Iminophosphorane-mediated regioselective umpolung alkylation reaction of α-iminoesters

Article abstract of DOI:10.1039/d1ob00596k

Umpolung reactions of imines, especially the asymmetric reactions, have been extensively studied as they provide access to important chiral amines in an efficient manner. The reactions studied range from simple Michael reactions to several kinds of other reactions such as the aza-benzoin reaction, aza-Stetter reaction, addition with MBH carbonate, and Ir-catalysed allylation. Herein, we report the first umpolung alkylation reaction of α-iminoesters with alkyl halides mediated by iminophosphorane as an organic superbase. The desired products were obtained in up to 82% yield with almost perfect regioselectivities. The key to the regioselectivity of this reaction was the use of 4-trifluoromethyl benzyl imines as a substrate. The products were successfully derivatised into the more functionalised molecules in good yields.

Full text of DOI:10.1039/d1ob00596k

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Iminophosphorane-mediated regioselective
umpolung alkylation reaction of α-iminoesters†
Cite this: DOI: 10.1039/d1ob00596k
Yasushi Yoshida, * Mayu Kukita, Kazuki Omori, Takashi Mino
Masami Sakamoto
and
Umpolung reactions of imines, especially the asymmetric reactions, have been extensively studied as they
provide access to important chiral amines in an efficient manner. The reactions studied range from simple
Michael reactions to several kinds of other reactions such as the aza-benzoin reaction, aza-Stetter reac-
tion, addition with MBH carbonate, and Ir-catalysed allylation. Herein, we report the first umpolung alkyl-
ation reaction of α-iminoesters with alkyl halides mediated by iminophosphorane as an organic superb-
ase. The desired products were obtained in up to 82% yield with almost perfect regioselectivities. The key
to the regioselectivity of this reaction was the use of 4-trifluoromethyl benzyl imines as a substrate. The
products were successfully derivatised into the more functionalised molecules in good yields.
Received 29th March 2021,
Accepted 30th April 2021
DOI: 10.1039/d1ob00596k
rsc.li/obc
the phase-transfer catalysed asymmetric umpolung Michael/
cascade reaction of α-imino carbonyl compounds with various
Introduction
Umpolung reactions have been utilised as an efficient method α,β-unsaturated carbonyls to afford the corresponding amino
for the preparation of complex molecules.1 Catalytic umpolung acid derivatives, enamides, and aminals in high yields and
reactions, especially the asymmetric umpolung reactions of with high enantioselectivities (Fig. 1).13 Despite the extensive
aldehydes such as the benzoin reaction2 and Stetter reaction,3 research in this area, transition metal-free umpolung alkyl-
have been extensively studied in the presence of chiral NHC ation of imines with alkyl halides still remains unexplored.
catalysts. Many excellent chiral catalysts have been developed
so far, and the chemistry has been expanded to other classes
of reactions such as the homoenolate reactions,4 cross benzoin
reactions,5 and radical coupling reactions.6
The asymmetric umpolung reaction of imines is of great
importance because useful chiral amines can be obtained in
an efficient manner.7–9 In 2015, Deng and co-workers devel-
oped the first catalytic asymmetric umpolung reaction of aldi-
mines and trifluoromethyl ketimines with Michael acceptors
via chiral phase-transfer catalysis; the products were obtained
in high yields with excellent stereoselectivities (Fig. 1).7a
Following their study, the research on asymmetric umpolung
reaction of imines was expanded to the addition with MBH
adducts,8 allylation of carbonates,9a and the aza-benzoin10 and
aza-Stetter reactions.11 Recently, Weng, Lin, and Lu et al.
reported the first asymmetric umpolung cross-Mannich reac-
tion of imines with cyclic ketimines catalysed by a bifunctional
organocatalyst; the corresponding products were obtained in
high yields with up to 99% ee (Fig. 1).12 We previously reported
Molecular Chirality Research Center, Graduate School of Engineering, Chiba
University, 1-33, Yayoi-cho, Inage-ku, Chiba-shi, Chiba 263-8522, Japan.
E-mail: yoshiday@chiba-u.jp
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00596k
Fig. 1 Metal-free umpolung reaction of imines.
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Herein, we report the first highly regioselective umpolung
alkylation of α-iminoesters with alkyl halides mediated by imi-
nophosphoranes14 as an organic superbase. α-Tetrasubstituted
α-amino acids were obtained in high yields with excellent
regioselectivities and were derivatised into useful molecules.
Furthermore, the origin of the regioselectivity of the umpolung
reaction was investigated based on the density functional
theory (DFT) calculations.
Organic & Biomolecular Chemistry
Table 1 Optimisation of reaction conditions for umpolung alkylation of
α-iminoester 1a with benzyl bromide (2a)a
Entry
Solvent
Temp. (°C)
Yield of 4a b (%)
Yield of 7a b (%)
1c
2c
3
4
5
Et2O
THF
CH2Cl2
CHCl3
MeCN
MeCN
MeCN
−20
−20
−20
−20
−20
−30
0
15
11
28
5
11
10
25
5
Results and discussion
First, the umpolung alkylation reaction of (4-nitrobenzyl)
imino ester 1a with benzyl bromide (2a) was conducted under
our previously optimised chiral phase-transfer conditions
using 3 as a catalyst; the same substrate was used previously
for the umpolung Michael reaction (Scheme 1).13b
Unfortunately, the desired umpolung alkylation product 4a
was not obtained, and only isomerised product 5a was gener-
ated as the main product. Thus, the previously used catalytic
system was inappropriate for the present alkylation reaction.
Next, the same reaction was conducted in diethyl ether in
the presence of iminophosphorane 6, a strong Brønsted base.
Consequently, the desired product 4a and its regioisomer 7a
were obtained in 15% and 11% yields (Table 1, entry 1),
respectively. Following this, various solvents and temperatures
were screened. At −20 °C, low product yields were obtained in
non-polar solvents such as chloroform, while good yields of 4a
were obtained in polar solvents such as dichloromethane,
THF, and acetonitrile (entries 2–5).
40d
40
40
52d
40
39
6
7
a Reactions were performed with 1a (1.0 eq.), 2a (2.0 eq.), and 6 (1.0
eq.) in an appropriate solvent (0.05 M), unless otherwise stated. b 1H
NMR yields using 1,3,5-trimethoxybenzene as an internal standard.
c Reaction time was 48 hours. d Isolated product yields.
Table 2 Substrate optimisation of the umpolung alkylation of
α-iminoester 1 with benzyl halide (2)a
The product yields at −30 °C and 0 °C were lower than that
at −20 °C (entries 6 and 7). Although, the desired product 4a
was obtained in moderate yield, the regioselectivities of 4a and
7a were still low.
To improve the regioselectivity of the reaction, the substrate
was optimised (Table 2). Although tert-butyl ester 1a gave 4a
with almost no regioselectivity (entry 1), the reaction with
methyl ester 1b gave 4b in 54% isolated yield, together with 7b
at a 4b : 7b ratio of 4.5/1 (entry 2). With a benzyl imine moiety,
(4-trifluoromethylbenzyl) imine 1c gave 4c in 68% yield with
almost perfect regioselectivity (entry 3). Finally, benzyl iodide
(2b) was employed as a highly active reactant, and the desired
Yield of 4 or Regioisomeric ratio (4
8
Entry R1
R2
X
Base
b (%)
or 8/7)c
1
2
NO2 tBu Br
NO2 Me Br
CF3 tBu Br
6
6
6
6
40 (4a)
54 (4b)
68 (4c)
82 (8a)
1/1.3
4.5/1
>20/1
>20/1
—
3
4d
5d
6d
7d
CF3 tBu
CF3 tBu
CF3 tBu
CF3 tBu
I
I
I
I
K2CO3 N. R.
Et3N
DBU
Trace
30 (8a)
—
>20/1
a Reactions were performed with 1 (1.0 eq.), 2 (2.0 eq.), and a base (1.0
eq.) in MeCN (0.05 M) at −20 °C, unless otherwise stated. b Yields of
1
isolated products. c Determined by H NMR analyses of crude adducts.
d
8a was isolated without NaBH4 reduction.
product 8a was isolated in 89% yield even without NaBH4
reduction due to high stability of product itself (entry 4).15
With the optimal substrate in hand, the base was screened
next (Table 2, entries 5–7). The yield of 8a was lower in the
presence of DBU than in the presence of iminophosphorane 6.
Scheme 1 Chiral phase-transfer catalysed umpolung alkylation of
α-iminoester 1a.
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The use of triethylamine or potassium carbonate either gave a
trace amount of the desired products or no product at all.
Thus, iminophosphorane 6 was determined to be the optimal
base for this reaction.
Next, the substrate was screened under the optimal con-
ditions (Scheme 2). Both electron-donating and electron-with-
drawing substituents on the aryl group of the imine moiety
were well tolerated in this reaction, forming the corresponding
products 8a–8k in high yields with excellent regioselectivities.
Longer reaction times were required for methoxy-substituted
8f and 8g (36 hours) probably due to their low reactivities.
Only o-tolyl substituted 8d was obtained as a regioisomeric
mixture, probably due to its steric hinderance.
The scope of the electrophiles was investigated next
(Scheme 3). The benzyl iodide derivatives could be successfully
employed for the present transformation, irrespective of their
steric and electronic nature, to give the corresponding pro-
ducts in 70–82% isolated yields. Other activated electrophiles
such as allyl iodide also reacted smoothly to give 8t in high
yields and high regioselectivities, irrespective of its steric and
electronic nature. However, the use of propargyl bromide and
1-iodobutane gave complex mixture or did not afford any alkyl-
ation products.
Scheme 3 Electrophile
scope for the umpolung alkylation
α-iminoester (1c). Unless noted, reactions were performed with 1c (1.0
eq.), 2 (2.0 eq.), and 6 (1.0 eq.) in MeCN (0.05 M) at −20 °C for 24 hours.
Yields of isolated products are shown. aReactions were conducted for
12 hours. bPropargyl bromide was used as an electrophile.
To demonstrate the applicability of the present reaction,
the products were derivatised (Scheme 4). The reduction of 8a
was conducted in the presence of LiAlH4 in THF at 0 °C to
afford the corresponding amino alcohol 10 in 72% yield. The
Mukaiyama–Mannich reaction of 8a with silyl ketene acetal 11
was conducted in the presence of a catalytic amount of
TBSOTf to afford 12 in a good yield and with a good diastereo-
meric ratio.
To gain mechanistic insights into the present umpolung
alkylation reaction, control experiments were conducted
(Scheme 5). Although an α-iminoester can be easily isomerised
into the corresponding aldiminoester under basic conditions,
Scheme 2 Scope of α-iminoester for the umpolung alkylation with
benzyl iodide (2b). Reactions were performed with 1 (1.0 eq.), 2b (2.0
eq.), and 6 (1.0 eq.) in MeCN (0.05 M) at −20 °C for 24 hours, unless
otherwise stated. Yields of isolated products are shown. aReactions were
conducted for 36 hours.
Scheme 4 Derivatisation of α-tetrasubstituted-iminoester 8a.
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Scheme 5 Control experiments.
