Stereoselective Direct Chlorination of Alkenyl MIDA Boronates: Divergent Synthesis of E and Z α-Chloroalkenyl Boronates

Article abstract of DOI:10.1002/anie.201709070

The individual molecules of α-chloroalkenyl boronates include both an electrophilic C?Cl bond and a nucleophilic C?B bond, which makes them intriguing organic synthons. Reported herein is a stereodivergent synthesis of both E and Z α-chloroalkenyl N-methyliminodiacetyl (MIDA) boronates through the direct chlorination of alkenyl MIDA boronates using tBuOCl and PhSeCl reagents, respectively. Both reaction processes are stereospecific and the use of sp³-B MIDA boronate is the key contributor to the reactivity. The synthetic value of the boronate products was also demonstrated.

Full text of DOI:10.1002/anie.201709070

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Stereoselective Direct Chlorination of Alkenyl MIDA Boronates:
Divergent Synthesis of E and Z- α-Chloro Alkenyl Boronates
Authors: Honggen Wang, Yao-Fu Zeng, Wei-Wei Ji, Wen-Xin Lv,
Yunyun Chen, Dong-Hang Tan, and Qingjiang Li
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709070
Angew. Chem. 10.1002/ange.201709070
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10.1002/anie.201709070
Angewandte Chemie International Edition
ICATION
elective Direct Chlorination of Alkenyl MIDA Boronates:
nt Synthesis of E and Z- α-Chloro Alkenyl Boronates
g, Wei-Wei Ji, Wen-Xin Lv, Yunyun Chen, Dong-Hang Tan, Qingjiang Li, and Honggen
ndividual molecules of α-chloro alkenyl boronates
electrophilic C-Cl bond and a nucleophilic C-B bond,
m intriguing organic synthons. Reported herein is a
synthesis of both E and Z-α-chloro alkenyl N-
etyl (MIDA) boronates by the direct chlorination of
boronates using t-BuOCl and PhSeCl reagents,
h reaction processes are stereospecific and the use
oronate is the key contributor to the reactivity. The
f the boronate products was demonstrated.
synthesis of halogenated and trifluoromethylated α-boryl
ketones.[10] The use of sp3-B MIDA boronates,[11] which are
typically bench-top and chromatographically stable solids,[12]
circumvented the potential C-to-O 1,3-boryl migration, and was
the key to successful synthesis. This result suggests the
possibility of assembling α-halo alkenyl boronates by the direct
halogenation of the corresponding alkenyl MIDA boronates. If
this could be successfully conducted, the resulting α-halo alkenyl
MIDA boronates, with the boron presenting in its protected form,
might serve as ideal synthons for chemoselective iterative
[13]
coupling reactions. To realize such a process, however, the
mbly of complex molecules has been a long-
nge in modern organic synthesis.[1] For this
iscovery and application of easily accessible
that combine multiple functional groups with
emical reactivities represents an appealing
noboron compounds are of vital importance in
chemistry due to their versatility for involvement
ansformations.[2] The introduction of easily
unctional groups into organoborons would, in
y enhance the synthetic values of organoboron
facilitating the modular and rapid synthesis of
ules, provided reactions could be performed in a
manner.[3] As an excellent example of this high
e, α-halo alkenyl boronates are amphoteric
ntaining both nucleophilic (C-B bond) and
halo bond) sites (Figure 1).[4] These organoboron
e, for instance, been utilized as synthons in poly-
ene synthesis.[5] They have also served as
he synthesis of α-amino boronic acids,[6,7] which
armacophores in proteasome inhibitors.[8]
nly a handful of methods have been developed
synthesis of α-halo alkenyl boronates.[9] Among
alkenyl boronates can typically be prepared via
ion of corresponding 1-halogenated alkynes
following potential challenges must be addressed. 1) The well-
known deborylative halogenation reaction process may lead to
an undesired alkenyl halide product.[14] With respect to this
challenge, we note that the attenuated nucleophilicity of the C-
B(MIDA) bond can be expected to make this process less likely
for both electronic and steric reasons.[15] 2) The unselective
alkene halogenation may result in the formation of different
regioisomers and stereoisomers, and thus render the reaction
unproductive. Herein, we report on our realization of
a
stereodivergent synthesis of both E and Z-α-chloro alkenyl MIDA
boronates via the direct chlorination of E-alkenyl MIDA
boronates with a Cl+ and Cl source, respectively (Figure 1c).
