Novel bifunctional thiourea-ammonium salt catalysts derived from amino acids: Application to highly enantio- and diastereoselective aza-Henry reaction

Article abstract of DOI:10.1016/j.tet.2013.04.079

The development of new efficient and easily accessible catalysts has been one of the focuses in asymmetric phase-transfer catalysis. In this paper, a novel class of chiral bifunctional thiourea-ammonium phase-transfer catalysts were synthesized from commercially available α-amino acids. The structural modularity of these catalysts permits facile tunings to achieve optimum results, which was demonstrated in catalyzing the aza-Henry reaction with excellent enantioselectivities (up to 99.5% ee) and diastereoselectivities (up to >25:1 dr).

Full text of DOI:10.1016/j.tet.2013.04.079

Tetrahedron 69 (2013) 5104e5111
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel bifunctional thioureaeammonium salt catalysts derived
from amino acids: application to highly enantio- and
diastereoselective aza-Henry reaction
,b,
Hong-Yu Wang a, Zhuo Chai b, Gang Zhao a
*
a Department of Chemistry, University of Science and Technology of China, Hefei 230026, Anhui, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 LingLing Lu,
Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of new efficient and easily accessible catalysts has been one of the focuses in asym-
metric phase-transfer catalysis. In this paper, a novel class of chiral bifunctional thioureaeammonium
Received 19 March 2013
Received in revised form 12 April 2013
Accepted 17 April 2013
phase-transfer catalysts were synthesized from commercially available
a-amino acids. The structural
modularity of these catalysts permits facile tunings to achieve optimum results, which was demon-
strated in catalyzing the aza-Henry reaction with excellent enantioselectivities (up to 99.5% ee) and
diastereoselectivities (up to >25:1 dr).
Available online 20 April 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Asymmetric catalysis
Phase-transfer catalyst
Amino acid
Aza-Henry reaction
Thioureaeammonium
1. Introduction
novel catalytic systems are still of key importance for the con-
tinuing advancement of this methodology.
As an inexpensive and readily accessible chiral source, chiral
a
-
Our group have focused on the development of novel bi-
functional chiral organocatalysts from simple acyclic -amino
amino acids have attracted much interest as an arsenal for the
development of diverse organocatalysts, which have found exten-
sive applications in asymmetric synthesis.1 One of the recent re-
markable advances in this field is the development of novel
bifunctional or multifunctional organocatalysts based on simple
a
acid.7 Bi- or multifunctionality, especially with an emphasis on H-
bond interaction, has been one of the key concepts with great
success in the design of new organocatalysts for asymmetric ca-
talysis.8 However, the application of such a concept in the de-
velopment of new chiral phase-transfer catalysts has been still
rather limited,9 especially in the case of amino acid-based phase-
transfer catalysts. Notably, Ooi and co-workers have developed
chiral acyclic
a
-amino acids.2 Representative catalysts including
primary-secondary diamines,3 tertiary amine-thioureas,4 and
aminophosphines5 have been successfully applied to a variety of
reactions. The success of these catalysts is closely related to the two
a new family of chiral 1,2,3-triazoliums using a-amino acids over 10
obvious advantages endowed with chiral
pool: ready availability at affordable costs and modular structures
enabling facile fine tunings.
The catalytic asymmetric phase-transfer catalysis has been well-
established as one of the major commonly utilized methodology for
the synthesis of kinds of organic compounds.6 In this realm, while
most catalysts are derived from cinchona alkaloids6g,h (Scheme 1, I),
chiral binols6i,j (Scheme 1, II) or chiral guanidines6k (Scheme 1, III)
with great success achieved, the development and applications of
a
-amino acids as a chiral
steps, and applied them to some reactions with excellent results.10
Our previous good results obtained with the bifunctional pri-
maryetertiary diamine catalysts have inspired us to the de-
velopment of structurally-related novel bifunctional ammonium
salt phase-transfer catalysts (Fig. 1).11 The highly modular struc-
tures of these bifunctional catalysts allow for easy fine tunings at
different positions for efficiency improvement. To demonstrate the
great potential of these new catalysts for applications in asym-
metric phase-transfer catalysis, we applied them to catalyze the
aza-Henry reaction as a model, which is an important method for
the synthesis of numerous biologically active compounds and
building blocks of natural products, such as vicinal diamines and
a-
* Corresponding author. Tel.: þ86 21 54925182; fax: þ86 21 64166128; e-mail
amino acids.12
address: zhaog@mail.sioc.ac.cn (G. Zhao).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.079

H.-Y. Wang et al. / Tetrahedron 69 (2013) 5104e5111
5105
Scheme 1. Chiral quaternary ammonium catalysts (anions are omitted).
Fig. 1. Design and synthesis of bifunctional thioureaeammonium salt catalysts.
2. Results and discussion
tolerated in the reaction to give the desired products in high yields
and with good to excellent enantioselectivities (entries 1e9). While
substrates with electron-donating groups on the benzene ring are
favoured over those with electron-withdrawing ones in terms of
yield and ee value, the influence of the positions of these sub-
stituents seemed negligible. However, a significant drop in enan-
tioselectivity was observed with the aliphatic substrate 2j, while
the yield remained excellent (entry 10). To our delight, the em-
ployment of nitroethane 4b also provided excellent yields and ee
values, although the dr values were sensitive to the substitution
changes of the aryl groups, fluctuating between moderate to ex-
cellent (entries 11 and 13e15). The 1-nitropropane 4c bearing
a longer alkyl chain also gave an excellent yield, high ee value and
a moderate dr value (entry 12). Notably, the reaction between 2a
and nitromethane 4a could be performed on a gram-scale with only
a slight decrease in the yield and enantioselectivity (entry 16).
To get some insights into the catalytic mechanism of the re-
action, we performed two control experiments to test the role of
the H-bond sites (the thiourea moiety) and the quaternary am-
monium centre of the bifunctional phase-transfer catalysts
(Scheme 2). When we employed the thiourea-tertiary amine cata-
The N-Boc imines used in the aza-Henry reaction for this study
were in situ generated from amidosulfones.9c,f,13 The results of the
optimization of the reaction condition parameters, such as
screenings of catalysts (Fig. 2), solvents were listed in Table 1. We
chose the reaction between amidosulfone 2a and nitromethane 4a
in the presence of 5 equiv of KOH at ꢀ20 ꢁC in toluene as a model
reaction for catalyst evaluation (entries 1e8). Firstly, catalysts 1aee
derived from L-leucine and L-isoleucine with different substitutions
at the ammonium centre (R1) and thiourea moieties (R2) were
tested (entries 1e5). The enantioselectivity of the reaction seemed
susceptible to changes on both sites and a suitable combination of
the substituent groups was identified as in the catalyst 1d (R1¼4-
BrC6H4, R2¼4-NO2C6H4, entry 4). Subsequent examination of the
chiral backbones of these ammonium salts revealed a superior
catalyst 1f derived from tert-butyl leucine (entry 6). The ensuing
investigation of solvent effect indicated that this reaction gave
a higher level of enantiocontrol in CH2Cl2 (entry 9), with the best ee
value (92%) obtained at ꢀ30 ꢁC (entry 13). The use of weaker bases
led to inferior results (entries 14e17).
R1 = Ph, R2 = 4-NO2C6H3, R3 = i-Bu, X = S
R1 = 4-BrC6H4, R2 = 3,5-(CF3)2C6H3, R3 = i-Bu, X = S
R1 = 4-BrC6H4, R2 = 3,5-(CF3)2C6H3, R3 = i-Bu, X = O
R1 = 4-BrC6H4, R2 = 4-NO2C6H4, R3 = i-Bu, X = S
R1 = 4-NO2C6H4, R2 = 4-NO2C6H4, R3 = 2-(S)-Bu, X = S
R1 = 4-BrC6H4, R2 = 4-NO2C6H4, R3 = t-Bu, X = S
R1 = 4-BrC6H4, R2 = 4-NO2C6H4, R3 = Bn, X = S
R1 = 4-BrC6H4, R2 = 4-NO2C6H4, R3 = 2-(S)-Bu, X = S
1a :
1b :
R3
N
R1
1c :
1d :
1e :
X
NH
Br
NH
1f :
1g :
1h :
R2
Fig. 2. Catalysts screened in this study.