Scheme 7 Synthesis of chiral iminophosphorane precursor.
for the benzylation of 1c′, affording the desired product 4c′ in
a low yield with racemic form.
it was speculated that the present reaction was not a direct
alkylation reaction but an isomerization reaction followed by
alkylation. To verify this possibility, aldiminoester 13c was syn-
thesised by the treatment of 1c with a catalytic amount of DBU
and employed as a substrate along with benzyl iodide under
the optimal conditions. After 30 minutes of the reaction,
product 8a was obtained in 65% yield when 1c was used as the
substrate. On the other hand, the same product was obtained
in only 26% yield when 13c was used as the substrate. This
confirmed that the present reaction scarcely involved an iso-
merization step.
To gain insights into the origin of the characteristic regio-
selectivity of the present reaction, DFT calculations were per-
formed (Scheme 6). Both 4-nitrobenzyl imine-derived anion 14
and 4-trifluoromethylbenzyl imine-derived anions 15 were
optimised in acetonitrile by Gaussian (RB3LYP/6-31+G(d,p)),17
and the atomic polar tensor (APT) charge distributions18 for
C1 and C3 were compared. The APT charges for C1 and C3
were found to be almost same for 14, while the APT charge for
C1 was considerably negatively than that for C3 in the case of
15. The higher electron density on the carbon atom ascertains
higher nucleophilicity of a moiety, thus explaining the experi-
mentally observed excellent regioselectivity of this reaction.
The preliminary attempt for the asymmetric umpolung
reaction is shown in Scheme 8. The cyclohexyl diamine-
derived chiral iminophosphorane precursor 20·HCl was syn-
thesised from the known compound 16 in 4 steps (Scheme 7),
and employed with sodium hexamethyldisilazide (NaHMDS)
Conclusions
In conclusion, the umpolung alkylation reactions of
α-iminoesters with alkyl iodides were accomplished using imi-
nophosphorane 6 as an organic superbase to afford the
desired products in up to 82% yield. The key to the excellent
regioselectivity of the present reaction was the use of
4-trifluoromethylbenzyl imines as the substrate instead of the
previously used 4-nitrobenzyl imines. DFT calculations of the
2-azaallyl anion intermediate revealed that the APT charge dis-
tributions of the 4-trifluoromethylbenzyl imine-derived anion
had a superior balance for the excellent umpolung selectivity.
The products were successfully derivatised into the more func-
tionalised molecules in good yields. Further applications of
our present transformation into asymmetric synthesis of chiral
amines are ongoing.19
Experimental
1H-, 13C-, 19F-, 31P-NMR spectra were recorded with Bruker
AVANCEIII-400 M (1H-NMR 400 MHz, 13C-NMR 100 MHz,
19F-NMR 376 MHz, 31P-NMR 122 MHz). 1H-NMR spectra are
reported as follows: chemical shift in ppm (δ) relative to the
chemical shift of CHCl3 at 7.26 ppm or TMS at 0.00 ppm, inte-
gration, multiplicities (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), and coupling constants (Hz). 13C-NMR
spectra reported in ppm (δ) relative to the central line of triplet
for CDCl3 at 77 ppm. CF3CO2H used as external standards for
19F-NMR. ESI-MS spectra were obtained with Thermo Fisher,
Exactive. Optical rotations were measured with JASCO P-2100
polarimeter. HPLC analyses were performed on a JASCO HPLC
system (JASCO PU 980 pump and UV-975 UV/Vis detector).
FT-IR spectra were recorded on a JASCO FT-IR system (FT/
IR-460 Plus). Mp was measured with AS ONE ATM-02. Column
chromatography on SiO2 and neutral SiO2 was performed with
Scheme 6 pKa values16 of 1 and APT charge distributions in 14 and 15
computed at RB3LYP/6-31+G(d,p) in MeCN.
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Kanto Silica Gel 60 (40–50 μm). All reactions were carried out 134.00, 131.43, 129.49 (q, J = 32.4 Hz), 128.70, 128.18, 127.44,
under Ar atmosphere unless otherwise noted. Commercially 125.42 (q, J = 3.69 Hz), 124.31 (q, J = 273.13 Hz), 57.93, 52.07;
available organic and inorganic compounds were used without 19F-NMR (377 MHz, chloroform-D) δ −62.34; HRMS (ESI+ in
+
further purification. All dehydrated solvents were purchased MeCN) calcd for C17H15F3NO2 (M + H) 322.1049 found
from Wako Pure Chemical Industries, Ltd, and were used 322.1043; IR (NaCl) ν 3029, 2955, 1917, 1733, 1633, 1620, 1580,
without further purification. Catalysts 3 was prepared accord- 1495, 1449, 1434 cm−1
.
ing to the reported procedure.13c Iminophosphorane 6 was pre-
4-Trifluoromethyl benzylamine (2.0 eq.), α-iminoesters (1.0
eq.), MS 4A (300 g mol−1) in CHCl3 (0.2 M) was added AcOH
(3.0 eq.). After that the reactions were stirred for overnight at
room temperature. The reactions were quenched by the
pared according to the reported procedure.14a
Synthesis of alkyl halides
Propargyl bromide and allyl iodide were purchased, and other addition of NaHCO3 aq., extracted with CH2Cl2, dried over
alkyl iodides were synthesised as follows. Na2SO4, filtered and solvents were removed under vacuum to
To a solution of Ph3P (1.5 eq.) in CH2Cl2 (0.2 M), I2 (1.5 eq.) give crude material. The crude products were purified by
and DMAP (40 mol%) were added and stirred for 2 minutes at column chromatography (neutral silica-gel, ethyl acetate/
room temperature. Then, the corresponding alkyl alcohol (1.0 hexane) to give the corresponding α-iminoesters 1d–1m.
eq.) was added and stirred for 2 hours at room temperature.
tert-Butyl
(Z)-2-(p-tolyl)-2-((4-(trifluoromethyl)benzyl)imino)
The solvent was removed under vacuum to give crude material. acetate (1d). White solid, 0.135 g, 0.359 mmol, 72%
The crude product was purified by column chromatography (0.499 mmol scale reaction); 1H-NMR (400 MHz, chloroform-
(silica-gel, ethyl acetate/hexane) to give the corresponding alkyl D) δ 7.68–7.70 (m, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0
iodide 2. The NMR data for the synthesised alkyl iodides were Hz, 2H), 7.22–7.24 (m, 2H), 4.80 (s, 2H), 2.40 (s, 3H), 1.61 (s,
matched with the reported values.20
9H); 13C-NMR (101 MHz, chloroform-D) δ 165.03, 161.65,
143.09, 141.58, 131.42, 129.63 (q, J = 23.1 Hz), 129.32, 128.13,
127.27, 125.30 (q, J = 3.7 Hz), 124.21 (q, J = 271.5 Hz), 84.31,
Synthesis of α-ketoesters
All α-ketoesters were purchased or synthesised according to 57.07, 28.28, 21.51; 19F-NMR (376 MHz, chloroform-D) δ
the reported procedure.21
−62.40; HRMS (ESI+ in MeCN) calcd for C21H23O2NF3+ (M + H)
378.1675 found 378.1666; IR (KBr) ν 2968, 2856, 1675, 1601,
1520, 1348, 1049 cm−1; m.p. 84–85 °C.
General procedure for the synthesis of α-iminoester 1
1a and 1b were synthesised according to the reported proce-
dure.13a Other α-iminoesters were synthesised as follows.
tert-Butyl (Z)-2-(m-tolyl)-2-((4-(trifluoromethyl)benzyl)imino)
acetate (1e). Colorless oil, 0.158 g, 0.419 mmol, 77%
4-Trifluoromethyl benzylamine (2.0 eq.), α-ketoesters (1.0 (0.545 mmol scale reaction); 1H-NMR (400 MHz, chloroform-
eq.) in CHCl3 (0.2 M) was added AcOH (1.0 eq.). After that the D) δ 7.60–7.65 (m, 3H), 7.50–7.57 (m, 3H), 7.27–7.34 (m, 2H),
reactions were stirred for overnight under reflux condition. 4.81 (s, 2H), 2.39 (s, 3H), 1.62 (s, 9H); 13C-NMR (101 MHz,
The reactions were quenched by the addition of NaHCO3 aq., chloroform-D) δ 164.96, 161.97, 142.95, 138.40, 134.04, 131.99,
extracted with CH2Cl2, dried over Na2SO4, filtered and solvents 129.19 (q, J = 33.1 Hz), 128.45, 128.17, 127.67, 125.33 (q, J = 3.4
were removed under vacuum to give crude material. The crude Hz), 124.66, 124.19 (q, J = 273.2 Hz), 84.48, 57.07, 28.29, 21.42;
products were purified by column chromatography (neutral 19F-NMR (376 MHz, chloroform-D) δ −62.42; HRMS (ESI+ in
+
silica-gel, ethyl acetate/hexane) to give the corresponding MeCN) calcd for C21H23O2NF3 (M + H) 378.1675 found
α-iminoesters 1c and 1c′.
tert-Butyl (Z)-2-phenyl-2-((4-(trifluoromethyl)benzyl)imino) 1151 cm−1
acetate (1c). Colorless oil, 0.272 g, 0.749 mmol, 98% tert-Butyl (Z)-2-(o-tolyl)-2-((4-(trifluoromethyl)benzyl)imino)
378.1664; IR (NaCl) ν 2981, 2936, 1734, 1607, 1331, 1223,
.
(0.767 mmol scale reaction); 1H-NMR (400 MHz, chloroform- acetate (1f). White solid, 0.256 g, 0.678 mmol, 68%
D) δ 7.83 (d, J = 6.8 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.55 (d, J = (0.998 mmol scale reaction); 1H-NMR (400 MHz, chloroform-
8.1 Hz, 2H), 7.43–7.52 (m, 3H), 4.86 (s, 2H), 1.65 (s, 9H); D) δ 7.57 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.31–7.35
13C-NMR (101 MHz, chloroform-D) δ 164.87, 161.72, 143.06, (m, 1H), 7.25–7.27 (m, 2H), 7.02–7.05 (m, 1H), 4.53 (s, 2H),
134.15, 131.16, 129.76 (q, J = 32.4 Hz), 128.62, 128.18, 127.37, 2.17 (s, 3H), 1.50 (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ
125.36 (q, J = 3.68 Hz), 124.27 (q, J = 273.1 Hz), 84.46, 57.19, 165.28, 163.34, 142.66, 134.92, 134.14, 130.24, 129.13, 129.08
28.33; 19F-NMR (377 MHz, chloroform-D) δ −62.39; HRMS (q, J = 32.5 Hz), 128.01, 126.62, 125.89, 125.29 (q, J = 3.7 Hz),
+
(ESI+ in MeCN) calcd for C20H21F3NO2 (M + H) 364.1519 124.18 (q, J = 274.2 Hz), 82.80, 57.06, 27.83, 19.39; 19F-NMR
found 364.1513; IR (NaCl) ν 3065, 2981, 2936, 1726, 1633, (376 MHz, chloroform-D) δ −62.43; HRMS (ESI+ in MeCN)
1620, 1578, 1478, 1449, 1418 cm−1
.
calcd for C21H23O2NF3 (M + H) 378.1675 found 378.1675; IR
+
Methyl
acetate (1c′). Colorless oil, 0.174 g, 0.542 mmol, 89% m.p. 71–72 °C.