The reaction provides a high tolerance for the use of diversely
substituted alkenyl MIDA boronate substrates by retaining a high
product yield. Moreover, the synthetic utility of the products are
explored and the reaction mechanisms of both processes are
proposed.
electrophilic
R2
R3
NH2
BR'2
X
R1
R
R
BR'2
nucleophilic
amphoteric synthon
rrepresentative synthetic applications
Previous Work
a) Synthesis of Z--halo alkenyl boronates
H
R2BH
BR2
R'
d]
R'
X
The E isomer, on the other hand, can be
THF, -10 oC - 25 oC
X
b) Synthesis of E--halo alkenyl boronates
ough the hydrozirconation of alkynylboronates
reagent (Cp2Zr(H)Cl) followed by quenching with
ogenation reagents (Figure 1b).[9e] Although the
Cp2Zr(H)Cl, THF
RR
HH
Bpin
X
R
Bpin
then X+
c) This Work: stereodivergent synthesis of EE- and Z- -chloro alkenyl MIDA boronates

o
alkenyl boronates are stereoselective and
MMe
eful, the features of the synthesis methods, such
ed harsh reaction conditions, the use of
reagents, and the relatively poor functional group
imit their potential range of applications.
N
BMIDA
Cl
Cl
Cl
Cl
B
OO
OO
BMMIDA
O
R
R
R
t-BuOCl
PhSeCl
BMIDA
O
(Z)
(E)
+ stereodivergent synthesis
+ mild reaction conditions
+ broad substrate scope
+ high yielding
+ synthetic applications
tly developed an oxidative difunctionalziation of
N-methyliminodiacetyl (MIDA) boronates for the
Figure 1. Synthesis of α-chloro alkenyl bboronates
, W.-W. Ji, W.-X. Lv, Y. Chen, D.-H. Tan, Q. Li, H. Wang*
Pharmaceutical Sciences, Sun Yat-sen University,
u 510006, China
We initially examined the reaction of alkenyl MIDA boronate 1a
with PhSeCl[16] at room temperature (r.t.) employing different
concentrations of PhSeCl in conjunction with various solvents
(DCM, CH3CN, and THF) and additives (pyridine and
isonicotinic acid). Delightedly, we observed a predominant
formation of the Z-ɑ-chlorinated product 2a when employing
nghg3@mail.sysu.edu.cn
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ent.((Please delete this text if not appropriate))
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10.1002/anie.201709070
Angewandte Chemie International Edition
ICATION
additive in DCM, albeit in only 7% yield (Table 1,
Table 2. Synthesis of (Z)-(α-chlorophenyylalkenyl) MIDA boronates
ion of the base provided a higher yield of 24%
ugh the use of isonicotinic acid as an additive
parable yield (entry 2). It was found the addition
ular sieve (MS) was beneficial for the reaction,
an improved yield of 31% (entry 4). Further
fferent solvents revealed that THF was optimal
), affording an optimal yield of 81%. Decreasing
he PhSeCl loading provided lower yields (70%
s 7 and 8).
