Guanidine–Copper Complex Catalyzed Allylic Borylation for the Enantioconvergent Synthesis of Tertiary Cyclic Allylboronates

Article abstract of DOI:10.1002/anie.201813490

An enantioconvergent synthesis of chiral cyclic allylboronates from racemic allylic bromides was achieved by using a guanidine–copper catalyst. The allylboronates were obtained with high γ/α regioselectivities (up to 99:1) and enantioselectivities (up to 99 % ee), and could be further transformed into diverse functionalized allylic compounds without erosion of optical purity. Experimental and DFT mechanistic studies support an S_N2′ borylation process catalyzed by a monodentate guanidine–copper(I) complex that proceeds through a special direct enantioconvergent transformation mechanism.

Full text of DOI:10.1002/anie.201813490

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Accepted Article
Title: Enantioconvergent Synthesis of Tertiary Cyclic Allylboronates
Using (Guanidine)copper Complex-Catalyzed Allylic Borylation
Authors: Choon Hong Tan, Yicen Ge, Xi-Yang Cui, Siu Min Tan, Huan
Jiang, Jingyun Ren, Nicholas Lee, and Richmond Lee
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813490
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10.1002/anie.201813490
Angewandte Chemie International Edition
COMMUNICATION
Enantioconvergent Synthesis of Tertiary Cyclic Allylboronates
Using (Guanidine)copper Complex-Catalyzed Allylic Borylation
Yicen Ge,a Xi-Yang Cui,a Siu Min Tan,b Huan Jiang,a Jingyun Ren,a Nicholas Lee,a Richmond Leeb*
and Choon-Hong Tana*
Abstract: An enantioconvergent synthesis of chiral cyclic
allylboronates is demonstrated with racemic allylic bromides using a
(guanidine)copper catalyst. The allylboronates were acquired with
high γ/α regioselectivities (up to 99:1) and enantioselectivities (up to
99% ee) and could be further transformed into diverse functionalized
allylic compounds without erosion of optical purity. Experimental and
DFT mechanistic studies indicated an SN2’ borylation process
catalyzed by a monodentate guanidine-copper(I) complex via a
special direct enantio-convergent transformation mechanism.
ligands or co-catalysts in transition metal-catalyzed asymmetric
reactions.15 Recently, an efficient dynamic kinetic copper-
catalyzed asymmetric allylic alkynylation reaction was reported
by our group using chiral bicyclic guanidine.16a Such
(guanidine)copper complex was also found to catalyze the
formation of secondary and tertiary allylboronates. This
regioselective SN2’ allylic borylation was achieved using various
racemic allylic bromides in good yields and excellent
enantioselectivities (Scheme 1e).
(a) Lithiation/borylation (Aggarwal, ref. 3)
Chiral tertiary allylboronates are useful synthetic building
blocks,1–3 which boryl-substituted stereocenters can be
transformed into diverse chiral quaternary functionalities or be
utilized to form homoallylic alcohols or amines via allylboration.
While there is a myriad of approaches to synthesizing chiral
secondary allylboronates,4–12 ranging from hydroboration to
conjugated borylation, direct access to tertiary ones is still very
limited (Scheme 1). Using enantio-enriched secondary alcohols,
the corresponding vinyl-substituted tertiary allylboronates can be
prepared through a lithiation/borylation protocol (Scheme 1a).3
Separately, tertiary allylboronates can be obtained through
conjugated borylation of dienones or dienoates, catalyzed with a
chiral copper complex (Scheme 1b)11a or through a palladium-
catalyzed diboration of allene (Scheme 1c).2j Remarkably,
