Catalytic Mannich-type reactions of α-aminoacetonitrile using fluorenylidene as a protecting and activating group

Article abstract of DOI:10.1016/j.tet.2012.06.044

Catalytic Mannich-type reactions of 9-fluorenylidene-protected α-aminoacetonitrile with imines were investigated. The desired reactions proceeded smoothly to afford the Mannich-type adducts in high yields with high diastereoselectivities in the presence of a catalytic amount of 1,1,3,3-tetramethylguanidine (TMG). A chiral guanidine catalyzed the reaction with good enantioselectivity.

Full text of DOI:10.1016/j.tet.2012.06.044

Tetrahedron 68 (2012) 7558e7563
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic Mannich-type reactions of
as a protecting and activating group
a-aminoacetonitrile using fluorenylidene
*
ꢀ
Yasuhiro Yamashita, Masatoshi Matsumoto, Yi-Jing Chen, Shu Kobayashi
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 April 2012
Received in revised form 20 May 2012
Accepted 8 June 2012
Available online 16 June 2012
Catalytic Mannich-type reactions of 9-fluorenylidene-protected
were investigated. The desired reactions proceeded smoothly to afford the Mannich-type adducts
in high yields with high diastereoselectivities in the presence of catalytic amount of
a-aminoacetonitrile with imines
a
1,1,3,3-tetramethylguanidine (TMG). A chiral guanidine catalyzed the reactionwith good enantioselectivity.
Ó 2012 Elsevier Ltd. All rights reserved.
Dedicated to Professor Manfred Reetz for
celebration of Tetrahedron Prize
Keywords:
9-Fluorenylidene
Mannich-type reaction
Organobase
Catalysis
Asymmetric reaction
1. Introduction
high yields with high stereoselectivities in the presence of a weak
base, such as metal phenoxide or guanidine.10 Moreover, we have
a
-Aminoacetonitrile is a useful reactant for the synthesis of ni-
found that simple primary aminoalkanes such as ethyl- or me-
thylamine could be activated for catalytic carbonecarbon bond
forming reactions.11 These results indicate that the fluorenylidene
group is a very promising protecting and activating group for
primary amine compounds. We then decided to apply this
trile compounds bearing a nitrogen functionality on the
a-posi-
tion.1 It can be activated to form a reactive carbanion at the
a-
position for carbonecarbon bond forming reactions via deproto-
nation by a base,2 although the corresponding
a
-hydrogen is less
reactive because of the electron donating effect of the neighboring
amino group. Use of a protecting group for the amino group is one
way to solve the problem. Benzylidene or diphenylmethylene
group is used as a typical imino protecting group (Schiff base),
methodology to the activation of
report a catalytic, highly stereoselective Mannich-type reaction of
a-aminoacetonitrile. Here we
N-fluorenylidene-protected
a-aminoacetonitrile (1) using a base
catalyst (Scheme 1).
which can enhance acidity of the a-hydrogen via conjugated sta-
bilization of the formed carbanion, and they can be removed under
weak acidic conditions.3 Up till now, carbonecarbon bond forming
reactions using N-alkylidene-protected
a-aminoacetonitrile have
been well-investigated,4e8 however, a stoichiometric amount of
a strong base has been employed in many cases, and only a few
examples using a catalytic amount of base species have been
reported.2d,9
Scheme 1. Catalytic Mannich-type reaction of
group (1).
a-aminonitrile with 9-fluorenylidene
Recently we have shown that 9-fluorenylidene is a good pro-
tecting and activating group for primary amine compounds, and
2. Results and discussion
that N-fluorenylidene-protected glycine esters or
a-amino-
phosphonates reacted with imines to afford Mannich adducts in
N-Fluorenylidene-protected
prepared from 9-fluorenone imine and
(Scheme 2). 9-Fluorenone imine was prepared by the reaction of 9-
a
-aminoacetonitrile (1) was easily
a
-aminoacetonitrile
* Corresponding author. E-mail address: shu_kobayashi@chem.s.u-tokyo.ac.jp (S.
Kobayashi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.044

Y. Yamashita et al. / Tetrahedron 68 (2012) 7558e7563
7559
fluorenone and ammonia gas in the presence of titanium(IV)
chloride. The imine was then treated with -aminoacetonitrile
fluorenylidene part was crucial; the aminoacetonitrile protected
with a diphenylmethylene group did not work well (12% yield,
entry 8). The effect of solvents was then examined (entries 9e12),
and it was found that Et2O gave the highest diastereoselectivity
among the solvents employed (entry 12). Interestingly, in-
vestigation of the temperature effect suggested that the reaction at
around room temperature showed the most promising result (en-
try 12 vs entries 13 and 14). The reactions using lower catalyst
loadings also proceeded well, and a good yield was obtained even
using 2.5 mol % of TMG (entry 16).
a
hydrochloric acid salt to afford the desired product 1 in good
yield.12
The scope of substrates was then examined (Table 2). A Et2O/
CH2Cl2 (9:1) mixed solvent was used to improve the solubility of DPP
imine 2 in the solvent. The aminoacetonitrile 1 successfully reacted
with aromatic or aliphatic DPP imines, and the desired products
wereobtainedin highyields with goodtohigh diastereoselectivities.
Reactions of aromatic imines with electron-withdrawing (entry 2)
or -donating groups (entries 3 and 4) did not affect the reactivity
significantly, and high diastereoselectivities were also obtained.
Large steric bulkiness on the aromatic part was found to affect the
selectivity. Whereas the reaction of ortho-tolyl or 2-naphthyl DPP
imine gave similar good results (entries 5 and 6), a somewhat lower
diastereoselectivity was obtained in the case of 1-naphthyl DPP
imine (entry 7). Heteroaromatic DPP imines also reacted with 1
smoothly, and good to high yields with high diastereoselectivities
(except for the 2-thienyl imine) were obtained (entries 8e10). We
also conducted the reactions using aliphatic imines, which were
sometimes less stable and less reactive compounds compared with
aromatic imines. The reaction of DPP imines with secondary ali-
phatic groups, cyclohexyl or iso-propyl, proceeded smoothly to af-
ford the desired products in high yields with high selectivities
(entries 11 and 12). On the other hand, a primary aliphatic imine also
reacted, however, the selectivity decreased (entry 13). It should be
noted that the current reaction system using TMG has a wide
Scheme 2. Preparation of 1.
