Transition-Metal-Free Stereospecific Cross-Coupling with Alkenylboronic Acids as Nucleophiles

Article abstract of DOI:10.1021/jacs.6b06285

We herein report a transition-metal-free cross-coupling between secondary alkyl halides/mesylates and aryl/alkenylboronic acid, providing expedited access to a series of nonchiral/chiral coupling products in moderate to good yields. Stereospecific S_N2-type coupling is developed for the first time with alkenylboronic acids as pure nucleophiles, offering an attractive alternative to the stereospecific transition-metal-catalyzed C(sp²)-C(sp³) cross-coupling.

Full text of DOI:10.1021/jacs.6b06285

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Communication
Transition-Metal-Free Stereospecific Cross-
Coupling with Alkenylboronic Acids as Nucleophiles
Chengxi Li, Yuanyuan Zhang, Qi Sun, Tongnian Gu, Henian Peng, and Wenjun Tang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 12 Aug 2016
Downloaded from http://pubs.acs.org on August 12, 2016
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Transition-Metal-Free Stereospecific Cross-Coupling with Alkenyl-
boronic Acids as Nucleophiles
Chengxi Li, Yuanyuan Zhang, Qi Sun, Tongnian Gu, Henian Peng, Wenjun Tang*
State Key Laboratory of BioꢀOrganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China
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Due to relative low nucleophilicity, aryl/alkenylboronic acids
ABSTRACT: We herein report a transitionꢀmetalꢀfree crossꢀ
are less reported as pure nucleophiles, but mostly as coupling
coupling between secondary alkyl halides/mesylates and arꢀ
reagents in transitionꢀmetal catalyzed SuzukiꢀMiyaura crossꢀ
coupling reaction.1 One of most known examples of arꢀ
yl/alkenylboronic acids as pure nucleophiles is Petasis boronoꢀ
Mannich reaction,8 where the addition of an aryl/alkenylboronic
acid or equivalent to a C=N π bond takes place. Accordingly, the
nucleophilic addition of aryl/alkenylboronic acids or equivalents
to π systems such as C=N, C=O, and C=C double bonds are most
reported,7b,9 whereas little study is available on nucleophilic subꢀ
stitution of aryl/alkenylboronic acids to tetravalent (sp3) carbons.
yl/alkenylboronic acid, providing expedite access to a series of
nonchiral/chiral coupling products in moderate to good yields.
Stereospecific SN2ꢀtype coupling is developed for the first
time with alkenylboronic acids as pure nucleophiles, offering
an attractive alternative to the stereospecific transitionꢀmetalꢀ
catalyzed C(sp2)ꢀC(sp3) crossꢀcoupling
.
Thanks to the continuing advances in transitionꢀmetal catalysis,
the crossꢀcoupling in particular C(sp2)ꢀC(sp2) SuzukiꢀMiyaura
coupling is enjoying its unprecedented broad scope and applicaꢀ
tions in organic synthesis.1 In contrast, the C(sp2)ꢀC(sp3) crossꢀ
coupling2 remains relatively underdeveloped due to issues related
to βꢀhydride elimination. A few enantioselective aryl/alkenylꢀ
alkyl couplings3,4 have appeared with the employment of chiral
transitionꢀmetal catalysts (Scheme 1). Alternatively, enantiospeꢀ
cific aryl/alkenylꢀalkyl couplings are accomplished by employing
chiral reagents such as chiral secondary alkyl organometallic reaꢀ
gents5 or chiral secondary alkyl electrophiles with considerable
amount of transition metal catalysts (mostly 5ꢀ10 mol %).6 The
traditional SN2 reactions using lithium or Grignard reagents often
require cryogenic reaction conditions and usually suffer from poor
functional group compatibility. An attractive alternative would be
an transitionꢀmetalꢀfree enantiospecific C(sp2)ꢀC(sp3) crossꢀ
coupling7 with stable, nontoxic, and environmentally friendly
aryl/alkenylboronic acids as nucleophiles. Herein we report for
the first time a stereospecific transitionꢀmetalꢀfree crossꢀcoupling
between chiral secondary benzylic mesylates and alkenylboronic
acids that have led to a series of chiral coupling products with
functionalities in excellent stereochemical fidelity.
