Enantioselective synthesis of 2,5-dihydrobenzo[b]azepine derivatives via iridium-catalyzed asymmetric allylic amination with 2-allylanilines and ring-closing-metathesis reaction

Article abstract of DOI:10.1039/c2ob00036a

Iridium-catalyzed asymmetric allylic amination of allylic carbonates with 2-allylanilines was realized. With a catalyst generated from 2 mol% of [Ir(dbcot)Cl]₂ (dbcot = dibenzo[a,e]cyclooctatetraene) and 4 mol% of phosphoramidite ligand (L3), the amination products were obtained in up to 99% yield and 99% ee. Subjecting amination products to trifluoroacetyl protection and ring-closing-metathesis reaction provided an efficient synthesis of enantioenriched 2,5-dihydrobenzo[b]azepine derivatives.

Full text of DOI:10.1039/c2ob00036a

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PAPER
Enantioselective synthesis of 2,5-dihydrobenzo[b]azepine derivatives via
iridium-catalyzed asymmetric allylic amination with 2-allylanilines and
ring-closing-metathesis reaction†‡
Ke-Yin Ye, Li-Xin Dai and Shu-Li You*
Received 5th January 2012, Accepted 2nd March 2012
DOI: 10.1039/c2ob00036a
Iridium-catalyzed asymmetric allylic amination of allylic carbonates with 2-allylanilines was realized.
With a catalyst generated from 2 mol% of [Ir(dbcot)Cl]2 (dbcot = dibenzo[a,e]cyclooctatetraene) and
4 mol% of phosphoramidite ligand (L3), the amination products were obtained in up to 99% yield and
99% ee. Subjecting amination products to trifluoroacetyl protection and ring-closing-metathesis reaction
provided an efficient synthesis of enantioenriched 2,5-dihydrobenzo[b]azepine derivatives.
However, substitution on the 1-benzazepine moiety was limited
to only a 2-vinyl group despite the high efficiency of this
Introduction
Benzannulated nitrogen heterocycles constitute the core structure
of numerous biologically active compounds that display a wide
range of pharmacological activities.1 Among them, benzazepines
represent an interesting class of these heterocycles.2 In particular,
compounds bearing the 1-benzazepine moiety have exhibited
biological activity toward various targets. For example,
OPC-312603 (A1) and OPC-410614 (A2) (potent orally effective
non-peptide vasopressin V2 receptor antagonists), B5 (against
Trypanosoma cruzi and Leishmania chagasi parasites), all have
1-benzazepine as a key structural element (Fig. 1). Due to their
widespread occurrence and extensive utilization as building
blocks in pharmaceuticals, efficient diversity-oriented syntheses6
of 1-benzazepine derivatives, especially via a catalytic asym-
metric approach,7 are highly desirable.
method. Therefore, a novel approach to 1-benzazepine which
would allow the diverse variation of substituents is required.
Recently, enantioenriched 1,2-dihydroquinolines were suc-
cessfully obtained via the combination of Ir-catalyzed enantio-
selective allylic amination with o-aminostyrenes and
a
subsequent RCM reaction, reported by our group.14 Pioneered
by Evans et al.,15 transition-metal-catalyzed allylic amination
and RCM reaction strategy led to various optically active nitro-
gen-containing heterocycles including natural products and phar-
maceutically interesting compounds.16,17 We envisaged that this
Ir-catalyzed asymmetric allylic substitution reactions have
gained rapid development in recent years.8 With respect to
nucleophiles, a wide range of carbon9 and heteroatom10 (e.g., O,
N, S) nucleophiles have been employed. The utilization of substi-
tuted anilines as suitable nucleophiles in Ir-catalyzed asymmetric
allylic substitution reactions has also been documented in the lit-
erature.11 As part of our ongoing program towards Ir-catalyzed
allylic substitution reaction,12 we developed an Ir-catalyzed domino
allylic vinylation/asymmetric allylic amination reaction for the con-
struction of enantioenriched 1-benzazepine (a, Scheme 1).13
Fig. 1 Biologically active compounds with 1-benzazepine moiety.
State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Science, 345 Lingling,
Shanghai, 200032, P. R. China. E-mail: slyou@sioc.ac.cn; Fax: (+86)
21-54925087
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available. CCDC 859342.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2ob00036a
Scheme 1 Methods for the preparation of enantioenriched 1-
benzazepines.
5932 | Org. Biomol. Chem., 2012, 10, 5932–5939
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Table 1 Optimization of reaction conditions for Ir-catalyzed allylic
Table 2 Screening of various chiral phosphoramidite ligandsa
amination with 2-allylanilinea
Entry
L
Yieldb (3aa + 4aa, %)
3aa/4aac
eed (%)
Yieldb
Entry Solvent
Base
(3aa + 4aa, %) 3aa/4aac eed (%)
1
2
L1
L2
L3
L3
L4
Trace
Trace
94
Trace
26
—
—
97 : 3
—
—
—
99
—
12
1
2
3
4
5
6
7
THF
THF
THF
THF
THF
THF
THF
K3PO4
Cs2CO3
KOAc
91
56
54
94 : 6
98 : 2
97 : 3
95 : 5
98 : 2
97 : 3
95 : 5
96 : 4
97 : 3
97 : 3
93 : 7
94 : 6
94
97
98
15
48
99
97
99
98
92
96
98
3
4e
5
75 : 25
DABCO 15
a Reaction conditions: [Ir(dbcot)Cl]2/L/1a/2a/Et3N = 0.02/0.04/1.0/1.1/
DBU
Et3N
—
48
94
87
83
97
96
78
86
1.1, 0.1 M of 1a in THF. b Isolated yield. c Determined by H NMR of
1
the crude reaction mixture. d Determined by HPLC analysis. e [Ir(cod)-
Cl]2 was employed instead of [Ir(dbcot)Cl]2.
8
9
10
11
12
Dioxane Et3N
CH2Cl2
CH3CN
Toluene
Et2O
Et3N
Et3N
Et3N
Et3N
a Reaction conditions: [Ir(dbcot)Cl]2/L3/1a/2a/base = 0.02/0.04/1.0/1.1/
1.1, 0.1 M of 1a. b Isolated yield. c Determined by 1H NMR of the crude
reaction mixture. d Determined by HPLC analysis.
strategy could be applicable to the synthesis of enantioenriched
1-benzazepine derivatives using 2-allylanilines as nucleophiles
(b, Scheme 1). In this paper, we report such an efficient synthesis
of enantioenriched 2,5-dihydrobenzo[b]azepine derivatives via
Ir-catalyzed allylic asymmetric amination with 2-allylanilines
and a subsequent RCM reaction.
Fig. 2 Chiral phosphoramidite ligands.
Next, several readily available chiral phosphoramidite ligands
were examined as summarized in Table 2. Phosphoramidite
ligands L1 and L2 (Fig. 2), varying the substituents on the
phenyl ring of amine moiety, only afforded trace amount of pro-
ducts (entries 1, 2, Table 2). Low yield and enantioselectivity
were obtained when L4 was used (entry 5, Table 2). We also
found that the proper choice of iridium precursor is critical. Only
a trace amount of desired products was observed when [Ir(cod)-
Cl]2 was employed instead of [Ir(dbcot)Cl]2 in the presence of
L3 (entry 4, Table 2).
