Catalyst-controlled regiodivergent ring-opening C(sp3)-Si bond-forming reactions of 2-arylaziridines with silylborane enabled by synergistic palladium/copper dual catalysis

Article abstract of DOI:10.1039/c9sc02507c

A catalyst-controlled regiodivergent and stereospecific ring-opening C(sp³)-Si cross-coupling of 2-arylaziridines with silylborane enabled by synergistic Pd/Cu dual catalysis has been developed. Just by selecting a suitable combination of catalysts, the regioselectivity of the coupling is completely switched to efficiently provide two regioisomers of β-silylamines (i.e., β-silyl-α-phenethylamines and β-silyl-β-phenethylamines) in good to high yields. Furthermore, a slight modification of the reaction conditions caused a drastic change in reaction pathways, leading to a tandem reaction to produce another regioisomer of silylamine (i.e., α-silyl-β-phenethylamines) in an efficient and selective manner.

Full text of DOI:10.1039/c9sc02507c

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DOI: 10.1039/C9SC02507C
ARTICLE
Catalyst-Controlled Regiodivergent Ring-Opening C(sp3)–Si Bond-
Forming Reactions of 2-Arylaziridines with Silylborane Enabled by
Synergistic Palladium/Copper Dual Catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
Youhei Takeda,*a Kaoru Shibuta,a Shohei Aoki,a Norimitsu Tohnaib and Satoshi Minakata*a
DOI: 10.1039/x0xx00000x
A catalyst-controlled regiodivergent and stereospecific ring-opening C(sp3)–Si cross-couplings of 2-arylaziridines with
silylborane enabled by a synergistic Pd/Cu dual catalysis has been developed. Just by selecting suitable combination of
catalysts, the regioselectivity of the coupling is completely switched to efficiently provide two regioisomers of -silylamines
(i.e., -silyl--phenethylamines and -silyl--phenethylamines) in good to high yields. Furthermore, a slight modification of
the reaction conditions caused a drastic change in reaction pathways, leading to a tandem reaction to produce another
regioisomer of silylamine (i.e., -silyl--phenethylamines) in an efficient and selective manner.
alkylamines, respectively. In conjunction with the fact that
alkylamines bearing a C(sp3)–Si bond have been recognized as
unique bioisosters of pharmacological agents in medicinal
Introduction
Alkylsilanes are ubiquitous motifs in industrial products, and
they serve as useful synthetic building blocks.1 A wide variety of
synthetic methods for alkylsilanes including silyl-SN2 reaction,2
silyl-Negishi and silyl-Kumada-Tamao reactions of silyl halides,3
hydrosilylation of alkenes,4 C–H silylation of alkanes,5 the
addition of Si–E (e.g., E = Si, B) bond across C=C double bonds,6
Cu-catalyzed nucleophilic substitution of alkyltriflates,7 and
chemistry,21 regiodivergent ring-opening C(sp3)–Si cross-
coupling of azridines with a silyl (pro)nucleophile would open
up a new avenue to the preparation of a set of regioisomeric -
silyl-alkylamines. A seminal work on regioselective ring opening
of aziridines with silylnucleophile was reported by Fleming,
where silyllithium was applied as a nucleophile (Scheme 1a).22
The reaction exclusively gives one regioisomer of silylamine (-
silyl--substituted ethylamines), however, the regiochemistry
(opening at the 3-position) seems to be governed by the
combination of reagents, and it requires excess amounts of
silyllithium (3 equivalents) that can deteriorate electro-
withdrawing functionalities.22 During the preparation of this
manuscript, as a related work with our present work, a Cu-
catalyzed reagent-controlled regiodivergent nucleophilic ring
opening of 2-arylaziridines with silyl Grignard reagents has been
reported by the Oestreich group (Scheme 1b).23 Although an
example using a silylborone (Me2PhSi–Bpin) as a pronucleophile
was also shown in the same paper to give 3-position selective
silylative ring opening coupling,24 as is generally the case,
reagent-controlled approach quite limits the diversity of
products. To the best of our knowledge, catalyst-controlled
regiodivergent ring-opening C(sp3)–Si cross-coupling of
aziridines has not been achieved yet. Herein, we disclose a
catalyst-controlled regiodivergent and stereospecific ring-
opening C(sp3)–Si cross-couplings of 2-arylaziridines with a
silylborane to selectively give two different regioisomers of
silylphenethylamines enabled by Pd/Cu synergistic dual
catalysis (the upper and middle equations, Scheme 1).24
radical-mediated
C(sp3)–Si
coupling
of
unactivated
alkylhalides8a,c and carboxylate derivatives8b,c with silylboranes,
have been developed. Avobe, more recently, transition-metal
(Ni and Pd)-catalyzed C(sp3)–Si cross-coupling of an alkyl
electrophile with a silyl (pro)nucleophile (Si–M, M = Zn, B) has
been emerging as a powerful synthetic method for alkylsilanes,
because of high chemoselectivity and functional tolerance.9–12
Nevertheless, to data, alkyl electrophiles that are applicable to
the couplings are limited to branch-type alkyl halides,9 benzyl
halides,10,11 and benzyl ethers.12 Therefore, the development of
C(sp3)–Si cross-coupling using hitherto unexplored alkyl
electrophiles with a silyl (pro)nucleophile holds a great promise
for widening diversity of available alkylsilanes.
