Conjugated imines and iminium salts as versatile acceptors of nucleophiles

Article abstract of DOI:10.1039/b814930e

Growing interests in nitrogen-containing molecules involving bioactive and functional materials have stimulated the recent development of synthetic methodologies where nucleophilic addition reactions to imino carbons are utilized in crucial steps. This article summarizes double nucleophilic addition reactions with α,β-unsaturated aldimines, addition reactions using alkynyl imines, "umpoled" reactions of α-imino esters, and the use of iminium salts as reactive electrophiles. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b814930e

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FEATURE ARTICLE
www.rsc.org/chemcomm | ChemComm
Conjugated imines and iminium salts as versatile acceptors
of nucleophiles
Makoto Shimizu,* Iwao Hachiya and Isao Mizota
Received (in Cambridge, UK) 27th August 2008, Accepted 6th November 2008
First published as an Advance Article on the web 7th January 2009
DOI: 10.1039/b814930e
Growing interests in nitrogen-containing molecules involving bioactive and functional materials
have stimulated the recent development of synthetic methodologies where nucleophilic addition
reactions to imino carbons are utilized in crucial steps. This article summarizes double
nucleophilic addition reactions with a,b-unsaturated aldimines, addition reactions using alkynyl
imines, ‘‘umpoled’’ reactions of a-imino esters, and the use of iminium salts as reactive
electrophiles.
(1) 1,4- and 1,2- double nucleophilic addition reactions with
Introduction
a,b-unsaturated aldimines (eqn (1)), (2) addition reactions
using alkynyl imines (eqn (2)), and (3) reactions of a-imino
esters and iminium salts (eqn (3) and (4)).
The widespread existence of nitrogen-containing compounds
such as amino acids, alkaloids, and functional materials
coupled with their use as useful synthons has prompted
exploration of new activation methods for imino compounds
and subsequent intriguing reactions. For the synthesis
of nitrogen-containing compounds, addition reactions to
a,b-unsaturated imines constitute one of the most straight-
forward approaches. However, since there are two electrophilic
carbons in a,b-unsaturated imines, difficulties are always
encountered regarding the regioselectivity. On the other hand,
imino compounds do not always have enough electrophilicity
as compared with their parent carbonyl counterparts. For
the activation of imino carbons, use as iminium salts offers
one solution. The following new reactions are discussed:
Department of Chemistry for Materials, Graduate School of
Engineering, Mie University, Tsu, Mie 514-8507, Japan.
E-mail: mshimizu@chem.mie-u.ac.jp; Fax: +81-59-231-9413;
Tel: +81-59-231-9413
Makoto Shimizu received his PhD from Tokyo Institute of
Technology (1981). After postdoctoral work with Professor
B. M. Trost, he became an Assistant Professor of the University
of Tokyo (1983), a Senior Research Associate at Riken Institute
of Physical and Chemical Research (1984), an Associate
Professor of Mie University (1989), and a Full Professor there
(1999).
Iwao Hachiya received his PhD from Science University of Tokyo
(1996). After postdoctoral work with Professor B. M. Trost, he
became an Assistant Professor of Science University of Tokyo
(1998), and an Associate Professor of Mie University (2000).
Isao Mizota is currently a PhD student at the Department of
Chemistry for Materials, Graduate School of Engineering, Mie
University.
Isao Mizota, Makoto Shimizu and Iwao Hachiya
Their research interests focus on the exploration into new C–C bond forming and/or asymmetric reactions using organometallics and
application to the synthesis of new functional materials and bioactive natural or unnatural products, where imino and iminium species
are utilized in crucial steps.
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acetals and/or thioacetals gave 1,4- and 1,2-addition products
in good yields.2 The use of 4 A MS (H2O) promoted the
isomerization after 1,4-addition. The intermediary metalloen-
amine and/or a-metalloimine were successfully trapped by a
TMS group when the reaction was carried out in the absence
of 4 A MS (H2O) (Scheme 2).
1,4- and 1,2-double nucleophilic addition reactions
to a,b-unsaturated aldimines
1. Ketene silyl acetals and allylstannanes as nucleophiles1,2
a,b-Unsaturated aldimines are readily accessible from the
parent aldehydes via simple condensation with amines.
Although a,b-unsaturated imines potentially possess two
electrophilic centers, use of both the carbons for carbon to
carbon bond forming reactions in a stereocontrolled fashion
has been a difficult task.3 Tandem alkylation reaction to
a,b-unsaturated imines appears to eliminate several drawbacks,
and therefore, it is highly desirable to develop an operationally
simple procedure for the addition reaction of two nucleophiles
to a,b-unsaturated imines in a single-step. The first example of
double nucleophilic addition to a,b-unsaturated aldimines
induced by TiX4 was reported in 1999.1 In the presence of
TiCl4, ketene silyl acetals underwent 1,4- and subsequently
1,2-addition to a,b-unsaturated aldimines 1 to give doubly
alkylated products 2 in good yields. The best result was
obtained when the reaction was carried out in the presence
of 4 A molecular sieves (4 A MS) using the N-anisyl derivative,
and the desired double alkylation product 2 was formed in
72% yield. Moreover, the reaction of a mixture of a ketene
silyl acetal and an allyltributylstannane with a,b-unsaturated
aldimine 1 gave regio- and chemoselectively 1,4- and 1,2-doubly
alkylated products 3, in which the ketene silyl acetal underwent
a 1,4-addition, while the allyltributylstannane did a 1,2-addition.
In these cases, the formation of the syn-adduct predominated
(Scheme 1).
2. Thiols and allylstannanes as nucleophiles4
Conjugate addition of thiols to a,b-unsaturated carbonyl
compounds constitutes one of the most popular modes of
reactions in organic synthesis.5 However, its imino versions
have received little attention, since the addition products
to a,b-unsaturated imines, b-sulfenyl imines and/or their
enamine counterparts, are readily hydrolyzed to the parent
carbonyl compounds.6 A double nucleophilic addition reaction
of thiols and tetraallyltin to a,b-unsaturated aldimines was
also reported, where the presence of added water was not
necessary due to the acidic hydrogen of the thiol (Scheme 3).
3. TMSCN as the nucleophile7,8
The Strecker reaction is one of the most efficient methods for
the synthesis of a-amino acids.9 A variety of asymmetric
Strecker reactions have been reported to date. The double
nucleophilic addition of ketene silyl (thio)acetals and trimethylsilyl
cyanide to a,b-unsaturated aldimines also proceeds.7 Among
the Lewis acids, AlCl3 and TMSI were found to be the most
efficient promoters (Table 1). Although there is much room for
the improvement of diastereoselectivities, the imines having
not only an aromatic group but also an aliphatic group work
well (Table 2).
