Ring-opening reaction of unactivated 3-arylaziridine-2-carboxylates with nitrile reagents

Article abstract of DOI:10.1016/j.tet.2010.03.063

Ring-opening reactions of unactivated 3-arylaziridine-2-carboxylates with nitrile reagents, using trans-1-benzyl-3-(3,4-methylenedioxyphenyl)aziridine-2-carboxylate as a typical aziridine substrate, were examined. Formation of azomethine ylide by C2-C3 bond cleavage was observed when the aziridine was treated with trimethylsilyl cyanide under thermal conditions. On the other hand the use of bromine cyanide (BrCN) and diethylaluminum cyanide (Et₂AlCN) led to N-C3 bond cleavage and the stereospecificity was found to be dependent on the reagent used. Additional aluminum-catalyzed ring-opening reactions disclosed that the potential cationic character of the C3 benzylic position and stereochemical requirements of substituents in the arylaziridine system control the reactivity. Furthermore, the synthetic utility of the ring-opening reaction was demonstrated not only by application to the cyclization of a ring-opened cyanopropanoate to an isoquinoline skeleton but also by the extension of other carbon nucleophile from nitrile (C1) to a ketene acetal (C2).

Full text of DOI:10.1016/j.tet.2010.03.063

Tetrahedron 66 (2010) 3836–3841
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ring-opening reaction of unactivated 3-arylaziridine-2-carboxylates with
nitrile reagents
,
Yukiko Hayashi a, Takuya Kumamoto a, Masatoshi Kawahata b, Kentaro Yamaguchi b, Tsutomu Ishikawa a
*
a Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
b Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Ring-opening reactions of unactivated 3-arylaziridine-2-carboxylates with nitrile reagents, using trans-1-
benzyl-3-(3,4-methylenedioxyphenyl)aziridine-2-carboxylate as a typical aziridine substrate, were ex-
amined. Formation of azomethine ylide by C2–C3 bond cleavage was observed when the aziridine was
treated with trimethylsilyl cyanide under thermal conditions. On the other hand the use of bromine
cyanide (BrCN) and diethylaluminum cyanide (Et2AlCN) led to N–C3 bond cleavage and the stereo-
specificity was found to be dependent on the reagent used. Additional aluminum-catalyzed ring-opening
reactions disclosed that the potential cationic character of the C3 benzylic position and stereochemical
requirements of substituents in the arylaziridine system control the reactivity. Furthermore, the syn-
thetic utility of the ring-opening reaction was demonstrated not only by application to the cyclization of
a ring-opened cyanopropanoate to an isoquinoline skeleton but also by the extension of other carbon
nucleophile from nitrile (C1) to a ketene acetal (C2).
Received 22 January 2010
Received in revised form 10 March 2010
Accepted 12 March 2010
Available online 20 March 2010
Keywords:
Aziridine
Ring-opening
Trimethylsilyl cyanide
Bromine cyanide
Diethylaluminum cyanide
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives) are produced. These findings prompted us to in-
vestigate the unexplored ring-opening reaction of unactivated
Three-membered nitrogen heterocycles, aziridines, are very
important molecules not only as key components of biologically
active natural products such as mitomycins, but also as reactive
synthetic precursors for a wide variety of nitrogen-containing
compounds.1 Among them aziridine-2-carboxylates are, in partic-
ular, versatile synthetic intermediates1–3 for the preparation of
biologically active nitrogen-containing compounds because they
aziridines effectively formed and, thus, the nucleophilic ring-
opening reactions of ‘unactivated’ 3-arylaziridine-2-carboxylates
using oxygen (O-) and aromatic carbon (Ar-) nucleophiles were
examined15 (Scheme 1). As a result, N–C3 bond cleavage prefer-
entially occurred and the stereospecificity in the products was
found to be dependent on substrates and conditions used. Stereo-
chemical inversion at the C3 was observed as a major reaction path
in the ring-opening reactions of 3-arylaziridines carrying an
electron-withdrawing group (EWG) on the aromatic ring with
O-nucleophiles, whereas syn-preferred diastereomeric mixtures
were generally obtained when aziridines with electron-donating
group (EDG)-substituted aryl function were used. In addition, in
the ring-opening reactions of EDG-substituted arylaziridines with
Ar-nucleophiles, only SN2 reaction yielding anti-type products was
observed as the preferred reaction.
are convertible to
a- or b-amino acid derivatives, including
unnatural amino acids, by regioselective ring-opening reactions.1,4–
6
Aziridines are classified into two groups, activated and unac-
tivated (or non-activated) aziridines, dependent upon substituent
on the ring N-atom;1,4 the former category includes electron-
withdrawing substituents such as tosyl or acyl functions, whereas
hydrogen and alkyl substituents are typical for the latter one.
Although the reactivity of activated aziridines has been well in-
vestigated, only limited reports7–12 discussed on unactivated
aziridines.
Recently, we found a unique atom-economical aziridine syn-
thesis from guanidinium salts and aryl aldehydes13 (or unsaturated
aldehydes14) applicable to asymmetric synthesis, in which 1-alkyl-
3-arylaziridine-2-carboxylates (or the corresponding unsaturated
inversion
retention
PhCH2HN
Nu
PhCH2HN
Nu
CO2R
Ar
2
CO2R
Ar
CO2R
at C3
at C3
PhCH2
N
3
Ar
Nu = O in the EDG-Ar
Nu = O in the EWG-Ar
Nu = Ar in the EDG-Ar
* Corresponding author. Tel./fax: þ81 43 290 2910; e-mail address: benti@
Scheme 1. Nucleophilic ring-opening reactions of unactivated 3-arylaziridine-2-car-
boxylates using O- and Ar-nucleophiles.
p.chiba-u.ac.jp (T. Ishikawa).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.063

Y. Hayashi et al. / Tetrahedron 66 (2010) 3836–3841
3837
Table 1
We further examined ring-opening reactions with aliphatic
Reaction of aziridine-2-carboxylate trans-1a with TMSCN in MeCN
carbon (C-) nucleophiles for advanced synthetic utility of unac-
tivated aziridines; however, several trials for the C–C bond forma-
tion using C-nucleophiles such as organocuprates,7 allylsilane, and
Grignard reagent failed. Thus, we decided to investigate cyanation
reaction using nitrile reagents as a particularly interesting C-nu-
cleophile because of its low cost and the synthetic versatility of the
additive
3
+
TMSCN
trans-1a
MeCN
Conditions
Run
Additive
3 (%)
1
2
3
4
TEA (0.3 equiv)
TEA (0.3 equiv)
None
Reflux, 5 d
20
100
96
MW, 120 ꢀC, 30 min
MW, 120 ꢀC, 30 min
Reflux, 5 d
nitrile-inserted ring-opened products leading to
a- or b-function-
alized - or -amino acid derivatives after suitable chemical mod-
b
a
None
56
ifications. In this paper we will discuss on the reactions of
unactivated aziridines with nitrile reagents, such as trimethylsilyl
cyanide (TMSCN), bromine cyanide (BrCN), and diethylaluminum
cyanide (Et2AlCN), using trans-tert-butyl 1-benzyl-3-(3,4-methyl-
enedioxyphenyl)aziridine-2-carboxylate13,15 (trans-1a) as a typical
EDG-substituted arylaziridine substrate.