The Mannich-type reaction of 1 with diphenylphosphinylimine
(DPP imine) 2a prepared from benzaldehyde in the presence of
potassium tert-butoxide (KOtBu) was first investigated using our
previous reaction conditions.11 The desired reaction proceeded in
THF at room temperature to afford the corresponding Mannich
product in moderate yield with low syn/anti selectivity (Table 1,
entry 1). When 18-crown-6 ether was used for activation of KOtBu,
the yield was improved, but the selectivity was still moderate
(entry 2). The reaction using weaker potassium bases was then
investigated. While potassium phenoxide prepared from KOtBu and
2,6-dimethylphenol did not work well (entry 3), the yield dropped
but the diastereoselectivity was improved when potassium car-
bonate was used (entry 4). These results indicated that the use of
weaker bases was a key for high diastereoselectivity. On the other
hand, organobases were found to be promising (entries 5e7).
Whereas triethylamine did not work at all, DBU or 1,1,3,3-
tetramethylguanidine (TMG) promoted the reaction successfully,
and TMG especially was the best base to obtain the desired product
(94% yield, entry 7). In the current reaction system, the
Table 1
substrate scope for the synthesis of a,b-diaminonitriles 3.
Transformation of Mannich product 3 was then conducted. Both
protecting groups were selectively removed under different acidic
Stereoselective Mannich-type reactions of N-fluoronylidene-protected
a-amino-
acetonitrile (1)a
Table 2
Substrate scopea
Entry
Base
Additive
Solvent
Yieldb (%)
syn/antib
1
2
3
KOtBu
KOtBu
KOtBu
d
THF
THF
THF
68
91
62
60:40
64:36
59:41
18-Crown-6
2,6-Me2e
phenol
d
Entry
R1
Isolated yield (%)
syn/antib
4
5
6
K2CO3
Et3N
DBU
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
THF
THF
THF
THF
33
Trace
90
94
12
91
95
96
89
91
76
90
77
72:28
d
d
1
2
3
4
Ph (2a)
90
99
85
95
84
92
99
70
93
92
99
97
85
97:3
92:8
95:5
96:4
96:4
93:7
86:14
94:6
94:6
73:27
93:7
89:11
74:26
d
63:37
78:22
76:24
95:5
60:40
86:14
97:3
91:9
77:23
97:3
4-BrC6H4 (2b)
4-MeOC6H4 (2c)
4-MeC6H4 (2d)
2-MeC6H4 (2e)
2-Naphthyl (2f)
1-Naphthyl (2g)
3-Pyridyl (2h)
2-Furyl (2i)
2-Thienyl (2j)
Cyclohexyl (2k)
iso-Propyl (2l)
n-Hexyl (2m)
7
d
8c
d
THF
9
d
CH3CN
CH2Cl2
Toluene
Et2O
Et2O
Et2O
Et2O
Et2O
5
10
11
12
13d
14e
15f
16g
d
6c
7
d
d
8
9
10
11d
12d
13d
d
d
d
d
97:3
a
The reaction of 1 (0.24 mmol) with 2a (0.20 mmol) was performed in the
presence of base (10 mol %) at 25 ꢀC for 30 min in 0.05 M unless otherwise noted.
TMG¼1,1,3,3-tetramethylguanidine.
a
The reaction of 1 (0.24 mmol) with 2 (0.20 mmol) was performed in the pres-
ence of TMG (5 mol %) in a Et2O/CH2Cl2 (9:1) mixed solvent system at 25 ꢀC for
30 min in 0.05 M unless otherwise noted. The crude product was purified by using
preparative TLC (CH2Cl2/MeOH¼100:3).
Yield and selectivity were determined by 1H NMR spectroscopic analysis of the
b
crude product using an internal standard (benzyl).
c
b
Diphenylmethylene-protected
a
-aminoacetonitrile was used instead of 1.
syn/anti selectivity was determined by 1H NMR spectroscopic analysis of the
d
e
f
At 0 ꢀC.
crude product.
c
At ꢁ20 ꢀC.
The crude product was purified by using silica gel column chromatography
Catalyst of 5 mol % was used.
Catalyst of 2.5 mol % was used.
(CH2Cl2/MeOH¼100:3).
g
d
Compounds 1 (0.20 mmol) and 2 (0.30 mmol) were employed for the reaction.

7560
Y. Yamashita et al. / Tetrahedron 68 (2012) 7558e7563
conditions (Scheme 3, Eq. 1). The fluorenylidene group of 3a was
first cleaved immediately under mild acidic conditions to afford
mono-protected product 4a, and 1,2-diaminonitrile 5a was
obtained as a hydrochloric acid salt after concd HCl/MeOH treat-
ment. Further hydrolysis of the nitrile part of 5a could be achieved
by additional acid treatment to afford 1,2-diaminocarboxylic acid in
high yield without loss of stereoselectivity.13 Moreover, the acid
free form of 1,2-diaminonitrile 5a was converted into the corre-
sponding 1,2,3-triamine under reducing conditions using NiCl2 and
NaBH4 in the presence of Boc2O,14 and the desired compound 7a
was obtained as a Boc-protected form in 69% yield.
3. Conclusion
Catalytic Mannich-type reactions of 9-fluorenylidene-protected
a-aminoacetonitrile (1) with DPP-protected imines were de-
veloped. The desired reactions proceeded smoothly to afford the
Mannich adducts 3 in high yields with high diastereoselectivities in
the presence of
and further transformations of the product obtained were suc-
cessfully achieved, and 1,2-diaminonitrile and 1,2,3-triamine
derivatives were obtained in high yields. The catalytic asymmet-
ric Mannich-type reaction was also investigated to afford the de-
sired adduct in high yield with good diastereo- and
enantioselectivities.
a catalytic amount of TMG. Deprotection
4. Experimental section
4.1. General
1H, 13C, and 31P NMR spectra were recorded on JEOL JNM
ECX400, JNM ECX500, and JNM-ECX600 spectrometers in CDCl3
unless otherwise noted. Tetramethylsilane (TMS) served as in-
ternal standard (
d
¼0) for 1H NMR, and CDCl3 (
¼77.0) was used as
d
internal standard for 13C NMR. In 13C NMR analysis, detectable
peaks were written in cases of the DPP imine adducts. IR spectra
were measured on a JASCO FT/IR-610 or JASCO FT/IR-4200 spec-
trometer. Specific rotations were recorded with a JASCO P-1200
polarimeter. High-resolution mass spectrometry was recorded
with a JEOL JMS-T100TD (ESI or DARTÒ). Column chromatography
was conducted on Silica gel 60N (spherical, neutral, Kanto Chem.