In the presence of 1.0 equiv. of AlCl3 and 4 A MS containing
1.0 equiv. of H2O, reaction of ketene silyl acetals with
a,b-unsaturated aldimines also gave 1,4- and 1,2-alkylated
products in good yields with excellent diastereoselectivities.2
Under these reaction conditions, a variety of ketene silyl
To clarify the reaction mechanism, the reaction of imine
with ketene silyl acetal was carried out in the presence of 3 A
MS pretreated with D2O (treated with D2O and dried) to give
the deuterated product 11 in 73% yield with 56% deuterium
incorporation. The same reaction conducted in the absence of
Scheme 3 Double nucleophilic addition with thiol and allyltin.
Table 1 Examination of Lewis acids
Scheme 1 Double nucleophilic addition to a,b-unsaturated aldimine
1 induced by titanium tetrachloride.
Entry
Lewis acid
7 (%)
syn : anti
8 (%)
1
2
3
4
5
6
7
8
SnCl4
TiCl4
35
56
74
62
47
73
67
61
47 : 53
48 : 52
56 : 44
45 : 55
35 : 65
45 : 55
50 : 50
48 : 52
—
5
2
7
20
7
TMSI
EtAlCl2
Et2AlCl
AlCl3
AlBr3
AlI3
5
7
Scheme 2 Double nucleophilic addition to a,b-unsaturated aldimines
1 in the presence or absence of 4 A MS containing H2O.
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Table 2 Examination of a,b-unsaturated aldimines
R1
R2
Yield (%)
syn : anti
Ph
PMP
PMP
PMP
CHPh2
84
81
55
78
47 : 53
49 : 51
52 : 48
49 : 51
Me
nPr
Ph
Scheme 6 Double nucleophilic addition of the imines possessing
chiral auxiliaries derived from (R)-phenylglycinol.
HPLC, indicating that the first conjugate addition was not
diastereoselective (Scheme 6).
3 A MS followed by quenching with CD3COOD gave the
adduct in 53% yield with only trace of deuterium incorporation.
(Scheme 4).
4. Use as latent a,b-unsaturated aldehydes10,11
Moreover, close examination of the reaction of imine with
ketene silyl acetal and TMSCN in the presence of AlCl3 as
monitored by TLC revealed that the initial 1,2-addition of
TMSCN occurred at À20 1C. A new spot which was assigned
to be a 1,4- and 1,2-adduct gradually appeared at À10 to 0 1C.
From these results, a plausible reaction mechanism was pro-
posed as shown in Scheme 5. The initial 1,2-addition of
TMSCN occurs, which, however, is a reversible process to
regenerate the parent imine 12. Metalloenamine 14 would be
generated via an AlCl3-promoted 1,4-addition reaction of
ketene silyl (thio)acetal 13 and reacts with a certain proton
source to give imine 15, which in turn is attacked by TMSCN
to afford 1,4- and 1,2-adduct 16.
TMSCN9d is also an excellent nucleophile for both the
1,4- and 1,2-additions to a,b-unsaturated aldimines to give
2-aminopentanedinitriles. The imines possessing chiral auxiliaries
derived from (R)-phenylglycinol underwent diastereoselective
addition.8 Regarding the derivatives, methyl, allyl, and
methallyl ethers induced good diastereoselectivities. In order
to check the diastereoselectivity in the first conjugate addition
reaction, the tert-butyldimethylsilylated derivative 19 was
subjected to these double addition conditions. In this case,
however, three peaks for the adducts 20 were detected by
One of the most important functional groups in organic
transformations involves vinyl sulfides, since C–C bond
forming reactions,12 hydrolysis to carbonyl compounds,13
and desulfenylation to olefins14 are readily carried out using
the characteristics of such functionalities. For the preparation
of a useful vinylsufenyl functionality, the most direct way
appears to be the addition of thiols to triple bonds. However,
control of the resulting olefin geometry is not trivial under the
radical addition conditions. On the other hand, conjugate
addition of thiols to the electron-deficient alkynes also
enables direct access to vinyl sulfides.15 Stereoselective access
to (Z)-1-sulfenyl-1,5-alkadien-3-ols is possible using a double
nucleophilic addition of thiols and allylstannane to the imines
derived from 2-alkynals with SnCl4Á5H2O, where in situ
hydrolysis of an intermediary imine to an aldehyde is crucial
for the success of this approach. Switching the anisyl imine to
a sterically more hindered diphenylmethyl derivative increased
the product yields. The tert-butyl, cyclohexyl, and 1-phenylethyl
imines can also be used with equal efficiency in terms of
stereoselectivity. Regarding thiols, n-hexanethiol also serves
as a stereoselective 1,4-addition nucleophile (Table 3).
This reaction most probably proceeds via the following
mechanisms. First, the initial addition of thiol is promoted
by SnCl4Á5H2O. The subsequent protonation is effected by the
liberated HCl from SnCl4Á5H2O and the thiol to generate the
vinyl sulfide possessing an aldehyde moiety 25, which in turn is
attacked by the allyltin to give the double nucleophilic addition
product (Scheme 7). The diastereoselectivity is explained by
Table 3 Examination of thiols and substituents at the nitrogen
Scheme 4 Examination into D-incorporation.
R1
R2/equiv.
Yield (%)
Z : E
CHPh2
t-Bu
c-Hex
4-ClC6H4
CH(Me)Ph
CH(Me)Ph
4-t-BuC6H4/2.5
MeO2CCH2/1.5
MeO2CCH2/1.5
MeO2CCH2/1.5
MeO2CCH2/1.5
n-Hex/1.5
79
70
68
51
76
96
71 : 29
100 : 0
100 : 0
65 : 35
100 : 0
100 : 0
Scheme 5 Proposed mechanism of double nucleophilic addition.
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Scheme 9 Synthesis of a 1,3-diamine.
tetramethallyltin underwent a double nucleophilic addition
with a,b-unsaturated aldimines to give 1,3-amino azides in
good yields. Reduction to 1,3-diamines 30 was readily carried
out using LiAlH4 as a reducing agent (Scheme 9).
6. Regioselectivity18
Scheme 7 Proposed mechanism of vinyl sulfide formation.
The regioselectivity of the double nucleophilic addition was
highly dependent on the substituents of the ketene silyl acetals
31a,b, and the factors mainly derived from the ability of
the ketene silyl acetals to undergo the silicon–aluminium
exchange reaction, where the aluminium enolate preferentially
underwent 1,4-addition (Scheme 10). The formation of the
aluminium enolate was confirmed by spectroscopic methods.
Scheme 8 Synthesis of 1,3-hydroxy azide 27.
7. Pyrrole synthesis19
There are a variety of biologically important pyrrole derivatives.
A potentially effective approach to construct a pyrrole ring
involves cyclization of g-amino carbonyl compounds followed
by dehydrogenation. For the synthesis of g-amino carbonyl
compounds, crucial intermediates in this strategy, nucleophilic
addition to g-oxoimines constitutes a straightforward pathway.
