2-Amino-1,3,5-triazine chemistry: hydrogen-bond networks, Takemoto thiourea catalyst analogs, and olfactory mapping of a sweet-smelling triazine

Article abstract of DOI:10.1007/s00706-015-1515-7

Abstract The chemistry of 4,6-dialkyl-2-amino-1,3,5-triazines with bulky alkyl substituents was investigated and their use as building blocks for preparing chiral thiourea organocatalysts explored. Reaction of ammonia with 4,6-di-tert-butyl-2-chloro-1,3,5-triazine gave 4,6-di-tert-butyl-1,3,5-triazin-2-amine which formed extended hydrogen-bond networks in the solid state according to X-ray crystallography. Selected heterocyclic amines were converted to isothiocyanates, and the latter reacted with (S,S)-2-(dimethylamino)cyclohexylamine to give enantiopure 1-hetaryl-3-[2-(dimethylamino)cyclohexyl]thioureas, with hetaryl representing either 4,6-dimethyl-1,3-diazin-2-yl, 4,6-diisopropyl-1,3,5-triazin-2-yl, or 4,6-di-tert-butyl-1,3,5-triazin-2-yl groups. These compounds are structural analogs of Takemotos's chiral thiourea organocatalysts (1-[3,5-bis(trifluoromethyl)phenyl]-3-[(1S,2S)-2-(dimethylamino)cyclohexyl]thiourea) with an aza-aryl instead of the 3,5-bis(trifluoromethyl)phenyl group. They feature a strong intramolecular N-H to N-1 hydrogen bond, as shown by X-ray crystallography of 1-(4,6-di-tert-butyl-1,3,5-triazin-2-yl)-3-[2-(dimethylamino)cyclohexyl]thiourea in the solid state and by ¹H NMR spectroscopy of all derivatives in CDCl₃ solution, which prevents them from acting as bifunctional organocatalyst. In the reaction of 4,6-di-tert-butyl-2-chloro-1,3,5-triazine with ammonia, 4,6-di-tert-butyl-2-ethoxy-1,3,5-triazine was identified as side-product displaying a mildly sweet, floral odor that is unusual for a 1,3,5-triazine. Analogs (>35) of 4,6-di-tert-butyl-2-ethoxy-1,3,5-triazine were prepared to define the important structural factors of the olfactophore.

Full text of DOI:10.1007/s00706-015-1515-7

Monatsh Chem (2015) 146:1529–1539
DOI 10.1007/s00706-015-1515-7
ORIGINAL PAPER
2-Amino-1,3,5-triazine chemistry: hydrogen-bond networks,
Takemoto thiourea catalyst analogs, and olfactory mapping
of a sweet-smelling triazine
1
Li Xiao1 Alexander Pothig Lukas Hintermann1
•
•
¨
Received: 29 March 2015 / Accepted: 12 June 2015 / Published online: 1 July 2015
Ó Springer-Verlag Wien 2015
Abstract The chemistry of 4,6-dialkyl-2-amino-1,3,5-
triazines with bulky alkyl substituents was investigated and
their use as building blocks for preparing chiral thiourea
organocatalysts explored. Reaction of ammonia with 4,6-
di-tert-butyl-2-chloro-1,3,5-triazine gave 4,6-di-tert-butyl-
1,3,5-triazin-2-amine which formed extended hydrogen-
bond networks in the solid state according to X-ray crys-
tallography. Selected heterocyclic amines were converted
to isothiocyanates, and the latter reacted with (S,S)-2-
(dimethylamino)cyclohexylamine to give enantiopure
1-hetaryl-3-[2-(dimethylamino)cyclohexyl]thioureas, with
hetaryl representing either 4,6-dimethyl-1,3-diazin-2-yl,
4,6-diisopropyl-1,3,5-triazin-2-yl, or 4,6-di-tert-butyl-1,3,
5-triazin-2-yl groups. These compounds are structural
analogs of Takemotos’s chiral thiourea organocatalysts
(1-[3,5-bis(trifluoromethyl)phenyl]-3-[(1S,2S)-2-(dimethyl-
amino)cyclohexyl]thiourea) with an aza-aryl instead of the
3,5-bis(trifluoromethyl)phenyl group. They feature a strong
intramolecular N–H to N-1 hydrogen bond, as shown by
X-ray crystallography of 1-(4,6-di-tert-butyl-1,3,5-triazin-
2-yl)-3-[2-(dimethylamino)cyclohexyl]thiourea in the solid
butyl-2-chloro-1,3,5-triazine with ammonia, 4,6-di-tert-
butyl-2-ethoxy-1,3,5-triazine was identified as side-product
displaying a mildly sweet, floral odor that is unusual for a
1,3,5-triazine. Analogs ([35) of 4,6-di-tert-butyl-2-ethoxy-
1,3,5-triazine were prepared to define the important struc-
tural factors of the olfactophore.
Graphical abstract
H
NH2
N
tBu
N
N
S
N
N
N
N
H
tBu
N
tBu
tBu
Me2N
Keywords Amines Á Heterocycles Á Hydrogen bonds Á
Odoriferous substances Á Triazines
Introduction
1
state and by H NMR spectroscopy of all derivatives in
Symmetric 1,3,5-triazines have been used as architectural
elements in the building of designed target structures in
coordination chemistry and crystal engineering [1–3], for
UV-filters [4–7], molecular opto-electronics [8–10],
extended organic solids [11, 12], or symmetric molecules
in general [13]. The bulk availability of cyanuric chloride
by trimerization of cyanogen chloride [14] and the possi-
bility of performing gradual SNAr substitutions of chloride
at the triazine core provide synthetic opportunities [15]
which facilitate the finding and structural optimization of
lead structures, as exemplified in the search for triazine-
based herbicides [16]. The high reactivity of halotriazines,
which is nevertheless readily controlled by adapting reac-
tion conditions, has enabled their use as carboxylic acid
CDCl3 solution, which prevents them from acting as
bifunctional organocatalyst. In the reaction of 4,6-di-tert-
Dedicated to Prof. Dr. Walter Weissensteiner on the occasion of his
retirement.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1515-7) contains supplementary
material, which is available to authorized users.
& Lukas Hintermann
lukas.hintermann@tum.de
1
¨
Department Chemie, Technische Universitat Munchen,
Lichtenbergstr. 4, 85748 Garching bei Mu¨nchen, Germany
¨
123

1530
L. Xiao et al.
activating reagents [14, 17–22] or reactive linker units for
reactive anchor-dyes in textile dyeing [23, 24].
has an acidifying function upon the thiourea unit and
cannot be easily replaced by other substituents. We hoped
that introduction of heterocyclic aza-aryl groups would
produce analogs of 3 for asymmetric organocatalysis with
more strongly acidic thiourea NH-bonds, while allowing
for additional structural variety in the heterocyclic unit.
