Study on 1,3,5-triazine chemistry in dehydrocondensation: Gauche effect on the generation of active triazinylammonium species

Article abstract of DOI:10.1002/chem.201202236

The reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) with various nitrogen-containing compounds, particularly tertiary amines (tert-amines), has been studied for the preparation of 2-(4,6-dimethoxy-1,3,5-triazinyl) trialkylammonium salts [DMT-Am(s)]. DMT-Ams derived from aliphatic tert-amines exhibited activity for the dehydrocondensation between a carboxylic acid and an amine to form an amide in a model reaction. Based on a conformational analysis of DMT-Ams and tert-amines by NMR and X-ray diffraction methods, we concluded that a β-alkyl group maintained in a gauche relationship with the nitrogen lone pair of tert-amines significantly hinders the approach of CDMT to the nitrogen. Thus, trimethylamine and quinuclidine without such alkyl groups readily react with CDMT whereas triethylamine, possessing two or three such gauche β-alkyl groups in the stable conformations, does not react at all. The theory of "gauche β-alkyl group effect" proposed here provides useful guidelines for the preparation of DMT-Ams possessing various tertiary amine moieties. An investigation of the dehydrocondensation activity of tert-amines in a CDMT/tert-amine system that involves in situ generation of DMT-Am, showed that the gauche effect of the β-alkyl group becomes quite pronounced; the yield of the amide decreases significantly with tert-amines possessing an unavoidable gauche β-alkyl group. Thus, the tert-amine/CDMT systems are useful for judging whether tert-amines can readily react with CDMT without isolation of DMT-Ams. The right approach! The structure-activity relationship of nitrogen-containing compounds including aliphatic tertiary amines in the reaction with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) has been investigated (see scheme). The theory of "gauche β-alkyl group effect" proposed here provides useful guidelines for the preparation of triazine-based dehydrocondensation reagents (DMT-Ams) possessing various tertiary amine moieties. Copyright

Full text of DOI:10.1002/chem.201202236

DOI: 10.1002/chem.201202236
Study on 1,3,5-Triazine Chemistry in Dehydrocondensation: Gauche Effect
on the Generation of Active TriazinylACHTNUTRGNEUNGammonium Species
Munetaka Kunishima,*[a, c] Takae Ujigawa,[b] Yoshie Nagaoka,[b] Chiho Kawachi,[b]
Kazuhito Hioki,[b, c] and Motoo Shiro[d]
Abstract: The reaction of 2-chloro-4,6-
dimethoxy-1,3,5-triazine (CDMT) with
in a gauche relationship with the nitro-
gen lone pair of tert-amines significant-
ly hinders the approach of CDMT to
the nitrogen. Thus, trimethylamine and
quinuclidine without such alkyl groups
readily react with CDMT whereas trie-
thylamine, possessing two or three such
gauche b-alkyl groups in the stable con-
formations, does not react at all. The
theory of “gauche b-alkyl group effect”
proposed here provides useful guide-
lines for the preparation of DMT-Ams
possessing various tertiary amine moi-
eties. An investigation of the dehydro-
condensation activity of tert-amines in
various
nitrogen-containing
com-
pounds, particularly tertiary amines
(tert-amines), has been studied for the
preparation of 2-(4,6-dimethoxy-1,3,5-
a
CDMT/tert-amine system that in-
triazinyl)trialkylammonium
salts
volves in situ generation of DMT-Am,
showed that the gauche effect of the b-
alkyl group becomes quite pronounced;
the yield of the amide decreases signifi-
cantly with tert-amines possessing an
unavoidable gauche b-alkyl group.
Thus, the tert-amine/CDMT systems
are useful for judging whether tert-
amines can readily react with CDMT
without isolation of DMT-Ams.
[DMT-Am(s)]. DMT-Ams derived
from aliphatic tert-amines exhibited ac-
tivity for the dehydrocondensation be-
tween a carboxylic acid and an amine
to form an amide in a model reaction.
Based on a conformational analysis of
DMT-Ams and tert-amines by NMR
and X-ray diffraction methods, we con-
cluded that a b-alkyl group maintained
Keywords: amides · amines · con-
formation analysis · reaction mech-
anisms · structure–activity relation-
ships
Introduction
chloride (DMT-MM),[1,2] and proposed that DMT-MM
would be a superior dehydrocondensation reagent for the
formation of amides and esters (Scheme 1a).[3] The most
outstanding property of DMT-MM is that it enables the for-
mation of amide bonds from carboxylic acids and amines in
aqueous or alcoholic solvents.[5] In fact, in the past decade,
many applications of DMT-MM conducted in an aqueous or
alcoholic solvent have been reported for the preparation or
chemical modification of peptides,[6] nucleic acids,[7]
Dehydrocondensation reactions that form amides and esters
are essential tools for a wide range of organic chemistry be-
cause these functional groups occur in many drugs, natural
products, polymers, and biomolecules. It has been more than
ten years since we first correctly assigned the structure of 4-
(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
[a] Prof. Dr. M. Kunishima
Faculty of Pharmaceutical Sciences
Institute of Medical, Pharmaceutical
and Health Sciences
Kanazawa University
Kakuma-machi, Kanazawa 920-1192 (Japan)
Fax : (+81)76-264-6201
E-mail: kunisima@p.kanazawa-u.ac.jp
[b] T. Ujigawa, Y. Nagaoka, C. Kawachi, Dr. K. Hioki
Faculty of Pharmaceutical Sciences
Kobe Gakuin University
1-1-3 Minatojima Chuo-ku, Kobe 655-8586 (Japan)
[c] Prof. Dr. M. Kunishima, Dr. K. Hioki
Cooperative Research Center of Life Sciences
Kobe Gakuin University
1-1-3 Minatojima Chuo-ku, Kobe 655-8586 (Japan)
[d] Dr. M. Shiro
Rigaku Corporation
3-9-12 Matsubara, Akishima, Tokyo 196-8666 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202236.
Scheme 1. a) Dehydrocondensation reaction using DMT-MM to produce
amides or esters. b) Synthetic route to DMT-MM from cyanuric chloride.
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Chem. Eur. J. 2012, 18, 15856 – 15867

FULL PAPER
sugars,[8,9] polysaccharides,[10] polymers or hydrogels,[11] vari-
ous other materials,[12–14] and other common polar or less
polar amides,[15] and for analytical chemistry.[16] As a result,
the usefulness of this versatile reagent has now been well
demonstrated.
DMT-MM is synthesized from cyanuric chloride via 2-
chloro-4,6-dimethoxy-1,3,5-triazine (CDMT),[1,17] and as can
be readily seen from the synthetic process given in
ACHTUNGTRENNUNGScheme 1b, the compound has the remarkable advantage
that the methoxy and N-methylmorpholinio groups and the
counter anion (chloride ion) can be readily substituted with
other similar types of functional groups to form various de-
rivatives (Figure 1a). Substitution of the methoxy group
with other alkoxy groups seems to mainly affect the physical
properties, such as the solubility of the triazinyl com-
pounds.[18,19]
Figure 2. Dehydrocondensation reagents with a specific function based
on DMT-Am.
tivity of tert-amines toward CDMT has not yet been investi-
gated, which should be of great importance for developing
new reagents for dehydrocondensation. The enigmatic pro-
pensity of tert-amines to react with CDMT may prevent the
development of new dehydrocondensation reagents that are
superior to DMT-MM. Herein, we describe the results of a
systematic study focused on elucidating the reactivity of var-
ious nitrogen-containing compounds, particularly tert-
amines, toward CDMT for the preparation of the corre-
sponding DMT-Ams. The dehydrocondensation activity of
the resulting DMT-Am is also discussed.
Figure 1. Structure of triazine-based dehydrocondensation reagents.
a) General structure of triazine-based dehydrocondensation reagents.
b) Structure of DMTM. c) General structure of dimethoxytriazine-based
dehydrocondensation reagents [DMT-Am(X)].[21]
We have found that DMT-MM undergoes decomposition
with liberation of chloromethane leading to the formation
of DMTM (Figure 1b).[1,2,3a] This reaction occurs through
attack of the chloride ion on the N-methyl group and is par-
ticularly promoted in less polar solvents. To avoid this de-
composition, DMT-MM containing non-nucleophilic counter
À
À
anions such as TfOÀ, BF4 , and PF6 , instead of chloride,
Results and Discussion
have been prepared.[18c,20]
On the other hand, the ammonium moiety may relate di-
rectly to the dehydrocondensation activity of DMT-MM,
and thus seems to be more important. Recently, several de-
rivatives of 2-(4,6-dimethoxy-1,3,5-triazinyl)trialkylammoni-
Synthesis and condensation activity of DMT-Ams: The reac-
tion between CDMT and various tert-amines or related ni-
trogen-containing compounds was examined, and the results
are shown in Table 1, together with the results for the reac-
tion of N-methylmorpholine (NMM), for comparison, which
proceeds quantitatively within 30 min to yield DMT-
MM.[1,3a] When NMP was treated with CDMT in tetrahydro-
furan (THF) at room temperature, the reaction readily oc-
curred to give a precipitate that appeared to be DMT-MP,
but it was difficult to isolate in pure form, presumably be-
cause of partial demethylation.[2,25] To avoid the decomposi-
tion of DMT-MP caused by attack of the chloride ion on the
N-methyl group, the reaction was conducted in the presence
of lithium perchlorate (LiClO4) dissolved in THF and, as a
um salts (DMT-Am(s): Figure 1c)[21] that include tri
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
been prepared.[18c,20b,c,22] However, these compounds do not
seem, to the best of our knowledge, to be remarkably supe-
rior to DMT-MM with respect to their reactivity, stability,
and cost. We have achieved dehydrocondensations with a
specific function, such as molecular recognition, by using
N,N-dimethylglycine attached to a cyclodextrin, a crown
ether, hydrophobic alkyl chains, or a protein ligand, through
the ester group (Figure 2).[23] More recently, the asymmetric
activation of racemic amino acids in moderate-to-good se-
lectivity (20–90% ee) was reported by using DMT-Ams with
strychnine or brucine as the tertiary amine moiety.[24]
result, DMT-MPACTHNUTRGNEUNG(ClO4) was isolated as a precipitate in 96%
yield. In contrast to NMM, the reactivity of N-ethylmorpho-
line (NEM) toward CDMT was considerably lower; the re-
action resulted in production of DMT-EM in only 3% yield
after 1 h. Furthermore, after 24 h, the yield increased to
only 36%, and a complex mixture was formed; thus, a pro-
Although it is empirically known that tertiary amines
(tert-amine) do not all react equally with CDMT, the reac-
Chem. Eur. J. 2012, 18, 15856 – 15867
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15857

