Mechanistic Studies and Expansion of the Substrate Scope of Direct Enantioselective Alkynylation of α-Ketiminoesters Catalyzed by Adaptable (Phebox)Rhodium(III) Complexes

Article abstract of DOI:10.1021/jacs.6b01590

Mechanistic studies and expansion of the substrate scope of direct enantioselective alkynylation of α-ketiminoesters catalyzed by adaptable (phebox)rhodium(III) complexes are described. The mechanistic studies revealed that less acidic alkyne rather than more acidic acetic acid acted as a proton source in the catalytic cycle, and the generation of more active (acetato-κ²O,O′)(alkynyl)(phebox)rhodium(III) complexes from the starting (diacetato)rhodium(III) complexes limited the overall reactivity of the reaction. These findings, as well as facile exchange of the alkynyl ligand on the (alkynyl)rhodium(III) complexes led us to use (acetato-κ²O,O′)(trimethylsilylethynyl)(phebox)rhodium(III) complexes as a general precatalyst for various (alkynyl)rhodium(III) complexes. Use of the (trimethylsilylethynyl)rhodium(III) complexes as precatalysts enhanced the catalytic performance of the reactions with an α-ketiminoester derived from ethyl trifluoropyruvate at a catalyst loading as low as 0.5 mol % and expanded the substrate scope to unprecedented α-ketiminophosphonate and cyclic N-sulfonyl α-ketiminoesters.

Full text of DOI:10.1021/jacs.6b01590

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Article
Mechanistic Studies and Expansion of the Substrate Scope
of Direct Enantioselective Alkynylation of #-Ketiminoesters
Catalyzed by Adaptable (Phebox)Rh(III) Complexes
Kazuhiro Morisaki, Masanao Sawa, Ryohei Yonesaki,
Hiroyuki Morimoto, Kazushi Mashima, and Takashi Ohshima
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01590 • Publication Date (Web): 19 Apr 2016
Downloaded from http://pubs.acs.org on April 25, 2016
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Mechanistic Studies and Expansion of the Substrate Scope of Direct
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Adaptable (Phebox)Rhodium(III) Complexes
Kazuhiro Morisaki,†,‡ Masanao Sawa,†,‡ Ryohei Yonesaki,† Hiroyuki Morimoto,*,† Kazushi Mashima,§
Takashi Ohshima*,†
†Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
§Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531, Japan
ABSTRACT: Mechanistic studies and expansion of the substrate scope of direct enantioselective alkynylation of α-ketiminoesters
catalyzed by adaptable (phebox)rhodium(III) complexes are described. The mechanistic studies revealed that less acidic alkyne
rather than more acidic acetic acid acted as a proton source in the catalytic cycle, and the generation of more active (acetato-
κ2O,O’)(alkynyl)(phebox)rhodium(III) complexes from the starting (diacetato)rhodium(III) complexes limited the overall reactivity
of the reaction. These findings, as well as facile exchange of the alkynyl ligand on the (alkynyl)rhodium(III) complexes led us to
use (acetato-κ2O,O’)(trimethylsilylethynyl)(phebox)rhodium(III) complexes as
kynyl)rhodium(III) complexes. Use of the (trimethylsilylethynyl)rhodium(III) complexes as precatalysts enhanced the catalytic
performance of the reactions with an α-ketiminoester derived from ethyl trifluoropyruvate at a catalyst loading as low as 0.5 mol %
and expanded the substrate scope to unprecedented α-ketiminophosphonate and cyclic N-sulfonyl α-ketiminoesters.
a
general precatalyst for various (al-
enantioselectivity from a broad range of alkynes 3 with vari-
ous functional groups, such as O-TBS, N-Cbz, N-Fmoc, acetal,
1. INTRODUCTION
Asymmetric alkynylation of imines is a highly efficient ap-
proach toward synthesizing optically active propargylamines,1
a valuable intermediate for the synthesis of natural products
and bioactive compounds.2 Various alkynylation methodolo-
gies have been developed using stoichiometric amounts of
metal reagents, such as alkyllithium and dialkylzinc.3 Despite
the robustness of these methodologies, however, reduced
compatibility with base-labile functional groups is inevitable.
In contrast, in situ catalytic generation of metal acetylide spe-
cies directly from terminal alkynes is a more atom-economical
way to promote nucleophilic addition to imines.4 Such direct
alkynylation is effective for imines derived from aldehydes
using Cu(I) and Ag(I) catalysts under proton-transfer condi-
tions.5 On the other hand, direct catalytic alkynylation of
imines derived from ketones (ketimines), which allows for the
construction of tetrasubstituted carbon stereocenters at the
propargylic position, has not been established due to the low
reactivity of the ketimines and difficulty in their stereocon-
trol.6 Some examples of Cu(I)-catalyzed enantioselective al-
kynylation to ketimines were recently reported,7,8 but there is
much room for improvement in terms of the scope of the
ketimines, especially those applicable for the synthesis of α,α-
disubstituted α-amino acid derivatives.9
tertiary alcohol, and a formyl group. The limited catalytic ac-
tivity of 1a, however, made it difficult to further reduce the
catalyst loading, and the substrate scope of the electrophile
was limited to α-ketiminoesters derived from highly electro-
philic ethyl trifluoropyruvate.
Scheme 1. (Diacetato)rhodium(III)-Catalyzed Direct Enan-
tioselective Alkynylation of
α
-Ketiminoesters
NO2
O
O
OAc
Rh
OH2
N
N
AcO
H
1a
Cbz
Cbz
N
N
H
(2.5–5.0 mol %)
+
OEt
F3C
EtO
F3C
toluene
0 ˚C–rt, 12–96 h
R
R
O
O
2
3
via proton transfer
4
In the effort to improve the catalytic activity, we aimed to
elucidate the reaction mechanism. Such mechanistic studies
often lead to an improved catalytic performance and expansion
of the substrate scope, as exemplified by seminal Pd-catalyzed
cross-coupling reactions.12 Few mechanistic studies have been
performed on the catalytic asymmetric alkynylation of
imines,13 however, even well-established aldimines. We envi-
sioned that the Rh(III)-catalyzed system would be suitable for
mechanistic studies because of the high stability of (phe-
box)Rh(III) complexes, and that such mechanistic studies
To overcome these problems, we previously reported direct
enantioselective alkynylation of α-ketiminoester 2 catalyzed
by (aqua)(diacetato)(phebox)Rh(III) complex
1 (Scheme
1).10,11 Using C2-symmetric indane-substituted (phebox)Rh(III)
complex 1a as the optimal catalyst, the reaction provided α,α-
disubstituted α-amino acid derivatives 4 in high yield and
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Journal of the American Chemical Society
Page 2 of 12
would lead to an improved reaction conditions applicable to
other α-ketiminoesters.