However, difficulty has often been encountered for the
synthesis of g-oxoimines due to susceptibility to hydrolysis
and/or isomerization. For circumvention of such a drawback
of isolating relatively unstable imine intermediates as well as
use of an operationally simple experimental procedure, a
straightforward approach to g-amino carbonyl compounds
was reported, and the subsequent transformation led to
2,3,5-trisubstituted pyrroles. This approach enables a six-step
synthesis of imidazole glycerol phosphate dehydratase inhibitors
(IGPDIs) of herbicidal activity.20 A synthesis of the IGPDI 37
possessing herbicidal activity was carried out as follows
(Scheme 11). The ketene silyl acetal and trimethylsilyl cyanide
were treated with N-4-methoxyphenylcrotylidenamine 4 in the
presence of AlCl3 to give the doubly alkylated product 34 in
95% yield. Switching of the PMP group into a Boc analogue
was carried out before cyclization into the pyrrole. The
the direct protonation of the adduct derived from
a
relatively reactive alkylmercaptan as a nucleophile to give
(Z)-isomer 24, whereas in the cases with aromatic thiols, the
involvement of non-selective protonation of the allenyl species
23 may account for the formation of a mixture of (E)- and
(Z)-isomers.
Based on these results, it is possible to use a,b-unsaturated
aldimines as latent a,b-unsaturated aldehydes for the double
nucleophilic addition. 1,3-Amino alcohols have received
considerable attention as useful units for the synthesis of a
variety of biologically important materials. For the synthesis
of such units, Mannich-type reactions offer convenient
precursors, and several important methodologies have been
developed. Addition of a nitrogen atom to a,b-unsaturated
carbonyl compounds also enables a rapid access to precursors
to 1,3-amino alcohols. However, a,b-unsaturated aldehydes
are not always good acceptors of nitrogen nucleophiles due to
the concomitant side reactions involving polymerization.
SnCl4Á5H2O also promoted a double nucleophilic addition of
azide and allylstannane to a,b-unsaturated aldimines to give
1,3-hydroxy azides (Scheme 8).11
5. HN3 as the nucleophile16
Although there are several reports on 1,3-amino alcohols and
1,3-diols, limited examples are available for their 1,3-diamine
analogues.17 This is due in part to lack of general synthetic
methodologies for 1,3-diamines. However, recent interests in
1,3-diamine derivatives for use as catalysts in the asymmetric
synthesis and medicinal chemistry involving HIV protease
inhibitors have prompted exploration of simple approaches
to them. In contrast to the above reaction using SnCl4Á5H2O,
in the presence of AlCl3 a mixture of hydrogen azide and
Scheme 10 Double addition using two kinds of ketene silyl acetals.
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Table 4 Double nucleophilic addition of N-allylideneamine
With 38
40a (42)b
(%)
With 39
41a (42)b
(%)
Entry
R1
R2
R3
Scheme 11 Synthesis of monopyrrole aldehyde 37.
1
2
3
4
5
6
7
Me
Me
Me
Me
–(CH2)5–
OEt
H
Me
Me
Me
Me
OEt
83 (78)
87 (57)c
— (47)
— (27)
87 (76)
— (40)
56
80 (56)
64 (67)
58 (54)
68 (59)
59 (61)
51 (12)
22 (—)d
OMe
OnPr
OiPr
OMe
OEt
Boc-protected double-addition product 35 was treated with
MeSO3H and DDQ to afford the pyrrole 36 in 92% yield
(2 steps), where the NH-free dihydropyrrole intermediate was
not isolated. Finally reduction of the cyano group with
Raney-Ni W4 in the presence of NaPH2O2 gave the desired
monopyrrole aldehyde 37 in 73% yield.
OEt
H
StBu
a
b
Under the conditions A. Under the conditions A followed by TFA
c
treatment. Formation of the cyclized valerolactam (17%) was
d
observed. Although formation of valerolactam was confirmed by
1H NMR, isolation was not successful.
8. Synthesis and reaction of N-allylideneamines21
N-Allylideneamines derived from acrolein are expected to be
important intermediates for the preparation of amino acid
derivatives, when these imines are used as acceptors of
nucleophiles in a 1,4- and 1,2-double nucleophilic addition.
However, difficulties have been always reported for their
syntheses, and therefore, there are only a few reports available
for the synthesis of this type of imine.3a,22 The preparation of
N-allylideneamines derived from acrolein has been reported.
The condensation of acrolein with amines was carried out in
the presence Ti(OEt)4, the reaction proceeded smoothly to
afford 38, 39 having a diphenylethyl or a trityl group
(Scheme 12).
Scheme 13 Synthesis of amino acid 44.
(entries 2–6). Hydrolysis of the nitrile moiety of amino nitrile
43 gave amino acid 44 in high yield (Scheme 13).
Regarding the 1,4- and 1,2-double nucleophilic additions
of ketene silyl acetals and trimethylsilyl cyanide with
N-allylideneamines 38, 39, among the promoters examined,
silica gel, a weak acid, was found to be the most effective. The
use of ketene silyl acetals derived from ethyl isobutyrate and
methyl isobutyrate gave the desired 1,4- and 1,2-adducts 40 in
high yields (Table 4, entries 1 and 2). Use of ketene silyl
thioacetal (KSTA) also gave the desired 1,4- and 1,2-addition
adduct 40 in 56% yield (entry 7). Upon quenching with TFA
after double nucleophilic addition, the reaction gave the amino
nitrile 42 in 78% yield (entry 1). Using the in situ hydrolysis,
the reaction gave amino nitriles 42 in moderate to high yields
Alkynyl imines
1. Synthesis of 3,4,5-trisubstituted-2-pyridones23,24
Alkynyl imines are one of the most important nitrogen-
containing starting materials due to their extensive use for
the synthesis of heterocycles such as pyrazoles,25 pyrimidines,25
pyrrolinones,26 pyrroles,3j indolizines,3j quinolines,27 fused
pyrrolines,27 and pyridines.28 Alkynyl imines are used in
[2 + 2]-cycloaddition reactions with ketenes or the reaction
with several enolates to give b-lactams.6 The reactivity at the
b-position of alkynyl imines is of interest. The reaction of
alkynyl imine 45 with ketene silyl acetal 46 in the presence of
TiCl4 as a Lewis acid proceeded to give only the 1,2-addition
product 47 in quantitative yield (Scheme 14). A Mannich-type
reaction proceeded under these reaction conditions.29
To facilitate the conjugate addition, dimethyl malonate 48,
a ‘‘soft’’ carbon nucleophile frequently employed in conjugate
addition reactions, was used as a nucleophile. The reaction of
sodio dimethyl malonate 50 gave 2-pyridone 49, formed by the
mechanism shown in Scheme 15. Metalloallenamine 51 is
generated by the 1,4-addition reaction of the sodio dimethyl
malonate 50 to alkynyl imine 45. The metalloallenamine 51 in
Scheme 12 Synthesis of N-allylideneamines.