It is known that thermolysis of aziridine produces the corre-
sponding azomethine ylide, resulted from cleavage between C2–C3
bond, which undergoes 1,3-dipolar cycloaddition to electron-
deficient alkenes.20 In particular, carbonyl-stabilized azomethine
ylide is conveniently generated by thermolytic ring-opening when
substitution of carbonyl group at C2 (or C3) position. Thus,
aziridine-participated [3þ2] cycloaddition reactions have been
reported as typical reaction paths in both activated and unactivated
aziridines when treated with an appropriate dipolarophile. It may
be difficult to straightforwardly discuss the above thermal cyana-
tion because of no role of TMSCN as a dipolarophile; however, it
could be reasonable that azomethine ylide species formed from
aziridine under thermal condition reacts with a potentially polar-
ized TMSCN to afford N-benzyl-N-(tert-butoxycarbonylmethyl)-
2. Results and discussion
Ring-opening reactions with nitrile reagents such as sodium
cyanide (NaCN),16 TMSCN,16a,17 and Et2AlCN16a have been reported
on only activated aziridine substrates. In general, NaCN and Et2AlCN
act as nucleophiles even in the absence of catalyst, whereas acti-
vation of the reagent by either Lewis acid or Lewis base, including
tetrabutylammonium fluoride (TBAF), is needed for the completion
of ring-opening reaction in the case of TMSCN. We at first examined
the ring-opening of trans-3-(3,4-methylenedioxyphenyl)aziridine-
2-carboxylate trans-1a with TMSCN either in the presence of Lewis
acid or Lewis base. In the former reactions, although only epime-
rization of the starting aziridine was observed when treated in
dichloromethane (CH2Cl2) in the presence of zinc chloride or in-
dium chloride,18 the reaction in the presence of stannic chloride
(SnCl4) unexpectedly and interestingly afforded a decarboxylated
aziridine 2 in 48% yield. Chirality of trans-1a was not preserved in
the product 2 when an optically active trans-1a13 was used as
a starting material. Thus, mechanism for the decarboxylation could
be supposed as shown in Scheme 2, in which a complex of TMSCN
and SnCl4 triggered the reaction, albeit not clearly explained at this
stage.
a-cyano-(3,4-methylenedioxyphenyl)methylamine (3), as shown in
Scheme 3. In this reaction chirality in the product, as expected,
disappeared.
t
CO2 Bu
-
PhCH2
N
+
t
CO2 Bu
Ar
t
CO2 Bu
TMSCN
H2O
PhCH2
N
PhCH2 N
CN
Δ
Ar
t
BuO
O-
Ar
trans-1a
TMSδ+
CNδ-
3
PhCH2
N
+
Ar = 3,4-methylenedioxyphenyl
Ar
SnCl4
TMS+Sn-(CN)Cl4
TMSCN
Scheme 3. Thermal cyanation of aziridine-2-carboxylate trans-1a with TMSCN.
Sn-Cl4
CN
TMS
N
t
H
CO2 Bu
O
C
- CH2=CMe2
CH2
CMe2
O
TMS+
PhCH2
N
This speculation was experimentally supported by successful
cycloaddition reactions using ethyl trimethylsilylpropiolate (TMS-
propiolate) and methyl vinyl ketone (MVK) as dipolarophiles
(Scheme 4). Heating trans-1a with TMS-propiolate at 120 ꢀC for
30 min under MW-irradiation afforded 1-benzyl-2-(tert-butox-
ycarbonyl)-4-ethoxycarbonyl-5-(3,4-methylenedioxyphenyl)-3-tri-
methylsilyl-2,5-dihydropyrrole (4) as an isolable, but unstable,
product together with the corresponding aromatized product 5.
Regiochemistry in the reaction and relative stereochemistry
between 2- and 5-substituents in 4 could not be determined
O
O
C
Ar
- HCN
- SnCl4
PhCH2
trans-1a
Ar
PhCH2
N
SnCl4
Ar
Ar = 3,4-methylenedioxyphenyl
NC
TMS
Cl
Sn-Cl3
O
C
H
HCN
- TMSCl
- CO2
SnCl3
N
PhCH2
N
O
N+
- Sn(CN)Cl3
Ar
PhCH2
PhCH2
Ar
Ar
2
Scheme 2. Supposed mechanism for the decarboxylation of aziridine-2-carboxylate
trans-1a with TMSCN and SnCl4.
due to the easy aromatization of
4 to 5 during the NMR
measurement. On the other hand, treatment with MVK afforded
isomeric cycloadducts as colorless prisms and a colorless oil in
60% and 18% yields, respectively. The structure of the major
crystalline isomer was deduced to be a 4-acetylprolinate 6,
which was formed by a regiochemically expected approach of
MVK to an intermediate azomethine ylide, based on precise
NMR analysis including HMBC experiments. Thus, newly born
methylene signal [dH 1.80 (1H, dd, J¼13.2, 8.1 Hz), 2.72 (1H, ddd,
J¼13.2, 10.0, 8.1 Hz); dC 29.5] was coupled with C2 [dH 3.64 (d,
On the other hand, no reaction occurred when TMSCN was used
together with Lewis bases such as tetramethylethylenediamine,
TBAF, and tetramethylguanidine in acetonitrile (MeCN); however,
a ring-opened product 319 was yielded as colorless prisms even in
20% yield when refluxed for a longer time (5 days) in the presence of
a catalytic amount of triethylamine (TEA) (run 1 in Table 1). Micro-
wave (MW) greatly improved the product formation and, thus,
treatment at 120 ꢀC for 30 min under irradiation of MWafforded the
same product quantitatively (run 2 in Table 1). The product was
found to be formed even without Et3N (runs 3 and 4 in Table 1).