BMIDA
BMIDA
PhSeCl (2.5 equivv)
(Z)
R
R
Cl
4Å MS, THF, r.t. overrnight
1
2
2c, R = t-Bu, 71%, Z/E = 12:1
2d
BMIDA
BMIDA , R = Cl, 66%, Z/E > 30:1
2e
, R = Br, 80%, Z/E > 30:1
Cl
, 84%, Z/E > 30:1
BMIDA
Cl
2f
R
, R = OMe, 43%, Z/E = 5:1
2b
[a]
2g
Z/E > 30:1
,
, R = COOMe, 69%
2h, R = CN, 74%[a,b]
,
Z/E > 30:1
Cl
Cl
BMIDA
BMIDA
S
R
Cl
CCl
2i
2j
, R = Me 85%, Z/E > 30:1
[b]
, R = Br, 88%, Z/E > 30:1
2m, 53%, Z/E > 30:1
2l
, 90% , ZZ/E > 30:1
[a,b]
2k
on of the reaction conditions[a]
, R = CF3, 85%
, Z/E > 30:1
BMIDA
O
HO
BMMIDA
Cl
BMIDA
Cl
BMIDA
BMIDA
Cl
BnO
PhSeCl
Cl
[c]
[a,b,dd]
additive, solvent, r.t.
overnight
F
2p, 52% [a,b], Z/E > 30:1
2n
, 52% (19%)
, Z/E > 20:1
2o, 44%
, Z/E > 30:1
Me
1a
2a
BMIDA
BMIDA
yield (%)[b]
Cl
2q, 67%, Z/E = 12:1
Cl
additive
(2.5 equiv)
solvent
4Å MS
(mg)
[a,e]
, Z/E > 30:1
2r
, 89%
[a]
[c]
[d]
At 50°C. [b] PhSeCl (3.0 equiv). Reccovered starting material. The TBS
Py
DCM
DCM
DCM
DCM
CH3CN
THF
–
7
group on hydroxyl was deprotected. [e] PhhSeCl (3.5 equiv).
isonicotinic acid
–
23
24
31
30
corresponding alkenyl MIDA boronate with t-BuOCl (1.5 equiv)
in DCM in the presence of a 4 Å MS at r.t.. The scope of this
transformation was found to be again impressive. The resulting
yields indicate that a variety of important functional groups, such
as fluoro (3i), chloro (3d, 3h), bromo (3e), ester (3f), and methyl
groups (3g, 3i, 3j), could be tolerated. Intriguingly, for cases
where the solubilities of the substrates were low (3c, 3f, 3h, 3i,
3l), the use of isonicontic acid (0.2 equiv) as an additive
increased the reaction rate, thereby providing higher yields.
Unfortunately, the use of alkyl-substituted substrate (3m) led
only to the decomposition of the starting material.
–
–
–
–
–
–
–
15
15
15
15
15
81(77[c]
)
THF
70
THF
78
ons: 1a (0.1 mmol, 1.0 equiv), PhSeCl (2.5 equiv), THF, 4Å
MR yield based on 1a using 4-fluoro-benzoic acid as the
Isolated yield.
Table 3. Synthesis of (E)-(α-chlorophenyylalkenyl) MIDA boronates
BMIDA
t-BuOCl (1.5 equiiv)
Cl
(E)
BMIDA
R
R
4Å MS, DCM, r.t., 5 h
1
3
ized reaction conditions established (Table 1,
amined the generality of this Z-α-chloro alkenyl
synthesis process. Thus, diversely substituted
MIDA boronates were employed as the substrates
were gratified to find that a number of commonly
nctionalities, such as chloro (2d, 2l), bromo (2e,
), ester (2g), cyano (2h) and trifluoromethyl (2k),
ated, affording moderate to good yields of the
geometry of 2b was confirmed to be Z-α-chloro
oronate by single-crystal X-ray diffraction.[17] Of
substituent residing at the ortho-position of the
) did not interfere with the efficiency of the
over, the heterocyclic thiophen-2-yl vinyl MIDA
was also moderately amenable to chlorination.