Under these optimized reaction conditions, we then surveyed
the substrate scope of this reaction with different amidosulfones
and nitroalkanes (Table 2). With nitromethane 4a, in general, var-
ious amidosulfones with diverse aromatic groups (Rx) were well
lyst 1l, which lacks the quaternary ammonium centre compared to
1b (Table 1, entry 1), the enantioselectivity slumped to 3% ee,
though the yield was excellent. Similarly, the use of catalyst 1m
with one blocked H-donor site also gave much inferior results.

5106
H.-Y. Wang et al. / Tetrahedron 69 (2013) 5104e5111
Table 1
Screening of phase-transfer catalystsa
NHBoc
NHBoc
NO2
1 (5 mol %)
KOH (5.0 eq)
SO2Ph
CH3NO2
4a
Solvent
-20 oC, 8 h
3a
2a
Entry
Catalyst
Solvent
Base
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1f
1f
1f
1f
1f
1f
1f
1f
1f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CHCl3
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
85
90
80
81
73
78
85
80
85
80
88
85
94
85
40
Trace
Trace
75
77
62
80
65
87
73
80
90
70
79
70
92
84
56
nd
nd
Scheme 2. Control experiments for mechanistic study.
9
10
11
12
13d
14d
15d
16d
17d
nitromethane would be directed by the quaternary ammonium
centre by the Coulomb force (static interaction). Such an assembly
would make the Re-face attack of the nucleophile more favourable.
To extend the utility of this reaction, we studied some useful
transformations of the products 3 (Scheme 3). Firstly, we developed
a four-step transformation of the product 3a to the chiral com-
pound 5 in high yields (56% over four steps) while maintaining the
optical purity of the product. Using a known method, compound 5
could be transformed into taurine,14 which belongs to a family of
molecules with useful pharmaceutical values. Then we achieved
the conversion of 3k into chiral amine 6,15 which is an important
building block in organic synthesis,16 by a radical process to get rid
of the nitro group. The stereochemical integrity was also well
maintained in this process.
PhCF3
TBME
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
KOH
NaOH
Cs2CO3
K2CO3
Na2CO3
a
Unless otherwise noted, the reaction was carried out with 2a (0.2 mmol) and
CH3NO2 (1.0 mmol) in CH2Cl2.
b
Yield of the isolated product.
Determined by HPLC analysis.
At ꢀ30 ꢁC.
c
d
Table 2
Substrate scope study of the asymmetric aza-Henry reactiona
NHBoc
SO2Ph
NHBoc
NO2
1f (5 mol %)
3. Conclusion
Ry
NO2
+
Rx
KOH, CH2Cl2
Rx
-30 o
C
Ry
In conclusion, we have developed a novel family of bifunctional
2
4
3
(thio)ureaeammonium salts as chiral phase-transfer catalysts
based on simple acyclic a-amino acids. These new catalysts dem-
Entry
2 (Rx)
2a (Ph)
2b (4-FC6H4)
2c (4-MeC6H4)
2d (4-CF3C6H4)
2e (4-MeOC6H4)
2f (3-MeOC6H4)
2g (2-MeOC6H4)
2h (1-Naphthyl)
2i (2-Furyl)
2j (PhCH2CH2)
2a (Ph)
2a (Ph)
4 (Ry)
3
Yieldb (%)
eec (%)
drd
onstrated high efficiency in the aza-Henry reaction between ami-
dosulfones and nitroalkanes, in which H-bond and ammonium
salts are crucial to achieve excellent enantioselectivities and dia-
stereoselectivities. Highly modular structures as well as their ready
accessibility render them promising catalysts in organic catalysis.
Efforts towards a deep understanding of the reaction mechanism as
well as the application of these catalysts to other relevant reactions
are currently underway in our laboratories.
1
2
3
4
5
6
7
8
4a (H)
4a (H)
4a (H)
4a (H)
4a (H)
4a (H)
4a (H)
4a (H)
4a (H)
4a (H)
4b (Me)
4c (Et)
4b (Me)
4b (Me)
4b (Me)
4a (H)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3a
94
80
92
85
90
90
98
99
80
98
99
99
99
99
99
92
92
89
93
89
94
96
94
91
88
68
96
89
99
97
99.5
89
d
d
d
d
d
d
d
d
9
d
10
11
12
13
14
15
16
d
20:1
8:1
6:1
>25:1
9:1
d
4. Experimental
2b (4-FC6H4)
2d (4-MeOC6H4)
2f (3-MeOC6H4)
2a (Ph)
4.1. General
The 1H NMR spectra were recorded on a Bruker (400 MHz). All
chemical shifts (d) were given in parts per million. Data were re-
a
Unless otherwise noted, all reactions were carried out with 2 (0.2 mmol) and 4
(1.0 mmol) in CH2Cl2 (8 mL) catalyzed by 1f (5 mol %) at ꢀ30 ꢁC.
ported as follows: chemical shift, integration, multiplicity (s¼single,
d¼doublet, t¼triplet, q¼quartet, br¼broad, m¼multiplet) and
coupling constants hertz (Hz). 13C NMR spectra were recorded on
a DPX-400 (400 MHz). Flash column chromatography was per-
formed using H silica gel. For thin-layer chromatography (TLC), silica
gel plates (HSGF 254) were used and compounds were visualized by
irradiation with UV light. Analytical high performance liquid chro-
matography (HPLC) was carried out on SHIMADZU equipment using
chiral columns. Melting points were determined on an SGW X-4
melting point and were uncorrected. Optical rotations were mea-
b
Isolated yield.
c
Determined by 1H NMR or chiral HPLC analysis.
d
The reaction was run on a gram scale of 2a (1.8 g, 5.2 mmol).
These results suggested that both the quaternary ammonium
centre and the double H-bond donors were crucial for the asym-
metric induction.
On the basis of our experiment results and previous relevant
studies,9c we proposed a possible transition state model to ratio-
nalize the stereochemical results of the reaction (Fig. 3) (see the SD
for more details). Its assumed that the in situ generated imine
might have H-bonding interaction with the thiourea moiety of the
catalyst, while the nitro group anion of the nucleophile
sured on a JASCO P-1010 Polarimeter at
l
¼589 nm. IR spectra were
recorded on a PerkineElmer 983G instrument. Mass spectra anal-
ysis was performed on API 200 LC/MS system (Applied Biosystems
Co. Ltd.).

H.-Y. Wang et al. / Tetrahedron 69 (2013) 5104e5111
5107
Fig. 3. A possible transition state.
Scheme 3. Useful transformation of the products 3.
All reagents purchased from commercial sources were used as
sold and purified by standard techniques. All starting amido-
sulfones were synthesized by condensation of the corresponding
aldehyde with tert-butyl carbamate and benzenesulfinic acid so-
dium salt mediated by formic acid in an aqueous media.
a suspension of LiAlH4 (6.0 mmol) in dried THF (30 mL) at 0 ꢁC,
when finished, the mixture was stirred at 75 ꢁC for 24 h before
being carefully quenched by sequential addition of water until the
stop of gas evolution. Then anhydrous Na2SO4 was added into the
mixture, then the mixture was filtered through silica gel and the
filtrate was concentrated under reduced pressure. The crude
product was then dissolved into CH2Cl2, and the isothiocyanate or
isocyanate was added into this solution, and stirred overnight.