Under the optimal reaction conditions (that is, 2 mol% of [Ir-
(dbcot)Cl]2, 4 mol% of L3, 110 mol% of Et3N, 0.2 mmol of 1,
0.22 mmol of 2 in THF at 50 °C, entry 3, Table 2), substrate
scope of the Ir-catalyzed enantioselective allylic amination reac-
tion was explored (Table 3). Substrates bearing either an elec-
tron-donating group (4-MeO, entry 2, Table 3) or electron-
withdrawing group (4-Cl, 3-Cl, entries 3, 4, Table 3) on the
phenyl ring of the cinnamyl methyl carbonates were well toler-
ated and led to their corresponding amination products in excel-
lent yields (81–99%) and enantioselectivities (92–99% ee).
Notably, o-methoxy substituted cinnamyl methyl carbonate also
reacted smoothly but the yield, regio- and enantioselectivity
were decreased slightly (entry 5, Table 3). Reaction with the
hetero-aromatic substituted carbonate such as 2-thienyl allylic
carbonate occurred with the same level of regio- and enantio-
selectivity (entry 6, Table 3). It is worth mentioning that even
the alkyl substituted allylic carbonates were well tolerated
(entries 7, 8, Table 3). On the other hand, it was found that reac-
tions with substrates bearing both electron-donating and elec-
tron-withdrawing groups on the phenyl ring of 2-allylanilines all
Results and discussion
We began our studies by utilizing 2-allylaniline (1a) and cinna-
myl methyl carbonate (2a) as the model substrates. [Ir(dbcot)-
Cl]2, introduced by Helmchen and coworkers in an Ir-catalyzed
allylic substitution reaction,18 was chosen as the iridium precur-
sor based on our previous work on asymmetric allylic amination
with o-aminostyrenes.14 The results are summarized in Table 1.
With the Ir-catalyst generated in situ from 2 mol% of [Ir-
(dbcot)Cl]2 and 4 mol% of L3, the reaction of 1a and 2a in the
presence of 110 mol% of K3PO4 in THF gave the desired
branched amination product with excellent results (91% yield,
94% ee and b (branched) : l (linear) = 94 : 6, entry 1, Table 1).
Examination of bases disclosed that various bases tested all
afforded good regioselectivities. However, yields dramatically
decreased in the reactions with bases such as Cs2CO3 and KOAc
although slightly better enantioselectivities were obtained
(entries 2, 3, Table 1). Both DABCO and DBU had a deleterious
effect on yields and enantioselectivities of the allylic amination
reaction (entries 4, 5, Table 1). Finally, Et3N was found as the
best choice of base in terms of yield, regioselectivity and enan-
tioselectivity (94% yield, b : l = 97 : 3, 99% ee, entry 6, Table 1).
Notably, excellent ee could also be obtained in the reaction
without additional base but the yield was slightly decreased
(entry 7, Table 1). Various solvents (such as dioxane, CH2Cl2,
CH3CN, toluene, and Et2O) were well tolerated and THF
afforded the best results (entries 8–12, Table 1).
This journal is © The Royal Society of Chemistry 2012
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Table 3 Substrate scope of Ir-catalyzed allylic amination with 2-
Table 4 Synthesis of enantioenriched 1-benzazepine derivativesa
allylanilinesa
Entry
3 R1, R2
5, yieldb (%)
eec,d (%)
Entry
R1, R2
Yieldb (3 + 4, %)
3/4c
eed (%)
1
2
3
4
5
6
7
8
3aa H, C6H5
5aa, 75
5ab, 75
5ac, 99
5ad, 92
5ae, 83
5af, 96
5ag, 99
5ah, 75
5ba, 83
5ca, 72
5da, 88
5ea, 84
99 (99)
94 (92)
99 (99)
95 (98)
84 (86)
98 (96)
92 (92)
94 (96)
96 (96)
98 (99)
99 (99)
98 (99)
1
2
3
4
5
6
7
8
H, C6H5
94
99
81
99
86
97
86
74
96
94
65
61
97 : 3
98 : 2
98 : 2
93 : 7
90 : 10
96 : 4
92 : 8
96 : 4
98 : 2
99 : 1
97 : 3
99 : 1
3aa 99
3ab 92
3ac 99
3ad 98
3ae 86
3af 96
3ag 92
3ah 96
3ba 96
3ca 99
3da 99
3ea 99
3ab H, 4-MeO-C6H4
3ac H, 4-Cl-C6H4
3ad H, 3-Cl-C6H4
3ae H, 2-MeO-C6H4
3af H, 2-thienyl
3ag H, c-C3H5
3ah H, Et
3ba 4-F, C6H5
3ca 4-Br, C6H5
3da 4-Me, C6H5
3ea 3,5-(MeO)2, C6H5
H, 4-MeO-C6H4
H, 4-Cl-C6H4
H, 3-Cl-C6H4
H, 2-MeO-C6H4
H, 2-thienyl
H, c-C3H5
H, Et
4-F, C6H5
4-Br, C6H5
4-Me, C6H5
3,5-(MeO)2, C6H5
9
9
10
11
12
10
11
12
a (1) Reaction conditions: 3/TFAA/Et3N = 1.0/1.5/2.0, 0.1 M of 3 in
CH2Cl2; (2) 0.004 mmol of Zhan-1B in 2 mL of CH2Cl2. b Isolated
yield. c Determined by HPLC analysis. d ee of 3 is given in parentheses.
a Reaction conditions: [Ir(dbcot)Cl]2/L3/1/2/Et3N = 0.02/0.04/1.0/1.1/
1.1, 0.1 M of 1 in THF. b Isolated yield. c Determined by 1H NMR of the
crude reaction mixture. d Determined by HPLC analysis.
proceeded with excellent enantioselective control. The yields of
substrates with electron-donating groups were comparably lower
than their electron-withdrawing counterparts (entries 9–12,
Table 3).
With these highly enantioenriched amination products in
hand, then the synthesis of 1-benzazepine derivatives was exam-
ined. This was achieved in a two-step process including protec-
tion with trifluoroacetic anhydride and then a RCM reaction with
Zhan-1B as catalyst (2 mol%). Zhan-1B was chosen as the
appropriate catalyst rather than other conventional ring-closing-
metathesis catalysts based on our previous work.14,17 The results
are summarized in Table 4. In general, 1-benzazepine derivatives
were obtained in good yields without notable loss of enantio-
meric purity.
Fig. 3 X-Ray crystal structure of (S)-5ca [CCDC 859342] (thermal
ellipsoids are set at 30% probability).
The resulting 1-benzazepines could further undergo versatile
transformations. For example, the double bond of the enantioen-
riched 1-benzazepine 5aa could be easily hydrogenated with Pd/
C in methanol at room temperature in almost quantitative yield
(eqn (1)). The convenient cleavage of the trifluoroacetyl group
of 5aa with NaBH4 makes it particularly appealing for further
transformation with 7 as an optically active secondary amine
(eqn (2)).19 In these two cases, the enantiomeric purity could be
well preserved. The absolute configuration of 5ca was assigned
to be (S) by X-ray crystallographic analysis (Fig. 3).
