Asymmetric catalytic Mannich-type reaction of hydrazones with difluoroenoxysilanes using imidazoline-anchored phosphine ligand-zinc(II) complexes

Article abstract of DOI:10.1039/c2ob07022g

Asymmetric Mannich-type reaction of hydrazones with difluoroenoxysilanes using chiral zinc(II)-imidazoline-phosphine complexes as catalysts have been established, giving the corresponding adducts in good to excellent enantioselectivity and chemical yields under mild conditions. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob07022g

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Organic &
Biomolecular
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Volume 10 | Number 13 | 7 April 2012 | Pages 2489–2700
ISSN 1477-0520
PAPER
G. Li, M. Shi et al.,
Asymmetric catalytic Mannich-type reaction of hydrazones with
difluoroenoxysilanes using imidazoline-anchored phosphine ligand–zinc(II)
complexes
1477-0520(2012)10:13;1-H

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COMMUNICATION
Asymmetric catalytic Mannich-type reaction of hydrazones with
difluoroenoxysilanes using imidazoline-anchored phosphine ligand–zinc(II)
complexes†
Zhiliang Yuan,a Liangyong Mei,a Yin Wei,a Min Shi,*a Padmanabha V. Kattamuri,b Patrick McDowellb and
Guigen Li*b
Received 1st December 2011, Accepted 6th January 2012
DOI: 10.1039/c2ob07022g
β-amino-α,α-difluoro carbonyl compounds via the reaction of N-
Boc-protected imines with difluoroenoxysilanes in the presence
of chiral phosphoric acid.8c We also reported the zinc-catalyzed
asymmetric difluorination reaction of readily available hydra-
zones with difluoroenoxysilane, providing the corresponding
adducts in moderate yields and enantioselectivities.9 Herein, we
would like to disclose the enantioselective Mannich-type reac-
tion of difluoroenoxysilanes with hydrazones by using the cata-
lytic complexes formed from zinc salt and novel chiral
imidazoline–phosphine ligands. Our previous study revealed the
use of Zn(OTf)2–oxazoline–phosphine ligand complexes (L5–
L8, Fig. 1) as catalysts for the asymmetric difluorination of
hydrazones with difluoroenoxysilane can lead to the formation
of corresponding difluorination adducts in low yields and enan-
tioselectivities (up to 51% ee with 23% isolated yield),9 while
their chiral phosphine-anchored Schiff’s base counterparts (L1–
L4, Fig. 1) do nor show any effectiveness. Recently, we switched
our strategy to the design and synthesis of N-containing hetero-
cycle–phosphine ligands for Mannich-type difluorination reac-
tion. Since the five-membered imidazoline ring can easily
coordinate onto metal cations, which is similar to its oxazoline-
based situation.10 We envisioned that they would offer an oppor-
tunity to render the asymmetric catalytic Mannich-type reaction
of difluoroenoxysilanes with hydrazones. Following an efficient
route developed by You and Kelly,11 we prepared a series of
novel chiral imidazoline–phosphine ligands, L9–L14, based on
a binaphthyl scaffold (Fig. 2). In addition, the structure of
L9 has been unambiguously determined by X-ray diffraction
analysis (see ESI†).
Asymmetric Mannich-type reaction of hydrazones with
difluoroenoxysilanes using chiral zinc(II)–imidazoline–phos-
phine complexes as catalysts have been established, giving
the corresponding adducts in good to excellent enantioselec-
tivity and chemical yields under mild conditions.