enantioselective synthesis of linear tertiary allylboronates was
also demonstrated through allylic borylation of trisubstituted
allylic carbonates using a Cu-NHC catalyst (Scheme 1d).2h
In copper-catalyzed asymmetric allylic borylation, it is often
observed that rather than a metal-allyl complex, a copper-boryl
intermediate is first formed followed by stereoselective SN2’
attack.2h,4 Racemic allylic substrates, though easy to obtain, are
challenging to be used in stereo-convergent borylation.13 Only
OCb
1) sBuLi, Et2O, -78 ºC
Bpin
Ph
2º alcohol
2)
Ph
allylboronates
Bpin
, heat
derivatives
(b) Conjugated borylation (Kobayashi, ref. 11a)
Ligand:
R3
O
O
R3
Bpin
Cu(OAc)2, ligand
R1
N
N
R2
R1
dienone/dienoate
R2
tBu
tBu
B2pin2, H2O
OH
HO
allylboronates
O
(c) Diboration (Chung, Tang and Ding, ref. 2j)
Ligand:
R1
R1
R2
Bpin
Bpin
P
Pd2(dba)3, ligand
B2pin2, CyH
tBu
OMe
R2
ꢁ
MeO
allylboronates
allene
(d) Allylic borylation (Hoveyda, ref. 2h)
Ph
Ph
NAr
NHC:
R1
Bpin
Cu(OTf)2, NHC
R1
R2
N
R2
B2pin2
OCO2Me
(E)-allylic carbonate
linear allylboronates
SO3
Ar = 2,4,6-Me3C6H2
(e) Allylic borylation (This work)
R
(±)
Cu(NO3)2ꢀ3H2O
chiral guanidine
B2pin2, base
R
Br
chiral guanidine:
N
Bpin
n
n
tBu
tBu
N
N
cyclic allylboronates
up to 99% ee, 99:1 regioselectivity
racemic
2º allylic bromides
H
recently
Ito
developed
a
direct
enantio-convergent
Scheme 1. Synthesis of enantio-enriched tertiary allylboronates.
transformation (DECT), where two enantiomers of the allylic
ethers underwent the anti- or syn-SN2’ pathways respectively,
leading to the same borylated product.4d
In the past decade, we have developed asymmetric
transformations using chiral guanidines as Brønsted base
catalysts, as well as guanidinium salts as phase-transfer or ion-
pairing catalysts.14 It is still rare to employ chiral guanidine as
Initially, we employed commercially available (±)-3-
bromocyclohexene 1a and bis(pinacolate)diboron (B2pin2) as
model substrates. After exploring several guanidinium catalysts
and investigating various reaction conditions, we obtained the
best results when copper nitrate was used in combination with
bicyclic guanidinium CG1 (for full optimization details see
Supporting Information S26). Under the optimized conditions,
(±)-3-bromocyclohexene 1a was completely converted to the
desired allylboronate 2a with 97% ee (Table 1, entry 1). The
yield and enantioselectivity remained the same when the
[a]
Dr. Y. Ge, Dr. X.-Y. Cui, Dr. H. Jiang, Dr. J. Ren, N. Lee, Prof. Dr.
C.-H. Tan
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
E-mail: choonhong@ntu.edu.sg
-
counter-anion of guanidinium catalyst was changed to PF6
(entry 2). Dimethylated guanidinium salt CG3 led to a dramatic
decrease in both yield and enantioselectivity (entry 3), as did the
use of PN and BG (entries 8 and 9). Less bulky guanidiniums
CG4–6 furnished the product in high yields but with diminished
ee values (entries 4–6), whereas the usage of bisguanidinium
salt BCG rendered the reaction sluggish (entry 7).
[b]
Dr. S. M. Tan, Dr. R. Lee
Singapore University of Technology and Design
8 Somapah Road
Singapore 487372
Email: richmond_lee@sutd.edu.sg
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201813490
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COMMUNICATION
Table 1. Allylic borylation of (±)-3-bromocyclohexene 1a.[a]
was unlikely to undergo pathways involving radical intermediates.
1-Benzylic
allylic bromides
gave 2l–2n with
good
O
B
Br
Cu(NO3)2･3H2O (1 mol%)
guanidine (1.5 mol%)
nhexane, 0 oC, air, 12 h
O
O
O
O
enantioselectivities regardless of the electron density on the aryl
groups.