878 | Chem. Commun., 2009, 874–889
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Table
nucleophilic addition of malonic esters 59 to alkynyl imines 60
5
Synthesis of 3,4,5-trisubstituted-2-pyridones 61 using
Scheme 14 Mannich-type reaction of alkynyl imine 45 with ketene
silyl acetal 46.
Entry
R1
R2
Yield (%)
1
2
3
4
5
6
7
Me
Me
Me
Me
Allyl
Allyl
Allyl
Ph
91
57
82
71
59
46
63
TBSO(CH2)3
1-Cyclohexenyl
n-Bu
Ph
TBSO(CH2)3
1-Cyclohexenyl
Table 6 Synthesis of 5-acetyl-2-pyridones 64 using nucleophilic
addition of b-keto esters 62 to alkynyl imines 63
Scheme 15 Possible mechanism for the synthesis of 2-pyridone 49.
Entry
R1
R2
Yield (%)
turn isomerizes into metalloenamine 52, and the cyclization
gives 2-pyridone 49.
1
2
3
4
5
6
Me
Me
Me
Me
Allyl
Allyl
Ph
66
69
31
58
49
33
TBSO(CH2)3
1-Cyclohexenyl
n-Bu
Ph
TBSO(CH2)3
The reaction of diethyl methylmalonate 53 possessing a
single acidic proton was examined to prevent isomerization
of the double bond. The reaction of sodio diethyl methyl-
malonate 55 with alkynyl imine 45 afforded 2-pyridone 54 in 55%
yield. A possible reaction mechanism is shown in Scheme 16.
The metalloallenamine 56 would be generated via a 1,4-addition
reaction of sodio diethyl methylmalonate 55 to alkynyl
imine 45 and undergoes an intramolecular cyclization to give
cyclobutenoxide 57. Cyclobutenoxide 57 would collapse into
metalloenamine 58 via a ring-opening reaction to release ring
strain in the cyclobutene, and the subsequent cyclization gives
2-pyridone 54.
7
Ph
43
The development of synthetic methods for functionalized
2-pyridone is of importance as a result of the large number
of biologically active compounds containing a 2-pyridone
structure.30 Representative examples of this 2-pyridone synthesis
are summarized in Table 5.
Not only aromatic but also aliphatic groups as a substituent
in the alkynyl imines are used to give 2-pyridones 61 in
moderate to good yields. Numerous methods for the synthesis
of 2-pyridones have been reported.31 However, this 2-pyridone
synthesis is an attractive alternative method because alkynyl
imines and substituted malonic esters are readily available.
Based on the results, the use of other active methine
compounds was examined instead of 2-substituted malonic
esters. When b-keto esters 62 were used as active methine
compounds, the reactions with imines 63 gave 5-acetyl-2-
pyridones 64. Several 5-acetyl-2-pyridones 64 were obtained
in moderate yields (Table 6).
2. Synthesis of 3,4,5,6-tetrasubstituted-2-pyridones32
3,4,5,6-Tetrasubstituted-2-pyridone synthesis was carried out
by the nucleophilic addition of active methine compounds to
Scheme 16 Possible mechanism for the synthesis of 2-pyridone 54.
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Table 7 Synthesis of 3,4,5,6-tetrasubstituted-2-pyridones 67 using
addition of active methine compounds 65 to alkynyl imines 66
Scheme 17 Synthesis of 6H-pyrido[1,2-a]pyrimidin-6-ones 73.
Entry
R1
R2
R3
R4
Yield (%)
Table 9 Synthesis of 5H-thiazolo[3,2-a]pyridin-5-ones 76
1
2
3
4
5
6
7
8
9
OEt
OEt
Me
Me
Me
Me
Me
Ph
n-Bu
Ph
n-Bu
Ph
n-Bu
Ph
n-Bu
n-Bu
Ph
n-Bu
Ph
n-Bu
TBS
TBS
TBS
TBS
TBS
66
44
52
56
71
55a
40
51
42
Me
OEt
OEt
Me
Me
Me
Me
Allyl
Me
Me
Allyl
Entry
R1
R2
Yield (%)
1
2
3
4
Me
Ph
Ph
n-Bu
n-Bu
83
61
75
53
10
OEt
H
TBS
51
Allyl
Me
Allyl
a
2-Pyridone (R2 = (E)-1-propenyl) possessing a double bond that
isomerized internally was obtained.
2-alkynylpyridines 68 with several malonic esters 69 proceeded
to give 4H-quinolizin-4-ones 70, in moderate to good yields
(Table 8).
dialkynyl imines, directed to the synthesis of (À)-A58365A,
which was obtained from a fermentation broth of the bacterium
Streptomyces chromofuscus in the Eli Lilly laboratories and
found to be an angiotensin-converting enzyme inhibitor at
nanomolar concentrations.33,34 The reaction of active methine
compounds such as malonic esters or b-keto esters with
dialkynyl imines proceeded to give 3,4,5,6-tetrasubstituted-
2-pyridones in moderate to good yields (Table 7). The reaction
of unsymmetrical dialkynyl imine 66 proceeded regioselectively
to give only 2-pyridone 67 where the less hindered sp carbon
reacted preferentially (entries 5–10).
The reaction of 2-phenylethynylpyrimidine 71 with dimethyl
methylmalonate (R
= Me) or dimethyl allylmalonate
(R = allyl) 72 gave the desired 6H-pyrido[1,2-a]pyrimidin-6-ones
73 in 48% and 30% yields, respectively (Scheme 17).
The reaction of 2-alkynylthiazole 74 with malonic esters 75
proceeded to give 5H-thiazolo[3,2-a]pyridin-5-ones 76 in good
to high yields (Table 9).
4. Synthesis of multi-substituted 2-iminopyridines
and 2-aminopyridines38
Biologically active compounds containing a 2-iminopyridine
structure are less known than those containing the 2-pyridone
counterpart.39 However, 2-iminopyridines are highly attractive
compounds compared with members of the large group of
biologically active 2-pyridones.30,40 Several methods for the
synthesis of 2-iminopyridines by condensation reactions of
cyano derivatives41 and other reactions42 using transition
metals have already been reported. However, the former
methods are not yet satisfactory from the viewpoint of
synthesizing 2-iminopyridines possessing the desired substituents.
Therefore, it is strongly desired to develop alternative
synthetic methods for multi-substituted 2-iminopyridines from
easily available starting materials. On the basis of the
2-pyridone synthesis, the reaction of alkynyl imines 77 was
carried out with ethyl cyanoacetate derivatives 78 (Table 10).
The reaction of the alkynyl imines 77 (R3 = MPM) bearing
a p-methoxyphenylmethyl group at the nitrogen with ethyl
cyanoacetate derivatives 78 proceeded to give the corresponding
2-iminopyridines 79 (R3 = MPM) in moderate yields (entries
1–4). Those bearing a p-methoxyphenyl group 77 (R3 = PMP)
also gave 2-iminopyridines 79 (R3 = PMP) in moderate to
good yields (entries 5–12).