This line of thinking came from a comparison of pKa
values of trifluoromethyl substituted anilines [40, 41]
including 4 with those of several amino-azaarenes (Fig. 1)
[13].
We have recently introduced a copper-catalyzed cross-
coupling of doubly or triply halogenated azacycles with
tertiary alkyl Grignard reagents that gave direct access,
among a variety of products, to 2-alkylated 4,6-dichloro-
1,3,5-triazines and 2,4-dialkylated 6-chloro-1,3,5-triazines,
and thus to bulky azacyclic building blocks with elec-
trophilic sites for further synthetic manipulation [25]. The
building blocks obtained using that methodology have led,
inter alia, to new syntheses of geometrically restrained
selenacalix [3] triazines [26], bulky ligands for studying
organometallic coordination chemistry [27, 28], metal
complexes for dye-sensitized solar cells [29–31], ligands
for transition metal catalysis [32], or building blocks for
medicinal chemistry [33, 34]. Compound 2,4-di-tert-butyl-
6-chloro-1,3,5-triazine (1) in particular lends itself for
introducing the bulky, symmetric, and electron-withdraw-
ing 4,6-di-tert-butyl-2-triazinyl group, which we hoped
might act as steric and electronic analog (isostere) of the
3,5-bis(trifluoromethyl)phenyl group (Scheme 1).
The estimated N–H acidity of 4 in aqueous solution is
comparable to that of 2-aminopyridine,1 whereas
2-aminopyrimidine and 2-amino-1,3,5-triazine with their
additional ring-nitrogen are considerably more acidic. On
the other hand, aza-arylamines are stronger bases than 4,
with ring nitrogen acting as site of protonation [42]. Still,
the basicity is not marked, and we assumed that the pres-
ence of bulky groups in positions 4/6 would prevent the
endocyclic nitrogen from acting as Brønsted base.
To synthesize the target thioureas 5, we opted for a
disconnection to the known (1S,2S)-2-(dimethylamino)-1-
aminocyclohexane (6) [43] and the heterocyclic isothio-
cyanates 7, which should be accessible from the
heterocyclic amines 8 (Scheme 2).
The latter is a structural element of hydrogen-bond donor
catalysts of the Schreiner (2) [35] and Takemoto (3) [36–39]
type (Scheme 1). An immediate aim of the project was to
develop syntheses of analogs of Takemoto’s catalyst 3
bearing heteroaryl groups like 1,3,5-triazin-2-yl or related
1,3-pyrimidin-2-yl. In the course of those studies, an addi-
Triazinylamines 8 and pyrimidylamines 9 were obtained
by several methods: first, reaction of chlorotriazine 1 [25]
with aqueous ammonia in ethanol gave 2-aminotriazine 8a,
accompanied by a trace of ethoxy derivative 10a (Sche-
me 3a). This side-product will be commented upon in
detail later. The bulky triazinylamines 8b/c and 2-pyrim-
idylamine 9a emerged from similar SNAr reactions of
chlorinated precursors [25] and the respective amines.
Pyrimidylamine 9b was prepared by condensation of the b-
diketone with guanidine [44], while 2-aminotriazines 8d–
8g with less bulky substituents R were synthesized from
nitriles (RCN) and guanidine according to Kabbe et al.
(Scheme 3b) [45].
tional aspect transpired—literally—when
a
triazine
derivative displayed a faintly sweet, floral odor. We then
perform a qualitative structure–activity profiling, i.e.,
‘‘mapping’’ of its olfactophore.
Results and discussion
The family of bifunctional Takemoto catalysts 3 combines
a basic tertiary amine with an N-arylthiourea unit. The
privileged 3,5-bis(trifluoromethyl)phenyl aryl substituent
Aminotriazine 8a formed large, transparent, colorless
crystal blocks by slow evaporation of a solution in hexane.
The X-ray crystal structure shows the importance of
hydrogen-bonding patterns. Each NH2 group acts as two-
fold H-bond donor to N-5 in one, and to N-1 in another
adjacent molecule (Fig. 2).
Scheme 1
Cl
X
X
isostere
N
N
N
N
F
F
F
F
N
N
F
F
The structure can be interpreted as consisting of
hydrogen-bonded dimers involving two symmetrically
independent molecules A and B which are joined via two
NH to N-1 hydrogen bonds [N…N0 = 305.5(2)/307.4(2)
pm for A/B] in an 8-membered ring, with the planes of the
aza-arene rings being tilted toward one another by 68°
1
CF3
CF3
CF3
S
S
F3C
N
H
N
H
F3C
N
H
N
H
CF3
NMe2
1
2
3
The pKa value for NH2-ionization of 4 was derived from that of
aniline by taking into account incremental substitution effects of the
CF3-group [40], or by applying a relationship given in Ref. [41].
123

2-Amino-1,3,5-triazine chemistry: Hydrogen-bond networks, Takemoto thiourea catalyst analogs,…
Fig. 1 N–H acidity of some
1531
NH2
NH2
NH2
NH2
N
NH2
N
NH2
arylamines in neutral and
protonated form, compared to
that of aza-arylamines
N
N
N
F3C
F3C
CF3
N
4
pKa (RNH2) [NH3 (l)]
pKa (RNH2) [H2O]
pKa (RNH3+) [H2O]
21.2
18.7
15.6
27.3
4.9
25.4
3.5
(22-23)
1.15
23.5
6.7
20.5
3.5
14.9
2.9
(Fig. 3). The A–B dimers are further stacked [A…A0/
B…B0 stacking distance 474 pm] and connected by two
weaker N-5 to H–N hydrogen bonds [325.4(2)/330.1(2) pm
for A/B]—which are severely out of linearity compared to
the aromatic heterocyclic core—along the c-axis, forming
an infinite channel structure with a hydrophilic interior and
a hydrophobic outside.
Scheme 2
NMe2
S
Ar
+
Ar N C S
N
H
N
H
NH2
7
NMe2
5
6
Ar NH2
Heterocyclic amines including aminopyridines or
aminopyrimidines have been converted to isothiocyanates
8
Scheme 3
(a)
Cl
NH2
N
OEt
NH3 (aq)
N
N
N
N
N
+
EtOH
45 °C,
10 h
tBu
N
tBu
tBu
N
tBu tBu
N
tBu
1
8a (99%)
10a (trace)
related products:
NHMe
NH2
NH2
N
N
N
N
N
N
R
tBu
N
tBu
N
R
8b (92%)
8c (>99%)
9a (R = tBu; 57%)
9b (R = Me)
(b)
NH2
NH·HCl
NH2
NaOEt
RCN +
N
N
H2N
EtOH
85 °C,
30 min
R
N
R
8d (R = Me) 8f (R = nPr)
8e (R = Et) 8g (R = iPr)
123

1532
L. Xiao et al.
[46] by reaction with thiophosgene and base [47, 48].