Organofluorine chemistry has attracted a considerable interest in
the past several decades because, the introduction of fluorine
atoms onto target molecules can cause significant enhancement
in their chemical, physical, and pharmacological properties.1,2 In
fact, the development of more efficient approaches to optically
active fluorinated compounds has become one of the most chal-
lenging topics in modern organic chemistry.3,4 Several method-
ologies and reagents have been established for the asymmetric
fluorination, trifluoromethylation, and perfluoroalkylation reac-
tions.5 However, the progress on assembling chiral difluoro-
methylene structural scaffolds via asymmetric catalytic
difluorination has been slow.6 The enantioselective Reformatsky
reaction of bromodifluoroacetate with aldehydes was disclosed
by Braun7 and co-workers in 1995, affording the corresponding
α, α-difluoro-β-hydroxy esters in up to 84% ee and moderate
yields in the presence of an excess amount of (1R,2S)-N-methyl-
ephedrine. The asymmetric Mukaiyama aldol reaction of difluoro-
ketene silyl with various aldehydes afforded the corresponding
products in good enantioselectivities (up to 97% ee) and excel-
lent yields by using Masamune’s8a or Kiyooka’s catalysts.8b
Very recently, Akiyama and his co-workers have es-
tablished a successful catalytic enantioselective synthesis of
aState Key laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, P. R. China. E-mail: mshi@mail.sioc.ac.cn;
Fax: (+86) 21-6416-6128 (+1) 806-742-3015
bDepartment of Chemistry and Biochemistry, Texas Tech University,
Lubbock, TX 79409-1061. E-mail: guigen.li@ttu.edu;
Fax: (+1) 806-742-3015
†Electronic supplementary information (ESI) available: Spectroscopic
data and chiral HPLC traces of the compounds shown in Tables 1–4, the
detailed descriptions of experimental procedures and the crystal struc-
tures of L9 and 5c. CCDC 785244 and 798183. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2ob07022g
Fig. 1 Selected chiral ligands for Mannich-type difluorinations.
Org. Biomol. Chem., 2012, 10, 2509–2513 | 2509
This journal is © The Royal Society of Chemistry 2012

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Our study was started with the use of hydrazone 1a.12,13 The
initial reaction of hydrazone 1a with difluoroenoxysilane 2a14
was conducted in 1.0 mL of THF in the presence of Lewis acid,
Zn(OTf)2 (10 mol%) together with imidazoline–phosphine
ligand (Ra,S,S)-L9 (10 mol%) as the catalytic combination. We
found that the reaction proceeded smoothly to give the desired
product 3a in 76% yield and 62% ee (Table 1, entry 1), which
was greater than the results of using Zn(OTf)2–oxazoline–phos-
phine ligand as reported previously.9 The use of Zn(NTf2)2
together with L9 showed no improvement in enantioselectivity
(Table 1, entry 2). Inspired by the work performed by Mikami’s
group,15 the use of Zn(OTf)2 and the chiral imidazoline–phos-
phine ligand L9 in a 1 : 2 ratio led to 78% ee with a slightly
Fig. 2 Novel imidazoline–phosphine ligands L9–L14.
Table 1 Screening of ligands in the asymmetric catalytic Mannich-type reaction of hydrazone 1a with difluoroenoxysilane
Yieldb (%)
3a
eec (%)
3a
Absolute
Entrya
Zinc salt (x mol%)
Ligand (y mol%)
configurationd
1
2
3
4
5
6
7
8
9
Zn(OTf)2 (10)
Zn(NTf2)2 (10)
Zn(OTf)2 (10)
Zn(OTf)2 (5)
Zn(OTf)2 (10)
Zn(OTf)2 (10)
Zn(OTf)2 (10)
Zn(OTf)2 (10)
Zn(OTf)2 (10)
(Ra,S,S)-L9 (10)
(Ra,S,S)-L9 (10)
(Ra,S,S)-L9 (20)
(Ra,S,S)-L9 (10)
(Ra,R,R)-L10 (20)
(Sa,S,S)-L11 (20)
(Sa,R,R)-L12 (20)
(Ra,S,S)-L13 (20)
(Ra,S,S)-L14 (20)
76
79
82
59
81
74
71
78
67
62
61
78
65
13
9
77
87
82
S
S
S
S
S
R
R
S
S
a Reaction conditions: 1a (0.10 mmol), 2a (0.30 mmol), zinc salt (x mol%), ligand (y mol%), THF (1.0 mL), and the reaction was carried out at 25 °C
for 24 h. b Isolated yield after column chromatography. c Determined by chiral HPLC analysis. d Determined by X-ray diffraction.
Table 2 Optimization of conditions of the zinc(II)-catalyzed asymmetric Mannich-type reaction
Yieldb (%)
3a
eec (%)
3a
Entrya
Zinc salt
Solvent
T (°C)
Additive
Absolute configurationd
1
2
3
4
5
6
7
8
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(NTf2)2
Zn(NTf2)2
MTBE/THF = 1/1
MeOH/THF = 1/1
EtOH/THF = 1/1
iPrOH/THF = 1/1
tBuOH/THF = 1/1
CF3CH2OH/THF = 1/1
HFIP/THF = 1/1
t-amyl-OH/THF = 1/1
tBuOH/THF = 1/5
tBuOH/THF = 1/10
MeOH/THF = 1/5
MeOH/THF = 1/10
MeOH/THF = 2/1
MeOH/THF = 1/1
MeOH/THF = 1/1
MeOH/THF = 1/1
MeOH/THF = 1/1
25
25
25
25
25
25
25
25
25
25
25
25
25
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
23
88
92
84
49
81
60
trace
23
31
70
71
80
57
trace
71
79
82
89
59
53
90
80
71
n.d.e
86
83
80
81
87
93
n.d.