(Z)-2-phenyl-2-((4-(trifluoromethyl)benzyl)imino) (KBr) ν 2982, 2932, 1732, 1647, 1617, 1416, 1152 cm−1
;
1
(0.61 mmol scale reaction); H-NMR (400 MHz, chloroform-D)
tert-Butyl
(Z)-2-(naphthalen-2-yl)-2-((4-(trifluoromethyl)
δ 7.77 (d, J = 6.8 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.50 (d, J = benzyl)imino)acetate (1g). White solid, 0.084 g, 0.204 mmol,
1
8.1 Hz, 2H), 7.38–7.46 (m, 3H), 4.76 (s, 2H), 3.95 (s, 3H); 87% (0.234 mmol scale reaction); H-NMR (400 MHz, chloro-
13C-NMR (101 MHz, chloroform-D) δ 165.73, 161.26, 142.91, form-D) δ 8.11 (d, J = 3.6 Hz, 1H), 8.05 (dd, J = 8.7, 1.8 Hz, 1H),
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7.85–7.90 (m, 3H), 7.63 (d, J = 8.1 Hz, 2H), 7.51–7.57 (m, 4H), (ESI+ in MeCN) calcd for C20H20O2NClF3 (M + H) 398.1129
4.88 (s, 2H), 1.67 (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ found 398.1124; IR (NaCl) ν 2991, 2871, 1718, 1634, 1490,
164.96, 161.81, 142.98, 134.64, 132.70, 131.55, 129.23 (q, J = 1329, 815 cm−1; m.p. 78–79 °C.
+
32.7 Hz), 128.93, 128.57, 128.49, 128.18, 127.77, 127.57,
tert-Butyl (Z)-2-(4-fluorophenyl)-2-((4-(trifluoromethyl)benzyl)
126.58, 125.37 (q, J = 3.7 Hz), 124.22 (q, J = 273.6 Hz), 123.48, imino)acetate (1l). Colorless oil, 0.112 g, 0.295 mmol, 73%
84.54, 57.31, 28.34; 19F-NMR (376 MHz, chloroform-D) δ (0.502 mmol scale reaction); 1H-NMR (400 MHz, chloroform-
−62.40; HRMS (ESI+ in MeCN) calcd for C24H23O2NF3+ (M + H) D) δ 7.78–7.80 (m, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0
414.1675 found 414.1670; IR (KBr) ν 2989, 2936, 1729, 1624, Hz, 2H), 7.09–7.13 (m, 2H), 4.80 (s, 2H), 1.62 (s, 9H); 13C-NMR
1328, 1155, 1066 cm−1; m.p. 78–79 °C.
tert-Butyl
(101 MHz, chloroform-D) δ 164.63, 164.58 (d, J = 250.0 Hz),
(Z)-2-(4-methoxyphenyl)-2-((4-(trifluoromethyl) 160.39, 142.90, 130.47 (d, J = 2.9 Hz), 129.45 (d, J = 8.8 Hz),
benzyl)imino)acetate (1h). White solid, 0.119 g, 0.303 mmol, 129.33 (q, J = 34.3 Hz), 128.14, 125.37 (q, J = 3.7 Hz), 124.21 (q,
1
65% (0.466 mmol scale reaction); H-NMR (400 MHz, chloro- J = 274.2 Hz), 115.73 (d, J = 22.0 Hz), 4.64, 57.14, 28.31;
form-D) δ 7.74–7.76 (m, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.51 (d, J 19F-NMR (377 MHz, chloroform-D) δ −62.52, −108.65; HRMS
= 8.1 Hz, 2H), 6.92–6.95 (m, 2H), 4.79 (s, 2H), 3.85 (s, 3H), 1.62 (ESI+ in MeCN) calcd for C20H20F4NO2 (M + H) 382.1425
+
(s, 9H); 13C-NMR (101 MHz, chloroform-D) δ 165.13, 161.92, found 382.1423; IR (NaCl) ν 2991, 1722, 1636, 1508, 1329,
161.09, 143.24, 128.99, 128.87 (q, J = 73.3 Hz), 128.11, 126.84, 1154, 1066 cm−1
.
125.29 (q, J = 3.7 Hz), 124.22 (q, J = 273.6 Hz), 113.95, 84.27,
tert-Butyl (Z)-2-(3-chlorophenyl)-2-((4-(trifluoromethyl)benzyl)
56.97, 55.39, 28.29; 19F-NMR (376 MHz, chloroform-D) δ imino)acetate (1m). Colorless oil, 0.333 g, 0.838 mmol, 84%
−62.40; HRMS (ESI+ in MeCN) calcd for C21H23O3NF3+ (M + H) (0.997 mmol scale reaction); 1H-NMR (400 MHz, chloroform-
394.1625 found 394.1615; IR (KBr) ν 2985, 2933, 1718, 1604, D) δ 7.83–7.84 (m, 1H), 7.60–7.63 (m, 3H), 7.51 (d, J = 8.4 Hz,
1513, 1329, 1065 cm−1; m.p. 85–86 °C.
tert-Butyl
2H), 7.43–7.46 (m, 1H), 7.34–7.38 (m, 1H), 4.82 (s, 2H), 1.63 (s,
(Z)-2-(3-methoxyphenyl)-2-((4-(trifluoromethyl) 9H); 13C-NMR (101 MHz, chloroform-D) δ 164.24, 160.32,
benzyl)imino)acetate (1i). Colorless oil, 0.276 g, 0.702 mmol, 142.60, 135.91, 134.81, 131.12, 129.85, 129.36 (q, J = 33.9 Hz),
1
69% (1.016 mmol scale reaction); H-NMR (400 MHz, chloro- 128.16, 127.28, 125.58, 125.41 (q, J = 3.4 Hz), 124.17 (q, J =
form-D) δ 7.61 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 273.7 Hz), 84.87, 57.22, 28.25; 19F-NMR (376 MHz, chloroform-
7.40–7.41 (m, 1H), 7.30–7.36 (m, 2H), 7.01–7.04 (m, 1H), 4.82 D) δ −62.45; HRMS (ESI+ in MeCN) calcd for C20H20O2NClF3
+
(s, 2H), 3.84 (s, 3H), 1.62 (s, 9H); 13C-NMR (101 MHz, chloro- (M + H) 398.1129 found 398.1127; IR (NaCl) ν 2982, 2936,
form-D) δ 164.82, 161.59, 159.69, 142.88, 135.45, 129.58, 1726, 1371, 1326, 1152, 1057 cm−1
129.20 (q, J = 33.7 Hz), 128.16, 125.32 (q, J = 3.7 Hz), 124.20 (q,
.
J = 272.1 Hz), 120.13, 117.57, 111.58, 84.45, 57.17, 55.33, 28.26;
General procedure for Tables 1 and 2
19F-NMR (376 MHz, chloroform-D) δ −62.42; HRMS (ESI+ in
Base (1.0 eq.) solution in appropriate solvent was stirred at the
designated temperature for 10 minutes. Then the α-iminoester
1 (1.0 eq., 0.15 M) in the same solvent and benzyl halides 2
were successively added. The reaction was vigorously stirred at
the same temperature for 24 hours, which was passed the
short silica-gal pad (neutral silica-gel, EtOAc) to give the crude
products. The crude product was dissolved in CH2Cl2 (0.05 M)
and EtOH (0.5 M) at −20 °C, and NaBH4 (5.0 eq.) was added.
The reaction was continued for 1 hour, which was quenched
by the addition of excess AcOH (until the gas evolution
stopped), and stirred for 10 minutes. Then it was neutralised
by NaHCO3 aq., extracted by CH2Cl2, dried over Na2SO4 and fil-
tered to give crude 4 and 7, which was purified by column
chromatography (silica-gel, ethyl acetate/hexane) to give the 4
and 7. 8 was obtained without the treatment of NaBH4.
+
MeCN) calcd for C21H23O3NF3 (M + H) 394.1625 found
394.1620; IR (NaCl) ν 2980, 2936, 1724, 1582, 1325, 1149,
1066 cm−1
.
tert-Butyl (Z)-2-((4-(trifluoromethyl)benzyl)imino)-2-(4-(tri-
fluoromethyl)phenyl)acetate (1j). Colorless oil, 0.108 g,
0.251 mmol, 81% (0.310 mmol scale reaction); 1H-NMR
(400 MHz, chloroform-D) δ 7.91 (d, J = 8.1 Hz, 2H), 7.69 (d, J =
8.1 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H),
4.85 (s, 2H), 1.63 (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ
164.12, 160.36, 142.53, 137.41, 132.69 (q, J = 32.0 Hz), 129.46
(q, J = 32.7 Hz), 128.16, 127.69, 125.57 (q, J = 3.7 Hz), 125.43
(q, J = 3.7 Hz), 124.15 (q, J = 273.57 Hz), 123.69 (q, J = 273.6
Hz), 84.98, 57.39, 28.30; 19F-NMR (377 MHz, chloroform-D) δ
+
−62.44, −62.93; HRMS (ESI+ in MeCN) calcd for C21H20O2NF6
(M + H) 432.1393 found 432.1387; IR (NaCl) ν 2983, 1729,
1372, 1327, 1129, 1067, 1017 cm−1
.
General procedure for Schemes 2 and 3
tert-Butyl (Z)-2-(4-chlorophenyl)-2-((4-(trifluoromethyl)benzyl)
imino)acetate (1k). White solid, 0.127 g, 0.320 mmol, 76% 6 (1.0 eq.) solution in MeCN (0.05 M) was stirred at −20 °C for
(0.457 mmol scale reaction); 1H-NMR (400 MHz, chloroform- 10 minutes. Then, the α-iminoester 1 (1.0 eq., 0.15 M in
D) δ 7.73 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.50 (d, J = MeCN) and alkyl halides 2 (2.0 eq.) were successively added.
8.0 Hz, 2H), 7.45–7.41 (m, 2H), 4.81 (s, 2H), 1.62 (s, 9H); The reaction was vigorously stirred at the same temperature
13C-NMR (101 MHz, chloroform-D) δ 164.45, 160.49, 142.71, for 24 hours, which was passed the short silica-gal pad
137.29, 132.57, 128.96 (q, J = 32.7 Hz), 128.87, 128.61, 128.13, (neutral silica-gel, EtOAc) to give the crude products. The
125.37 (q, J = 3.7 Hz), 124.16 (q, J = 273.4 Hz), 84.76, 57.21, crude product was purified by column chromatography (silica-
28.27; 19F-NMR (376 MHz, chloroform-D) δ −62.44; HRMS gel, diethyl ether/hexane) to give the 8 and 9.