Conclusions
In summary, we have successfully developed an efficient method
for the synthesis of enantioenriched 1-benzazepine derivatives
by employing Ir-catalyzed asymmetric allylic amination with 2-
allylanilines and a subsequent RCM reaction. The current meth-
odology features high enantioselectivity and ready availability of
the starting materials, which make it particularly attractive in
organic synthesis.
Experiment section
General
Unless stated otherwise, all reactions were carried out in flame-
dried glassware under argon atmosphere. All solvents were
purified and dried according to standard methods prior to use.
1H NMR spectra were obtained at 300 MHz or 400 MHz and
recorded relative to tetramethylsilane signal (0 ppm) or residual
protio-solvent. 13C NMR spectra were obtained at 75 MHz or
5934 | Org. Biomol. Chem., 2012, 10, 5932–5939
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100 MHz, and chemical shifts were recorded relative to the
solvent resonance (CDCl3, 77.0 ppm). Data for 1H NMR are
recorded as follows: chemical shift (δ, ppm), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet or
unresolved, br s = broad singlet, coupling constant(s) in Hz, inte-
gration). Data for 13C NMR are reported in terms of chemical
shift (δ, ppm).
3ac. Pale yellow oil, Rf = 0.8 (petroleum ether : EtOAc =
10 : 1), b : l = 98 : 2, 81% yield, 99% ee [Daicel Chiralcel OD-H,
hexane : 2-propanol = 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t
(major) = 15.51 min, t (minor) = 16.51 min]; [α]2D0 + 47.1 (c
1
1.00, CHCl3). H NMR (400 MHz, CDCl3) δ 3.34 (d, J = 6.0
Hz, 2H), 4.15 (br s, 1H), 4.89–4.96 (m, 1H), 5.06–5.25 (m, 4H),
5.89–6.04 (m, 2H), 6.45 (d, J = 7.6 Hz, 1H), 6.68 (t, J = 7.2 Hz,
1H), 6.99–7.09 (m, 2H), 7.24–7.33 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 36.8, 59.8, 111.8, 116.3, 116.4, 117.6,
123.6, 127.5, 128.3, 128.8, 129.9, 132.9, 136.0, 138.8, 140.4,
144.9; IR (thin film): νmax (cm−1) = 3423, 3079, 1636, 1506,
1490, 1313, 1261, 1090, 995, 919, 811, 747; MS (EI, m/z, rel.
intensity) 283 (M+, 23), 115 (100); HRMS (EI) calcd for
C18H18NCl (M+): 283.1128. Found: 283.1127.
The phosphoramidite ligands,20 the substituted allylic carbon-
ates,21 and the substituted 2-allylanilines22 were prepared accord-
ing to known procedures.
General procedure for the Ir-catalyzed allylic amination
A flame-dried Schlenk tube was cooled to room temperature and
filled with argon. To this flask were added [Ir(dbcot)Cl]2
(3.5 mg, 0.004 mmol, 2 mol%), phosphoramidite ligand L3
(4.8 mg, 0.008 mmol, 4 mol%), THF (0.5 mL) and n-propyl-
amine (0.5 mL). The reaction mixture was heated at 50 °C for
0.5 h, and the color of the solution was changed from orange to
light yellow. Then the reaction mixture was cooled to room
temperature, and the solvent was removed in vacuo. To the same
flask, 2-allylaniline derivative 1 (0.20 mmol), allylic carbonate 2
(0.22 mmol), Et3N (22.2 mg, 0.22 mmol) and THF (2 mL) were
added. The reaction mixture was stirred at 50 °C. After the reac-
tion was complete (monitored by TLC), the crude reaction
mixture was filtered through celite and washed with EtOAc. The
solvents were removed under reduced pressure. Then the crude
residue was purified by silica gel column chromatography (pet-
roleum ether : EtOAc = 100 : 1) to afford the product 3.
3ad. Pale yellow oil, Rf = 0.7 (petroleum ether : EtOAc =
10 : 1), b : l = 93 : 7, 99% yield, 98% ee [Daicel Chiralcel OD-H,
hexane : 2-propanol = 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t
(major) = 14.99 min, t (minor) = 22.17 min]; [α]2D0 + 50.1 (c
1
1.00, CHCl3). H NMR (400 MHz, CDCl3) δ 3.36 (d, J = 6.0
Hz, 2H), 4.18 (br s, 1H), 4.89–4.97 (m, 1H), 5.07–5.27 (m, 4H),
5.91–6.06 (m, 2H), 6.46 (d, J = 8.0 Hz, 1H), 6.69 (t, J = 7.2 Hz,
1H), 7.01–7.09 (m, 2H), 7.20–7.31 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 36.8, 60.1, 111.8, 116.5, 117.7, 123.6,
125.1, 127.1, 127.5, 127.6, 129.9, 134.5, 136.0, 138.7, 144.2,
144.9; IR (thin film): νmax (cm−1) = 3423, 3078, 1636, 1588,
1507, 1312, 1253, 996, 920, 785, 747; MS (EI, m/z, rel. inten-
sity) 283 (M+, 33), 115 (100); HRMS (EI) calcd for C18H18NCl
(M+): 283.1128. Found: 283.1124.
3ae. Pale yellow oil, Rf = 0.5 (petroleum ether : EtOAc =
10 : 1), b : l = 90 : 10, 86% yield, 86% ee [Daicel Chiralcel
OD-H, hexane : 2-propanol = 99 : 1, ν = 0.5 mL min−1, λ =
3aa. Pale yellow oil, Rf = 0.8 (petroleum ether : EtOAc =
10 : 1), b : l = 97 : 3, 94% yield, 99% ee [Daicel Chiralcel OJ-H,
hexane : 2-propanol = 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t
(major) = 20.40 min, t (minor) = 27.88 min]; [α]2D0 + 20.5 (c
254 nm, t (minor) = 25.26 min, t (major) = 33.71 min]; [α]D20
+
1
17.7 (c 1.00, CHCl3). H NMR (300 MHz, CDCl3) δ 3.34 (d, J
= 6.3 Hz, 2H), 3.84 (s, 3H), 4.36 (br s, 1H), 5.05–5.28 (m, 4H),
5.33–5.45 (m, 1H), 5.88–6.13 (m, 2H), 6.53 (d, J = 8.1 Hz, 1H),
6.64 (t, J = 7.5 Hz, 1H), 6.84–6.94 (m, 2H), 6.99–7.10 (m, 2H),
7.18–7.31 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 36.8, 54.3,
55.4, 110.6, 111.6, 114.8, 116.2, 117.0, 120.8, 123.5, 127.5,
128.3, 129.7, 129.8, 136.1, 138.8, 145.2, 156.8; IR (thin film):
νmax (cm−1) = 3432, 2929, 1637, 1603, 1508, 1491, 1242, 996,
919, 755; MS (EI, m/z, rel. intensity) 279 (M+, 17), 147 (100);
HRMS (EI) calcd for C19H21NO (M+): 279.1623. Found: 279.1620.