Then the solvent was removed in vacuo to afford the crude prod-
uct, which could be used directly in the next step. The crude
product was dissolved in a solution of CH3CN (5.0 mL)/R0Br
(2 equiv), and the resulting mixture was stirred at room temper-
ature overnight and monitored by TLC. After completion of the
reaction, the solvent was removed under reduced pressure using
a rotary evaporator and the residue was purified by silica gel
chromatography (CH2Cl2, CH2Cl2/methanol as the eluent) to afford
the desired products 1.
4.2. Typical procedure for the preparation of bifunctional
ammonium salts 1
With a modified method according to the Ref. 4: to a stirred
solution of Boc-protected
(10.0 mL) were added HBTU (3.0 mmol) and DIPEA (4.0 mmol) at
ꢁC. Then dimethylamine (2 mmol) was added and the reaction
a-amino acid (2.0 mmol) in CH2Cl2
0
mixture was vigorously stirred at room temperature and moni-
tored by TLC. After 2 h, the resulting solution was poured into
100 mL of H2O, the organic layer was separated, washed with 1.0 M
HCl, and dried over Na2SO4. The solvent was removed under re-
duced pressure and the crude product was dissolved into a mix-
ture of TFA (4.0 mmol)/CH2Cl2 (20 mL), and the resulting mixture
was stirred at room temperature overnight. The mixture was
extracted by water firstly and then the combined aqueous layer
was basified with satd aq NaHCO3 solution, which was then
extracted with CH2Cl2. The combined organic phases were dried
over anhydrous Na2SO4, and concentrated under reduced pressure.
After that, the crude product was added dropwise into
4.2.1. (S)-N-Benzyl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-
N,N,4-trimethylpentan-1-ammonium bromide (1a). Yield: 60%; yel-
26
low solid; [
a]
ꢀ20.6 (c 3.5, CHCl3); mp¼107e109 ꢁC; IR (neat):
D
2958, 1552, 1511, 1329, 1255, 730; 1H NMR (400 MHz, CDCl3)
d 10.39
(s, 1H), 9.34e9.32 (d, J¼8.0 Hz, 1H), 8.12e8.10 (d, J¼8 Hz, 2H),
8.03e8.00 (d, J¼12 Hz, 2H), 7.56e7.53 (m, 1H), 7.49e7.48 (d,
J¼4.0 Hz, 4H), 5.55e5.48 (m, 1H), 4.87e4.84 (d, J¼12.0 Hz, 1H),

5108
H.-Y. Wang et al. / Tetrahedron 69 (2013) 5104e5111
4.70e4.67 (d, J¼12.0 Hz, 1H), 4.35e4.29 (m, 1H), 3.27e3.23 (br, 7H),
1.85e1.76 (m, 2H), 1.38e1.31 (m, 1H), 1.07e1.05 (d, J¼8 Hz, 3H),
62.2, 60.7, 60.5, 40.2, 24.6, 14.4, 11.2; HRMS (ESI): calcd for [MꢀBr]þ
(C22H30N5O4S) requires 460.2019, found 460.2008.
0.99e0.97 (d, J¼8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 180.42,
145.81, 142.95, 132.88, 131.19, 129.44, 128.90, 128.81, 128.62, 126.56,
124.22, 121.23, 69.68, 68.45, 51.20, 50.21, 47.75, 43.86, 24.33, 23.14,
22.66; HRMS (ESI): calcd for [MꢀBr]þ (C22H31N4O2S) requires
415.2168, found 415.2171.
4.2.6. (S)-N,N,3,3-Tetramethyl-N-(4-bromobenzyl)-2-(3-(4-nitrophe
nyl)thioureido)butan-1-ammonium bromide (1f). Yield: 76%; yellow
solid; [
a
]
26 ꢀ119.9 (c 1.0, CHCl3); mp¼112e114 ꢁC; IR (neat): 2963,
D
1575, 1508, 1330, 1257, 1109, 851, 727; 1H NMR (400 MHz, CDCl3)
d
10.54 (s, 1H), 9.43e9.40 (d, J¼12.0 Hz, 1H), 8.13e8.11 (d, J¼8.0 Hz,
4.2.2. (S)-2-(3-(3,5-Bis(trifluoromethyl)phenyl)thioureido)-N-(4-
bromobenzyl)-N,N,4-trimethylpentan-1-ammonium bromide (1b). Yield:
2H), 8.05e8.02 (d, J¼12.0 Hz, 2H), 7.63e7.61 (d, J¼8.0 Hz, 2H),
7.42e7.40 (d, J¼8.0 Hz, 2H), 5.26e5.21 (t, J¼12.0 Hz, 1H), 4.97e4.93
(d, J¼16.0 Hz, 1H), 4.65e4.62 (d, J¼12.0 Hz, 1H), 4.41e4.35 (m, 1H),
3.61e3.58 (d, J¼12.0 Hz, 1H), 3.25 (s, 3H), 3.18 (s, 3H), 1.13 (s, 9H);
70%; white solid; [a D26
]
ꢀ30.5 (c 2.0, CHCl3); mp¼113e116 ꢁC; IR (neat):
2960, 1593, 1544, 1473, 1383, 1133, 885, 738; 1H NMR (400 MHz, CDCl3)
d
9.80 (s, 1H), 8.82e8.79 (d, J¼8.0 Hz, 1H), 8.24 (s, 2H), 7.59e7.55 (t,
13C NMR (100 MHz, CDCl3)
d 181.20, 145.66, 143.13, 134.55, 132.74,
J¼8.0 Hz, 3H), 7.39e7.37 (d, J¼8.0 Hz, 2H), 5.56e5.48 (m, 1H),
4.95e4.92 (d, J¼12.0 Hz, 1H), 4.69e4.66 (d, J¼12.0 Hz, 1H), 4.51e4.44
(dd, J¼8.0, 4.0 Hz, 1H), 3.35e3.31 (d, J¼12.0 Hz, 1H), 3.23 (s, 6H),
1.89e1.82 (m, 1H), 1.81e1.74 (m, 1H), 1.40e1.43 (m, 1H), 1.05e1.04 (d,
J¼4.0 Hz, 3H), 0.97e0.96 (d, J¼4.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
131.72, 131.71, 130.73, 130.64, 126.11, 125.51, 124.25, 121.26, 67.83,
67.56, 56.35, 50.69, 49.86, 37.15, 26.44; HRMS (ESI): calcd for
[MꢀBr]þ (C22H30BrN4O2S) requires 493.1273, found 493.1261.
4.2.7. (S)-N-(4-Bromobenzyl)-N,N-dimethyl-2-(3-(4-nitrophenyl)thi-
d
181.06, 140.74, 134.45, 134.40, 132.72, 131.73, 131.44 (q, JCeF¼33.0 Hz),
oureido)-3-phenylpropan-1-ammonium bromide (1g). Yield: 70%;
130.62, 130.57, 126.06, 125.43, 124.58 (q, JCeF¼279.0 Hz), 123.02, 121.64,
117.66, 70.07, 67.35, 51.04, 50.34, 48.15, 43.84, 24.37, 23.06, 22.63; HRMS
(ESI): calcd for [MꢀBr]þ (C24H29BrF6N3S) requires 584.1170, found
584.1167.