J¼8.1 Hz); dC 61.6] and C4 methine protons
[dH 3.75 (ddd,
J¼10.1, 10.0, 8.1 Hz); dC 55.4]. In addition, the lowest field-
shifted methine signal assignable to C5 proton was observed

3838
Y. Hayashi et al. / Tetrahedron 66 (2010) 3836–3841
at dH 4.67 as doublet (J¼10.1 Hz). The stereochemical alignments
of substituents were reasonably deduced to be (2S ,4R ,5S )-con-
figurations by coupling constants of ring protons, which were sup-
ported by NOE experiments. Similar analysis on a minor isomer
based on the NMR spectral data allowed us to deduce to be
constant (J¼10.8 Hz)15 between C2–H and C3–H and the (Z)-con-
figuration of the acrylate 9 was established by NOE experiment [(a)
in Fig. 1], respectively, indicating that bromo anion attacks the C3
carbon of trans-1a with retention of the configuration. On the other
hand, treatment of trans-1a with excess amount (5 equiv) of
a commercially available 1 M solution of Et2AlCN in toluene at room
temperature (rt) for 1 day afforded 3-aryl-2-benzylamino-3-cya-
nopropanoate as an inseparable mixture of diastereoisomers 10a
and 11a in 72% yield. The regioisomeric ratio of the products was
estimated to be 10a/11a¼40:1 by the 1H NMR spectrum. Coupling
constant15 between C2–H and C3–H strongly indicated that the
major 10a is anti (J¼5.1 Hz) and the minor 11a syn (J¼7.0 Hz), re-
spectively. Thus, it was found that the ring-opened process with
a nitrile function as a C-nucleophile is controlled by SN2 type re-
action at C3 position of the aziridine system with inversion of the
configuration, even the major formation of syn-product like 11a in
the ring-opening reaction of trans-1a with O-nucleophile.15
*
*
*
(2S
*
,3S
*
,5S )-tert-butyl 3-acetyl-1-benzyl-5-(3,4-methylenedioxy-
*
phenyl)pyrrolidine-2-carboxylate (7).
t
t
BuO2C
BuO2C
TMS
TMS
CO2Et
TMS
PhCH2
N
PhCH2
N
(a)
+
Δ
CO2Et
CO2Et
Ar
Ar
4
t
5
CO2 Bu
PhCH2
N
12%
8%
Ar
trans-1a
t
t
BuO2C
BuO2C
COMe
Δ
PhCH2
N
PhCH2
N
+
(b)
MVK
COMe
NC
NC
Ar
Ar
t
t
PhCH2N
PhCH2N
CO2 Bu
CO2 Bu
6
7
BrCN
Ar = 3,4-methylenedioxyphenyl
+
60%
18%
CH2Cl2
Br
Ar
Ar
H
Scheme 4. MW-mediated [3þ2]-cycloadditions of aziridine-2-carboxylate trans-1a
8
9
t
CO2 Bu
with TMS-propiolate and MVK.
36%
7%
PhCH2
N
Huisgen and Maeder20b had demonstrated that cis-aziridine
affords trans-cycloadduct through trans-(E,Z)-azomethine ylide,
whereas trans-aziridine affords cis-cycloadduct through cis-(E,E)-
azomethine ylide, by conrotatory thermal ring cleavage. However,
in the reaction with less reactive dipolarophiles a trans-1,3-dipolar
addition product is expected from either cis- or trans-aziridine after
equilibrium to the more stable trans-(E,Z)-azomethine ylide.20c
Furthermore, an endo approach had been observed in the [3þ2]-
cycloaddition reaction of azomethine ylide with dipolar-
ophile.20a,d Thus, it could be reasonably supposed that the reaction
of trans-3-arylaziridine-2-carboxylate trans-1a with MVK was
stereochemically controlled as follows: (1) conrotatory ring-
opening of the trans-aziridine to cis-(E,E)-azomethine ylide, (2)
isomerization to a more stable trans-(E,Z)-azomethine ylide under
the MW conditions, and (3) [3þ2] cycloaddition via an endo ap-
proach of the dipolarophile, resulting in the formation of cyclo-
adducts 6 and 7 with trans-alignment of substituents at 2 and 5
positions (Scheme 5).
Ar
trans-1a
t
t
PhCH2HN
PhCH2HN
NC
CO2 Bu
CO2 Bu
Et2AlCN
+
PhH
72%
Ar
Ar
NC
10a
40
:
1
11a
Ar = 3,4-methylenedioxyphenyl
Scheme 6. Ring-opening reactions of aziridine-2-carboxylate trans-1a with BrCN and
a commercially available Et2AlCN.
1.0-2.2%
(c)
(b)
(a)
1.4%
NC
PhCH2-N
2.5%
1.9-2.8%
Ph-CH2
2.2%
t
CO2 Bu
Ph-CH2
t
H
H
CO2 Bu
H
H
N
3.1%
N
0.8%
O
t
H
H
CO2 Bu
0.9-1.7%
Ph
O
Ph
cis-1b
1.7-2.3%
9
trans-1b
Figure 1. Selected NOE enhancements of (a) the acrylate 9, (b) trans-3-phenyl-
aziridine-2-carboxylate trans-1b, and (c) cis-3-phenylaziridine-2-carboxylate cis-1b.
t
CO2 Bu
+
N
-
PhCH2
Et2AlCN can be prepared from triethylaluminum (Et3Al) and
TMSCN.21 Ring-opening reactions of some kinds of aziridines using
a freshly prepared Et2AlCN were summarized in Table 2. Product
formation from trans-1a was greatly improved, in which the anti-
cyanopropanoate 10a was given in 92% yield as a single di-
astereoisomer (run 1 in Table 2). Similar ring-opening products 10b
and 10c with inversion at the C-3 benzylic position were produced,
albeit less effectively, when trans-phenylaziridine-2-carboxylate
trans-1b or trans-4-chlorophenylaziridine-2-carboxylate13,15 trans-
1c were subjected to the ring-opening reaction (runs 2 and 3 in
Table 2). On the other hand, no reactions occurred when di-
astereomeric cis-aziridines13,15 cis-1a and cis-1b were used as
staring materials (runs 4 and 5 in Table 2). We15 have observed that
ring-opening reaction of 3-arylaziridine-2-carboxylates 1 with
O-nucleophile is dependent upon the electronic character of the
3-aryl pendant rather than the relative configuration of the C2- and
C3-substituents in aziridine system. The difference of stereo-
selectivity in the ring-opening reactions with C-nucleophile from
that with O-nucleophile could be explained based on their ste-
reochemical alignment of the substituents on the aziridine system.
Ar
t
BuO2C
cis-(E,E)-azomethine
t
ylide
CO2 Bu
Δ
a(b)
b(a)
PhCH2
N
PhCH2
N
a
b
Ar
-
Ar
+
N
t
trans-1a
CO2 Bu
PhCH2
trans-cycloadduct
Ar
Ar = 3,4-methylenedioxyphenyl
trans-(E,Z)-azomethine
ylide
Scheme 5. Formation of 2,5-trans-cycloadducts from trans-3-arylaziridine-2-carbox-
ylate trans-1a through equilibrium between cis-(E,E)- and trans-(E,Z)-azomethine
ylides.