Co., Inc.), and preparative thin-layer chromatography (PTLC) was
carried out using plates with Wakogel B-5F. All reactions were
carried out under argon atmosphere in well-dried glassware. All
solvents were dried and distilled by following standard pro-
cedures. 9-Fluorenylidene-protected a-aminoacetonitrile (1) was
prepared according to a literature method.10 N-Diphenylphos-
phinyl imines were prepared according to the reported method.16
The chiral guanidines (8a and 8b) were prepared using a literature
method.15 Relative configuration of 3a was determined by com-
parison of 1H NMR spectra of 6a and the reported compound after
acid hydrolysis.13 The others were determined by analogy to 3a by
1H NMR spectroscopic analysis.
Scheme 3. Transformations of the Mannich adduct 3a.
The catalytic asymmetric Mannich-type reaction of 1 was then
investigated (Scheme 4). In our previous study, chiral guanidine
derivative 8a15 was found to be a good catalyst for Mannich-type
reactions of a glycine ester protected by 9-fluorenylidene.10 It was
found that 8a was also successfully employed in the Mannich-type
reaction of 1, and the desired product 3a was obtained in high yield
with good syn selectivity and moderate enantioselectivity. Further
improvement of the enantioselectivity was achieved by modifying
the chiral guanidine structure, and good selectivity was obtained
using 8b bearing the iPr group on the chiral side chain of 8.
4.2. General procedure for the preparation of 9-
fluorenylidene-protected a-aminoacetonitrile (1)
9H-Fluoren-9-imine (fluorenone imine, 1.00 g, 5.58 mmol) and
a-aminoacetonitrile hydrochloric acid salt (5.58 mmol) were com-
bined in CH2Cl2 (30 mL), and the mixture was stirred overnight at
room temperature. The reaction mixture was filtered to remove
the ammonium salt and concentrated in vacuo to remove all
volatile materials, and the residue was dissolved in Et2O. The
ether solution was then washed with H2O and dried over
anhydrous Na2SO4. The desired product was obtained in a pure
form after filtration and concentration of the ether solution (full
conversion). The product was further purified by recrystallization
(AcOEt/hexane) before use.
4.2.1. 2-(9H-Fluoren-9-ylideneamino)acetonitrile (1). Yellow fine
needles, mp 170 ꢀC (dec); IR (neat): 3154, 3063, 2986, 2924, 2313,
2254, 1648, 1453, 1098; 1H NMR (CDCl3, 399.78 MHz):
d 7.82 (d,
J¼7.3 Hz, 1H), 7.63 (dd, J¼10.3, 7.6 Hz, 2H), 7.54 (d, J¼7.3 Hz, 1H),
7.50e7.40 (m, 2H), 7.31e7.29 (m, 2H), 5.00 (s, 2H); 13C NMR (CDCl3,
150.92 MHz):
d 168.6, 144.1, 141.2, 137.4, 132.6, 132.0, 131.0, 128.8,
128.1, 127.3, 123.2, 120.9, 119.6, 117.4, 40.9; HRMS (DARTÒ): exact
mass calcd for C15H11N2 [MþH]þ 219.09222, found 219.09325.
Scheme 4. Asymmetric Mannich-type reaction of 1.

Y. Yamashita et al. / Tetrahedron 68 (2012) 7558e7563
7561
4.3. General procedure for the catalytic Mannich-type
addition of 1 to DPP imines 2
128.7, 128.7, 128.6, 128.6, 128.6, 127.8, 127.3, 123.2, 120.7, 119.6, 57.9
(JPC¼4.2 Hz), 57.7, 21.1; 31P NMR (CDCl3, 242.83 MHz):
d 23.4; HRMS
(ESI): exact mass calcd for C35H29N3OP [MþH]þ 538.20482, found
Compounds 1 (0.24 mmol) and 2 (0.20 mmol) were placed in
a flame-dried 30 mL round-bottom flask. Anhydrous Et2O (3.6 mL)
was added to the flask. 1,1,3,3-Tetramethylguanidine (0.020 mmol)
was then added to the mixture at room temperature, and CH2Cl2
(0.4 mL) was added. The resulting yellow solution was stirred at
25 ꢀC for 30 min under Ar and quenched with a saturated aqueous
NH4Cl solution. The mixture was extracted with CH2Cl2, and the
organic layers were combined and dried over Na2SO4. After filtra-
tion and concentration in vacuo, the obtained crude product was
purified by PTLC or silica gel column chromatography (CHCl3/
MeOH) to afford the desired product.
538.20692.
4.3.5. syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-ylideneami-
no)-3-(o-tolyl)propanenitrile (3e). Yellow fine needles, mp: 195 ꢀC
(dec); IR (neat): 3168, 3051, 2788, 2373, 2349, 1764, 1694, 1641,
1597, 1436, 1288, 1211, 1180, 1012; 1H NMR (CDCl3, 600.17 MHz):
d
7.85 (m, 4H), 7.71 (d, J¼8.2 Hz, 1H), 7.65 (d, J¼7.6 Hz, 1H),
7.50e7.29 (m, 11H), 7.23e7.10 (m, 4H), 7.01 (d, J¼7.6 Hz, 1H), 5.53
(d, J¼4.1 Hz, 1H), 4.99 (dt, J¼9.3, 4.1 Hz, 1H), 4.49 (dd, J¼10.3,
7.6 Hz, 1H), 1.93 (s, 3H); 13C NMR (CDCl3, 150.92 MHz):
d 168.7,
144.2, 141.3, 137.5, 137.1, 135.5, 132.8, 132.5, 132.4, 132.4, 132.2,
132.2, 132.1, 132.0, 132.0, 131.3, 130.7, 130.2, 128.7, 128.6, 128.6,
128.6, 128.6, 128.5, 128.1, 127.8, 126.7, 126.4, 123.2, 120.7, 119.6,
117.0, 57.4 (JPC¼6.0 Hz), 53.1, 19.4; 31P NMR (CDCl3, 242.95 MHz):
4.3.1. (1R,2S)-syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-
ylidene)amino-3-phenylpropanenitrile (3a). Yellow fine needles, mp
200 ꢀC (dec); IR (neat): 3401, 3165, 3058, 2917, 2361, 2344, 1646,
1597, 1451,1436, 1309, 1178, 1124, 1108,1072; 1H NMR (CDCl3,
d
23.7; HRMS (ESI): exact mass calcd for C35H29N3OP [MþH]þ
538.20482, found 538.20229.