yellow solid; [
a
]
26 ꢀ53.3 (c 3.5, CHCl3); mp¼113e116 ꢁC; IR (neat):
D
2964, 1510, 1329, 1253, 1110, 850; 1H NMR (400 MHz, CD3CN)
d
10.10 (s, 1H), 9.56e9.53 (d, J¼8.0 Hz, 1H), 8.14e8.12 (d, J¼8.0 Hz,
2H), 8.00e7.98 (d, J¼8.0 Hz, 2H), 7.53e7.51 (d, J¼8.0 Hz, 2H),
7.36e7.30 (br, 5H), 7.17e7.15 (d, J¼8.0 Hz, 2H), 5.64e5.56 (br, 1H),
4.70e4.67 (d, J¼12.0 Hz, 1H), 4.51e4.47 (br, 1H), 4.43e4.39 (d,
J¼12.0 Hz, 1H), 3.32e3.29 (br, 1H), 3.27e3.23 (d, J¼12.0 Hz, 1H),
4.2.3. (S)-2-(3-(3,5-Bis(trifluoromethyl)phenyl)ureido)-N-(4-
bromobenzyl)-N,N,4-trimethylpentan-1-ammonium bromide (1c). Yield:
65%; white solid; [a D26
2962, 1698, 1573, 1474, 1277, 1131, 881, 738, 703; H NMR (400 MHz,
]
ꢀ77.8 (c 1.0, CHCl3); mp¼106e107 ꢁC; IR(neat):
3.07 (br, 4H), 2.97 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 180.0, 145.4,
1
143.0, 135.7, 134.3, 132.6, 131.6, 130.5, 129.4, 127.5, 126.0, 125.1,
124.3, 121.3,67.9, 66.3, 51.1, 51.0, 50.2, 40.4; HRMS (ESI): calcd for
[MꢀBr]þ (C25H28BrN4O2S) requires 527.1116, found 527.1099.
CDCl3)
d
9.31 (s, 1H), 8.03 (s, 2H), 7.61e7.59 (d, J¼8.0 Hz, 2H), 7.50e7.48
(d, J¼8.0 Hz, 1H), 7.44 (s, 2H), 7.42 (s, 1H), 4.91e4.88 (d, J¼12.0 Hz, 1H),
4.77e4.74 (d, J¼12.0 Hz, 1H), 4.58e4.51 (m, 1H), 4.24e4.18 (br, 1H),
3.34e3.31 (d, J¼12.0 Hz,1H), 3.27 (s, 3H), 3.23 (s, 3H),1.85e1.81 (m, 1H),
1.78e1.70 (m, 1H), 1.29e1.22 (m, 1H), 0.96e0.93 (br, 6H); 13C NMR
4.2.8. (2S,3S)-N-(4-Bromobenzyl)-N,N,3-trimethyl-2-(3-(4-nitrophe
nyl)thioureido)pentan-1-ammonium bromide (1h). Yield: 69%; yel-
26
(100 MHz, CDCl3)
d
155.4, 140.9, 134.4, 132.7, 131.9 (q, J¼33.0 Hz), 126.1,
low solid; [
a]
ꢀ30.3 (c 3.5, CHCl3); mp¼105e106 ꢁC; IR (neat):
D
125.3, 124.5 (q, J¼271.0 Hz), 117.8, 115.1, 69.3, 67.8, 50.8, 50.2, 43.9, 43.2,
24.2, 23.0, 21.4; HRMS (ESI): calcd for [MꢀBr]þ (C24H29BrF6N3O) re-
quires 568.1398, found 584.1383.
2964, 1572, 1508, 1328, 1253, 1110, 1013, 851, 734; 1H NMR
(400 MHz, CDCl3)
d
10.32 (s, 1H), 9.39e9.37 (d, J¼8.0 Hz, 1H),
8.14e8.12 (d, J¼8.0 Hz, 2H), 8.03e8.01 (d, J¼8.0 Hz, 2H), 7.63e7.61
(d, J¼8.0 Hz, 2H), 7.42e7.39 (d, J¼8.0 Hz, 2H), 5.42e5.36 (m, 1H),
4.94e4.91 (d, J¼12.0 Hz, 1H), 4.66e4.63 (d, J¼12.0 Hz, 1H),
4.42e4.36 (m, 1H), 3.46e3.43 (d, J¼12.0 Hz,1H), 3.24 (s, 3H), 3.19 (s,
3H), 1.57e1.48 (m, 1H), 1.39e1.30 (m, 1H), 1.09 (d, J¼8.0 Hz, 3H),
0.99e0.96 (t, J¼8.0 Hz, 3H), 0.87e0.82 (m, 1H); 13C NMR (100 MHz,
4.2.4. (S)-N-(4-Bromobenzyl)-N,N,4-trimethyl-2-(3-(4-nitrophenyl)
thioureido)pentan-1-ammonium bromide (1d). Yield: 77%; yellow
26
solid; [
a
]
ꢀ54.5 (c 0.5, CHCl3); mp¼111e114 ꢁC; IR (neat): 2960,
D
1593, 1544, 1383, 1277, 1133, 885, 847; 1H NMR (400 MHz, CDCl3)
d
10.26 (s, 1H), 9.34e9.31 (d, J¼8.0 Hz, 1H), 8.14e8.12 (d, J¼8.0 Hz,
CDCl3) d 180.47, 145.69, 143.03, 134.56, 132.68, 131.66, 130.58,
2H), 8.02e8.00 (d, J¼8.0 Hz, 2H), 7.65e7.63 (d, J¼8.0 Hz, 2H),
7.40e7.38 (d, J¼8.0 Hz, 2H), 5.54e5.47 (br, 1H), 4.95e4.91 (d,
J¼12.0 Hz, 1H), 4.70e4.67 (d, J¼12.0 Hz, 1H), 4.40e4.34 (m, 1H),
3.32e3.26 (br, 6H), 3.20e3.18 (d, J¼8.0 Hz, 1H), 1.83e1.75 (m, 2H),
1.37e1.30 (m, 1H), 1.06e1.05 (d, J¼4.0 Hz, 3H), 0.99e0.98 (d,
126.03, 125.59, 124.26, 121.17, 52.45, 50.71, 50.02, 40.15, 36.82,
36.78, 25.10, 15.10, 11.89; HRMS (ESI): calcd for [MꢀBr]þ
(C22H30BrN4O2S) requires 493.1273, found 493.1289.
4.3. Preparation of 1m
J¼4.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 180.38, 145.54, 143.16,
134.44, 132.81, 131.69, 130.58, 126.17, 125.47, 125.03, 124.29, 124.25,
121.38, 121.29, 69.83, 67.44, 51.17, 50.41, 47.75, 43.93, 24.38, 23.14,
22.63; HRMS (ESI): calcd for [MꢀBr]þ (C22H30BrN4O2S) requires
493.1273, found 493.1283.
To a stirred solution of Boc-protected a-amino acid (2.0 mmol) in
CH2Cl2 (10.0 mL) were added HBTU (3.0 mmol) and DIPEA
(4.0 mmol) at 0 ꢁC. Then dimethylamine (2 mmol) was added and
the reaction mixture was vigorously stirred at room temperature
and monitored by TLC. After 2 h, the resulting solution was diluted
with 100 mL of H2O, the organic layer was separated, washed with
1.0 M HCl and dried over Na2SO4. The solvent was removed under
reduced pressure and the crude product was added dropwise into
a suspension of LiAlH4 (6 mmol) in dried THF (30 mL) at 0 ꢁC. The
resulting mixture was stirred at 75 ꢁC for 24 h, and was then care-
fully quenched by sequential addition of water until the stop of gas
evolution. Anhydrous Na2SO4 was added into the mixture and after
filtration through silica gel, the filtrate was concentrated under re-
duced pressure. The crude product was then dissolved in CH2Cl2 to
form a solution, to which the isothiocyanate was added and fol-
lowed by stirring overnight. Then the solvent was removed in vacuo
to afford the crude product, which was used directly in the next step.
