Kinetic and Dynamic Kinetic Resolution of Racemic Tertiary Bromides by Pentanidium-Catalyzed Phase-Transfer Azidation

Article abstract of DOI:10.1002/anie.202000138

We have developed a method to afford enantiomerically enriched tertiary azides and bromides through pentanidium-catalyzed kinetic resolution (KR) of racemic tertiary bromides under base-free conditions. We found that the absence of water is crucial to attain a high selectivity factor (s). On the other hand, new experimental observations and DFT modeling led us to propose that enantioconvergent azidation of tertiary bromides proceeded through dynamic kinetic resolution (DKR). The investigations particularly identified the crucial roles of base and water in the enantioconvergent process, thus supporting the proposal that the tertiary bromide isomerizes in the presence of base and water through a S_N2X pathway.

Full text of DOI:10.1002/anie.202000138

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Accepted Article
Title: Kinetic and Dynamic Kinetic Resolution of Racemic Tertiary
Bromides byPentanidium-Catalyzed Phase-Transfer Azidation
Authors: Choon Hong Tan, Jingyun Ren, Xin Zhang, Siu-Min Tan,
Richmond Lee, and Xu Ban
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000138
Angew. Chem. 10.1002/ange.202000138
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10.1002/anie.202000138
Angewandte Chemie International Edition
COMMUNICATION
Kinetic and Dynamic Kinetic Resolution of Racemic Tertiary
Bromides by Pentanidium-Catalyzed Phase-Transfer Azidation
Jingyun Ren, Xu Ban, Xin Zhang, Siu Min Tan, Richmond Lee* and Choon-Hong Tan*
Abstract: We have developed
a
methodology to afford
(a) SN2 substitution: sensitive to steric hindrance, stereospecific
enantioenriched tertiary azides and bromides through pentanidium-
catalyzed kinetic resolution (KR) of racemic tertiary bromides under
base free condition. We found that the absence of water is crucial to
obtain high selectivity factor (s). On the other hand, new experimental
observations and DFT modelling led us to propose that
enantioconvergent azidation of tertiary bromides proceeded through
dynamic kinetic resolution (DKR). The investigations particularly
identified the crucial roles of base and water in the enantioconvergent
process, supporting the proposal that tertiary bromide isomerizes in
the presence of base and water through a SN2X pathway.
"backside attack"
R1
R1
Nu
R3
R1
-X
Nu
X
X
Nu
R2
R2
R2
R3
R3
pentacoordinate
transition state
(b) SN2X substitution: insensitive to steric hindrance
R1
R1
"frontside attack"
R1
R1
Nu
R3
-X
X
X
Nu
Nu
X
Nu
R2
R2
R2
R2
R3
R3
R3
prochiral
halogen-bonded
intermediate
(c) Kinetic and dynamic kinetic resolutions of tertiary azides
R
fast
R
R
R
PN
N3
Br
Br
Br
N3
(DKR)
COOtBu
base-mediated
racemization
(SN2X)
NC
SN2
NC
NC
NC
COOtBu
COOtBu
COOtBu
racemic
Nucleophilic substitutions are textbook organic chemistry
reactions. One of the main types of nucleophilic substitution,
called bimolecular nucleophilic substitution (SN2), involves the
nucleophile attacking and the leaving group departing at the same
time and can be considered as nucleophile substitution via
“backside attack” of the C-X bond (Scheme 1a).[1] A significant
drawback of the SN2 reaction is that it’s sensitive to the steric
hindrance of both the nucleophile and electrophile, which is often
unsuccessful for bulky substrates, especially tertiary
electrophiles.[2] For enantioselective versions, SN2 reactions are
likely to undergo kinetic resolution, which the theoretical
maximum yield of the desired enantiopure product is 50%.[3] We
have recently shown that an unusual substitution pathway is the
halogenophilic SN2X reaction, which the nucleophile break the C-
X bond via a “frontside attack” (Scheme 1b).[4],[5] In contrast with
SN2 reaction, SN2X reaction is amenable to bulky substrates and
through formation of a prochiral anionic intermediate, allowed the
formation of enantioenriched product in high yields making it a
useful tool for synthesis of sterically congested tertiary or
quaternary stereocenters.