not limited to aryl-substituted MIDA boronates,
tutes (2n-2r) were tolerated as well. It should be
, R = t-Bu, 60%[a], E/Z = 8:1
Cl
BMIDA
3b
3c
Cl
[b]
, R = Ph, 73% , E/Z = 8:1
3d, R = Cl, 66%, E/Z = 7:1
BMIDA
R
3a, 75%, E/Z = 7:1
3e, R = Br, 70%, E/Z = 7:1
3f, R = COOMe, 36%[b], E/Z = 8:1
Cl
Cl
Cl
Cl
BMIDA
BMIDA
BMIDA
F
MMe
Me
3h, 61%[b], E/Z = 13:1
3i, 558%[b], E/Z = 6:1
3g, 67%, E/Z = 9:1
Cl
Me
Cl
Cl
BMIDA
BMIDA
Cl
BMIDA
3j, 65%[a], E/Z = 10:1
Me
BMIDA
[b]
3m, 0%
3k, 58%[a], E/Z = 10:1
, 46% E/Z = 6:1
33l
[a] t-BuOCl (2.0 equiv). [b] t-BuOCl (2.0 eqquiv) and isonicontic acid (0.2 equiv).
The synthetic utility of the products was then explored. Upon
treatment with m-CPBA, 2a was converted to epoxide 4 with the
C-B(MIDA) bond being intact in 48% yield (Scheme 1a).[3g] It is
of interest that the C-B bond is generally susceptible to
peroxide.[18] As such, the retention of the C-B bond in the
product demonstrated a major advantage of our approach. The
Lewis acid-mediated ring-opening of 4 yielded a chlorine-
migration product acylborane 5, rather than the expected boryl-
shift product.[3g] The copper-mediated Chan-Lam type oxidative
cyanation gave ɑ-chlorine alkenyl cyanide 6 in good efficiency
(Scheme 1b).[19a] In addition, the alkenyl C-B(MIDA) bond could
be transformed to the C-I bond upon the treatment with I2
(Scheme 1c).[19b] And the BMIDA group in 3a could be converted
to its congener Bpin 8 via ligand exchange (Scheme 1d).[20] The
presence of both C-B(MIDA) and C-Cl bonds in the product
r
substrates bearing electron-withdrawing or
nding groups, increasing the loading of PhSeCl
sing the temperature (50 °C), or both were
suring a higher degree of conversion.
cess promoted us to investigate the reactivity of
s reaction. Interestingly, we found that the use of
of PhSeCl also delivered a α-chlorinated product,
se stereoselectivity (Table 3).[17] Thus, both
of the α-chlorinated alkenyl MIDA boronate can
in a divergent manner by simply employing a
t. A reaction optimization investigation showed
m isolated yield of 75% for E-α-chloro alkenyl
3a could be obtained when reacting the
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10.1002/anie.201709070
Angewandte Chemie International Edition
ICATION
al synthon for chemoselective iterative coupling
acetone, the formation of 15 predominated. However, control
experiment showed 15 could not be converted to the final
product under various reaction conditions, thus ruling out its
s is illustrated in Scheme 1e, where, under slow-
n conditions, the Suzuki-Miyaura coupling of 2a
ovided the alkenyl chloride 10 with a 76% yield.[22] intermediacy in the reaction.[25]
Kumada coupling provided the tri-substituted
Cl
or
% yield), which is a key intermediate for the
(a)
or
Cl
antiestrogen agent Clomiphene.[23] On the other
Cl
Cl
trace
trace
trace
trace
PhSeCl condditions:
t-BuOCl condditions:
Kumada
coupling
of
3a
with
(4-
magnesium bromide led to the formation of the
l-retentive alkene 12, although in low yield
ot unexpectedly, 12 could be transformed into the
kene 13 though Suzuki-Miyaura coupling.