Next, trans-3-(3,4-methylenedioxyphenyl)aziridine-2-carboxyl-
ate trans-1a was subjected to the reactions with BrCN and Et2AlCN
(Scheme 6). Treatment with excess amount of BrCN in CH2Cl2 under
reflux for 10 h afforded an N–C3 cleaved product 8 in 36% yield as
a single diastereoisomer together with 3-aryl-2-cyanoaminoacry-
late 9 (7%). The syn stereochemistry of 8 was deduced by coupling

Y. Hayashi et al. / Tetrahedron 66 (2010) 3836–3841
3839
Examination of the 1H NMR spectrum of a crude 13 based on the
coupling constant (J2,3¼4.0 Hz), as expected, suggested an anti-type
ring-opening in the latter Lewis acid-catalyzed reaction.15 Fur-
thermore, the fact that a larger coupling constant (J¼9 Hz) between
the C4–H and C5–H had been observed in cis-5-ethoxycarbonyl-
1-methyl-4-phenylpyrrolidin-2-one (cis-15) compared to that
(J¼4 Hz) in the trans-derivative trans-15 [(a) in Figure 2]23 also
supported the cis-configuration of 14 due to the coupling constant
of J4,5¼7.2 Hz. These speculations were confirmed by NOE experi-
ment [(b) in Fig. 2]. Thus, the Lewis acid-catalyzed ring-opening
reaction with a ketene acetal occurred with the same inversion
mode as in the cyanation with Et2AlCN.
Table 2
Reactions of aziridines 1 with a freshly prepared Et2AlCN
t
t
t
PhCH2HN
NC
PhCH2HN
NC
CO2 Bu
CO2 Bu
CO2 Bu
Et2AlCN
PhH
PhCH2
N
Ar
Ar
Ar
11
1
10
Run
1
Conditions
ꢀC, 2.5 h
rt, 24 h
0 ꢀC, 2 h then rt, 15 h
ꢀC, 2.5 h
rt, 24 h
Results
1
2
3
4
5
trans-1a
0
10a (92%)
10b (40%)a
10c (27%)
NRb
trans-1b
trans-1c
cis-1a
0
cis-1b
NRb
a
Starting trans-1b was recovered in 43% yield.
No reaction occurred.
b
(b)
(a)
Me
N
It is possible for some substituted aziridines to exist as inver-
H
PhCH2
CO2Et
H
H
tomers due to the steric requirement of substituents.13,22 NOE ex-
periments of 3-phenylaziridine-2-carboxylates trans-1b and cis-1b
showed trans-configuration between N-benzyl and 3-phenyl
groups in both diastereomers [(b) and (c) in Fig. 1]. The nitrile-
inserted reaction should be triggered by coordination of reagent
itself (Et2AlCN) to aziridine nitrogen, while protonation leads to
ring-opening in the reaction with O-nucleophiles. Thus, loose co-
ordination of more bulky Et2AlCN than proton to aziridine nitrogen
due to steric hindrance of the 3-aryl substituent causes SN2 type
reaction, not SNi type one, to give a product with stereochemical
inversion at C3 position when trans-aziridines are used as starting
materials. On the other hand, in the cases of cis-3-arylaziridine-
2-carboxylates impossible coordination of Et2AlCN with aziridine
nitrogen due to profound steric hindrance generated from an ad-
ditional C2-ester substituent resulted in leading to no reaction.
Pictet–Spengler reaction of the cyanopropanoate 10a smoothly
afforded an isoquinoline skeleton 12 (Scheme 7), showing the
synthetic utility of a nitrile-inserted ring-opened product. Fur-
thermore, ring-opening reaction using a ketene acetal as a C2 car-
bon nucleophile was also examined for the further potentiality of
the Lewis acid-catalyzed ring-opening reaction on trans-tert-butyl
3-(3,4-methylenedioxyphenyl)aziridine-2-carboxylate (trans-1a)
(Scheme 7). Treatment of trans-1a with 2,2-dimethyl-1-methoxy-
1-trimethylsilyloxyethene in CH2Cl2 in the presence of aluminum
chloride gave a pyrrolidone product 14 in 82% yield, which could be
produced through spontaneous amidation of the expected ring-
cleaved product 13 incorporating the carbon nucleophile at the
C3 position of aziridine-2-carboxylate system during work-up. Al-
though other Lewis acids such as indium chloride and triethylalu-
minum were ineffective as catalysts, the reaction in the presence of
boron trifluoride-etherate afforded 14 albeit in lower yield (37%).
t
CO2 Bu
5
N
O
4
O
6.1%
5.0%
O
O
H
Me
Me
cis-15: J4,5 = 9 Hz
trans-15: J4,5 = 4 Hz
14
Figure 2. (a) Coupling constants of cis- and trans-5-ethoxycarbonyl-1-methyl-4-phe-
nylpyrrolidin-2-one (cis- and trans-15) and (b) selected NOE enhancements of 14.
In conclusion, in the ring-opening reactions of unactivated
trans-3-(3,4-methylenedioxyphenyl)aziridine-2-carboxylate with
nitrile reagents formation of azomethine ylide by C2–C3 bond
cleavage was observed when TMSCN was treated under thermal
conditions. On the other hand the uses of BrCN and Et2AlCN led to
N–C3 bond cleavage and stereochemical retention at the C3 was
observed as a major reaction path in the case of the former BrCN,
whereas inversion in the case of the latter Et2AlCN. Et2AlCN-
participating ring-opening reactions using trans-3-arylaziridine-
2-carboxylates carrying electron-deficient aromatic substituent
and their cis-derivatives disclosed that the potential cationic
character of the C-3 benzylic position and stereochemical re-
quirements of substituents in the arylaziridine system controls
the reactivity. Furthermore, synthetic utilities of the ring-opening
reaction for unactivated, but electron-rich, 3-arylaziridine-2-car-
boxylate was demonstrated not only by application to the cycli-
zation of
a ring-opened cyanopropanoate product to an
isoquinoline skeleton under Pictet–Spengler reaction condition
but also by the extension of other C-nucleophiles from nitrile (C1)
to a ketene acetal (C2).
3. Experimental
3.1. General
CN
CN
t
t
CO2 Bu
CO2 Bu
O
O
HCHO
O
O
N
N
CF3CO2H
in CH2Cl2
40 oC, 5 h
CH2Ph
H
10a
CH2Ph
IR spectra were recorded on a JASCO IR-230E spectrophotome-
ter. EIMS, FABMS, and ESIMS spectra were measured by JEOL GC-
Mate, JEOL JMS-HX 110A and JMS-AX 500, and Thermo Scientific
Exactive Bentitop Orbitrap spectrometers, respectively. 1H NMR
spectra were obtained on JEOL JNM ECP 600 (600 MHz) or 400
(400 MHz). 13C NMR spectra were obtained on JEOL JNM ECP 600
(150 MHz), JEOL GSX-500
(100 MHz). For TLC was used SiO2 60F254, 0.25 mm (Merck) and for
column chromatography SiO2 60 (63–210 m) (Kanto-Cica) or
FL100D SiO2 (Fuji Silysia Chemical Ltd). Reactions under MW irra-
diation were carried out using CEM Discover with sealed tube. Dry
tetrahydrofuran (THF) was purchased from Kanto Chemical Co. Inc.
as ‘Dehydrated’.