3af. Pale yellow oil, Rf = 0.8 (petroleum ether : EtOAc =
10 : 1), b : l = 96 : 4, 97% yield, 96% ee [Daicel Chiralcel OD-H,
hexane : 2-propanol = 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t
(major) = 14.20 min, t (minor) = 15.45 min]; [α]2D0 + 46.5 (c
1
1.00, CHCl3). H NMR (300 MHz, CDCl3) δ 3.34 (d, J = 6.0
Hz, 2H), 4.18 (br s, 1H), 4.90–5.00 (m, 1H), 5.03–5.28 (m, 4H),
5.87–6.10 (m, 2H), 6.52 (d, J = 8.7 Hz, 1H), 6.67 (t, J = 7.5 Hz,
1H), 6.99–7.11 (m, 2H), 7.21–7.42 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 36.8, 60.4, 111.8, 115.8, 116.4, 117.3,
123.5, 127.0, 127.3, 127.5, 128.7, 129.8, 136.0, 139.2, 141.9,
145.1; IR (thin film): νmax (cm−1) = 3424, 1636, 1604, 1586,
1451, 1314, 1261, 1027, 919, 799, 748, 701; MS (EI, m/z, rel.
intensity) 249 (M+, 16), 117 (100); HRMS (EI) calcd for
C18H19N (M+): 249.1517. Found: 249.1519.
3ab. Pale yellow oil, Rf = 0.5 (petroleum ether : EtOAc =
10 : 1), b : l = 98 : 2, 99% yield, 92% ee [Daicel Chiralcel OD-H,
hexane : 2-propanol = 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t
(minor) = 14.43 min, t (major) = 16.96 min]; [α]2D0 + 14.0 (c
1
1.00, CHCl3). H NMR (400 MHz, CDCl3) δ 3.33 (d, J = 6.0
Hz, 2H), 4.20–4.22 (m, 1H), 5.07–5.13 (m, 2H), 5.24–5.35 (m,
3H), 5.91–6.00 (m, 1H), 6.06 (ddd, J = 17.2, 10.4, 6.0 Hz, 1H),
6.66 (d, J = 8.0 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 6.95–7.01 (m,
2H), 7.06–7.12 (m, 2H), 7.21–7.26 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 36.7, 56.0, 111.9, 116.4, 116.5, 117.8,
123.8, 124.4, 124.7, 126.9, 127.5, 130.0, 135.9, 138.4, 144.8,
146.5; IR (thin film): νmax (cm−1) = 3416, 3076, 1636, 1586,
1311, 1253, 993, 920, 747, 699; MS (EI, m/z, rel. intensity) 255
(M+, 10), 123 (100); HRMS (EI) calcd for C16H17NS (M+):
255.1082. Found: 255.1080.
1
1.00, CHCl3). H NMR (400 MHz, CDCl3) δ 3.32 (d, J = 6.0
Hz, 2H), 3.78 (s, 3H), 4.12 (br s, 1H), 4.88–4.93 (m, 1H),
5.05–5.24 (m, 4H), 5.88–6.05 (m, 2H), 6.54 (d, J = 8.8 Hz, 1H),
6.71 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 7.6 Hz, 2H), 7.01–7.08 (m,
2H), 7.26 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
36.8, 55.2, 59.8, 111.8, 114.0, 115.5, 116.4, 117.2, 123.4, 127.5,
128.1, 129.7, 134.0, 136.0, 139.4, 145.2, 158.8; IR (thin film):
νmax (cm−1) = 3421, 2834, 1636, 1605, 1507, 1246, 1174, 1034,
994, 918, 825, 747; MS (EI, m/z, rel. intensity) 279 (M+, 16),
147 (100); HRMS (EI) calcd for C19H21NO (M+): 279.1623.
Found: 279.1622.
3ag. Pale yellow oil, Rf = 0.8 (petroleum ether : EtOAc =
10 : 1), b : l = 92 : 8, 86% yield, 92% ee [Daicel Chiralcel OD-H,
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hexane : 2-propanol = 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t
(minor) = 8.34 min, t (major) = 9.50 min]; [α]2D0 − 18.0 (c 1.00,
CHCl3). 1H NMR (300 MHz, CDCl3) δ 0.19–0.40 (m, 2H),
0.45–0.61 (m, 2H), 0.96–1.10 (m, 1H), 3.21–3.31 (m, 1H), 3.34
(d, J = 6.0 Hz, 2H), 4.06 (br s, 1H), 5.07–5.27 (m, 4H), 5.82
(ddd, J = 16.2, 10.5, 5.7 Hz, 1H), 5.90–6.05 (m, 1H), 6.55 (d, J
= 8.1 Hz, 1H), 6.66 (t, J = 7.5 Hz, 1H), 6.95–7.14 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 2.5, 3.2, 16.8, 36.8, 59.9, 111.6,
115.0, 116.3, 116.9, 123.2, 127.4, 129.7, 136.2, 138.7, 145.9; IR
(thin film): νmax (cm−1) = 3413, 3005, 1604, 1507, 1314, 995,
916, 745; MS (EI, m/z, rel. intensity) 213 (M+, 41), 81 (100);
HRMS (EI) calcd for C15H19N (M+): 213.1517. Found:
213.1514.
3ah. Pale yellow oil, Rf = 0.8 (petroleum ether : EtOAc =
10 : 1), b : l = 96 : 4, 74% yield, 96% ee [Daicel Chiralcel OD-H,
hexane : 2-propanol = 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t
(minor) = 16.41 min, t (major) = 18.89 min]; [α]2D0 + 5.4 (c 1.00,
CHCl3). 1H NMR (300 MHz, CDCl3) δ 0.97 (t, J = 7.2 Hz, 3H),
1.57–1.70 (m, 2H), 3.31 (d, J = 6.3 Hz, 2H), 3.65–3.84 (m, 2H),
5.04–5.24 (m, 4H), 5.73 (ddd, J = 16.5, 10.5, 5.4 Hz, 1H),
5.88–6.03 (m, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.65 (t, J = 7.5 Hz,
1H), 7.03 (d, J = 7.5 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 10.3, 28.6, 36.9, 56.9, 111.3, 115.0,
116.3, 116.7, 123.1, 127.5, 129.9, 136.3, 139.8, 145.7; IR (thin
film): νmax (cm−1) = 3430, 2963, 1636, 1605, 1512, 1462, 1316,
1260, 1094, 1018, 917, 801, 747; MS (EI, m/z, rel. intensity)
201 (M+, 28), 172 (100); HRMS (EI) calcd for C14H19N (M+):
201.1517. Found: 201.1513.
3da. Pale yellow oil, Rf = 0.8 (petroleum ether : EtOAc =
10 : 1), b : l = 97 : 3, 65% yield, 99% ee [Daicel Chiralcel OD-H,
hexane : 2-propanol = 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t
(major) = 12.71 min, t (minor) = 13.65 min]; [α]2D0 + 13.5 (c
1
1.00, CHCl3). H NMR (300 MHz, CDCl3) δ 3.21 (s, 3H), 3.32
(d, J = 6.0 Hz, 2H), 4.04 (br s, 1H), 4.92–4.93 (m, 1H),
5.04–5.29 (m, 4H), 5.87–6.09 (m, 2H), 6.44 (d, J = 7.8 Hz, 1H),
6.81–6.90 (m, 2H), 7.21–7.38 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 20.3, 36.8, 60.6, 112.1, 115.7, 116.3, 123.7, 126.5,
127.0, 127.2, 127.8, 128.6, 130.6, 136.1, 139.4, 142.1, 142.9;
IR (thin film): νmax (cm−1) = 3414, 2962, 1636, 1617, 1512,
1452, 1309, 1261, 1026, 919, 803, 701; MS (EI, m/z, rel. inten-
sity) 263 (M+, 42), 117 (100); HRMS (EI) calcd for C19H21N
(M+): 263.1674. Found: 263.1678.