Reaction of 9b with thiophosgene and sodium bicarbonate
gave the known isothiocyanate 11 (Scheme 4a) [47], but
the same reaction conditions failed with triazinylamines 8a
or 8g, presumably due to the low nucleophilicity of their
amino group.
immediately gave isothiocyanates 7a/g in fair yields
(Scheme 4b). Dolman has reported a related approach to
convert amines to isothiocyanates for amines that fail to
give dithiocarbamates with NEt3 and CS2, but using tosyl
chloride as activator [53]. The heterocyclic isothiocyanates
11 and 7a/g are stable to aqueous workup, but decompose
when washed with ammonium chloride solution. Purifica-
tion by quick chromatography over methanol-deactivated
silica gel was possible, albeit with some losses, to give the
products in moderate, unoptimized yields. Their reactivity
toward amines was explored in a test reaction of 7a with
aniline to give thiourea 12 (Scheme 5a). Takemoto catalyst
analogs 5 were then prepared by stirring chiral amine 6
[43] with each of 11 and 7a/g in toluene solution
(Scheme 5b).
Other approaches for converting amines to isothio-
cyanates [46], including reactions with CS2 and DCC [49],
or with thiophosgene and strong base in one pot showed
little success; at least, minor amounts of product (from 8g)
were observed by GC–MS analysis in the latter case.
Eventually, we developed a two-step procedure based on
the Andreasch–Kaluza isothiocyanate synthesis [50–52] by
stirring 8a/g overnight with NaH and CS2 in THF to gen-
erate a presumed dithiocarbamate, followed by addition of
ethyl chloroformate and triethylamine [52], which
1
The H NMR spectra of both 5 and 12 displayed char-
acteristic signals for NH groups, with each one signal at
high and one at low frequency [12, 13.02 and 8.59 ppm;
5–1, 11.48 (d, J = 5.7) and 8.37 ppm; 5–2, 11.11 (d,
J = 6.3) and 8.38 ppm; 5–3, 11.07 (d, J = 6.1) and
8.37 ppm]. The presence of a vicinal coupling for the
higher frequency NH signals in 5 places them at a cyclo-
hexyl position. Given their considerable high field shift,
they must be involved in a hydrogen bond, but not to the
dimethylamino nitrogen, since this would be sterically
challenging in trans-diaminocyclohexane derivatives. The
hydrogen bond must be connected to a N-1/3 ring-nitrogen
of the triazine or pyrimidine unit. The finding of an anal-
ogous hydrogen bond in 12, where a basic amino group is
not available, corroborates this. In 12, the hydrogen bond is
R
N
N
H
H
R
5 N
R
5'N
N
N3
N1
H
H
1N
A'
R
N
R
B
N
N
N
H
H
R
N
R
R
R
N
H
H
N
N
N
H
5
R
A
N
N
R
H
H
N
N
H
3 N
B'
N
N
R
Fig. 2 Sketch of sheet-forming hydrogen-bonding patterns in the
crystal structure of 8a
Fig. 3 X-ray molecular
structure of 8a. Characteristic
hydrogen-bonded dimer formed
by parallel amino-NH to
azacyclic N-1/3 hydrogen
bonding between two
independent molecules (A/B) in
the asymmetric unit
123

2-Amino-1,3,5-triazine chemistry: Hydrogen-bond networks, Takemoto thiourea catalyst analogs,…
1533
Scheme 4
(a)
NCS
N
NH2
N
CSCl2
NaHCO3
N
N
CH2Cl2
40 °C, 6 h, 72%
Me
Me
Me
Me
9b
11
Ref. [42]
(b)
1. NaH, CS2
THF, r.t., 16 h
NH2
N
NCS
N
N
N
2. ClCO2Et, NEt3
r.t., 30 min
R
N
R
R
N
R
8a (R = tBu)
8g (R = iPr)
7a (R = tBu; 58%)
7g (R = iPr; 45%)
Scheme 5
(a)
H
N
tBu
N
S
neat
N
N
N
PhNH2 + 7a
r.t., 5 min
H
tBu
12 (74%)
(b)
H
N
R
N
R
S
NCS
N
NMe2
PhMe
r.t., 1−16 h
Z
N
N
+
N
H
NH2
R
Z
R
Me2N
11 (R = Me, Z = CH)
7g (R = iPr, Z = N)
7a (R = tBu, Z = N)
6
5-1 (R = Me, Z = CH; 99%)
5-2 (R = iPr, Z = N; quant.)
5-3 (R = tBu, Z = N; 75%)
sufficiently strong to block rotation of the heterocyclic
fragment around the C-2–NH axis, leading to separate
signals for the tert-butyl groups and ring carbons in 1H and
13C NMR spectroscopy. In 5, that rotation is faster, and the
heteroaromatic groups show twofold local symmetry on the
NMR timescale. The 13C NMR spectra of 5 and 12 display
a signal for the thiourea carbon (177.8–178.4 ppm). An
X-ray structure determination for 5–3 supports the NMR
assignments by showing the presence of a six-membered
ring set up by an intramolecular hydrogen bond from one
thiourea NH to triazine N-1/3 (Fig. 4).
The HNCS-units of two symmetrically independent
molecules form antiparallel, double C=S…H–N-hydrogen
bonds [S…N0 = 341.1(2)/341.4(2) pm for A/B], thereby
123

1534
L. Xiao et al.
Fig. 4 X-ray molecular
structure of 5–3. A dimeric unit
of two independent molecules in
the asymmetric unit created by
antiparallel hydrogen bonding
along C=S…H–N is shown.
Disordered tert-butyl
substituents are omitted for
clarity
forming hydrogen-bonded dimers. Surprisingly, the lone-
pair of the basic dimethylamino unit is not involved in any
hydrogen-bonding interaction or close contact. The tert-
butyl groups are disordered. Similar intramolecular hydro-
gen bonds have already been found in 2-pyridylthioureas,
triazinylureas, and -thioureas by either 1H NMR spec-
troscopy or X-ray crystallography [54–57]. The spectral
properties of azacyclic thioureas 5 in CDCl3 differ from
those of Takemoto’s catalyst 3, NH signals of which are not
visible at ambient temperature in the same solvent due to
chemical exchange, but can be resolved at low temperature,
where the presence of two monomeric conformers and two
dimeric associates is revealed [58]. Compounds 5 show a
preference for the same intramolecular hydrogen-bonded
structure in solution and the solid state.
