Asymmetric transfer hydrogenation of γ-aryl α,γ-dioxo-butyric acid esters

Article abstract of DOI:10.1039/c6ra02500e

The asymmetric transfer hydrogenation (ATH) of a series of γ-aryl-α,γ-dioxo-butyric acid esters has been accomplished smoothly. Six ferrocene-based chiral ligands have been prepared and applied in the reactions respectively. Simultaneously, enantiopure Ts

Full text of DOI:10.1039/c6ra02500e

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Asymmetric transfer hydrogenation of g-aryl a,g-
dioxo-butyric acid esters†
Cite this: RSC Adv., 2016, 6, 33126
Yuan-Zhao Mo, Hui-Fang Nie, Yang Lei, Dong-Xu Zhang, Xiao-Ye Li,
*
*
Sheng-Yong Zhang and Qiao-Feng Wang
Received 27th January 2016
Accepted 22nd March 2016
The asymmetric transfer hydrogenation (ATH) of a series of g-aryl-a,g-dioxo-butyric acid esters has been
accomplished smoothly. Six ferrocene-based chiral ligands have been prepared and applied in the reactions
respectively. Simultaneously, enantiopure Ts-DPEN's utilization in the ATH also has been investigated and
the products were obtained in 30–85% chemical yields with 37–95.5% ee.
DOI: 10.1039/c6ra02500e
www.rsc.org/advances
successfully used in many asymmetric transformations.32 Our
group have also developed a series of ferrocene-based chiral
Introduction
ligands. They possessed excellent enantioselectivities in many
reactions.33–36 Herein, we have chose two of them (L1, L2) as well
as other four new prepared ligands (L3–L6) (Fig. 1) to carry out
the research of the ATH of a,g-dioxo-butyric acid esters.
Simultaneously, the classical Noroyi's catalysts RuCl(p-cymene)
[Ts-DPEN] (Fig. 2) have also been examined in this reaction to
prepare chiral a-hydroxy-g-keto-butyric acid ethyl esters in
detail.
Chiral a-hydroxy-g-keto-butyric acid ethyl esters are key building
blocks for some important bioactive compounds, such as Croo-
mia,1,2 Citrafungins3 and other natural extracts.4–10 The synthesis
of the chiral pharmaceutical a-hydroxy-g-keto intermediates is of
great interest in organic chemistry. However, only a few methods
have been reported on their preparation such as asymmetric
reduction via enzymatic catalysis,11–13 enantioselective aza-ene-
type reactions14,15 as well as Brønsted acid catalyzing asym-
metric aldol reactions16 and heterogeneous enantioselective
hydrogenations.17,18 Compared with the above reported methods,
transition metal-catalyzed asymmetric transfer hydrogenation
(ATH) should be a more facile access because of concise proce-
dure and easy operation. As a kind of powerful method for
asymmetric transformation,19 ATH is widely used in both
academics and industrials. Since it was reported in early 1980s,20
many excellent chiral ligands have been found and various
substrates have also been investigated.21 Nowadays the pursuit
for novel chiral ligands22 and the new applications of the existed
ligands23–25 for ATH were still attractive. As far as the substrates in
ATH were concerned, the class of chemicals with several carbonyl
moieties in one molecule26–29 were very interesting because
multiple-carbonyl groups mean many synthetic applications. But
there were limited papers on the ATH of multi-carbonyl
compounds.30 It was worthy of notice that the ATH of g-aryl-
a,g-dioxo-butyric acid esters is seldom reported to date (Scheme
1).