Bpin
+
Cl
PhSeCl (2.5 equiv)
Ph
Ph
Bpin
(b)
(c)
Ph
Cl
trace
4Å MS, THF, r.t.
t-BuOCl (1.5 equiv)
4Å MS, DCM, r.t.
major product
full conversion
Cl
Bpin
Ph
Ph
Cl
+
Ph
Bpin
O
mostly recovered
trace
not detected
R
O
Mg(ClO4)2
BMIDA
50 oC, overnight
BMIDA
Cl
PhSeCl
Cl
4
R
5
Cl
77%
(d)
THF, 4Å MS
m-CPBA
DCM, 60 oC
BMIDA
BMIDA
48%
CN
Cl
b)
Zn(CN)2, CsF
33a, R = Ph, 38%, E/Z = 9:1
33n, R = phenethyl, 61%, E/Z = 16:1
M NaOH
BMIDA
33q
, R = cyclohexanyl, 67%, E/Z = 13:1
Cu(NO3)2 • 3H2O
F, r.t.
7%
Cl
2a
MeOH/H2O, 70 o
C
t-BuOCl
BMIDA
63%
6
(e)
(f)
BMIDA
DCM, 4Å MS, r.tt.
Cl
14
Cl
pinacol, NaHCO3
Cl
2a, 69%, Z/E = 7:1
MIDA
Bpin
MeOH, r.t., Ar, 3 h
62%
OH
8
Cl
t-BuOCl (1.5 equiv)
BMIDA
BMIDA
Ph
Ph
Ph
he synthesis of tri-substituted alkenes
+
BMIDA
(E)
OH
r.t. 5 h
Cl
15
33aa
BMIDA
Pd(OAc)2 (10 mol %)
DCM + 4Å MS
75%
trace
14%
84%
Cl
, 0.2 mmol
Sphos (20 mol %)
1M NaOH, THF, r.t.
DCM+ H2O (5.0 equiv)
55%
Cl
10, 76%
2a
acetone + H2O (5.0 equiv)
< 10%
O
OH
N(C2 H5)2
Scheme 2. Mechanistic studies.
Cl
ref. 23
ol %)
Ph
Ph
Ph
r
OMe
11
, 63%
Clomiphene
OMe
Based on the above experiments and the precedents
established by the literature, we propose the reaction
mechanism described according to Scheme 3. For the synthesis
of the Z-type product, the reaction of PhSeCl with alkenyl MIDA
boronate firstly forms a seleniranium ion. The anti-Markovnikov
nucleophilic attack of A by Cl− produces an anti-addition adduct
B. Subsequently, B reacts with excess PhSeCl to produce the
selenium (IV) dichloride C.[16f] In this process, PhSeCl is reduced
to PhSeSePh, which was detected by GC-MS. Thereafter, the -
syn-elimination of the benzylic proton leads to the stereospecific
formation of the Z-type product.[[226] For the t-BuOCl protocol,[27]
the Cl+ adds to the alkene in a Markovnikov fashion. In this
process, the development of vacant p-orbital is accompanied by
the rotation of C-B(MIDA) bond which leads to the parallel
1-iodo-4-methoxybenzene
Pd(OAc)2 (10 mol %)
Xphos (20 mol %)
Me-PhMgBr
Ph3)2 (10 mol %)
Ph
K3PO4 (7.5 equiv)
F, 40 oC, Ar
1,4-dioxane/ H2O, 80 oC, Ar
Ph
BMIDA
12
OMe
13, 77%
, 34%
t derivatization.