3. Synthesis of bicyclo-2-pyridones35
Bicyclic compounds containing a 2-pyridone structure are
key intermediates for the total synthesis of anagyrine,36
lupinine,36a and ipalbidine.37 There are also biologically active
compounds having 2-pyridone structures such as (À)-A58365A.
2-Alkynylpyridine, 2-alkynylpyrimidine, and 2-alkynylthiazole
were used as a cyclic alkynyl imine equivalent. The reaction of
Table 8 Synthesis of 4H-quinolizin-4-ones 70
Entry
R1
R2
Yield (%)
1
2
3
4
Me
Me
4-MeOC6H4
2-Pyridyl
Ph
n-Bu
H
38
36
77
43
H
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Table 10 Synthesis of 2-iminopyridines 79 by the conjugate addition
reaction of ethyl cyanoacetate derivatives 78 to alkynyl imine 77
Table 11 Synthesis of 2-aminopyridines 85 by deprotection of
2-iminopyridines 79 (R3 = MPM)
Entry R1
R2
Ph
R3
Conditionsa Yield (%)
Entry
R1
R2
Yield (%)
1
2
3
Me
Me
Me
Ph
MPM
A
A
A
B
C
C
C
B
B
B
B
B
70
57
47
51
81
84
48
84
45
50
66
66
1
2
3
Me
Me
Ph
Ph
n-Bu
Ph
70
59
62
1-Cyclohexenyl MPM
n-Bu
Ph
MPM
MPM
PMP
4
5
Allyl Ph
6
Allyl 1-Cyclohexenyl PMP
79 (R3 = PMP) under several reaction conditions was
attempted. However, the desired 2-aminopyridine was not
obtained. Trifluoromethanesulfonic acid (TfOH) was found
7
8
9
10
11
12
Me
Ph
Ph
Ph
n-Bu
Ph
PMP
PMP
1-Cyclohexenyl PMP
n-Bu
PMP
PMP
Allyl 1-Cyclohexenyl PMP
to promote the deprotection of 79 (R3
= MPM) in
trifluoroacetic acid (TFA) under reflux to give the desired
2-aminopyridine 85 in moderate to good yields (Table 11).
Allyl Ph
a
Conditions A: in (CH3OCH2CH2)2O–toluene (3 : 1 : 1) at 160 1C.
Conditions B: in 1,4-dioxane under reflux. Conditions C: in
1,4-dioxane–toluene (2.4–3 : 1 : 1) under reflux.
5. Synthesis of functionalized medium-sized carbocycles45
Although the development of synthetic methods for medium-
sized carbocycles (8, 9, and 10) is important as a result of many
biologically active compounds in naturally occurring products,
the formation of medium-sized carbocycles is relatively
difficult as compared with those of other small or large-sized
carbocycles because of well-known entropic and enthalpic
factors.46 Many synthetic methods have been reported to
overcome these drawbacks for medium-sized carbocycles,47
e.g., cycloadditions,48 cyclizations,49 cross-coupling reactions,50
a ring-closing metathesis,51 and so on.52 Ring expansion
reactions of small-sized carbocycles (4, 5, 6, and 7) are the
most useful methods because many small-sized carbocycles
are easily available.53 Especially, ring expansion reactions
including Grob-type fragmentation have an attractive
characteristic, the fragmentation proceeds under moderately
mild conditions in excellent yields.54
Scheme 18 Synthesis of bicyclo-2-iminopyridine 82.
Alkynylthiazole 80 was used instead of alkynyl imines 77 to
synthesize a bicyclic compound containing a 2-iminopyridine
structure. The reaction of 80 with ethyl 2-cyanopropanoate 81
gave the cyclized product 82 in 64% yield (Scheme 18).
The synthesis of a 3,4,5,6-tetrasubstituted-2-iminopyridine
was carried out. The reaction of dialkynyl imine 83 with 81
gave 2-iminopyridine 84 in 52% yield (Scheme 19).
The transformation of 2-iminopyridine into 2-aminopyridine
was also conducted by deprotection of the substituent at
the nitrogen.43 2-Aminopyridines are one of the most
important heterocycles due to their biological activity.44
Deprotection of the p-methoxyphenyl group of 2-iminopyridine
The initial examination of the ring expansion reaction of
cyclic b-keto esters 86 (n = 1 or 2) with phenylpropynal gave
the two-atom enlarged carbocyclic products in low yields,
because of the high reactivity of the formyl group. On
the other hand, when alkynyl imines, which have different
reactivity from the parent alkynyl aldehydes, were used as
electrophiles in conjugate additions, the ring expansion
reactions proceeded via a cyclobutenoxide as a Grob-type
fragmentation intermediate to give two-atom enlarged carbo-
cyclic products 88 possessing
a masked formyl group
(Table 12).55 Not only aromatic but also aliphatic groups as
substituent R in imines 87 worked well. Even with the use of
cyclic b-keto ester 89 which has a double bond, the reaction of
alkynyl imine 90 proceeded to give the desired ring expansion
product 91 in 84% yield. Since bicyclic lactones have been
found in many natural products,56 desilylation–lactonization
of the ring expansion product 91 with TBAF was successfully
conducted to give bicyclic lactone 92 in high yield (Scheme 20).
Cyclic a-cyano ketones 93 were used as nucleophiles
(Table 13). The reactions proceeded in 1,4-dioxane under
Scheme 19 Synthesis of 3,4,5,6-tetrasubstituted-2-iminopyridine 84.
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Table 12 Synthesis of medium-sized carbocycles 88 by ring-expansion
reaction of cyclic b-keto esters 86 with alkynyl imines 87
Entry
n
R
Yield (%)
Scheme 21 Synthesis of bicyclo-2-pyridone 98 by a ring-expansion
reaction.
1
2
3
4
5
6
7
8
9
1
1
2
3
3
3
4
4
4
Ph
n-Bu
Ph
Ph
68
58
70
87
56
71
86
52
63
n-Bu
TBSO(CH2)3
Ph
n-Bu
TBSO(CH2)3
Scheme 20 Synthesis of bicyclic lactone 92 via a ring-expansion
reaction.
Table 13 Synthesis of medium-sized carbocycles 95 by ring-expansion
reaction of cyclic a-cyano ketones 93 with alkynyl imines 94
Scheme 22 Possible reaction mechanism of the ring-expansion
reaction.
When ethyl 2-oxocyclododecanecarboxylate 96, a more
flexible molecule, was used as the nucleophile, the reaction
with alkynyl imine 97 gave the bicyclo-2-pyridone 98 in 53%
yield (Scheme 21).
Entry
n
R
Yield (%)
1
2
3
4
5
6
1
1
1
2
3
3
Ph
76
A plausible reaction mechanism is shown in Scheme 22.