Results and discussion
The synthesis of ferrocene-based chiral ligands
The preparation of the six ferrocene-based chiral ligands (Fig. 1)
was straightforward and as shown in Scheme 2. According to
literature,36 ortho-lithiation of (R)-Ugi's amine and subsequent
treatment with ClPAr2, Ac2O and a large excess of ammonia,
intermediate 1a could be obtained. Then the reductive amina-
tion of 1a with picolinaldehydes resulted in the formation of
ligands L1–L3 in 30–54% isolated yields.37 Similar process also
could lead to L4 (50% yield). If (R)-Ugi's amine was stirred with
Ac2O at 100 ꢀC under nitrogen conditions, acetate 2 was fur-
nished and could be used in the next step without further
purication.36 Aer amination of 2 by (S,S) or (R,R)-1,2-diphenyl-
1,2-ethanediamine in CH3OH, L5 or L6 was produced directly.36
As to the structure of the above ligands, L1, L2 and L3 had
both central chirality and planar chirality while L4, L5 and L6
only possessed stereogenic carbon. They were designed for
Ferrocene was an outstanding skeleton for ligand design.31
There were lots of excellent ferrocene-based chiral ligands
Department of Medicinal Chemistry, School of Pharmacy, The Fourth Military Medical
University, Changle West Road 169, Xi'an, 710032, P. R. China. E-mail: zytwqf@
fmmu.edu.cn; syzhang@fmmu.edu.cn; Fax: +86-29-84776945; Tel: +86-29-84776807
ext. 611
† Electronic supplementary information (ESI) available: 1H, 13C NMR of products
4a–g, 1H, 31P, 13C NMR and HRMS of compounds L1–L6, HPLC charts of products
4a–g. X-ray crystal of 4b, 4g. See DOI: 10.1039/c6ra02500e
Scheme 1 Asymmetric transfer hydrogenation (ATH) of g-aryl a,g-
dioxo-butyric acid ester.
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hand, reaction in HCOOH/Et3N (5 : 2) system have proceeded
smoothly and afforded a-hydroxy ester with the yield of 85%
and 84% ee (Table 1, entry 1). So HCOOH/Et3N (5 : 2) was
selected as hydrogen source for further experiments.
To optimize the reaction efficiency, several solvents have
been examined. We have observed that the ee in proton solvent
(MeOH) was moderate (73% ee), but the yield was low (30%)
(Table 1, entry 2). Moreover, the results in nonproton solvents,
such as DMF, dioxane, DCM, EtOAc and t-BuOMe, were better
than that in proton solvent (Table 1, entry 2–8). Especially, polar
nonproton solvent DMF gave the highest yield (85%) and the
highest ee (84% ee). The solvent inuence on the reaction may
related to the formation of transition state. Bigger steric
hindrance solvent corresponded to better enantioselectivity.
In order to investigate temperature effect on the reaction, we
Fig. 1 The structure of ferrocene-based chiral ligands used in the
ATH.
ꢀ
have decreased the temperature from r.t. to 0 C. But the ees
ꢀ
didn't change (Table 1, entry 1 vs. entry 10). At ꢁ20 C, much
higher optical yield (94% ee) accompanied with lower chemical
yield (68%) was observed (Table 1, entry 11). However, at more
lower temperature (ꢁ40 ꢀC), the reaction only had trace
conversion (Table 1, entry 12). Lastly, ꢁ20 ꢀC was determined as
the optimal temperature.
Fig. 2 The structure of RuCl(p-cymene)[Ts-DPEN].
We have also found that the conguration of the product was
controlled by the ligand. Switching the conguration of the Ts-
DPEN from (S,S) to (R,R), the product conguration also
changed to (R)-conguration (Table 1, entry 13).
Under the optimized conditions, a wide range of substrates
have been put into the reaction and RuCl(p-cymene)[(R,R)-Ts-
DPEN] has been employed (Table 2). Form these reaction, we
noticed that substituent on the g-phenyl had not effect on the
Table 1 The ATH reactions catalyzed by Ru-(S,S)-Ts-DPEN complex
Scheme 2 The route to ferrocene-based chiral ligands.
Entrya
Temp.
Solvent
Yield (%)
eee (%) (conf.)
1b
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
DMF
MeOH
Et2O
DCM
THF
EtOAc
Dioxane
t-BuOMe
—
DMF
DMF
DMF
DMF
85
30
Trace
Trace
73
80
77
82
75
80
68
Trace
68
84(S)
73(S)
ND
detection of the planer chirality and the match of multicentre
chirality on the effect of the ATH reaction.
2b
3b
4b
ND
5b
50(S)
23(S)
60(S)
81(S)
79(S)
84(S)
94(S)
ND
The ATH catalyzed by RuCl(p-cymene)(Ts-DPEN)
6b
Noroyi's catalysts, RuCl(p-cymene)[(S,S)-Ts-DPEN] and its
enantiomer have been star catalysts in ATH and they can be got
in a commercial way. So their applications in ATH of g-aryl-a,g-
dioxo-butyric acid esters (Scheme 1) have been carried out
rstly.
A survey of reaction media was nished with g-phenyl-a,g-
dioxo-butyric acid ester (3a)38,39 as model substrate. Different
hydrogen sources, various solvents and temperature were
probed.