495.13 MHz):
d
8.01e7.94 (m, 4H), 7.80 (d, J¼7.9 Hz, 1H), 7.63e7.38
(m, 13H), 7.32e7.22 (m, 5H), 5.61 (d, J¼3.4 Hz, 1H), 4.82e4.77 (m,
4.3.6. syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-ylideneami-
no)-3-(2-naphthyl)propanenitrile (3f). Yellow fine needles, mp
206 ꢀC (dec); IR (neat): 3054, 2986, 2373, 2348, 2306, 1698,
1649, 1436, 1421, 1265, 1203, 1174, 1157; 1H NMR (CDCl3,
1H), 4.65 (dd, J¼10.2, 7.4 Hz, 1H); 13C NMR (CDCl3, 150.92 MHz):
d
168.6, 144.3, 141.4, 138.5, 137.5, 132.8, 132.5, 132.5, 132.4, 132.3,
132.2,132.2, 132.1,132.0,131.7,131.2,130.7,128.8,128.7,128.6,128.6,
128.6, 128.5, 128.3, 127.8, 127.5, 123.2, 120.7, 119.6, 117.1, 57.9, 57.7
600.17 MHz):
d 7.99e7.94 (m, 4H), 7.82e7.79 (m, 5H), 7.61 (d,
(JPC¼5.7 Hz); 31P NMR (CDCl3, 161.83 MHz):
d
23.5; HRMS (DARTÒ):
J¼7.6 Hz, 1H), 7.56e7.20 (m, 15H), 5.67 (d, J¼3.4 Hz, 1H), 4.94
exact mass calcd for C34H27N3OP [MþH]þ 524.18917, found
(m, 1H), 4.75 (dd, J¼10.7, 7.2 Hz, 1H); 13C NMR (CDCl3,
524.19125; chiral HPLC: Daicel Chiralcel AD-H: hexane/iPrOH¼2:1,
150.92 MHz): d 174.3, 144.3, 141.4, 137.5, 136.1, 135.1, 134.3,
20
flow rate¼0.7 mL/min; tR¼15.9 min (1R,2S), 47.7 min (1S,2R). [
a
]
133.2, 133.0, 132.9, 132.5, 132.4, 132.3, 132.2, 132.2, 132.2, 132.0,
131.7, 128.8, 128.7, 128.6, 128.6, 128.2, 127.9, 127.8, 127.6, 126.7,
126.7, 126.3, 126.2, 125.2, 123.2, 120.7, 119.6, 117.1, 58.1, 57.9
D
þ9.6 (c 0.50, CH2Cl2) 73% ee.
4.3.2. syn-3-(p-Bromophenyl)-3-diphenylphosphinylamino-2-(9H-
fluoren-9-ylidene)aminopropanenitrile (3b). Yellow fine needles,
mp 210 ꢀC (dec); IR (neat): 3054, 2986, 2685, 2372, 2348, 2308,
(JPC¼4.2 Hz); 31P NMR (CDCl3, 242.95 MHz):
d 23.6; HRMS (ESI):
exact mass calcd for C38H29N3OP [MþH]þ 574.20482, found
574.20844.
1698, 1636, 1421, 1265; 1H NMR (CDCl3, 600.17 MHz):
d 7.93e7.88
(m, 4H), 7.71 (d, J¼7.6 Hz, 1H), 7.56e7.30 (m, 12H), 7.26e7.17 (m,
4.3.7. syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-ylideneami-
no)-3-(1-naphthyl)propanenitrile (3g). Yellow fine needles, mp
210 ꢀC (dec); IR (neat): 3149, 2373, 2348, 1701, 1646, 1599, 1509,
5H), 5.47 (d, J¼3.4 Hz, 1H), 4.68e4.66 (m, 1H), 4.57 (dd, J¼10.3,
6.9 Hz, 1H); 13C NMR (CDCl3, 150.92 MHz):
d 169.0, 144.3, 141.6,
141.4, 137.6, 137.4, 133.0, 132.4, 132.4, 132.3, 132.3, 132.3, 132.2,
131.6, 131.6, 131.5, 131.5, 130.0, 129.2, 128.8, 128.8, 128.7, 128.7,
128.6, 128.6, 128.6, 128.3, 127.8, 123.2, 122.5, 120.8, 119.7, 116.8,
1436, 1261, 1182, 1111; 1H NMR (CDCl3, 495.13 MHz):
d 8.13 (d,
J¼6.7 Hz, 1H), 7.94 (dd, J¼2.7, 12.4 Hz, 1H), 7.90e7.71 (m, 8H), 7.65
(d, J¼18.7 Hz, 1H), 7.58e7.15 (m, 14H), 5.87 (dt, J¼3.9, 10.2 Hz, 1H),
5.76 (d, J¼4.4 Hz, 1H), 4.29 (dd, J¼7.9, 9.6 Hz, 1H); 13C NMR (CDCl3,
57.4, 57.4; 31P NMR (CDCl3, 242.95 MHz):
d 23.4; HRMS (ESI): exact
mass calcd for C34H26BrN3OP [MþH]þ 602.09914, found
150.92 MHz): d 173.3, 145.2, 139.2, 137.8, 137.0, 134.2, 134.3, 133.2,
602.09948.
133.0, 132.6, 132.4, 132.4, 132.2, 132.2, 132.2, 131.6, 128.8, 128.7,
128.6, 128.5, 128.2, 128.2, 127.8, 127.6, 126.7, 126.7, 126.3, 126.2,
125.3, 123.2, 120.7, 120.0, 117.1, 58.1, 57.0 (JPC¼4.2 Hz); 31P NMR
4.3.3. syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-ylideneami-
no)-3-(p-methoxyphenyl)propanenitrile (3c). Yellow fine needles,
mp 204 ꢀC (dec); IR (neat): 2921, 2851, 2363, 2328, 1698, 1682,
(CDCl3, 242.95 MHz):
d 23.7; HRMS (ESI): exact mass calcd for
C38H29N3OP [MþH]þ 574.20482, found 574.20459.
1649, 1456, 1273; 1H NMR (CDCl3, 600.17 MHz):
d 7.93e7.92 (m,
4H), 7.78 (d, J¼7.6 Hz, 1H), 7.62e7.36 (m, 10H), 7.30e7.21 (m, 5H),
4.3.8. syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-ylideneami-
no)-3-(3-pyridyl)propanenitrile (3h). Yellow fine needles, mp:
130 ꢀC (dec); IR (neat): 3055, 2374, 2349, 2316, 1757, 1693, 1645,
6.81 (d, J¼8.9 Hz, 2H), 5.57 (d, J¼3.4 Hz, 1H), 4.73 (m, 1H), 4.55 (m.