M. Kunishima et al.
Table 1. Preparation, stability, and condensation activity of DMT-Ams. A) Preparation of DMT-Am; B) Stability of DMT-Am in CH2Cl2; C) Dehydro-
condensation between 3-phenylpropionic acid 1 and phenethylamine 2 with DMT-Am.
Tertiary amines (pKa)[b]
Abbreviation
of DMT-Am
A: Preparation of DMT-Am
B: Stability of DMT-Am
RT, 3 h, in CH2Cl2
C: Condensation with
DMT-Am to form 3
[c]
XÀ
Conditions
RT, 30 min
Yield [%]
Conditions
Yield [%]
DMT-MM
DMT-MP
DMT-EM
ClÀ
100[a]
demethylation: 96%
recovery: 100%
nc[d]
RT, 4 h
84[a]
NMM (7.41)
NMP (10.08)
NEM (7.70)
À
ClO4
ClÀ
RT, 30 min
96
RT, 3 h
77
35
RT, 1 h
3
508C, 48 h
ClÀ
ClO4
RT, 24 h
RT, 25 h
36[e]
65
nc
À
À
recovery: 74%
DMT-EP
ClÀ
RT, 1 h
30
31
97
96
97
deethylation: 62%
RT, 3 h
RT, 3 h
RT, 3 h
58
90
91
NEP (10.40)
QD (11.3)
ClO4
ClÀ
RT, 1 h
DMT-QD
DMT-MPD
RT, 1 h
decomposition: 100%
nc
À
À
ClO4
ClO4
RT, 1 h
08C, 20 min
recovery: 97%
MPD (10.46)
Me3N (TMA) (9.76)
Me2NEt (EDMA) (9.99)
DMT-TMA
DMT-EDMA
ClÀ
ClÀ
RT, 45 min
RT, 30 min
85
86
demethylation: 100%
demethylation: 93%
deethylation: 7%
demethylation: 22%
deethylation: 62%
–
RT, 3 h
RT, 4 h
98
90
MeNEt2 (DEMA) (10.29)
Et3N (TEA) (10.65)
DMT-DEMA
ClÀ
RT, 1 h
80
RT, 6 h
86
A
ClÀ
ClÀ
RT, 24 h
RT, 1 h
0
0
–
–
–
–
A
–
DMAN (5.07)
PDN (5.23)
DMT-PDN
DMT-DMAP
DMT-MIm
ClÀ
RT, 1 h
32
recovery: 100%
nc
nc
–
0
0
À
ClO4
ClÀ
RT, 1 h
30[e]
RT, 30 min
87
recovery: 91%
RT, 30 h
RT, 3 h
À
À
DMAP (9.7)
MIm (6.95)
ClO4
ClÀ
RT, 1 h
RT, 24 h
RT, 1 h
96[e]
69
nc
recovery: 97%
ClO4
56[e]
nc
[a] The data was cited from literature (see ref. [1]). [b] The pKa values were cited from literature (see ref. [27]). [c] Estimated by 1H NMR analysis.
[d] nc=reaction was not conducted. [e] Prepared for elemental analysis. [f] DMT-Am in parentheses could not be prepared.
longed reaction time leads to decomposition of the DMT-
EM. The yield increased to 65% upon the addition of
LiClO4 to give DMT-EMACHTUNTGRENUNG(ClO4). N-Ethylpiperidine (NEP)
had a slightly higher reactivity than NEM, affording DMT-
EP in 30% yield after 1 h. QD and N-methylpyrrolidine
(MPD) reacted similarly to NMM, providing the corre-
sponding DMT-Ams in high yields (97% in both cases).
With regard to acyclic tert-amines, TMA was found to
react readily with CDMT to give DMT-TMA in 85% yield
within 45 min, whereas triethylamine (TEA) did not react at
all with CDMT, even after 24 h. Interestingly, the reactivity
of TEA was dramatically improved by the substitution of
only one ethyl group for a methyl group; N,N-diethyl-N-
methylamine (DEMA) readily reacted with CDMT to give
DMT-DEMA in 80% yield within 1 h. Thus, it seems that at
least one methyl group is essential for the formation of
DMT-Ams in acyclic tert-amines. However, in spite of pos-
sessing two methyl groups, N,N-dimethylaniline (DMAN),
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1,3,5-Triazine Chemistry
FULL PAPER
an aromatic tert-amine, did not react with CDMT. Nitrogen-
containing compounds with an sp2-hybridized lone pair of
electrons, such as pyridine (PDN), 4-(N,N-dimethylamino)-
pyridine (DMAP), and N-methylimidazole (MIm), which
are known to form active acylating reagents, react with
CDMT to form precipitates. In particular, the yield using
DMAP was good.
We examined the stability of DMT-Ams in CH2Cl2 at
room temperature for 3 h; the conditions under which
DMT-MM is decomposed through demethylation to give
DMTM in 96% yield (Table 1B).[1] When DMT-TMA pos-
sessing a chloride ion was suspended and stirred in CH2Cl2,
the solid disappeared within a few minutes and 4,6-di
oxy-2-dimethylamino-1,3,5-triazine was formed. Similarly,
DMT-Ams prepared from aliphatic tert-amines decomposed
rapidly, whereas DMT-Ams(ClO4) with the less nucleophilic
ACHTUNGTNERmNUNG eth-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
perchlorate ion was recovered in high yields. DMT-PDN,
-DMAP, and -MIm, possessing an sp2-hybridized nitrogen
moiety, were also found to be quite stable, even with chlo-
Figure 3. Conformational analyses of DMT-Ams with cyclic N-methyl-
G
1
amines by H and 13C NMR spectroscopic analysis.
ACHTUNGTRENNUNG
was examined by the reaction of 3-phenylpropionic acid (1)
and phenethylamine (2) in THF as a model system. The re-
sults are shown in Table 1C. The DMT-Ams that were ob-
tained in good yields exhibited good condensation activity;
the reactions occurred with the formation of amide 3 in high
yields. However, DMT-EM and DMT-EP, which were ob-
tained in low yields, exhibited poor activity; 3 was produced
in 35 and 58% yield, respectively. Interestingly, DMT-
DMAP and -MIm, containing an sp2-hybridized nitrogen,
did not form 3 at all.
shows a correlation of the N-CH3 (d=3.52 ppm) with the
axial H at the 3- and 5-positions (ca. d=1.95 ppm), indicat-
ing that the N-methyl group occupies an axial position in
this compound. In fact, the X-ray structure of DMT-MBP-
AHCTUNGRTEG(NUNN SbF6) unequivocally shows the expected structure, with the
triazinyl group in the equatorial position (Figure 4b). Thus,
the structure with the axial triazinyl group is not always
common in DMT-Ams composed of six-membered cyclic
tert-amines.
Conformational analyses for DMT-Ams: In the 13C NMR
spectrum of 4-tert-butyl-1,1-dimethylpiperidinium iodide, the
conformation of which should be fixed because of the steri-
cally large tert-butyl group, an approximately 9 ppm upfield
shift of the peak for the axial N-methyl group (d=
47.8 ppm) compared with the equatorial N-methyl group
(d=56.8 ppm) due to the g-gauche compression effect was
observed (Figure 3).[26] The chemical shift for the N-methyl
Because the conformation of the piperidine ring possess-
ing the 4-tert-butyl group in the equatorial position will be
maintained during the reaction with CDMT to give DMT-
MBP, the observed structure of DMT-MBP indicates that
CDMT approaches the lone pair of electrons of the nitrogen
exclusively from the equatorial side of N-methyl piperidine.
Thus, it is reasonable to conclude that DMT-MM and DMT-
MP were formed in a manner similar to DMT-MBP through
equatorial attack of CDMT on NMM and NMP, and that
the resulting DMT-Ams then underwent conformational in-
version to the more stable alternative chair conformations
with the flattened triazinyl group in the axial position
(Figure 5).