(Scheme 3, equation 1).15 Complex 5a was isolated after col-
1
2
3
4
5
6
7
8
umn chromatography, and was stable in air and moisture. Alt-
hough attempts to obtain single crystal X-ray diffraction struc-
ture of 5a were unsuccessful, related complex 7a (equation 2)
was isolated and its X-ray crystallographic structure deter-
mined (Figure 1). The acetato ligand of 7a was coordinated to
the rhodium center in a κ2 fashion, which is consistent with
related Rh(III) complexes.15
Herein we describe our mechanistic studies on the rhodi-
um(III)-catalyzed direct enantioselective alkynylation of α-
ketiminoesters. We isolated and identified (acetato-
κ2O,O’)(alkynyl)(phebox)Rh(III) complexes, and found that
the generation of this species determined the overall reactivity
of the reaction. We also succeeded in generating this species
via an alkynyl ligand exchange using (acetato-
κ2O,O’)(phebox)(trimethylsilylethynyl)Rh(III) complexes as a
precatalyst. Use of this precatalyst improved the performance
of the reaction compared with the original (diacetato)Rh(III)
complexes, and allowed us to reduce the catalyst loading to as
low as 0.5 mol %. In addition, by acting as precatalysts, less-
reactive α-ketiminophosphonates and cyclic N-sulfonyl
ketiminoesters, which have not previously been reported as
substrates for direct catalytic enantioselective alkynylations,
afforded α,α-disubstituted α-amino acid derivatives in good
yield and enantioselectivity.
Scheme 3. Isolation of (Alkynyl)rhodium(III) Complexes
9
NO2
NO2
Ph
H
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3a
(5.0 equiv)
O
O
O
O
OAc
O
(1)
N
Rh
N
Me
N
Rh
N
toluene
60 ˚C, 6 h
AcO
OH2
O
Ph
1a
5a
53%
Ph
H
3a
(5.0 equiv)
O
O
O
O
O
OAc
Rh
(2)
2. RESULTS AND DISCUSSION
N
Rh
N
N
N
toluene
60 ˚C, 13 h
O
Me
Ph
Ph
2.1 Isolation of (Alkynyl)(phebox)rhodium(III) Com-
plexes and Identification of the Proton Source. We initiated
our mechanistic studies by identifying the proton source in the
catalytic cycle. We first postulated two catalytic cycles with
different proton sources to close the catalytic cycle based on
previous reports (Scheme 2).14,15 In the first catalytic cycle
(cycle 1), (aqua)(diacetato)(phebox)Rh(III) complex 1 reacted
OH2
AcO
Ph
Ph
Ph
7a
48%
1b
with alkynes
3
to give the corresponding (acetato-
κ2O,O’)(alkynyl)(phebox)Rh(III) complex 5, followed by re-
action with α-ketiminoester 2 to give (amido)Rh(III) interme-
diate 6. The resulting intermediate 6 was protonated with ace-
tic acid, which was generated during the formation of 5, to
close the catalytic cycle. In the second cycle (cycle 2), alkyne
3 acted as a proton source instead of acetic acid to give 4 and
regenerate 5.
Scheme 2. Two Possible Catalytic Cycles
–H2O
OAc
1
•
C
N
N
4
Rh
3
AcOH
O
Figure 1. X-ray crystallographic structure of 7a.
O
cycle 1
Me
We then investigated the reactivity of (alkynyl)Rh(III) com-
plex 5a to clarify the proton source acting under the reaction
conditions. Treatment of stoichiometric amounts of 5a and 2
with either acetic acid or alkyne 3a would give product 4a if
such reaction pathways were operative. The results shown in
equations 3 and 4 suggested that the less acidic alkyne 3a (pKa
= 28.8 in DMSO) was the proton source to release the product
4a and close the catalytic cycle, while the more acidic acetic
acid (pKa = 12.6 in DMSO) was not. These findings are con-
sistent with the observation in (phebox)Rh(III)-catalyzed al-
kynylation of dimethyl acetylenedicarboxylate.15 Although
these stoichiometric studies may not completely reflect the
actual catalytic reaction conditions, the conclusion that alkyne
3a acts as the proton source was further supported when 5a
was used as a catalyst under the reaction conditions (equation
5 and Figure 2). Using a catalytic amount of 5a, the reaction
proceeded even in the absence of acetic acid. Addition of a
catalytic amount of acetic acid under the same reaction condi-
tion did not change the reaction rate,16 suggesting that the cata-
Me
R
O
•
O
CO2Et
CF3
C
N
•
Rh
H
C
N
3
Rh
N
N
NCbz
4
OAc
OAc
cycle 2
R
6
R
AcOH
•
Rh
C
N
N
O
O
2
5
Me
To gain further insight into the proton source, we first syn-
thesized (alkynyl)Rh(III) complex 5. We prepared (acetato-
κ2O,O’)(phenylethynyl)(phebox)Rh(III) complex 5a in good
yield by heating 1a with phenylacetylene (3a) in toluene ac-
cording to the reported protocol for analogous complexes
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Journal of the American Chemical Society
of active species from 1a is the rate-limiting step at the initial
lytic cycle 1 is not operative or not kinetically competent with
1
2
3
4
5
6
7
8
the catalytic cycle 2. These results suggest that catalytic cycle
2, in which alkynes 3 act as the proton source, is operative
under the reaction conditions, and support the importance of
alkynes as a proton source in the transition metal-catalyzed
alkynylation reactions under proton-transfer conditions.13,15
stage of the reaction. Thus, when 1a is used, the generation of
5a from 1a determines the overall reactivity of the reaction.