1H), 3.74 (s, 3H); 13C NMR (CDCl3, 150.92 MHz):
d 168.5, 159.4,
144.2, 141.4, 137.5, 132.8, 132.6, 132.5, 132.4, 132.2, 132.2, 132.2,
132.1,131.7,131.2,130.8,130.6,129.4, 128.7,128.6,128.6, 128.6,127.8,
123.2, 120.7, 119.6, 117.2, 113.8, 113.7, 57.9 (JPC¼5.8 Hz), 57.4, 55.2;
1591, 1435, 1187, 11s09; 1H NMR (CDCl3, 600.17 MHz):
d 8.48 (d,
J¼4.8 Hz, 1H), 7.86e7.83 (m, 4H), 7.63e7.33 (m, 11H), 7.23e7.13 (m,
6H), 5.84 (d, J¼5.5 Hz, 1H), 4.96 (dt, J¼10.1, 5.7 Hz, 1H), 4.58 (dd,
31P NMR (CDCl3, 242.95 MHz):
d
23.4; HRMS (ESI): exact mass calcd
J¼5.7 Hz, 1H); 13C NMR (CDCl3, 150.92 MHz):
d 168.1, 157.0, 149.2,
for C35H29N3O2P [MþH]þ 554.19974, found 554.19886.
144.2,141.4,136.8,132.6, 132.5,132.4,132.1,132.1,132.2,132.0,131.9,
131.9, 130.7, 128.6, 128.5, 128.5, 128.5, 128.4, 128.4, 127.9, 123.3,
123.3, 123.2, 120.6, 119.5, 117.2, 58.9, 57.6 (JPC¼7.2 Hz); 31P NMR
4.3.4. syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-ylideneami-
no)-3-(p-tolyl)propanenitrile (3d). Mp 200 ꢀC (dec); IR (neat): 3161,
2361, 1772, 1646, 1600, 1449, 1435, 1179, 1106; 1H NMR (CDCl3,
(CDCl3, 242.95 MHz):
d 24.9; HRMS (ESI): exact mass calcd for
C33H26N4OP [MþH]þ 525.18442, found 525.18497.
600.17 MHz):
d
7.94 (m, 4H), 7.77 (d, J¼10.0 Hz, 1H), 7.59e7.34 (m,
10H), 7.28e7.17 (m, 5H), 7.07 (d, J¼7.6 Hz, 2H), 5.56 (d, J¼4.1 Hz,
1H), 4.73e4.70 (m, 1H), 4.57 (dd, J¼10.3, 6.9 Hz, 1H), 2.33 (s, 3H);
4.3.9. syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-ylideneami-
no)-3-(2-furyl)propanenitrile (3i). Yellow fine needles, mp 115 ꢀC
(dec): IR (neat): 2360, 2340, 1646, 1598, 1437, 1191, 1107; 1H NMR
13C NMR (CDCl3, 150.92 MHz):
d 168.5, 144.2, 141.3, 138.0, 137.5,
135.6,132.8,132.5,132.4,132.3,132.2,132.2,132.1,132.1,130.7,129.1,
(CDCl3, 495.13 MHz):
d
7.95e7.90 (m, 4H), 7.83 (d, J¼7.9 Hz, 1H),

7562
Y. Yamashita et al. / Tetrahedron 68 (2012) 7558e7563
7.44e7.30 (m, 15H), 6.51 (s, 1H), 5.70 (d, J¼3.4 Hz, 1H), 4.69e4.64
(m, 1H), 4.18 (dd, J¼11.1, 7.1 Hz, 1H); 13C NMR (CDCl3, 124.51 MHz):
(ESI): exact mass calcd for C34H35N3OP [MþH]þ 532.25177, found
532.25399.
d
168.3, 144.2, 143.2, 141.4, 140.8, 137.5, 132.8, 132.4, 132.3, 132.3,
132.3,132.2,132.1,132.0,132.0,131.1,130.6,128.8,128.8,128.7,128.7,
128.7, 128.6, 127.9, 123.8, 123.8, 123.2, 120.7, 119.6, 117.2, 109.6, 57.9
4.4. Synthesis of syn-3-diphenylphosphinylamino-2-amino-
3-phenylpropanenitrile (4a)
(JPC¼4.7 Hz), 51.0; 31P NMR (CDCl3, 242.95 MHz):
d 23.7; HRMS
(ESI): exact mass calcd for C32H25N3O2P [MþH]þ 514.16844, found
A solution of 3a (100 mg, 0.183 mmol) in a mixture of THF (9 mL)
and 0.5 M HCl (1 mL) was stirred at 0 ꢀC for 10 min and then diluted
with H2O (15 mL), and the aqueous layer was separated and washed
with Et2O (10 mLꢂ3). The aqueous layer was basified with satu-
rated NaHCO3 (5 mL), and then the aqueous phase was extracted
with EtOAc (15 mLꢂ3). The organic layers were combined, then
dried over Na2SO4 and evaporated under reduced pressure to afford
4a (69 mg, 98%).
514.16835.
4.3.10. syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-ylidenea-
mino)-3-(thiophen-2-yl)propanenitrile (3j). Yellow fine needles,
mp 120 ꢀC (dec); IR (neat): 2360, 2340, 1647, 1541, 1437, 1186,
1107; 1H NMR (CDCl3, 600.17 MHz):
d 7.95e7.90 (m, 1H), 7.79 (m,
2H), 7.71e7.66 (m, 2H), 7.50e7.15 (m, 14H), 7.04 (d, J¼3.4 Hz, 1H),
6.93 (dd, J¼3.6, 4.8 Hz, 1H), 5.67 (d, J¼3.4 Hz, 1H), 5.17 (dt, J¼3.6,
7.6 Hz, 1H), 4.12 (dd, J¼11.0, 7.6 Hz, 1H); 13C NMR (CDCl3,
4.4.1. syn-3-Diphenylphosphinylamino-2-amino-3-phenylpropanen-
itrile (4a). Colorless fine needles, mp 165 ꢀC; IR (neat): 2922, 2368,
2351, 2326, 1716, 1698, 1635, 1619, 1557, 1473, 1456, 1264; 1H NMR
150.92 MHz):
d 170.2, 144.3, 144.2, 141.5, 141.4, 132.9, 132.6, 132.6,
132.3, 132.0, 131.5, 130.7, 128.7, 128.7, 128.5, 128.5, 128.5, 128.2,
127.9, 127.3, 126.6, 126.2, 123.5, 120.7, 119.6, 116.6, 115.9, 58.2
(CDCl3, 495.13 MHz):
4.27e4.23 (m, 1H), 4.10e4.06 (m, 1H), 1.7 (br, 2H); 13C NMR (CDCl3,
150.92 MHz): 132.5, 132.5, 132.3, 132.2, 131.7, 131.6, 131.4, 129.0,
d 7.84e7.65 (m, 5H), 7.48e7.25 (m, 10H),
(JPC¼4.4 Hz), 54.4; 31P NMR (CDCl3, 242.95 MHz)
d 24.8; HRMS
(ESI): exact mass calcd for C32H25N3OPS [MþH]þ 530.14425,
d
found 530.14464.