Scheme 6
catalyst (10 mol%)
Ph
Et2N
R
Ph
Et2N
Ph
P
P
MeCN
20 h, 50 °C
O
O
13
14
catalyst, and that neither the lowered basicity of triazines
nor the steric shielding present in 5–3 due to the tert-butyl
groups is sufficient to preclude this interaction. The ques-
tion of whether 4,6-di-tert-butyl-2-triazinyl can replace the
3,5-bis(trifluoromethyl)phenyl substituent in thiourea-type
hydrogen-bonding catalysts therefore found a clear-cut
answer that was negative.
We have tested the aza-aryl analogs 5 of Takemoto’s
catalyst (3) as bifunctional organocatalysts in an
organocatalytic, asymmetric isomerization of meso-trans-
trans-2,5-diphenyl-1-(diethylamino)-2,5-dihydrophosphole
oxide (13) to the corresponding 2-phospholene oxide 14
[59] (Scheme 6).
However, as often in experimental research, we made an
unrelated and surprising observation in the course of the
above studies: while working up the reaction mixture of
2,4-di-tert-butyl-6-chloro-1,3,5-triazine (1) with ammonia
in ethanol (Scheme 3a), a sweet smell was noted, and the
crude crystalline heterocyclic amine 8a obtained emitted a
sweet, floral odor. This was rather surprising, since neither
triazines in general, nor any heterocyclic amine derivatives
in particular would appear to be suitable candidates for
sweet-smelling compounds. Yet, it turned out that purified
Takemoto’s catalyst 3 had induced an ee of 88 % at
quantitative conversion in this reaction [60]. Unfortunately,
neither 5–1 nor 5–3 display catalytic activity in this reac-
tion under the above or similar conditions. Consequently, it
appears that the intramolecular hydrogen bond offsets the
bifunctional properties of aza-aryl analogs of Takemoto’s
123

2-Amino-1,3,5-triazine chemistry: Hydrogen-bond networks, Takemoto thiourea catalyst analogs,…
1535
samples of 8a are odorless. Inspection of the GC/MS-trace
1
and the H NMR data of crude 8a indicated that ethoxy-
Scheme 7
OR
SEt
triazine 10a was present as impurity to the extent of
1.5 mol% in the crude product. Compound 10a was inde-
pendently synthesized from 1 and sodium ethoxide (vide
infra), and indeed had olfactory properties similar to those
of crude amine 8a with the 10a impurity. Numerous aro-
matic nitrogen heterocycles are known to the perfumer, but
are described as having burnt, meaty (acetylpyrimidine),
burnt, earthy, nutty, roasted (pyrazines), popcorn (acet-
ylpyridine), nutty, green, fatty, vegetable or tobacco
(alkylpyridines), sweaty (picoline), floral (terpenyl-substi-
tuted pyridines) or marine (4-alkadienylpyridines), roasted
(pyrazoles), animalic (alkylquinolines) or leather, green
woody, moss, earthy (sec-alkyl quinolines) notes [61, 62].
The presence of a sweet, floral odor note in a triazine
motivated us to perform structure/odor relationship studies
to analyze the olfactophore in 10a, and possibly vary the
olfactory profile. Structural variations included exchange
or removal of ring-substituents, or the replacement of ring-
nitrogen by methine (CH) units. Over 35 derivatives, 28 of
them new compounds, were prepared, using various com-
binations of established methodology. The outlines of the
syntheses will be indicated briefly, but details can be found
in the supporting information. Olfactory properties of the
compounds have been evaluated, though not by profes-
sionals, and are given in general terms, without claim for
particular accuracy.
N
N
N
N
tBu
N
tBu
tBu
N
tBu
10a (R = Et)
10b (R = Me)
10c (R = nPr)
10d (R = nBu)
10e (R = nAm)
15
10f (R = iPr)
10g (R = iBu)
10h (R = iAm)
10i (R = sec-Bu)
10j (R = tBu)
OEt
OR'
N
N
N
N
R
N
R'
R
R
16a (R, R' = tAm)
16b (R, R' = tBu, tAm)
16c (R, R' = CEt3)
16d (R, R' = iPr)
16e (R, R' = Et)
17-1a (R, R' = tBu, Et)
17-2a (R, R' = iPr, Et)
17-3a (R, R' = Me, Et)
17-3b (R, R' = Me, Me)
17-3c (R, R' = Me, iPr)
17-3d (R, R' = Me, nAm)
of the chloro-precursors with sodium alkoxides. Analog
17–1a has a similar, but slightly weaker odor compared to
10a. Ethoxydiisopropylpyrimidine 17–2a has a weak odor
with fennel and clover aspects. The low melting solid
17–3b had a rather intense, aggressive, ammoniacal, and
camphoresque odor with sweet fennel undertones. Ethyl
ether 17–3a and isopropyl ether 17–3c have similar, but
overall milder odor properties like 17–3b, but n-amyl ether
17–3d displays only weak odor. Removal of nitrogen from
10a to give 17–1a retains the odor characteristics, at lower
intensity. Further replacements of nitrogen with methine
(CH) and de-alkylations were studied systematically; the
required compounds (Scheme 8) were obtained by a
combination of known methods, as detailed in the sup-
porting information.
Since the sweet smell had initially been detected in an
amino-triazine sample, a range of amino-azacycles (al-
ready shown Scheme 3) was obtained, but had either no
discernible, or only a faint, uncharacteristic smell. A series
of alkoxy-triazines were then synthesized by SNAr reaction
of 1 with sodium alkoxide to give alkoxytriazines 10a–10j,
or with NaSEt as nucleophile to give thioether 15
(Scheme 7).