H
Cbz
(a)
Cbz
1a or 5a
(1.5 mol %)
N
N
H
+
F3C
EtO
OEt
F3C
Ph
toluene (0.25 M)
rt
H
Ph
Cbz
O
O
N
O
2
3a
(1.5 equiv)
4a
+
+
F3C
EtO
(3)
5a
2
(1.0 equiv)
toluene-d8
rt, 10 min
Me
OH
Ph
9
O
100"
90"
80"
70"
60"
50"
40"
30"
20"
10"
0"
(1.0 equiv)
4a
not detected
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H
+
+
5a
(4)
2
(1.0 equiv)
4a
54% yield
93% ee
toluene-d8
rt, 15 min
Ph
3a
(1.0 equiv)
5a (2.5 mol %)
AcOH
(0 or 2.5 mol %)
(alkynyl)Rh(III)"5a"
H
Cbz
Cbz
H
OEt
N
O
(diacetato)Rh(III)"1a"
N
+
(5)
F3C
EtO
F3C
toluene (0.25 M)
29 °C
Ph
Ph
O
0"
300"
600"
900"
2
4a
3a
(1.5 equiv)
6me"(min)ꢀ
H
Cbz
(b)
Cbz
N
0.3"
0.25"
0.2"
N
cat. 1a
H
+
F3C
EtO
OEt
F3C
Ph
toluene
rt
Ph
O
O
4a
2
3a
(1.5 equiv)
0.15"
0.1"
w/o"AcOH"
w/"AcOH"
0.3"
0.25"
0.2"
0.15"
0.1"
0.05"
0"
0.05"
0"
[2]0"="0.25"(M)"
[2]0"="0.15"(M)"
0"
500"
1000"
1500"
2000"
2500"
3000"
-me"(s)ꢀ
Figure 2. Reaction profiles using (alkynyl)Rh(III) complex 5a in
the absence or presence of acetic acid. Conditions: [2]0 = 0.25 M,
[3a]0 = 0.375 M, [5a]0 = 6.3 mM, [AcOH]0 = 0 or 6.3 mM, 29 °C.
0"
200"
400"
600"
800"
1000"
1200"
1400"
2.2 Kinetic Experiments. To examine the kinetic aspects of
the reaction, we first performed experiments to examine
whether generation of (alkynyl)Rh(III) complex 5a from (di-
acetato)Rh(III) complex 1a is the slowest step in the catalytic
cycle. Comparison of the reaction profiles of 5a with 1a re-
vealed that the reaction proceeded much faster with 5a than
with 1a (Figure 3 (a)), suggesting that the generation of 5a
from 1a is the slowest step in the overall reaction pathway
when 1a is used as a catalyst. This finding is consistent with
the observation that preparation of (alkynyl)Rh(III) complexes
5 required a reaction temperature of 60 °C, while the alkynyla-
tion reactions of α-ketiminoester 2 proceeded at or below
room temperature. To clarify the presence of induction period
using 1a as catalyst, we performed reaction progress kinetic
analysis under same [e] reaction conditions (Figure 3 (b)),17
and we observed non-overlapped reaction progress curves
using time-scale adjustment protocol,17d in which the rate for
higher initial concentration of 2 ([2]0 = 0.25 M) was faster than
that for lower initial concentration of 2 ([2]0 = 0.15 M) at the
time-adjusted point (t = 360 min), supporting the presence of
induction period using 1a as catalyst. The observed induction
period using 1a as the catalyst also suggests that the formation
0me"(min)ꢀ
Figure 3. (a) Comparison of catalytic activity of Rh(III) complex-
es. Conditions: [2]0 = 0.25 M, [3a]0 = 0.375 M, [1a]0 or [5a]0 =
3.8 mM, room temperature. (b) Same [e] experiments for (diace-
tato)Rh(III) complex 1a (time-scale was adjusted as t + 360 min
for [2]0 = 0.15 M). Conditions: [2]0 = 0.25 or 0.15 M, [3a]0 =
0.375 or 0.275 M, [1a]0 = 6.3 mM, room temperature.
We next investigated the kinetic profiles of the catalytic cy-
cle using (alkynyl)Rh(III) complex 5a as the catalyst.16 We
used 1.25 mol % of 5a as the standard condition for the initial
rate kinetic studies to accurately determine the product for-
mation rate because the reaction was too fast with 2.5 mol %
of the catalyst. The initial rate kinetic studies revealed nearly
the first-order rate dependency for both the catalyst 5a and the
alkyne 3a, suggesting that these species are involved in the
turnover-limiting step of the catalytic cycle. In contrast, the
kinetic profile of α-ketiminoester 2 differed from that of the
above species: no significant rate dependency was observed
when the concentration of 2 was high (0.25–0.13 M), whereas
partial rate dependency was observed when the concentration
of 2 was low (0.13–0.04 M). To further confirm this kinetic
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Journal of the American Chemical Society
Page 4 of 12
under same [e] conditions (time-scale was adjusted as t + 420 s
for [2]0 = 0.15 M). Conditions: [2]0 = 0.25 or 0.15 M, [3a]0 =
0.375 or 0.275 M, [5a]0 = 6.3 mM, 29 °C.
behavior of α-ketiminoester 2, we conducted reaction progress
kinetic analysis according to the reported procedure.17 We
monitored the formation of 4a using 19F NMR spectroscopy to
elucidate overall reaction profile under the standard conditions
where [2]0 = 0.25 M, [3a]0 = 0.375 M and [e] = 0.125 M as
well as a different [e] condition where [2]0 = 0.25 M, [3a]0 =
0.45 M and [e] = 0.20 M. Plots of (d[4a]/dt)/[3a] versus [2]
were curved lines (Figure 4 (a)), suggesting that the reaction
order of [2] is complex, and the shape of the line suggests
saturation kinetic behavior in [2], which is consistent with the
observation in the initial rate kinetic experiments. These re-
sults suggest a change in the resting state between 5 and 6 over
the reaction course, where 6 is the major form at the beginning
of the reaction and 5 is the major form at the late stage of the
reaction.17b The overlay of the plots under different [e] condi-
tions in Figure 4 (a) suggests the first-order dependency for 3a,
which is consistent with the results of the initial rate kinetic
study.17b In addition, time-adjusted overlay of plots under same
[e] conditions (Figure 4 (b))17d indicated that the catalyst 5a is
stable under the reaction conditions.