Aziridines have emerged as
a relatively new alkyl
electrophile in transition-metal-catalyzed regioselective ring-
opening C–C13–18 and C–B19,20 cross-couplings with organoboron
and organozinc nucleophiles to give -organo- and borylated
a. Department of Applied Chemistry, Graduate School of Engineering, Osaka
University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan. E-mail:
takeda@chem.eng.osaka-u.ac.jp; minakata@chem.eng.osaka-u.ac.jp
b. Department of Material and Life Science, Graduate School of Engineering, Osaka
University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan.
Notably,
a catalytic tandem reaction to give another
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: experimental procedures for
synthesis and screening, spectroscopic data of new compounds, X-ray
crystallographic data, copies of 1H and 13C NMR charts, and HPLC analysis data. See
DOI: 10.1039/x0xx00000x
regioisomer of silylamines was also discovered (the bottom
equation, Scheme 1c).
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to promote the coupling, and the effect of Cu additives was
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investigated (Table S4, ESI). Importantly,DtOheI: 1a0d.1d0i3t9io/Cn9oSCf0C2u5S0O7C4
drastically improved the chemical yield of 3a up to 89% (Table
1, entry 1 vs entry 2). Other copper salts such as CuF2 and
Cu(OH)2 gave 3a in comparable yields (Table 1, entries 3 and 4),
while the addition of CuCl resulted in lower yield (Table 1, entry
5), possibly due to the poorer solubility of the salt in the
solvents. Without the Pd complex and phosphine ligand, no
reaction occurred (Table 1, entries 6 and 7), excluding the
possibility of direct nucleophilic ring-opening substitution with
Cu–Si species.23 Furthermore, bpy should play an important role
in the coupling, because coupled product 3a was not produced
at all in the absence of bpy (Table 1, entry 8). In addition, -
methoxy--phenethylamine 7 was produced in a substantial
yield, which should be produced through the nucleophilic ring
opening of 1a with MeOH under the electrophilic activation of
1 by the Cu Lewis acid,24 implying that bpy adjusts the Lewis
acidity of the Cu additive to suppress the background side
reaction. Another possible role is to enhance the solubility of
the Cu-species by coordination to increase the concentration of
the active Cu species. A proton source was required for the
reaction to smoothly proceed (Table 1, entries 9 and 10),
indicating the M–OMe species (M = Pd, Cu) generated in situ
would promote the stepwise transmetalation (Si–B → Si–Cu →
Si–Pd) through Lewis acid-base interactions. The C(sp3)–Si
coupling proceeds smoothly under neutral conditions without
adding any explicit strong Lewis bases, which are usually
required to activate silylboranes to transfer the silyl
unit.7,8a,b,10,11 Other silylboranes such as Ph2MeSi–Bpin,
Ph2tBuSi–Bpin, and Et3Si–Bpin did not give any silylated
products.
Scheme 1 Regioselective C(sp3)–Si bond-forming reactions of 2-
arylaziridines with silylboranes.