The olfactory properties of 10a and 10b were similar in
quality, and of moderate intensity for both. The odor of
isopropoxy-analog 10f was reminiscent of 10a, but weaker,
whereas other alkoxy analogs had either faint, unspecific
odors, or none at all. Purified thioether 15 had a faint smell
reminiscent of 10a, but assumed a hydrocarbon, gas-like
odor on standing, presumably due to degradation to sulfur-
containing compounds. The change of tert-butyl to larger
tert-amyl (16a) or 3-ethylpentyl (16c) groups gave faintly
smelling or odorless compounds; only the mixed tert-butyl-
tert-amyl compound 16b had an odor reminiscent of 10a,
but with lower intensity. Isopropyl analog 16d had a
weaker, sweetish smell, with an aspect of clover (eugenol-
like). Diethyl triazine 16e had a sweetish, green, fennel-
type odor with aggressive ammoniacal overtones. A similar
dependency of odor properties on structure was seen with
pyrimidines 17, which were prepared by SNAr substitution
The regioisomeric de-aza analog 18 had only a faint
smell with hydrocarbon aspect. Di-de-aza analog 20 was
almost odorless, while 21 had a very faint, sweet smell with
hydrocarbon tones, while arene 26 displayed a faint,
sweetish smell of different character and lower intensity
than 10a. De-alkylation generally increased odor intensity
relative to fully alkylated reference compounds: 19 had a
mild, sweet and carrot, clover (eugenol-like)-type odor; 22
had a medium intensity, green, carrot-like odor, 23 a very
weak sweetish fennel odor, 24 a medium intensity, pyr-
idine-like, sweaty odor that was neither sweet nor
agreeable. Finally, 4-ethoxypyridine had a moderate
123

1536
L. Xiao et al.
for generating that odor were explored by structure-varia-
tion studies.
Scheme 8
OEt
OEt
OEt
N
N
N
N
N
Experimental
tBu
tBu
tBu
tBu
tBu
N
tBu
tBu
tBu
Reagents and solvents were obtained from commercial
suppliers and used without further purification. Solvents
were dried by passing through a column of Al2O3 and then
17-1a
18
19
OEt
OEt
˚
kept over 3 A molecular sieves under an argon atmosphere.
OEt
Column chromatography (CC) was performed on silica gel
60 (35–70 lm particle size) as flash chromatography with
0.2 bar positive air pressure. Thin layer chromatography
was performed on glass plates coated with silica gel 60 F254
and visualized with UV light (254 nm). NMR spectra were
recorded at the indicated frequencies at ambient tempera-
ture (19–25 °C) and referenced to tetramethyl-silane
[TMS, d (1H) = 0.00 ppm] or residual solvent peaks [in
N
N
N
tBu
tBu
20
21
22
OEt
OEt
OEt
OEt
N
CDCl3:
d
(1H) = 7.26 ppm; in DMSO-d6:
d
tBu
N
tBu
N
tBu
tBu
(1H) = 2.50 ppm]. 13C NMR spectra were referenced to
solvent peaks (CDCl3, d = 77.16 ppm; DMSO-d6,
d = 39.52 ppm). All new compounds gave corresponding
elemental analyses (C, H, N, typically 0.3 %). The
experimental section gives selected experimental data for
the most important compounds. Additional data including
experimental details and copies of 1H and 13C NMR
spectra for all compounds prepared are provided as sup-
porting information.
23
24
25
26
pyridine-like, ammoniacal odor. In conclusion, the olfac-
tory ‘‘mapping’’ of 10a shows that the presence of N-1 and
N-3 together with a small alkoxy group (OMe, OEt) at C-2
are key elements of the olfactophore. Steric shielding of
ring nitrogens by bulky groups at C-4/6 appears to reduce
aggressive pyridine- and ammoniacal-type odors.
4,6-Di-tert-butyl-1,3,5-triazin-2-amine (8a, C11H20N4)
To a solution of 8.66 g 2-chloro-4,6-di-tert-butyl-1,3,5-
triazine (1 [25]; 38.0 mmol) in 70 cm3 EtOH, 50 cm3
aqueous 25 % NH3 was added and the mixture stirred at
45 °C for 7.5 h. After cooling, the volume was reduced to
ca. 50 cm3 in vacuum, and the resulting crystals were
filtered off (fraction 1, 6.16 g). The filtrate was extracted
with CH2Cl2, the extract dried over MgSO4, filtered, and
evaporated to dryness (fraction 2, 1.68 g). Total yield was
7.84 g (99 %). X-ray quality crystals were obtained by
slow evaporation from a CH2Cl2/hexanes solution in an
open flask. Larger crystals were washed with hexanes,
crushed into smaller parts, and dried in air. M.p.:
Conclusions
In this work, we have explored the use of 2-amino-1,3,5-
triazines as readily available building blocks for preparing
new types of chiral organocatalysts of the Takemoto type.
Triazineamines were successfully converted to isothio-
cyanates, and the latter were found to react with amines to
form the desired thiourea derivatives. However, the struc-
ture of those compounds is characterized by the presence of
a strong intramolecular hydrogen bond from thiourea NH
to aza-aryl N-1/3, which cancels any hydrogen-bond donor
characteristics required for bifunctional organocatalysis,
and therefore 4,6-di-tert-butyl-1,3,5-triazine-2-yl is not a
suitable isosteric replacement for 3,5-bis(trifluoromethyl)-
phenyl. Nevertheless, the 2-amino-1,3,5-triazine unit is a
reliable hydrogen-bond donor and acceptor unit for crystal
engineering, and bulky 2,6-dialkyl-1,3,5-triazine-2-amines
are useful materials for such purposes. In the course of the
synthesis of triazin-2-yl-amines, an alkoxy triazine with
sweet odor characteristics was found, and the requirements
1
117–119 °C; H NMR (400 MHz, CDCl3): d = 1.29 (s,
18H, CH3), 5.37 (br s, 2H, NH2) ppm; 13C NMR
(100 MHz, CDCl3): d = 29.01 (CH3), 39.17 (C), 167.05
(C), 185.15 (C) ppm; IR (KBr): vꢀ = 3435, 3309, 3202,
2967, 1632, 1535, 1232, 1186, 1001, 846 cm-1; GC–MS
(EI?): m/z = 208 (M?), 193.
2,4-Di-tert-butyl-6-ethoxy-1,3,5-triazine
(10a, C13H23N3O)
2-Chloro-4,6-di-tert-butyl-1,3,5-triazine (1 [25]; 5.00 g,
22.0 mmol) was added to a solution of 1.01 g sodium
123

2-Amino-1,3,5-triazine chemistry: Hydrogen-bond networks, Takemoto thiourea catalyst analogs,…
1537
metal (44.0 mmol) in 30 cm3 EtOH at r.t. After stirring for
1 h, most of the EtOH was removed in vacuum, 10 cm3
water was added, and the mixture extracted with tBuOMe
(3 9 50 cm3) to give a crude product (5.279 g). Purifica-
tion by CC (tBuOMe/hexanes 1:50) gave 5.198 g (99.6 %)
of slightly yellow oil, which was further purified by
Kugelrohr distillation (130 °C, ca. 10 mbar) to give a
d = 21.10 (CH3), 37.41 (CH), 147.58 (C), 186.24 (C) ppm,
one (C) not detected; IR (capillary): vꢀ = 2972, 2932, 2875,
1983 (br 1900–2100), 1542, 1516, 1378 cm-1; GC–MS
(EI?): m/z = 222 (M?), 207, 194, 111, 85, 70.