128.9, 128.8, 128.7, 128.7, 128.7, 128.6, 128.6, 128.5, 127.3, 120.3, 57.8,
50.7 (JPC¼3.6 Hz); 31P NMR (CDCl3, 242.95 MHz):
d 24.8; HRMS
4.3.11. syn-3-Cyclohexyl-3-diphenylphosphinylamino-2-(9H-fluoren-
9-ylideneamino)propanenitrile (3k). Yellow amorphous solid, mp
187 ꢀC (dec); IR (neat): 3054, 2986, 2372, 2348, 2308, 1748, 1733,
1716, 1698, 1540, 1508, 1455, 1421, 1374; 1H NMR (CDCl3,
(DARTÒ): exact mass calcd for C21H21N3OP [MþH]þ 362.14222,
found 362.14189.
4.5. Synthesis of syn-2,3-diamino-3-phenylpropanenitrile
bishydrochloric acid salt (5a$2HCl)
600.17 MHz):
d
8.03e7.96 (m, 4H), 7.74 (d, J¼7.6 Hz, 1H), 7.61 (d,
J¼7.6 Hz, 1H), 7.56 (d, J¼7.6 Hz, 1H), 7.48e7.32 (m, 9H), 7.23e7.17
(m, 2H), 5.54 (d, J¼3.4 Hz, 1H), 3.33 (m, 1H), 2.18 (d, J¼12.4 Hz,
1H), 1.79e1.69 (m, 3H), 1.57e1.48 (m, 3H), 1.19e0.97 (m, 5H); 13C
Asolutionof4a (60.0 mg,0.146 mmol)inamixtureofMeOH(4 mL)
and concd HCl (1 mL) was stirred at room temperature for 1 h, and
then diluted with H2O (10 mL). After the aqueous phase was washed
with EtOAc (10 mLꢂ3), the aqueous layers were combined and evap-
orated under reduced pressure to afford 5a (31.8 mg, 93% yield).
NMR (CDCl3, 150.92 MHz):
d 167.8, 144.3, 141.3, 137.6, 133.1,
132.7, 132.6, 132.5, 132.5, 132.2, 132.2, 132.0, 131.9, 131.0, 130.7,
128.7, 128.6, 128.6, 128.5, 128.5, 127.7, 123.2, 120.7, 119.6, 118.1,
58.7, 54.6 (JPC¼5.7 Hz), 41.0 (JPC¼3.0 Hz), 30.3, 28.8, 26.3, 26.1,
26.0; 31P NMR (CDCl3, 242.95 MHz):
d
22.6; HRMS (ESI): exact
4.5.1. syn-2,3-Diamino-3-phenylpropanenitrile bishydrochloric acid
salt (5a$2HCl). Colorless fine needles, mp 123 ꢀC (dec): IR (neat.):
3434, 2522, 1661, 1641, 1585, 1442, 1204; 1H NMR (CD3OD,
mass calcd for C34H33N3OP [MþH]þ 530.23612, found
530.23378.
600.17 MHz):
d
7.81e7.48 (m, 5H), 5.53 (d, J¼6.2 Hz, 1H), 5.43e4.83
4.3.12. syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-ylideneam-
ino)-3-iso-propylpropanenitrile (3l). Yellow amorphous solid, mp
186 ꢀC (dec); IR (neat): 3057, 2962, 2360, 2340, 1645, 1598, 1451,
(br, 5H); 13C NMR (CDCl3, 150.92 MHz):
d 133.3, 132.3, 130.9, 129.7,
113.8, 55.2, 45.6; HRMS (DARTÒ): exact mass calcd for C9H12N3
[MꢁHꢁ2Cl]þ 162.1026, found 162.1029.
1308, 1188; 1H NMR (CDCl3, 600.17 MHz):
d 8.00 (m, 1H), 7.88 (dd,
J¼11.7, 7.6 Hz, 2H), 7.73 (m, 3H), 7.56 (d, J¼7.6 Hz, 1H), 7.39e7.26
(m, 11H), 5.46 (d, J¼4.8 Hz, 1H), 3.58e3.54 (m, 1H), 3.34 (dd,
J¼10.9, 6.8 Hz, 1H), 2.23 (m, 1H), 1.13 (d, J¼6.8 Hz, 3H), 1.09 (d,
4.6. Neutralization of 5a$2HCl
A saturated NaHCO3 aqueous solution was added to a stirred
solution of 5a$2HCl (11.8 mg, 0.078 mmol) in MeOH (10 mL). The
solution was then stirred for 10 min at ambient temperature. CH2Cl2
was added, and the reaction mixture was extracted with CH2Cl2,
then the organic layers were combined and dried over Na2SO4. The
desired product was obtained in a pure form after filtration and
concentration of the CH2Cl2 solution (5.3 mg, 67% yield).
J¼6.8 Hz, 3H); 13C NMR (CDCl3, 150.92 MHz):
d 168.8, 144.3, 141.4,
137.8, 132.9, 132.7, 132.5, 132.5, 132.4, 132.4, 132.2, 132.1, 132.0,
132.0, 131.8, 131.7, 130.7, 128.6, 128.6, 128.5, 128.5, 128.5, 128.4,
128.0, 123.2, 120.7, 119.6, 117.2, 58.9, 55.2 (JPC¼4.4 Hz), 31.0
(JPC¼5.9 Hz), 21.2, 18.0; 31P NMR (CDCl3, 242.95 MHz):
d 24.5;
HRMS (ESI): exact mass calcd for C31H29N3OP [MþH]þ 490.20482,
found 490.20612.