92
93
S
S
S
S
S
S
S
—
S
S
S
S
S
S
—
S
S
9
10
11
12
13
14
15
16
17
−5
5
5
MS4A
a Reaction conditions: 1a (0.10 mmol), 2a (0.30 mmol), zinc salt (10 mol%), L13 (20 mol%), solvent (1.0 mL) and MS4A (50 mg), the reaction was
carried out for 24 h. b Isolated yield after column chromatography. c Determined by chiral HPLC analysis. d Determined by X-ray diffraction. e n.d. =
not determined.
2510 | Org. Biomol. Chem., 2012, 10, 2509–2513
This journal is © The Royal Society of Chemistry 2012

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improved yield (Table 1, entry 3). However, 5 mol% of Zn
(OTf)2 with 10 mol% of L9 did not show effectiveness in both
the yield and enantioselectivity (Table 1, entry 4). Next, we
examined different imidazoline–phosphine ligands, L10–L14.
We found that ligands (Ra,R,R)-L10 and (Sa,S,S)-L11 afforded
the desired Mannich-type adduct 3a in up to 81% yield and low
enantioselectivities (Table 1, entries 5 and 6). Ligand (Sa,R,R)-
L12 produced the opposite enantiomer of 3a in a similar yield
and enantioselectivity, which was observed in the reaction of
hydrazone 1a with difluoroenoxysilane 2a catalyzed by (Ra,S,S)-
L9/Zn(OTf)2 (Table 1, entry 7). As compared to ligand (Ra,S,S)-
L14, (Ra,S,S)-L13, bearing a di(3,5-dimethylphenyl)phosphine
group, led to the corresponding product 3a in 78% yield and
87% ee (Table 1, entries 8 and 9). With the effective chiral
ligand (Ra,S,S)-L13 in hand, we further optimized the condition
by changing solvents, temperatures, additives, and zinc salts
(Table 2). Since the ligand L13 and hydrazone 1a have low solu-
bility in MTBE (tert-butyl methyl ether) and various alcohols,
we combined THF with these solvents in 1 : 1 ratio. Interestingly,
we found that when MeOH–THF (1 : 1) was employed, the cor-
responding adduct 3a was obtained in 88% yield along with
89% ee (Table 2, entry 2). However, the combination of MeOH
with other solvents, such as MeCN, CH2Cl2 and toluene gave
poor yield and enantioselectivity.9 Screening of the alcohols
Table 3 Substrate scope of the Zn(NTf2)2-catalyzed asymmetric
Mannich-type reaction of hydrazone with difluoroenoxysilane 2a
t
revealed that both MeOH–THF (1 : 1) and BuOH–THF (1 : 1)
resulted in higher enantioselectivity than the combinations of
other alcohols (Table 2, entries 2–8). The ratios of MeOH–THF
and tBuOH–THF were also examined, but lower ee was
obtained, albeit a similar chemical yield was retained (Table 2,
entries 9–13). When the reaction was performed at 5 °C, adduct
3a was obtained in 57% yield and 93% ee (Table 2, entry 14).
Whereas, only a trace amount of 3a was formed when the reac-
tion was performed at −5 °C (Table 2, entry 15). To further acti-
vate the hydrazone 1a at lower temperature, we utilized Zn
(NTf2)2 instead of Zn(OTf)2 as Lewis activator. Pleasantly,
product 3a was generated in 71% yield and 92% ee when the
reaction was carried out at 5 °C in the presence of Zn(NTf2)2
(Table 2, entry 16). With the addition of 4 Å MS (50 mg), a
higher enantioselectivity of 93% ee and yield (93%) were
achieved (Table 2, entry 17).