1-[(1S,2S)-2-(Dimethylamino)cyclohexyl]-3-(4,6-
dimethylpyrimidin-2-yl)-thiourea (5–1, C15H25N5S)
(1S,2S)-2-(Dimethylamino)cyclohexylamine
(4
[43];
1
colorless oil. H NMR (300 MHz, CDCl3): d = 1.35 (s,
1.07 g, 7.5 mmol) was added to a solution of 830 mg
2-isothiocyanato-4,6-dimethylpyrimidine (11 [47, 48];
5.02 mmol) in 10 cm3 toluene and stirred for 3 h at r.t.
The solvent was removed and the residue separated by CC
(CH2Cl2/MeOH 30:1–20:1–12.5:1). Evaporation gave
crude 5–1 as foam (1.598 g, quantitative), which retained
some tBuOMe solvent. 1H NMR (400 MHz, CDCl3):
d = 1.10–1.47 (m, 4H), 1.66-1.76 (m, 1H), 1.80–1.94 (m,
2H), 2.29 (s, 6H, NMe2), 2.39 (s, 6H, 2 Me), 2.56 (td,
J = 10.5, 3.4 Hz, 1H), 2.71–2.76 (m, 1H), 4.15 (ddd,
J = 10.5, 6.6, 4.0 Hz, 1H), 6.66 (s, 1H), 8.37 (br s, 1 NH),
11.48 (br d, J = 5.7 Hz, 1 NH) ppm; 13C NMR (100 MHz,
CDCl3): d = 22.55 (CH2), 23.97 (CH3), 24.77 (CH2),
25.24 (CH2), 32.00 (CH2), 40.67 (CH3), 56.81 (CH), 66.77
(CH), 114.27 (CH), 157.20 (C), 167.51 br (C), 178.02
(C=S) ppm; MS (CI, CH4): m/z = 308.3 (M?H?), 166,
124; IR (ATR): vꢀ = 3429, 3178, 3030, 2929, 2858, 1598,
18H, CH3), 1.44 (t, J = 7.0 Hz, 3H, CH3), 4.49 (q,
J = 7.0 Hz, 2H, CH2) ppm; 13C NMR (75 MHz, CDCl3):
d = 14.41 (CH3), 28.89 (CH3), 39.48 (C), 63.49 (CH2),
170.57 (C), 187.32 (C) ppm; IR (capillary): vꢀ = 2965,
1537, 1336, 1239, 1069, 920 cm-1; GC–MS (EI?):
m/z = 237 (M?), 222, 208, 194.
2,4-Di-tert-butyl-6-isothiocyanato-1,3,5-triazine
(7a, C12H18N4S)
2-Amino-4,6-di-tert-butyl-1,3,5-triazine
(8a;
2.08 g,
10 mmol) was added to a suspension of 1.28 g NaH
(32 mmol, 3.2 equiv) in 30 cm3 THF. After 30 min of
stirring at r.t., 3.02 cm3 CS2 (50 mmol, 5 equiv.) was
added at 0 °C and the mixture stirred overnight for 20 h at
r.t. Ethyl chloroformate (1.43 cm3, 15 mmol, 1.5 equiv.)
was added, followed by 2.8 cm3 Et3N (20 mmol, 2 equiv.),
and the mixture stirred at r.t. for 30 min. The reaction was
quenched with the addition of 18 cm3 2.4 M aq HCl and
tBuOMe for extraction of the product. Washing of the
organic phase with water, drying (Na2SO4), filtration, and
evaporation gave 3.63 g of crude product. Purification by
CC on 150 g of MeOH-deactivated SiO2 (hexanes, then
tBuOMe/hexanes 1:50) gave 1.45 g (58 %) of 7a as
slightly brownish-yellow liquid. 1H NMR (300 MHz,
CDCl3): d = 1.37 (s, 18H) ppm; 13C NMR (75 MHz,
CDCl3): d = 28.88 (CH3), 39.86 (C), 147.48 (C), 162.03
(C), 188.08 (C-2/4) ppm; IR (capillary): vꢀ = 2965, 2929,
2870, 2125, 2100–1900 br, 1983, 1537, 1507, 1372, 1134,
912, 845 cm-1; GC–MS (EI?): m/z = 250 (M?), 235, 208,
84.
1511, 1371, 1164, 1040, 788, 706 cm-1
.
1-(4,6-Diisopropyl-1,3,5-triazin-2-yl)-3-[(1S,2S)-2-
(dimethylamino)cyclohexyl]thiourea (5–2, C18H32N6S)
(4
(1S,2S)-2-(Dimethylamino)cyclohexylamine
[43];
594 mg, 4.18 mmol) was added to a solution of 773 mg
isothiocyanate 7g (3.48 mmol) in 5 cm3 toluene, and the
reaction mixture stirred overnight. Evaporation and purifi-
cation by CC (CH2Cl2 and then CH2Cl2/MeOH 30:1–20:1)
gave a foam which was crushed to powder, washed with
tBuOMe, and dried in vacuum to give colorless solid
(1300 mg, quant.), retaining some tBuOMe. A sample for
analysis was further dried in vacuum. 1H NMR (400 MHz,
CDCl3): d = 1.07–1.19 (m, 1H), 1.21–1.46 (m, 16H),
1.72–1.79 (m, 1H), 1.84–1.96 (m, 2H), 2.25 (s, 6H, NMe2),
2.55 (td, J = 10.9, 3.3 Hz, 1H), 2.60–2.67 (m, 1H), 1.98
(br s, 2H, iPr-CH), 4.21 (m, 1H), 8.38 (s, 1 NH), 11.11 (d,
J = 6.3 Hz, 1 NH) ppm; 13C NMR (100 MHz, CDCl3):
d = 20.96 (CH3), 21.00 (CH3), 21.75 (CH2), 24.98 (CH2),
25.34 (CH2), 32.33 (CH2), 37.19 br (CH3), 40.37 (CH),
57.29 (CH), 66.87 (CH), 162.00 (C), 177.93 (C), 184.67 br
(C) ppm; MS (CI, CH4): m/z = 393.4 (M ? C2H5?), 365.3
(M ? H?); IR (ATR): vꢀ = 3419, 3198, 2931, 2861, 1570
2,4-Diisopropyl-6-isothiocyanato-1,3,5-triazine
(7g, C10H14N4S)
2-Amino-4,6-diisopropyl-1,3,5-triazine (8g [45]; 901 mg,
5.0 mmol), 640 mg NaH (16 mmol, 3.2 equiv), and
1.5 cm3 CS2 (25 mmol) were stirred in 20 cm3 THF
overnight. Ethyl chloroformate (0.71 cm3, 7.5 mmol, 1.5
equiv.) and 1.4 cm3 NEt3 (10 mmol) were successively
added, and the mixture was stirred for 30 min at r.t. The
reaction was quenched with H2O and extracted with
tBuOMe. After drying of the organic phase (Na2SO4),
filtration, and evaporation, the crude product was purified
by CC on MeOH-deactivated SiO2 (tBuOMe/hexanes 1:50)
to give an oily product (499 mg, 45 %). 1H NMR
(400 MHz, CDCl3): d = 1.32 (d, J = 6.9 Hz, 12H), 3.07
(sept, J = 6.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3):
br, 1536 br, 1391, 1150, 840 cm-1
.