7b
8b
9c
10b
11b
12b
13b,d
0
ꢀC
ꢁ20 ꢀC
ꢁ40 ꢀC
ꢁ20 ꢀC
94(R)
a
1 mmol 3a with 0.0025 mmol of Ru(p-cymene)Cl and 0.005 mmol of
b
(S,S)-Ts-DPEN for each entry. Dissolution in 4 mL HCOOH/Et3N
(5 : 2) and 1 mL solvent. Using 5 mL of HCOOH/Et3N (5 : 2) without
c
d
Initially, at room temperature (r.t.), two most common solvent. 0.005 mmol of (R,R)-Ts-DPEN instead of (S,S)-Ts-DPEN was
e
employed. The enantiomeric excess (ee) and conguration (conf.) of
hydrogen source: both i-PrOH-KOH system and HCOOH/Et3N
product were determined by chiral HPLC with Chiralpak OD-H
column and according to literature or X-ray crystal.
(5 : 2) system have been tested. But aer monitored by TLC, no
transformation has happened in i-PrOH system. On the other
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Table 2 Different substrates of the ATH catalyzed by RuCl [(R,R)- Table 3 The ATH reactions catalyzed by L2
TsDPEN](p-cymene)
Entrya
Solvent
Temp.
Yield (%)
eeb (%) (conf.)
Entrya Substrate Ar
R
Product Yield (%) eeb (%) (conf.)
1
2
3
4
5
6
DMF
MeOH
THF
CH2Cl2
CH3CN
DMF
r.t.
r.t.
r.t.
r.t.
72
5(R)
ND
ND
ND
ND
Trace
Trace
Trace
Trace
60
1
2
3
4
5
6
7
8
3b
3c
3d
3e
3f
3g
3h
3i
4-F-Ph
4-Cl-Ph
4-Br-Ph
4-OMe-Ph
2-Furyl
2-Thienyl
Ph
H
H
H
H
H
H
Me
Ph
4b
4c
4d
4e
4f
61
58
60
58
55
71
—
—
91(R)
91(R)
91(R)
94.5(R)
96(R)
96(R)
ND
r.t.
ꢁ20 ꢀC
65(R)
a
4g
—
—
1 mmol of 3a with 0.0025 mmol of Ru(p-cymene)Cl and 0.005 mmol of
L2 in 4 mL HCOOH/Et3N (5 : 2) and 1 mL DMF at ꢁ20 ꢀC stir 4 days for
b
Ph
ND
each entry. The ee and conguration of product were determined by
chiral HPLC with Chiralpak OD-H column and according to literature
or X-ray crystal.
a
1 mmol of substrate with 0.0025 mmol of Ru(p-cymene)Cl and 0.005
mmol of (R,R)-Ts-DPEN in 4 mL HCOOH/Et3N (5 : 2) and 1 mL DMF
b
at ꢁ20 ꢀC stir 4 days for each entry. The ee and conguration of
product were determined by chiral HPLC with Chiralpak OD-H, OJ-H
or AD-H column and according to literature or X-ray crystal.
Then screen of these chiral ligands was necessary. The
results were described in Table 4. All the six chiral ligands
induced moderate chemical yield while their optical results
were much different. L1 had P, N, N three special elements and
achieved the best optical yield (90% ee) (Table 4, entry 1).
Comparing with L1, L2's result was much worse though it had
little structure difference with L1. The ee was only 65% (Table 4,
entry 2). In order to check pyridine unit's impact on the reac-
tion, L3 was prepared and the ee from L3 was a little lower than
that of L2 (Table 4, entry 3). This implied that the N atom on
pyridine of ligand inuenced stereoselectivity and chemical
yield but not too much. On the other hand, L4 only had one
chiral element and the chiral centre was far from the metal
center. Then its racemic result was not surprising (Table 4, entry
4). What’ more, L5 and L6's behaviours were almost the same.
Their ees were 40% and 37%, but the congurations were
results. 3b–3d, which separately possessed electron with-
drawing group (F, Cl, Br), afforded almost the same results as 3e
did (Table 2, entry 1–4). They all provided products with the ee
exceeded 91% and the chemical yields were moderate. More-
over, for all substrates, there only a-carbonyl group could
transfer into hydroxyl and got corresponding chiral a-hydroxy-
g-keto-butyric acid ethyl esters. To our delight, furan and thio-
phene derivatives (3f or 3g) also gave satisfactory optical selec-
tivity results (Both ees were more than 96%). It's should known
that this two kind of compounds were widely used in pharmacy.
