Generation and exploitation of acyclic azomethine imines in chiral Bronsted acid catalysis

Article abstract of DOI:10.1038/nchem.1096

Successful implementation of a catalytic asymmetric synthesis strategy to produce enantiomerically enriched compounds requires the adoption of suitable prochiral substrates. The combination of an azomethine imine electrophile with various nucleophiles could give straightforward access to a number of synthetically useful chiral hydrazines, but is used rarely. Here we report the exploitation of acyclic azomethine imines as a new type of prochiral electrophile. They can be generated in situ by the condensation of Ng€2-benzylbenzoylhydrazide with a variety of aldehydes in the presence of a catalytic amount of an axially chiral dicarboxylic acid. By trapping these electrophiles with alkyl diazoacetate or (diazomethyl)phosphonate nucleophiles, we produced a diverse array of chiral α-diazo-β- hydrazino esters and phosphonates with excellent enantioselectivities.

Full text of DOI:10.1038/nchem.1096

ARTICLES
PUBLISHED ONLINE: 22 JULY 2011 | DOI: 10.1038/NCHEM.1096
Generation and exploitation of acyclic azomethine
imines in chiral Brønsted acid catalysis
Takuya Hashimoto, Hidenori Kimura, Yu Kawamata and Keiji Maruoka
*
Successful implementation of a catalytic asymmetric synthesis strategy to produce enantiomerically enriched compounds
requires the adoption of suitable prochiral substrates. The combination of an azomethine imine electrophile with various
nucleophiles could give straightforward access to a number of synthetically useful chiral hydrazines, but is used rarely.
Here we report the exploitation of acyclic azomethine imines as a new type of prochiral electrophile. They can be
generated in situ by the condensation of N′-benzylbenzoylhydrazide with a variety of aldehydes in the presence of a
catalytic amount of an axially chiral dicarboxylic acid. By trapping these electrophiles with alkyl diazoacetate or
(diazomethyl)phosphonate nucleophiles, we produced a diverse array of chiral a-diazo-b-hydrazino esters and
phosphonates with excellent enantioselectivities.
hiral organic compounds with a hydrazine moiety are found materials. Although the thus-generated acyclic azomethine imines
in a variety of natural and synthetic biologically active com- have some application in 1,3-dipolar cycloadditions22–24, the requi-
C
pounds, as represented by piperazimycins1,2 (potent cancer- site harsh reaction conditions are apparently not suitable for use in
cell cytotoxins) and the antiretroviral drug atazanavir3,4. In addition, asymmetric catalysis.
they have many applications as the synthetic precursors of chiral
Nevertheless, there are some indications that the generation of
amines, which can be generated easily by reductive cleavage of the acyclic azomethine imines could be facilitated by the action of
N–N bond. To date, one of the most reliable and flexible methods acid additives, which resembles the well-known acid-catalysed pro-
for the asymmetric synthesis of chiral hydrazines is the catalytic motion of imine formation from the corresponding hemiaminals. A
asymmetric addition of nucleophiles to prochiral hydrazones, as a study by Kanemasa et al. revealed that treatment of a hydrate form
diverse array of enantiomerically enriched hydrazines can be of acyclic azomethine imines (V) with acetic acid in the presence of
obtained by judiciously choosing nucleophilic reaction partners a dipolarophile provided the corresponding cycloadduct at room
and catalysts5–9. However, hydrazones are intrinsically less electro-
a
philic than the corresponding imines10, a drawback that means
their application in asymmetric catalysis has been limited and has
left untouched the possibility of using many mild nucleophiles
in the synthetic toolbox. A promising and innovative, but as yet
unexplored strategy to overcome this issue is to develop more
reactive, highly electrophilic, substrates that are structurally related
to hydrazones.
In this context, N-acyl azomethine imines, with the key
C¼ Nþ2N2 1,3-dipole structure, are powerful candidates because
their structural similarity to hydrazones and their inherent ionic
property could be beneficial in terms of reactivity (Fig. 1a). In the
literature, N,N′-cyclic azomethine imines I are utilized widely in
asymmetric catalysis in the context of 1,3-dipolar cycloaddi-
tions11–13; a couple of notable examples using these templates for
nucleophilic additions were published recently14,15. In addition,
C,N-cyclic azomethine imines II emerged as a viable option in
our research16,17. However, acyclic azomethine imines III, which
are ideal substrates as hydrazone surrogates of high generality,
have not been the subject of asymmetric catalysis.