12
t
CO2 Bu
PhCH2
N
87%
O
O
trans-1a
PhCH2
-78 o
2 h
C
t
AlCl3
in CH2Cl2
PhCH2HN
MeO2C
CO2 Bu
t
CO2 Bu
a (125 MHz), or JEOL JNM ECP 400
N
O
O
O
O
OTMS
OMe
Me
82%
Me
m
Me Me
13
Me
O
Me
14
Scheme 7. Pictet–Spengler reaction of 10a and the aluminum-catalyzed ring-opening
reaction of trans-1a with a ketene acetal.

3840
Y. Hayashi et al. / Tetrahedron 66 (2010) 3836–3841
3.2. 1-Benzyl-2-(3,4-methylenedioxyphenyl)aziridine (2)
benzyl-5-(3,4-methylenedioxyphenyl)pyrrolidine-2-carboxylate (6):
colorless prisms, mp 114–116 ꢀC. IR nmax (cmꢂ1): 1712 (CO). 1H NMR
To a solution of trans-1a (93 mg, 0.26 mmol) in CH2Cl2 (1.5 mL),
TMSCN (0.07 mL, 0.53 mmol) and SnCl4 (0.03 mL, 0.27 mmol) were
dropwise added at 0 ꢀC. The mixture was stirred at 0 ꢀC for 90 min,
quenched by addition of satd aqueous NaHCO3 solution (4 mL), and
extracted with CH2Cl2 (4 mLꢁ4). The organic solution was dried
and evaporated under reduced pressure. Column chromatography
of the residue (n-hexane/AcOEt¼10:1) afforded 2 (32 mg, 48%) as
(400 MHz):
d
(ppm) 1.46 (s, 9H), 1.68 (s, 3H), 1.80 (dd, J¼13.2, 8.1 Hz,
1H), 2.72 (ddd, J¼13.2, 10.0, 8.1 Hz, 1H), 3.57 (d, J¼13.4 Hz, 1H), 3.64
(d, J¼8.1 Hz, 1H), 3.69 (d, J¼13.4 Hz, 1H), 3.75 (ddd, J¼10.1, 10.0,
8.1 Hz,1H), 4.67 (d, J¼10.1 Hz,1H), 5.94 (m, 2H), 6.73(d, J¼8.0 Hz,1H),
6.80 (br d, J¼8.0 Hz, 1H), 6.83 (br s, 1H), 7.19–7.28 (m, 5H). 13C NMR
(100 MHz): d (ppm) 28.1, 29.5, 31.0, 51.9, 55.4, 61.6, 67.5, 81.0, 101.0,
107.8, 108.9, 122.4, 126.9, 128.1, 128.6, 134.1, 138.8, 147.2, 147.4, 173.6,
207.4. Anal. Calcd for C25H29NO5: C, 70.90; H, 6.90; N, 3.31. Found: C,
70.73; H, 7.01; N, 3.32. (b) (2S
(3,4-methylenedioxyphenyl)pyrrolidine-2-carboxylate (7): a colorless
oil. IR nmax (cmꢂ1): 1736 and 1714 (CO). 1H NMR (400 MHz):
(ppm)
a yellow oil. 1H NMR (400 MHz):
d
(ppm) 2.94 (dd, J¼13.7, 7.1 Hz,
1H), 3.02 (dd, J¼13.7, 5.7 Hz, 1H), 3.69 (dd, J¼7.1, 5.7 Hz, 1H), 3.82
and 4.06 (each d, J¼13.1 Hz, 1H), 5.95 (s, 2H), 6.73 (dd, J¼8.1, 1.4 Hz,
1H), 6.76 (br s, 1H), 6.77 (d, J¼8.1 Hz, 1H), 7.25–7.35 (m, 5H). 13C
* * *
,4S ,5S )-tert-Butyl 3-acetyl-1-benzyl-5-
d
NMR (100 MHz):
d
(ppm) 39.0, 50.9, 51.5, 101.1, 108.5, 109.7, 119.4,
1.46 (s, 9H), 2.09 (ddd, J¼13.2, 7.9, 5.9 Hz,1H), 2.18 (s, 3H), 2.52 (ddd,
J¼13.2, 9.6, 7.9 Hz,1H), 3.03 (ddd, J¼9.6, 5.9, 2.2 Hz,1H), 3.60and3.69
(each d, J¼13.7 Hz,1H), 3.83 (d, J¼2.2 Hz,1H), 4.33 (dd, J¼7.9, 7.9 Hz,
1H), 5.93 and 5.94 (each d, J¼1.2 Hz, 1H), 6.75 (d, J¼7.8 Hz, 1H), 6.86
(br d, J¼7.8 Hz, 1H), 6.99 (s, 1H), 7.22–7.31 (m, 5H). 13C NMR
122.7, 127.6, 128.3, 128.6, 137.9, 147.1, 147.9. HREIMS m/z: 253.1097
(calcd for C16H15NO2: 253.1103).
3.3. N-Benzyl-N-(tert-butoxycarbonylmethyl)-a-cyano-(3,4-
methylenedioxyphenyl)methylamine (3)
(100 MHz): d (ppm) 27.8, 28.1, 36.2, 51.0, 53.4, 63.3, 66.1, 81.4, 100.9,
107.5, 108.0, 121.2, 126.9, 128.2ꢁ2, 136.7, 138.9, 146.9, 148.0, 172.3,
A solution of trans-1a (49 mg, 0.14 mmol) and TMSCN (0.05 mL,
0.34 mmol) in MeCN (1.5 mL) was stirred at 120 ꢀC for 30 min under
MW irradiation. After evaporation of the solvent, the residue was
purified by column chromatography (n-hexane/AcOEt¼20:1) to af-
ford 3 (50 mg, 96%) as colorless prisms, mp 105–106 ꢀC. IR nmax
206.5. HREIMS m/z: 423.2032 (calcd for C25H29NO5: 423.2045).
3.6. Reaction of trans-1a with BrCN
To a solution of BrCN (152 mg, 1.37 mmol) in CH2Cl2 (1.5 mL),
trans-1a (84 mg, 0.24 mmol) in CH2Cl2 (1.5 mL) was dropwise
added. The mixture was refluxed for 10 h, quenched by addition of
satd aqueous NaHCO3 solution (6 mL), and extracted with CH2Cl2
(5 mLꢁ3). The organic solution was dried and evaporated under
reduced pressure. Recrystallization of the residue from n-hexane/
AcOEt (5:1) afforded 8 (21 mg, 19%). Column chromatography of
the mother liquor with n-hexane/AcOEt (20:1) afforded an addi-
(cmꢂ1): 2235 (CN), 1734 (CO). 1H NMR (400 MHz):
d (ppm) 1.45 (s,
9H), 3.18, 3.26 (each d, J¼17.1 Hz, 1H), 3.51 and 3.97 (each d,
J¼13.4 Hz, 1H), 5.00 (s, 1H), 5.98 (d, J¼1.8 Hz, 2H), 6.79 (d, J¼8.1 Hz,
1H), 7.11 (br d, J¼8.1 Hz,1H), 7.13 (s,1H), 7.28 (d, J¼7.1 Hz,1H), 7.34 (t,
J¼7.1 Hz, 2H), 7.41 (d, J¼7.1 Hz, 2H). 13C NMR (100 MHz):
d (ppm)
28.1, 52.4, 55.4, 57.5, 81.6,101.4,108.1,108.2,115.9,121.3,127.2,127.8,
128.6, 128.8, 137.1, 148.2ꢁ2, 169.3. Anal. Calcd for C22H24N2O4: C,
69.46; H, 6.36; N, 7.36. Found: C, 69.38; H, 6.22; N, 7.39.