To clarify the reaction path of the N-ethyl derivatives, the
13C chemical shift for the methylene carbon of the N-ethyl
group of DMT-EBP, which was prepared by the reaction of
CDMT with N-ethyl-4-tert-butylpiperidine (EBP), was com-
pared with those of DMT-EP and DMT-EM. As shown in
Figure 6, the chemical shifts at approximately d=66 ppm for
the DMT-EP and DMT-EM indicate that the ethyl group
occupies the equatorial position, whereas the upfield shift of
12 ppm for DMT-EBP corresponds to an axial ethyl
group.[26] Thus, we conclude that the electrophilic reaction of
CDMT toward the nitrogen of NEM and NEP also occurred
from the equatorial side.
group of DMT-MPACHTUNGTRENNUNG
(ClO4) in the 13C NMR spectrum was ob-
served at d=55.5 ppm, and in the NOESY spectrum, no
cross peak was observed between the N-methyl and the
axial protons at the 3- and 5-positions. These results suggest
that the N-methyl group occupies an equatorial position and
that the triazinyl group occupies an axial position in the
stable conformation of DMT-MP. In fact, this structure was
confirmed by X-ray structural analysis, as shown in Fig-
ure 4a. This structural feature is similar to that of DMT-MM
shown in Figure 3, which was also reported previously.[20b]
On the other hand, a derivative of DMT-MP possessing a
tert-butyl group at the 4-position of the piperidine moiety
was prepared by reaction of CDMT and N-methyl-4-tert-bu-
tylpiperidine (MBP). Interestingly, the chemical shift of the
N-methyl group of the resulting DMT-MBPACTHNURGTNEUNG(ClO4) in the
13C NMR spectrum exhibits an upfield shift of 9 ppm in
comparison to DMT-MP. In addition, the NOESY spectrum
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M. Kunishima et al.
Mechanistic
considerations
for the synthesis of DMT-Ams:
The b-gauche effect: There
seems to be no correlation be-
tween the observed reactivity
of amines toward CDMT (i.e.,
chemical yield of DMT-Ams)
and the pKa of their conjugate
acids (see Table 1).[27] For ex-
ample, in spite of similar pKa
values near 7.5, NMM readily
reacts with CDMT to quantita-
tively give DMT-MM, whereas
NEM reacts giving a low yield.
The same tendency was ob-
served in NMP and NEP, each
having a pKa of approximately
10. Although the pKa values of
the acyclic tert-amines (TMA,
EDMA, DEMA, and TEA) fall
within a relatively narrow range
(9.7 to 10.7), only TEA does
not react with CDMT at all.
Thus, the type of substituent
(for example, methyl or ethyl)
on the nitrogen rather than the
basicity may be correlated with
the reactivity.
The N-methylation of 4-tert-
butyl-N-methylpiperidine
by
trideuteriomethyl iodide was
reported to proceed predomi-
nantly from the axial side in a
ratio of 78:22.[28] By contrast,
the above study indicates that
the reaction of CDMT occurs
exclusively from the equatorial
side of the morpholine or piper-
idine ring. Because the nucleo-
philic attack of tert-amines to
CDMT must occur in a direc-
tion perpendicular to the p-
plane of the triazine ring, the
Figure 4. X-ray structure of DMT-Ams. a) DMT-MPACHTUNTRGENNUG(ClO4) b) DMT-MBPACHUTNGTREN(NUGN SbF6).
approach of CDMT with a flat-
tened structure from the axial
side of six-membered tert-amines would be strongly hin-
dered by the 1,3-diaxial interaction (Figure 5). Based on the
free-energy difference between the two conformers (N-Me
axial and equatorial) of NMM and NMP,[29] the proportion
of the N-Me axial conformers that can undergo a reaction
with CDMT will be a few percent or less. However, the pro-
portion seems to be sufficiently large to enable a smooth re-
action according to the Curtin–Hammett principle.[30]
On the other hand, the observed substantial decrease in
the reaction rate of N-ethyl derivatives (NEM and NEP)
with CDMT is attributable to a steric effect of the N-ethyl
group, which is the only structural difference from NMM
Figure 5. Reaction path for the generation of DMT-Ams with cyclic N-
methylamines.
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1,3,5-Triazine Chemistry
FULL PAPER
A conformation of NEP. In addition, the fact that no reac-
tion occurs from the axial side of piperidines (and hence of
morpholines) can be explained by the 1,3-diaxial interaction,
À
which has a double gauche relationship with the C2 C3 and
À
C6 C5 bonds, which strongly sterically hinder the axial lone
pair.
To evaluate the effect of the gauche b-methyl group, we
examined the reaction of 1,2-dimethyl piperidine (DMP)
with CDMT (Figure 8). In the chair conformation with the
Figure 6. Conformational analyses of DMT-Ams with cyclic N-ethyla-
mines by 13C NMR spectroscopic analysis.
and NMP. Because CDMT reacts from the equatorial side of
NEM and NEP, the conformation of the axial N-ethyl group
À
based on the rotation about the N C bond should be a criti-
cal factor. To minimize the 1,3-diaxial repulsion, the methyl
group of the axial N-ethyl substituent should face outside
the ring. As a result, the b-methyl group is in a gauche rela-
tionship with the nitrogen lone pair orbital that undergoes
the reaction with CDMT (ax-G conformation) (Figure 7).[31]
Figure 8. Reaction of 1,2-dimethylpiperidine (DMP) for the evaluation of
the effect of the gauche b-methyl group. The 2-methyl group maintains a
gauche relationship with the lone pair irrespective of the axial or equato-
rial position.
axial N-methyl and the equatorial lone pair orbital, the
methyl group at the 2-position remains in a gauche relation-
ship with the lone pair, irrespective of its position (axial or
equatorial). Actually, the reaction of DMP is much slower
than that of NMP, and gives the corresponding DMT-DMP-
AHCTUNGTRENNUNG
(ClO4) in only 64% after 24 h. The 13C NMR chemical shift
for the N-methyl group of the resulting DMT-DMP is d=
39.8 ppm, and the NOESY spectrum shows a correlation be-
tween the vicinal methyl groups and between the N-methyl
and the 3- or 5-axial proton, indicating that the N-methyl
group and the 2-methyl group occupy axial and equatorial
positions, respectively. The upfield shifts of approximately
5 ppm for both the methyl groups can be attributed to a
steric compression of the g-gauche interaction between
them. Thus, the reaction can be considered to occur in the
1,2-cis structure [DMP-2-Me(eq)], as shown in Figure 8. Ac-
cordingly, we conclude that the introduction of one gauche
b-methyl group to the nitrogen lone pair of electrons in
NMP significantly retards the reaction with CDMT to give
DMT-Am.
Figure 7. Reaction path for generation of DMT-Ams with cyclic N-ethyla-
mines.
Such an inevitable gauche steric hindrance of a b-alkyl
group can be considered to significantly prevent the ap-
proach of CDMT to the nitrogen. Although the ax-A con-
formation, in which the b-methyl group is directed toward
the inside of the ring, is most suitable for the reaction, such
a conformation would be too unstable to exist. The good re-
activity of QD can be reasonably explained by its anti struc-
ture around the nitrogen lone pair, which is equal to the ax-
For acyclic tert-amines, the most suitable conformer of
TEA for the reaction with CDMT is AAA, which has all
methyl groups anti to the lone pair, as shown in Figure 9.
The relative conformational energy of the AAA conformer
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M. Kunishima et al.
completely repressed, by the addition of one gauche b-
methyl group. In the case of TEA, the least stable confor-
mation is AAA (7.36 kcalmolÀ1) followed by AAG (second
unstable conformer; 3.35 kcalmolÀ1). On the other hand,
other conformers (GAG and G’G’G’) are much more stable
(ca. 0 kcalmolÀ1). Thus, the concentration of the AAG con-
former should be very low.[32,34,35] As a result, because of the
synergistic effect of the low concentration of the AAG con-
former and the slow reaction via AAG involving the b-
gauche effect, no detectable amount of DMT-TEA was pro-
duced with TEA under ambient conditions.
In the case of DEMA, which reacted with CDMT giving
a good yield, it has been reported that the AG’ and AA con-
formers are approximately 0.47 and 3.82 kcalmolÀ1 higher in
energy, respectively, than the most stable GG’ conformer,
and that the AG’ conformers are present in concentrations
that are sufficiently high to be detected by NMR spectro-
scopic analysis (Figure 11).[32] However, based on the ob-
Figure 9. Conformational analysis of triethylamine (TEA) in the reaction
with CDMT.
is reported to be 7.36 kcalmolÀ1 higher than that of the most
stable G’G’G’ conformer, which has all b-methyl groups
gauche to the lone pair with C3 symmetry.[32] The fact that
the reaction did not occur at all according to the Curtin–
Hammett principle would indicate that TEA is virtually
non-existent in the very unstable AAA conformation. As
mentioned above, CDMT does not attack from the axial
side of NMP or NMM at all because of the 1,3-diaxial inter-
action corresponding to the double gauche effect; therefore,
we can exclude the reaction paths proceeding through the
GAG and G’G’G’ conformers of TEA, both of which have
two or three gauche b-methyl groups that will completely
block the approach of CDMT to the nitrogen lone pair.
Thus, to evaluate an alternative route to DMT-TEA via the
AAG conformer, which has only one b-methyl group gauche
to the lone pair, we examined the reaction of CDMT with
N-isopropyl-N,N-dimethylamine (IPDMA), the major con-
former of which (ca. 69% in proportion based on the free-
energy difference) has one isopropyl methyl group anti and
the other gauche to the lone pair and corresponds to the
AAG conformer of TEA (Figure 10).[33] The expected
DMT-IPDMA was obtained in only 48% yield after 1 h de-
spite the reaction proceeding via the major conformer, indi-
cating that the reaction is significantly retarded, but not
Figure 11. Conformational analysis of N,N-diethyl-N-methylamine
(DEMA) in the reaction with CDMT.
served slow reaction of CDMT with IPDMA, despite a high
proportion of the conformer (69%), the reaction proceeding
through the similarly hindered AG’ conformer of DEMA is
unlikely to explain the fact that 80% yield of DMT-DEMA
was obtained within 1 h. Thus, it is reasonable to conclude
that the reaction mainly proceeded via the AA conformer
following the Curtin–Hammett principle, rather than
through the AG’ conformer, indicating that the reaction rate
without b-gauche repulsion should be large.