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tert-Butyl 2-((4-nitrobenzyl)amino)-2,3-diphenylpropanoate 3.41 (d, J = 13.5 Hz, 1H), 2.25 (s, 1H); 13C-NMR (101 MHz,
(4a). Colorless oil, 10.6 mg, 0.0244 mmol, 40% (0.0611 mmol chloroform-D) δ 174.40, 148.28, 146.95, 140.35, 135.93, 130.23,
1
scale reaction); H-NMR (400 MHz, chloroform-D) δ 8.14 (dt, J 128.46, 128.43, 128.17, 127.86, 126.97, 123.51, 69.79, 52.19,
= 9.0, 2.1 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.41–7.44 (m, 2H), 46.97, 43.10 (one carbon peak is overlapped with other peak);
7.28–7.35 (m, 3H), 7.19–7.21 (m, 3H), 7.06–7.08 (m, 2H), 3.81 HRMS (ESI+ in MeCN) calcd for C23H23N2O4+ (M + H) 391.1652
(d, J = 14.4 Hz, 1H), 3.71 (d, J = 14.4 Hz, 1H), 3.56 (d, J = 13.7 found 391.1651; IR (NaCl) ν 3064, 3029, 2950, 2359, 1734,
Hz, 1H), 3.37 (d, J = 13.7 Hz, 1H), 2.25 (s, 1H), 1.42 (s, 9H); 1604, 1519, 1496, 1455, 1345 cm−1
.
13C-NMR (101 MHz, chloroform-D) δ 172.96, 148.48, 146.95,
Methyl 2-((1-(4-nitrophenyl)-2-phenylethyl)amino)-2-pheny-
141.11, 136.44, 130.49, 128.49, 128.25, 127.89, 127.50, 126.69, lacetate (7b, major). Colorless oil, 2.5 mg, 0.00640 mmol, 9.3%
1
123.51, 82.07, 69.35, 46.94, 41.94, 27.98 (one carbon peak is (0.0687 mmol scale reaction); H-NMR (400 MHz, chloroform-
overlapped with other peak); HRMS (ESI+ in MeCN) calcd for D) δ 8.17 (dt, J = 9.0, 2.0 Hz, 2H), 7.40 (dt, J = 9.0, 2.0 Hz, 2H),
+
C26H29N2O4 (M + H) 433.2122 found 433.2113; IR (NaCl) ν 7.22–7.30 (m, 6H), 7.00–7.03 (m, 2H), 6.87–6.91 (m, 2H), 4.05
3020, 2361, 1718, 1602, 1521, 1496, 1456, 1369, 1347, (s, 1H), 3.66 (t, J = 7.2 Hz, 1H), 3.58 (s, 3H), 2.88 (d, J = 7.2 Hz,
1326 cm−1
.
2H), 2.70 (s, 1H); 13C-NMR (101 MHz, chloroform-D) δ 172.53,
tert-Butyl 2-((4-nitrobenzyl)amino)-2-phenylacetate (5a). 150.64, 147.36, 137.20, 136.96, 129.19, 128.75, 128.63, 128.30,
1
Colorless oil, 8.25 mg, 0.0241 mmol, 47%; H-NMR (400 MHz, 127.42, 126.91, 123.78, 62.18, 59.99, 52.33, 44.82 (one carbon
chloroform-D) 8.19–8.16 (m, 2H), 7.52 (d, J = 8.8 Hz, 2H), peak is overlapped with other peak); HRMS (ESI+ in MeCN)
+
7.36–7.31 (m, 5H), 4.23 (s, 1H), 3.86 (d, J = 14.3 Hz, 1H), 3.81 calcd for C23H23N2O4 (M + H) 391.1652 found 391.1649; IR
(d, J = 14.3 Hz, 1H), 1.39 (s, 9H); 13C-NMR (101 MHz, chloro- (NaCl) ν 3020, 2954, 2927, 1738, 1600, 1522, 1496, 1455, 1437,
form-D) δ 171.91, 147.54, 147.12, 138.15, 128.81, 128.66, 1348 cm−1
.
128.01, 127.30, 123.62, 81.91, 65.08, 50.61, 27.93; HRMS (ESI
Methyl 2-((1-(4-nitrophenyl)-2-phenylethyl)amino)-2-pheny-
+
in MeCN) calcd for C19H23N2O4 (M + H) 343.1652 found lacetate (7b, minor). Colorless oil, 0.63 mg, 0.00161 mmol,
343.1645; IR (NaCl) ν 3343, 3032, 2978, 2931, 2852, 1727, 1601, 2.4% (0.0687 mmol scale reaction); 1H-NMR (400 MHz, chloro-
1521, 1455, 1393 cm−1
.
form-D) δ 8.15 (dt, J = 9.0, 2.2 Hz, 2H), 7.46 (dt, J = 9.0, 2.1 Hz,
tert-Butyl 2-((1-(4-nitrophenyl)-2-phenylethyl)amino)-2-phe- 2H), 7.29–7.35 (m, 4H), 7.20–7.28 (m, 4H), 7.07–7.15 (m, 2H),
nylacetate (7a, major). Colorless oil, 9.5 mg, 0.0220 mmol, 4.11 (s, 1H), 4.06 (t, J = 7.0 Hz, 1H), 3.64 (s, 3H), 2.90–3.01 (dd,
1
36% (0.0611 mmol scale reaction); H-NMR (400 MHz, chloro- J = 13.4, 7.7 Hz, 1H), 2.95 (dd, J = 13.4, 7.7 Hz, 1H), 2.68 (s,
form-D) δ 8.17 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 1H); 13C-NMR (101 MHz, chloroform-D) δ 173.39, 150.59,
7.31–7.20 (m, 6H), 7.04–7.02 (m, 2H), 6.85–6.83 (m, 2H), 3.93 147.35, 137.87, 137.02, 129.26, 128.75, 128.54, 128.38, 128.11,
(s, 1H), 3.64 (t, J = 7.1 Hz, 1H), 2.87 (d, J = 7.1 Hz, 2H), 2.67 (s, 126.92, 126.88, 123.67, 63.03, 62.90, 52.20, 45.22; HRMS (ESI+
+
1H), 1.27 (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ 171.22, in MeCN) calcd for C23H23N2O4 (M + H) 390.1580 found
150.98, 147.32, 137.61, 137.39, 129.20, 128.61, 128.52, 128.32, 391.1652; IR (NaCl) ν 3061, 3029, 2924, 2851, 2359, 1735, 1599,
127.91, 127.26, 126.85, 123.72, 81.59, 62.94, 60.01, 44.87, 1522, 1496, 1454 cm−1
.
+
27.75; HRMS (ESI+ in MeCN) calcd for C26H29N2O4 (M + H)
tert-Butyl
(E)-2,3-diphenyl-2-((4-(trifluoromethyl)benzyli-
433.2122 found 433.2118; IR (NaCl) ν 3020, 2359, 1726, 1600, dene)amino)propanoate (8a). Colorless oil, 38 mg,
1523, 1456, 1348, 1215, 1154, 767 cm−1 0.084 mmol, 82% (0.102 mmol scale reaction); 1H-NMR
.
tert-Butyl 2-((1-(4-nitrophenyl)-2-phenylethyl)amino)-2-phe- (400 MHz, chloroform-D) δ 7.99 (s, 1H), 7.84 (d, J = 8.1 Hz,
nylacetate (7a, minor). Colorless oil, 4.2 mg, 0.00978 mmol, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.43–7.46 (m, 2H), 7.27–7.37 (m,
1
16% (0.0611 mmol scale reaction); H-NMR (400 MHz, chloro- 3H), 7.07–7.15 (m, 5H), 3.72 (d, J = 13.5 Hz, 1H), 3.39 (d, J =
form-D) δ 8.13 (dt, J = 9.1, 2.1 Hz, 2H), 7.44 (dt, J = 9.1, 2.1 Hz, 13.5 Hz, 1H), 1.37 (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ
2H), 7.26–7.32 (m, 4H), 7.21–7.25 (m, 4H), 7.06–7.08 (m, 2H), 171.13, 160.89, 142.26, 139.59, 136.71, 132.36 (q, J = 32.5 Hz),
4.05 (t, J = 7.0 Hz, 1H), 3.94 (s, 1H), 3.00 (dd, J = 13.3, 7.5 Hz, 131.36, 128.50, 128.17, 127.48, 127.36, 126.94, 126.40, 125.50
1H), 2.91 (dd, J = 13.3, 7.5 Hz, 1H), 2.61 (s, 1H), 1.34 (s, 9H); (q, J = 3.7 Hz), 123.94 (q, J = 274.7 Hz), 82.10, 76.17, 46.28,
13C-NMR (101 MHz, chloroform-D) δ 172.09, 150.74, 147.32, 27.86; 19F-NMR (377 MHz, chloroform-D) δ −62.75; HRMS
+
138.40, 137.20, 129.29, 128.55, 128.43, 127.77, 126.81, 126.79, (ESI+ in MeCN) calcd for C27H27O2NF3 (M + H) 454.1988
123.62, 81.72, 63.69, 62.94, 45.33, 27.87 (one carbon peak is found 454.1982; IR (NaCl) ν 2979, 1724, 1369, 1324, 1165,
overlapped with other peak); HRMS (ESI+ in MeCN) calcd for 1065, 842 cm−1
.
+
C26H29N2O4 (M + H) 433.2122 found 433.2120; IR (NaCl) ν
tert-Butyl (E)-3-phenyl-2-(p-tolyl)-2-((4-(trifluoromethyl)ben-
3066, 3027, 2980, 2929, 2854, 1725, 1600, 1523, 1496, zylidene)amino)propanoate (8b). Colorless oil, 31 mg,
14 555 cm−1
.
0.0663 mmol, 66% (0.101 mmol scale reaction); 1H-NMR
Methyl
2-((4-nitrobenzyl)amino)-2,3-diphenylpropanoate (400 MHz, chloroform-D) δ 7.95 (s, 1H), 7.83 (d, J = 8.2 Hz,
(4b). Colorless oil, 14.4 mg, 0.0396 mmol, 54% (0.0687 mmol 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.30–7.32 (m, 2H), 7.13–7.17 (m,
1
scale reaction); H-NMR (400 MHz, chloroform-D) δ 8.13 (dt, J 7H), 3.71 (d, J = 13.5 Hz, 1H), 3.38 (d, J = 13.5 Hz, 1H), 2.36 (s,
= 9.0, 2.1 Hz, 2H), 7.42–7.47 (m, 4H), 7.27–7.36 (m, 3H), 3H), 1.37 (s, 9H); 13C-NMR (101 MHz, chloroform-D) 13C-NMR
7.21–7.23 (m, 3H), 7.01–7.03 (m, 2H), 3.81 (d, J = 14.3 Hz, 1H), (101 MHz, chloroform-D) δ 171.18, 160.90, 139.67, 137.01,
3.76 (s, 3H), 3.67 (d, J = 14.3 Hz, 1H), 3.58 (d, J = 13.5 Hz, 1H), 136.95, 132.26 (q, J = 31.8 Hz), 131.37, 128.91, 128.49, 128.02,
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127.48, 126.84, 126.36, 125.46 (q, J = 3.63 Hz), 123.96 (q, J = peak is overlapped with other peak); 19F-NMR (377 MHz,
273.5 Hz), 81.98, 76.01, 46.13, 27.86, 21.08; 19F-NMR(377 MHz, chloroform-D) δ −62.75; HRMS (ESI+ in MeCN) calcd for
chloroform-D) δ −62.74; HRMS (ESI+ in MeCN) calcd for C31H29O2NF3 (M + H) 504.2145 found 504.2137; IR (NaCl) ν
+
+
C28H29O2NF3 (M + H) 468.2145 found 468.2138; IR (NaCl) ν 2981, 1732, 1324, 1150, 1126, 1065, 842 cm−1
.