4.6.1. syn-2,3-Diamino-3-phenylpropanenitrile (5a). Colorless amo-
4.3.13. syn-3-Diphenylphosphinylamino-2-(9H-fluoren-9-ylideneam-
ino)nonanenitrile (3m). Yellow amorphous solid, mp 179 ꢀC (dec);
IR (neat): 2926, 2857, 2361, 1644, 1599, 1451, 1438, 1309, 1192, 1123,
rphous solid, mp 155 ꢀC; IR (neat): 2922, 2326, 1698, 1264; 1H NMR
(CDCl3, 600.17 MHz):
d
7.34e7.30 (m, 5H), 4.10 (d, J¼6.2 Hz, 1H),
3.75 (d, J¼6.2 Hz, 1H), 1.75 (s, 4H); 13C NMR (CDCl3, 150.92 MHz):
1108, 1027; 1H NMR (CDCl3, 600.17 MHz):
d
7.93 (m, 4H), 7.85 (d,
d
139.5, 128.8, 127.2, 126.6, 120.6, 58.6, 50.6; HRMS (DARTÒ): exact
J¼7.6 Hz, 1H), 7.60 (d, J¼7.6 Hz, 1H), 7.50 (d, J¼6.9 Hz, 1H),
7.47e7.13 (m, 11H), 5.67 (d, J¼4.1 Hz, 1H), 3.65 (dd, J¼7.6, 11.0 Hz,
1H), 3.45e3.44 (m, 1H), 1.22e1.13 (m, 10H), 0.81 (t, J¼6.2 Hz, 3H);
mass calcd for C9H12N3 [MþH]þ 162.1312, found 162.10369.
4.7. Synthesis of syn-2,3-diamino-3-phenylpropanoic acid (6a)
13C NMR (CDCl3, 150.92 MHz):
d 167.7, 144.0, 141.0, 141.3, 137.6,
132.5, 132.4, 132.2, 132.1, 132.1, 132.0, 132.0, 132.0, 131.9, 131.5,
131.5, 130.6, 128.7, 128.6, 128.5, 128.4, 127.8, 123.1, 123.0, 120.5,
119.5, 119.4, 117.7, 57.0 (JPC¼2.9 Hz), 54.6, 32.5 (JPC¼5.7 Hz), 31.5,
Compound 5a$2HCl (207.9 mg, 0.89 mmol) was dissolved in
concd HCl at 0 ꢀC, and the solution was heated at 80 ꢀC for 12 h.
After being cooled to ambient temperature, the solution was di-
luted with water and extracted with Et2O. The separated aqueous
28.8, 26.0, 22.5, 14.0; 31P NMR (CDCl3, 242.95 MHz):
d 23.3; HRMS

Y. Yamashita et al. / Tetrahedron 68 (2012) 7558e7563
7563
layer was evaporated under reduced pressure and the residue was
References and notes
dissolved in EtOH. Propylene oxide was then added and the mixture
was stirred at room temperature for 30 min. A white solid pre-
cipitated, which was collected by filtration and washed with cold
EtOH and Et2O to give the desired diamino acid (112 mg, 70% yield).
1. Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359.
2. (a) Stork, G.; Ozorio, A. A.; Leong, A. Y. W. Tetrahedron Lett. 1978, 5175; (b)
Albright, J. D. Tetrahedron 1983, 39, 3207; (c) Enders, D.; Kirchhoff, J.; Gerdes, P.;
Mannes, D.; Raabe, G.; Runsink, J.; Boche, G.; Marsch, M.; Ahlbrecht, H.; Som-
mer, H. Eur. J. Org. Chem. 1998, 63 and related references cited therein. See also;
(d) Kobayashi, S.; Matsubara, R. Chem.dEur. J. 2009, 15, 10694.
3. Related reviews: (a) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506; (c) Najera, C.;
Sansano, J. M. Chem. Rev. 2007, 107, 4584.
4.7.1. syn-2R,3S-Diamino-3-phenylpropanoic acid (6a).13 Colorless
fine needles, mp 202 ꢀC (dec); 1H NMR (D2O, 600.17 MHz):
4. Alkylation: (a) O’Donnell, M. J.; Eckrich, T. M. Tetrahedron Lett. 1978, 19, 4625;
(b) Ferroud, D.; Genet, J. P.; Kiolle, R. Tetrahedron Lett. 1986, 27, 23; (c) Genet, J.
P.; Juge, S.; Achi, S.; Mallart, S.; Ruiz, M. J.; Levif, G. Tetrahedron 1988, 44, 5263;
(d) Rose-Munch, F.; Aniss, K. Tetrahedron Lett. 1990, 31, 6351; (e) Baldwin, J. E.;
Adlington, R. M.; Crouch, N. P.; Schofield, C. J.; Turner, N. J.; Aplin, R. T. Tetra-
hedron 1991, 47, 9881; (f) Wyzlic, I. M.; Soloway, A. H. Tetrahedron Lett. 1992, 33,
7489; (g) Wu, Y. Q.; Lawrence, T.; Guo, J. Q.; Woster, P. M. Bioorg. Med. Chem.
1993, 3, 2811; (h) Chengzhi, C.; Buechler, D.; Lowe, D.; Urwyler, S.; Shapiro, G.
Tetrahedron 1994, 50, 5735; (i) Gaucher, A.; Dorizon, P.; Ollivier, J.; Salaun, J.
Tetrahedron Lett. 1995, 36, 2979; (j) Ridvan, L.; Abdallah, N.; Holakovsky, R.;
Tichy, M.; Zavada, J. Tetrahedron: Asymmetry 1996, 7, 231; (k) Dorizon, P.;
Ollivier, J.; Salauen, J. Synlett 1996, 1071; (l) Mazon, A.; Najera, C.; Ezqyerram, J.;
Pedregal, C. Tetrahedron Lett. 1997, 38, 2167; (m) Fox, M. E.; Lennon, I. C.; Farina,
V. Tetrahedron Lett. 2007, 48, 945; (n) Baldwin, J. E.; Adlington, R. M.; Bird, J. W.;
Schofield, C. J. J. Chem. Soc., Chem. Commun. 1989, 1615; (o) Selva, A.; Bomben,
A.; Tundo, P. Synth. Commun. 1999, 29, 1561; (p) Dorizon, P.; Su, G.; Ludvig, G.;
Nikitina, L.; Paugam, R.; Ollivier, J.; Salauen, J. J. Org. Chem. 1999, 64, 4712; (q)
Enright, A.; Alexandre, F.-R.; Roff, G.; Fotheringham, I. G.; Dawson, M. J.; Turner,
N. J. Chem. Commun. 2003, 2636; (r) McLaughlin, M.; Mohareb, R. M.; Rapoport,
H. J. Org. Chem. 2003, 68, 50; (s) Nawrath, T.; Dickschat, J. S.; Kunze, B.; Schulz, S.
Chem. Biodivers. 2010, 7, 2129; (t) Shinkevich, E.; Deblander, J.; Matthijs, S.;
Jacobs, J.; De, K. N.; Tehrani, K. A. Org. Biomol. Chem. 2011, 9, 538.