3ea. Pale yellow oil, Rf = 0.8 (petroleum ether : EtOAc =
5 : 1), b : l = 99 : 1, 61% yield, 99% ee [Daicel Chiralcel OD-H,
hexane : 2-propanol = 99 : 1, v = 0.5 mL min−1, λ = 254 nm, t
(minor) = 18.60 min, t (major) = 27.43 min]; [α]2D0 + 13.4 (c
1
1.00, CHCl3). H NMR (300 MHz, CDCl3) δ 3.36 (d, J = 5.7
Hz, 2H), 3.65 (s, 3H), 3.75 (s, 3H), 4.25 (br s, 1H), 4.92–4.95
(m, 1H), 4.97–5.07 (m, 2H), 5.15–5.28 (m, 2H) 5.78–6.09 (m,
4H), 7.20–7.39 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 27.8,
54.9, 55.7, 60.6, 88.0, 91.4, 103.7, 114.8, 115.8, 126.9, 127.3,
128.7, 136.4, 139.3, 142.0, 147.0, 158.2, 159.6; IR (thin film):
νmax (cm−1) = 3423, 2999, 1605, 1513, 1452, 1203, 1144, 1064,
995, 916, 806, 701; MS (EI, m/z, rel. intensity) 309 (M+, 25),
117 (100); HRMS (EI) calcd for C20H23NO2 (M+): 309.1729.
Found: 309.1730.
3ba. Pale yellow oil, Rf = 0.8 (petroleum ether : EtOAc =
10 : 1), b : l = 98 : 2, 96% yield, 96% ee [Daicel Chiralcel OD-H,
hexane : 2-propanol = 99 : 1, v = 0.5 mL min−1, λ = 254 nm, t
(major) = 16.08 min, t (minor) = 19.18 min]; [α]2D0 + 45.4 (c
General procedure for the trifluoroacetylation/RCM of 3
1
1.00, CHCl3). H NMR (400 MHz, CDCl3) δ 3.29 (d, J = 6.0
To a solution of amine 3 (0.2 mmol) and Et3N (60.6 mg,
0.6 mmol) in CH2Cl2 (2 mL) was added dropwise trifluoroacetic
anhydride (42.3 μL, 0.3 mmol) at −10 °C. The mixture was
stirred at this temperature for 30 min. The reaction was quenched
with NaHCO3 (aq.) and the mixture was extracted with CH2Cl2
(3 × 5 mL). The combined organic layers were washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(petroleum ether : EtOAc = 20 : 1) to afford the desired products,
to which in CH2Cl2 (2 mL) was added Zhan-1B catalyst
(2.9 mg, 0.004 mmol) under an argon atmosphere. The mixture
was refluxed for 3 h. Then the solvent was removed under
reduced pressure. The residue was purified by silica gel column
chromatography (petroleum ether : EtOAc = 20 : 1) to afford the
desired product 5.
Hz, 2H), 3.98 (br s, 1H), 4.85–4.91 (m, 1H), 5.05–5.27 (m, 4H),
5.86–6.06 (m, 2H), 6.43 (dd, J = 9.2, 4.8 Hz, 1H), 6.72 (dt, J =
8.4, 3.2 Hz, 1H), 6.79 (dd, J = 9.2, 2.8 Hz, 2H), 7.20–7.39 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 36.4, 61.0, 112.7, 112.8,
113.1, 113.4, 115.8, 116.3, 116.5, 117.0, 125.3, 125.4, 126.9,
127.4, 128.7, 135.1, 139.3, 141.4, 141.8, 154.4, 156.8; 19F
NMR (376 MHz, CDCl3) δ −128.0 (m); IR (thin film): νmax
(cm−1) = 3418, 1639, 1509, 1261, 1218, 1027, 922, 867, 803,
701; MS (EI, m/z, rel. intensity) 267 (M+, 20), 117 (100);
HRMS (EI) calcd for C18H18NF (M+): 267.1423. Found:
267.1422.
3ca. Pale yellow oil, Rf = 0.9 (petroleum ether : EtOAc =
10 : 1), b : l = 99 : 1, 94% yield, 99% ee [Daicel Chiralcel OD-H,
hexane : 2-propanol = 99 : 1, v = 0.5 mL min−1, λ = 254 nm, t
(minor) = 10.88 min, t (major) = 11.97 min]; [α]2D0 + 3.5 (c 1.00,
5aa. White solid, Rf = 0.6 (petroleum ether : EtOAc = 10 : 1),
75% yield, 99% ee [Daicel Chiralcel OD-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (major) = 12.07 min, t
1
CHCl3). H NMR (400 MHz, CDCl3) δ 3.27 (d, J = 6.4 Hz,
2H), 4.14–4.16 (m, 1H), 4.90 (t, J = 5.2 Hz, 1H), 5.05–5.24 (m,
4H), 5.84–5.94 (m, 1H), 6.00 (ddd, J = 16.8, 10.4, 6.0 Hz, 1H),
6.37 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 8.4, 2.4 Hz, 1H), 7.14 (d,
J = 2.4 Hz, 1H), 7.22–7.35 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 36.3, 60.4, 109.1, 113.4, 116.0, 117.1, 125.6, 126.9,
127.5, 128.7, 130.0, 132.2, 135.0, 138.8, 141.3, 144.1; IR (thin
film): νmax (cm−1) = 3429, 2963, 1637, 1594, 1499, 1261, 1096,
1025, 921, 802, 701; MS (EI, m/z, rel. intensity) 327 (M+, 19),
117(100); HRMS (EI) calcd for C18H18NBr (M+): 327.0623.
Found: 327.0626.
1
(minor) = 13.51 min]; [α]2D0 − 204.8 (c 1.00, CHCl3). H NMR
(300 MHz, CDCl3) δ 3.12 (dd, J = 16.5, 8.1 Hz, 1H), 3.87 (ddd,
J = 16.5, 5.7, 2.7 Hz, 1H), 5.61 (dt, J = 12.0, 3.6 Hz, 1H),
6.17–6.28 (m, 1H), 6.31 (d, J = 7.8 Hz, 1H), 6.81–6.89 (m, 1H),
7.00–7.16 (m, 3H) 7.26–7.40 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 31.6, 58.1, 116.4 (q, J = 286.9 Hz), 126.4, 126.5,
127.3, 128.2, 128.3, 128.5, 128.9, 129.1, 130.2, 135.1, 137.0,
140.0, 156.5 (q, J = 34.3 Hz); 19F NMR (282 MHz, CDCl3) δ
−68.5; IR (thin film): νmax (cm−1) = 2962, 1696, 1495, 1413,
5936 | Org. Biomol. Chem., 2012, 10, 5932–5939
This journal is © The Royal Society of Chemistry 2012

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1187, 1146, 800, 747, 734, 671; ESI-MS: 317 (M+); HRMS
(ESI) calcd for C18H14F3NO (M+): 317.1027. Found: 317.1025;
m.p. 119–121 °C.