Table 1. Effect of reaction parameters in the 3-position-
selective C(sp3)–Si cross-coupling of 1a with 2[a]
Results and Discussion
We previously reported that NHC/Pd and PtBu2Me/Pd
catalysts allow for regioselective and stereospecific (stereo-
invertive) ring-opening Suzuki-Miyaura arylation and borylation
of 2-arylaziridines13a at the 2- and 3-position, respectively.19
Theoretical calculations on the mechanisms suggested the
regioselectivity and stereospecificity are determined in an SN2-
type oxidative addition step through the interaction between
catalyst and aziridine.13b,19 Based on the borylation conditions,19
as an initial attempt, racemic aziridine 1a was treated with
silylborane (Me2PhSi–Bpin, 2) (1.2 equiv) in the presence of
Variations
Entry the “standard
from Yield (%)
Recove
ry of
1a (%)
0
3a
4
5
conditions A”
none
w/o CuSO4
CuF2 in place of
CuSO4
Cu(OH)2 in place of
CuSO4
CuCl
w/o Cp(ally)Pd and
PtBu2Me
w/o Cp(allyl)Pd
w/o bpy
H2O in place of
MeOH
1
89
13
6
0
Cp(allyl)Pd/PtBu2Me and bipyridine (bpy) catalyst in
a
2b
trace 39 46
CPME/H2O co-solvent. Although the expected coupled product
3a was formed, the chemical yield was very low even at an
elevated temperature (Table 1, entry 2), suggesting that the
transmetalation between Si–B and Pd–OMe species would be
energetically much higher than that of the C–B coupling. At a
temperature higher than 60 °C, -hydride elimination from the
oxidative adduct was accelerated,19 indicating the difficulty of
identifying suitable reaction conditions for the coupling with
single metallic catalytic system (for the details, see the Table
S1–S8, ESI). We envisaged that the addition of a Cu salt could
allow for stepwise transmetalation (i.e., Si–B → Si–Cu → Si–Pd)
3
83
0
5
0
4
5
6
83
35
0
0
0
0
7
4
0
0
55
99
7
8c
0
0
0
23
0
0
99
13
9
75
4
0
8
2 | J. Name., 2012, 00, 1-3
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10 w/o MeOH
ARTICLE
revealed that 3a-d1 has the trans-configuration, iVniedwicAartticinlegOntlhinee
C(sp )–Si cross-coupling proceeds in a stereo-invertive manner.
This indicates that regio- and sterespecificity-determining step
would be an SN2-type oxidative addition even in the dual
catalytic system.
trace
0
0
93
a The “standard conditions A”: 1a (0.2 mmol), 2 (0.24 mmol),
Cp(allyl)Pd (8 mol), PtBu2Me (8 mol), CuSO4 (8 mol), and
bpy (20 mol) were stirred in CPME/MeOH (1 mL, v/v 9:1) at
3
DOI: 10.1039/C9SC02507C
b
c
40 °C for 3 h. The reaction was conducted at 60 °C.
Phenethylamines 6 and 7 were obtained in 12% and 51%,
respectively.
With the optimized reaction conditions in hand, the
substrate scope of aziridines was investigated (Table 2). A
variety of 2-arylaziridines 1 having a functional group on the
aromatic ring were applicable, giving -silyl--phenethylamines
3 in a regioselective manner in good to high yields. Specifically,
it is noted that chlorine and ester functionalities tolerated the
reaction conditions to give the corresponding coupling products
(3d, 3f, 3g, and 3h). On the other hand, the reactions with 2,3-
disubstituted (1j), 2-alkylated (1k), 2-(o-Br-C6H4)-substituted
(1l), and cyclic (cis-1m) aziridines were not successful (Table 2).
Since N-tosyl-2-(p-Br-C6H4)-aziridine was not also applicable to
the reaction conditions (recovery of aziridine 87%), the reason
why the coupling reaction using 1l did not proceed would be
electronic effect rather than steric effect of the o-Br
substituent. The preference of the oxidative addition of the C–
Br bond to the Pd(0) complex might be the side reaction to
inhibit the desired reaction.
Delighted with the validity of the Pd/Cu dual catalysis in the
3-position-selective C(sp3)–Si coupling, we turned our attention
to switching the regioselectivity of the ring-opening silylative
coupling. Although NHC-ligated Pd(II) complexes are suitable
pre-catalysts for Suzuki-Miyaura arylation of 1a,13a the attempts
with those Pd(II) complexes failed only to recover the aziridine,
indicating less nucleophilic ability of the silylborane to reduce
Pd(II) to Pd(0) than arylboronic acid.13b To circumvent the
reduction process, we applied NHC-ligated Pd(0) complexes26 as
a Pd pre-catalyst and found it successful: a coupling reaction
proceeded exclusively at the 2-position to give regioisomeric
coupled product (-silyl--phenethylamine) (for the detailed
results, see Table S9–S16, ESI). Among tested, a catalytic system
comprising of SIPr–Pd(0)–PPh3, CuF2, and 1,10-phenanthroline
(phen) was found suitable for the 2-position-selective ring-
opening C(sp3)–Si coupling to give 8a in a high yield (standard
conditions B) [eqn (2)]. Intriguingly, along with 8a, 11% of -
silyl--phenethylamine 9a, which is another regioisomer of 8a,
was produced [eqn (2)]. Although the detailed mechanism
leading to 9a should await further study, a putative pathway
involves a tandem processes comprising of i) a Pd-catalyzed
isomerization of 1a into aldimines through the oxidative
addition of 1a into Pd(0) complex at the 2-position followed by
-hydride elimination/tautomerization27 and ii) a subsequent
nucleophilic attack of the resulting aldimines by the Cu–Si
species generated in situ (vide infra).28 Delighted with the
discovery of this hitherto unknown reaction, we surveyed the
effect of reaction parameters on the product distribution (for
the details, see the ESI). It turned out that the tandem reaction
was drastically promoted by simply adding extra PPh3 and
changing the additive from phen to bpy (Table S10 and S16, ESI),
which led to exclusive and quantitative formation of 9a
(standard conditions C) [eqn (3)].