4.2.5. (2S,3S)-N,N,3-Trimethyl-N-(4-nitrobenzyl)-2-(3-(4-nitrophenyl)
thioureido)pentan-1-ammonium bromide (1e). Yield: 80%; yellow
26
solid; [
a
]
ꢀ18.0 (c 0.5, CHCl3); mp¼119e121 ꢁC; IR (neat): 2964,
D
1524,1329,1251,1110, 852, 732; 1H NMR (400 MHz, CD3CN)
d 11.19 (s,
1H), 9.52e9.49 (d, J¼8.0 Hz, 1H), 8.31e8.29 (d, J¼8.0 Hz, 2H),
8.15e8.12 (d, J¼8.0 Hz, 2H), 8.10e8.07 (d, J¼8.0 Hz, 2H), 7.85e7.83 (d,
J¼8.0 Hz, 2H), 5.41e5.35 (m, 1H), 4.93e4.90 (d, J¼12.0 Hz, 1H),
4.83e4.80 (d, J¼12.0 Hz, 1H), 3.93e3.87 (m, 1H), 3.66e3.63 (d,
J¼12.0 Hz, 1H), 3.19e3.18 (br, 6H), 1.84e1.79 (m, 1H), 1.58e1.51 (m,
1H), 1.45e1.35 (m, 1H), 1.07e1.05 (d, J¼8.0 Hz, 3H), 0.99e0.96 (t,
J¼8.0 Hz, 3H); 13C NMR (100 MHz, CD3CN)
d 180.7, 149.3,146.2, 142.9,
134.6, 134.1, 129.7, 124.8, 124.2, 124.0, 121.6, 120.7, 117.3, 67.3, 66.8,

H.-Y. Wang et al. / Tetrahedron 69 (2013) 5104e5111
5109
The crude product was dissolved in a solution of 1-bromo-4-(bro-
momethyl)benzene (2.0 equiv) in CH3CN (5.0 mL) and then the
mixturewas stirred at room temperature overnight. The solvent was
removed under reduced pressure using a rotary evaporator and the
residue was purified by silica gel chromatography (CH2Cl2, CH2Cl2/
methanol as the eluent) to afford the desired product 1m.
d
7.23e7.21 (d, J¼8.0 Hz, 2H), 6.91e6.89 (d, J¼8.0 Hz, 2H), 5.30 (br, 1H),
5.16 (br, 1H), 4.85 (br, 1H), 4.69e4.64 (m, 1H), 3.80 (s, 3H), 1.44 (s, 9H);
Enantiomeric excess: 94%, determined by HPLC (Chiralpak OD-H col-
umn, hexane/i-PrOH 90:10,
tmajor¼46.6 min; tminor¼40.9 min).
l¼214 nm, flow rate 0.7 mL/min;
4.4.6. (S)-tert-Butyl 1-(4-fluoropenyl)-2-nitrothylcarbamate (3f). Yield:
4.3.1. (S)-N-(4-Bromobenzyl)-N,N,4-trimethyl-2-(1-methyl-3-(4-
90%; White solid; [
a
]
25 þ39.2 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
D
nitrophenyl)thioureido)-pentan-1-ammonium bromide (1m). Yield:
d
7.32e7.28 (t, J¼8.0 Hz, 1H), 6.87e6.83 (m, 3H), 5.34 (br, 1H), 5.25 (br,
26
70%; yellow solid; [
a
]
ꢀ33.1 (c 3.5, CHCl3); mp¼112e115 ꢁC; IR
1H), 4.83 (br, 1H), 4.71e4.67 (m, 1H), 3.81 (s, 3H), 1.44 (s, 9H); Enan-
D
(neat): 2958, 1594, 1510, 1326, 1110, 1074, 854; 1H NMR (400 MHz,
tiomeric excess: 96%, determined by HPLC (Chiralpak AD-H column,
CDCl3)
d
9.23 (s, 1H), 8.16e8.13 (d, J¼12.0 Hz, 2H), 7.83e7.80 (d,
hexane/i-PrOH 90:10,
tmajor¼27.9 min; tminor¼42.1 min).
l
¼214 nm, flow rate 0.7 mL/min;
J¼12.0 Hz, 2H), 7.61e7.59 (d, J¼8.0 Hz 2H), 7.49e7.47 (d, J¼8.0 Hz,
2H), 6.51e6.45 (m, 1H), 5.25e5.22 (d, J¼12.0 Hz, 1H), 5.00e4.94 (dd,
J¼16.0, 12 Hz, 1H), 4.90e4.87 (d, J¼12.0 Hz, 1H), 3.58 (s, 3H),
3.34e3.31 (d, J¼12.0 Hz, 6H), 3.14e3.11 (d, J¼12.0 Hz, 1H), 1.68e1.60
(m, 1H), 1.52e1.46 (m, 1H), 1.35e1.28 (m, 1H), 1.06e1.04 (d, J¼8.0 Hz,
4.4.7. (S)-tert-Butyl 1-(4-fluoropenyl)-2-nitrothylcarbamate (3g). Yield:
98%; White solid; [
a
]
25 þ48.9 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
D
d
7.33e7.29 (t, J¼8.0 Hz, 1H), 7.24 (br, 1H), 6.97e6.93 (t, J¼7.6 Hz, 1H),
3H), 0.98e0.96 (d, J¼8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
182.21,
6.92e6.90 (d, J¼8.0 Hz, 1H), 5.71 (br, 1H), 5.56 (br, 1H), 4.79 (m, 1H),
4.69 (m, 1H), 3.90 (s, 3H), 1.44 (s, 9H); Enantiomeric excess: 94%, de-
termined by HPLC (Chiralpak AD-H column, hexane/i-PrOH 90:10,
146.26, 144.10, 134.60, 132.60, 125.84, 125.46, 123.77, 66.68, 53.51,
50.27, 49.61, 41.50, 33.29, 24.54, 23.04, 22.98; HRMS (ESI): calcd for
[MꢀBr]þ (C23H32BrN4O2S) requires 507.1429, found 507.1427.
l¼214 nm, flow rate 0.7 mL/min; tmajor¼23.4 min; tminor¼22.0 min).
4.4. General procedure for the asymmetric aza-Henry reaction
4.4.8. (S)-tert-Butyl1-(4-fluoropenyl)-2-nitrothylcarbamate (3h). Yield:
99%; White solid; [
a
]
25 þ11.0 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
D
To
a
stirred solution of the corresponding amidosulfone
d
8.13e8.11 (d, J¼8.0 Hz, 1H), 7.91e7.89 (d, J¼8.0 Hz, 1H), 7.86e7.83 (m,
(0.2 mmol) in CH2Cl2 (8.0 mL) were added nitroalkane (1.0 mmol)
and catalyst 1 at ꢀ30 ꢁC under argon. The reaction mixture was
vigorously stirred and then grounded KOH (1.0 mmol) was added.
After 8 h (monitored by TLC), 10 mL of satd aq NaHCO3 was added
and the mixture was allowed to warm to ambient temperature and
extracted with CH2Cl2. The combined organic extracts were con-
centrated under reduced pressure using a rotary evaporator and the
residue was purified by silica gel chromatography (hexane/EtOAc as
the eluent) to afford the desired products 3.
1H), 7.63e7.59 (t, J¼7.2 Hz, 1H), 7.56e7.54 (d, J¼8.0 Hz, 1H), 7.46e7.44
(m, 2H), 6.28 (br, 1H), 5.36 (br, 1H), 4.89 (br, 1H), 1.43 (s, 9H);
Enantiomeric excess: 91%, determined by HPLC (Chiralpak AD-H
column, hexane/i-PrOH 90:10,
tmajor¼24.2 min; tminor¼44.1 min).
l
¼214 nm, flow rate 0.7 mL/min;
4.4.9. (S)-tert-Butyl 1-(4-fluoropenyl)-2-nitrothylcarbamate (3i). Yield:
80%; White solid; [
a
]
25 þ37.9 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
D
d
7.38 (br, 1H), 6.35 (m, 1H), 6.32 (m, 1H), 5.46 (br, 1H), 5.27 (br, 1H),
4.85 (br,1H), 4.75e4.71 (m, 1H),1.46 (s, 9H); Enantiomeric excess: 88%,
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH 90:10,
4.4.1. (S)-tert-Butyl 2-nitro-1-phenylethylcarbamate (3a). Yield:
25
94%; White solid; [
CDCl3)
a]
þ20.5 (c 0.5, CHCl3); 1H NMR (400 MHz,
l¼214 nm, flow rate 0.7 mL/min; tmajor¼14.5 min; tminor¼13.5 min).