R
R
R
PN
N3
2
Br
Br
N3
COOtBu
+
(KR)
NC
SN
base free
NC
NC
COOtBu
racemic
COOtBu
Scheme 1. SN2, SN2X reactions and kinetic resolutions of tertiary bromides.
In our previous report,[4] an enantioconvergent substitution of
racemic activated tertiary bromides was achieved using different
nucleophiles (thiocarboxylates or azides) with cationic
pentanidiums (PN)[6] as catalysts, affording a wide variety of
enantioenriched tertiary thioesters and azides. On the basis of
experimental and computational mechanistic studies using the
thiocarboxylate substitution,[7] a SN2X pathway was proposed with
a pre-transition state intermediate that was stabilized with
halogen bonding.[8] A more in-depth investigation of the azide
substitution was done and found that different reaction pathways
operated under basic and base free conditions, leading to
different reaction products. In this report, supported with
additional experimental and computational studies, we like to
propose that activated tertiary bromides undergo dynamic kinetic
resolution under basic conditions and kinetic resolution under
base free conditions (Scheme 1c).
[*]
Dr. J. Ren
Chiral organic azides,[9] especially chiral tertiary organic
azides, are valuable structural motifs but are synthetically
challenging.[10] There are only few reports on catalytic asymmetric
methods to prepare chiral tertiary azides including the
electrophilic azidation of b-keto esters and oxindoles,[10b] the
enantioselective palladium-catalyzed decarboxylative allylation,
[10c] asymmetric haloazidation of α,b-unsaturated ketones[10d] and
azidation of racemic tertiary α-bromo oximes.[10e] Formation of
chiral tertiary azides via a nucleophilic substitution reaction is
possible through the preparation of enantiopure tertiary halide
precursors.[11] We found that activated tertiary bromides, under
the base free conditions, proceeded through kinetic resolution
(Table 1). Using racemic activated tertiary bromide 1a as a model
and with PN1 as catalyst, the conversions were low even after 7
days when 100 and 50 equivalents of water were added to the
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of Ministry of Education
College of Chemistry & Materials Science, Northwest University
Xi’an, Shaanxi 710127, P.R. China
Dr. J. Ren, Dr. X. Zhang, Prof. Dr. C.-H. Tan
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
21 Nanyang Link, 637371 Singapore (Singapore)
E-mail: choonhong@ntu.edu.sg
Dr. S. M. Tan, Dr. R. Lee
Science and Mathematics Cluster
Singapore University of Technology and Design
8 Somapah Road, Singapore 487372 (Singapore)
E-mail: richmond_lee@sutd.edu.sg
Supporting information for this article is given via a link at the end
of the document. ((Please delete this text if not appropriate))
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10.1002/anie.202000138
Angewandte Chemie International Edition
COMMUNICATION
reaction (entries 1 and 2). Reducing the amount of water
increased the conversions as well as the selectivity factors
(entries 3-5). The best selectivity factor (s = 76) was obtained in
the absence of water, affording recovered tertiary bromide (-)-1a
with 97% ee, while optically active tertiary azide 2a with 89% ee
substrates and provided moderate selectivity (s = 22, 47, 24 and
30 respectively). Substrates bearing ester groups, such as acetyl-
and benzoyl-protected alcohol (1f and 1g), were also examined
and afforded good selectivity factors (s = 98 and 57 respectively).
Notably, substrates possessing terminal alkenyl group (1h) and
internal alkenyl group (1i) were also resolved efficiently (s = 44
and 27 respectively). However, we were not successful when we
attempted 2-aryl and 2-benzyl substituted substrates.