Evidence for the reaction mechanism: In situ generation of
DMT-Am: The dehydrocondensation of carboxylic acids
and amines using CDMT in the presence of NMM had been
believed to proceed through the direct reaction between car-
boxylates and CDMT.[17b,36] However, in 2001, we showed
that the reaction using CDMT without NMM became much
slower, and only a trace amount of amide was produced, but
that the reaction was promoted by the addition of N,N-di-
methylglycine esters.[23a] This fact indicates that the forma-
tion of DMT-Ams from CDMT and tert-amines is essential
for dehydrocondensation. Because tert-amine is regenerated
in the reaction of DMT-Ams and carboxylates, it can act as
a catalyst. Thus, the combination of CDMT and a catalytic
amount of tert-amine constitutes a novel, aqueous, catalytic
amide-forming reaction. By introducing various functional
Figure 10. Reaction of N,N-dimethyl-N-isopropylamine (IPDMA) with
CDMT. The proportions of each conformer at 258C calculated based on
the DG values are given in parentheses.
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1,3,5-Triazine Chemistry
FULL PAPER
groups such as a cyclodextrin, a crown ether, hydrophobic
alkyl chains, and protein ligands, novel useful catalytic sys-
tems can be developed for dehydrocondensation
(Figure 2).[23] In this context, the dehydrocondensation activ-
ity of the tert-amines employed in the present study was in-
vestigated in the reaction of 1 and 2 in a CDMT/tert-amine
system, in which DMT-Ams would be formed in situ during
the reaction, and not isolated. A mixture of 1 and a stoichio-
metric amount of the tert-amine dissolved in CH2Cl2 was
treated with CDMT for 1 h, and then 2 was added; the re-
sults are shown in Table 2.[37] Using the tert-amines (NMM,
and NMM. The signal for butyryl chloride appeared after
15 min and increased with time. Because there are no nucle-
ophiles such as amines or alcohols present to produce
amides or esters, the chloride ion, which is the only nucleo-
phile generated from CDMT in the system, attacked the ac-
tivated triazinyl ester to form the acid chloride. On the
other hand, when the reaction was conducted in the pres-
ence of TEA instead of NMM, most of the reactants
(CDMT and the acid) remained unchanged, even after 1 h
(Figure 12b). At this time, small amounts of the activated
triazinyl butyrate and butyric anhydride were observed, sug-
gesting that the carboxylate anion can react directly
with CDMT at a very slow rate. In this case, be-
cause the chloride ion concentration is very low, the
activated ester undergoes reaction with the unreact-
ed starting acid to form the anhydride.
Table 2. Dehydrocondensation of 1 and 2 in the CDMT/tert-amine system.
Thus, as expected from our proposed reaction
mechanism for the CDMT/tert-amine system, a
Tertiary
amines
Yield of
3 [%]
Tertiary
amines
Yield [%][a]
clear relationship was observed between the reac-
tivity of tert-amines toward CDMT and their reac-
tion activity for the CDMT/tert-amine system.
Using the tert-amines that exhibit a good reactivity
toward CDMT, amides can be obtained in good
yields in the CDMT/tert-amine system. The advant-
age of the CDMT/tert-amine system is that, even if
reactions involve the generation of a DMT-Am
chloride that is difficult to isolate because of de-
3
4
96
97
71
86
0
82
24
0
55
75
34
8
ACHUTNGRENaNUG lkylACHTUNGTRENaNUNG tion, the amide can be obtained in a good
yield, as observed in the case of NMP in Table 2. In
contrast, when the reactivity of tert-amines toward
CDMT is low because of the gauche repulsion, an
alternative reaction of the primary amine 2 with
CDMT to produce 4 predominates. This side reac-
tion should be particularly critical in the CDMT/
Me2NEt
MeNEt2
96
84
0
0
72
90
Et3N
[a] CDMT-phenethylamine coupling product 4 was formed as a byproduct.
NMP) that readily undergo coupling with CDMT to form
DMT-Ams, we obtained amide 3 in good yields. In contrast,
when tert-amines NEM and TEA, which either reacted
slowly or not at all with CDMT, were used, amide 3 was not
obtained, and instead, compound 4, resulting from direct
coupling between CDMT and phenethylamine 2, was ob-
tained in significant yields.
tert-amine catalytic system, because a catalytic amount of
the tert-amine coexists with a stoichiometric amount of the
reactant primary or secondary amine in the same reaction
medium.[38] Thus, the CDMT/tert-amine system should be
useful for determining whether a tert-amine can readily gen-
erate the corresponding DMT-Am without isolating it.
Recently, Kaminski reported that quinine and quinidine
readily react with CDMT at 08C for 30 min; however, the
resulting DMT-Ams could be neither isolated nor identified
because of their instability.[24] If these results are confirmed,
they are the only counterexamples to our theory of the
gauche b-alkyl effect, because these amines have a branched
We monitored the reaction of CDMT and butyric acid in
1
the presence of either NMM or TEA by H NMR spectro-
scopic analysis. A solution of the acid and the tert-amine in
[D3]acetonitrile was mixed with CDMT under anhydrous
conditions, and the resulting solution was analyzed. As
shown in Figure 12a, in the presence of NMM, the inter-
mediate triazinyl butyrate was formed in a significant
amount after 5 min, and the yield of the ester was estimated
to be more than 50% based on a comparison of the
amounts of the product and the remaining starting acid,
which disappeared within 45 min. A small amount of DMT-
MM was detected after 5 min, and it did not increase signifi-
cantly until 1 h. In addition, no DMT-MM precipitate was
observed during the analysis, indicating that the rate of dis-
appearance of DMT-MM by attack of the butyrate is almost
same as or faster than that of its generation from CDMT
alkyl
group
[hydroxy-(6-methoxyquinolin-4-yl)methyl
group] at the a-position of the nitrogen of the QD moiety.
Thus, to evaluate whether the DMT-Am is quantitatively
generated, we attempted the condensation of 1 and 2 in the
CDMT/quinine system. As a result, amide 3 was produced
in only 22% yield along with 31% yield of 4. Because this
result is similar to that obtained for NEP, we can conclude
that quinine (and similarly quinidine) cannot quantitatively
react with CDMT within 30 min at 08C. For further confir-
mation, we attempted the preparation of the relevant DMT-
Am by reaction of quinine and CDMT in THF at 08C in the
Chem. Eur. J. 2012, 18, 15856 – 15867
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15863

M. Kunishima et al.
Figure 12. NMR spectroscopic analysis of a mixture of butyric acid and CDMT in the presence of a tert-amine. a) NMM b) TEA. Conditions: 0.1 mm of
each compound in [D3]acetonitrile.
presence or absence of LiClO4. No precipitate was observed
after 1 h, and both the starting compounds remained, as de-
termined by TLC analysis. Consequently, these amines are
not an exception to our postulate.
Am is susceptible to auto-decomposition through dealkyla-
tion by the chloride ion, the more stable perchlorate DMT-
AmACTHNUGTRNENG(U ClO4) can be obtained in high yields by simply conduct-
ing the reaction in the presence of LiClO4. A methyl or
larger substituent maintained in a gauche relationship with
the nitrogen lone pair sterically hinders the approach of
CDMT to the lone pair. In the case of tert-amines possessing
a single gauche b-alkyl group, such as the ax-G-conformers
of NEM and NEP, and a-branched amines such as DMP or
IPDMA, the reaction with CDMT proceeds considerably
more slowly, but can still occur. However, the resulting
DMT-Ams exhibited only moderate dehydrocondensation
activity. In the case of tert-amines possessing two gauche b-
alkyl groups, such as NMM, NMP, NEM, and NEP, having
an N-alkyl group in the equatorial position, and TEA, the
approach of CDMT to the lone pair is completely inhibited.
For the CDMT/tert-amine system involving the in situ for-
mation of DMT-Ams, tert-amines without gauche b-alkyl
groups need to be employed to prevent the formation of by-
products such as 4 that result from the direct reaction of a
primary or secondary amine reactant with CDMT. The pres-
Conclusion
We have shown that the direct reaction of CDMT with car-
boxylates is very slow, whereas DMT-Ams, represented by
DMT-MM, resulting from the substitution of the chloride of
CDMT with tert-amines, react rapidly with carboxylates to
give the activated triazinyl carboxylates, which undergo cou-
pling with amines or alcohols to give amides or esters. Nitro-
gen-containing compounds that successfully react with
CDMT to form DMT-Ams are limited to aliphatic tert-
amines, and aromatic N,N-dimethylaniline does not react
with CDMT. Although compounds containing an sp2-hybri-
dized nitrogen, such as pyridines and 1-methylimidazole,
were found to react with CDMT, the resulting DMT-Ams
did not exhibit dehydrocondensation activity. When DMT-
15864
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1,3,5-Triazine Chemistry
FULL PAPER
2H); elemental analysis calcd (%) for C12H21ClN4O6: C 40.86, H 6.00;
found: C 40.62, H 5.72.
ent study provides a foundation for developing a range of
triazine-based dehydrocondensation reagents with new func-
tionality that can be applied in various fields of chemistry.