Having established the above optimal conditions, we next
investigated the substrate scope of this reaction with the results
summarized in Table 3 and Table 4. As for substrates 1b–1i, the
reactions proceeded smoothly to afford the corresponding
Mannich-type adducts 3b–3i in moderate to good yields (up to
87% yield) and good to excellent enantioselectivities (from 87%
ee to 96% ee), regardless of electronic nature of the substituents
on the aromatic rings (Table 3, entries 1–8). Using hydrazone
Yieldb (%)
3
eec (%)
3
Absolute
Entrya
Hydrazone 1 (R)
configurationd
1
2
3
4
1b (4-ClC6H4)
1c (4-BrC6H4)
1d (4-FC6H4)
3b, 75
3c, 79
95
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
96
3d, 83/67e
3e, 73
87/93e
92
1e (4-MeC6H4)
1f (4-MeOC6H4)
1g (4-NO2C6H4)
1h (4-CNC6H4)
1i (4-CF3C6H4)
1j (3-ClC6H4)
1k (1-Naphthyl)
1l (2-Naphthyl)
1m (2-Furyl)
1n (2-Thienyl)
1o (3-Thienyl)
1p [CH3(CH2)6]
1q (Cyclohexyl)
5
3f, 87
3g, 79
3h, 67
3i, 69
3j, 71
3k, 69
3l, 72
3m, 77
3n, 59/51e
3o, 79/69e
3p, 53
3q, 52
94
90
91
90
94
91
94
57
6f
7
8
9
10
11
12
13
14
15
16
83/90e
87/94e
60
78
a Reaction conditions: 1 (0.10 mmol), 2a (0.30 mmol), Zn(NTf2)2
(10 mol%), L13 (20 mol%), THF (0.50 mL), MeOH (0.50 mL) and
MS4A (50 mg), the reaction was carried out at 5 °C for 24 h. b Isolated
yield after column chromatography. c Determined by chiral HPLC
analysis. d Determined by the X-ray diffraction. e The reaction was
carried out at 0 °C. f The reaction was carried out at 25 °C.
Table 4 The scope of Zn(NTf2)2-catalyzed asymmetric Mannich-type reaction of aromatic hydrazones with difluoroenoxysilane
Yieldb (%)
3
eec (%)
3
Entrya
Hydrazone 1 or 4 (R1/R2)
Difluoroenoxysilane 2 (R3)
Absolute configurationd
1
2
3
4
5
6
4a (C6H5/4-MeOC6H4)
4b (C6H5/4-NO2C6H4)
4c (4-BrC6H4/4-BrC6H4)
4d (C6H5/4-C6H5C6H4)
1b (4-ClC6H4/C6H5)
1b (4-ClC6H4/C6H5)
2a (C6H5)
2a (C6H5)
2a (C6H5)
2a (C6H5)
2b (4-MeC6H4)
2c (2-Thienyl)
5a, 81
94
S
S
S
S
S
S
5b, 59e/54f
5c, 71e/52f
5d, 72e/52f
5e, 88/59g
5f, 81/50g
86/92f
82/95f
89/96f
88/92g
51/76g
a Reaction conditions: 1 or 4 (0.10 mmol), 2 (0.30 mmol), Zn(NTf2)2 (10 mol%), L13 (20 mol%), THF (0.50 mL), MeOH (0.50 mL) and MS 4A
(50 mg), the reaction was carried out at 5 °C for 24 h. b Isolated yield after column chromatography. c Determined by chiral HPLC analysis.
d Determined by the X-ray diffraction. e The reaction was carried out at 25 °C. f The reaction was carried out at 10 °C and 5.0 equiv of 2a was utilized.
g The reaction was carried out at −5 °C and 5.0 equiv of 2b or 2c was utilized.
This journal is © The Royal Society of Chemistry 2012
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appeared at δ −14.84 ppm along with an additional signal at
δ −1.88 ppm. The signal at δ −1.88 ppm was strengthened in the
2 : 1 mixture of L13 and Zn(OTf)2, as compared to that of the
1 : 1 mixture of L13 and Zn(OTf)2. These results indicate that
the 2 : 1 mixture of imidazoline–phosphine ligands and zinc(II)
would be able to generate the active species for the present cata-
lytic system.
Scheme 1 Transformation of 3a
Finally, it should be noted that adduct 3a has been easily
transformed to the heterocyclic compound 7 upon treatment with
NaBH4 and triphosgene in a good yield of 73% (Scheme 1, see
ESI†).
bearing a 3-chlorobenzene group gave the corresponding product
3j in 71% yield and 94% ee (Table 3, entry 9). The naphthyl,
furyl or thienyl-containing hydrazones 1k–1o afforded difluori-
nation adducts 3k–3o in moderate to good yields and excellent
enantioselectivities (up to 77% yield and 94% ee, Table 3,
entries 10–14). It should be noted that the enantioselectivities of
3d, 3n and 3o were slightly improved when the reactions were
carried out at 0 °C, but chemical yields were diminished due to
the lower solubility of hydrazones at this temperature (Table 3,
entries 3, 13 and 14).