-
(entry 5). Switching the counter anion from BF4 to Cl- (PN2)
caused a decrease in selectivity (s = 56, entry 6). Diminished
selectivity factors were also observed when changing the 2-
chloro-substituted benzyl groups of PN1 to 2-bromo- (PN3) or 2-
iodo-substituted benzyl groups (PN4) (entries 7-8). Alternatively,
employing pentanidium catalysts (PN5-7) without the halogen-
substituted on the 2-position of the benzyl group facilitated the
reactions with poor selectivities (entries 9-11). Variation of
solvents and azide sources (such as KN3 and LiN3) did not
improve the selectivity factors (See SI, page S3).
R
R
Br
R
NaN3 (4.0 equiv.)
PN1 (5.0 mol%)
N3
Br
NC
NC
COOtBu
NC
iPr2O (1.0 mL)
COOtBu
2
COOtBu
(-)-1
(±)-1
-40 oC, 5~7 days
(0.1 mmol, 1.0 equiv.)
Br
N3
Br
N3
NC
NC
COOtBu
(-)-1b
36% yield
COOtBu
2b
51% yield
NC
NC
COOtBu
(-)-1a
COOtBu
2a
42% yield
97% ee
48% yield
89% ee
87% ee
conv. = 53%; s = 22
79% ee
Table 1. Kinetic resolution of racemic 1a under base free conditions.
conv. = 52%; s = 76
NaN3 (4.0 equiv.)
H2O (x equiv.)
catalyst (5.0 mol%)
Ph
Ph
+
Br
Br
N3
Br
N3
NC
NC
NC
COOtBu
COOtBu
COOtBu
NC
NC
iPr2O (1.0 mL)
-40 oC, 5~7 days
base free
Br
N3
COOtBu
(-)-1d
41% yield
81% ee
COOtBu
(±)-1a
(-)-1a
2a
NC
NC
(0.1 mmol, 1.0 equiv.)
2d
COOtBu
COOtBu
49% yield
82% ee
(-)-1c
2c
PN1: R1, R2 = 2-Cl-3,5-(tBu)2C6H2CH2; X = BF4
PN2: R1, R2 = 2-Cl-3,5-(tBu)2C6H2CH2; X = Cl-
PN3: R1, R2 = 2-Br-3,5-(tBu)2C6H2CH2; X = Cl-
PN4: R1, R2 = 2-I-3,5-(tBu)2C6H2CH2; X = Cl-
PN5: R1, R2 = 3,5-(tBu)2C6H3CH2; X = Cl-
PN6: R1, R2 = 3,5-(CF3)2C6H3CH2; X = Cl-
-
32% yield
42% yield
conv. = 50%; s = 24
R1 R1
Ph
Ph
91% ee
86% ee
conv. = 51%; s = 47
N
N
AcO
AcO
Ph
Ph
N
R2
N
N
X
Br
N3
Br
COOtBu
N3
R2
NC
NC
PN7: R1 = 3,5-(tBu)2C6H3CH2, R2 = 3,5-(CF3)2C6H3CH2;
COOtBu
(-)-1f
32% yield
COOtBu
NC
NC
COOtBu
X = Cl-
2f
(-)-1e
2e
46% yield
85% ee
39% yield
42% yield
93% ee
84% ee
95% ee
conv. = 52%; s = 44
Entry
Cat.
H2O
Calculated
Conversion
(C) (%)[a]
(-)-1a ee
2a ee
(%)[b]
s[c]
conv. = 47%; s = 98
(x equiv.)
(%)[b]
O
O
O
Ph
Ph
Br
N3
O
NC
NC
COOtBu
(-)-1h
32% yield
93% ee
COOtBu
2h
46% yield
85% ee
Br
COOtBu
N3
180 μL
(100)
1
2
3
4
PN1
PN1
PN1
PN1
12
19
35
46
-
-
-
NC
(-)-1g
NC
COOtBu
2g
conv. = 52%; s = 44
40% yield
32% yield
Ph
Ph
85% ee
conv. = 51%; s = 57
82% ee
90 μL
(50)
-
-
-
Br
N3
NC
NC
COOtBu
COOtBu
(-)-1i
2i
36 μL
(20)
47
72
87
84
23
26
30% yield
84% ee
31% yield
83% ee
conv. = 50%; s = 27
18 μL
(10)
Scheme 2. Kinetic resolution of activated tertiary bromides. Yields are of
isolated products; ee values were determined by GC or HPLC on chiral
columns; calculated conversion (C) (%): C = ee(˗)-1/(ee(˗)-1+ee2); Selectivity
factor: s = ln[(1-C)(1-ee(˗)-1)]/ln[(1-C)(1+ee(˗)-1)]. The absolute configurations
were determined by previous report.