R2
O
O
O
–
N
N
–
N
–
N
+
N
N
+
+
R3
R
R
R1
N,N´-Cyclic I
C,N-Cyclic II
Acyclic III
R2
O
R2
R1
O
b
O
Heat, –H2O
R1
N
N
+
–
N
+
N
R3
R3
O
H
+H2O
R1
H
N
OH
III
V
R2
N
H
R3
1,3-Dipolar
–H2O
HX*
IV
cycloaddition
R2
Asymmetric
nucleophilic
addition
R2
R2
O
O
O
N
Nu
N
N
R3
*
R1
+
R1
N
R3
N
H
N
R3
R1
H
X*–
VI
A straightforward method to access acyclic azomethine imines is Figure 1 | Classification and reactivity of azomethine imines. a, Azomethine
th′e simple condensation of the corresponding aldehydes and imines can be split into three classes, N,N′-cyclic (I), C,N-cyclic (II) and
N -alkylacylhydrazides IV (Fig. 1b)18–21. Oppolzer’s seminal study acyclic (III). Acyclic azomethine imines (III) are difficult to generate and
indicates that they are reluctant to form azomethine imines by have thus not been explored as electrophiles in asymmetric catalysis.
simple condensation and remain at the stage of the hydrates V b, Acyclic azomethine imines are normally generated under harsh thermal
(refs 18–21). Accordingly, it is considered necessary to generate conditions. We assumed that the related acyclic azomethine imminium ion
the labile species III via the azeotropic removal of water from the VI could be generated in the presence of a chiral Brønsted acid (HX*) and
reaction flask, in sharp contrast to other N,N′-cyclic and then exploited as prochiral electrophiles for asymmetric
C,N-cyclic azomethine imines, which are prepared as isolable nucleophilic addition.
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan. e-mail: maruoka@kuchem.kyoto-u.ac.jp
*
642
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1096
ARTICLES
temperature, which suggests the possibility that an acid additive
accelerates the formation of acyclic azomethine imines from their
hydrates25. Even more clearly, our work and that by Tamura et al.
on C,N-cyclic azomethine imines, which are prone to form the cor-
responding hydrates in the presence of excess water or alcohols,
showed that protonation of these azomethine imines or hydrates
Table 1 | Optimization of reaction conditions.
(R)-1
(5mol%)
Bn
Cy
NHBz
N
H
CO2R´
N
Bz
+
+
CyCHO
CO2R´
Bn
N
Solvent
MS4A
0 °C, 20h
N2
H
2a
3
N2
4 R´ =tBu
resulted in the formation of stable azomethine iminium salts16,26
.
5a R´ =tBu
6 R´ =CH(iPr)2
7a R´ =CH(iPr)2
In addition, a literature survey revealed a single report by Portlock
et al. that the Petasis reaction of N′-alkyl-N-carbamoylhydrazides,
glyoxylic acid and arylboronic acids gave racemic a-hydrazino
acids. Presumably, this proceeded via the formation of an acyclic
azomethine imine and the nucleophilic addition of arylboronic
acid, although neither the intermediacy of the azomethine imine
nor the effect of acidic conditions derived from the use of glyoxylic
acid as substrate was described27.
Taking these facts into consideration, we set out to investigate the
possibility of generating the elusive acyclic azomethine imines in the
presence of a catalytic amount of chiral Brønsted acid28,29 and trap-
ping the thus-activated azomethine iminium salt VI by a mild
nucleophile in an asymmetric manner to give chiral hydrazines.
R
(R)-1a R=H
(R)-1b R=2,6-Me2-4-tBu-C6H2
(R)-1c R=2,6-Me2-4-(Ph3C)-C6H2
(R)-1d R=Ph3Si
CO2H
CO2H
(R)-1e R=Ph2MeSi
R
Entry
Catalyst
Solvent
R′
Yield (%)*
e.e. (%)†
1
1b
1c
1d
1e
1e
1e
1e
1e
1e
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
PhMe
PhCF3
PhCF3
PhCF3
tBu
84
74
57
73
84
19
89
84
72
43
60
89
90
91
93
93
96
96
2
3
4
5
6
7
8
9‡
tBu
tBu
tBu
tBu
tBu
tBu
CH(iPr2)
CH(iPr2)
Results and discussion
We began our research to realize this unestablished but highly
promising synthetic procedure by building on the use of the
axially chiral dicarboxylic acid 1, originally developed in our labora-
tory as a highly efficient chiral Brønsted acid catalyst17,30–34. As a
model, we set up a three-component reaction system35 composed
of cyclohexanecarbaldehyde 2a and N′-benzylbenzoylhydrazide 3
Conditions: performed with 2a (0.15 mmol), N′-benzylbenzoylhydrazide
diazoacetate (0.12 mmol) in the presence of 5 mol% (R)-1 (0.005 mmol) and MS4A (100 mg).