Previous research showed that aliphatic hydrazones, such as 1t
[R = CH3(CH2)3], was inefficient in the Zn(OTf)2-promoted
Mannich-type reaction of hydrazones with difluoroenoxysila-
nes.8c,9 However, under this new Zn(NTf2)2/L13-based catalytic
system, aliphatic hydrazones showed effectiveness leading to
moderate yields and enantioselectivities (Table 3, entries 15 and
16). More examples are provided in the Supporting Information
(Table S1).†
In conclusion, we have established a novel catalytic system of
using chiral zinc(II)–imidazoline–phosphine complexes as cata-
lysts for the asymmetric Mannich-type difluorinations of hydra-
zones with difluoroenoxysilanes. The reaction can smoothly
occur under mild conditions, affording the corresponding
Mannich-type adducts in moderate to good yields and excellent
enantioselectivities. The catalytic complexes was studied by
direct NMR observations, which indicated that the ratio 2 : 1 of
imidazoline–phosphine ligand with zinc(II) salt was sufficient to
give the active species for this asymmetric difluorination
reaction.
Acknowledgements
We thank the National Basic Research Program of China (973)-
2010CB833302, and the National Natural Science Foundation of
China for financial support (20928001, 21072206, 20472096,
20872162, 20672127, 20821002 and 20732008), Robert
A. Welch Foundation (D-1361) and NIH (R21DA031860-01).
Hydrazones having a different R2 group were subjected to the
reaction with several difluoroenoxysilanes 2 under the optimized
conditions. When R2 is a 4-methoxyphenyl group, the reaction
proceeded smoothly leading to the corresponding adduct 5a in
81% yield and 94% ee (Table 4, entry 1). As revealed in
Table 4, when hydrazones 4b–4d were used as substrates, the
corresponding adducts were obtained in moderate to good yields
(59–72%) and enantioselectivity (up to 89% ee) regardless of
the electronic nature of R2 group (Table 4, entries 2–4). Lower-
ing the reaction temperature from r.t. to 10 °C resulted in the cor-
responding products 5b–5d in 92–96% ee but in lower yields
due to the low solubility of hydrazones (Table 4, entries 2–4).
Adduct 5c was obtained in 95% ee, which enabled successful
formation of single crystals for the X-ray diffraction analysis
which has proven to be (S)-absolute configuration (Fig. SI-1 in
the ESI†). In addition, the reaction of hydrazone 1b with difluoro-
enoxysilane 2b or 2c occurred smoothly to give the correspond-
ing adducts 5e and 5f in good yields (up to 88%) and moderate
to good enantioselectivities (up to 88% ee) (Table 4, entries 5
and 6). Furthermore, when the reaction was carried out at –5 °C,
5e and 5f were formed in 59% yield/92% ee and 50% yield/76%
ee, respectively (Table 4, entries 5 and 6). The reaction of 4c
with 2a was also performed on a 1.0 mmol scale (536 mg),
giving 5c in 63% yield and 95% ee.
Notes and references
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X. H. X. Xu, S. Couve-Bonnaire and X. Pannecoucke, Chem. Soc. Rev.,
2010, 39, 558; (f) R. P. Singh and J. M. Shreeve, Acc. Chem. Res., 2004,
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Synth. Catal., 2001, 343, 235; (i) R. William, J. Dolbier and A. B. Merle,
Chem. Rev., 2003, 103, 1071; ( j) S. Fustero, J. F. Sanz-Cervera, J.
L. Aceńa and M. Sánchez-Roselló, Synlett, 2009, 4, 525.
2 H. Schofield, J. Fluorine Chem., 1999, 100, 7.
3 (a) J. Welch, Tetrahedron, 1987, 43, 3123; (b) J. A. Wilkinson, Chem.
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To obtain direct evidence of the coordination pattern between
the imidazoline–phosphine ligand and Zn(II) salt, we conducted
1H NMR and 31P NMR spectroscopic studies of (Ra,S,S)-L13 by
using a 1 : 1 mixture of L13 : Zn(OTf)2 and 2 : 1 mixture of
L13/Zn(OTf)2 in CDCl3 at ambient temperature (Fig. SI-2†).
The phosphorus signal of L13 appeared at δ −14.87 ppm. For a
1 : 1 mixture of L13 : Zn(OTf)2, the phosphorus signal of L13
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