When more sterically crowded substrate 3h or 3i has been
tested, no product was detected (Table 2, entry 7–8). This indi-
cated that steric-hindrance on the b-site inuenced coordina-
tion between substrate and metal. All the products'
congurations were consistent with that of the ligand. They
were (R)-conguration. Product 4b and 4e were also character-
ized by X-ray single crystal diffraction analysis. The structure of
4e was shown in Fig. 3.
Table 4 The ATH reactions catalyzed by ferrocene-based chiral
catalysts
The ATH catalyzed by ferrocene-based chiral catalysts
With ferrocene-based chiral ligands at hand, our initial survey
has focused on evaluating the possibility of using these ligands
L1–L6 for the chiral induction in ATH of 3a. Employing L2 as
ligand, we have tested the solvent and temperature of the
reaction. They were shown in Table 3. Lastly, DMF and ꢁ20 ꢀC
proved to be the optimized condition.
Entrya
Ligand
Yield (%)
eeb (%) (conf.)
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
57
60
55
47
50
52
90(R)
65(R)
50(R)
Rac
40(S)
37(R)
a
1 mmol of 3a with 0.0025 mmol of Ru(p-cymene)Cl and 0.005 mmol of
ligand in 4 mL HCOOH/Et3N (5 : 2) and 1 mL DMF at ꢁ20 ꢀC stir 4 days
for each entry. b The ee and conguration of product were determined
by chiral HPLC with Chiralpak OD-H column and according to
literature or X-ray crystal.
Fig. 3 X-ray crystal structure of (R)-4e.
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Table 5 Different substrates of the ATH reactions catalyzed by L1
Experimental
General
All reactions involving air- or moisture-sensitive species were
nished under N2 atmosphere. High-resolution mass spectra
were performed on a Bruker smartapex II CCD Mass Spec-
trometer with ES ionization (ESI). The 1H and 13C NMR spectra
were recorded on a Bruker AV-400 spectrometer with TMS as an
internal reference. Coupling constant (J) values were given in
Hz. Multiplicities are designated by the following abbreviations/
s, singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multi-
Entrya Substrate Ar
Product Yield (%) eeb (%) (conf.)
1
2
3
4
5
6
3b
3c
3d
3e
3f
4-F-Ph
4-Cl-Ph
4-Br-Ph
4-OMe-Ph 4e
2-Furyl 4f
2-Thienyl 4g
4b
4c
4d
55
58
53
50
48
50
69(R)
67(R)
75(R)
69(R)
75(R)
87(R)
ꢀ
plet. Melting points were uncorrected and expressed in C by
MRS-2 melting point apparatus from Shanghai Apparatus Co.,
Ltd. An Agilent 1200 series apparatus and Chiralpak AD-H, OD-
3g
a
1 mmol of substrate with 0.0025 mmol of Ru(p-cymene)Cl and 0.005
mmol of L1 in 4 mL HCOOH/Et3N (5 : 2) and 1 mL DMF at ꢁ20 ꢀC stir H and OJ-H columns, purchased from Daicel Chemical Indus-
b
4 days for each entry. The ee and conguration of product were
tries, were used in Chiral High Performance Liquid Chroma-
determined by chiral HPLC with Chiralpak OD-H, OJ-H or AD-H
column and according to literature or X-ray crystal.
tography (HPLC) analyses. All commercially available reagents
were used as received. Thin layer chromatography on silica
(with GF254) was used to monitor all reactions. Products were
puried by ash column chromatography on silica gel
purchased from Qingdao Haiyang Chemical Co., Ltd. Optical
rotations were measured on a Perkin Elmer 343 polarimeter.
The conguration of the products had been assigned by
comparison to the literature data or single crystal diffraction.
different (Table 4, entry 5 and 6). So we can know that the chiral
carbon centre of Ugi's amine almost had not attribution to the
stereocontrol in the ATH. The planer chiral elements and the P
unit on the ferrocene ring were essential for the high enantio-
selectivity. At the same time, the Ar groups on P provides
bulkiness which caused better enantiocontrol in the reaction
(Table 4 entry 1 vs. entry 2). N atom on pyridine also helped to
improve this kind of selectivity (Table 4, entry 2 vs. entry 3). It's
noteworthy that these six ligands' behavior were not as good as
that of chiral RuCl(p-cymene)[Ts-DPEN]. Maybe it was due to the
activity of H on N in these six ligands was lower than RuCl(p-
cymene)[Ts-DPEN], which resulted in establishing Ru–H–C–O–
H–N–Ru transition state ring harder.