Table 2. Scope of aziridines in the 3-position-selective C(sp3)–Si
cross-coupling[a]
a
The reaction was conducted at 0.50 mmol (1) scale under
“standard conditions A”.
To gain the stereochemical information about the reaction,
a deuterated aziridine (cis-1a-d1) was coupled with silylborane
under the standard conditions A [eqn (1)]. Derivatization of the
coupled product 3a-d1 (for the detailed procedures to
determine the relative stereochemistry, see the Scheme S1, ESI)
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J. Name., 2013, 00, 1-3 | 3
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The scope of the 2-position-selective ring-opening C(sp3)–Si
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DOI: 10.1039/C9SC02507C
cross-coupling was investigated (Table 3). The cross-coupling of
enantiopure aziridine (R)-1a (>99% ee) under the standard
conditions B proceeded regioselectively and enantiospecifically
to give enantiopure product 8a in 89% yield (99% ee). The
absolute configuration of 8a was unambiguously determined to
be S by the single crystal X-ray diffraction analysis (Table 3, the
inset figure; for the detailed crystallographic data, see the Table
S17, ESI). This indicates that the coupling proceeds with stereo-
inversion, which is fully consistent with an SN2-type oxidative
addition of aziridine.13a The coupling conditions were applicable
to 2-arylaziridines bearing a variety of functional groups, giving
rise to the corresponding coupled products in good to high
yields in a regioselective and stereospecific manner (Table 3).
Again, the reactions using aziridines 1j–1m were not successful.
a
The reaction was conducted at 0.20 mmol (1) scale under
the “standard conditions C”.
A proposed reaction mechanism of the 2-position-selective
C(sp3)–Si coupling and the tandem reaction are illustrated in
Scheme 2. The catalytic cycle would start from the pre-
coordination of SIPr–Pd(0)to the aryl moiety of 1 to stabilize the
complex (Scheme 2a),13b which then undergoes the oxidative
addition into the complex from the backside of the C(2)–N(1)
bond with the stereo-inversion (Scheme 2b). The
regioselectivity for the ring opening would be determined by
the pre-coordination of the Ar moiety to the Pd center to gain
large interaction energy (INT), which was reasonably suggested
by the energy decomposition analysis (EDA) of the computed
oxidative addition process of the aziridines into a Pd(0)–NHC
compex.13b In sharp contrast, in the case of phosphine-Pd
catalyst system, the oxidative addition takes place at the
opposite side (i.e., C(3)–N(1)) in a regioselective fashion. This
would be caused by the larger deformation energy (DEF) than
INT gained when the V-shaped bisphosphine-Pd complex
[(tBu)2MeP–Pd(0)–PMe(tBu)2] approaches from the backside of
the C(2)–N(1) bond.19 Therefore, we can conclude that the
regioselectivity of the ring opening would be mainly governed
by the balance between i) how large interactions between Pd
catalyst and aziridine operate and ii) how large deformations
the Pd catalyst and aziridine experience when they approach to
each other. The resulting zwitter ionic oxidative adduct A can be
protonated with MeOH to form alkoxide complex B (Scheme
2c).19 This intermediate would then undergo the
transmetalation with PhMe2Si–Cu(phen) complex D, giving an
alkyl(silyl)Pd complex E (Scheme 2e), where silylcopper D could
be generated from the transmetalation between Cu–OMe
species C with silylborane (Scheme 2d).29 The reactions of 1a
with the silylborane in the presence of Cu catalysts in different
oxidation states [(phen)CuIF30a and (phen)CuIIF230b] gave 8a in
almost the same yields (see the Table S15, ESI), implying that
the oxidation level of the actual Cu species in the optimized
conditions would be either CuI or CuII. To probe the oxidation
level of the actual Cu active species, the reaction mixtures
starting with a CuI and CuII addtive were monitored with
electron paramagnetic resonance (EPR) technique. As the