tional 8 (18 mg, 16%) and 9 (7 mg, 7%). (a) (2S
*
,3R )-tert-Butyl 2-
*
(N-benzyl-N-cyanoamino)-3-bromo-3-(3,4-methylenedioxyphenyl)-
3.4. Reaction of trans-1a with ethyl TMS-propiolate under
MW irradiation
propanoate (8): colorless prisms, mp 132–135 ꢀC. IR nmax (cmꢂ1):
2212 (CN), 1716 (CO). 1H NMR (400 MHz):
d (ppm) 1.16 (s, 9H), 3.76
(d, J¼10.8 Hz, 1H), 4.38, 4.44 (each d, J¼14.1 Hz, 1H), 5.19 (d,
J¼10.8 Hz, 1H), 5.96 and 5.97 (each d, J¼1.6 Hz, 1H), 6.72 (d,
J¼8.1 Hz, 1H), 6.82 (dd, J¼8.1, 1.8 Hz, 1H), 6.86 (d, J¼1.8 Hz, 1H),
A solution of trans-1a (60 mg, 0.17 mmol) and ethyl TMS-
propiolate (0.03 mL, 0.17 mmol) in MeCN (1.0 mL) was stirred at
120 ꢀC for 30 min under MW irradiation. After evaporation of the
solvent the residue was purified by PTLC (n-hexane/AcOEt¼5:1) to
give a labile 4 (11 mg, 12%) and 5 (7 mg, 8%), respectively. (a) 1-
Benzyl-2-(tert-butoxycarbonyl)-4-ethoxycarbonyl-5-(3,4-methylene-
dioxyphenyl)-3-trimethylsilyl-2,5-dihydropyrrole (4): a colorless oil.
7.39–7.41 (m, 5H). 13C NMR (100 MHz):
d (ppm) 27.5, 51.5, 57.2,
68.8, 83.7, 101.5, 108.1, 108.7, 114.5, 122.4, 128.95, 129.05, 130.1,
133.7, 147.9, 148.5, 165.6. Anal. Calcd for C22H23BrN2O4: C, 57.53; H,
5.05; N, 6.10. Found: C, 57.46; H, 4.93; N, 6.07. (b) (Z)-tert-Butyl 2-
(benzylcyanoamino)-3-(3,4-methylenedioxyphenyl)propenoate (9):
a colorless oil. IR nmax (cmꢂ1): 2216 (CN), 1707 (CO). 1H NMR
IR nmax (cmꢂ1): 1716 (CO). 1H NMR (400 MHz):
d (ppm) 0.23 (s, 9H),
1.05 (t, J¼7.1 Hz, 3H), 1.47 (s, 9H), 3.73 and 3.88 (each br s, 1H), 3.99
(m, 2H), 4.55 (br s, 1H), 5.20 (br s, 1H), 5.94 and 5.95 (each d,
J¼1.5 Hz, 1H), 6.72 (d, J¼8.1 Hz, 1H), 6.77–6.83 (m, 2H), 7.24–7.26
(m, 5H). (b) 1-Benzyl-2-(tert-butoxycarbonyl)-4-ethoxycarbonyl-5-
(3,4-methylenedioxyphenyl)-3-trimethylsilylpyrrole (5): a colorless
(400 MHz):
J¼8.1 Hz, 1H) 7.09 (dd, J¼8.1, 1.6 Hz, 1H), 7.21 (d, J¼1.6 Hz, 1H),
7.28–7.34 (m, 5H), 7.38 (s, 1H). 13C NMR (100 MHz):
(ppm) 28.0,
d (ppm) 1.48 (s, 9H), 4.32 (s, 2H), 6.05 (s, 2H), 6.84 (d,
d
57.5, 82.8, 101.7, 108.6, 109.4, 115.0, 126.0 126.6, 126.8, 128.7, 128.9,
129.7, 133.6, 136.3, 148.3, 149.7, 162.8. HREIMS m/z: 378.1577 (calcd
for C22H22N2O4: 378.1579).
oil. IR nmax (cmꢂ1): 1700 (CO). 1H NMR (400 MHz):
d (ppm) 0.31 (s,
9H), 1.10 (t, J¼7.1 Hz, 3H), 1.28 (s, 9H), 4.08 (q, J¼7.1 Hz, 2H), 5.24 (s,
2H), 5.96 (s, 2H), 6.65–6.68 (m, 2H), 6.74 (dd, J¼7.7, 0.7 Hz, 1H),
6.77–6.80 (m, 2H), 7.18–7.19 (m, 1H), 7.22–7.26 (m, 2H). 13C NMR
3.7. Reaction of trans-1a with a commercially available
(150 MHz):
d
(ppm) 0.78, 13.9, 27.8, 49.4, 60.2, 82.2, 101.2, 108.0,
Et2AlCN: a 40:1 mixture of (2S
*
,3S
*
)- (10a) and (2S
*
,3R )-
*
110.9, 121.4, 124.2, 124.3, 124.7, 125.6, 127.0, 128.5, 132.1, 138.3,
140.4, 147.2, 147.9, 161.9, 166.5. HREIMS m/z: 521.2233 (calcd for
C29H35NO6Si: 521.2234).
tert-butyl 2-(N-benzylamino)-3-cyano-3-
(3,4-methylenedioxyphenyl)propanoate (11a)
To a solution of trans-1a (102 mg, 0.29 mmol) in benzene
(1.5 mL), a 1 M solution of Et2AlCN in toluene (1.5 mL, 1.50 mmol)
was added. The mixture was stirred at room temperature for 1 day,
quenched by slow addition of 2 N NaOH solution (2 mL), and
extracted with AcOEt (4 mLꢁ5). The organic solution was dried and
evaporated under reduced pressure. Column chromatography of
the residue (n-hexane/AcOEt¼10:1) afforded a 40:1 mixture of 10a
and 11a (80 mg, 72%) as a colorless oil.