1-(4,6-Dimethoxy-1,3,5-triazin-2-yl)quinuclidinium chloride (DMT-QD):
Yield: 97%; pale-yellow crystals; m.p. 97–998C; IR (KBr): n˜ =1606,
1
1548, 1475, 1363, 1110, 1008, 838, 815 cmÀ1; H NMR (CD3OD): d=2.13–
2.22 (m, 6H), 2.33 (sept, J=3.3 Hz, 1H), 4.00–4.08 (m, 6H), 4.16 ppm (s,
6H); 13C NMR (CD3OD): d=20.1 (CH), 23.5 (CH2), 56.0 (OCH3), 56.3
(N+CH2), 172.6 (NCN+), 173.6 ppm (COCH3); Because of the instability
of the chloride, elemental analysis was carried out with its perchlorate;
elemental analysis calcd (%) for C12H19ClN4O6·1/2H2O: C 40.06, H 5.60;
found: C 40.09, H 5.30.
Experimental Section
General methods: Anhydrous dichloromethane was prepared by distilla-
tion from CaH2 prior to use. N-Methyl and N-ethyl-4-tert-butylpiperidine
were prepared by methylation[39] or ethylation[40,41] of 4-tert-butylpiperi-
dine, prepared from 4-tert-butylpyridine according to the reported
method.[42] Other solvents and chemicals were obtained from commercial
sources and used as received unless otherwise noted. 1H and 13C NMR
spectra were recorded with a Bruker DPX 400 spectrometer. Chemical
shifts are reported as d values relative to tetramethylsilane as internal
standard. Infrared spectra were recorded with a Thermo Nicolet FTIR
AVATAR 360 spectrometer. ESI-MS and EI-MS spectra were recorded
with a Waters Micromass ZQ 2000 spectrometer and JEOL JMS-700
spectrometer, respectively. HRMS were measured with a Bruker Dalton-
ics micrOTOF-Q II spectrometer. Preparative thin-layer chromatography
(TLC) was performed with Merck precoated silica gel plates. Melting
points are uncorrected. Unless otherwise noted, the chloride salts of
DMT-Ams were synthesized from CDMT with the corresponding tertiary
amine according to the preparation of DMT-MM reported previously.[3a]
1-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-1-methylpyrrolidinium
[DMT-MPD(ClO4)]: Yield: 97%; colorless crystals; m.p. 122–1258C; IR
(KBr): n˜ =1618, 1477, 1373, 1328, 1251, 1083, 935, 823 cmÀ1 1H NMR
perchlorate
AHCTUNGTRENNUNG
;
(D2O): d=2.19–2.42 (m, 4H), 3.55 (s, 3H), 3.82–3.92 (m, 2H), 4.16 (s,
6H), 4.42–4.52 ppm (m, 2H); 13C NMR (D2O): d=22.0 (CH2), 51.6 (N+
CH3), 57.0 (OCH3), 65.8 (N+CH2), 170.1 (NCN+), 173.6 ppm (COCH3);
MS: m/z: 225 [MÀClO4]+; elemental analysis calcd (%) for
C10H17ClN4O6: C 36.99, H 5.28; found: C 37.07, H 5.24.
N-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-N,N,N-trimethylammonium chloride
(DMT-TMA): To
a solution of CDMT (1.0 g, 5.70 mmol) in THF
(20 mL) was bubbled excess trimethylamine gas, generated by neutraliza-
tion of its hydrochloride, through a drying tube filled with sodium hy-
droxide for 30 min. The resultant crystals were filtered and washed with
THF. Yield: 1.14 g (85%); colorless crystals; m.p. 96–1018C; IR (KBr):
n˜ =1604, 1523, 1481, 1376, 1054, 821 cmÀ1 1H NMR (CD3OD): d=3.60
;
(s, 9H), 4.17 ppm (s, 6H); 13C NMR (CD3OD): d=55.0 (N+CH3), 57.6
(OCH3), 174.0 (NCN+), 175.2 ppm (COCH3); MS: m/z: 199 [MÀCl]+.
Because of the hygroscopicity of the chloride, elemental analysis was car-
ried out after counteranion exchange to perchlorate; elemental analysis
calcd (%) for C8H15ClN4O6: C 32.17, H 5.06; found: C 32.21, H 4.99.
General procedure for the preparation of DMT-Am perchlorate—1-(4,6-
dimethoxy-1,3,5-triazin-2-yl)-1-methylpiperidinium perchlorate [DMT-
MPACHTUNGTRENNUNG(ClO4)]: 1-Methylpiperidine (621 mg, 6.27 mmol) was added to a solu-
tion of CDMT (1.0 g, 5.7 mmol) and lithium perchlorate (667 mg,
6.27 mmol) in THF (19 mL) at RT. After stirring for 30 min, the precipi-
tate was collected by suction, washed with THF, and dried under reduced
N-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-N-ethyl-N,N-dimethylammonium
chloride (DMT-EDMA): Yield: 86%; colorless crystals; m.p. 80–848C;
pressure to give DMT-MP
ACHTUNGTRENNUNG
(KBr): n˜ =1606, 1523, 1461, 1367, 1103, 1054, 956, 823 cmÀ1
;
1
IR (KBr): n˜ =1616, 1540, 1484, 1375, 1045, 821 cmÀ1; H NMR (CD3OD):
(CD3OD): d=1.59–2.00 (m, 6H), 3.42 (s, 3H), 3.61–3.70 (m, 2H), 4.01 (s,
6H), 4.46–4.55 ppm (m, 2H); 13C NMR (D2O): d=20.3 (CH2), 21.0
(CH2), 55.5 (N+CH3), 56.9 (OCH3), 62.0 (N+CH2), 170.8 (NCN+),
173.9 ppm (COCH3); MS: m/z: 239 [MÀClO4]+; elemental analysis calcd
(%) for C11H19ClN4O6: C 39.00, H 5.65, N 16.54; found: C 38.98, H 5.52,
N 16.34.
d=1.27 (t, J=7.2 Hz, 3H), 3.53 (s, 6H), 3.98 (q, J=7.2 Hz, 2H),
4.17 ppm (s, 6H); 13C NMR (D2O): d=8.3 (CH2CH3), 51.1 (N+CH3),
57.1 (OCH3), 63.7 (CH2CH3), 171.1 (NCN+), 173.6 ppm (COCH3); MS:
m/z: 213 [MÀCl]+. Elemental analysis was carried out with its perchlo-
rate; elemental analysis calcd (%) for C9H17ClN4O6: C 34.57, H 5.48;
found: C 34.51, H 5.36.
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-ethylmorpholinium
(DMT-EM): Yield: 36%; colorless crystals; m.p. 132–1358C; IR (KBr):
n˜ =1633, 1544, 1490, 1390, 1133, 950, 908, 815 cmÀ1 1H NMR (CD3OD):
chloride
N-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-N,N-diethyl-N-methylammonium
chloride (DMT-DEMA): Yield: 80%; colorless crystals; m.p. 90–928C;
;
1
IR (KBr): n˜ =1606, 1477, 1365, 1249, 1047, 815 cmÀ1; H NMR (CD3OD):
d=1.21 (t, J=7.3 Hz, 3H), 3.78–3.91 (m, 4H), 3.97 (q, J=7.3 Hz, 2H),
4.02–4.10 (m, 2H), 4.19 (s, 6H), 4.52–4.60 ppm (m, 2H); 13C NMR
(CD3OD): d=8.0 (CH2CH3), 57.6 (OCH3), 59.9 (CH2), 63.3 (CH2), 66.9
(CH2CH3), 170.1 (NCN+), 175.3 ppm (COCH3).
d=1.26 (t, J=7.2 Hz, 6H), 3.44 (s, 3H), 3.81–3.92 (m, 2H), 4.08 (q, J=
7.2 Hz, 1H), 4.11 (q, J=7.2 Hz, 1H), 4.17 ppm (s, 6H); 13C NMR (D2O):
d=8.0 (CH2CH3), 44.4 (N+CH3), 57.1 (OCH3), 62.4 (CH2CH3), 170.1
(NCN+), 173.6 ppm (COCH3); MS: m/z: 227 [MÀCl]+. Elemental analy-
sis was carried out with its perchlorate; elemental analysis calcd (%) for
C10H19ClN4O6: C 36.76, H 5.86; found: C 36.75, H 5.77.
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-ethylmorpholinium
[DMT-EM(ClO4)]: Yield: 65%; colorless crystals; m.p. 214–2168C; IR
(KBr): n˜ =1612, 1525, 1483, 1378, 1085, 1041, 910, 817 cmÀ1 1H NMR
perchlorate
ACHTUNGTRENNUNG
;
1-(4,6-Dimethoxy-1,3,5-triazin-2-yl)pyridinium chloride (DMT-PDN);
Yield: 32%; colorless crystals; m.p. 138–1428C; IR (KBr): n˜ =1621, 1560,
(CD3OD): d=1.22 (t, J=7.3 Hz, 3H), 3.78–3.89 (m, 4H), 3.95 (q, J=
7.3 Hz, 2H), 4.07–4.16 (m, 2H), 4.20 (s, 6H), 4.53–4.62 ppm (m, 2H); ele-
mental analysis calcd (%) for C11H19ClN4O7: C 37.24, H 5.40; found: C
36.99, H 5.31.