1
2
3
4
5
6
7
8
We also investigated the kinetic isotope effects18 using 3a
and mono-deuterated phenylacetylene (3a-d) to determine
whether deprotonation of terminal alkynes is involved in the
turnover-limiting step of the catalytic cycle. We observed in-
verse kinetic isotope effects (kH/kD = 0.85) when the reactions
were performed independently with 3a or 3a-d (equations 6
and 7 and Figure 5).16 The result suggests that C–H bond
cleavage is not involved in the turnover-limiting step because
normal kinetic isotope effects (kH/kD > 1) are expected under
such conditions. The observed inverse kinetic isotope effects
could be due to hybridization-induced changes of the terminal
carbon of the alkyne 3 from sp to sp2 in the transition state.19
Based on the fact that hybridization of the carbon on alkynes
changes from sp to sp2 upon coordination to transition metal
complexes, coordination of alkyne 3 to (amido)rhodium(III)
complex 6, rather than deprotonation of the terminal alkyne 3,
would be the turnover-limiting step in the overall catalytic
cycle.20
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H
Cbz
(a)
Cbz
5a
(2.5 mol %)
N
N
H
H
Cbz
5a
Cbz
+
F3C
EtO
OEt
N
N
(1.25 mol %)
F3C
H
Ph
toluene (0.25 M)
29 °C
+
F3C
EtO
(6)
OEt
Ph
O
O
F3C
toluene (0.25 M)
29 °C
Ph
2
3a
(1.5 or 1.8 equiv)
4a
Ph
Ph
O
O
N
3a
(1.5 equiv)
2
4a
0.0009"
0.0008"
0.0007"
0.0006"
0.0005"
0.0004"
0.0003"
0.0002"
0.0001"
0"
D
Cbz
5a
Cbz
N
(1.25 mol %)
D
+
F3C
EtO
(7)
OEt
F3C
toluene (0.25 M)
29 °C
Ph
O
O
3a-d
kH/kD = 0.85
(1.5 equiv)
2
4a-d
0.05"
0.04"
0.03"
0.02"
0.01"
0"
[e]"="0.125"M"
[e]"="0.200"M"
y"="1.448E)04x")"1.750E)05"
R²"="9.990E)01ꢀ
0"
0.05"
0.1"
0.15"
0.2"
0.25"
[2]"(M)ꢀ
y"="1.225E)04x")"1.725E)04"
H
Cbz
(b)
Cbz
N
R²"="9.996E)01ꢀ
N
cat. 5a
H
+
F3C
EtO
OEt
with"3a"
F3C
Ph
toluene
29 °C
with"3a)d"
Ph
O
O
0"
50"
100"
150"
200"
250"
300" 350"
2
3a
(1.5 equiv)
4a
9me"(sec)ꢀ
0.3"
0.25"
0.2"
Figure 5. Kinetic Isotope Effects. Conditions: [2]0 = 0.25 M,
[3a]0 or [3a-d]0 = 0.375 M, [5a]0 = 3.1 mM, 29 °C
[2]0"="0.25"M"
[2]0"="0.15"M"
As the last kinetic experiments, we performed an Eyring
plot analysis to determine the activation energy parameters of
the catalytic cycle. Kinetic experiments using 5a as the cata-
lyst from –30 to 29 °C yielded two lines: one from –30 to –
10 °C and the other from –10 °C to 29 °C (Figure 6a). Each of
the lines yielded the following activation parameters: ΔH‡ =
11.1 kcal mol–1, ΔS‡ = –21.8 cal mol–1 K–1 and ΔG‡ = 17.8 kcal
mol–1 at 29 °C from the former line and ΔH‡ = 5.7 kcal mol–1,
ΔS‡ = –42.5 cal mol–1 K–1 and ΔG‡ = 18.6 kcal mol–1 at 29 °C
from the latter line.16 Such non-linear behavior of the Eyring
plots implies the presence of competitive rate-limiting steps in
the catalytic cycle,21 and we assumed that coordination of the
alkynes would be the latter step (ΔG‡ = 18.6 kcal mol–1)
0.15"
0.1"
0.05"
0"
0"
500"
1000"
1500"
-me"(s)ꢀ
2000"
2500"
3000"
Figure 4. (a) Reaction progress kinetic analysis under different
[e] conditions. Conditions: [2]0 = 0.25 M, [3a]0 = 0.375 or 0.45 M,
[5a]0 = 6.3 mM, 29 °C. (b) Reaction progress kinetic analysis
ACS Paragon Plus Environment

Page 5 of 12
Journal of the American Chemical Society
sence of water.16 In contrast, the presence of additional alkyne
whereas the addition of alkynyl ligand to α-ketiminoester 2
3a facilitated the formation of 5a,16 implying that 3a is in-
volved in the rate-determining step in the formation of 5a.
Taken together, these findings suggest that the formation of 5a
involves the reversible dissociation of water from 1a, followed
by an irreversible deprotonation of terminal alkyne 3, as de-
picted in Scheme 2, although the same process was depicted as
reversible steps in a previous report.15 Additionally, treatment
of product 4b in the presence of (alkynyl)Rh(III) complex 5b
and alkyne 3a did not form any crossover product 4a even at
60 °C (equation 9), suggesting that the formation of 4 from
(amido)rhodium(III) complex 6 is irreversible after protona-
tion of the amido ligand with terminal alkyne 3.