1-(4,6-Di-tert-butyl-1,3,5-triazin-2-yl)-3-[(1S,2S)-2-
(dimethylamino)cyclohexyl]thiourea (5–3, C20H36N6S)
Isothiocyanate 7a (116 mg, 0.46 mmol) was combined
with 79 mg (1S,2S)-2-(dimethylamino)cyclohexylamine (4
123

1538
L. Xiao et al.
[43]; 0.56 mmol) in 1 cm3 PhMe and stirred overnight.
Evaporation and purification by CC (CH2Cl2–CH2Cl2/
MeOH 30:1–20:1) gave colorless solid 5–3 (136 mg,
75 %). X-ray quality crystals were obtained by slow
evaporation from a concentrated toluene solution. 1H NMR
(400 MHz, CDCl3): d = 1.08–1.50 (m, 4H), 1.33 (br s,
18H, tBu), 1.72–1.99 (m, 3H), 2.24 (br s, 6H, NMe2),
2.51–2.62 (m, 2H), 4.23–4.35 (m, 1H), 8.37 (br s, 1 NH),
11.07 (br d, J = 6.1 Hz, NH) ppm; 13C NMR (100 MHz,
CDCl3): d = 21.68 (CH2), 25.12 (CH2), 25.42 (CH2), 28.84
(CH3), 32.69 (CH2), 39.62 (C), 40.36 (CH3), 57.33 (CH),
66.89 (CH), 161.85 (C), 178.00 (C), 187.30 br (C) ppm;
MS (CI, CH4): m/z = 393.4 (M + H+); IR (ATR): = 3190,
3127, 3047, 2935, 2862, 1573, 1510, 1173, 1151,
or http://www.ccdc.cam.ac.uk. Any request to the CCDC for
this material should quote the full literature citation.
Acknowledgments This project received funding from the
Deutsche Forschungsgemeinschaft (SPP 1179). We thank Dr. Marco
Schmitz (RWTH Aachen, 2009) for performing catalysis tests.
References
1. Xu L, Liao G-L, Chen X, Zhao C-Y, Chao H, Ji L-N (2010) Inorg
Chem Commun 13:1050
2. Safin DA, Xu Y, Korobkov I, Bryce DL, Murugesu M (2013)
Cryst Eng Comm 15:10419
3. Lerner EI, Lippard SJ (1976) J Am Chem Soc 98:5397
4. Fletcher IJ, Kaschig J, Metzger G, Reinehr D, Hayoz P (2001)
Biphenyl-substituted triazines. US Patent 6,255,483 B1, Jul 3,
2001
683 cm-1
.
5. Fletcher IJ, Kaschig J, Metzger G, Reinehr D, Hayoz P (2001)
Chem Abstr 135:77694
1-(4,6-Di-tert-butyl-1,3,5-triazin-2-yl)-3-phenylthiourea
(12, C18H25N5S)
6. Ehlis T, Mu¨ller S, Hayoz P (2004) Symmetrical triazine deriva-
tives. Patent WO 2004/085412 A2, Oct 7, 2004
7. Ehlis T, Mu¨ller S, Hayoz P (2004) Chem Abstr 141:300991
8. Ishi-i T, Yaguma K, Thiemann T, Yashima M, Ueno K, Mataka S
(2004) Chem Lett 33:1244
9. Esteghamatian M, Hu N-X, Popovic ZD, Hor A-M, Ong BS
(2001) Triazine derivatives and electroluminescent (EL) devices
using them. US Patent 6,225,467, Mai 1, 2001
10. Esteghamatian M, Hu N-X, Popovic ZD, Hor A-M, Ong BS
(2001) Chem Abstr 134:333997
11. Vodak DT, Kim K, Iordanidis L, Rasmussen PG, Matzger AJ,
Yaghi OM (2003) Chem Eur J 9:4197
12. Tragl S, Gibson K, Meyer HJ (2004) Zeitschr Anorg Allg Chem
630:2373
13. Fukushima Y, Nohara N, Hashida Y, Sekiguchi S, Matsui K
(1971) Bull Chem Soc Japan 44:794
14. Huthmacher K, Most D (2012) Cyanuric acid and cyanuric
chloride. In: Ullmann’s encyclopedia of industrial chemistry.
Wiley-VCH, Weinheim
15. Knu¨sli E (1977) The s-triazine herbicides. In: Plimmer JR (ed)
Pesticide chemistry in the 20th Century, ACS Symposium Series,
vol 37. American Chemical Society, Washington, pp 76–92
16. LeBaron HM, McFarland JE, Burnside OC (2008) The triazine
herbicides. Elsevier, Amsterdam
It was obtained by reaction of 70 mm3 distilled aniline
(0.77 mmol) with 160 mg isothiocyanate 7a (0.64 mmol)
neat for 5 min. Addition of 5 cm3 hexanes and filtration
gave 132 mg of colorless solid. The filtrate was evapo-
rated, and the residue crystallized from CH2Cl2/hexanes
(overlayering) to give 30 mg of needles; total yield 162 mg
(74 %) of 12 as colorless solid. 1H NMR (400 MHz,
CDCl3): d = 1.35 (br s, 9H, tBu), 1.39 (br s, 9H, tBu), 7.27
(t, J = 7.5 Hz, 1 H-Ar), 7.43 (t, J = 7.8 Hz, 2 H–Ar), 7.71
(d, J = 7.7 Hz, 2 H–Ar), 8.59 (br s, 1 NH), 13.02 (br s, 1
NH) ppm; 13C NMR (100 MHz, CDCl3): d = 28.87 (br s,
CH3), 29.00 (br s, CH3), 39.81 (br s, 39.81), 125.05 (CH),
126.54 (CH), 128.5 (CH), 138.20 (C), 161.67 (C), 178.40
(C), 184.78 (br s, C), 187.27 (br s, C) ppm; IR (ATR):
vꢀ = 3184, 3071, 2963, 1581, 1516, 1322, 1175, 1153, 744,
685 cm-1; MS (CI, CH4): m/z = 372.2 (M ? C2H5?),
344.2 (M ? H?), 343.2 (M?), 251, 209.