Metalloallenamine 101 would be generated via conjugate addi-
tion of the sodium or potassium salt of active methine compound
99 to alkynyl imine 100 and would undergo a chemoselective
intramolecular cyclization at the keto carbonyl group to give
cyclobutenoxide intermediate 102. The cyclobutenoxide 102
would collapse into metalloenamine 103 via a ring-opening
reaction to release the ring strain in the cyclobutene, and the
subsequent protonation with water to quench the reaction would
give the ring expansion product 104. On the other hand, in
the reaction of ethyl 2-oxocyclododecanecarboxylate 96,
(E)-metalloenamine 105 generated via the ring-opening reaction
would isomerize into (Z)-metalloenamine 106 due to the
n-Bu
TMS
Ph
n-Bu
TMS
33
43a
54
37
44a
a
Desilylated ring-expansion products (R = H) were obtained.
reflux or in diethylene glycol dimethyl ether at 140 1C to give
the desired ring expansion products 95 in moderate to good
yields. Reaction of the alkynyl imine 94 bearing a TMS group
(R = TMS) gave the desilylated ring expansion product 95
(R = H) in moderate yield (entries 3 and 6).
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flexibility of the large carbocycle, and the subsequent cyclization
would give bicyclo-2-pyridone 98.
Reactions of a-imino esters and iminium salts
Nucleophilic addition to the nitrogen atom of simple imines is,
in principal, difficult due to the electronegativity of the
imino functionality. Only limited examples are available for
nucleophilic addition to the nitrogen atom of a-imino esters.57
The reactivity of a-imino esters is of interest and several
intriguing features have been discovered. N-alkylation of
the imines derived from glyoxylate esters was conducted
with dialkylaluminium chloride in acetonitrile to give an
N-monoalkylated intermediate, which in turn underwent a
subsequent addition reaction with another imine. When
the N-monoalkylated intermediate was oxidized with BPO
(benzoyl peroxide) in the presence of allyltributyltin,
N-alkylation–C-allylation products were obtained in good
yields. When an imine had two electron-withdrawing groups,
i.e., 2-[N-(p-methoxyphenyl)imino]malonate, this derivative
served as an excellent N-alkylation reagent for Grignard
reagents. Subsequent oxidative removal of the malonate and
p-methoxyphenyl (PMP) moieties offered a new amination
methodology for carbanions.
Scheme 23 1,2-Diamine synthesis using homo-coupling.
of dioctylaluminium chloride, the desired product 108c
was obtained in high yield. In each case, anti-selectivity
was observed, in which a bulky ester group caused a good
diastereoselectivity. When triethylaluminium or ethylaluminium
dichloride was used, the coupling product was not formed but
the C-ethylation product or a mixture of C- and N-ethylation
products was obtained, respectively. The amount of diethyl-
aluminium chloride was also important. For example, the use
of 3 equivalents of diethylaluminium chloride decreased the
formation of the desired coupling product to 33% yield
along with the ethylation products. This may be due to the
competing C-alkylation reaction caused by the low aggregated
alkylaluminium species, whereas the use of a large excess of
the aluminium reagent suppressed C-alkylation.
As mentioned above, aluminium enolates were readily
oxidized with BPO to give iminium species, which were very
reactive and attractive electrophiles in organic synthesis. An
easy and convenient method was found for the generation of
such species using the oxidation of amino ketene silyl acetals
with certain oxidants. The iminium salts thus generated
showed excellent reactivities as electrophiles to give, after
addition reaction with nucleophiles, a-amino esters in good
to excellent yields.
A possible mechanism of the present coupling reaction is
shown in Scheme 23. Dialkylaluminium chloride which has a
strong oxophilicity initially coordinates with the ester carbonyl
group (A), making the electron density of the nitrogen atom
decrease. Then, 1,4-addition of an alkyl group of the aluminium
reagent proceeds on the nitrogen atom to form the ester
enolate (B) which has a five-membered (Z)-conformation
because of coordination of the aluminium with the nitrogen
atom. This ester enolate attacks another imine via a chair-like
six-membered cyclic transition state (C) to give the
anti-coupling product.
1. N-Alkylation-coupling reaction of a-imino esters
1,2-Diamines are useful units for the synthesis of biologically
active compounds58 and are widely used as ligands in many
transition metal-mediated reactions,59 and therefore, new
synthetic methods for 1,2-diamines have been studied
extensively.60 A coupling reaction of the imines derived from
ethyl glyoxylate proceeded with alkylaluminium reagents to
give 1,2-diamines in good yields (Table 14).61a
As a related ‘‘umpoled’’ reaction, tris(trimethylsilyl)aluminium
is used as a chemoselective reducing reagent for a-imino esters
to give a-amino esters in good yields. Application to the
reduction of 3,5-disubstituted 5,6-dihydro-2H-1,4-oxazine-2-
ones offers a stereoselective conversion into cis-3,5-disubstituted
morpholine-2-one (Scheme 24).61b
Diethylaluminium chloride effected the N-alkylation-coupling
reaction, and the product 108a was obtained, whereas the
use of diisobutylaluminium chloride gave the coupling
product 108b along with the reduction product. In the case
Table 14 Coupling reaction using R12AlCl
R12AlCl (eq)
Yield (%)
anti : syn
Et2AlCl (5 eq)
79
59
61
81
95
70 : 30
90 : 10
88 : 12
62 : 38
72 : 28
i-Bu2AlCl (5 eq)
i-Bu2AlCl (7 eq)
n-Oct2AlCl (5 eq)
n-Oct2AlCl (7 eq)
Scheme 24 Stereoselective reduction with (TMS)3AlÁOEt2.
Chem. Commun., 2009, 874–889 | 883
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Table 15 Tandem N-ethylation–C-allylation reaction with a-imino
esters
Entry
R (109)
Time/h
Product
Yield (%)
1
2
3
4
5
6
7
8
9
Ph (109a)
7
8
7
7
7
7
7
7
8
110a
110b
110c
110d
110e
110f
110g
110h
110i
75
47
62
63
76
34
50
39
18
o-MeOC6H4 (109b)
p-MeOC6H4 (109c)
p-MeC6H4 (109d)
p-ClC6H4 (109e)
2-Thienyl (109f)
Cyclopropyl (109g)
Cyclohexyl (109h)
H (109i)
Scheme 25 Control experiments.
2. Tandem N-alkylation–C-allylation reaction of a-imino
esters
On treatment of the imino ester 109a with Et2AlCl, EtAlCl2,
and allyltributyltin in the presence of BPO, N-alkylation–
C-allylation product 110a was obtained. The reaction was
carried out as follows: to a solution of BPO and the
imino ester in propionitrile were added Et2AlCl, EtAlCl2,
and allyltributyltin successively at À20 1C. After the starting
material disappeared on TLC, a usual work-up followed by
purification gave the N-ethylation–C-allylation product
110a–i. The aliphatic as well as aromatic imino esters
underwent the tandem N-ethylation–allylation to give the
addition products in moderate to good yields (Table 15).62
A tandem N-silylation–C-allylation reaction also proceeded
with bis(trimethylsilyl)aluminium chloride on heating the
mixture to 50 1C to afford the homoallylamine 111a. The
allylation did not proceed in the absence of BPO. Other
a-imino esters could also be used for the present N-silylation–
C-allylation reaction to give the products in good to excellent
yields (Table 16).