2976, 2933, 1718, 1650, 1323, 1127, 1065 cm−1
.
tert-Butyl (E)-2-(4-methoxyphenyl)-3-phenyl-2-((4-(trifluoro-
tert-Butyl (E)-3-phenyl-2-(m-tolyl)-2-((4-(trifluoromethyl)ben- methyl)benzylidene)amino)propanoate (8f). Colorless oil,
zylidene)amino)propanoate (8c). Colorless oil, 43.9 mg, 33.4 mg, 0.0693 mmol, 70% (0.098 mmol scale reaction);
0.091 mmol, 75% (0.121 mmol scale reaction); 1H-NMR 1H-NMR (400 MHz, chloroform-D) δ 7.95 (s, 1H), 7.83 (d, J =
(400 MHz, chloroform-D) δ 7.97 (s, 1H), 7.86 (d, J = 8.1 Hz, 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.34–7.37 (m, 2H),
2H), 7.69 (d, J = 8.1 Hz, 2H), 7.25–7.27 (m, 3H), 7.13–7.19 (m, 7.10–7.17 (m, 5H), 6.88–6.90 (m, 2H), 3.83 (s, 3H), 3.71 (d, J =
6H), 3.74 (d, J = 13.4 Hz, 1H), 3.40 (d, J = 13.4 Hz, 1H), 2.38 (s, 13.4 Hz, 1H), 3.36 (d, J = 13.4 Hz, 1H), 1.37 (s, 9H); 13C-NMR
3H), 1.39 (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ 171.13, (101 MHz, chloroform-D) δ 171.24, 160.81, 158.66, 139.56,
161.00, 142.14, 139.62, 137.77, 136.90, 132.28 (q, J = 32.3 Hz), 136.83, 134.29, 132.3 (q, J = 30.5 Hz), 131.35, 128.48, 128.13,
131.38, 128.51, 128.12, 128.06, 127.65, 127.47, 126.39, 125.47 127.49, 126.38, 125.47 (q, J = 3.7 Hz), 123.9 (q, J = 273 Hz),
(q, J = 3.7 Hz), 123.99, 123.94 (q, J = 273.3 Hz), 82.03, 76.21, 113.46, 81.99, 75.67, 55.24, 46.11, 27.85; 19F-NMR (377 MHz,
46.16, 27.86, 21.65; 19F-NMR (377 MHz, chloroform-D) δ chloroform-D) δ −62.42; HRMS (ESI+ in MeCN) calcd for
−62.72; HRMS (ESI+ in MeCN) calcd for C28H29O2NF3+ (M + H) C28H29O3NF3 (M + H) 484.2094 found 484.2088; IR (NaCl) ν
+
468.2145 found 468.2137; IR (NaCl) ν 2969, 2916, 1731, 1652, 2981, 1725, 1582, 1487, 1326, 1256, 1148 cm−1
.
1369, 1329, 1066 cm−1
tert-Butyl (E)-3-phenyl-2-(o-tolyl)-2-((4-(trifluoromethyl)ben- methyl)benzylidene)amino)propanoate (8g). Colorless oil,
.
tert-Butyl (E)-2-(3-methoxyphenyl)-3-phenyl-2-((4-(trifluoro-
zylidene)amino)propanoate (8d)
47.9 mg, 0.099 mmol, 78% (0.127 mmol scale reaction);
tert-Butyl (Z)-2-((2-phenyl-1-(4-(trifluoromethyl)phenyl)ethyl) 1H-NMR (400 MHz, chloroform-D) δ 7.97 (s, 1H), 7.84 (d, J =
imino)-2-(o-tolyl)acetate (9d). Colorless oil, 37.9 mg, 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.26–7.30 (m, 1H),
0.081 mmol, 61% (5 : 1 mixture of 8d and 9d, 0.132 mmol 7.10–7.17 (m, 5H), 7.00–7.05 (m, 2H), 6.83–6.86 (m, 1H), 3.78
+
scale reaction); HRMS (ESI+ in MeCN) calcd for C28H29O2NF3
(s, 3H), 3.69 (d, J = 13.5 Hz, 1H), 3.37 (d, J = 13.5 Hz, 1H), 1.38
(M + H) 468.2145 found 468.2140; IR (NaCl) ν 2969, 1730, (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ 170.99, 160.88,
1651, 1369, 1328, 1150, 1065 cm−1
.
159.34, 143.72, 139.48, 136.66, 132.27 (q, J = 33.3 Hz), 131.33,
8d: 1H-NMR (400 MHz, chloroform-D) δ 8.19 (s, 1H), 7.86 129.13, 128.50, 127.48, 126.41, 125.48 (q, J = 3.9 Hz), 123.90 (q,
(d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.30–7.04 (m, 7H), J = 273.8 Hz), 119.25, 112.96, 112.61, 82.12, 76.10, 55.19, 46.26,
6.95–6.98 (m, 2H), 3.64 (d, J = 13.3 Hz, 1H), 3.48 (d, J = 13.3 27.83; 19F-NMR (376 MHz, chloroform-D) δ −62.77; HRMS
+
Hz, 1H), 2.27 (s, 3H), 1.37 (s, 9H); 13C-NMR (101 MHz, chloro- (ESI+ in MeCN) calcd for C28H29O3NF3 (M + H) 484.2094
form-D) δ 171.39, 158.93, 140.21, 136.42, 135.75, 131.82, found 484.2085; IR (NaCl) ν 2979, 1724, 1600, 1324, 1164,
131.13, 129.61, 128.57, 128.24, 127.63, 127.35, 126.34, 125.58 1065, 842 cm−1
.
(q, J = 3.7 Hz), 125.37, 81.99, 75.49, 45.62, 27.81, 21.27 (two
tert-Butyl
(E)-3-phenyl-2-((4-(trifluoromethyl)benzylidene)
carbon peaks (CF3 and its ipso carbon) were difficult to amino)-2-(4-(trifluoromethyl)phenyl)propanoate (8h). Colorless
assign); 19F-NMR (377 MHz, chloroform-D) δ −62.78.
oil, 51 mg, 0.0896 mmol, 80% (0.112 mmol scale reaction);
9d: H-NMR (400 MHz, chloroform-D) δ 7.55 (d, J = 8.1 Hz, 1H-NMR (400 MHz, chloroform-D) δ 8.03 (s, 1H), 7.85 (d, J =
2H), 7.45–7.48 (m, 4H), 7.30–7.04 (m, 7H), 4.95 (dd, J = 6.5 Hz, 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.60 (s, 4H), 7.10–7.16 (m,
7.2 Hz, 1H), 3.29 (dd, J = 13.4, 6.5 Hz, 1H), 3.18 (dd, J = 13.4, 3H), 6.96–6.98 (m, 2H), 3.69 (d, J = 13.4 Hz, 1H), 3.35 (d, J =
7.2 Hz, 1H), 2.34 (s, 3H), 1.46 (s, 9H); 13C-NMR (101 MHz, 13.4 Hz, 1H), 1.39 (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ
chloroform-D) δ 164.02, 146.64, 139.61, 137.87, 137.04, 131.22, 170.66, 160.96, 146.30, 139.19, 135.80, 132.61 (q, J = 32.3 Hz),
129.45, 128.50, 128.19, 127.82, 127.58, 127.25, 126.43, 125.66, 131.30, 129.43 (q, J = 32.5 Hz), 128.52, 127.58, 127.29, 126.62,
125.19 (q, J = 4.0 Hz), 83.74, 69.89, 45.43, 28.06, 20.73 (two 125.62 (q, J = 3.9 Hz), 125.01 (q, J = 3.7 Hz), 124.08 (q, J = 272.5
carbon peaks (CF3 and its ipso carbon) were difficult to Hz), 123.84 (q, J = 272.8 Hz), 82.64, 75.99, 46.48, 27.83;
1
assign); 19F-NMR (377 MHz, chloroform-D) δ −62.39.
tert-Butyl
19F-NMR (376 MHz, chloroform-D) δ −62.45, −62.82; HRMS
(E)-2-(naphthalen-2-yl)-3-phenyl-2-((4-(trifluoro- (ESI+ in MeCN) calcd for C28H26O2NF6 (M + H) 522.1862
+
methyl)benzylidene)amino)propanoate (8e). Colorless oil, found 522.1851; IR (NaCl) ν 2982, 1726, 1370, 1325, 1127,
31.2 mg, 0.062 mmol, 64% (0.0967 mmol scale reaction); 1066, 1017 cm−1
1H-NMR (400 MHz, chloroform-D) δ 8.03 (s, 1H), 7.94 (d, J =
tert-Butyl
.
(E)-2-(4-chlorophenyl)-3-phenyl-2-((4-(trifluoro-
1.5 Hz, 1H), 7.82–7.87 (m, 5H), 7.68 (d, J = 8.1 Hz, 2H), methyl)benzylidene)amino)propanoate (8i). Colorless oil,
7.49–7.53 (m, 3H), 7.12–7.15 (m, 5H), 3.81 (d, J = 13.4 Hz, 1H), 31 mg, 0.0635 mmol, 63% (0.101 mmol scale reaction);
3.51 (d, J = 13.4 Hz, 1H), 1.37 (s, 9H); 13C-NMR (101 MHz, 1H-NMR (400 MHz, chloroform-D) δ 8.01 (s, 1H), 7.83 (d, J =
chloroform-D) δ 171.12, 161.08, 139.56, 136.66, 133.08, 132.62, 8.2 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.39–7.40 (m, 2H),
132.41 (q, J = 33.4 Hz), 131.35, 128.57, 128.35, 127.87, 127.54, 7.30–7.32 (m, 2H), 7.10–7.15 (m, 3H), 6.99–7.02 (m, 2H), 3.66
127.51, 126.45, 126.10, 126.04, 125.53 (q, J = 3.9 Hz), 125.09, (d, J = 13.5 Hz, 1H), 3.33 (d, J = 13.5 Hz, 1H), 1.38 (s, 9H);
123.94 (q, J = 272.2 Hz), 82.22, 76.34, 46.22, 27.88 (one carbon 13C-NMR (101 MHz, chloroform-D) δ 170.87, 160.82, 140.87,
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139.35, 136.14, 133.15, 132.56 (q, J = 32.5 Hz), 131.32, 128.51, 3.72 (d, J = 13.3 Hz, 1H), 3.31 (d, J = 13.3 Hz, 1H), 2.17 (s, 3H),
128.38, 128.24, 127.55, 126.53, 125.58 (q, J = 3.4 Hz), 123.88 (q, 1.39 (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ 171.05,
J = 273.7 Hz), 82.39, 75.75, 46.40, 27.86; 19F-NMR (377 MHz, 160.92, 142.29, 139.55, 136.78, 136.47, 132.47, 132.24 (q, J =
chloroform-D) δ −62.34; HRMS (ESI+ in MeCN) calcd for 34.0 Hz), 128.45, 128.35, 128.15, 127.36, 127.07, 126.91, 125.42
+
C27H26O2NClF3 (M + H) 488.1599 found 488.1594; IR (NaCl) ν (q, J = 3.6 Hz), 123.91 (q, J = 273.5 Hz), 82.04, 76.15, 45.95,
2977, 2932, 1725, 1647, 1323, 1128, 1061 cm−1
tert-Butyl
.