*Isolated yield. †Determined by chiral high-performance liquid chromatography analysis.
‡Performed in the presence of Na2SO4 (300 mg) for 72 h.
3
(0.10 mmol) and
to generate a postulated protonated acyclic azomethine imine corresponding a-diazo-b-hydrazino esters in good yields with
under the influence of the catalyst (R)-1b and t-butyl diazoacetate 96% e.e., respectively (Table 2, entries 2 and 4). For cyclopropane-
as a mild nucleophile (Table 1). Aliphatic aldehyde was chosen carbaldehyde, it was found to be advantageous to run the reaction
because the related Mannich-type reactions, catalysed by chiral at a lower temperature (220 8C) to attain high enantioselectivity
Brønsted acid, of diazoacetate with preformed N-aryloyl or (Table 2, entry 3). One limitation we faced in this study was the
N-t-butyloxycarbonyl (N-Boc) imines were applicable only to aromatic use of pivalaldehyde, with which no appreciable amount of the
imines, as reported in both Terada’s research and ours30,31,36. To our product was detected (Table 2, entry 5). Our attention then
delight, the desired product, a-diazo-b-hydrazino ester 5a, was moved to the reactions of a-unbranched aliphatic aldehydes, for
isolated in 84% yield with a promising 43% enantiomeric excess which the reaction temperature was generally set to 220 8C to
(e.e.) (Table 1, entry 1) by carrying out the reaction in CH2Cl2 at obtain optimal results. Irrespective of the chain length and steric
0 8C in the presence of 4A molecular sieves (MS4A) as a water sca- bulk, the desired products were obtained in good yields with e.e.
venger (see Supplementary Information). An effort to identify the values that ranged from 93% to 99% (Table 2, entries 6–8). Even
optimal catalyst using 3,3′-diaryl dicarboxylic acids failed to attain acetaldehyde could be utilized without significantly compromising
an acceptable level of enantioselectivity, at most no more than the enantioselectivity by carrying out the reaction at 228 8C
60% e.e. with (R)-1c (Table 1, entry 2), so we turned our attention (Table 2, entry 9). As for functional group tolerance, protected
to the use of 3,3′-disilyl-substituted dicarboxylic acids 1d and 1e hydroxy and amino functionalities were all tolerated to give
(refs 37,38). Using these sterically demanding catalysts, a drastic densely functionalized b-hydrazino esters with high enantioselec-
increase of the enantioselectivity was observed (Table 1, entries 3 tivities (Table 2, entries 10–12). Use of b-ketoaldehyde led to the
and 4). After establishing (R)-1e, which bears methyldiphenylsilyl selective functionalization of the aldehyde, with the keto group
moieties, as the optimal catalyst, we focused on the screening of unaffected (Table 2, entry 13).
solvents. Halogenated solvents were preferred with regard to the
The substrate scope of this reaction was extended further to
reaction yield owing to the good solubility of N′-benzylbenzoyl- aromatic aldehydes without difficulty. The electronic property of
hydrazide 3, whereas an aromatic solvent, toluene, was advantageous the aromatic rings had no influence on the selectivity, although
in terms of the selectivity (Table 1, entries 4–6). We therefore use of 2-tolualdehyde resulted in a slight decrease of the enantios-
opted for the use of a,a,a-trifluorotoluene as the solvent, with electivity (Table 2, entries 14–17). This reaction system could not
which the a-diazo-b-hydrazino ester 5a could be produced in be applied to a,b-unsaturated aldehydes, such as cinnamaldehyde,
89% yield with 93% e.e. (Table 1, entry 7). Finally, use of diisopro- because of the facile 1,4-addition of the hydrazide 3 (ref. 39), but
pylmethyl diazoacetate 6 in place of t-butyl diazoacetate 4 gave rise 3-phenylpropiolaldehyde was transformed successfully into the
to a-diazo-b-hydrazino ester 7a in 84% yield with 96% e.e. (Table 1, desired product, incorporating an alkynyl moiety in 75% yield
entry 8). Although we carried out the reaction routinely in a reaction with 87% e.e. (Table 2, entry 18).