B
B
+
O
sat. aq. K2CO3
(R)-2a
1.5 equiv. B2pin2
rac-1a
Table 2. Enantioconvergent synthesis of secondary allylboronates. [a]
CG1: R = tBu, R' = H, X = I
CG2: R = tBu, R' = H, X = PF6
Me Me
Ph
Ph
Cl
N
N
N
CG3: R = tBu, R' = Me, X = OTf
CG4: R = iPr, R' = H, X = I
R
R
O
B
Br
Cu(NO3)2.3H2O (1 mol%)
O
O
O
O
N
N
CG1 (1.5 mol%)
Ph
B B
N
Ph
+
N
N
O
CG5: R = Bn, R' = H, X = I
n( )
rac-1a-e
R'
R'
nhexane
sat. aq. K2CO3
X
Me
Me
CG6: R = (S)-iBu, R' = H, X = I
PN
R
n( )
2a-e
1.5 equiv. B2pin2
R
R
R
R
R
Cl
N
Ph
Ph
Ph
N
N
O
B
N
N
O
O
N
N
N
B
B
N
N
O
O
O
O
Ph
NH
HN
Br
Br
R
R
Cl
R
R
2a
86% yield
97% ee
2b
75% yield
92% ee
2c
80% yield
78% ee
BG: R= (3,5-di-tBuC6H4)CH2
BCG: R = tBu
Yield (%)[b]
ee (%)[c]
O
O
Entry
Catalyst
O
B
B
B
O
O
O
CG1
CG2
CG3
CG4
CG5
> 99
> 99
12
97
97
11
71
77
1
2
3
4
5
2d
65% yield
97% ee
2aa[b]
2e
69% yield
45% ee
(86)% yield
92% ee
> 99
86
[a] Reagents and conditions: allylbromide (0.10 mmol), Cu(NO3)2×3H2O (0.001
mmol), catalyst (0.0015 mmol), bis(pinacolato)diboron (0.15 mmol), 0.2 mL
saturated K2CO3 aqueous solution in nhexane (1 mL) at 0 °C for 12~24h.
Isolated (NMR) yields reported. Enantiomeric excesses were determined by
chiral GC analysis. [b] Bis(hexyleneglycolato)diboron was used instead.
CG6
BCG
PN
71
31
25
22
72
90
17
23
6
7
Table 3. Enantio-convergent synthesis of tertiary allylboronates.
8
9
O
B
Br
O
O
O
O
Cu(NO3)2.3H2O (1 mol%)
BG
R
B
B
CG1 (1.5 mol%)
+
O
nhexane
[a] Reagents and conditions: rac-1a (0.10 mmol), Cu(NO3)2×3H2O (0.001
mmol), catalyst (0.0015 mmol), bis(pinacolato)diboron (0.15 mmol), 0.2 mL
saturated K2CO3 aqueous solution in nhexane (1 mL) at 0 °C for 12h. [b]
Calibrated GC yield with biphenyl as internal standard. [c] Determined by GC
analysis with a chiral column.
sat. aq. K2CO3
2f-n
1.5 equiv. B2pin2
rac-1f-n
R
O
O
O
B
B
B
O
O
O
2f
2g
2h
77% yield, 78% ee
SN2':SN2 = 95:5
74% yield, 95% ee
SN2':SN2 = 93:7
80% yield, 99% ee
SN2':SN2 = 94:6
With the optimized conditions, we first investigated the scope
of the reaction with racemic cyclic allylic bromides bearing
various ring structures and functionalities. A series of secondary
allylboronates 2a-2e was successfully prepared with moderate
yields and good ee values (Table 2). Substituents at the 2-
position led to a significant decrease in enantioselectivity (Table
2, 2e). In most cases, NMR yields were excellent and the
isolation of these unstable products were successful but
precarious. When racemic allylic chloride was used instead, the
(guanidine)copper catalyst gave satisfactory results but more
diboron reagents were required (SI S29). Interestingly, switching
to bis(hexyleneglycolato)diboron (B2hex2) as the boryl source did
not affect the reaction significantly; the additional chiral center
on the Bhex group did not perturb the reaction (Table 2, 2aa).
Excited by the good reaction profile, we next examined the
more attractive scenario of preparing allylic boronates bearing
boryl-substituted quaternary stereocenters (Table 3). Various
racemic 1-substituted cyclic allylbromides 1f–1n were evaluated
and those carrying methyl 1f, ethyl 1g and nbutyl 1i substitutions
were all converted into the desired tertiary allylboronates with
high ee values. The high α/γ regioselectivity (above 1:20)
suggested that the borylation proceeded in a regioselective SN2’
substitution pathway. Notably, the sterically bulky substrate 1h
led to a decreased enantioselectivity. Use of a radical-probe 1j,
did not lead to cyclized by-products, indicating that the reaction
O
O
O
B
B
B
O
O
O
2i
2j
2k
61(95)% yield, 95% ee
SN2':SN2 = 96:4
55(88)% yield, 94% ee
SN2':SN2 = 97:3
95% yield, 96% ee
SN2':SN2 = 97:3
MeO
Cl
O
O
B
O
B
B
O
O
O
2l
65(82)% yield, 96% ee
SN2':SN2 = 99:1
2m
2n
77% yield, 96% ee
SN2':SN2 = 98:2
49(70)% yield, 93% ee
SN2':SN2 = 99:1
Reagents and conditions: allylbromide (0.10 mmol), Cu(NO3)2×3H2O (0.001
mmol), catalyst (0.0015 mmol), bis(pinacolato)diboron (0.15 mmol), 0.2 mL
saturated K2CO3 aqueous solution in nhexane (1 mL) at 0 °C for 18h.