Scheme 26 Possible reaction mechanism.
obtained in 76%. After the N-ethylation, BPO or DDQ with
allyltributyltin was added, which actually gave the desired
allylation product 110a. The tandem reaction was carried out
in the presence of galvinoxyl or 1,4-cyclohexadiene as a radical
scavenger. However, the yields did not decrease, indicating
that an ionic mechanism might be involved.
Based on these results, a possible mechanism of this tandem
reaction is shown in Scheme 26. Firstly, 1,4-addition of the
ethyl group proceeds at the nitrogen atom of the imino ester to
give an enolate species. The enolate (A) is subsequently
oxidized with BPO (B) to form an iminium salt (C), which is
attacked by allyltributyltin to afford the C-allylation product.
The tandem reaction was also carried out using trimethylsilyl
cyanide instead of allyltributyltin to give the amino nitrile
113. It is interesting to note that in the presence of BPO,
diethylaluminium cyanide acted as both ethylation and
subsequent cyanation reagent to afford the amino nitrile 113
(Scheme 27). Although diethylaluminium cyanide has been
Several reaction conditions were examined to clarify the
reaction mechanism (Scheme 25). When the imino ester 109a
was treated with a mixture of diethylaluminium chloride and
ethylaluminium dichloride, N-ethylation product 112a was
Table 16 Tandem N-silylation–C-allylation reaction
Entry
R
Time/h
Product
Yield (%)
1
2
3
4
5
6
7
Ph (109a)
Ph (109a)
23
25
25
24
24
28
23
111a
111a
111c
111d
111e
111f
111g
93
0a
p-MeOC6H4 (109c)
p-MeC6H4 (109d)
p-ClC6H4 (109e)
2-Thienyl (109f)
Cyclopropyl (109g)
84
83
73
61
58
a
In the absence of BPO.
Scheme 27 N-Alkylation–cyanation reaction.
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used as the cyanide source in the Strecker reaction,63 its
intriguing behavior as an ethylating reagent is unknown.
Table 17 Synthesis of N-alkyl-p-anisidine by electrophilic amination
3. Iminomalonate as an electrophilic amination reagent
Electrophilic amination is a useful method for C–N bond
formation, and several reagents including azodicarboxylates
have been developed for this purpose.64 New reagents, such as
oxaziridines,65 oximes,66 and oxime O-sulfonates67 have also
been developed as electrophilic amination reagents. However,
because amination reactions using these reagents were not
always readily carried out, the development of a new electrophilic
amination reagent has been highly desirable. On the other
hand, some N-alkylation reactions to a-imino esters are
known.57 In particular, the Grignard reagent is one of the
most convenient N-alkylation reagents for a-imino esters.
Imines with two electron-withdrawing substituents possess a
good ability to react with nucleophiles at the nitrogen atom
in a regioselective manner. 2-[N-(p-Methoxyphenyl)imino]-
malonate is an efficient reagent for the electrophilic amination
of Grignard reagents to give N-alkylation products, and the
subsequent oxidation of the malonate moiety affords N-alkyl-
p-anisidines in good yields.
Entry
R
116 (%)
117 (%)
1
2
3
4
5
6
7
8
9
10
Methyl
Ethyl
98
91
81
86
93
86a
48
80
59
56
63
93
79
89
91
57
29
64
55
67
n-Propyl
n-Phenethyl
Cyclohexylmethyl
Isopropyl
Cyclohexyl
Benzyl
Phenyl
tert-Butyl
a
Carried out at À95 1C.
The following sequence shows the strategy. The new
electrophilic amination methodology consists of two reactions:
(1) a nucleophilic addition to the nitrogen atom, and (2) an
oxidative removal of the malonate moiety (Scheme 28). Among
various imine derivatives possessing electron-withdrawing
groups, iminomalonate was chosen as an amination reagent.
Several iminomalonates are already known and have been used
for the synthesis of heterocycles. However, the nucleophilic
addition of organometals to this imine has not received much
attention. Due to a ready oxidative removal from the nitrogen
atom after the addition of nucleophiles, the p-methoxyphenyl
group was chosen as the substituent at the nitrogen.
Scheme 30 Removal of the PMP group.
À95 1C, the yield was improved (entry 6). However, additives
such as CuI, BF3ÁOEt2, CeCl3, and MgBr2 were not effective.
The N-methylation and tert-butylation of a-iminoacetate were
reported to be highly difficult.69 In strong contrast to the
previous observations, due to the introduction of two ester
groups onto the imino carbon, this amination tolerated a wide
range of Grignard reagents, and showed high regioselectivity
onto the nitrogen atom for the nucleophilic addition.70
The p-methoxyphenyl moiety of N-alkyl-p-anisidine was
readily deprotected with ammonium cerium(IV) nitrate to give
a primary amine (Scheme 30). N-Ethyl-p-anisidine 117a was
firstly converted into benzylcarbamate 118a with benzyl
chloroformate. This carbamate was exposed to CAN in the
usual manner to give benzyl N-ethylcarbamate 119a.
The amination reagent, diethyl 2-[N-(p-methoxyphenyl)-
imino]malonate 115,68 was easily prepared by the condensation
of commercially available diethyl 2-oxomalonate 114 with
p-anisidine in 93% yield (Scheme 29).
Electrophilic amination using primary alkyl Grignard
reagents afforded the aminated products in good to excellent
yields. Subsequent oxidative cleavage of the N-alkylated products
also proceeded smoothly to give N-alkyl-p-anisidines
(Table 17). Various alkylations including the use of secondary
or tertiary alkyl and aryl Grignard reagents could be carried
out (entries 6–10). Isopropylation gave N-isopropyl-p-
anisidine in low yield. When the reaction was carried out at
4. Formation of alkoxycarbonyl iminium salts
Iminium salts are very reactive and attractive species in
organic synthesis, and therefore, the search for an easy
preparation method for these species has received considerable
attention.71 Reported examples using iminium species involve
addition of organometallic reagents to the iminium salt for the
synthesis of b-amino acids,72 b-amino ketones, and 1,3-amino
alcohols,73 and so on.74 Use of acyl iminium and related
species has been also reported.75 Control of the reactivity of
formaldehyde was successfully accomplished by the use of the
Mannich reaction and Eschenmoser’s salt, which have been
used extensively for the introduction of an aminomethyl
functionality into enolate equivalents.76
Scheme 28 Reaction strategy.
The generation of the iminium salt was carried out using the
reaction of amino ketene silyl acetal 120 with oxidizing
reagents followed by the reaction with diethylaluminium
cyanide (Scheme 31, Table 18). BPO, N-chlorosuccinimide
(NCS), and DDQ worked with comparable efficiency in the
Scheme 29 Synthesis of iminomalonate.