flask filled with argon in the presence of powdered MS4A, it may be
During the course of this study, we became aware of the intri-
run more conveniently in a glass-stoppered test tube containing guing phenomenon that the catalyst structure not only affects the
Na2SO4 as a water scavenger without the deliberate displacement enantioselectivity of the products, but also the entire course
of air and moisture (Table 1, entry 9).
of the reaction when a-unbranched aliphatic aldehydes are used
With the optimized conditions in hand, next we explored the as substrates (Fig. 2). As demonstrated above, use of 3,3′-bis(methyl-
substrate scope of this novel synthetic transformation, as shown in diphenylsilyl)-substituted dicarboxylic acid (R)-1e in the reaction of
Table 2. With regard to other a-branched aldehydes, cyclopentane- 3-phenylpropionaldehyde provided the corresponding b-hydrazino
carbaldehyde and isobutyraldehyde could be converted into the ester 7f selectively in fairly good yield. In contrast, 3,3′-unsubstituted
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1096
ARTICLES
Table 2 | Substrate scope.
Bn
R
NHBz
CO2R'
N
H
(R)-1e (5mol%)
N
Bz
+
+
RCHO
CO2R'
Bn
N
PhCF3, MS4A
0 °C, 20h
N2
H
2
3
6 R' =CH(iPr)2
N2
7
Entry
Product
Yield
(%)*
e.e.
(%)†
Entry
Product
Yield
(%)*
e.e.
(%)†
Entry
Product
Yield
(%)*
e.e.
(%)†
Bn
NHBz
Bn
NHBz
Bn
NHBz
1
84
89
84
69
97
96
89
96
7‡
84
80
57
83
99
96
86
95
13‡
87
80
57
70
95
N
N
N
CO2R'
CO2R'
CO2R'
N2
N2
O
N2
7g
7m
7a
Bn
NHBz
Bn
NHBz
Bn
NHBz
2
8‡
14
15
16
91
N
N
N
CO2R'
CO2R'
CO2R'
N2
N2
7h
N2
7b
7n
Bn
NHBz
Bn
NHBz
Bn
NHBz
3‡
9§
90
92
N
N
N
CO2R'
CO2R'
Cl
CO2R'
N2
7c
N2
7i
N2
7o
Bn
Bn
NHBz
Bn
NHBz
Bn
NHBz
4
10‡
N
N
N
CO2R'
CO2R'
CO2R'
TBSO
N2
7d
N2
N2
MeO
7j
7p
NHBz
Bn
NHBz
Bn
NHBz
5
N.R.
11‡
50
84
91
17
64
75
81
N
N
N
CO2R'
CO2R'
CO2R'
BocHN
N2
7e
N2
N2
Me
7q
7k
Bn
NHBz
Bn
NHBz
Bn
NHBz
6‡
85
93
12‡
93
18‡
87
N
N
N
CO2R'
CO2R'
CO2R'
Ph
BnO(CH2)4
7l
N2
N2
Ph
N2
7f
7r
Conditions: Performed with 2 (0.15 mmol), N′-benzylbenzoylhydrazide 3 (0.10 mmol) and diazoacetate 6 (0.12 or 0.20 mmol) in the presence of 5 mol% (R)-1e (0.005 mmol) and MS4A (100 mg). *Isolated
yield. †Determined by chiral HPLC analysis. ‡Performed at 220 8C. §Performed at 228 8C. N.R. ¼ no reaction.