1467, 1363, 1145, 1097, 1027, 939, 798 cmÀ1 1H NMR (CD3OD): d=3.14
;
(s, 6H), 8.34–8.40 (m, 2H), 8.96–9.03 (m, 1H), 10.10–10.14 ppm (m, 2H);
13C NMR (CD3OD): d=57.7 (OCH3), 129.4 (m-pyr), 142.4 (o-pyr), 153.4
(p-pyr), 166.4 (NCN+), 175.2 ppm (COCH3); MS: m/z: 219 [MÀCl]+. El-
emental analysis was carried out with its perchlorate; elemental analysis
calcd (%) for C10H11ClN4O6: C 37.69, H 3.48; found: C 37.76, H 3.47.
1-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-1-ethylpiperidinium chloride (DMT-
EP). Yield: 30%; colorless crystals; m.p. 74–808C; IR (KBr): n˜ =1614,
1544, 1484, 1378, 1110, 1041, 900, 817 cmÀ1 1H NMR (CD3OD): d=1.18
;
(t, J=7.3 Hz, 3H), 1.59–1.88 (m, 4H), 1.88–1.98 (m, 2H), 3.55–3.65 (m,
2H), 3.83 (q, J=7.3 Hz, 2H), 4.17 (s, 6H), 4.46–4.55 ppm (m, 2H);
13C NMR (CD3OD): d=8.3 (CH2CH3), 22.3 (CH2), 22.4 (CH2), 57.5
(OCH3), 61.0 (N+CH2), 66.2 (N+CH2CH3), 170.7 (NCN+), 175.4 ppm
(COCH3); elemental analysis calcd (%) for C12H21ClN4O2·1/2H2O: C
39.84, H 6.13; found: C 39.63, H 5.82.
1-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-(dimethylamino)pyridinium chlor-
ide (DMT-DMAP): Yield: 87%; colorless crystals; m.p. 2908C (dec.); IR
(KBr): n˜ =1662, 1558, 1456, 1363, 1184, 1143, 1099, 1010, 931, 840, 813,
754 cmÀ1 1H NMR (D2O): d=3.39 (s, 6H), 4.10 (s, 6H), 7.06 (d, J=
;
7.9 Hz, 2H), 9.02 ppm (d, J=7.9 Hz, 2H); 13C NMR (CD3OD): d=40.7
[NACHTUNRTGNEUNG(CH3)2], 56.7 (OCH3), 107.8 (m-pyr), 136.0 (o-pyr), 158.6 (p-pyr), 163.9
1-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-1-ethylpiperidinium
perchlorate
(NCN+), 173.0 ppm (COCH3); MS: m/z: 262 [MÀCl]+. Elemental analy-
sis was carried out with its perchlorate. elemental analysis calcd (%) for
C12H16ClN5O6: C 39.84, H 4.46; found: C 39.78, H 4.44.
[DMT-EP
ACHTUNGTRENNUNG
d=1.18 (t, J=7.2 Hz, 3H), 1.59–1.88 (m, 4H), 1.88–1.98 (m, 2H), 3.55–
3.65 (m, 2H), 3.83 (q, J=7.2 Hz, 2H), 4.17 (s, 6H), 4.46–4.55 ppm (m,
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15865

M. Kunishima et al.
1-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-3-methyl-1H-imidazolium
chloride
(Ph), 139.2 (Ph), 168.5 (2-triazine), 172.4 (COCH3), 173.0 ppm (COCH3);
HRMS: m/z calcd for C13H17N4O2: 261.1346 [M+H]+; found: 261.1346.
(DMT-MIm): Yield: 69%; colorless crystals; m.p. 166–1708C; IR (KBr):
n˜ =1614, 1554, 1515, 1483, 1367, 1259, 1187, 1143, 1103, 1083, 981, 923,
817, 781 cmÀ1 1H NMR (CD3OD): d=4.08 (s, 3H), 4.17 (s, 6H), 7.80 (d,
;
J=2.2 Hz, 1H), 8.41 (d, J=2.2 Hz, 1H), 10.04 ppm (s, 1H); 13C NMR
(CD3OD): d=37.6 (N+CH3), 57.2 (OCH3), 120.4 (5-imid.), 126.4 (4-
imid.), 138.5 (2-imid.), 163.2 (NCN+), 175.0 ppm (COCH3); MS: m/z:
222 [MÀCl]+. Elemental analysis was carried out with its perchlorate; el-
emental analysis calcd (%) for C9H12ClN5O6·1/2H2O: C 32.69, H 3.96;
found: C 32.72, H 3.62.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research (No.
20390007) from the Japan Society for the Promotion of Science (JSPS).
4-tert-Butyl-1-(4,6-dimethoxy-1,3,5-triazin-2-yl)-1-methylpiperidinium
perchlorate [DMT-MBPACHTUNGTRENNUNG(ClO4)]: Yield: 95%; colorless crystals; m.p. 98–
[1] M. Kunishima, C. Kawachi, F. Iwasaki, K. Terao, S. Tani, Tetrahe-
dron Lett. 1999, 40, 5327–5330.
1048C; IR (KBr): n˜ =1618, 1546, 1479, 1378, 1101, 933, 815 cmÀ1
;
1H NMR (CD3OD): d=0.99 (s, 9H), 1.50–1.61 (m, 1H), 1.90–2.12 (m,
[2] Although preparation and reactions of DMT-MM was also reported
from another group (ref. [4]), the spectral data of the compound
identified by them agree with those of 4-(4,6-dimethoxy-1,3,5-tria-
zin-2-yl)morpholine (DMTM), which resulted from decomposition
of DMT-MM. See, ref [1] and [3a]. The structure of DMTM is
shown in Figure 1b.
4H), 3.52 (s, 3H), 3.93–4.08 (m, 4H), 4.16 ppm (s, 6H); 13C NMR
(CD3OD): d=22.7 (CH2), 27.4 (CACHTNUTRGENNUG(CH3)3), 32.9 (CAHCUTNGTREN(NUGN CH3)3), 44.7 (CH-
tBu), 46.6 (N+CH3), 57.4 (OCH3), 63.2 (N+CH2), 175.0 (NCN+),
175.2 ppm (COCH3). Structural details were determined by X-ray crystal-
lographic analysis.
4-tert-Butyl-1-(4,6-dimethoxy-1,3,5-triazin-2-yl)-1-ethylpiperidinium per-
[3] a) M. Kunishima, C. Kawachi, J. Morita, K. Terao, F. Iwasaki, S.
Tani, Tetrahedron 1999, 55, 13159–13170; b) M. Kunishima, J.
Morita, C. Kawachi, F. Iwasaki, K. Terao, S. Tani, Synlett 1999,
1255–1256.
chlorate [DMT-EBP
142.58C; IR (KBr): n˜ =1608, 1567, 1519, 1471, 1376, 1103, 1070,
815 cmÀ1 1H NMR (CD3OD): d=0.98 (s, 9H), 1.14 (t, J=7.2 Hz, 3H),
ACHTUNGTRENNUNG(ClO4)]: Yield: 89%; colorless crystals; m.p. 141.5–
;
1.45–1.56 (m, 1H), 1.84–1.98 (m, 2H), 2.00–2.10 (m, 2H), 3.78 (dt, J=
3.3, 13.3 Hz, 2H), 4.02 (q, J=7.2 Hz, 2H), 4.13–4.20 ppm (m, 8H);
[4] Z. J. Kaminski, P. Paneth, J. Rudzinski, J. Org. Chem. 1998, 63,
4248–4255.
[5] M. Kunishima, C. Kawachi, K. Hioki, K. Terao, S. Tani, Tetrahedron
2001, 57, 1551–1558.
13C NMR (CD3OD): d=8.3 (CH2CH3), 22.7 (CH2), 27.5 (C
ACTHNUGTRNEUGN(CH3)3), 33.0
(CACHTUNGTRENNUNG
(CH3)3), 44.8 (CH-tBu), 54.4 (CH2CH3), 57.5 (OCH3), 60.6 (N+CH2),
173.8 (NCN+), 175.2 ppm (COCH3); MS: m/z: 309 [MÀClO4]+; elemen-
tal analysis calcd (%) for C16H29ClN4O6: C 47.00, H 7.15; found: C 47.04,
H 6.89.
[6] a) F. Augꢁ, W. Hornebeck, M. Decarmeb, J.-Y. Laronze, Bioorg.
Med. Chem. Lett. 2003, 13, 1783–1786; b) S. Higashibayashi, M.
Kohno, T. Goto, K. Suzuki, T. Mori, K. Hashimoto, M. Nakata, Tet-
rahedron Lett. 2004, 45, 3707–3712; c) K. Hojo, M. Maeda, N. Tana-
kamaru, K. Mochida, K. Kawasaki, Protein Pept. Lett. 2006, 13,
189–192; d) Y. Tachibana, K. Monde, S.-I. Nishimura, Macromole-
cules 2004, 37, 6771–6779.
[7] a) R. Chhabra, J. Sharma, Y. Liu, H. Yan, Nano Lett. 2006, 6, 978–
983; b) Z. J. Gꢂrtner, M. W. Kanan, D. R. Liu, Angew. Chem. Int.
Ed. 2001, 40, 1796–1800; c) X. Li, Z. J. Gartner, B. N. Tse, D. R.
Liu, J. Am. Chem. Soc. 2004, 126, 5090–5092; d) Y. Liu, R. Sha, R.
Wang, L. Ding, J. W. Canary, N. C. Seeman, Tetrahedron 2008, 64,
8417–8422.