D
d
7.40e7.26 (m, 5H), 5.37 (br, 1H), 5.27 (br, 1H), 4.85 (br, 1H),
4.73e4.68 (m, 1H), 1.44 (s, 9H); Enantiomeric excess: 92%, de-
termined by HPLC (Chiralpak PC-II column, hexane/i-PrOH 90:10,
4.4.10. (S)-tert-Butyl 1-(4-fluoropenyl)-2-nitrothylcarbamate (3j). Yield:
98%; White solid; [a D25
]
ꢀ29.9 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
l¼214 nm, flow rate 0.7 mL/min; tmajor¼17.9 min; tminor¼15.5 min).
d
7.31e7.28 (t, J¼8.0 Hz, 2H), 7.23e7.21 (d, J¼8.0 Hz, 1H), 7.18e7.16 (d,
J¼8.0 Hz, 2H), 4.87 (br, 1H), 4.54 (br, 2H), 4.10 (m, 1H), 2.77e2.65 (m,
2H), 1.93e1.89 (m, 2H), 1.46 (s, 9H); Enantiomeric excess: 68%,
determined by HPLC (Chiralpak PC-II column, hexane/i-PrOH 90:10,
4.4.2. (S)-tert-Butyl1-(4-fluoropenyl)-2-nitrothylcarbamate (3b). Yield:
80%; White solid; [
a
]
25 þ19.8 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
D
d
7.31e7.29 (d, J¼5.2 Hz, 1H), 7.28e7.27 (d, J¼8.0 Hz, 1H)7.10e7.05 (t,
l¼214 nm, flow rate 0.7 mL/min; tmajor¼7.8 min; tminor¼8.4 min).
J¼8.4 Hz, 3H), 5.34 (br, 1H), 5.27 (br, 1H), 4.84 (br, 1H), 4.71e4.66 (m,
1H), 1.44 (s, 9H); Enantiomeric excess: 89%, determined by HPLC
4.4.11. (S)-tert-Butyl 1-(4-fluoropenyl)-2-nitrothylcarbamate (3k). Yield:
99%; White solid; [a D25
7.36e7.33 (m, 3H), 7.24e7.22 (m, 2H), 5.30 (br, 1H), 5.19e5.17 (m, 1H),
]
þ19.1 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3)
1
(Chiralpak AD-H column, hexane/i-PrOH 90:10,
0.7 mL/min; tmajor¼17.4 min; tminor¼23.5 min).
l¼214 nm, flow rate
d
4.93 (br, 1H), 1.54e1.52 (d, J¼8.0 Hz, 3H), 1.43 (s, 9H); Enantiomeric excess:
4.4.3. (S)-tert-Butyl1-(4-fluoropenyl)-2-nitrothylcarbamate (3c). Yield:
96%, determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH 90:10,
92%; White solid; [
a
]
25 þ30.8 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
l¼214 nm, flow rate 0.7 mL/min; tmajor¼15.6 min; tminor¼21.4 min).
D
d
7.18 (s, 4H), 5.33 (br, 1H), 5.21 (br, 1H), 4.83 (br, 1H), 4.70e4.66 (m,
1H), 2.34 (s,1H),1.44 (s, 9H); Enantiomeric excess: 93%, determined by
4.4.12. (S)-tert-Butyl 1-(4-fluoropenyl)-2-nitrothylcarbamate (3l). Yield:
HPLC (Chiralpak PC-II column, hexane/i-PrOH 90:10,
rate 0.7 mL/min; tmajor¼17.4 min; tminor¼15.2 min).
l¼214 nm, flow
99%; White solid; [a D25
]
þ33.1 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.36e7.32 (m, 3H), 7.24e7.22 (m, 2H), 5.14 (br, 2H), 4.74 (br, 1H),
2.10e2.00 (m,1H),1.91e1.85 (m,1H),1.43 (s, 9H),1.00e0.97 (t, J¼7.2 Hz,
4.4.4. (S)-tert-Butyl1-(4-fluoropenyl)-2-nitrothylcarbamate (3d). Yield:
3H); Enantiomeric excess: 89%, determined by HPLC (Chiralpak AS-H
85%; White solid; [
a
]
25 þ12.3 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
column, hexane/i-PrOH 90:10,
tmajor¼83.4 min; tminor¼5.3 min).
l¼214 nm, flow rate 0.7 mL/min;
D
d
7.66e7.64 (d, J¼8.0 Hz, 2H), 7.46e7.44 (d, J¼8.0 Hz, 2H), 5.47 (br, 2H),
4.89 (br, 1H), 4.75 (m, 1H), 1.44 (s, 9H); Enantiomeric excess: 89%,
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH 90:10,
4.4.13. (S)-tert-Butyl 1-(4-fluoropenyl)-2-nitrothylcarbamate (3m). Yield:
l¼214 nm, flow rate 0.7 mL/min; tmajor¼14.1 min; tminor¼23.2 min).
99%; White solid; [a D25
]
þ23.0 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.23e7.20 (br, 2H), 7.07e7.03 (t, J¼8.8 Hz, 2H), 5.36 (br, 1H), 5.16e5.12
4.4.5. (S)-tert-Butyl 1-(4-fluoropenyl)-2-nitrothylcarbamate (3e). Yield:
(m, 1H), 4.90 (br, 1H), 1.54e1.52 (d, J¼8.0 Hz, 3H), 1.43 (s, 9H); Enan-
90%; White solid; [
a
]
25 þ37.2 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
tiomeric excess: 99%, determined by HPLC (Chiralpak AD-H column,
D

5110
H.-Y. Wang et al. / Tetrahedron 69 (2013) 5104e5111
hexane/i-PrOH 90:10,
tminor¼15.4 min).
l
¼214 nm, flow rate 0.7 mL/min; tmajor¼13.4 min;
optical pure); 1H NMR (400 MHz, CDCl3)
d 7.61 (br, 1H), 7.42e7.37
(m, 5H), 5.33e5.29 (t, J¼8.0 Hz, 1H), 3.87e3.82 (dd, J¼11, 8.0 Hz,
1H), 3.53e3.48 (dd, J¼11.0, 8.0 Hz, 1H).
4.4.14. (S)-tert-Butyl 1-(4-fluoropenyl)-2-nitrothylcarbamate (3n). Yield:
99%; White solid; [a D25
]
þ36.8 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
Acknowledgements
d
7.16e7.13 (d, J¼8.0 Hz, 2H), 6.88e6.86 (d, J¼8.0 Hz, 2H), 5.25 (br, 1H),
5.12e5.08 (br, 1H), 4.90 (br, 1H), 3.76 (s, 3H), 1.53e1.52 (d, J¼4.0 Hz, 3H),
This work was financially supported by National Basic Research
Program of China (973 Program, 2010CB833300), the National
Natural Science Foundation of China (Nos. 21032006, 203900502,
20532040, 21290180), Science and Technology Commission of
Shanghai Municipality (11XD1406400) and Excellent Young
Scholars Foundation of National Natural Science Foundation of
China (20525208).