5
6
PN1
PN2
PN3
PN4
PN5
PN6
PN7
0
0
0
0
0
0
0
52
52
51
54
54
53
43
97
95
88
87
19
42
35
89
87
84
75
16
37
46
76
56
34
20
2
7
We had previously found that activated tertiary bromides,
under basic conditions, instead of proceeding through kinetic
resolution, give enantiopure tertiary azides in high yields and ee
values (Scheme 3a). For example, using racemic activated
tertiary bromide 1a with PN1 as catalyst, excess NaN3 (2.0
equivalents) and saturated aqueous K2CO3, tertiary azide 2a was
obtained in 86% yield and 94% ee. We had previously proposed
a halogenophilic nucleophilic substitution (SN2X) mechanism for
this reaction. In view of the discovery of conditions leading to
kinetic resolution under base free condition, we decided to
conduct further investigations. We found that, at any time of the
enantioconvergent azidation, in the presence of base, tertiary
bromide 1a always remains as a racemate; and optically active
tertiary bromide (-)-1a (97% ee) racemized under basic conditions
rapidly (Scheme 3b). This additional information led us to
8
9
10
11
3
4
[a] Calculated conversion (C) (%): C = ee(˗)-1a/(ee(˗)-1a+ee2a). [b] Determined by
GC analysis with a chiral column. [c] Selectivity factor: s = ln[(1-C)(1-ee(˗)-
1a)]/ln[(1-C)(1+ee(˗)-1a)]. The absolute configurations were determined by
previous report.
With the optimal reaction conditions in hand, we next studied
the substrate generality of the kinetic resolution (Scheme 2).
Other 2-alkyl substituted tert-butyl 2-bromo-2-cyanoacetates,
such as methyl-, pentyl-, phenylethyl- and phenylpropyl-
substituted bromides (1b, 1c, 1d and 1e), were all suitable
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10.1002/anie.202000138
Angewandte Chemie International Edition
COMMUNICATION
reconsider the mechanism and the role of base in the
enantioconvergent azidation. With guidance from computational
modelling, we propose that a base-mediated fast dynamic kinetic
resolution (DKR) process of racemic tertiary bromide is involved,
whereby one enantiomer undergoes azidation via SN2 much
faster than the other to facilitate the quantitative enantioselective
transformation (Scheme 1c). This mechanism is different from the
enantioconvergent thiocarboxylation as it proceeded readily
under non-basic conditions.
hydroxide anion (generated from K2CO3 and H2O) through SN2X
mechanism were highly energetically feasible (activation free
energy, DG‡ = ~16 kcal/mol relative to starting materials; see SI,
Figures S2 and S3, page S10-11).
We took a step further to calculate the isomerization pathway
with the full catalyst structure using hybrid DFT/MM ONIOM
method for optimization on the proposed hydroxide mediated Br
abstraction via SN2X pathway (Scheme 4). The calculations
showed that isomerization of both R- (TS-K, DG‡ = 17.4 kcal/mol)
and S-bromide (TS-L, DG‡ = 15.2 kcal/mol) were energetically
favorable. Halogen bonding between the hydroxide and bromine
were observed in the catalyst-substrate complexes of (R)- (int-K,
DG = -1.7 kcal/mol, Br⋯O 2.18 Å) and (S)-bromides (int-L, DG =
-5.8 kcal/mol, Br⋯O 2.18 Å). The calculations are congruent with
experiment, suggesting that base is an important reagent for (±)-
1 isomerization via a SN2X process, helping to achieve enantio-
convergence (Scheme 1c).