19F NMR (376 MHz, CDCl3) δ −68.3; IR (thin film): νmax
(cm−1) = 2944, 1688, 1491, 1430, 1246, 1189, 1149, 1111,
1026, 753, 731; ESI-MS: 348 (M+ + 1); HRMS (ESI) calcd for
C19H16F3NO2 (M+): 347.1133. Found: 347.1134; m.p.
94–95 °C.
5ab. White solid, Rf = 0.4 (petroleum ether : EtOAc = 10 : 1),
75% yield, 94% ee [Daicel Chiralcel OD-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (minor) = 24.41 min, t
5af. Yellow oil, Rf = 0.6 (petroleum ether : EtOAc = 10 : 1),
96% yield, 98% ee [Daicel Chiralcel OD-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (major) = 17.22 min, t
1
(major) = 29.08 min]; [α]2D0 − 181.2 (c 1.00, CHCl3). H NMR
(300 MHz, CDCl3) δ 3.10 (dd, J = 16.8, 9.0 Hz, 1H), 3.75 (s,
3H), 3.85 (dd, J = 17.1, 3.0 Hz, 1H), 5.58 (dt, J = 11.7, 3.9 Hz,
1H), 6.01–6.13 (m, 1H), 6.34 (d, J = 8.1 Hz, 1H), 6.63–6.74 (m,
3H), 6.84–7.00 (m, 3H) 7.16–7.24 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 31.5, 55.1, 57.6, 113.4, 116.3 (q, J = 286.9 Hz),
126.1, 126.5, 127.7, 128.4, 129.1, 130.1, 130.3, 135.1, 140.0,
156.4 (q, J = 34.9 Hz), 159.4; 19F NMR (282 MHz, CDCl3) δ
−68.6; IR (thin film): νmax (cm−1) = 2998, 2960, 1729, 1694,
1260, 1152, 1071, 1038, 798, 734; ESI-MS: 347 (M+); HRMS
(ESI) calcd for C19H16F3NO2 (M+): 347.1133. Found: 347.1131;
m.p. 93–94 °C.
1
(minor) = 19.87 min]; [α]2D0 − 140.0 (c 1.00, CHCl3). H NMR
(300 MHz, CDCl3) δ 3.13 (dd, J = 16.5, 8.4 Hz, 1H), 3.83 (ddd,
J = 17.1, 6.9, 3.3 Hz, 1H), 5.70 (ddd, J = 11.7, 4.2, 3.3 Hz, 1H),
6.01–6.10 (m, 1H), 6.57 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 3.3
Hz, 1H), 6.80–6.81 (m, 2H), 6.97–7.03 (m, 1H), 7.16–7.26 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 31.6, 53.1, 116.3 (q, J =
286.4 Hz), 126.4, 126.5, 126.6, 126.7, 127.3, 127.8, 128.6,
129.2, 130.0, 135.2, 139.8, 140.1, 156.3 (q, J = 36.0 Hz); 19F
NMR (282 MHz, CDCl3) δ −68.6; IR (thin film): νmax (cm−1) =
2962, 1696, 1496, 1413, 1259, 1188, 1145, 1017, 852, 709;
ESI-MS: 324 (M+ + 1); HRMS (ESI) calcd for C16H12F3NO2S
(M+): 323.0592. Found: 323.0594.
5ac. White solid, Rf = 0.7 (petroleum ether : EtOAc = 10 : 1),
99% yield, 99% ee [Daicel Chiralcel OD-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (minor) = 25.22 min, t
5ag. Yellow oil, Rf = 0.7 (petroleum ether : EtOAc = 10 : 1),
99% yield, 92% ee [Daicel Chiralcel OJ-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (minor) = 18.96 min, t
1
(major) = 33.79 min]; [α]2D0 − 194.7 (c 1.00, CHCl3). H NMR
(300 MHz, CDCl3) δ 3.13 (dd, J = 16.5, 8.7 Hz, 1H), 3.86 (dd, J
= 16.8, 3.0 Hz, 1H), 5.57 (dt, J = 11.7, 4.2, 3.0 Hz, 1H),
6.05–6.18 (m, 1H), 6.34 (d, J = 7.5 Hz, 1H), 6.64–6.73 (m, 1H),
6.86–7.03 (m, 3H) 7.10–7.29 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 31.5, 57.3, 116.3 (q, J = 286.8 Hz), 126.7, 126.9,
127.0, 128.4, 128.6, 129.3, 130.2, 130.3, 134.3, 134.8, 135.5,
139.9, 156.6 (q, J = 35.6 Hz); 19F NMR (282 MHz, CDCl3) δ
−68.6; IR (thin film): νmax (cm−1) = 2963, 1691, 1493, 1412,
1260, 1185, 1151, 1088, 1019, 795, 763, 734; ESI-MS: 351
(M+); HRMS (ESI) calcd for C18H13ClF3NO2 (M+): 351.0638.
Found: 351.0637; m.p. 136–138 °C.
1
(major) = 20.62 min]; [α]2D0 − 16.1 (c 1.00, CHCl3). H NMR
(300 MHz, CDCl3) δ 0.42–0.56 (m, 5H), 3.03 (dd, J = 15.3, 7.2
Hz, 1H), 3.74 (dd, J = 16.8, 3.3 Hz, 1H), 4.59 (br s, 1H),
5.54–5.59 (m, 1H), 5.77–5.84 (m, 1H), 7.20–7.35 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 3.0, 4.7, 14.4, 31.6, 59.8, 116.4 (q, J
= 287.4 Hz), 124.5, 126.5, 126.7, 128.5, 128.7, 129.3, 129.9,
135.8, 140.3, 156.4 (q, J = 35.0 Hz); 19F NMR (282 MHz,
CDCl3) δ −68.5; IR (thin film): νmax (cm−1) = 2962, 1698,
1604, 1500, 1418, 1260, 1209, 1152, 1101, 1022, 799, 734;
ESI-MS: 281 (M+); HRMS (ESI) calcd for C15H14F3NO (M+):