Of course, L1 would applied to more substrates' ATH reac-
tions. As Table 5 showed, at ꢁ20 ꢀC and in HCOOH/Et3N (5 : 2)
system, L1 exhibited moderate to good inducing ability. The ees
ranged from 67% to 87% with the yield of 50% or so. Like the
results in Table 2, the substituent, F, Cl, Br or OMe on the g-
phenyl of the substrate had no inuence on the ATH (Table 5,
entry 1–4). Furthermore, furan derivative 3f and thiophene
derivative 3g also gave corresponding a-hydroxy-g-keto-butyric
acid ethyl ester with 75% ee and 87% ee respectively (Table 5,
entry 5 and 6).
The synthesis of ferrocene-based chiral ligand
The synthesis of L1. Corresponding 1a (1.284 g, 2 mmol),
which could be prepared from (R)-Ugi's amine,36 and 6-methyl-
2-pyridylaldehyde (0.3025 g, 2.5 mmol) were dissolved in 10 mL
MeOH. At r.t., the system was stirred for 6 hours under N2
atmosphere. With NaBH4 (0.19 g, 5 mmol) added, the reaction
was proceeded overnight. Aer that, 10 mL H2O was added and
subsequently extracted with CH2Cl2 (10 mL) for three times. The
organic layers were dried over Na2SO4. L1 can be puried by
column chromatography (n-hexane/EtOAc/Et3N ¼ 8/1/0.03, v/v).
Yield 54%; yellow foam; [a]2D5 ¼ ꢁ184.6ꢀ (c ¼ 0.25, CH2Cl2);
1H NMR (400 Hz, CDCl3) d 7.42–7.37 (m, 3H), 7.24 (s, 2H), 7.23–
7.21 (m, 1H), 7.17–7.10 (m, 1H), 6.81 (d, J ¼ 7.5 Hz, 1H), 5.89 (d, J
¼ 8 Hz, 1H), 4.51 (s, 1H), 4.30–4.23 (m, 2H), 4.06 (s, 5H), 3.75 (s,
1H), 3.54 (d, J ¼ 14.5 Hz, 1H), 3.48 (d, J ¼ 14.5 Hz, 1H), 2.39 (s,
3H), 1.55 (d, J ¼ 6.5 Hz, 3H), 1.29 (s, 18H), 1.13 (s, 18H); 31P NMR
(202 Hz, CDCl3) d ꢁ24.98 (s); 13C NMR (101 Hz, CDCl3) d 159.4
(d, J ¼ 5.9 Hz), 157.1, 150.5 (d, J ¼ 6.6 Hz), 150.0 (d, J ¼ 7.4 Hz),
138.5 (d, J ¼ 7.7 Hz), 136.3, 135.6 (d, J ¼ 7.3 Hz), 129.1 (d, J ¼
21.4 Hz), 127.4 (d, J ¼ 20.7 Hz), 125.3, 122.7 (d, J ¼ 20.5 Hz),
120.8, 117.8, 96.9, 75.1 (d, J ¼ 14.1 Hz), 71.1 (d, J ¼ 4.2 Hz), 69.6,
Conclusion
This paper presented a convenient method toward chiral a- 69.4 (d, J ¼ 3.8 Hz), 68.6, 51.8, 51.1 (d, J ¼ 10.1 Hz), 34.9, 34.8,
hydroxy-g-keto-butyric acid ethyl esters. The preparation of six 31.5, 31.3, 24.3, 19.2; HRMS (ESI) calcd for C47H63FeN2P [M +
chiral ferrocene-based ligands and their utilization in ATH of H]+ ¼ 743.4157, found/743.4148.
multiple-carbonyl compounds were discussed. Several optical a-
The synthesis L2. L2 is prepared from 1a through the same
hydroxy-g-keto-butyric acid ethyl esters were achieved with procedure as described above for L1.
moderate to excellent ees and moderate chemical yields.
1
Yield 50%; red foam; [a]2D5 ¼ ꢁ243.8ꢀ (c ¼ 0.65, CH2Cl2); H
Enantiopure RuCl(p-cymene)[Ts-DPEN] catalysts' application in NMR (400 MHz, CDCL3) d 7.56–7.50 (m, 2H), 7.40–7.33 (m, 3H),
the asymmetric transformation were also developed. Our six 7.28–7.20 (m, 3H), 7.17–7.10 (m, 3H), 6.84 (d, J ¼ 7.5 Hz, 1H),
ferrocene-based ligands and the reaction for further utilization 6.33 (d, J ¼ 7.5 Hz, 1H), 4.53 (s, 1H), 4.33–4.28 (m, 1H), 4.25–4.17
are both on going.