Isolated (NMR) yields reported. Enantiomeric excesses were determined
by the chiral GC or HPLC analysis of the corresponding alcohols. The α/γ
regioselectivities were identified by GC.
To obtain a clearer picture of the reaction mechanism, a
series of control experiments were conducted (SI S52). The
formation of metallic copper was observed without air, which
resulted in lower yields and enantioselectivities (Table S2, entry
4). Besides copper, base and guanidine catalyst, water was also
found essential to afford the desired borylation products (Table
S2, entry 5). Intrigued by the above observations, we carried out
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10.1002/anie.201813490
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COMMUNICATION
Cu(NO3)2･3H2O (1 mol%)
CG1 (1.5 mol%)
nhexane, 0 oC, air, 5 h
further studies using electronic paramagnetic resonance (EPR)
to distinguish the oxidation state of the copper catalytic species
(SI S53). When treated with basified guanidine CG1’ and B2pin2,
the EPR signal of paramagnetic Cu(II) species was diminished
rapidly but recovered if the resulting mixture was exposed to air.
We proposed that Cu(II) was reduced to diamagnetic Cu(I)
species by B2pin2 with the aid of basic guanidine, which acted as
the catalyst in borylation process.
Cl
O
O
O
O
O
B
(±)
B
B
+
(1)
O
4a 78% yield
Z:E = 1:3
rac-3a
sat. aq. K2CO3
3 equiv. B2pin2
X
Cu(NO3)2･3H2O (1 mol%)
CG1 (1.5 mol%)
nhexane, 0 oC, air, 5 h
O
O
O
O
3b X = Cl
Z:E = 1:5.5
(2)
(3)
26% yield, 50% ee
O
O
B
B
+
(from 3b)
B
>99% yield, 53% ee
3c X = Br
Z:E = 1:6
sat. aq. K2CO3
3 equiv. B2pin2
(from 3c)
4b
To better understand the role of bicyclic guanidine in this
Scheme 2. Investigation of SN2’ selectivity using allylic-isomeric halides.
transformation, the crystal of Cu(CG1’)Cl complex
I was
In contrast to our previous studies on alkynylation of allyl
bromides,16a we found that the ee of allyl bromides increased
over time as the borylation reaction proceeded (SI S59). This
observation indicates that if the racemization of allylbromides is
taking place, it is much slower than borylation and the rates of
borylation for (R)- and (S)-1a are different. More insights into the
resolution process were provided with density functional theory
(DFT) calculations. Based on current experimental observations
and previous mechanistic studies (SI S60), we postulated that
the active catalyst to be an anionic Cu(I)-guanidine species.16
The rate determining step involves oxidative addition of
allylbromide 1a to the anionic catalytic species [LCuBpin(OH2)]-,
where L represents the guanidine motif. Based on the solution
free energies, the kinetically competitive pathways transforming
(R)- and (S)-1a to the allylboronate product are transition states
TSAanti-R and TSAsyn-S (Scheme 3). After oxidative addition and
the release of bromide, the transition states lead to a common
intermediate intB-R (SI S62), which ultimately forms the (R)-
product. Although the reaction is different from Ito’s previous
obtained. X-ray crystallographic studies showed the existence of
two ligand-coordination patterns in a 1:1 ratio (Figure 1). Form A
(Figure 1, left) was a simple mono-ligated CuCl complex with
CG1’, bearing a weak Cu–Cu interaction. However, form B
(Figure 1, right) was shown to be a dichloridocuprate salt with
bis-ligated Cu(I) cation as the counterion, which was detected by
CSI-MS in our previous work.16a Such an observation indicated a
possible isomerization between the two structures in solution.