1.43 (s, 9H); Enantiomeric excess: 97%, determined by HPLC (Chiralpak
AD-H column, hexane/i-PrOH 90:10,
tmajor¼19.5 min; tminor¼21.4 min).
l¼214 nm, flow rate 0.7 mL/min;
4.4.15. (S)-tert-Butyl 1-(4-fluoropenyl)-2-nitrothylcarbamate (3o). Yield:
99%; White solid; [a D
]
25 22.3 (c þ0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.29e7.25 (t, J¼8.0 Hz, 1H), 6.87e6.84 (dd, J¼8.0, 1.2 Hz, 1H),
6.82e6.80 (d, J¼8.0 Hz, 1H), 6.76 (br, 1H), 5.26 (br, 1H), 5.20e5.16 (m,
1H), 4.90 (br, 1H), 3.80 (s, 3H), 1.54e1.52 (d, J¼8.0 Hz, 3H), 1.43 (s, 9H);
Enantiomeric excess: 99.5%, determined by HPLC (Chiralpak AD-H
Supplementary data
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2013.04.079.
column, hexane/i-PrOH 80:20,
tmajor¼12.0 min; tminor¼7.8 min).
l¼214 nm, flow rate 0.7 mL/min;
References and notes
4.5. Preparation of 6
1. For selected recent reviews: (a) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J.
Chem. Rev. 2007, 107, 5759e5812; (b) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 6,
2047e2053; (c) Paradowska, J.; Stodulski, M.; Mlynarski, J. Angew. Chem., Int. Ed.
2009, 48, 4288e4297; (d) Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009,
1807e1821; (e) Xu, L.-W.; Li, L.; Shi, Z.-H. Adv. Synth. Catal. 2010, 352, 243e279;
(f) Chai, Z.; Zhao, G. Catal. Sci. Technol. 2012, 2, 29e41.
2. For selected recent reviews: (a) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem.
2010, 2, 167e178; (b) Albrecht, L.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2011, 50, 8492e8509; (c) Piovesana, S.; Schietroma, D. M. S.; Bella, M. An-
gew. Chem., Int. Ed. 2011, 50, 6216e6232.
3. For selected recent examples about primaryesecondary diamines: (a) Yang, Y.-Q.;
Zhao, G. Chem.dEur. J. 2008, 14, 10888e10891; (b) Hong, L.; Sun, W.; Liu, C.;
Wang, L.; Wong, K.; Wang, R. Chem.dEur. J. 2009, 15, 11105e11108; (c) Liu, J.;
Yang, Z.; Liu, X.; Wang, Z.; Liu, Y.; Bai, S.; Lin, L.; Feng, X. Org. Biomol. Chem.
2009, 7, 4120e4127; (d) Yang, Y.-Q.; Chai, Z.; Wang, H.-F.; Chen, X.-K.; Cui, H.-F.;
Zheng, C.-W.; Xiao, H.; Li, P.; Zhao, G. Chem.dEur. J. 2009, 15, 13295e13298; (e)
Cui, H.-F.; Yang, Y.-Q.; Chai, Z.; Li, P.; Zheng, C.-W.; Zhu, S.-Z.; Zhao, G. J. Org.
Chem. 2010, 75, 117e122; (f) Yang, Y.-Q.; Chen, X.-K.; Xiao, H.; Liu, W.; Zhao, G.
Chem. Commun. 2010, 4130e4132; (g) Lu, Y.; Zheng, C. W.; Yang, Y.-Q.; Zhao, G.;
Zou, G. Adv. Synth. Catal. 2011, 353, 3129e3133; (h) Sun, W.; Hong, L.; Wang, R.
Chem.dEur. J. 2011, 17, 6030e6033.
The method of Barber was employed:
a mixture of 3k
(0.4 mmol) in toluene was degassed and flushed with nitrogen
several times before AIBN (0.08 mmol) and (Bu)3SnH (0.8 mmol)
were added, followed by heating at reflux for 4 h. The reaction
mixture was allowed to cool to room temperature and then directly
purified by flash column chromatography (hexane/EtOAc as the
eluent) to afford the desired product 6 as a colourless oil. On
standing the product crystallized in to a white solid.
4.5.1. (R)-tert-Butyl 1-phenylpropylcarbamate (6). Yield: 80%;
25
White solid; [
d
a
]
þ72.9 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
D
7.34e7.22 (m, 5H), 4.81 (br, 1H), 4.52 (br, 1H), 1.78e1.76 (m, 2H),
1.41 (s, 9H), 0.90e0.87 (t, J¼7.4 Hz, 3H); Enantiomeric excess: 87%,
determined by HPLC (Chiralpak AD-H column, hexane/i-PrOH 90:10,
l¼214 nm, flow rate 0.7 mL/min; tmajor¼7.8 min; tminor¼8.4 min).
4. For selected recent examples about tertiary amine-thioureas: (a) Andres, J. M.;
Manzano, R.; Pedrosa, R. Chem.dEur. J. 2008, 14, 5116e5119; (b) Pu, X.; Li, P.;
Peng, F.; Li, X.; Zhang, H.; Shao, Z. Eur. J. Org. Chem. 2009, 4622e4626; (c) Zhao, S.-L.;
Zheng, C.-W.; Wang, H.-F.; Zhao, G. Adv. Synth. Catal. 2009, 351, 2811e2816; (d)
Zhao, S.-L.; Zheng, C.-W.; Zhao, G. Tetrahedron: Asymmetry 2009, 20, 1046e1051;
(e) Chen, X.-K.; Zheng, C.-W.; Zhao, S.-L.; Chai, Z.; Yang, Y.-Q.; Zhao, G.; Cao, W.-G.
Adv. Synth. Catal. 2010, 352, 1648e1652; (f) Manzano, R.; Andres, J. M.;
Muruzabal, M. D.; Pedrosa, R. Adv. Synth. Catal. 2010, 352, 3364e3372; (g)
Manzano, R.; Andres, J. M.; Muruzabal, M.-D.; Pedrosa, R. J. Org. Chem. 2010, 75,
5417e5420; (h) Pu, X.-W.; Peng, F.-Z.; Zhang, H.-B.; Shao, Z.-H. Tetrahedron
2010, 66, 3655e3661; (i) Li, P.; Zhao, G.; Zhu, S. Chin. J. Chem. 2011, 29,
2749e2758; (j) Li, X.-J.; Peng, F.-Z.; Li, X.; Wu, W.-T.; Sun, Z.-W.; Li, Y.-M.; Zhang, S.-X.;
Shao, Z.-H. Chem.dAsian J. 2011, 6, 220e225; (k) Manzano, R.; Andres, J. M.;
Alvarez, R.; Muruzabal, M. D.; de Lera, A. R.; Pedrosa, R. Chem.dEur. J. 2011, 17,
5931e5938; (l) Wang, H.-F.; Li, P.; Cui, H.-F.; Wang, X.-W.; Zhang, J.-K.; Liu, W.;
Zhao, G. Tetrahedron 2011, 67, 1774e1780; (m) Ye, Z.; Zhao, G. Chimia 2011, 65,
902e908; (n) Joerres, M.; Schiffers, I.; Atodiresei, I.; Bolm, C. Org. Lett. 2012, 14,
4518e4521; (o) Li, G.-X.; Qu, J. Chem. Commun. 2012, 5518e5520.