would be the former step (ΔG‡ = 17.8 kcal mol–1) at room tem-
perature, based on the results of the initial rate kinetic experi-
ments. The large negative value of the activation entropy in
the latter step (ΔS‡ = –42.5 cal mol–1 K–1) implies the associa-
tion of molecules in the turnover-limiting step, which is con-
sistent with the assumption that the coordination of alkyne 3 to
(amido)Rh(III) complex 6 is the turnover-limiting step at room
temperature. On the other hand, the Eyring plot for enantio-
meric excesses was a single line between –30 °C and 29 °C,
and yielded the following differential activation parameters:
ΔΔH‡ = –4.1 kcal/mol, ΔΔS‡ = –7.3 cal mol–1 K–1, and ΔΔG‡ =
–1.9 kcal mol–1 at 27 °C (Figure 6b). The result suggests that
differential enthalpy is a major contributor for determining the
enantioselectivity.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NO2
NO2
AcOH
(1.0 + 5.0 equiv)
O
O
O
O
H
Cbz
O
Rh
OAc
Cbz
5a
(2.5 mol %)
(8)
N
N
N
N
Me
H
N
Rh
N
toluene-d8
rt
+
F3C
EtO
OEt
O
AcO
OH2
F3C
Ph
toluene (0.25 M)
–30, –20, –10,
0 or 29 °C
Ph
Ph
5a
1a
not detected
O
O
2
3a
(1.5 equiv)
4a
NO2
(a)ꢀ
$6.5"
O
O
O
$7"
N
Rh
N
Me
from"–10"to"29"°C"
y"="$2886.1x"+"2.2465"
R²"="0.99588ꢀ
$7.5"
$8"
O
from"–30"to"–10"°C"
H
Cbz
N
O
5b
Ar
$8.5"
$9"
+
4a
not detected
(9)
F3C
EtO
3a
(11 equiv)
toluene-d8
60 °C, 18 h
y"="$5601.5x"+"12.655"
Ar
$9.5"
$10"
$10.5"
$11"
$11.5"
R²"="0.99249ꢀ
4b
(Ar = 4-CF3-C6H4-)
Finally, we performed experiments to clarify whether non-
linear effects are present when using (alkynyl)Rh(III) complex
5a as catalyst.16 We observed a liner relationship between the
enantiomeric excess of (alkynyl)Rh(III) complex 5a and that
of 4a, suggesting that 5a acts as monomeric species.
0.003" 0.0032" 0.0034" 0.0036" 0.0038" 0.004" 0.0042" 0.0044"
1/T"(K–1)ꢀ
To support the experimental results of our mechanistic stud-
ies, we performed density functional theory (DFT) calcula-
tions of the key intermediates in the catalytic cycle using (al-
kynyl)Rh(III) complex 5’ bearing an unsubstituted phebox
ligand, N-methoxycarbonyl α-ketiminoester 2’, and alkyne 3a
as a model system (Figure 7).16 Migratory insertion of the phe-
nylethynyl ligand on 5’ to 2’ via a six-membered transition
state (TS1) showed an activation energy barrier of 20.7 kcal
mol–1 at 25 °C, whereas the coordination of 3a to (ami-
do)Rh(III) complex 6’ (TS2) resulted in a transition state en-
ergy of 24.2 kcal mol–1 at 25 °C. The comparable energies
between TS1 and TS2 are in agreement with the presence of
competitive rate-limiting steps based on the activation ener-
gies from the Eyring plot, and the higher energy in TS2 than
in TS1 supports the assumption that coordination of the alkyne
3 is involved in the turnover-limiting step. In addition, depro-
tonation of the coordinated terminal alkyne 3 (TS3) exhibited
a lower activation energy (16.7 kcal mol–1 at 25 °C) than the
coordination step (TS2), supporting the interpretation of the
observed inverse kinetic isotope effects.
5"
(b)ꢀ
4.8"
4.6"
4.4"
4.2"
4"
y"="2076.9x"+"3.6967"
R²"="0.99652ꢀ
3.8"
3.6"
3.4"
3.2"
3"
ꢀꢁꢀꢀꢂꢀ
ꢀꢁꢀꢀꢂꢃꢀ
ꢀꢁꢀꢀꢄꢀ
ꢀꢁꢀꢀꢄꢃꢀ
1/T"(K–1)ꢀ
Figure 6. Eyring plots. (a) Effect of temperature on activation
energies. (b) Effect of temperature on enantioselectivity. Condi-
tions: [2]0 = 0.25 M, [3a]0 = 0.375 M, [5a]0 = 6.3 mM, –30, –20,
–10, 0 or 29 °C.
2.3 Additional Experiments and Proposed Mechanism.
We performed additional experiments to determine the revers-
ibility of the reaction steps. Treatment of (alkynyl)Rh(III)
complex 5a with acetic acid did not yield (diacetato)Rh(III)
complex 1a, but resulted in the recovery of 5a (equation 8),
indicating that the formation of 5a from 1a involves at least
one irreversible step. On the other hand, the dissociation of
water from 1a seems reversible as the formation of 5a in the
presence of additional water was slower than that in the ab-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 12
Ph
tion 11), presumably due to the thermodynamic preference of
aryl-substituted (alkynyl)Rh(III) complex 5a over alkyl-
substituted (alkynyl)Rh(III) complex 5c.
Ph
O
Ph
F3C
Ph
O
1
2
3
4
5
6
7
8
Ph
O
OMe
CF3
H
OMe
OMe
CF3
H
O
N
N
N
N
C
N
N
C
N
C
N
NO2
NO2
Rh
N
Ar
H
Rh
O
Rh
OMe
OMe
O
OMe
3b
O
O
O
O
O
O
(5.0 equiv)
O
O
O
O
O
O
(10)
Me
Me
Me
TS1
N
Rh
N
Me
N
Rh
N
Me
toluene-d8
rt, 30 min
(Ar = 4-CF3-
C6H4-)
O
O
TS2
TS3
ΔG‡ = 20.7 kcal mol–1 ΔG‡ = 24.2 kcal mol–1 ΔG‡ = 16.7 kcal mol–1
Ph
Ar
5a
5b
9
>95%
Figure 7. Transition state of key intermediates by DFT calcula-
tion. Gibbs energies are given at 25 °C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
NO2
H
3c
On the basis of these findings, we propose the mechanism
of Rh(III)-catalyzed direct alkynylation of α-ketiminoester 2
shown in Scheme 4. First, (aqua)(diacetato)(phebox)Rh(III)
O
(5.0 equiv)
O
O
Rh
(11)
N
N
toluene-d8
80 ˚C, 2 h
Me
O
complex
1
reacts with alkyne
3
to give (acetato-
κ2O,O’)(alkynyl)Rh(III) complex 5, as illustrated in Scheme 2,
and this reaction is the rate-limiting step at the initial stage of
the reaction when 1 is used as the catalyst. Once 5 is generated,
it reacts with α-ketiminoester 2 to give (amido)Rh(III) com-
plex 6. After the formation of complex 6, coordination of al-
kyne 3 gives complex 8 and this coordination process is the
turnover-limiting step in the catalytic cycle. Complex 8 then
irreversibly releases product 4 after deprotonation of the coor-
dinated terminal alkyne 3 with the amido ligand.
