74c)
–
–
3
68
80:20
80:20
80:20
80:20
80:20
80:20
–
4
CuPF6
>99
>99
>99
>99
>99
<5
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Rh2(OAc)4
CuCl
6
7
8
THF
9
CO2Bn
acetone
acetone
acetone
acetone
acetone
THF
10
12
13
14
15
16
17
18
19
20
<5
–
–
40
25
32
42
48c)
54c)
74c)
–
75:25
75:25
75:25
75:25
85:15
90:10
–
CuPF6
74
Pd(OAc)2
>99
>99
>99
>99
<5
d)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
e)
CO2t-Bu
THF
f)
CF3
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
Rh2(OAc)4
CuCl
>99
46
11
15c)
27
–
90:10
90:10
85:15
–
CuPF6
21 CNf)
Pd(OAc)2
Rh2(OAc)4
CuClg)
>99
<5
22
23
24
25
>99
>99
30
45
60c)
85:15
85:15
85:15
g)
CuPF6
g)
Cu(acac)2
>99
1
a) Relative configurations are shown. b) Unless noted otherwise, yields are detected by H NMR. c) Isolated yields. g) 2%
mol. of catalyst, 5 eq of diazoalkane. g) 2% mol. of catalyst. f) Used as a CH2Cl2 solution. g) 3.6% mol. of catalyst
3
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