1-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-1,2-dimethylpiperidinium perchlorate
[DMT-DMP
ACHTUNGTRENNUNG
(KBr): n˜ =1611, 1558, 1524, 1470, 1369, 1096, 1051, 822 cmÀ1
;
(CD3OD): d=1.19 (d, J=6.6 Hz, 3H), 1.70–1.84 (m, 1H), 1.90–2.18 (m,
5H), 3.40 (s, 3H), 3.63–3.71 (m, 1H), 4.01–4.11 (m, 1H), 4.17 (s, 6H),
4.58–4.68 ppm (m, 1H); 13C NMR (CD3OD): d=16.2 (CHCH3), 21.1 (5-
piper.), 22.3 (4-piper.), 28.6 (3-piper.), 39.8 (N+CH3), 57.5 (OCH3), 67.0
(6-piper.), 69.4 (2-piper.), 174.2 (NCN+), 175.3 ppm (COCH3); MS: m/z:
253 [MÀClO4]+; elemental analysis calcd (%) for C12H21ClN4O6: C 40.86,
H 6.00; found: C 40.74, H 5.84.
[8] a) E. Gemma, A. N. Hulme, A. Jahnke, L. Jin, M. Lyon, R. M. Mu-
eller, D. Uhrin, Chem. Commun. 2007, 2686–2688; b) E. Gemma,
O. Meyer, D. Uhrin, A. N. Hulme, Mol. BioSyst. 2008, 4, 481–495;
c) B. D. Maxwell, J. C. Bronstein, J. Labelled Compd. Radiopharm.
2005, 48, 1049–1054; d) A. Miyazaki, I. Matsuo, S. Hagihara, A. Ka-
kegawa, T. Suzuki, Y. Ito, Glycoconjugate J. 2009, 26, 133–140;
e) K. Totani, Y. Ihara, I. Matsuo, H. Koshino, Y. Ito, Angew. Chem.
2005, 117, 8164–8168; Angew. Chem. Int. Ed. 2005, 44, 7950–7954.
[9] For glycosylation using DMT-MM, see: a) A. Kobayashi, T. Tanaka,
K. Watanabe, M. Ishihara, M. Noguchi, H. Okada, Y. Morikawa, S.-
i. Shoda, Bioorg. Med. Chem. Lett. 2010, 20, 3588–3591; b) T.
Tanaka, M. Noguchi, A. Kobayashi, S.-i. Shoda, Chem. Commun.
2008, 2016–2018.
[10] a) N. Aoki, R. Arai, K. Hattori, J. Inclusion Phenom. Macrocyclic
Chem. 2004, 50, 115–120; b) N. Aoki, K. Kinoshita, K. Mikuni, K.
Nakanishi, K. Hattori, J. Inclusion Phenom. Macrocyclic Chem.
2007, 57, 237–241; c) P. Farkas, S. Bystricky, Carbohydr. Polym.
2007, 68, 187–190; d) A. J. Worthen, Y. Lapitsky, Colloid Polym.
Sci. 2011, 289, 1589–1596.
[11] a) M. Breunig, U. Lungwitz, R. Liebl, A. Goepferich, Proc. Natl.
Acad. Sci. USA 2007, 104, 14454–14459; b) J. Hao, Z. Li, H. Cheng,
C. Wu, C. C. Han, Macromolecules 2010, 43, 9534–9540; c) M. Ishi-
kawa, D. Taura, K. Maeda, E. Yashima, Chem. Lett. 2004, 33, 550–
551; d) S. Murakami, N. Aoki, S. Matsumura, Polym. J. 2011, 43,
414–420; e) J. M. Pelet, D. Putnam, Bioconjugate Chem. 2011, 22,
329–337; f) K. Thompson, S. Michielsen, J. Polym. Sci. Part A 2006,
44, 126–136.
N-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-N-isopropyl-N,N-dimethylammoni-
um chloride (DMT-IPDMA): Yield: 58%; colorless crystals; m.p. 110–
1118C; IR (ATR): n˜ =1613, 1544, 1488, 1380, 1337, 1105, 1034, 821 cmÀ1
;
1H NMR (D2O): d=1.37 (d, J=6.6 Hz, 6H), 3.43 (s, 6H), 4.15 (s, 6H),
4.54 ppm (sept, J=6.6 Hz, 1H); 13C NMR (CD3OD): d=15.9 (CHCH3),
47.2 (N+CH3), 56.5 (OCH3), 70.9 (CH3CHCH3), 172.6 (NCN+),
174.0 ppm (COCH3); elemental analysis calcd (%) for C10H19ClN4O2: C
45.71, H 7.29; found: C 45.44, H 7.24.
Demethylation of DMT-Ams: A suspension of DMT-Am (0.22 mmol) in
CH2Cl2 (2 mL) was stirred for 3 h at RT. The reaction mixture was fil-
tered and the filtrate was concentrated to give a residue that was ana-
lyzed by NMR spectroscopy.
General procedure for the dehydrocondensation with CDMT/tert-amine
system: CDMT (35.1 mg, 0.20 mmol) was added to a solution of phenyl-
propionic acid (30.0 mg, 0.20 mmol) and N-methylmorpholine (18.4 mg,
0.18 mmol) in anhydrous dichloromethane (3 mL) at RT. After stirring
for 1 h at RT, phenethylamine (22.0 mg, 0.18 mmol) was added at RT.
The mixture was stirred for 3 h and extracted with ether. The organic
phase was washed successively with water, sat. Na2CO3, 5% HCl, and
brine, dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by preparative TLC (AcOEt) to give N-phenethyl-3-
phenylpropanamide.[3a]
N-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-N-phenethylamine (4): Colorless
crystals; m.p. 113.5–1148C; IR (ATR): n˜ =1621, 1581, 1476, 1461, 1363,
1106, 815 cmÀ1 1H NMR (CD3OD): d=2.90 (t, J=7.0 Hz, 2H), 3.71 (td,
;
J=7.0, 6.2 Hz, 2H), 3.91 (s, 3H), 3.98 (s 3H), 5.54–5.63 (m, 1H), 7.19–
7.34 ppm (m, 5H); 13C NMR (CD3OD): d=36.1 (CH2CH2Ph), 42.6
(CH2CH2Ph), 54.9 (OCH3), 55.0 (OCH3), 126.9 (Ph), 129.0 (Ph), 129.2
[12] a) R. Breslow, S. Wei, C. Kenesky, Tetrahedron 2007, 63, 6317–6321;
b) B. S. Creaven, T. L. Gernon, J. McGinley, A.-M. Moore, H. Toft-
15866
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 15856 – 15867

1,3,5-Triazine Chemistry
FULL PAPER
lund, Tetrahedron 2006, 62, 9066–9071; c) H. Hyun, N. Yui, Macro-
mol. Rapid Commun. 2011, 32, 326–331; d) Y. Liu, A. Kuzuya, R.
Sha, J. Guillaume, R. Wang, J. W. Canary, N. C. Seeman, J. Am.
Chem. Soc. 2008, 130, 10882–10883; e) S. Maniam, M. M. Cieslinski,
S. F. Lincoln, H. Onagi, P. J. Steel, A. C. Willis, C. J. Easton, Org.
Lett. 2008, 10, 1885–1888.
nishima, S. Nakanishi, J. Nishida, H. Tanaka, D. Morisaki, K. Hioki,
H. Nomoto, Chem. Commun. 2009, 5597–5599; c) M. Kunishima, K.
Hioki, T. Moriya, J. Morita, T. Ikuta, S. Tani, Angew. Chem. 2006,
118, 1274–1277; Angew. Chem. Int. Ed. 2006, 45, 1252–1255; d) M.
Kunishima, M. Tokaji, K. Matsuoka, J. Nishida, M. Kanamori, K.
Hioki, S. Tani, J. Am. Chem. Soc. 2006, 128, 14452–14453; e) M. Ku-
nishima, H. Imada, K. Kikuchi, K. Hioki, J. Nishida, S. Tani, Angew.
Chem. 2005, 117, 7420–7423; Angew. Chem. Int. Ed. 2005, 44, 7254–
7257; f) M. Kunishima, K. Kikuchi, Y. Kawai, K. Hioki, Angew.
Chem. Int. Ed. 2012, 51, 2080–2083.
[13] a) J. Jang, S. Ko, Y. Kim, Adv. Funct. Mater. 2006, 16, 754–759; b) S.
Ko, J. Jang, Biomacromolecules 2007, 8, 182–187; c) H. J. Lee, S.
Michielsen, J. Polym. Sci. Part B 2007, 45, 253–261; d) K. Tanaka,
K. Inafuku, Y. Chujo, Bioorg. Med. Chem. 2008, 16, 10029–10033;
e) J. Wrzesien, D. Graham, Tetrahedron 2012, 68, 1230–1240; f) X.
Zhang, S. Mohandessi, L. W. Miller, P. T. Snee, Chem. Commun.
2011, 47, 3532–3534.
[14] a) F. E. Alemdaroglu, N. C. Alemdaroglu, P. Langguth, A. Herr-
mann, Adv. Mater. 2008, 20, 899–902; b) M. Ito, F. Nakamura, A.
Baba, K. Tamada, H. Ushijima, K. H. A. Lau, A. Manna, W. Knoll,
J. Phys. Chem. C 2007, 111, 11653–11662; c) T. Suehiro, C. Kojima,
S. Tsumura, A. Harada, K. Kono, Biopolymers 2010, 93, 640–648;
d) K. Totani, I. Matsuo, Y. Ihara, Y. Ito, Bioorg. Med. Chem. 2006,
14, 5220–5229; e) M. Zhang, S. Xu, S. D. Minteer, D. A. Baum, J.