3.5. Reaction of trans-1a with MVK under MW irradiation
A solution of trans-1a (60 mg, 0.17 mmol) and MVK (0.03 mL,
0.31 mmol) in THF (1.2 mL) was stirred at 120 ꢀC for 15 min under
MW irradiation. After evaporation of the solvent, the residue was
purified by PTLC (n-hexane/Et2O¼4:1) to afford 6 (43 mg, 60%) and 7
(11 mg, 15%), respectively. (a) (2R
*
,4R
*
,5R )-tert-Butyl 4-acetyl-1-
*

Y. Hayashi et al. / Tetrahedron 66 (2010) 3836–3841
3841
3.8. Reaction of 1 with a freshly prepared Et2AlCN (Table 2)
3.10. Reaction of trans-1a with 2,2-dimethyl-1-methoxy-
1-trimethylsilyloxyethene: (2S ,3R )-1-benzyl-5-
(tert-buthoxycarbonyl)-4-(3,4-
methylenedioxyphenyl)pyrrolidin-2-one (14)
*
*
According to the reported method,21 distilled TMSCN (2.5 mL,
20.2 mmol) was added to a 1 M solution of Et3Al in toluene (20 mL,
20.2 mmol) under ice-cooling and then the colorless solution was
refluxed for 30 min. A pale yellow solution given was used in the
ring-opening reaction as a freshly prepared Et2AlCN without fur-
ther purification.
To a suspension of AlCl3 (25 mg, 0.19 mmol) in CH2Cl2 (1.5 mL),
trans-1a (60 mg, 0.17 mmol) in CH2Cl2 (1.5 mL) and a ketene silyl
acetal (0.1 mL, 0.49 mmol) were dropwise added at ꢂ78 ꢀC. After
being stirred at the same temperature for 2 h, the mixture was
quenched by addition of satd NaHCO3 solution (1 mL) and extracted
with AcOEt (10 mLꢁ3). The organic solution was successively
washed with satd NaHCO3 solution, H2O, and brine, dried, and
evaporated under reduced pressure. Column chromatography of the
residue (n-hexane/AcOEt¼20:1) afforded 14 (59 mg, 82%) as color-
less needles, mp 138–141 ꢀC. IR nmax (cmꢂ1): 1743 and 1683 (CO). 1H
3.8.1. On trans-1a (run 1): (2S
*
,3S )-tert-butyl 2-(N-benzylamino)-3-
*
cyano-3-(3,4-methylenedioxyphenyl)propanoate (10a). A mixture of
trans-1a (60 mg, 0.17 mmol) in benzene (0.5 mL) and a 1 M solution
of Et2AlCN in toluene (0.9 mL, 0.9 mmol) was reacted for 2.5 h at 0 ꢀC
to give 10a (59 mg, 92%) as a colorless oil. IR nmax (cmꢂ1): 3340 (NH),
2247 (CN),1728(CO).1H NMR (400 MHz) for10a:
d (ppm) 1.43 (s, 9H),
2.08 (br s, 1H), 3.56 (d, J¼5.1 Hz, 1H), 3.74, 3.90 (each d, J¼13.2 Hz,
1H), 4.16 (d, J¼5.1 Hz,1H), 5.96 (s, 2H), 6.75 (d, J¼8.0 Hz,1H), 6.78 (dd,
J¼8.0, 1.6 Hz, 1H), 6.84 (d, J¼1.6 Hz, 1H), 7.24–7.32 (m, 5H). 13C NMR
NMR (400 MHz): d (ppm) 0.92 (s, 3H), 1.12 (s, 9H), 1.14 (s, 3H), 3.14
and 4.03 (each d, J¼7.2 Hz,1H), 4.36 and 5.36 (each d, J¼14.0 Hz,1H),
5.91 (d, J¼3.5 Hz, 2H), 6.58 (dd, J¼8.0, 1.7 Hz, 1H), 6.65 (d, J¼1.7 Hz,
1H), 6.68 (d, J¼8.0 Hz, 1H), 7.18–7.20 (m, 2H), 7.29–7.34 (m, 3H). 13C
(100 MHz) for 10a:
d (ppm) 28.0, 40.7, 52.3, 63.5, 83.0, 101.4, 108.3,
108.9,118.8,122.2,125.0,127.4,128.3,128.5,138.8,147.9,148.0,170.0.
NMR (100 MHz): d (ppm) 20.5, 25.6, 27.5, 45.0, 45.5, 53.1, 60.4, 81.7,
HREIMS m/z: 378.1577 (calcd for C22H22N2O4: 378.1579).
100.9, 107.7,109.7,122.8,127.8,128.7, 128.9, 131.2, 135.8,146.8, 147.2,
168.2, 180.2. Anal. Calcd for C25H29NO5: C, 70.90; H, 6.90; N, 3.31.
Found: C, 70.74; H, 6.93; N, 3.34.
3.8.2. On trans-1b (run 2): (2S
*
,3S )-tert-butyl 2-(N-benzylamino)-
*
3-cyano-3-phenylpropanoate (10b). A mixture of trans-1b (60 mg,
0.19 mmol) in benzene (0.5 mL) and a 1 M solution of Et2AlCN in
toluene (0.9 mL, 0.9 mmol) was reacted for 24 h at rt to give 10b
(26 mg, 40%) as a colorless oil. IR nmax (cmꢂ1): 3320 (NH), 2244 (CN),
Supplementary data
NMR charts of new compounds characterized and X-ray data of
3 (CIF). Supplementary data associated with this article can be
found in online version, at doi:10.1016/j.tet.2010.03.063.
1727 (CO).1H NMR (400 MHz):
d
(ppm) 1.39 (s, 9H), 3.60 (d, J¼5.4 Hz,
1H), 3.73,and 3.89 (each d, J¼13.4 Hz, 1H), 4.23 (d, J¼5.4 Hz, 1H),
7.25–7.34 (m, 10H). 13C NMR (100 MHz):
(ppm) 27.9, 41.2, 52.2,
d
63.5, 82.9, 118.7, 127.3, 128.2, 128.4, 128.5, 128.6, 128.7, 131.5, 139.0,
169.9. HRFABMS m/z: 375.1487 (calcd for C21H24KN2O2: 375.1475).
References and notes
1. Yudin, A. K. Aziridines and Epoxides in Organic Synthesis; Wiley-VCH: New York,
NY, 2006.