results, the concentration of CuII species significantly decreased
under the optimized conditions (see the Fig. S1 in ESI),
indicating that the reduction of CuII to CuI occurs in situ. Taken
together, we assume that putative Cu active species in Cu
catalysis is (phen)CuI–L (L = F or OMe). The reductive elimination
from E should produce 8 and regenerate Pd(0) catalyst (Scheme
2f). Almost the same dual catalysis would be involved in the C–
Table 3. Scope of aziridines in the 2-position-selective C(sp3)–Si
cross-coupling[a]
SiMe2Ph
NHTs
SiMe2Ph
NHTs
SiMe2Ph
NHTs
Me
F
(S)-8a (with R-1a)
89%b (99% es)c
(S)-8c (with (R)-1c)
(±)-8b (with (±)-1b)
70% (99% es)c
82%d
X-ray crystallographic
structure of (S)-8a
SiMe2Ph
SiMe2Ph
NHTs
SiMe2Ph
SiMe2Ph
NHTs
NHTs
NHTs
Cl
F3C
AcO
MeO2C
(S)-8d (with (R)-1d)
(±)-8e (with (±)-1e)
84%e
(±)-8g (with (±)-1g)
(±)-8f (with (±)-1f)
86% (99% es)c
48%e
80%b
a
The reaction was conducted at 0.50 mmol (1) scale under
the “standard conditions B”. b The reaction was run for 3 h. c
es (enantiospecificity) = ee (8)/ee (1) × 100; ee (enantiometic
d
excess) was determined by chiral HPLC analysis.
The
reaction was conducted with MeIPr–Pd–PPh3 catalyst at 60 °C.
e The reaction was conducted at room temperature.
The substrate scope of the tandem C(sp3)–Si bond-forming
reaction was also investigated (Table 4). A variety of 2-
arylaziridines with a functional group were efficiently converted
into the corresponding -silyl--phenethylamine products,
which often found in bioisosters of protease.21
Table 4. Scoep of aziridines in the C(sp3)–Si bond-forming
tandem reaction[a]
4 | J. Name., 2012, 00, 1-3
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Si cross-coupling at the 3-position, except for the 3-position- “Coordination Asymmetry” (KAKENHI, JP19H04580, to NT). We
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selective oxidative addition.19 A possible pathway to 9 would also acknowledge Professors Yuma MoriDmOoI:t1o0.a10n3d9/SCh9iSnCo0b2u50I7tCo
involve i) a PPh3/Pd-catalyzed isomerization of 1 into aldimine F for the assistance of EPR measurements and fruitful discussions.
via -hydride elimination and tautomerization (Scheme 2g)27
and ii) the following nucleophilic addition of Si–Cu species D to
the imine (Scheme 2h).28 Since the treatment of separately
prepared aldimine F with silylborane 2 under the similar
reaction conditions (“standard conditions C”) gave 9 in a
moderate yield (when Ar = Ph, 31% of 9a was obtained with no
recovery of aldimine substrate; for the details, see the Scheme
S2, ESI), this scenario is likely to occur.
Notes and references
1
(a) M. A. Brook, Silicon in Organic, Organometallic, and
Polymer Chemistry, Wiley-Interscience, New York, 2000; (b) N.
Anner and J. Weis, Organosilicon Chemistry V, Wiley-VCH
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P. J. Lennon, D. P. Mack and Q. E. Thompson, Organometallics,
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Scheme 2 A proposal dual catalysis in the 2-position-selective
C(sp3)–Si cross-coupling and tandem reaction.
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Conclusions
In conclusion, we have succeeded in developing catalyst-
controlled highly regiodivergent ring-opening C–Si bond
formation reactions to selectively provide three regioisomers of
silylamines via synergistic Pd/Cu dual catalysis. It is noted that
the balance between the efficiency of Pd and Cu catalysis should
be the origin of the discovery of the tandem reaction, and this
knowledge would provide us with insights for designing more
intricated and sophisticated transformations in the future.
Detailed catalytic reaction mechanisms are investigated
experimentally and theoretically in our laboratory.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This work was supported by Grant-in-Aid for Scientific Research
on Innovative Areas “Precisely Designed Catalysts with
Customized Scaffolding” (KAKENHI, JP16H01023, to YT) and
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