eactivity along with the intriguing stereoselectivity
d synthesis process promoted us to investigate
mechanism. Firstly, the use of 1-chloro-4-
r methyl substituted styrene rather than alkenyl
for both reaction processes led to only trace
chlorination product (Scheme 2a). The use of the
trate in the PhSeCl process led predominately to
e chlorination product (Scheme 2b), while its
the t-BuOCl process resulted in mostly the
starting material (Scheme 2c). These results
que role of the BMIDA substituent for enhancing
addition, we noted that both reactions are
The use of the Z-type styryl MIDA boronate
n conjunction with the PhSeCl and t-BuOCl
s the opposite stereoisomers of the products as
when employing the E-type substrate (Scheme
y taking advantage of this stereospecificity, the
ementary stereoisomers for 2n and 2q can be
- Synthesis of Z product with PhSeCl
Ph
Se
Ph Se
Ph
BMIDA
PhSeCl
anti-Markovnikov
BMIDA
Ph
Ph
BMIDA
A
B
Cl
Cl
Cl
Cl
HH
Cl
Cl
Se
2 x PhSeCl
BMIDA
Ph
syn-elimination
Ph Se
BMIDA
Cl
H
Ph
Cl
Ph
PhSeSePh
detected by GC-MS
C
Cl
BMIDA
Z product
Ph
D
- Synthesis of E product with t-BuOCl
BMIDA
Cl
BMIDA
Cl
H
F
H
path a
H2O
BMIDA
H
BMIDA t-BuOCl
H
H
Ph
Ph
Ph
rotation
Ph
H2O
H
b
Cl
E
g
the PhSeCl protocol starting with the
path b
Z-substrates (Scheme 2d). Moreover, the
adical scavengers such as TEMPO or butylated
(BHT) did not interfere with the reactivities, and
ns exclude potential radical pathways.[25] A cis-
product 15 was detected in the t-BuOCl reaction
By adding H2O and changing the solvent to
ADDIMB
OH
Cl
Ph
BMIDA
elimination
Ph
H
Cl
Phh
H
BMIDA
E product
Cl
cis addition product
15
G
Scheme 3. Proposed mechanism.
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10.1002/anie.201709070
Angewandte Chemie International Edition
ICATION
2012, 51, 1014; b) S. J. Rosebladde, E. Casas-Arcé, U. Nettekoven, I. G.
Smilović, A. Zanotti-Gerosa, Z. Čaasar, Synthesis, 2013, 45, 2824.
S. Touchet, F. Carreaux, B. Carbooni, A. Bouillon, J.-L. Boucher, Chem.
Soc. Rev. 2011, 40, 3895.
C-B(MIDA) σ-bond with the vacant p-orbital.
-H elimination from E via TS G gives the final E
he significant steric repulsion between the phenyl
MIDA group may account for the reduced E/Z
On the other hand, in the presence of water, a
of H2O on E would deliver a cis addition product,
cted as a side product.
[8]
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a stereodivergent
oth E and Z-α-chloro alkenyl boronates by the
on of E-alkenyl MIDA boronates using t-BuOCl
agents, all of which are readily available starting
use of the sp3-B MIDA boronate is an important
e observed reactivity. The scope of the reaction
good functional group tolerance and good yields
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ucts was demonstrated and the reaction
both processes were proposed.
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for the support of this work by the Key Project of
nal Programs for Fundamental Research and
016YFA0602900), the National Natural Science
China (81402794 and 21472250), and the "1000-
lan".
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10.1002/anie.201709070
Angewandte Chemie International Edition
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Y.-F. Zeng, W.-W. Ji, W.-X. Lv, Y. Chen,
D.-H. Tan, Q. Li, H. Wang*
Page No. – Page No.
Stereoselective Direct Chlorination of
Alkenyl MIDA Boronates: Divergent
Synthesis of
E and Z- α-Chloro
Alkenyl Boronates
orrow Me a Handle: The amphoteric α-chloro alkenyl boronates are intriguing organic synthons. Reported herein is a
ereodivergent synthesis of both E and Z-α-chloro alkenyl N-methyliminodiacetyl (MIDA) boronates by the direct chlorination
f E-alkenyl MIDA boronates using t-BuOCl and PhSeCl reagents, respectively. Both reaction processes are stereospecific
nd the sp3-B MIDA boronate plays the key role to the reactivity. Broad substrate scope was observed and the synthetic value
f the boronate products was demonstrated.
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