281.1027. Found: 281.1023.
5ad. Yellow oil, Rf = 0.6 (petroleum ether : EtOAc = 10 : 1),
92% yield, 95% ee [Daicel Chiralcel OD-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (major) = 15.56 min, t
5ah. Yellow oil, Rf = 0.7 (petroleum ether : EtOAc = 10 : 1),
75% yield, 94% ee [Daicel Chiralcel OJ-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (major) = 18.68 min, t
1
(minor) = 17.02 min]; [α]2D0 − 92.1 (c 1.00, CHCl3). H NMR
1
(300 MHz, CDCl3) δ 3.14 (dd, J = 16.8, 8.4 Hz, 1H), 3.86 (ddd,
J = 16.5, 6.0, 2.7 Hz, 1H), 5.57 (ddd, J = 12.0, 4.5, 3.3 Hz, 1H),
6.07–6.19 (m, 1H), 6.36 (d, J = 7.8 Hz, 1H), 6.64–6.72 (m, 1H),
6.86–7.03 (m, 3H) 7.13 (t, J = 7.8 Hz, 1H), 7.18–7.30 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 31.5, 57.5, 116.3 (q, J = 286.4
Hz), 126.6, 126.7, 127.1, 127.2, 128.6, 128.7, 129.1, 129.4,
129.5, 130.2, 134.2, 134.8, 139.0, 139.9, 156.2 (q, J = 35.4 Hz);
19F NMR (282 MHz, CDCl3) δ −68.6; IR (thin film): νmax
(cm−1) = 2962, 2925, 1691, 1494, 1409, 1260, 1182, 1150,
1016, 801, 788, 733; ESI-MS: 351 (M+); HRMS (ESI) calcd for
C18H13ClF3NO2 (M+): 351.0638. Found: 351.0642.
(minor) = 22.25 min]; [α]2D0 − 87.2 (c 1.00, CHCl3). H NMR
(300 MHz, CDCl3) δ 1.11 (t, J = 7.5 Hz, 3H), 1.14–1.16 (m,
2H), 3.13 (dd, J = 16.8, 8.7 Hz, 1H), 3.70–3.95 (m, 1H),
5.41–5.50 (m, 1H), 5.61 (d, J = 11.4 Hz, 1H), 5.91 (t, J = 10.8
Hz, 1H), 7.30–7.51 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
10.8, 26.0, 31.5, 56.4, 116.4 (q, J = 286.7 Hz), 124.3, 126.8,
128.9, 129.3, 129.4, 129.6, 135.1, 140.8, 157.0 (q, J = 35.1 Hz);
19F NMR (282 MHz, CDCl3) δ −67.2; IR (thin film): νmax
(cm−1) = 2968, 1695, 1496, 1417, 1186, 1148, 851, 759, 729,
672; ESI-MS: 269 (M+); HRMS (ESI) calcd for C14H14F3NO
(M+): 269.1027. Found: 269.1030.
5ae. White solid, Rf = 0.4 (petroleum ether : EtOAc = 10 : 1),
83% yield, 84% ee [Daicel Chiralcel OD-H, hexane : 2-propanol
= 99 : 1, ν = 1.0 mL min−1, λ = 254 nm, t (major) = 7.31 min, t
5ba. White solid, Rf = 0.7 (petroleum ether : EtOAc = 10 : 1),
83% yield, 96% ee [Daicel Chiralcel OJ-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (minor) = 13.15 min, t
1
1
(minor) = 8.47 min]; [α]2D0 − 159.8 (c 1.00, CHCl3). H NMR
(major) = 14.30 min]; [α]2D0 − 215.0 (c 1.00, CHCl3). H NMR
(400 MHz, CDCl3) δ 3.05 (dd, J = 17.2, 8.4 Hz, 1H), 3.81–3.89
(ddd, J = 17.6, 5.2, 1.6 Hz, 1H), 3.82 (s, 3H), 5.54 (ddd, J =
11.6, 4.8, 3.3 Hz, 1H), 5.97–6.03 (m, 1H), 6.31 (d, J = 8.0 Hz,
1H), 6.47–6.49 (m, 2H), 6.76–6.83 (m, 3H) 7.02–7.12 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 32.2, 53.0, 55.4, 110.0, 116.5 (q,
J = 287.0 Hz), 119.7, 124.6, 126.5, 126.6, 127.6, 128.5, 128.8,
129.4, 129.6, 130.0, 136.0, 139.4, 155.4 (q, J = 34.8 Hz), 157.3;
(400 MHz, CDCl3) δ 3.08 (dd, J = 16.4, 8.4 Hz, 1H), 3.78 (dd, J
= 16.4, 3.2 Hz, 1H), 5.63 (ddd, J = 11.6, 4.4, 3.2 Hz, 1H),
6.04–6.08 (m, 1H), 6.25–6.29 (m, 1H), 6.57–6.62 (m, 1H),
6.68–6.71 (m, 1H) 6.93 (dd, J = 8.4, 2.8 Hz, 1H), 6.97–7.00 (m,
2H), 7.10–7.26 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 31.4,
58.0, 113.1, 113.3, 115.4, 115.6, 116.6 (q, J = 287.2 Hz), 125.9,
127.6, 128.2, 128.4, 128.7, 128.9, 131.0, 131.0, 131.8, 131.9,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5932–5939 | 5937

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136.8, 142.5, 142.6, 156.6 (q, J = 35.2 Hz), 161.1, 163.6; 19F
NMR (282 MHz, CDCl3) δ −68.6, −112.2 (m); IR (thin film):
νmax (cm−1) = 2962, 1695, 1497, 1260, 1210, 1208, 1179, 1144,
1017, 780, 699; ESI-MS: 336 (M+ + 1); HRMS (ESI) calcd for
C18H13F4NONa (M+ + Na): 358.0826. Found: 358.0826;
m.p. 74–76 °C.
atmosphere. Then the reactor was charged with 1 atm of H2 and
then the reaction mixture was stirred at room temperature. When
5aa was fully consumed (monitored by TLC), the reaction
mixture was filtered through a celite pad. After removal of the
solvent, the residue was purified by silica gel column chromato-
graphy (petroleum ether : EtOAc = 20 : 1) to give 6 (11.3 mg,
99% yield).
5ca. White solid, Rf = 0.7 (petroleum ether : EtOAc = 10 : 1),
72% yield, 98% ee [Daicel Chiralcel OJ-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (major) = 12.13 min, t
6 Colorless oil, Rf = 0.5 (petroleum ether : EtOAc = 10 : 1),
99% ee [Daicel Chiralcel OD-H, hexane : 2-propanol = 99 : 1, ν
= 0.5 mL min−1, λ = 254 nm, t (major) = 7.42 min, t (minor) =
1
(minor) = 13.00 min]; [α]2D0 − 125.7 (c 1.00, CHCl3). H NMR
1
(400 MHz, CDCl3) δ 3.01 (dd, J = 16.8, 8.8 Hz, 1H), 3.78 (ddd,
J = 16.8, 6.0, 3.2 Hz, 1H), 5.57 (ddd, J = 11.6, 7.6, 4.4 Hz, 1H),
5.98–6.05 (m, 1H), 6.12 (d, J = 8.4 Hz, 1H), 6.64–6.66 (m, 1H),
6.95 (d, J = 7.2 Hz, 2H), 7.00 (dd, J = 8.4, 2.4 Hz, 1H),
7.13–7.21 (m, 3H), 7.32 (d, J = 2.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 31.2, 57.9, 116.2 (q, J = 287.0 Hz), 123.1,
125.8, 127.5, 128.4, 128.5, 128.8, 129.6, 131.5, 131.6, 134.2,
136.7, 142.1, 156.4 (q, J = 35.3 Hz); 19F NMR (376 MHz,
CDCl3) δ −68.1; IR (thin film): νmax (cm−1) = 2961, 1699,
1487, 1418, 1262, 1189, 1102, 1081, 813, 699; ESI-MS: 418
(M+ + Na); HRMS (ESI) calcd for C18H13F3NONa (M+ + Na):