5. For selected recent examples about aminophosphines: (a) Cowen, B. J.; Miller, S. J.
J. Am. Chem. Soc. 2007, 129, 10988e10989; (b) Xiao, H.; Chai, Z.; Zheng, C.-W.;
Yang, Y.-Q.; Liu, W.; Zhang, J.-K.; Zhao, G. Angew. Chem., Int. Ed. 2010, 49,
4467e4470; (c) Zhu, Q.; Lu, Y. Angew. Chem., Int. Ed. 2010, 49, 7753e7756; (d)
Gong, J.-J.; Li, T.-Z.; Pan, K.; Wu, X.-Y. Chem. Commun. 2011, 1491e1493; (e) Han, X.;
Wang, Y.; Zhong, F.; Lu, Y. Org. Biomol. Chem. 2011, 9, 6734e6740; (f) Han, X.;
Wang, Y.; Zhong, F.; Lu, Y. J. Am. Chem. Soc. 2011, 133, 1726e1729; (g) Zhong, F.;
Han, X.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 7837e7841; (h) Zhong, F.;
Wang, Y.; Han, X.; Huang, K.-W.; Lu, Y. Org. Lett. 2011, 13, 1310e1313; (i) Jin, Z.;
Yang, R.; Du, Y.; Tiwari, B.; Ganguly, R.; Chi, Y. R. Org. Lett. 2012, 14, 3226e3229;
(j) Shi, Z.; Yu, P.; Loh, T.-P.; Zhong, G. Angew. Chem., Int. Ed. 2012, 51, 7825e7829;
(k) Wang, D.; Wei, Y.; Shi, M. Chem. Commun. 2012, 2764e2766; (l) Zhong, F.;
Chen, G.-Y.; Han, X.; Yao, W.; Lu, Y. Org. Lett. 2012, 14, 3764e3767; (m) Zhong, F.;
Han, X.; Wang, Y.; Lu, Y. Chem. Sci. 2012, 3, 1231e1234.
4.6. Preparation of 5
According to the reported methods:17 a solution of the nitro
compound 1a (5.0 mmol, 1.3 g, 89% ee), sodium nitrite (700 mg,
10 mmol) and acetic acid (50 mmol) in DMSO (30 mL) was heated at
40 ꢁC for 1 day. After cooling to room temperature,1.0 M HCl (50 mL)
was added and the aqueous phase was extracted with CH2Cl2, dried
over MgSO4 and concentrated under reduced pressure. The crude
product was purified by flash column chromatography, followed by
treatment with TFA in CH2Cl2 (10 mL) with stirring at room tem-
perature for 24 h. Then satd aq Na2CO3 was added to adjust the pH
value to around 9, followed by extraction with CH2Cl2, and the
combined organic phases were dried over Na2SO4, filtered and con-
centrated under reduced pressure. The crude product was added to
a suspension of NaBH4 (3 equiv) inTHF(10 mL), followed by dropwise
addition of a solution of I2 in THF (5 mL) over 1 h at 0 ꢁC. When fin-
ished, the solution was refluxed for 18 h before being cooled to room
temperature. Methanol (10 mL) and aqueous NaOH (20%,10 mL)were
added, and the resulting mixture was extracted with CH2Cl2, dried
over Na2SO4, filtered and concentrated under reduced pressure. The
crude product was mixed with Et3N (2.5 equiv), CS2(3 equiv) in 10 mL
of DMSO and the mixture was warmed to 100 ꢁC with irradiation
at 40 W of power for 2 h. Then water was added and the
resulting mixture was extracted with EtOAc, dried over Na2SO4,
concentrated and purified by silica gel chromatography to afford 5.
6. For representative examples: (a) O’Donnell, M. J. Acc. Chem. Res. 2004, 37,
506e517; (b) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518e525; (c) Ooi, T.;
Maruoka, K. Acc. Chem. Res. 2004, 37, 526e533; (d) Hashimoto, T.; Maruoka, K.
Chem. Rev. 2007, 107, 5656e5682; (e) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed.
2007, 46, 4222e4266; (f) Gomez Arrayas, R.; Carretero, J. C. Chem. Soc. Rev.
2009, 38, 1940e1948; (g) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem.
4.6.1. (S)-4-Phenylthiazolidine-2-thione (5). Yield: 56%; White
solid; [
a
]
26 þ182.9, c 0.5 in CHCl3 ([
a
]
207.0, c 1.0 in CHCl3 for
D
D(Lit.)

H.-Y. Wang et al. / Tetrahedron 69 (2013) 5104e5111
5111
Soc. 1989, 111, 2353e2355; (h) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc.
1997, 119, 12414e12415; (i) Ooi, T.; Ksmeda, M.; Maruoka, K. J. Am. Chem. Soc.
1999, 121, 6519e6520; (j) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am.
Chem. Soc. 2000, 122, 5228e5229; (k) Kita, T.; Georgieva, A.; Hashimoto, Y.;
Nakata, T.; Nagasawa, K. Angew. Chem., Int. Ed. 2002, 41, 2832e2834.
7. (a) Xiao, H.; Chai, Z.; Wang, H.-F.; Wang, X.-W.; Cao, D.-D.; Liu, W.; Lu, Y.-P.;
Yang, Y.-Q.; Zhao, G. Chem.dEur. J. 2011, 17, 10561e10564; (b) Cui, H.-F.; Li, P.;
Wang, X.-W.; Zhu, S.-Z.; Zhao, G. J. Fluorine Chem. 2012, 133, 120e126; (c) Xiao, H.;
Chai, Z.; Cao, D.-D.; Wang, H.; Chen, J.; Zhao, G. Org. Biomol. Chem. 2012, 10,
3195e3201.
50, 10565e10569; (f) Johnson, K. M.; Rattley, M. S.; Sladojevich, F.; Barber, D. M.;
Nunez, M. G.; Goldys, A. M.; Dixon, D. J. Org. Lett. 2012, 14, 2492e2495.
10. (a) Ohmatsu, K.; Kiyokawa, M.; Ooi, T. J. Am. Chem. Soc. 2011, 133,
1307e1309; (b) Ohmatsu, K.; Hamajima, Y.; Ooi, T. J. Am. Chem. Soc. 2012,
134, 8794e8797.
11. See the preparations of the catalysts for more details.
12. (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37,
2580e2627; (b) Kotti, S.; Timmons, C.; Li, G. G. Chem. Biol. Drug Des. 2006, 67,
101e114; (c) Marques-Lopez, E.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J. Org.
Chem. 2009, 2401e2420.
8. For selected examples about H-bonding: (a) Takemoto, Y. Org. Biomol. Chem.
2005, 3, 4299e4306; (b) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006,
45, 1520e1543; (c) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713e5743.
9. Chiral phase-transfer catalyst about H-bonding: (a) Ooi, T.; Ohara, D.; Tamura, M.;
Maruoka, K. J. Am. Chem. Soc. 2004, 126, 6844e6845; (b) Berkessel, A.; Guixa, M.;
Schmidt, F.; Neudoerfl, J. M.; Lex, J. Chem.dEur. J. 2007, 13, 4483e4498; (c)
Gomez-Bengoa, E.; Linden, A.; Lopez, R.; Mugica-Mendiola, I.; Oiarbide, M.;
Palomo, C. J. Am. Chem. Soc. 2008, 130, 7955e7966; (d) Liu, Y.; Provencher, B. A.;
Bartelson, K. J.; Deng, L. Chem. Sci. 2011, 2, 1301e1304; (e) Provencher, B. A.;
Bartelson, K. J.; Liu, Y.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2011,
13. (a) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci, A. Angew.
Chem., Int. Ed. 2005, 44, 7975e7978; (b) Kumaraswamy, G.; Pitchaiah, A. Tet-
rahedron 2011, 67, 2536e2541.
14. Chen, N.; Jia, W.; Xu, J. Eur. J. Org. Chem. 2009, 5841e5846.
15. Barber, D. J.; Sanganee, H. J.; Dixon, D. J. Org. Lett. 2012, 14, 5290e5293.
16. Juaristi, E.; Leon-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron: Asymmetry
1999, 10, 2441e2495.
17. (a) Palomo, C.; Ooarbide, M.; Halder, R.; Laso, A.; Lopez, R. Angew. Chem., Int. Ed.
2006, 45, 117e120; (b) Morales-Nava, R.; Fernandez-Zertuche, M.; Ordonez, M.
Molecules 2011, 16, 8803e8814.