5c
Ph
not detected
Based on these results, we aimed to develop a new precata-
lyst to promote the alkynyl ligand exchange with both aryl-
and alkyl-substituted alkynes. Examination of several (phe-
box)Rh(III)
complexes
revealed
that
(trimethylsi-
lylethynyl)Rh(III) complex 5d promoted the desired ligand
exchange reactions with both aryl- and alkyl-substituted al-
kynes (equations 12 and 13). Although alkyl-substituted al-
kyne 3c showed equilibrium favorable to the starting complex
5d under stoichiometric reaction conditions, the equilibrium
could be shifted to 5c in the presence of a large excess of 3c
under the actual catalytic reaction conditions.16
Scheme 4. Proposed Reaction Mechanism
Cbz
N
R
OEt
CO2Et
F3C
NO2
NO2
CF3
•
Ph
H
C
N
N
O
2
3a
(5.0 equiv)
Rh
O
NCbz
O
O
O
O
O
Rh
(12)
OAc
R
N
Rh
N
Me
N
N
Me
toluene-d8
rt, 10 min
H
6
O
O
R
SiMe3
5d
Ph
•
C
N
N
3
5a
75%
1
Rh
O
O
Ph
NO2
H
Me
5
R
3c
(5.0 equiv)
O
O
H
O
Rh
O
R
(13)
N
N
Me
H
Cbz
•
Rh
toluene-d8
rt, 10 min
N
C
N
N
CO2Et
CF3
F3C
EtO
NCbz
5c
38%
Ph
OAc
R
O
8
4
We next performed experiments to verify the utility of (tri-
methylsilylethynyl)Rh(III) complex 5d as a general precatalyst
for the alkynylation of α-ketiminoester 2 (Scheme 5). A cata-
lytic amount of 5d promoted the reaction faster than 1a with
an aryl-substituted alkyne 3a, and the catalyst loading of 5d
could be reduced to 0.5 mol % without affecting the yield or
enantioselectivity (equation 14). The reaction with alkyl-
substituted alkyne 3c also gave the desired product 4c in 96%
yield and 87% ee using 2.5 mol % of 5d at 0 °C without pre-
activation of catalyst at 30 °C, which was required in our pre-
vious report with 5 mol % of (diacetato)Rh(III) complex 1a
(equation 15).10 Notably, the formation of trimethylsi-
lylethynyl adduct 4d was not detected under these catalytic
reaction conditions using 5d as the precatalyst.
2.4 Improvement of the Catalytic Activity Using (Trime-
thylsilylethynyl)rhodium(III) Complex as a Precatalyst.
The mechanistic studies described above revealed that effi-
cient generation of (alkynyl)Rh(III) complex 5 is important for
improving the reactivity of the alkynylation reaction. We
therefore sought to develop a better method for generating 5.
We first hypothesized that complex 5a could be used as a sub-
stitute for (diacetato)Rh(III) complex 1a if exchange of the
alkynyl ligand on 5a with other terminal alkynes 3 proceeded
faster than the formation of 5 from 1a and 3. The alkynyl lig-
and exchange indeed proceeded with an aryl-substituted al-
kyne 3b at room temperature within 30 min to give complex
5b in good yield (equation 10). Unfortunately, this was not the
case with an alkyl-substituted alkyne 3c, and no desired com-
plex 5c was observed even at an elevated temperature (equa-
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Journal of the American Chemical Society
Table 2. Substrate Scope of Alkyl-Substituted Alkynes
Scheme 5. Comparison of Reactivity of (Trimethylsi-
1
2
3
4
5
6
7
8
lylethynyl)Rh(III) Complex 5d with (Diacetato)Rh(III)
Complex 1a
Using (Trimethylsilylethyl)Rh(III) Complex 5d
H
Cbz
5d
(2.5 mol %)
Cbz
N
N
H
H
Cbz
5d
(0.5 mol %)
Cbz
N
O
+
OEt
F3C
EtO
N
F3C
toluene (1.0 M)
MS 4A
0 °C, 48 h
R
+
F3C
EtO
(14)
Ph
OEt
3a
(1.5 equiv)
R
F3C
O
O
toluene (0.25 M)
rt, 6 h
O
2
3
(3.0 equiv)
4
2
4a
97% yield, 92% ee
9
OEt
OEt
(with 1a: 8% yield, 92% ee)
OTBS
R =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
Cbz
5d
(2.5 mol %)
Cbz
N
N
4m
93% yield
91% ee
4n
86% yield
93% ee
4o
90% yield
89% ee
4p
92% yield
82% ee
+
F3C
EtO
(15)
Ph
OEt
3c
(3.0 equiv)
F3C
toluene (1.0 M)
MS 4A
0 °C, 48 h
O
O
OH
NHCbz
2
4c
96% yield, 87% ee
NO2
Me Me
4s
98% yield
85% ee
(at rt, 96 h)
H
Cbz
4q
4r
N
O
(with 1a: 8% yield, 89% ee)
92% yield
87% ee
(0.40 mmol scale)
95% yield
80% ee
(at rt)
4d
not detected
F3C
EtO
SiMe3
2.5 Expansion of the Substrate Scope Using the Precata-
lysts. Encouraged by the results using 5d as the precatalyst,
we turned our attention to expanding the substrate scope to
less reactive α-ketiminoesters, which have not been previously
applied to direct catalytic alkynylation reactions. We first ex-
amined Cbz-protected α-ketiminophosphonate 9,22 an analog
of α-ketiminoester, because optically active aminophosphonic
acid derivatives can serve as transition state analogs of the
corresponding amino acids and are important drug candi-
dates.23 We initially screened (diacetato)(phebox)Rh(III) cata-
lysts 1 with different substituents on bis(oxazoline) moiety for
an alkynylation reaction of 9 with alkyne 3a (Table 3),16 and
found that phenyl-substituted (diacetato)(phebox)Rh(III) com-
plex 1b showed better enantioselectivity thanks to the adapta-
ble nature of the (phebox)Rh(III) complexes for different sub-
strates (entries 1–2). Although the reactivity of these (diace-
tato)Rh(III) complexes 1 was low presumably due to slow
generation of the active (alkynyl)Rh(III) species, we anticipat-
ed that the use of (alkynyl)Rh(III) complexes could improve
the reactivity based on the results from the above study for α-
ketiminoester 2. Indeed, we found that both (phe-
Having established the utility of precatalyst 5d, we exam-
ined the full scope of direct catalytic asymmetric alkynylation
of α-ketiminoester 2. The catalyst loading was reduced to as
low as 0.5 mol % with aryl-substituted alkynes 3 without de-
creasing the yield or enantioselectivity (Table 1). A variety of
functional groups were tolerated, including electron-donating
and electron-withdrawing substituents, heterocycles, and
formyl and base-sensitive Fmoc groups.