5. Reaction with an aldehyde or an imine: (a) Dryanska, V. Synth. Commun. 1990,
20, 1055; (b) Dryanska, V.; Tasheva, D. Synth. Commun. 1992, 22, 63; (c)
Dryanska, V.; Angelova, O.; Macicek, J.; Shishkova, L.; Denkova, P.; Spassov, S. J.
Chem. Res. 1995, 268.
d
7.40e7.29 (m, 5H), 4.61 (m, 1H, overlap with D2O peaks, 1H), 4.09
(s, 1H), 13C NMR (D2O, 150.92 MHz standard: MeOH
d 4.95): d 172.2,
20
132.4, 132.2, 131.3, 129.4, 55.9, 55.13. [
(Ref. 13, [
a]
ꢁ18.0 (c 0.50, H2O)
D
26
a
]
þ39 (c 0.52, H2O) (99% ee, 2S,3R-form)).
D
4.8. Synthesis of syn-1-phenyl-1,2,3-tris(tert-
butoxycarbonylamino)propane (7a)
Boc2O (95.6 mg, 0.44 mmol) and NiCl2$6H2O (17.3 mg,
0.073 mmol) were added to a stirred solution of diaminonitrile
(11.8 mg, 0.078 mmol) in dry methanol (20 mL) in a 50 mL round-
bottom flask and cooled to 0 ꢀC. NaBH4 (19.3 mg, 0.51 mmol) was
then added in small portions over 30 min. The reaction was exo-
thermic and effervescent. The resulting reaction mixture contain-
ing a finely divided black precipitate was allowed to warm to room
temperature and stirred for a further 1 h, at which point dieth-
ylenetriamine (15.7 mL, 0.14 mmol) was added. The mixture was
stirred for 30 min before solvent evaporation. The purple residue
was dissolved in CH2Cl2 and extracted with saturated NaHCO3. The
organic layer was dried (Na2SO4) and the solvent removed in vacuo
to yield a residue, which was purified by column chromatography
to give desired tricarbamate as colorless liquid (23.4 mg, 69% yield).
6. 1,4-Addition: (a) Bergner, I.; Opatz, T. Synthesis 2007, 918; (b) Tasheva, D.;
Petrova, A.; Simova, S. Synth. Commun. 2007, 37, 3971.
7. [3þ2] Cycloaddition: (a) Tsuge, O.; Kanemasa, S.; Yorozu, K.; Ueno, K. Chem. Lett.
1985, 1601; (b) Tsuge, O.; Ueno, K.; Kanemasa, S.; Yorozu, K. Bull. Chem. Soc. Jpn.
1986, 59, 1809; (c) Tsuge, O.; Kanemasa, S.; Yorozu, K.; Ueno, K. Bull. Chem. Soc.
Jpn. 1987, 60, 3359; (d) Kanemasa, S.; Yamamoto, H.; Wada, E.; Sakurai, T.;
Urshido, K. Bull. Chem. Soc. Jpn. 1990, 63, 2857.
4.8.1. syn-1-Phenyl-1,2,3-tris(tert-butoxycarbonylamino)propane
(7a).17 Colorless liquid, IR (neat): 2977, 2933, 2249, 1698, 1519,
1479, 1414, 1392, 1249, 1174, 1068, 1038; 1H NMR (CDCl3,
8. Homologation of aromatic ketones to nitriles: see Ref. 4o.
9. Examples of carbonecarbon bond forming reactions using a catalytic amount of
base: (a) Marrec, O.; Christophe, C.; Billard, T.; Langlois, B.; Vors, J.-P.; Pazenok,
S. Adv. Synth. Catal. 2010, 352, 2825; (b) Robles-Machín, R.; Alonso, I.; Adrio, J.;
Carretero, J. C. Chem.dEur. J. 2010, 16, 5286.
600.17 MHz):
d
7.75e7.72 (m, 2H), 7.47 (d, J¼6.1 Hz, 1H), 7.40e7.37
(m, 2H), 5.07 (br, 1H), 4.96 (br, 1H); 3.70 (d, J¼10.9 Hz, 2H), 3.38 (br,
1H), 3.26 (br, 1H), 3.19 (br, 1H), 1.42e1.35 (m, 27H); 13C NMR (CDCl3,
150.92 MHz):
d
156.16 (br),131.6, 131.5,128.5, 128.4, 80.2, 50.5, 39.5,
10. Kobayashi, S.; Yazaki, R.; Seki, K.; Yamashita, Y. Angew. Chem., Int. Ed. 2008, 47,
28.3, 28.3. HRMS (DARTÒ): exact mass calcd for C24H40N3O6
5613.
11. Chen, Y.-J.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2010, 132,
3244.
12. (a) Meng, Q.; Thibblin, A. J. Am. Chem. Soc.1997, 119, 1224; (b) Maruoka, K.; Ooi, T.
Chem. Rev. 2003, 103, 3013.
13. Zhang, H.-H.; Hu, X.-Q.; Wang, X.; Luo, Y.-C.; Xu, P.-F. J. Org. Chem. 2008, 73,
3634.
14. Caddick, S.; Judd, D. B.; Lewis, A. K.; de, K.; Reich, M. T.; Williams, M. R. V.
Tetrahedron 2003, 59, 5417.
15. Isobe, T.; Fukuda, K.; Ishikawa, T. Tetrahedron: Asymmetry 1998, 9, 1729.
16. Wipf, P.; Coleman, C. M.; Janjic, J. M.; Iyer, P. S.; Fodor, M. D.; Shafer, Y. A.;
Stephenson, C. R. J.; Kendall, C.; Day, B. W. J. Comb. Chem. 2005, 7, 322.
17. Caddick, S.; Haynes, A. K.; de, K.; Judd, D. B.; Williams, M. R. V. Tetrahedron Lett.
2000, 41, 3513.
[MþH]þ 466.2912, found 466.2915.
Acknowledgements
M.M. thanks Japan Chemical Industry Association (JCIA) for
financial support. This work was partially supported by a Grant-in-
Aid for Science Research from the Japan Society for the Promotion
of Science (JSPS) and Global COE Program (Chemistry Innovation
through Cooperation of Science and Engineering), the University of
Tokyo, MEXT, Japan.