Based on the absence of non-linear effect (NLE) observed in the
reaction (SI S55), we proposed that the mono-ligated Cu(I)
complex is the active catalyst.
N
ligand
exchange
N
N
Cu
N
N
H
CuCl2
N
Cu
Cl
N
H
solvent
H
N
(CG1’2Cu)(CuCl2)
form B
Cu(CG1’)Cl
form A
N
report, we propose that
a
direct enantio-convergent
transformation mechanism is plausible, and consistent with the
definition as no erasure of the substrate chiral center is
involved.13f
Figure 1. The crystal structure of Cu(CG1’)Cl complex I and its ORTEP
representation (50% possibility level). Most of the hydrogen atoms have been
omitted for clarity.
Borylation of organohalides was previously reported by Fu18
to undergo a radical pathway; however, no cyclization product
was observed when a radical probe 1j was used. Radical
scavengers such as TEMPO and BHT did not significantly affect
both yield and enantioselectivity of the reactions (SI S56). High
regioselectivity on gamma-position of allylic bromides indicated
an SN2’ allylic substitution, similar to previous reported examples
on copper-catalyzed allylic borylation.2h,4 The SN2’ selectivity of
the reaction was demonstrated using acyclic allylic halides.
When branched allylic chloride rac-3a was employed, a mixture
of Z/E isomers of 4a was obtained, without the detection of any
branched allylboronate (Scheme 2, eqn. 1). On the other hand,
when linear allylic chloride 3b and allylic bromide 3c was used,
boronate 4b was obtained with up to 53% ee (Scheme 2, eqn. 2
and 3). Reactions of linear allylic chloride 3b was much slower
than with allylic bromide 3c.
Scheme 3. Transition states for the rate determining oxidative addition of 1a
and [LCuR(OH2)]-.
In summary, we reported the preparation of enantiopure
secondary and tertiary cyclic allylboronates from racemic allylic
bromides. Chiral guanidine and easily accessible copper salts
were used as catalysts under mild conditions. EPR experiments
and X-ray crystallographic analysis suggested that a mono-
ligated Cu(I)-guanidine complex to be the active catalytic specie.
We also proposed after experimental investigations and DFT
calculations that the borylation proceeded via a selective SN2’
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COMMUNICATION
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Acknowledgements
We are grateful to the Nanyang Technological University
(M4011633), Ministry of Education Tier 2 Grant (MOE2016-T2-
1-087) and Singapore University of Technology and Design
[8]
(T1MOE1706
&
IDG31800104) for financial support.
Computational resources from National Supercomputing Centre
(Singapore) are also gratefully acknowledged.
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Keywords: chiral tertiary allylboronate • asymmetric allylic
borylation • enantio-convergent synthesis • copper-guanidine
catalyst • direct enantio-convergent transformation
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10.1002/anie.201813490
Angewandte Chemie International Edition
COMMUNICATION
believed that the reaction proceeded through
intermediate (ref. 11a).
a
borylcopper(II)
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10.1002/anie.201813490
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
An enantioconvergent synthesis
of chiral cyclic allylboronates is
demonstrated with racemic allylic
Enantio-Convergent Synthesis
Br
(±)
Bpin
Yicen Ge, Xi-Yang Cui, Siu Min
Tan, Huan Jiang, Jingyun Ren,
Nicholas Lee, Richmond Lee* and
Choon-Hong Tan*
R
Cu(II) salt, chiral guanidine
B2pin2
R’
R’
R
K2CO3 (aq.), 0 °C, air
bromides
using
a
chiral tertiary allylboronates
racemic allylbromides
(guanidine)copper catalyst. The
allylboronates were acquired with
high γ/α regioselectivities (up to
99:1) and enantioselectivities (up
to 99% ee). The reaction is
believed to go through an SN2’
borylation process catalyzed by a
up to 99% ee, 99:1 regioselectivity
Page No. – Page No.
Syn coordination
Anti coordination
Enantioconvergent Synthesis of
Tertiary Cyclic Allylboronates
Using (Guanidine)copper
Complex-Catalyzed Allylic
Borylation
N
N
Favored
Transition
states
forming
(R)-product
N
N
N
N
Cu
OH2
Cu
OH2
H
O
O
B
O
B
Br
O
monodentated
guanidine-
Br
copper(I) complex with DECT
mechanism.
TSAsyn-S
TSAanti-R
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