Table 1. Substrate Scope of Aryl-Substituted Alkynes Us-
ing (Trimethylsilylethyl)Rh(III) Complex 5d
H
Cbz
5d
Cbz
N
N
(0.5 mol %)
H
+
F3C
EtO
OEt
F3C
toluene (0.25 M)
rt, 12 h
R
R
O
O
2
3
4
(1.5 equiv)
R =
Me
OMe
Br
4a
94% yield
92% ee
4e
84% yield
93% ee
4f
4g
nylethynyl)Rh(III)
complex
7a
and
(trimethylsi-
90% yield
92% ee
97% yield
94% ee
lylethynyl)Rh(III) precatalyst 7d promoted the reaction
smoothly at room temperature to give the desired product 10a
in high yield and enantioselectivity (entries 3–4).16 The reac-
tion using corresponding (diacetato)Rh(III) complex 1b as the
catalyst proceeded only sluggishly (entry 2), demonstrating the
advantage of using precatalyst 7d over (diacetato)Rh(III)
complex 1b.16 The reaction was also effective for other aryl-
substituted alkynes with electron-donating or electron-
withdrawing substituents and cyclopropylacetylene (entries 5–
9). The absolute configuration of product 10a was determined
unambiguously by single crystal X-ray diffraction.16
S
CF3
Me
4b
95% yield
93% ee
4h
4i
89% yield
88% ee
90% yield
93% ee
N
Boc
CHO
NHFmoc
4j
4k
4l
92% yield
95% ee
86% yield
95% ee
92% yield
92% ee
Table 3. Optimization of Catalysts and Scope of Alkynes
(1 mol % 5d) (1 mol % 5d in CH2Cl2)
for -Ketiminophosphonate 9
α
Alkyl-substituted terminal alkynes also gave the corre-
sponding propargylamines 4 in high yield and enantioselec-
tivity in the presence of 2.5 mol % of 5d (Table 2). An acid-
sensitive acetal group and a base-sensitive TBS group were
compatible under the reaction conditions. The reaction also
proceeded smoothly with alkynes 3r and 3s bearing acidic
protons.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 12
H
O
O
Cbz
Rh(III) complex
(5 mol %)
Cbz
O
O
N
Rh(III) complex
(5 mol %)
N
S
S
H
1
OEt
OEt
H
F3C
EtO
EtO
+
N
NH
+
2
F3C
P
toluene (0.25 M)
MS 4A
rt
P
R
X
X
toluene (0.25 M)
MS 4A
Ph
O
R
O
3
4
EtO
OEt
Ph
O
O
9
3
(1.5 equiv)
10
11a (X = H)
11b (X = OMe) (3.0 equiv)
11c (X = Cl)
3a
12a (X = H)
12b (X = OMe)
12c (X = Cl)
5
6
7
8
9
O
O
O
O
O
OAc
Rh
7a (R = Ph)
7d (R = SiMe3)
N
Rh
O
N
N
N
O
O
O
O
OAc
Rh
O
Me
13a (R = Ph)
13d (R = SiMe3)
OH2
Ph
Ph
Ph
AcO
Ph
N
Rh
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
1b
Me
OH2
R
Bn
Bn
AcO
Bn
Bn
1c
R
entry
R
Rh(III)
10
time yield
ee
(%)b
complex
(h)
24
24
24
18
18
18
18
18
24
(%)a
17c
8c
entry
X
Rh(III)
temp
time yield
ee
complex
(h)
45
43
45
45
45
48
48
48
48
48
48
48
48
48
(%)a
10c
12c
14c
30c
49c
91
(%)b
1
2
Ph
Ph
Ph
Ph
1a
1b
7a
7d
7d
7d
7d
7d
7d
10a
10a
10a
10a
10b
10c
10d
10e
10f
9
1
2
H
H
H
H
H
H
H
1a
1b
rt
12
92
90
96
91
86
86
67
88
79
88
85
86
87
87
89
88
88
87
88
93
80
rt
3
>95c
3
1c
rt
4
96
4
7a
rt
5
4-Me-C6H4-
91
5
13a
7a
rt
6
4-MeO-C6H4-
4-CF3-C6H4-
2-Me-C6H4-
cyclopropyl
99
6
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
7
97
7
13a
7a
93
8
97
8
OMe
OMe
Cl
74
9d
86
9
13a
7a
96
aIsolated yield. bEnantiomeric excess was determined by HPLC
c
1
analysis with chiral stationary phase. Determined by H NMR
10
11
12
13
14
92
analysis of the crude mixture. d3.0 equiv of alkyne 3 was used.
Cl
13a
13d
13d
13d
96
Next, we applied the precatalyst system to cyclic N-sulfonyl
α-ketiminoesters 11.24 With unsubstituted electrophile 11a (X
= H), we first screened a series of (diacetato)Rh(III) complex-
es 1 (Table 4) and found that both phenyl-and benzyl-
substituted (diacetato)Rh(III) complexes 1b and 1c gave prod-
uct 12a in high enantioselectivity (entries 1–3).16 The use of
(phenylethynyl)Rh(III) complexes 7a and 13a showed im-
provements on reactivity (entries 4–5),25 and the yields were
further increased by raising the temperature to 70 °C while
keeping the enantioselectivity in an acceptable level (entries
6–7). Further examination of related substrates 11b (X =
OMe) and 11c (X = Cl) revealed, however, that benzyl-
substituted (phebox)Rh(III) complex 13a gave higher enanti-
oselectivity (entries 8–11), and we chose 13a as the optimal
catalyst. At last, the use of (trimethylsilylethynyl)Rh(III) com-
plex 13d showed comparable reactivity as expected from the
above studies for α-ketiminoesters 2 and 9 (entries 12–14).