Am. Chem. Soc. 2011, 133, 15890–15893.
[15] a) A. Friggeri, C. van der Pol, K. J. C. van Bommel, A. Heeres,
M. C. A. Stuart, B. L. Feringa, J. van Esch, Chem. Eur. J. 2005, 11,
5353–5361; b) H. Kameya, H. Nakamura, M. Ukai, Y. Shimoyama,
Spectrochim. Acta Part A 2008, 69, 1367–1371; c) L. O. Kononov,
A. V. Orlova, A. I. Zinin, B. G. Kimel, I. B. Sivaev, V. I. Bregadze, J.
Organomet. Chem. 2005, 690, 2769–2774; d) T. Moriguchi, M.
Hosaka, A. Yoshinari, A. Ozaki, T. Takeuchi, K. Shinozuka, Chem.
Lett. 2009, 38, 966–967; e) T. Saitoh, M. Takeiri, Y. Gotoh, Y.-I. Ishi-
kawa, K. Umezawa, S. Nishiyama, Bioorg. Med. Chem. Lett. 2011,
21, 6293–6296; f) K. Tanaka, T. Hiratsuka, Z. Urbanczyk-Lipkow-
ska, Eur. J. Org. Chem. 2003, 3043–3046; g) M. Kunishima, Y. Wata-
nabe, K. Terao, S. Tani, Eur. J. Org. Chem. 2004, 4535–4540.
[16] a) S.-i. Endo, M. Morita, M. Ueno, T. Maeda, T. Terabayashi, Bio-
chem. Biophys. Res. Commun. 2009, 378, 890–894; b) D. J. Harvey,
L. Royle, C. M. Radcliffe, P. M. Rudd, R. A. Dwek, Anal. Biochem.
2008, 376, 44–60; c) Y. Sakaguchi, H. Yoshida, K. Todoroki, H.
Nohta, M. Yamaguchi, Anal. Chem. 2009, 81, 5039–5045; d) S.
Sekiya, Y. Wada, K. Tanaka, Anal. Chem. 2005, 77, 4962–4968.
[17] a) J. S. Cronin, F. O. Ginah, A. R. Murray, J. D. Copp, Synth.
Commun. 1996, 26, 3491–3494; b) Z. J. Kaminski, Tetrahedron Lett.
1985, 26, 2901–2904.
[24] B. Kolesinska, K. Kasperowicz, M. Sochacki, A. Mazur, S. Jankow-
ski, Z. J. Kaminski, Tetrahedron Lett. 2010, 51, 20–22.
[25] DMT-MP was found to be sometimes difficult to isolate in pure
form because it is susceptible to decomposition by demethylation.
[26] M. Sugiura, N. Takao, Org. Magn. Reson. 1982, 20, 37–39.
[27] a) H. K. Hall Jr., J. Am. Chem. Soc. 1957, 79, 5441–5444; b) V. K.
Aggarwal, I. Emme, S. Y. Fulford, J. Org. Chem. 2003, 68, 692–700;
c) M. M. Fickling, A. Fischer, B. R. Mann, J. Packer, J. Vaughan, J.
Am. Chem. Soc. 1959, 81, 4226–4230; d) B. G. Tehan, E. J. Lloyd,
M. G. Wong, W. R. Pitt, E. Gancia, D. T. Manallack, Quant. Struct.-
Act. Relat. 2002, 21, 473–485; e) P. Forsythe, R. Frampton, C. D.
Johnson, A. R. Katritzky, J. Chem. Soc. Perkin Trans. 2 1972, 671–
673.
[28] A. J. Jones, C. P. Beeman, M. U. Hasan, A. F. Casy, M. M. A.
Hassan, Can. J. Chem. 1976, 54, 126–135.
[29] Relative energies for the N-Me axial conformer to the stable N-Me
equatorial one based on 13C NMR spectroscopic study were calculat-
ed to be 1.6–2.5 kcalmolÀ1 for NMP, and 1.6 kcalmolÀ1 for NMM,
respectively, see: a) E. L. Eliel, F. W. Vierhapper, J. Am. Chem. Soc.
1975, 97, 2424–2430; b) A. Kolocouris, J. G. Outeirino, J. E. Ander-
son, G. Fytas, G. B. Foscolos, N. Kolocouris, J. Org. Chem. 2001, 66,
4989–4997; c) V. J. Baker, I. J. Ferguson, A. R. Katritzky, R. Patel,
Tetrahedron Lett. 1976, 17, 4735–4736.
[30] D. Y. Curtin, Rec. Chem. Prog. 1954, 15, 111–128.
[31] For conformational study of NEP, see: J. E. Anderson, A. I. Ijeh, C.
Storch, D. Casarini, L. Lunazzi, J. Org. Chem. 1998, 63, 3310–3317.
[32] C. H. Bushweller, S. H. Fleischman, G. L. Grady, P. McGoff, C. D.
Rithner, M. R. Whalon, J. G. Brennan, R. P. Marcantonio, R. P.
Dominigue, J. Am. Chem. Soc. 1982, 104, 6224–6236.
[33] J. H. Brown, C. H. Bushweller, J. Am. Chem. Soc. 1992, 114, 8153–
8158.
[34] It has been reported that neither the AAA nor AAG conformers
are present at concentrations sufficiently high to be detected by
NMR spectroscopic analysis (ref. [32]) or by gas electron diffraction
study (ref. [35]).
[35] H. Takeuchi, T. Kojima, T. Egawa, S. Konaka, J. Phys. Chem. 1992,
96, 4389–4396.
[36] a) J. E. Kaminska, Z. J. Kaminski, J. Gora, Synthesis 1999, 593–596;
b) Z. J. Kaminski, Synthesis 1987, 917–920.
[37] Although the reaction can proceed with a catalytic amount of tert-
amines as described in the literature (ref. [23]), we employed the
conditions of pretreatment (for 1 h) of CDMT with a stoichiometric
amount of tert-amines for the evaluation of the maximum condensa-
tion activity of the CDMT/tert-amine system. If the reaction does
not occur even under the employed conditions, the tert-amines un-
doubtedly cannot act as a catalyst.
[18] a) S. Masala, M. Taddei, Org. Lett. 1999, 1, 1355–1357; b) M. W.
Markowicz, R. Dembinski, Synthesis 2004, 80–86; c) K. Jastrzabek,
B. Kolesinska, G. Sabatino, F. Rizzolo, A. M. Papini, Z. J. Kaminski,
Int. J. Pept. Res. Ther. 2007, 13, 229–236.
[19] a) M. Kunishima, K. Yamamoto, Y. Watanabe, K. Hioki, S. Tani,
Chem. Commun. 2005, 2698–2700; b) M. Kunishima, K. Yamamoto,
K. Hioki, T. Kondo, M. Hasegawa, S. Tani, Tetrahedron 2007, 63,
2604–2612; c) K. Hioki, S. Kameyama, S. Tani, M. Kunishima,
Chem. Pharm. Bull. 2007, 55, 825–828.
[20] a) M. Kunishima, K. Hioki, A. Wada, H. Kobayashi, S. Tani, Tetra-
hedron Lett. 2002, 43, 3323–3326; b) Z. J. Kaminski, B. Kolesinska,
J. Kolesinska, G. Sabatino, M. Chelli, P. Rovero, M. Blaszczyk, M. L.
Glowka, A. M. Papini, J. Am. Chem. Soc. 2005, 127, 16912–16920;
c) S. A. Raw, Tetrahedron Lett. 2009, 50, 946–948.
[21] The abbreviation DMT-Am is used throughout the text. DMT and
Am represent the 4,6-dimethoxy-1,3,5-triazine moiety and tert-
amines or related nitrogen-containing moieties, respectively. Am is
replaced with other letter codes for individual nitrogen-containing
compounds. This systematic name for dehydrocondensation reagents
based on 4,6-dimethoxy-1,3,5-triazine has already been utilized for
DMT-MM (ref. [5]). When DMT-Ams possess a counter anion XÀ
other than chloride, the counter anion is indicated in parentheses:
DMT-Am(X).
[38] It is not clear why tert-amines without the gauche b-alkyl group
react with CDMT in preference to primary amines. This is an impor-
tant issue that has yet to be resolved.
[39] R. N. Icke, B. B. Wisegarver, G. A. Alles, Org. Synth., Coll. Vol. III
1955, 723–725.
[40] After acetylation of 4-tert-butylpiperidine with AcONa and DMT-
MM, the product was reduced with lithium alminum hydride to give
N-ethyl-4-tert-butylpiperidine, see: Refs. [5] and [41].
[41] A. C. Cope, E. Ciganek, Org. Synth. Coll. Vol. IV 1963, 339–342.
[42] A. I. Meyers, T. T. Shawe, L. Gottlieb, Tetrahedron Lett. 1992, 33,
867–870.
[22] A. A. Chesniuk, S. N. Mikhailichenko, V. S. Zavodnov, V. N. Zaplish-
ny, Chem. Heterocycl. Compd. 2002, 38, 177–182.
[23] a) M. Kunishima, K. Yoshimura, H. Morigaki, R. Kawamata, K.
Terao, S. Tani, J. Am. Chem. Soc. 2001, 123, 10760–10761; b) M. Ku-
Received: June 24, 2012
Published online: October 11, 2012
Chem. Eur. J. 2012, 18, 15856 – 15867
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
15867