27.84, 21.25 (one carbon peak is overlapped with other peak);
(E)-2-(4-fluorophenyl)-3-phenyl-2-((4-(trifluoro- 19F-NMR (376 MHz, chloroform-D) δ −62.75; HRMS (ESI+ in
+
methyl)benzylidene)amino)propanoate (8j). Colorless oil, MeCN) calcd for C28H29O2NF3 (M + H) 468.2145 found
35.1 mg, 0.074 mmol, 71% (0.105 mmol scale reaction); 468.2134; IR (NaCl) ν 2979, 1725, 1369, 1324, 1153, 1065,
1H-NMR (400 MHz, chloroform-D) δ 8.00 (s, 1H), 7.84 (d, J = 843 cm−1
.
8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.41–7.45 (m, 2H),
tert-Butyl (E)-2-phenyl-3-(o-tolyl)-2-((4-(trifluoromethyl)ben-
7.11–7.16 (m, 3H), 7.00–7.06 (m, 4H), 3.68 (d, J = 13.4 Hz, 1H), zylidene)amino)propanoate (8n). Colorless oil, 47.7 mg,
3.33 (d, J = 13.4 Hz, 1H), 1.38 (s, 9H); 13C-NMR (101 MHz, 0.102 mmol, 74% (0.138 mmol scale reaction); 1H-NMR
chloroform-D) δ 171.05, 161.91 (d, J = 246.4 Hz), 160.78, (400 MHz, chloroform-D) δ 7.77 (s, 1H), 7.75 (d, J = 8.1 Hz,
139.34, 138.01 (d, J = 2.9 Hz), 136.25, 132.46 (q, J = 32.6 Hz), 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.48–7.51 (m, 2H), 7.29–7.40 (m,
131.32, 128.59 (d, J = 7.8 Hz), 128.49, 127.53, 126.49, 125.55 (q, 4H), 7.05–7.10 (m, 2H), 6.92–6.95 (m, 1H), 3.86 (d, J = 14.0 Hz,
J = 3.9 Hz), 123.87 (q, J = 274.5 Hz), 114.93 (d, J = 21.5 Hz), 1H), 3.34 (d, J = 14.0 Hz, 1H), 1.91 (s, 3H), 1.38 (s, 9H);
82.30, 75.65, 46.42, 27.84; 19F-NMR (376 MHz, chloroform-D) δ 13C-NMR (101 MHz, chloroform-D) δ 171.42, 160.53, 142.91,
−62.79, −115.38; HRMS (ESI+ in MeCN) calcd for 139.59, 138.18, 135.50, 132.22 (q, J = 32.3 Hz), 130.72, 130.01,
+
C27H26O2NF4 (M + H) 472.1894 found 472.1884; IR (NaCl) ν 128.34, 128.14, 127.32, 126.88, 126.55, 125.40 (q, J = 3.7 Hz),
2932, 2118, 1724, 1506, 1324, 1253, 1164 cm−1
.
125.30, 123.92 (q, J = 274.5 Hz), 82.13, 76.89, 41.93, 27.82,
tert-Butyl
(E)-2-(3-chlorophenyl)-3-phenyl-2-((4-(trifluoro- 19.99; 19F-NMR (376 MHz, chloroform-D) δ −62.75; HRMS
+
methyl)benzylidene)amino)propanoate (8k). Colorless oil, (ESI+ in MeCN) calcd for C28H29O2NF3 (M + H) 468.2145
38 mg, 0.0722 mmol, 72% (0.101 mmol scale reaction); found 468.2142; IR (NaCl) ν 2980, 1725, 1369, 1324, 1154,
1H-NMR (400 MHz, chloroform-D) δ 7.99 (s, 1H), 7.84 (d, J = 1065, 735 cm−1
.
8.1 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.50–7.51 (m, 1H),
tert-Butyl (E)-3-(4-methoxyphenyl)-2-phenyl-2-((4-(trifluoro-
7.27–7.36 (m, 3H), 7.11–7.18 (m, 3H), 7.00–7.03 (m, 2H), 3.67 methyl)benzylidene)amino)propanoate (8o). Colorless oil,
(d, J = 13.4 Hz, 1H), 3.33 (d, J = 13.4 Hz, 1H), 1.39 (s, 9H); 36.8 mg, 0.0761 mmol, 76% (0.101 mmol scale reaction);
13C-NMR (101 MHz, chloroform-D) δ 170.68, 160.95, 144.43, 1H-NMR (400 MHz, chloroform-D) δ 7.97 (s, 1H), 7.85 (d, J =
139.32, 136.05, 132.57 (q, J = 32.5 Hz), 134.14, 131.35, 129.32, 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.43–7.46 (m, 2H),
128.54, 127.95, 127.56, 127.51, 127.27, 126.59, 125.58 (q, J = 7.28–7.38 (m, 3H), 6.98–7.02 (m, 2H), 6.67–6.71 (m, 2H), 3.75
3.7 Hz), 125.10, 123.89 (q, J = 272.6 Hz), 82.50, 75.88, 46.40, (s, 3H), 3.67 (d, J = 13.5 Hz, 1H), 3.30 (d, J = 13.5 Hz, 1H), 1.38
27.86; 19F-NMR (377 MHz, chloroform-D) δ −62.77; HRMS (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ 171.18, 160.80,
+
(ESI+ in MeCN) calcd for C27H26O2NClF3 (M + H) 488.1599 158.21, 142.35, 139.67, 132.38, 132.35 (q, J = 32.6 Hz), 128.67,
found 488.1593; IR (NaCl) ν 2929, 2116, 1727, 1328, 1152, 128.49, 128.15, 127.31, 126.97, 125.51 (q, J = 3.7 Hz), 123.96 (q,
1066, 841 cm−1
.
J = 273.29 Hz), 112.88, 82.02, 76.37, 55.16, 45.43, 27.90;
tert-Butyl (E)-2-phenyl-3-(p-tolyl)-2-((4-(trifluoromethyl)ben- 19F-NMR (376 MHz, chloroform-D) δ −62.76; HRMS (ESI+ in
+
zylidene)amino)propanoate (8l). Colorless oil, 44.7 mg, MeCN) calcd for C28H29O3NF3 (M + H) 484.2094 found
0.0902 mmol, 82% (0.110 mmol scale reaction); 1H-NMR 484.2086; IR (NaCl) ν 2979, 1724, 1512, 1369, 1324, 1249,
(400 MHz, chloroform-D) δ 8.00 (s, 1H), 7.84 (d, J = 8.2 Hz, 1065 cm−1
.
2H), 7.67 (d, J = 8.2 Hz, 2H), 7.44–7.46 (m, 2H), 7.27–7.37 (m,
tert-Butyl
(E)-3-(4-chlorophenyl)-2-phenyl-2-((4-(trifluoro-
3H), 6.95 (s, 4H), 3.68 (d, J = 13.4 Hz, 1H), 3.34 (d, J = 13.4 Hz, methyl)benzylidene)amino)propanoate (8p). Colorless oil,
1H), 2.27 (s, 3H), 1.38 (s, 9H); 13C-NMR (101 MHz, chloroform- 37.5 mg, 0.0701 mmol, 70% (0.1001 mmol scale reaction);
D) δ 171.19, 160.78, 142.29, 139.62, 135.86, 133.43, 132.29 (q, J 1H-NMR (400 MHz, chloroform-D) δ 8.07 (s, 1H), 7.86 (d, J =
= 32.3 Hz), 131.23, 128.49, 128.18, 128.13, 127.30, 126.96, 8.1 Hz, 2H), 7.69 (d,
J = 8.1 Hz, 2H), 7.27–7.40 (m,
125.48 (q, J = 3.7 Hz), 123.94 (q, J = 273.9 Hz), 82.02, 76.19, 5H),7.09–7.13 (m, 2H), 6.98–7.01 (m, 2H), 3.62 (d, J = 13.5 Hz,
45.79, 27.87, 21.04; 19F-NMR (377 MHz, chloroform-D) δ 1H), 3.37 (d, J = 13.5 Hz, 1H), 1.38 (s, 9H); 13C-NMR (101 MHz,
−62.71; HRMS (ESI+ in MeCN) calcd for C28H29O2NF3+ (M + H) chloroform-D) δ 170.99, 160.89, 141.76, 139.33, 135.15, 132.62,
468.2145 found 468.2134; IR (NaCl) ν 2976, 1724, 1369, 1324, 132.47 (q, J = 32.0 Hz), 132.25, 128.51, 128.24, 127.51, 127.49,
1253, 1165, 1065 cm−1
.
126.85, 125.59 (q, J = 3.7 Hz), 123.87 (q, J = 272.5 Hz), 82.30,
tert-Butyl (E)-2-phenyl-3-(m-tolyl)-2-((4-(trifluoromethyl)ben- 76.10, 45.89, 27.85; 19F-NMR (376 MHz, chloroform-D) δ
+
zylidene)amino)propanoate (8m). Colorless oil, 43.7 mg, −62.80; HRMS (ESI+ in MeCN) calcd for C27H26O2NClF3 (M +
0.094 mmol, 68% (0.1376 mmol scale reaction); 1H-NMR H) 488.1599 found 488.1593; IR (NaCl) ν 2980, 1726, 1687,
(400 MHz, chloroform-D) δ 7.93 (s, 1H), 7.83 (d, J = 8.0 Hz, 1132, 1211, 1152, 1065 cm−1
.
2H), 7.67 (d, J = 8.0 Hz, 2H), 7.46–7.49 (m, 2H), 7.28–7.39 (m,
tert-Butyl
(E)-3-(3-chlorophenyl)-2-phenyl-2-((4-(trifluoro-
3H), 7.03–7.06 (m, 1H), 6.96–6.98 (m, 1H)6.88–6.92 (m, 2H), methyl)benzylidene)amino)propanoate (8q). Colorless oil,
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37.0 mg, 0.0759 mmol, 76% (0.101 mmol scale reaction); 128.28, 126.92, 125.47 (q, J = 3.7 Hz), 123.89 (q, J = 267.6 Hz),
1H-NMR (400 MHz, chloroform-D) δ 8.04 (s, 1H), 7.85 (d, J = 118.82, 81.92, 75.17, 44.50, 27.90; 19F-NMR (377 MHz, chloro-
8.2 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.29–7.40 (m, 5H), form-D) δ −62.75.