Table 1. Metalꢀfree crossꢀcoupling between 1ꢀhaloethylbenzene
(1a/b) and (E)ꢀ(4ꢀmethylstyryl)boronic acid (2a)
Entrya
X
base
solvent
T (oC)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17c
18
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
KOH
NaOtBu
KF
NaHCO3
K2CO3
Cs2CO3
Et3N
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
dioxane
DCE
cyclohexane
DMF
80
80
80
80
80
80
80
80
80
80
80
80
80
110
50
rt
32
24
0
1
31
46
0
73
19
24
57
31
17
50
59
14
5
toluene
toluene
toluene
toluene
toluene
80
80
35
aUnless otherwise specified, all reactions were performed in the selected
o
solvent (10 mL) under nitrogen at 80 C for 4 h with 1a or 1b (1 mmol),
2a (1.5 mmol) with base (2 equiv). bIsolated yields. Pinacol boronate of
c
2a was employed as the reagent.
To the best of our knowledge, only reactions of arꢀ
yl/alkenylboronic acids with terminal allyl bromides were studꢀ
ied10 and no reports are available on nucleophilic substitution
between secondary alkyl halides/pseudohalides and arꢀ
yl/alkenylboronic acids under transitionꢀmetalꢀfree conditions.
We herein report the transitionꢀmetalꢀfree crossꢀcoupling between
secondary benzylic halides/mesylates and aryl/alkenylboronic
acids. Stereospecific SN2ꢀtype couplings between chiral functionꢀ
alized secondary benzylic mesylates and alkenylboronic acids are
observed for the first time, offering an attractive alternative to the
stereospecific transitionꢀmetalꢀcatalyzed C(sp2)ꢀC(sp3) crossꢀ
coupling.
We chose to study the crossꢀcoupling between 1ꢀ
bromoethylbenzene (1a) and (E)ꢀ(4ꢀmethylstyryl)boronic acid
(2a) under metalꢀfree conditions (Table 1). The reactions were
initially performed in toluene at 80 oC for 4 h. To our delight, the
desired coupling product was formed in 32% yield with KOH as
Figure 1. Asymmetric C(sp2)ꢀC(sp3) crossꢀcoupling
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the base (entry 1). Screening of different bases (entries 1ꢀ8) reꢀ
boronic acid was also applicable. Electronꢀrich arylboronic acids
1
2
3
4
5
6
7
8
vealed that strong inorganic bases promoted this reaction and an
organic base such as triethylamine was ineffective. Potassium
phosphate led to a good coupling yield (73%, entry 8). Solvent
screening (entries 8ꢀ13) showed polar solvents such as THF,
DCE, dioxane, and DMF were detrimental to the yields (entries 9ꢀ
13). This could be due to severe elimination sideꢀreaction of 1a in
a polar solvent. The coupling was sluggish at rt (entry 16), but
proceeded at both 50 C and 110 C to provide moderate yields
(entries 14ꢀ15). The boronic acid form of 2a was important for the
reactivity since its pinacol boronate under similar conditions ofꢀ
fered only 5% yield (entry 17). 1ꢀChlorethylbenzene was also
applicable to this protocol to provide the product in 35% yield
(entry 18).
such as 2,4,6ꢀ(MeO)3C6H2B(OH)2 and 4ꢀMeOC6H4B(OH)2 were
also employed to form the 1,1ꢀdiarylethane derivatives 3h-i albeit
in low yields. A secondary allyl bromide 3ꢀbromocyclohexꢀ1ꢀene
was also employed to couple with various alkenylboronic acids to
provide coupling products 3j-n in 59ꢀ72% yields. Diphenylmethyl
bromide and 9ꢀbromofluorene were also adaptable to provide
corresponding coupling products 3o-r in 52ꢀ82% yields. Cyclic
secondary benzyl bromides were also successfully employed to
couple with styrylboronic acid to give products 3s-u in good
yields. Various substituted benzyl bromides with different elecꢀ
tronic properties were applicable to react with styrylboronic acid,
leading to coupling products 3v-3bb in moderate to good yields.