(m, 1H), 4.00 (s, 5H), 3.85–3.80 (m, 1H), 3.62 (s, 1H), 2.41 (s, 3H),
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1.55 (d, J ¼ 6.5 Hz, 3H); 31P NMR (162 MHz, CDCL3) d ꢁ25.03 (s); 23.29 (s); HRMS (ESI+) calcd for C26H28FeN2 [M + H]+
¼
13C NMR (101 MHz, CDCl3) d 159.3, 157.1, 140.1 (d, J ¼ 9.8 Hz), 425.1680, found/425.1686.
137.4 (d, J ¼ 9.2 Hz), 136.3, 135.0 (d, J ¼ 21.3 Hz), 132.6 (d, J ¼
The synthesis of L6. L6 was prepared from (R,R)-DPEN
18.6 Hz), 131.5 (d, J ¼ 10 Hz), 129.1, 128.3 (d, J ¼ 5.9 Hz), 128.3, through the same procedure as described above toward L5.
1
120.9, 118.3, 97.8 (d, J ¼ 24.3 Hz), 75.1 (d, J ¼ 8.2 Hz), 71.3 (d, J ¼
Yield 40%; orange foam; [a]2D5 ¼ 34.8ꢀ (c ¼ 1, CH2Cl2); H
4 Hz), 69.6, 69.5 (d, J ¼ 4.4 Hz), 69.1, 52.1, 51.3 (d, J ¼ 9.2 Hz), NMR (400 MHz, CDCl3) d 7.32–7.15 (m, 10H), 4.23 (s, 1H), 4.14–
24.4, 19.4; HRMS (ESI) calcd for C31H31FeN2P [M + H]+
519.1653, found/519.1645.
¼
4.06 (m, 4H), 4.02 (s, 5H), 3.30 (m, 2H), 1.22 (d, J ¼ 6.3 Hz, 3H);
13C NMR (101 MHz, CDCl3) d 169.91 (s), 143.41 (s), 141.56 (s, J ¼
The synthesis of L3. Corresponding 1a (0.828 g, 2 mmol) and 69.1 Hz), 128.13 (d, J ¼ 1.6 Hz), 127.91 (s), 127.11 (s), 127.03 (s),
6-methyl-2-benzaldehyde (0.3 g, 2.5 mmol) were dissolved in 10 126.97 (s), 94.99 (s), 68.22 (s), 67.22 (s), 66.42 (s), 66.07 (d, J ¼ 6.5
mL MeOH. The system was stirred at r.t. for 6 hours under N2 Hz), 61.60 (s), 47.73 (s), 23.35 (s); HRMS (ESI+) calcd for
atmosphere. With 5 g Pd/C was added, the reaction was carried
out under 20 atm of H2 in autoclave overnight. Then ltered and
the ltrate was dried over Na2SO4. L3 can be puried by column
chromatography (n-hexane/EtOAc/Et3N ¼ 8/1/0.03, v/v).
C
26H28FeN2 [M + H]+ ¼ 425.1680, found/425.1679.
The general procedure for ATH in HCOOH/Et3N (5 : 2)
Yield 30%; red foam; [a]2D5 ¼ ꢁ139ꢀ (c ¼ 0.1, CH2Cl2); 1H 1 mmol of substrate with 0.0025 mmol of Ru(p-cymene)Cl and
NMR (400 MHz, CDCl3) d 7.89–7.75 (m, 2H), 7.73–7.60 (m, 2H), 0.005 mmol of chiral ligand were dissolved in 1 mL solvent and
7.59–7.47 (m, 3H), 7.42–7.30 (m, 3H), 6.99 (t, J ¼ 7.5 Hz, 1H), stirred at r.t. for 4 hours under N2 atmosphere. Then 4 mL
6.92 (d, J ¼ 7.5 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J ¼ 7.1 Hz, 1H), 4.68 HCOOH/Et3N (5 : 2) was injected by syringe. The mixture was
(d, J ¼ 27.6 Hz, 1H), 4.39 (d, J ¼ 2.3 Hz, 1H), 4.24 (s, 5H), 3.96 (s, stirred at ꢁ20 ꢀC for 4 days under N2 atmosphere. Saturated
1H), 3.37 (s, 2H), 3.30 (dd, J ¼ 7.1, 5.9 Hz, 1H), 2.23 (s, 3H), 1.53 NaHCO3 (5 mL) and H2O (5 mL) were added and then extracted
(d, J ¼ 6.6 Hz, 3H); 31P NMR (162 MHz, CDCl3) d ꢁ25.36 (s); 13
C
with EtOAc (10 mL) for three times and dried over Na2SO4. The
NMR (101 MHz, CDCl3) d 169.99 (s), 137.41 (s), 135.55 (s), 134.38 product was puried by column chromatography (n-hexane/
(d, J ¼ 26.6 Hz), 133.19 (s), 131.61 (d, J ¼ 2.7 Hz), 131.44 (d, J ¼ EtOAc ¼ 4/1, v/v).