(a) Previously reported basic conditions[4]
NaN3 (2.0 equiv.)
sat. aq. K2CO3 (0.2 mL)
PN1 (3.0 mol%)
Br
N3
NC
(±)-1a
NC
2a
86% yield, 94% ee
iPr2O (1.0 mL)
-40 oC, 3~4 days
base-mediated
COOtBu
COOtBu
(b) Further control experiments
Br
conditions
Br
NC
PN1 (3 mol%)
NC
CO2tBu
recovered 1a
iPr2O (1.0 mL) , -40 o
C
CO2tBu
(-)-1a 97% ee
Conditions:
Modelling with the full catalyst structure for the azide
substitution step, we calculated the transition state structures
leading to the R-product, TS-P, with free energy barrier, DG‡ =
21.5 kcal/mol, to be lower than that leading to the S-product, TS-
O with DG‡ = 24.7 kcal/mol. These calculations suggest R-
configuration enantiomer as preferred, which is consistent with
our experimental observations (Scheme 5).
(1) add nothing: after 10 h, ee value of (-)-1a maintained
(2) H2O (0.2 mL): after 10 h, ee value of (-)-1a maintained
(3) sat. aq. K2CO3 (0.2 mL): < 10 min, racemic 1a obtained
(4) solid K2CO3 (0.2 g): 2h, racemic 1a obtained
Scheme 3. Dynamic kinetic resolution of 1a under base-mediated conditions.
Ph
R1
R1
Ph
R1
R1
Ph
R1
R1
R1
R1
Ph
Ph
N
Ph
N
Ph
N
Ph
N
N
N
N
N
N
N
N
N
Ph
Ph
SN2X
Ph
N
N
N
N
Ph
N
R1
Ph
R1
N
R1
N
R1
N
R1
Ph
Ph
R1
Ph
R1
Ph
R1
R1
R1
O
Ph
O
R1
R1
Br
HO
O
Ph
N
HO
Ph
N
O
N
N
N
N
HO
(R) CN
O
Br
(R)CN
CN
Ph
cat-sm4
+
HO
Br
O
Ph
N
N
N
N
R1
R-bromide
ΔG = 0.0 kcal/mol
R1
Ph
R1
Ph
R1
O
CN
int-K
ΔG‡ = 15.7
ΔG = 15.7
ΔG = -1.7
TS-K
int-M
CN
O
MeO
Br
Br
N3
OMe
TS-P
N3
Me
Cl
tBu
Me
TS-O
TS-O
R1
=
Ph
Ph
R1
Ph
N
R1
R1
24.6
R1
Ph
N
R1
Ph
R1
Ph
tBu
N
N
N
N
Ph
Ph
Ph
SN2X
N
N
N
N
R1
R1
N
N
Ph
O
N
N
N
R1
R1
cat-sm4
+
S-bromide
Ph
R1
Ph
R1
Isomer
interconversion
mediated by cat OH
Br
CN
HO
O
CN
Br
O
(S)
HO
NC
16.8
HO
Br
ΔG = 0.0 kcal/mol
(S)
TS-P
OMe
OMe
OMe
int-L ΔG = -5.8
TS-L
ΔG‡ = 9.4
ΔG = 0.3
int-N
Scheme 4. Relative free energies of isomerization pathway with the full catalyst
structure and hydroxide ion. Values are gas-phase free energies with respect to
starting catalyst-sm4 complex and bromide. Computational method:
M11/def2TZVP//oniom:M11/6-31G(d,p):PM6.
0.0
0.0
-0.1
O
O
NC
N3
S-bromide
R-bromide
int-O
CN
N3
OMe
-4.7
MeO
-7.5
O
O
int-P
CN
-7.5
NC
cat N3
MeO
OMe
Br
Br
R-product
S-product
Ph
R1
R1
+
+
Ph
cat-Br
R1
cat-Br
Ph
N
R1
N
Ph
At this point, the question that needs to be answered is how
the two enantiomers of tertiary bromide racemize under the basic
conditions. Computational modelling was performed using density
functional theory (DFT). First, in order to cut down on
computational costs, a truncated-PN1 catalyst, which aryl groups
were replaced with methyl substituents, and the starting material
1g were used in the modelling. In a departure from our previously
reported halogenophilic substitution reaction involving thiolate,[4]
our calculations revealed that the direct SN2 pathway is more
energetically favorable than SN2X with azide nucleophile (see SI,
Figure S1, page S10). This is consistent with experimental
observation of a kinetic resolution process in the absence of base.