X-ray crystal structure analysis for 8a and 5–3
17. Kaminski ZJ, Paneth P, Rudzinski J (1998) J Org Chem 63:4248
18. Rayle HL, Fellmeth L (1999) Org Process Res Dev 3:172
19. Kangani CO, Day BW (2008) Org Lett 10:2645
20. De Luca L, Giacomelli G, Porcheddu A (2001) Org Lett 3:1519
21. Olah GA, Nojima M, Kerekes I (1973) Synthesis 487
22. Groß S, Laabs S, Scherrmann A, Sudau A, Zhang N, Nubbemeyer
U (2000) J Prakt Chem 342:711
23. Zollinger H (1991) Color chemistry, 2nd edn. VCH, Weinheim
24. Hunger K (2003) Industrial dyes. Wiley-VCH, Weinheim
25. Hintermann L, Xiao L, Labonne A (2008) Angew Chem Int Ed
47:8246
26. Thomas J, Van Rossom W, Van Hecke K, Van Meervelt L, Smet
M, Dehaen W, Maes W (2013) Synthesis 45:734
27. Braun M, Frank W, Ganter C (2011) J Organomet Chem
696:3580
28. Crosby SH, Clarkson GJ, Rourke JP (2012) Organometallics
31:7256
The single crystals of 8a and 5–3 were used for data col-
lection at 123.0(2) K on a four-circle Bruker Kappa APEX
II CCD system equipped with a MONTEL mirror
monochromator and
a Mo FR591 rotating anode
˚
(k = 0.71073 A). Integration of the intensities and cor-
rection for Lorenz and polarization effects were performed
using APEX2 suite of software [63]. The crystal structures
were solved by direct methods and refined by a full-matrix
least-squares method on F2 using the program SHELXL-
2014 [64] in conjunction with SHELXLE [65].
Complete crystallographic details for 8a and 5–3 are
available as Supplementary data [CCDC 1055819 (8a) and
1055820 (5–3)] and have been deposited at the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road,
Cambridge, CB21EZ, UK; e-mail: deposit@ccdc.cam.ac.uk
29. Hu F-C, Wang S-W, Planells M, Robertson N, Padhy H, Du B-S,
Chi Y, Yang P-F, Lin H-W, Lee G-H, Chou P-T (2013) Chem
Sus Chem 6:1366
123

2-Amino-1,3,5-triazine chemistry: Hydrogen-bond networks, Takemoto thiourea catalyst analogs,…
1539
30. Nishiura C, Abe S, Hashimoto M, Nitta H (2011) New iridium
complex and organic light-emitting element including the same.
Patent WO2011/070992 A1, Jun 16, 2011
48. Schultz O-E, Gauri KK (1962) Arch Pharm 295:146
49. Sasaki S, Mizuno M, Naemura K, Tobe Y (2000) J Org Chem
65:275
31. Nishiura C, Abe S, Hashimoto M, Nitta H (2011) Chem Abstr
155:68065
50. Andreasch R (1906) Monatsh Chem 27:1221
51. Kaluza L (1912) Monatsh Chem 33:363
52. Hodgkins JE, Ettlinger MG (1956) J Org Chem 21:404
53. Wong R, Dolman SJ (2007) J Org Chem 72:3969
32. Sonobe T, Oisaki K, Kanai M (2012) Chem Sci 3:3249
33. Gege C, Steeneck C, Kinzel O, Kleymann G, Hoffmann T (2013)
Carboxamide or sulfonamide substituted thiazoles and related
derivatives as modulators for the orphan nuclear receptor RORc.
Patent WO 2013/178362 A1, Dec 5, 2013
´
´ ´
54. Ruiz-Carretero A, Ramırez JR, Sanchez-Migallon A, de la Hoz A
(2014) Tetrahedron 70:1733
55. Kaminsky W, Goldberg KI, West DX (2002) J Mol Struct 605:9
´ ´
56. West DX, Hermetet AK, Ackerman LJ, Valdes-Martınez J,
´
34. Gege C, Steeneck C, Kinzel O, Kleymann G, Hoffmann T (2013)
Chem Abstr 160:45651
Hernandez-Ortega S (1999) Acta Cryst C55:811
57. Kreutzberger A, Loch M (1986) Arch Pharm 319:769
35. Schreiner PR (2003) Chem Soc Rev 32:289
36. Miyabe H, Takemoto Y (2008) Bull Chem Soc Jpn 81:785
37. Takemoto Y (2005) Org Biomol Chem 3:4299
38. Berkessel A, Seelig B (2009) Synthesis 2113
39. Okino T, Hoashi Y, Takemoto Y (2003) J Am Chem Soc
125:12672
´
´
´ ´
58. Tarkanyi G, Kiraly P, Soos T, Varga S (2012) Chem Eur J
18:1918
59. Hintermann L, Schmitz M (2008) Adv Synth Catal 350:1469
60. Hintermann L, Schmitz M, Maltsev OV, Naumov P (2013)
Synthesis 45:308
40. Harris MG, Stewart R (1977) Can J Chem 55:3800
41. Stewart R, Dolman D (1967) Can J Chem 45:925
42. Hirt RC, Schmitt RG, Strauss HL, Koren JG (1961) J Chem Eng
Data 6:610
43. Kaik M, Gawronski J (2003) Tetrahedron Asymmetry 14:1559
44. Combes A, Combes C (1892) Bull Soc Chim Fr 7:791
61. Maga JA (1981) J Agric Food Chem 29:895
62. The Good Scents Company Information System (1980–2015).
http://www.thegoodscentscompany.com. Accessed 9 Mar 2009
63. Bruker (2013) APEX suite of crystallographic software, APEX 2
Version 2013.4. Bruker AXS Inc., Madison, Wisconsin, USA
¨
64. Sheldrick GM (2014) SHELXL2014. University of Gottingen,
Germany
¨
45. Kabbe H-J, Eiter K, Moller F (1967) Liebigs Ann Chem 704:140
46. Drobnica L, Kristian P, Augustin J (1977) The chemistry of the
—NCS group, 1003. In: Patai S (ed) The chemistry of cyanates
and their thio derivatives, vol 2. Wiley, Chichester
47. Ohkata K, Ohsugi M, Yamamoto K, Ohsawa M, Akiba K (1996)
J Am Chem Soc 118:6355
65. Huebschle CB, Sheldrick GM, Dittrich B (2011) J Appl Cryst
44:1281
123