9.9 Hz), 131.19 (d, J ¼ 9.9 Hz), 128.65 (s), 128.46 (d, J ¼ 12.0 Hz),
Product 4a. Yellow oil; 1H NMR (400 MHz, CDCl3) d 7.97 (d, J
128.31–127.84 (m), 127.19 (s), 126.97 (s), 125.04 (s), 98.53–94.93 ¼ 7.3 Hz, 2H), 7.64–7.57 (m, 1H), 7.49 (t, J ¼ 7.7 Hz, 2H), 4.68
(m), 73.54 (d, J ¼ 15.2 Hz), 71.39 (s), 71.00 (d, J ¼ 9.9 Hz), 70.30 (m, 1H), 4.29 (q, J ¼ 7.1 Hz, 2H), 3.52 (m, 2H), 1.30 (t, J ¼ 7.1 Hz,
(s), 70.04 (d, J ¼ 11.5 Hz), 69.70–69.59 (m), 50.77 (s), 23.37 (s), 3H); 13C NMR (101 MHz, CDCl3) d 197.57 (s), 173.83 (s), 136.42
19.38 (s); HRMS (ESI) calcd for C32H32FeNP [M + H]+ ¼ 518.1700, (s), 133.63 (s), 128.70 (s), 128.18 (s), 67.20 (s), 61.85 (s), 42.19 (s),
found/518.1739.
14.11 (s).
Product 4b. Yellow solid; m.p. 71–72 ꢀC; 1H NMR (400 MHz,
The synthesis of L4. L4 was prepared from 1b (0.458 g, 2
mmol), which was also obtained from (R)-Ugi's amine,36 and 6- CDCl3) d 8.01 (m, 2H), 7.21–7.13 (m, 2H), 4.67 (t, J ¼ 5.7, 3.9 Hz,
methyl-2-pyridylaldehyde through the same procedure as 1H), 4.30 (q, J ¼ 7.1 Hz, 2H), 3.49 (qd, J ¼ 17.4, 4.9 Hz, 2H), 3.33
described above for L1.
(d, J ¼ 5.6 Hz, 1H), 1.31 (t, J ¼ 7.1 Hz, 3H); 13C NMR (101 MHz,
Yield 50%; red foam; [a]2D5 ¼ ꢁ8ꢀ (c ¼ 0.25, CH2Cl2); 1H NMR CDCl3) d 195.90 (s), 173.72 (s), 130.94 (s), 130.84 (s), 115.99 (s),
(400 MHz, CDCl3) d 7.53 (t, J ¼ 7.6 Hz, 1H), 7.11 (d, J ¼ 7.6 Hz, 115.77 (s), 67.18 (s), 61.96 (s), 42.06 (s), 14.13 (s).
1H), 7.03 (d, J ¼ 7.6 Hz, 1H), 4.26 (s, 1H), 4.20 (s, 6H), 4.13 (s,
Product 4c. Yellow oil; 1H NMR (400 MHz, CDCl3) d 7.95–7.88
2H), 3.92 (m, 2H), 3.57 (q, J ¼ 6.4 Hz, 1H), 2.56 (s, 3H), 1.42 (d, J (m, 2H), 7.51–7.44 (m, 2H), 4.67 (dd, J ¼ 5.5, 1.6 Hz, 1H), 4.30 (q,
¼ 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 158.94 (s), 158.01 J ¼ 7.1 Hz, 2H), 3.48 (qd, J ¼ 17.4, 4.9 Hz, 2H), 3.32 (d, J ¼ 5.5 Hz,
(s), 136.60 (s), 121.42 (s), 119.26 (s), 94.06 (s), 68.55 (s), 68.51 (d, J 1H), 1.31 (t, J ¼ 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 196.26
¼ 6.8 Hz), 67.29 (s), 66.69 (s), 66.26 (s), 52.95 (s), 52.02 (s), 24.47 (s), 173.69 (s), 140.15 (s), 134.80 (s), 129.86 (s), 129.51 (d, J ¼ 18.2
(s), 21.65 (d, J ¼ 69.8 Hz); HRMS (ESI) calcd for C19H22FeN2 [M + Hz), 129.13 (d, J ¼ 14.8 Hz), 67.13 (s), 61.98 (s), 42.13 (s), 14.13
H]+ ¼ 335.1211, found/335.1224.