To test our hypothesis of a base mediated isomerization, DFT
modelling using the truncated catalyst revealed that the
isomerization process mediated by either K2CO3 or H2O or a
N
Ph
N
N
Ph
N
Ph
N
R1
N
N
Ph
N
O
MeO
Br
R1
R1
CN
R1
Br
N3
CN
Me
MeO
N3
O
Me
Scheme 5. Top diagram showing the optimized transition state structures with
tube representing the catalyst and ball-and-stick representing the azide
attacking the bromide starting material. Bottom free energy surface diagram of
the SN2 process for the R and S-product forming pathways. Values are gas-
phase free energies with respect to starting catalyst-N3 complex and bromide.
Computational method: M11/def2TZVP//oniom:M11/6-31G(d,p):PM6.
In conclusion, we have developed a methodology to afford
enantioenriched tertiary azides and bromides through
pentanidium-catalyzed kinetic resolution of racemic tertiary
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10.1002/anie.202000138
Angewandte Chemie International Edition
COMMUNICATION
[5]
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bromides under base free condition. We found that the absence
of water is crucial to obtain high selective factor (s). It is
noteworthy that there are few synthetic strategies to access highly
enantiopure tertiary bromides.[11e,12] On the other hand, new
experimental observations and DFT modelling led us to propose
that enantioconvergent azidation of tertiary bromides proceeded
through dynamic kinetic resolution (DKR). The investigations
particularly identified the crucial roles of base and water in the
enantioconvergent process, supporting the proposal that tertiary
bromide isomerizes in the presence of base and water through a
SN2X pathway.
Acknowledgements
[7]
[8]
a) S. Kato, K. Miyagawa, S. Kawabata, M. Ishida, Synthesis 1982, 1982,
1013; b) A. Hassner, F. P. Boerwinkle, A. B. Levy, J. Am. Chem. Soc.
1970, 92, 4879.
We gratefully acknowledge financial support from Nanyang
Technological University for Tier 1 grant 2019-T1-001-107 and
Ministry of Education (Singapore) Tier 2 grants MOE2016-T2-1-
087 and MOE2019-T2-1-091. We also like to acknowledge
financial support from Singapore University of Technology and
Design for SUTD-MIT IDC grants T1MOE1706 and IDG31800104.
Computational resources from National Supercomputing Centre
Singapore (NSCC) is gratefully acknowledged.
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Keywords: SN2X substitution • dynamic kinetic resolution •
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10.1002/anie.202000138
Angewandte Chemie International Edition
COMMUNICATION
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Title
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COMMUNICATION
R
Jingyun Ren, Xu Ban, Xin Zhang, Siu
Min Tan, Richmond Lee* and Choon-
Hong Tan*
(DKR)
PN
SN
(KR)
Br
NC
R
R
R
R
COOtBu
fast
N3
2
Br
PN
N3
2
Br
Br
COOtBu
N3
+
NC
SN
NC
base-mediated NC
racemization
(SN2X)
NC
R
COOtBu
COOtBu
COOtBu
N3
base free
racemic
NC
Page No. – Page No.
COOtBu
We have developed a methodology to afford enantioenriched azides and bromides
through pentanidium-catalyzed kinetic resolution (KR) of racemic tertiary bromides
under base free condition. New experimental observations and DFT modelling of
the reaction pathways allowed for a better apprehension of the enantioconvergent
azidation of tertiary bromides, establishing it as a dynamic kinetic resolution (DKR).
Kinetic and Dynamic Kinetic
Resolutions of Racemic Tertiary
Bromides via Pentanidium-Catalyzed
Phase-Transfer Azidation
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