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Table 19 Oxidation–allylation of amino ketene silyl acetal 120
Scheme 31 Reaction strategy.
Entry R1
Allyl metal (equiv.)
Lewis acid R2
124 (%)
cases with the methyl derivative 120a, whereas iodobenzene
diacetate and its bistrifluoroacetate analogue gave slightly
decreased amounts of the desired product (entries 1–6). Better
yields of the adduct 122 were obtained using the ethyl ester
120b, and among the oxidants DDQ recorded good to
excellent results (entries 8, 9).77
1
2
3
4
5
6
TMS (Methallyl)4Sn (0.5) Et2AlCl Me 68
TBS (Methallyl)4Sn (0.5) Et2AlCl
Me 72
TMS (Allyl)4Sn (0.5)
TMS AllylSn(nBu)3 (1.0)
TBS
TBS
Et2AlCl
Et2AlCl
Et2AlCl
SnCl4
H
H
H
H
65
69
64
82
AllylSn(nBu)3 (1.0)
AllylSiMe3 (2.0)a
a
In EtCN.
Scheme 32 summarizes the addition of Grignard reagents to
the iminium species. Aliphatic Grignard reagents underwent
an addition reaction to the iminium salt to give the addition
products 123 in moderate to good yields. The reaction was
influenced by the steric bulk of the Grignard reagents, and
secondary Grignard reagents depressed the yields. t-BuMgBr
did not give the addition product, instead, the hydrolysis of
the ketene silyl acetal occurred to give the parent ester.
Functionalized Grignard reagents could also be used for
the present reaction. Aromatic Grignard reagents bearing
electron-donating and electron-withdrawing groups underwent
the nucleophilic addition to give the addition products 123 in
good yields. Cyclopropylmagnesium bromide and trimethylsilyl-
methylmagnesium chloride gave the addition products 123 in
moderate to good yields. Grignard reagents bearing an olefin
or an ether group were employable. Allylation was also carried
out (Table 19).
Tetraallyl- and tetramethallyltin reagents effected allylation
reactions to give the adducts in moderate yields (entries 1–3),
while allyltributyltin could also be used with comparable
efficiency under the influence of diethylaluminium chloride
as a Lewis acid (entries 4 and 5). Regarding the substituents at
the silicon atom, TMS and TBS derivatives gave essentially the
same range of product yields. A better result was obtained
using allyltrimethylsilane, and in this case the reaction of the
TBS derivative in propionitrile in the presence of tin(IV)
chloride proved to be superior (entry 6).
1
Close examination of the H and 13C NMR spectra of the
reaction mixture revealed a possible formation of the iminium
species 121. Upon treatment of the ketene silyl acetal 120b
with DDQ in CD3CN at À40 1C and gradual warming of the
mixture to room temperature over 12 h, new signals appeared
at 9.27 and 193.6 ppm in the 1H and 13C NMR spectra,
respectively, which actually indicated the formation of the
iminium species 121. The reaction was carried out in the
presence of galvinoxyl or 1,4-cyclohexadiene as a radical
scavenger. However, the yields did not considerably decrease,
indicating that an ionic mechanism might be involved. On the
basis of these results, a possible mechanism of the present
iminium formation and nucleophilic addition reaction is
shown in Scheme 33. First, DDQ reacts with the ketene silyl
acetal 120b to give the N,O-acetal 125, which collapses to the
iminium salt 121. The subsequent nucleophilic attack gives the
addition product 122.
Table 18 Oxidation–cyanation of amino ketene silyl acetal 120 under
various conditions
Entry
R
Solvent
Oxidant
Temp/1C
122 (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Et
Et2O
BPO
BPO
DDQ
NCS
PhI(OAc)2
PhI(OTFA)2
BPO
DDQ
DDQa
À78–rt
À78–rt
À50–rt
À50–rt
À78–rt
À78–rt
À78–rt
À50–rt
À78–rt
45
36
44
44
32
35
53
71
80
DME
DME
DME
DME
DME
Et2O
Et
Et
DME
DME
a
DDQ (0.7 equiv.) was used.
Scheme 32 Oxidation–alkylation of amino ketene silyl acetal 120b.
886 | Chem. Commun., 2009, 874–889
Scheme 33 Possible reaction mechanism.
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J. Chem. Soc., Perkin Trans. 1, 1998, 2663; (h) J. P. Porter,
W. G. Wirschun, K. W. Kuntz, M. L. Snapper and
A. H. Hoveyda, J. Am. Chem. Soc., 2000, 122, 2657;
(i) D. Berger and W. Imhof, Tetrahedron, 2000, 56, 2015;
(j) A. V. Kel’in, A. W. Sromek and V. Gevorgyan, J. Am. Chem.
Soc., 2001, 123, 2074.
Conclusions
The 1,4- and 1,2-double alkylation reaction studied here
provides a new entry into reactions using a,b-unsaturated
aldimines as a good acceptor of two kinds of nucleophiles
in one-pot. Since discrimination between two kinds of
nucleophiles upon addition to a,b-unsaturated aldimines is
highly controlled, this approach offers a new method for a
single-step double nucleophilic addition, an otherwise multi-
step and rather tedious procedure.
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An intriguing heterocycle synthesis was found in the
nucleophilic addition of active methine compounds to alkynyl
imines. Varying the active methine compounds leads to a
specific approach to otherwise non-trivial heterocycles. When
a transannular migration of the carbonyl group is involved,
this methodology offers a Grob-type fragmentation reaction
leading to ring-expansion products in
manner.
a chemoselective
a-Imino esters behave as acceptors of nucleophiles at their
nitrogen atoms in an ‘‘umpoled’’ manner, when appropriate
nucleophiles are used. The tandem N-alkylation–C-allylation
and N-alkylation–C-cyanation reactions of several a-imino
esters with organoaluminiums are carried out in good to
excellent yields, where two nucleophiles attack across the
CQN double bond. Iminomalonate is an efficient electrophilic
amination reagent for Grignard reagents. In particular, diethyl
2-[N-(p-methoxyphenyl)imino]malonate is the most efficient
amination reagent for primary alkyl Grignard reagents to give
N-alkyl-p-anisidines in excellent yields, although electrophilic
amination of secondary or tertiary alkyl, and aryl Grignard
reagents gives slightly lower yields of the amination products.
In view of preparing the iminomalonate and removing the
p-methoxyphenyl moiety, this method is a useful addition to
the existing methodologies for electrophilic amination.
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The alkoxycarbonyl iminium salt is easily prepared using the
oxidation of amino ketene silyl acetal with DDQ, and
subsequent nucleophilic addition to this iminium species
proceeds efficiently to afford the amino esters in good yields.
This methodology provides us with a new and easy entry into
reactive iminium salts, which are important synthetic intermedi-
ates for many nitrogen-containing bioactive compounds.
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Acknowledgements
We would like to thank our co-workers for their intellectual
and experimental contributions to the present project. This
work was supported by Grants-in-Aid for Scientific Research
from MEXT and JSPS.
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