418.0025. Found: 418.0020; m.p. 178–180 °C.
8.81 min]; [α]2D0 − 69.9 (c 1.00, CHCl3). H NMR (300 MHz,
CDCl3) δ 1.61–1.6 (m, 4H), 2.69–2.77 (m, 1H), 2.93–3.04 (m,
1H), 5.42 (dd, J = 12.0, 3.3 Hz, 1H), 7.06–7.09 (m, 1H),
7.25–7.41 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 22.1, 29.1,
29.2, 60.1, 116.1 (q, J = 286.8 Hz), 126.9, 127.2, 127.3, 127.8,
128.4, 129.0, 129.4, 129.7, 134.9, 138.8, 140.8, 156.8 (q, J =
35.9 Hz); 19F NMR (282 MHz, CDCl3) δ −68.9; IR (thin film):
νmax (cm−1) = 2958, 1693, 1491, 1453, 1202, 1180, 1024, 800,
699; ESI-MS: 319 (M+); HRMS (ESI) calcd for C18H16F3NO
(M+): 319.1184. Found: 319.1183.
Procedure for the deprotection of 5aa
5da. White solid, Rf = 0.6 (petroleum ether : EtOAc = 10 : 1),
88% yield, 99% ee [Daicel Chiralcel OJ-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (major) = 9.83 min, t
To a solution of 5aa (38.3 mg, 0.12 mmol) in MeOH (2 mL)
was added NaBH4 (27.5 mg, 0.72 mmol) under argon atmos-
phere. The resulting mixture was stirred at room temperature.
When 5aa was fully consumed (monitored by TLC), the solvent
was evaporated under reduced pressure. Then the residue was
purified by silica gel column chromatography (petroleum ether :
EtOAc = 20 : 1) to give 7 (22.9 mg, 86% yield).
1
(minor) = 10.94 min]; [α]2D0 − 206.4 (c 1.00, CHCl3). H NMR
(400 MHz, CDCl3) δ 2.28 (s, 3H), 3.05 (dd, J = 17.2, 7.2 Hz,
1H), 3.82 (ddd, J = 16.4, 6.0, 2.8 Hz, 1H), 5.59 (ddd, J = 11.2,
4.0, 2.8 Hz, 1H), 6.05–6.11 (m, 1H), 6.19 (d, J = 8.0 Hz, 1H),
6.67–6.72 (m, 2H), 6.97–6.99 (m, 3H), 7.15–7.24 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 21.1, 31.5, 58.1, 116.4 (q, J = 287.2
Hz), 126.6, 127.0, 127.3, 128.1, 128.2, 129.0, 129.2, 130.0,
132.4, 137.2, 139.1, 139.7, 156.7 (q, J = 34.9 Hz); 19F NMR
(376 MHz, CDCl3) δ −68.2; IR (thin film): νmax (cm−1) = 2962,
1682, 1503, 1417, 1260, 1211, 1179, 1017, 798, 753, 698;
ESI-MS: 332 (M+ + 1); HRMS (ESI) calcd for C19H16F3NONa
(M+ + Na): 354.1076. Found: 354.1083; m.p. 121–123 °C.
5ea. White solid, Rf = 0.6 (petroleum ether : EtOAc = 10 : 1),
84% yield, 98% ee [Daicel Chiralcel OJ-H, hexane : 2-propanol
= 99 : 1, ν = 0.5 mL min−1, λ = 254 nm, t (major) = 11.96 min, t
7 White solid, Rf = 0.4 (petroleum ether : EtOAc = 10 : 1),
99% ee [Daicel Chiralcel OD-H, hexane : 2-propanol = 99 : 1, ν
= 0.5 mL min−1, λ = 254 nm, t (major) = 16.74 min, t (minor) =
1
25.15 min]; [α]2D0 − 65.0 (c 1.00, CHCl3). H NMR (300 MHz,
CDCl3) δ 3.35 (dd, J = 15.9, 5.4 Hz, 1H), 3.74–3.81 (m, 1H),
4.85 (br s, 1H), 5.47 (d, J = 10.2 Hz, 1H), 5.92–5.95 (m, 1H),
6.66 (d, J = 7.5 Hz, 1H), 6.89–6.94 (m, 1H), 7.02–7.11 (m, 2H),
7.27–7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 32.6, 62.8,
121.8, 122.3, 125.5, 127.1, 127.6, 128.5, 128.7, 130.8, 135.7,
143.5, 146.9; IR (thin film): νmax (cm−1) = 3317, 2959, 2924,
1599, 1490, 1470, 1258, 1092, 1018, 838, 799, 757, 700; MS
(EI): 221 (M+); HRMS (EI) calcd for C16H15N (M+): 221.1204.
Found: 221.1203; m.p. 122–123 °C.
1
(minor) = 12.89 min]; [α]2D0 − 200.5 (c 1.00, CHCl3). H NMR
(400 MHz, CDCl3) δ 3.26 (ddd, J = 17.2, 6.8, 3.2 Hz, 1H), 3.38
(s, 3H), 3.68 (dd, J = 16.8, 8.8 Hz, 1H), 3.80 (s, 3H), 5.42 (br s,
1H), 5.60 (ddd, J = 11.2, 4.4, 3.2 Hz, 1H), 6.05–6.11 (m, 1H),
6.37 (d, J = 2.4 Hz, 1H), 6.66–6.68 (m, 1H), 7.01–7.04 (m, 2H),
7.14–7.24 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 21.4, 55.3,
55.7, 58.1, 99.4, 106.4, 116.4 (q, J = 287.1 Hz), 121.0, 127.1,
127.4, 128.2, 129.0, 136.7, 137.1, 156.3, 156.5 (q, J = 35.5 Hz),
158.0; 19F NMR (376 MHz, CDCl3) δ −68.3; IR (thin film):
νmax (cm−1) = 2961, 1682, 1610, 1588, 1457, 1261, 1195, 1145,
1112, 948, 802, 700; ESI-MS: 378 (M+ + 1); HRMS (ESI) calcd
for C20H19F3NO3 (M+ + 1): 378.1312. Found: 378.1327;
m.p. 81–83 °C.
Acknowledgements
We thank the National Basic Research Program of China (973
Program 2010CB833300) and the NSFC (20923005, 20932008,
21025209, 21121062) for generous financial support. We are
also very grateful to Prof. Günter Helmchen for providing dbcot.
Notes and references
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Procedure for the hydrogenation of 5aa
To a solution of 5aa (11.2 mg, 0.04 mmol) in MeOH (2 mL)
was added 10% Pd/C (3.5 mg, 0.004 mmol) under Ar
5938 | Org. Biomol. Chem., 2012, 10, 5932–5939
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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5932–5939 | 5939