2. Cardillo, G.; Gentilucci, L.; Tolomelli, A. Aldrichimica Acta 2003, 36, 39–50.
3. Lee, W. K.; Ha, H.-J. Aldrichimica Acta 2003, 36, 57–63.
4. McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365.
5. Hu, X. E. Tetrahedron 2004, 60, 2701–2743.
3.8.3. On trans-1c (run 3) (2S
*
,3S )-tert-butyl 2-(N-benzylamino)-3-
*
cyano-3-(4-chlorophenyl)propanoate (10c). A mixture of trans-1c
(61 mg, 0.18 mmol) in benzene (0.5 mL) and a 1 M solution of
Et2AlCN in toluene (0.9 mL, 0.9 mmol) was reacted at 0 ꢀC for 2 h
and then at rt for 15 h to give 10c (18 mg, 27%) as a colorless oil. IR
nmax (cmꢂ1): 3320 (NH), 2243 (CN), 1728 (CO). 1H NMR (400 MHz):
(ppm) 1.41 (s, 9H), 1.99 (br s, 1H), 3.58 (d, J¼5.3 Hz, 1H), 3.73 and
3.89 (each d, J¼13.2 Hz, 1H), 4.18 (d, J¼5.3 Hz, 1H), 7.26–7.51 (m,
9H). 13C NMR (100 MHz):
(ppm) 27.9, 40.6, 52.3, 63.4, 83.2, 118.4,
6. Pineschi, M. Eur. J. Org. Chem. 2006, 4979–4988.
7. Eis, M. J.; Ganem, B. Tetrahedron Lett. 1985, 26, 1153–1156.
8. Baldwin, J. E.; Adlington, R. M.; O’Neil, I. A.; Schofield, C.; Spivey, A. C.; Sweeney,
J. B. J. Chem. Soc., Chem. Commun. 1989, 1852–1854.
9. Legters, J.; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-Bas 1992, 111, 16–21.
10. Xiong, C.; Wang, W.; Cai, C.; Hruby, V. J. J. Org. Chem. 2002, 67, 1399–1402.
11. Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675–3678.
12. Cardillo, G.; Gentilucci, L.; Tolomelli, A. Tetrahedron Lett. 1999, 40, 8261–8264.
13. Hada, K.; Watanabe, T.; Isobe, T.; Ishikawa, T. J. Am. Chem. Soc. 2001, 123, 7705–
7706; Haga, T.; Ishikawa, T. Tetrahedron 2005, 61, 2857–2869.
d
d
127.4, 128.2, 128.5, 128.9, 129.9, 134.7, 138.8, 169.8. HRESIMS m/z:
371.1511 (calcd for C21H2435ClN2O2: 371.1521).
14. Disadee, W.; Ishikawa, T. J. Org. Chem. 2005, 70, 9399–9406; Disadee, W.; Ish-
ikawa, T.; Kawahata, M.; Yamaguchi, K. J. Org. Chem. 2006, 71, 6600–6603.
15. Manaka, T.; Nagayama, S.-I.; Disadee, W.; Yajima, N.; Kumamoto, T.; Watanabe,
T.; Ishikawa, T.; Kawahata, M.; Yamaguchi, K. Helv. Chim. Acta 2007, 90, 128–142.
16. (a) Fitremann, J.; Dureault, A.; Depezay, J.-C. Synlett 1995, 235–237; (b) Yadav, J. S.;
Subba Reddy, B. V.; Parimala, G.; Venkatram Reddy, P. Synthesis 2002, 2383–2386;
(c) Dolence, E. K.; Roylance, J. B. Tetrahedron: Asymmetry 2004, 15, 3307–3332.
17. (a) Matsubara, S.; Kodama, T.; Utimoto, K. Tetrahedron Lett. 1990, 31, 6379–
6380; (b) Wu, J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2000, 65, 1344–1348; (c)
Minakata, S.; Okada, Y.; Oderaotoshi, Y.; Komatsu, M. Org. Lett. 2005, 7, 3509–
3512; (d) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai,
M.; Shibasaki, M. Tetrahedron 2007, 63, 5820–5831; Mita, T.; Fujimori, I.; Wada,
R.; Wen, J.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 11252–11253.
18. Kumamoto, T.; Nagayama, S.-I.; Hayashi, Y.; Kojima, H.; Lemin, D.; Nakanishi,
W.; Ishikawa, T. Heterocycles 2008, 76, 1155–1170.
3.9. (2S
*
,3R )-tert-Butyl 2-benzyl-4-cyano-6,7-
*
methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-
carboxylate (12)
To a solution of 10a (25 mg, 0.07 mmol) in CH2Cl2 (0.2 mL), 37%
HCHO aqueous solution (0.2 mL, 2.69 mmol) was dropwise added.
After stirring at rt for 20 min, trifluoroacetic acid (0.2 mL,
2.69 mmol) was added and the mixture was stirred at 40 ꢀC for 4 h,
quenched by addition of satd NaHCO3 solution (3 mL), and
extracted with CH2Cl2 (5 mLꢁ4). The organic solution was washed
with H2O and brine, dried, and evaporated under reduced pressure.
Column chromatography of the residue (n-hexane/AcOEt¼10:1)
afforded 12 (22 mg, 87%) as a pale yellow oil. IR nmax (cmꢂ1): 2242
19. Crystal data for 3: C22H24N2O4; M¼380.43 g molꢂ1, monoclinic, bP21/c, colorless
prism measuring 0.40ꢁ0.35ꢁ0.25 mm, T¼90 K, a¼10.8630(17) Å, b¼11.
3675(17) Å, c¼16.727(3) Å,
b
,
¼97.242(3)ꢀ, V¼2049.1(5) Å3, Z¼4, Dcalcd¼1.
GOF on F2¼1.059, R1¼0.0553, wR2¼0.1439
(CN), 1719 (CO). 1H NMR (400 MHz):
d (ppm) 1.39 (s, 9H), 3.86 (s,
233 Mg mꢂ3
[I>2
,
m
¼0.085 mmꢂ1
s
(I)], R1¼0.0782, and wR2¼0.1574 (all data). CCDC 721783.
2H), 3.90 (d, J¼2.3 Hz, 1H), 4.06 and 4.12 (each d, J¼13.4 Hz, 1H),
4.20 (d, J¼2.3 Hz, 1H), 5.93 and 5.94 (each d, J¼0.9 Hz, 1H), 6.48 and
6.71 (each s,1H), 7.29 (d, J¼7.3 Hz,1H), 7.36 (t, J¼7.3 Hz, 2H), 7.47 (d,
20. (a) Dallas, G.; Lown, J. W.; Moser, J. P. J. Chem. Soc. C 1970, 2383–2394; (b)
Huisgen, R.; Maeder, H. J. Am. Chem. Soc. 1971, 93, 1777–1779; (c) Padwa, A.;
Dean, D.; Oine, T. J. Am. Chem. Soc. 1975, 97, 2822–2829; (d) Garner, P.; Dogan, O.
J. Org. Chem. 1994, 59, 4–6; (e) Ungureanu, I.; Bologa, C.; Chayer, S.; Mann, A.
Tetrahedron Lett. 1999, 40, 5315–5318.
J¼7.3 Hz, 2H). 13C NMR (100 MHz):
d (ppm) 28.1, 34.0, 50.0, 59.2,
60.8, 82.8, 101.2, 106.5, 108.3, 119.8, 120.0, 127.5, 127.8, 128.5, 128.9,
137.6, 146.7, 147.9, 168.4. HREIMS m/z: 392.1723 (calcd for
C23H24N2O4: 392.1736).
21. Fauss, R.; Findelsen, K.; Haebich, D. Ger. Offen. DE 3430019 A1, 1986.
22. Davoli, P.; Forni, A.; Moretti, I.; Prati, F.; Torre, G. Tetrahedron 2001, 57,1801–1812.
23. Hartwig, W. Ger. Offen. DE 3632589 A1, 1989.