(s).
The synthesis of L5. 2 (1.088 g, 4 mmol), which was prepared
Product 4d. Yellow oil; 1H NMR (400 MHz, CDCl3) d 7.81 (m,
from (R)-Ugi's amine,36 and (S,S)-DPEN (2.12 g, 10 mmol) were 2H), 7.61 (m, 2H), 4.70–4.61 (m, 1H), 4.26 (q, J ¼ 7.1 Hz, 2H),
dissolved in the mixture of 30 mL MeOH, 30 mL THF and 3 mL 3.46 (dd, J ¼ 17.2, 4.8 Hz, 2H), 1.28 (t, J ¼ 7.1 Hz, 3H); 13C NMR
H2O. The reaction was stirred at 70 ꢀC overnight under N2 (101 MHz, CDCl3) d 196.47 (s), 173.76 (s), 135.20 (s), 132.02 (s),
atmosphere. Aer vacuum distillation, the system was extracted 129.68 (s), 128.85 (s), 67.05 (s), 61.91 (s), 42.16 (s), 14.12 (s).
with Et2O (30 mL) three times and the organic layers were dried
over Na2SO4. L5 can be puried by column chromatography (n- CDCl3) d 7.93 (d, J ¼ 8.8 Hz, 2H), 6.94 (d, J ¼ 8.8 Hz, 2H), 4.65
Product 4e. Yellow solid; m.p. 65–66 ꢀC; 1H NMR (400 MHz,
hexane/EtOAc/Et3N ¼ 8/1/0.03, v/v).
(dd, J ¼ 5.8, 4.1 Hz, 1H), 4.26 (q, J ¼ 7.1 Hz, 2H), 3.87 (s, 3H),
Yield 40%; orange foam; [a]2D5 ¼ ꢁ17.8ꢀ (c ¼ 0.5, CH2Cl2); 1H 3.45 (qd, J ¼ 17.3, 5.0 Hz, 2H), 1.28 (t, J ¼ 7.2 Hz, 3H); 13C NMR
NMR (400 MHz, CDCl3) d 7.33–7.15 (m, 10H), 4.24 (m, 1H), 4.14– (101 MHz, CDCl3) d 196.16 (s), 173.83 (s), 163.95 (s), 130.54 (s),
4.06 (m, 4H), 4.01 (m, 5H), 3.34–3.20 (m, 2H), 1.23 (d, J ¼ 6.3 Hz, 129.55 (s), 113.87 (s), 67.42 (s), 61.81 (s), 55.52 (s), 41.75 (s),
3H); 13C NMR (101 MHz, CDCl3) d 170.18 (s), 143.20 (s), 141.45 14.14 (s).
(s), 128.20 (s), 127.92 (s), 127.14 (s), 127.11 (s), 127.05 (s), 94.93
(s), 68.27 (s), 67.29 (s), 66.44 (s), 66.06 (s), 61.53 (s), 47.71 (s), 1.0 Hz, 1H), 7.26 (s, 1H), 6.58 (dd, J ¼ 3.6, 1.7 Hz, 1H), 4.66 (s
Product 4f. Black oil; 1H NMR (400 MHz, CDCl3) d 7.63 (d, J ¼
33130 | RSC Adv., 2016, 6, 33126–33131
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1H), 4.29 (q, J ¼ 7.1 Hz, 2H), 3.45–3.31 (m, 2H), 1.30 (t, J ¼ 7.1 15 K. Zheng, X. Liu, J. Zhao, Y. Yang, L. Lin and X. Feng, Chem.
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Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (NSFC, No. 21102175, 21172262) are gratefully
acknowledged. In addition, special thanks are due to Professor
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RSC Adv., 2016, 6, 33126–33131 | 33131