Interestingly, αꢀbromo ketones were also able to react with variꢀ
ous substituted styrylboronic acids to form the coupling products
3cc-gg in acceptable yields.
o
o
9
10
11
12
13
14
15
16
17
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Table 2. Crossꢀcoupling between secondary bromides and
alkenyl/arylboronic acidsa
F
Cl
OMe
66%
3b
60%
3c
71%
3d
52%
3e
OMe
OMe
CF3
OMe
MeO
56%
3f
34%
3g
25%
3h
35%
3i
F
Cl
72%
3m
72%
3j
72%
3k
60%
3l
CF3
59%
3n
75%
3o
82%
3p
52%
3q
O
54%
3r
75%
3s
67%
3t
79%
3u
Figure 2. Mechanistic studies
To understand whether a radical process was involved (Figꢀ
ure 2), the reaction of 1a and (E)ꢀstyrylboronic acid (2b) was
performed in the presence of TEMPO and the coupling product
3b was obtained in 68% yield, indicating that the reaction was
unlikely to proceed through a radical pathway. A series of deuterꢀ
iumꢀlabeling experiments showed that the deuterium at the benꢀ
zylic position was well preserved during the reaction course and
in the deuterated coupling product 5, excluding the possibility of
deprotonation of the benzylic proton during the reaction. The
observation of a secondary kinetic isotope effect (1.2) indicated a
SN2ꢀtype reaction process. Finally, an enantiomerically enriched
bromide (R)ꢀ1a (88% ee) was employed to react with boronic acid
2b and the coupling product (R)ꢀ3b was isolated in 70% yield and
64% ee with inversed configuration, further supporting the SN2ꢀ
type coupling process. The slight erosion of ee in (R)ꢀ3b was
likely due to the proneꢀtoꢀracemization nature of (R)ꢀ1a.11
F
Cl
67%
3v
41%
3w
71%
3x
54%
3y
O
MeO
57%
3z
74%
3aa
53%
3bb
36%
3cc
O
O
O
O
CF3
Cl
OMe
68%
3dd
64%
3ee
66%
3ff
50%
3gg
aUnless otherwise specified, all reactions were performed in toluene (10
mL) under nitrogen at 80 oC for 4 h with bromide (1 mmol),
alkenyl/arylbronic acid (1.5 mmol), with K3PO4 (2 equiv) as the base.
Isolated yields.
We then looked into the substrate scope of this metalꢀfree
crossꢀcoupling reaction. As shown in Table 2, a variety of couꢀ
pling products were synthesized in moderate to good yields beꢀ
tween secondary benzylic bromides and phenyl/styrylboronic
acids under metalꢀfree conditions. A series of substituted styrylꢀ
boronic acids were reacted with 1ꢀbromoethylbenzene (1a) to
form coupling products 3b-i in good yields. Cyclopentenylꢀ
Figure 3. A proposed mechanism
A plausible mechanism was proposed for this transitionꢀmetalꢀ
free coupling process (Figure 3). Under basic conditions, hydroxꢀ
2
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yl ions coordinate with alkenylboronic acids 2b to form the speꢀ
sioned that chiral 1ꢀarylethanꢀ1,2ꢀdiyl dimesylates 6a-g could be
1
2
3
4
5
6
7
8
suitable substrates for SN2ꢀtype attack of an alkenylboronic acid.
Thus, the transitionꢀmetalꢀfree crossꢀcoupling between comꢀ
pounds 6a-g and alkenylboronic acids were studied. As shown in
Table 3, the coupling proceeded smoothly to provide a series of
chiral coupling products 7a-g containing terminal mesylates in
good yields and excellent chemoꢀ and regioꢀselectivity. A cyclic
alkenylboronic acid was also applicable (entry 3).15 Only the benꢀ
zylic mesylates were active for the coupling reaction under the
reaction conditions, demonstrating the excellent functional group
compatibility of the coupling. The terminal mesylates were opt for
further derivatizations. The chiral products 7a-g with inverted
stereochemistry and excellent stereochemical fidelity further veriꢀ
fied its SN2ꢀtype coupling process. A chiral benzylic mesylate 6h
with a terminal OTBS group was also employed to form the couꢀ
pling product 7h in 68% yield and 94% ee.
cies A, whose anionic nature leads to enhanced nucleophilicity at
the olefinic carbon. Nucleophilic attack of A to the chiral secondꢀ
ary benzyl halide 1 forms the desired coupling product (R)ꢀ3b
with inverted stereochemical outcome. Noteworthy is the active
nature of the secondary benzyl/allyl halide or αꢀbromo ketone12
which allows for the first time the successful SN2ꢀtype attack of a
weakly nucleophilic aryl/alkenylboronic acid.