dicarboxylic acid (R)-1a furnished, as a major product, a different are regarded as an analogue of b-amino acids. As a unique extension
species with a molecular weight that corresponded to the dimer of this study, we pursued further the synthesis of b-hydrazino phos-
of the acyclic azomethine imine. The structure was elucidated to phoric acids as a second-degree relative of b-amino acids that have
be the five-membered heterocycle 8, which was assumed to be both hydrazine and phosphoric acid in lieu of amine and carboxylic
generated via 1,3-dipolar cycloaddition of acid-activated acyclic acid41 on the premise that alkyl diazoacetate can be replaced by the
azomethine imine and its tautomerized N′-alkenylbenzoyl- corresponding dimethyl (diazomethyl)phosphonate 11 without
hydrazide 9 (ref. 40). This unwanted reaction pathway still affecting the selectivity in axially chiral dicarboyxlic acid catalysis
persisted when the 3,3′-diaryl substituted catalyst (R)-1b was used (Fig. 3a)30,31. This novel three-component reaction actually pro-
to give the homo coupling product 8 in 9% yield in conjunction ceeded smoothly irrespective of the nature of the aldehydes to
with the b-hydrazino ester, whereas the use of (R)-1e minimized give the corresponding a-diazo-b-hydrazino phosphonates 12
the yield of 8 to only 2%. Notably, chiral phosphoric acid (R)-10 with excellent enantioselectivities. To the best of our knowledge,
with the same 3,3′-disilyl substituents generated a considerable this is the first report of success in providing these compounds in
amount of the dimer 8 in addition to 7f (45% e.e.), which a catalytic asymmetric manner.
highlights the distinctive catalytic activity of the axially chiral
Next, the reaction with alkyl diazoacetate was performed on a
dicarboxylic acid (R)-1e. Slow tautomerization of acyclic 2.0 mmol scale under more elaborate reaction conditions to show
azomethine imine might be the reason for the selective formation the scalability of this methodology (Fig. 3b). In the presence of
of b-hydrazino ester in the case of 3,3′-disilyl substituted 1 mol% (R)-1e with smaller amounts of the solvent and molecular
dicarboxylic acid catalysis.
sieves, the reaction using cyclohexanecarbaldehyde 2a took place
The strategy described herein provides a facile organocatalytic without difficulty to give the adduct 7a in 74% yield with 96% e.e.
method for the asymmetric synthesis of b-hydrazino acids, which (see Supplementary Information).
644
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1096
ARTICLES
a
Ph
CHO
Bn
NHBz
CO2R´
N
Catalyst (5 mol%)
+
+
CO2R´
PhCF3, MS4A
–20°C, 20h
H
N2
Ph
N
Bz
b
Bn
N
N2
Bz
6 R´ =CH(iPr)2
SiMePh2
H
Catalyst
7f, yield (%)
8, yield (%)
3
7f
O
O
(R)-1a
(R)-1b
(R)-1e
(R)-10
34
74
87
41
9
Catalyst=HX*
+
P
O
(R)-10
OH
2
72 (45% e.e. (S)) 16
X*–
H
Bn
H
N
N
N
SiMePh2
Bn
N
Bz
NHBz
–HX*
Bn
+
N
[3+2]
N
Ph
N
Bz
Ph
Bn
Ph
Ph
9
8
Figure 2 | Influence of the catalyst structure on the reaction pathway. a, After formation of the acyclic azomethine imine, two reaction pathways are
possible. Reaction with the diazoacetate 6 leads to the desired product 7f; alternatively, tautomerization of the azomethine imine produces alkenyl hydrazide
9, which can undergo a [3 þ 2] cycloaddition with a further equivalent of the azomethine imine to produce the dimeric product 8. b, The reaction that
predominates is strongly dependent on the catalyst structure.
a
b
RCHO
CyCHO
Bn
R
NHBz
Bn
Cy
NHBz
N
N
2
2a
CO2R'
PO(OMe)2
(R)-1e (5mol%)
(R)-1e (5mol%)
+
PO(OMe)2
CO2R'
+
+
+
PhCF3, MS4A
0 °C, 20h
PhCF3 (0.33M)
MS4A (400mg)
0 °C, 4.5 days
N2
N2
H
N
N
H
H
N
N
H
Bz
Bz
N2
N2
11
6
Bn
Bn
R'=CH(iPr)2
12a R=Cy
7a R'=CH(iPr)2
74%, 96% e.e.
(742mg)
2.0mmol scale
3
3
68%, 95% e.e.