1
7.13–7.16 (m, 2H), 7.06–7.09 (m, 1H), 6.96–6.98 (m, 1H), 3.64
9t: H-NMR (400 MHz, chloroform-D) δ 7.80–7.78 (m, 2H),
(d, J = 13.4 Hz, 1H), 3.38 (d, J = 13.4 Hz, 1H), 1.40 (s, 9H); 7.59 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.47–7.35 (m,
13C-NMR (101 MHz, chloroform-D) δ 170.80, 161.11, 141.79, 3H), 5.75–5.65 (m, 1H), 5.07–5.01 (m, 2H), 4.65 (t, J = 6.7 Hz,
139.42, 138.84, 133.18, 132.53 (q, J = 33.5 Hz), 131.51, 129.53, 1H), 2.76–2.64 (m, 2H), 1.60 (s, 9H); 13C-NMR (101 MHz,
128.61, 128.56, 128.29, 127.57, 126.89, 126.53, 125.58 (q, J = chloroform-D) δ 164.87, 159.52, 146.79, 134.35, 130.99, 129.27
3.7 Hz), 123.92 (q, J = 273.6 Hz), 82.44, 77.00, 76.06, 46.10, (q, J = 33.5 Hz), 128.51, 127.48, 127.41, 127.39, 125.25 (q, J =
27.89; 19F-NMR (376 MHz, chloroform-D) δ −62.79; HRMS 3.7 Hz), 117.56, 84.16, 67.59, 42.97, 28.25 (one carbon peak
+
(ESI+ in MeCN) calcd for C27H26O2NClF3 (M + H) 488.1599 (CF3 group) was difficult to assign); 19F-NMR (377 MHz, chloro-
found 488.1592; IR (NaCl) ν 2929, 2116, 1727, 1328, 1152, form-D) δ −62.40.
841 cm−1
tert-Butyl
.
(E)-3-(2-chlorophenyl)-2-phenyl-2-((4-(trifluoro-
The synthesis of 10
methyl)benzylidene)amino)propanoate (8r). Colorless oil,
53.2 mg, 0.109 mmol, 79% (0.138 mmol scale reaction);
1H-NMR (400 MHz, chloroform-D) δ 8.08 (s, 1H), 7.82 (d, J =
8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.42–7.44 (m, 2H),
7.29–7.38 (m, 4H), 7.20–7.22 (m, 1H), 7.05–7.12 (m, 2H), 3.94
(d, J = 14.1 Hz, 1H), 3.63 (d, J = 14.1 Hz, 1H), 1.38 (s, 9H);
13C-NMR (101 MHz, chloroform-D) δ 171.35, 160.79, 141.98,
139.55, 135.58, 134.98, 132.27 (q, J = 33.1 Hz), 131.75, 129.10,
128.58, 128.24, 127.68, 127.46, 127.00, 126.02, 125.41 (q, J =
3.7 Hz), 123.91 (q, J = 271.4 Hz), 82.28, 76.18, 42.18, 27.78;
19F-NMR (376 MHz, chloroform-D) δ −62.77; HRMS (ESI+ in
To the suspension of LiAlH4 (3.8 mg, 0.1 mmol, 2.3 eq.) in
THF (2.0 mL), 8a (20.0 mg, 0.044 mmol, 1.0 eq.) in THF
(1.0 mL) was added at 0 °C. The reaction was stirred for 1 hour
at the same temperature, which was quenched by the addition
of Na2SO4 and filtered to give the crude product. The crude
product was purified by column chromatography (silica-gel,
ethyl acetate/hexane) to give 10.
2,3-Diphenyl-2-((4-(trifluoromethyl)benzyl)amino)propan-1-ol
(10). Colorless oil, 12.3 mg, 0.032 mmol, 72%; 1H-NMR
(400 MHz, chloroform-D) δ 7.59 (d, J = 8.1 Hz, 2H), 7.44 (d, J =
8.1 Hz, 2H), 7.27–7.38 (m, 3H), 7.12–7.18 (m, 5H), 6.76–6.78
(m, 2H), 3.86 (dd, J = 32.0, 10.6 Hz, 2H), 3.14 (d, J = 12.8 Hz,
1H), 2.99 (d, J = 12.8 Hz, 1H), 2.78 (s, 1H); 13C-NMR (101 MHz,
chloroform-D) δ; 144.35, 141.37, 136.03, 130.52, 129.34 (q, J =
31.9 Hz), 128.45, 128.20, 127.81, 127.18, 126.61, 126.52, 125.42
(q, J = 3.9 Hz), 124.12 (q, J = 269.8 Hz), 63.38, 61.86, 46.05,
44.90; 19F-NMR (377 MHz, chloroform-D) δ −62.38; HRMS
(ESI+ in MeCN) calcd for C23H23ONF3+ (M + H) 386.1726 found
+
MeCN) calcd for C27H26O2NClF3 (M + H) 488.1599 found
488.1590; IR (NaCl) ν 2980, 1724, 1369, 1324, 1155, 1065,
842 cm−1
tert-Butyl
.
(E)-3-(4-nitrophenyl)-2-phenyl-2-((4-(trifluoro-
methyl)benzylidene)amino)propanoate (8s). Colorless oil,
58.3 mg, 0.117 mmol, 75% (0.156 mmol scale reaction);
1H-NMR (400 MHz, chloroform-D) δ 8.18 (s, 1H), 7.99–8.01 (m,
2H), 7.87 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.29–7.38
(m, 5H), 7.21–7.23 (m, 2H), 3.68 (d, J = 13.4 Hz, 1H), 3.54 (d, J
= 13.3 Hz, 1H), 1.39 (s, 9H); 13C-NMR (101 MHz, chloroform-D)
δ 170.73, 161.18, 146.57, 144.84, 141.18, 139.06, 132.79 (q, J =
386.1716; IR (NaCl) ν 3410, 2925, 1616, 1325, 1123, 1065 cm−1
.
The synthesis of 12
34.5 Hz), 131.98, 128.56, 128.40, 127.75, 126.74, 125.72 (q, J = To a solution of 8a (40.0 mg, 0.088 mmol, 1.0 eq.), 11
3.7 Hz), 123.82 (q, J = 273.0 Hz), 122.49, 82.71, 76.05, 46.75, (49.0 mg, 0.26 mmol, 3.0 eq.) in toluene (0.9 mL), TBSOTf
27.86; 19F-NMR (376 MHz, chloroform-D) δ −62.85; HRMS (6.9 mg, 0.026 mmol, 30 mol%) was added. The reaction was
(ESI+ in MeCN) calcd for C27H26O2NClF3 (M + H) 499.1839 stirred for 48 hours at 25 °C, which was concentrated in vacuo
+
found 499.1836; IR (NaCl) ν 2977, 1724, 1602, 1520, 1323, to give the crude product. The crude product was purified by
1156, 1127 cm−1
tert-Butyl
amino)pent-4-enoate (8t)
.
column chromatography (silica-gel, ethyl acetate/hexane) to
(E)-2-phenyl-2-((4-(trifluoromethyl)benzylidene) give 12.
tert-Butyl 2-((3-methoxy-3-oxo-1-(4-(trifluoromethyl)phenyl)
tert-Butyl (Z)-2-phenyl-2-((1-(4-(trifluoromethyl)phenyl)but- propyl)amino)-2,3-diphenylpropanoate (12). Colorless oil,
3-en-1-yl)imino)acetate (9t). Colorless oil, 35.9 mg, 22.6 mg, 0.0428 mmol, 49%; HRMS (ESI+ in MeCN) calcd for
0.889 mmol, 76% (4 : 1 mixture of 8t and 9t, 0.116 mmol scale C30H33O4NF3 (M + H) 528.2356 found 528.2349; IR (NaCl) ν
+
reaction); HRMS (ESI+ in MeCN) calcd for C23H25O2NF3 (M + 2979, 1734, 1723, 1325, 1157, 1120 cm−1
.
H) 404.1832 found 404.1822; IR (NaCl) ν 3072, 2980, 2930,
1728, 1645, 1324, 841 cm−1
12-Major; 1H-NMR (400 MHz, chloroform-D) δ 7.35–7.32
(m, 2H), 7.28–7.04 (m, 12H), 3.97 (t, J = 7.0 Hz, 1H), 3.47 (s,
.
8t: 1H-NMR (400 MHz, chloroform-D) δ 8.18 (s, 1H), 7.91 (d, 3H), 3.34 (d, J = 13.8 Hz, 1H), 3.16 (d, J = 13.8 Hz, 1H), 3.02 (s,
J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.35–7.47 (m, 4H), 1H), 2.60 (dd, J = 14.5, 6.8 Hz, 1H), 2.44 (dd, J = 14.5, 6.8 Hz,
7.27–7.32 (m, 1H), 5.82–5.92 (m, 1H), 5.04–5.07 (m, 2H), 3.09 1H), 1.29 (s, 9H); 13C-NMR (101 MHz, chloroform-D) δ 173.39,
(dd, J = 13.8, 7.2 Hz, 1H), 2.92 (dd, J = 13.8, 7.2 Hz, 1H), 1.42 171.11, 148.55, 140.75, 137.04, 130.31, 128.75 (q, J = 31.9 Hz),
(s, 9H); 13C-NMR (101 MHz, chloroform-D) δ; 171.24, 160.35, 127.84, 127.54, 127.40, 126.93, 126.76, 126.50, 124.72 (q, J =
141.69, 139.51, 134.37, 133.41, 132.36 (q, J = 32.2 Hz), 128.58, 3.7 Hz), 124.20 (q, J = 269.9 Hz), 82.07, 69.08, 54.77, 51.54,
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43.61, 42.57, 27.70; 19F-NMR (377 MHz, chloroform-D) δ
−62.37.
3-(Chloromethyl)-N-((1R,2R)-2-(4-(trifluoromethyl)benzamido)
cyclohexyl)benzamide (18). White solid, 0.980 g, 2.23 mmol,
12-Minor; 1H-NMR (400 MHz, chloroform-D) δ 7.35–7.32 99% (2 steps from 8) (2.24 mmol scale reaction); 1H-NMR
(m, 2H), 7.28–7.04 (m, 12H), 4.19 (t, J = 7.2 Hz, 1H), 3.56 (d, J = (400 MHz, chloroform-D) δ 7.84 (d, J = 7.5 Hz, 1H), 7.65–7.67
13.8 Hz, 1H), 3.48 (s, 3H), 3.22 (d, J = 13.8 Hz, 1H), 2.70 (dd, J (m, 3H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.33
= 14.9, 6.6 Hz, 1H), 2.55 (dd, J = 14.9, 6.6 Hz, 1H), 1.21 (s, 9H); (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.3 Hz, 2H), 6.98 (t, J = 7.8 Hz,
13C-NMR (101 MHz, chloroform-D) δ 173.08, 171.24, 148.44, 1H), 4.34 (s, 2H), 4.18–4.31 (m, 2H), 2.19–2.29 (m, 2H), 1.92 (d,
141.45, 137.34, 130.31, 128.36 (q, J = 32.5 Hz), 127.85, 127.72, J = 7.5 Hz, 2H), 1.58–1.72 (m, 2H), 1.43–1.51 (m, 2H); 13C-NMR
127.63, 127.42, 127.20, 126.32, 124.89 (q, J = 3.6 Hz), 124.13 (q, (101 MHz, chloroform-D) δ 167.77, 166.76, 138.00, 137.24,
J = 268.21 Hz), 82.00, 68.91, 54.48, 51.60, 44.22, 41.11, 27.53; 134.58, 132.76 (q, J = 32.42 Hz), 131.55, 128.82, 127.39, 127.30,
19F-NMR (377 MHz, chloroform-D) δ −62.47.