Table 3. Stereospecific transitionꢀmetalꢀfree crossꢀcoupling beꢀ
tween chiral benzylic mesylate 6 and alkenylboronic acidsa
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
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The chiral coupling products 7a-h with functionalities are verꢀ
satile intermediates for further transformations. For example, 7a
was treated with LAH to remove the mesylate to form (R)ꢀ3b in
90% yield. Reaction of 7a with sodium azide provided azide 8 in
92% yield. Treatment of mesylate 7a with sodium iodide formed
chiral iodide 9 in 87% yield. Installation of an additional carbon
was successfully accomplished by treatment with sodium cyanide
to provide nitrile 10 in 68% yield.
Scheme 1. Synthetic utility of chiral coupling product 7a
In conclusion, we have developed for the first time the transiꢀ
tionꢀmetalꢀfree crossꢀcoupling between secondary benzyl/allyl
halides/mesylates and aryl/alkenylboronic acids in moderate to
good yields. Mechanistic studies have revealed its SN2ꢀtype proꢀ
cess. Stereospecific couplings between chiral functionalized benꢀ
zylic mesylates and alkenylboronic acids are developed, providing
a series of chiral coupling products with functionalities in good
yields, excellent regioꢀ and chemoꢀselectivities with great funcꢀ
tional group compatibility. The discovery and application of
alkenylboronic acids as pure nucleophile for SN2ꢀtype reaction not
only offers an attractive alternative to the stereospecific transitionꢀ
metalꢀcatalyzed C(sp2)ꢀC(sp3) crossꢀcouplings, but also enriches
the nucleophile repertoire for nucleophilic substitution.
aUnless otherwise specified, all reactions were performed in toluene (10
mL) under nitrogen at 50 oC for 2 h with mesylate 6 (1 mmol), alkenylꢀ
boronic acid (1.5 mmol), and K3PO4 (2 equiv) as the base, isolated yields,
enantiomeric excesses were determined by chiral HPLC. Compound 6a
was prepared from corresponding commercially available chiral diol by
dimesylation. Compounds 6d-g were prepared from corresponding olefins
by Sharpless dihydroxylation with ADꢀmixꢀα as the reagent. The absolute
configuration of 7a was determined by conversion to (R)ꢀ3b by treatment
with LAH and comparison of its optical rotation to the reported data.13
The absolute configuration of 7b-h was assigned by analogy. bT = 12 h.
Supporting Information
Full experimental details, characterization data, NMR spectra of
3a-gg, 6a-h, 7a-h, 8-10, chiral separation methods and HPLC
trace of 6a-h and 7a-h. This information is available free of
charge via the Internet at http://pubs.acs.org/.
Corresponding Author
tangwenjun@sioc.ac.cn
In order to develop a racemizationꢀfree coupling process, a
stable chiral secondary benzyl halide/pseudohalide is required.
While simple chiral 1ꢀhaloethylbenzene is prone to racemization
and 1ꢀphenylethyl mesylate is too unstable for isolation at rt,11 we
were pleased to learn that some functionalized benzylic mesylates
6a-h were relative stable solids free of racemization.14 We enviꢀ
Notes
The authors declare no competing financial interest.
Acknowledgments
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7. For recent reviews of transitionꢀmetalꢀfree coupling, see: (a) Sun,
This work is supported by NSFCꢀ21432007, 21272254,
21572246.
C.ꢀL.; Shi, Z.ꢀJ. Chem. Rev. 2014, 114, 9219. (b) Roscales, S.;
Csákÿ, A. G. Chem. Soc. Rev. 2014, 43, 8215. (c) Zhu, C.; Falck,
J. R. Adv. Synth. Cat. 2014, 356, 2395. (d) Roopan, S. M.;
Palaniraja, J. Res. Chem. Intermed. 2015, 41, 8111. For other
type of stereospecific metalꢀfree coupling, see: (e) Bonet, A.;
Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Nat.
Chem. 2014, 6, 584. (f) Llaveria, J.; Leonori, D.; Aggarwal, V.
K. J. Am. Chem. Soc. 2015, 137, 10958. (g) Leonori, D.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2015, 54, 1082.
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enantiomerically
enriched
1ꢀbromoethylbenzene
from
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stored at rt overnight. See details in Supporting Information. We
were unable to get corresponding chiral allylic halides or αꢀ
ketone halides for investigation. 1ꢀPhenylethyl mesylate is not
stable and cannot be isolated at room temperature.
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vinylboronate was employed.
Table of Contents:
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