12b R=PhCH2CH2
77%, 95% e.e. (–20 °C)
12c R=Ph
64%, 90% e.e.
c
d
i. SmI2
iPrOH
0 °C, 0.5h
Bn
Cy
NHBz
Bn
NHBz
N
N
Bn
NHBz
Bn
Cy
NHBz
Bn
i. TFAA, Et3N
THF, r.t., 2h
PtO2
H2 (balloon)
N
N
NH
CO2R'
CO2R'
ii. Boc2O
1N NaOH
r.t., 14h
Cy
CO2R'
CO2R'
CO2R'
ii. SmI2
THF
0 °C, 30min
CPME/HFIP
r.t., 6h
Cy
Cy
N2
HN
N2
Boc
7a R'=CH(iPr)2
15 R'=CH(iPr)2
85%, 92% e.e.
7a R'=CH(iPr)2
13 R'=CH(iPr)2
14 R'=CH(iPr)2
66%, 92% e.e.
96% e.e.
96% e.e.
80%, dr=4.4/1 (96% e.e.)
Figure 3 | Applications of axially chiral dicarboxylic acid catalysed reaction of acyclic azomethine imines. a, Use of dimethyl (diazomethyl)phosphonate
as the nucleophile in place of alkyl diazoacetate furnished a-diazo-b-hydrazino phosphonates with high enantioselectivities. b, An experiment scaled up to
2.0 mmol was conducted using 1 mol% catalyst and a smaller amount of MS4A to exemplify the robustness of the reaction. c, The diazo moiety of the
a-diazo-b-hydrazino ester can be converted into an amine by SmI2. d, The diazo moiety can be reduced to a methylene by hydrogenation using PtO2.
The N–N bond can be cleaved further by the one-pot trifluoroacetylation/SmI2-mediated reduction. d.r. ¼ diastereomeric ratio, r.t. ¼ room temperature,
TFAA ¼ trifluoroacetic anhydride, THF ¼ tetrahydrofuran.
Two synthetic derivatizations of chiral a-diazo-b-hydrazino
Conclusion
ester were then implemented. In one example, the diazo group The field of asymmetric catalysis has grown synergistically with
was converted into the Boc-amino group by a reductive treatment the development of novel catalysts and reaction systems to make
with samarium iodide to give the trans-a-amino-b-hydrazino available
a myriad of enantiomerically enriched materials.
ester 13 in good yield (Fig. 3c). Another application we devised is However, when we turn our attention to the prochiral substrates
the complete removal of the diazo moiety via hydrogenation cata- employed in these catalyses, it is not hard to recognize that generally
lysed by platinum oxide as a way to give the a-unsubstituted only a handful of electrophiles are used, whereas a variety of nucleo-
b-hydrazino ester 14 (Fig. 3d). After the screening of various philes exist as reaction partners. The research described herein
reaction conditions, we determined that the optimal condition is a reveals, for the first time, that acyclic azomethine imines can be uti-
co-solvent system that consists of cyclopentyl methyl ether lized as a new entry of prochiral electrophiles in association with
(CPME) and hexafluoroisopropanol (HFIP) at room temperature, state-of-the-art chiral Brønsted acid catalysis. From the viewpoint
both to give 14 and to minimize reduction of the e.e. value. of imine chemistry aimed at chiral amine synthesis, this study
To prove the viability of chiral hydrazine as a protected chiral could unfold a competitive alternative as acyclic azomethine
amine, next we examined the reaction conditions for the detach- imines have three major appreciated properties in imine chemistry:
ment of the benzoyl amide moiety of 14. This can be done via a no need for the preformation of imines, high reactivity towards mild
facile one-pot trifluoroacetylation/SmI2 reduction sequence to nucleophiles and applicability to alkyl, aryl and alkynyl aldehydes
give the b-amino acid ester 15 in 85% yield without deterioration with high functional group tolerance43–46. This discovery will open
in the enantioselectivity42.
up operationally simple and environmentally benign organocatalysed
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1096
ARTICLES
condensation of ethyl 3-benzylcarbazate with paraformaldehyde. Bull. Chem.
Soc. Jpn 62, 3944–3949 (1989).
26. Tamura, Y., Minamikawa, J-I., Miki, Y., Okamoto, Y. & Ikeda, M. The synthesis
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Received 21 March 2011; accepted 14 June 2011;
published online 22 July 2011
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Author contributions
T.H. conceived the study and wrote the manuscript. H.K. principally performed the
experiments. Y.K. assisted preliminary experiments. K.M. organized the research.
All authors contributed to designing the experiments, analysing data and editing
the manuscript.
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Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://www.
nature.com/reprints. Correspondence and requests for materials should be addressed to K.M.
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