126.71, 125.12 (q, J = 3.03 Hz), 123.42 (q, J = 273.71 Hz), 54.53,
54.42, 45.31, 32.20, 31.97, 25.14, 25.03; 19F-NMR (377 MHz,
chloroform-D) δ −63.20; HRMS (ESI+ in MeCN) calcd for
C22H23ClF3N2O2 (M + H) 439.1395 found 439.1386; IR (NaCl)
ν 3276, 3075, 2938, 2858, 1630, 1583, 1539, 1327, 1167, 1126,
1126 cm−1; [α]D20 = −44.95 (c = 1.31, CHCl3); m.p. 214 °C.
The synthesis of 13
+
To a solution of 1d (126 mg, 0.392 mmol, 1.0 eq.) in THF
(7.8 mL), DBU (59 μL, 0.392 mmol, 1.0 eq.) was added at room
temperature. After stirring it at the same temperature for
20 minutes, the reaction was evaporated to give the crude
product, which was purified by column chromatography
(silica-gel, ethyl acetate/hexane) to give 13.
Synthesis of 19
18 (1.0 eq.) was dissolved in DMF (0.08 M), which was added
NaN3 (5.0 eq.) was added. The reaction was stirred for
32 hours at room temperature, and the solvent was removed in
vacuo to give the crude product. The crude product was puri-
fied by column chromatography (silica-gel, ethyl acetate/
hexane = 1/1) to give 19.
tert-Butyl
(E)-2-phenyl-2-((4-(trifluoromethyl)benzylidene)
amino)acetate (13). White solid, 88.2 mg, 0.274 mmol, 70%;
1H-NMR (400 MHz, chloroform-D) δ 8.36 (s, 1H), 7.94 (d, J =
8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.48–7.50 (m, 2H),
7.29–7.39 (m, 3H), 5.12 (s, 1H), 1.42 (s, 9H); 13C-NMR
(101 MHz, chloroform-D) δ 169.81, 161.67, 138.97, 138.22,
132.60 (q, J = 34.66 Hz), 129.89, 128.81, 128.58, 127.97, 127.83,
125.48 (q, J = 3.7 Hz), 123.89 (q, J = 274.9 Hz), 81.94, 76.91,
27.93; 19F-NMR (376 MHz, chloroform-D) δ −62.88; HRMS
3-(Azidomethyl)-N-((1R,2R)-2-(4-(trifluoromethyl)benzamido)
cyclohexyl)benzamide (19). White solid, 0.483 g, 1.084 mmol,
95% (1.14 mmol scale reaction); 1H-NMR (400 MHz, chloro-
form-D) δ 7.71 (d, J = 8.3 Hz, 2H), 7.63 (s, 1H), 7.58 (d, J = 7.9
Hz, 2H), 7.26–7.34 (m, 3H), 7.13–7.18 (m, 2H), 4.21 (s, 2H),
4.08–4.18 (m, 2H), 2.19–2.27 (m, 2H), 1.91 (d, J = 6.8 Hz, 2H),
1.42–1.67 (m, 4H); 13C-NMR (101 MHz, chloroform-D) δ
167.73, 166.83, 137.31, 136.01, 134.53, 132.67 (q, J = 33.33 Hz),
130.87, 128.71, 127.44, 126.92, 126.60, 124.97 (q, J = 4.04 Hz),
123.37 (q, J = 273.71 Hz), 54.40, 54.33, 53.97, 32.16, 31.97,
25.22, 25.11; 19F-NMR (377 MHz, chloroform-D) δ −63.30;
(ESI+ in MeCN) calcd for C20H21O2NF3 (M + H) 364.1519
+
found 364.1511; IR (KBr) ν 2977, 2938, 1731, 1640, 1065, 831,
745 cm−1; m.p. 66–67 °C.
Calculation
All calculations were carried out using density functional
theory (DFT) as implemented in the Gaussian 16.17a The geo-
metries of stationary points were optimised with RB3LYP
method in MeCN. We used basis set of 6-31+G(d,p).
+
HRMS (ESI+ in MeCN) calcd for C22H23F3N5O2 (M + H)
446.1798 found 446.1791; IR (NaCl) ν 3281, 2939, 2859, 2097,
1632, 1543, 1452, 1328, 1169, 1126 cm−1; [α]D20 = −76.62 (c =
0.687, CHCl3); m.p. 168–169 °C.
Experimental procedure for Scheme 7
Synthesis of 20
Compound 16 was prepared according to the reported
procedure.22
19 (0.483 g, 1.08 mmol, 1.0 eq.) was dissolved in THF (5.4 mL,
0.2 M), which was added tris(4-methoxyphenyl)phosphine
(0.382 g, 1.0 eq.). The reaction was stirred for 13 hours at room
Synthesis of 18
16 (0.87 g, 2.25 mmol, 1.0 eq.) was dissolved in CH2Cl2 temperature, and the solvent was remover in vacuo to give
(45 mL, 0.05 M), then CF3COOH (3.4 mL) was added and crude iminophosphorane. The crude compound obtained
stirred for 33 hours at room temperature. The crude product above was added HCl (1.0 M diethyl ether solution, 6.5 mL, 6.0
was obtained by the direct evaporation of the reaction mixture, eq.) and stirred for 1 hour at room temperature. The solvent
which was used in the next step without further purification. was removed in vacuo, which was purified by column chrom-
The crude 17 obtained above was dissolved in CH2Cl2 (56 mL, atography (neutral silica-gel, CH2Cl2/MeOH = 20/1) to give
0.05 M), and iPr2EtN (3.0 mL, 6.0 eq.) and 3-chloromethyl 20·HCl.
benzoyl chloride (0.4 mL, 1.0 eq.) was added at room tempera-
1-(3-(((1R,2R)-2-(4-(Trifluoromethyl)benzamido)cyclohexyl)
ture. The reaction was stirred for 16 hours at the same temp- carbamoyl)phenyl)-N-(tris(4-methoxyphenyl)-λ5-phosphaneyli-
erature, which was directly evaporated to give the crude dene)methanaminium chloride (20·HCl). White solid,
product. The crude product was purified by column chromato- 0.4874 g, 0.605 mmol, 56% (1.08 mmol scale reaction);
graphy (silica-gel, ethyl acetate/hexane = 1/1) to give 18.
1H-NMR (400 MHz, chloroform-D) δ 8.75 (s, 1H), 8.52 (d, J =
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7.5 Hz, 1H), 8.32 (s, 1H), 8.12 (d, J = 6.3 Hz, 1H), 7.99 (d, J = 8.0 (q, J = 273.13 Hz), 69.76, 52.15, 47.15, 42.78; 19F-NMR
Hz, 2H), 7.77 (d, J = 7.8 Hz, 1H), 7.63 (td, J = 12.5, 8.7 Hz, 8H), (377 MHz, chloroform-D) δ −62.43; HRMS (ESI+ in MeCN)
+
7.18 (t, J = 7.5 Hz, 1H), 7.04 (dd, J = 8.8, 2.5 Hz, 6H), 6.90 (d, J = calcd for C24H23F3NO2 (M + H) 414.1675 found 414.1671; IR
7.8 Hz, 1H), 4.02–4.26 (m, 3H), 3.88–3.96 (m, 1H), 3.86 (s, 9H), (NaCl) ν 3064, 3020, 2952, 2359, 1732, 1619, 1497, 1436, 1418,
2.42 (d, J = 12.0 Hz, 1H), 2.17 (d, J = 11.3 Hz, 1H), 2.01 (m, 1H), 1326 cm−1; enantiomeric excess was determined by HPLC
1.86 (d, J = 11.0 Hz, 1H), 1.75 (d, J = 10.8 Hz, 1H), 1.36–1.51 (CHIRALPAK IB, hexane/2-propanol = 95/5, flow rate 0.3 mL
(m, 3H); 13C-NMR (101 MHz, chloroform-D) δ 169.26, 165.43, min−1, 25 °C, 254 nm) first peak: tR = 15.8 min, second peak:
164.37 (d, J = 1.01 Hz), 138.03, 137.66 (d, J = 5.05 Hz), 135.52 tR = 17.2 min.
(d, J = 13.13 Hz), 134.47, 132.39 (q, J = 33.33 Hz), 129.96,
128.72, 128.23, 127.66, 127.33, 125.24 (q, J = 4.04 Hz), 123.87
(q, J = 273.71 Hz), 115.35 (d, J = 14.14 Hz), 112.94, 111.84, Conflicts of interest
57.55, 55.68, 53.00, 46.09, 32.00, 31.39, 25.17, 24.31 (one
There are no conflicts to declare.
carbon peak is overlapped with other peak); 19F-NMR
(377 MHz, chloroform-D) δ −62.81; 31P-NMR (122 MHz, chloro-
form-D)
δ
38.61; HRMS (ESI+ in MeCN) calcd for
Acknowledgements
C43H45ClF3N3O5P+ (M + H) 804.2586 found 804.2609; IR (NaCl)
ν 3019, 2940, 1649, 1596, 1568, 1543, 1505, 1442, 1327, 1299,
1267 cm−1; [α]D20 = −37.83 (c = 1.34, CHCl3); m.p. 148–150 °C.
We are grateful for financial support from a Grant-in-Aid for
Early-Career Scientists (no. 20K15271) from the JSPS, and the
Leading Research Promotion Program ‘Soft Molecular
Activation’ of Chiba University, Japan.
Experimental procedure for Scheme 8
20·HCl (1.2 eq.) was dissolved in THF (0.05 M), and NaHMDS
(1.9 M in THF, 1.0 eq.) was added and stirred for 10 minutes at
room temperature. The solution was cooled to −20 °C and
stirred for 10 minutes, benzyl iodide (1.0 eq.) and 1d (1.0 eq.,
0.15 M in THF) were added, which was vigorously stirred for
24 hours at the same temperature. After that, the reaction was
passed the short silica-gal pad (neutral silica-gel, EtOAc) to
give the crude products. The crude product was dissolved in
CH2Cl2 (0.05 M) and EtOH (0.5 M) at −20 °C, and NaBH4 (5.0
eq.) was added. The reaction was continued for 1 hour, which
was quenched by the addition of excess AcOH (until the gas
evolution stopped), and stirred for 10 minutes. Then it was
neutralised by NaHCO3 aq., extracted by CH2Cl2, dried over
Na2SO4 and filtered to give crude 4, which was purified by
column chromatography (silica-gel, ethyl acetate/hexane) to
give the pure material. The enantiomeric excess pf the product
was determined by HPLC analysis with chiral stationary phase
column.
Methyl 2,3-diphenyl-2-((4-(trifluoromethyl)benzyl)amino)pro-
panoate (4c′). Colorless oil, 1H-NMR (400 MHz, chloroform-D) δ
7.54 (d, J = 8.2 Hz, 2H), 7.41–7.45 (m, 4H), 7.28–7.36 (m, 3H),
7.20 (m, 3H), 6.98–7.01 (m, 2H), 3.77 (m, 4H), 3.64 (d, J = 13.4
Hz, 1H), 3.56 (d, J = 13.7 Hz, 1H), 3.41 (d, J = 13.7 Hz, 1H), 2.20
(s, 1H); 13C-NMR (101 MHz, chloroform-D) δ 174.51, 144.54,
140.56, 136.04, 130.29, 129.15 (q, J = 32.39 Hz), 128.34, 128.14,
128.05, 127.73, 126.92, 126.82, 125.23 (q, J = 3.69 Hz), 124.25
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