H
98
OMe
Cl
92
90
aIsolated yield. bEnantiomeric excess was determined by HPLC
c
1
analysis with chiral stationary phase. Determined by H NMR
analysis of the crude mixture.
With the optimal precatalyst 13d in hand, we examined
scope of alkynes for cyclic N-sulfonyl α-ketiminoester 11a,
and the corresponding sultam derivatives 12 with tetrasubsti-
tuted carbon stereocenter were obtained in high yield and en-
antioselectivity for both aryl- and alkyl-substituted alkynes 3
(Table 5). The absolute configuration of 12a was determined
by single crystal X-ray analysis after derivatization to the cor-
responding amide.16
Table 5. Scope of Alkynes for Cyclic N-Sulfonyl
Ketiminoester 11a
α
-
Table 4. Optimization of Catalysts for Cyclic N-Sulfonyl -
α
Ketiminoesters 11
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O
O
Author Contributions
O
O
S
NH
13d
(5 mol %)
S
1
‡These authors contributed equally.
H
N
+
2
3
4
5
toluene (0.25 M)
MS 4A
70 °C, 48 h
R
Notes
The authors declare no competing financial interest.
EtO
OEt
R
O
O
12
11a
3
(3.0 equiv)
ACKNOWLEDGMENT
6
7
8
9
This work was supported by Grant-in-Aid for Scientific Research
(B) (24390004), Grant-in-Aid for Scientific Research (C)
(15K07860), Scientific Research on Innovative Area 2707 (Mid-
dle molecular strategy) and Platform for Drug Discovery, Infor-
matics, and Structural Life Science from MEXT, CREST from
JST, Uehara Memorial Foundation and Takeda Science Founda-
tion. K.M. thanks JSPS for Research Fellowships for Young Sci-
entists. We thank Prof. S. N. Osipov for generous discussion on
the synthesis of α-ketiminophosphonates and the research group
of Prof. Hiroshi Suemune at Kyushu University for the use of
their polarimeter.
R =
CF3
Me
OMe
12d
99% yield
86% ee
12e
92% yield
87% ee
12f
10
11
12
13
14
15
16
17
18
19
20
90% yield
78% ee
(96 h)
Ph
Me
12g
98% yield
82% ee
12h
12i
98% yield
84% ee
94% yield
82% ee
(96 h)
REFERENCES
(1) For reviews, see: (a) Cozzi, P. G.; Hilgraf, R.; Zimmer-
mann, N. Eur. J. Org. Chem. 2004, 4095. (b) Trost, B. M.;
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K. In Comprehensive Chirality; Carreira, E. M., Yamamoto, H.,
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(2) For selected examples, see: (a) Huffman, M. A.; Yasuda,
N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995,
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3. CONCLUSION
21
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, we present our mechanistic studies and expan-
sion of the substrate scope of direct enantioselective alkynyla-
tion
ua)(diacetato)(phebox)Rh(III) complex 1a. Based on the
mechanistic analysis, (acetato-
of
α-ketiminoester
2
catalyzed
by
(aq-
κ2O,O’)(alkynyl)(phebox)Rh(III) complex 5a was more active
than 1a and generation of 5a from 1a determined the overall
reactivity. This information, as well as the observed facile
exchange of alkynyl ligand on the (alkynyl)rhodium(III) com-
plexes,
led
us
to
synthesize
(acetato-
κ2O,O’)(trimethylsilylethynyl)(phebox)Rh(III) complex 5d as
a general precatalyst that reacts with both aryl- and alkyl-
substituted terminal alkynes to afford the corresponding (ace-
tato-κ2O,O’)(alkynyl)(phebox)Rh(III) complexes. The new
catalytic system reduced catalyst loading without loss of reac-
tivity, enantioselectivity, or functional group tolerance. The
precatalysts were also effective for less reactive α-
ketiminophosphonate
9
and cyclic N-sulfonyl α-
ketiminoesters 11, both of which could be applied in the direct
catalytic enantioselective alkynylation for the first time. These
successful applications were realized owing to the adaptable
nature of (phebox)Rh(III) complexes for each substrate. Alt-
hough preparation of the (alkynyl)Rh(III) complexes is not
optimal and needs to be improved, we hope the information
revealed from our study could shed light on the future studies
on direct catalytic alkynylation of imines.
ASSOCIATED CONTENT
Supporting Information
Supporting Information Available: Experimental procedures,
characterization of compounds and computational details (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*ohshima@phar.kyushu-u.ac.jp, hmorimot@phar.kyushu-u.ac.jp
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(25) Limited improvements on reactivity using (al-
Chem.—Eur. J. 2013, 19, 9447. (c) Takizawa, S.; Arteaga, F.
1
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8
A.; Yoshida, Y.; Suzuki, M.; Sasai, H. Asian J. Org. Chem.
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kynyl)Rh(III) complexes in the case of substrate 11a may be
due to the innate reactivity of 11a compared with other α-
ketiminoesters 2 and 9. Even in this case, however, the use of
(alkynyl)Rh(III) complexes was superior over (diace-
tato)Rh(III) complexes because of the difficulty in separation
of the starting material 11 and product 12; while the (al-
kynyl)Rh(III) complexes promoted the reactions to full con-
version, (diacetato)Rh(III) complexes were not able to achieve
full conversion under identical reaction conditions.
9
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OAc
•
H
Cbz
cat.
O
N
slow
C
N
N
O
O
Rh
Rh
F3C
EtO
OH2
N
N
Me
R3
PG
R3
OAc
previous work
SiMe3
O
O
N
R
R
H
Cbz
N
SiMe3
R1 R2
+
•
(0.5–5 mol %)
F3C
EtO
EtO
C
N
Rh
P
R3
via
proton transfer
O
N
O
•
H
C
N
N
O
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11
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O
Rh
O
R3
up to 98% yield
up to 95% ee
33 examples
Me
S
O
N
H
O
X
fast
Me
This Work
• improved reactivity
• expanded substrate scope
EtO
R3
O
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