Chiral oxazoline ligands with two different six-membered azaheteroaromatic rings - Synthesis and application in the Cu-catalyzed nitroaldol reaction

Article abstract of DOI:10.1515/hc-2016-0001

Synthesis and catalytic activity of chiral ligands 5,6-diphenyl-3-{3-[(4S/R)-4-R/Ar-4,5-dihydro-1,3-oxazol-2-yl]pyridin-2-yl}amino-1,2,4-triazines 2 and their analogs 3 possessing an N-oxide function in the pyridine ring are described. The pivotal step in the synthesis of ligands 2 is the Buchwald-Hartwig Pd-catalyzed cross-coupling reaction between 3-bromo-5,6-diphenyl-1,2,4-triazine (7a) and enantiopure 3-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-amines 6a-d. Aromatic nucleophilic substitution of chlorine in 3-chloro-5,6-diphenyl-1,2,4-triazine (7b) with 3-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-amine 1-oxides 12 was investigated as the key reaction in the synthesis of ligands 3. Two undesired derivatives 13 or 14, resulting from unexpected reactions of 3, were isolated depending on reaction conditions. Compounds 2 and 3 as well as the side products 13 and 14 were screened as chiral ligands in the copper catalyzed enatioselective nitroaldol reaction.

Full text of DOI:10.1515/hc-2016-0001

Heterocycl. Commun. 2016; aop
Ewa Wolińska*
Chiral oxazoline ligands with two different
six-membered azaheteroaromatic rings –
synthesis and application in the Cu-catalyzed
nitroaldol reaction
DOI 10.1515/hc-2016-0001
These ligands were applied to the copper catalyzed
enantioselective nitroaldol reaction of several aromatic
and aliphatic aldehydes providing products with enan-
tiopurity up to 92% and yield up to 95% [1–3]. Thus, the
ligands with the phenyl substituent in the oxazoline ring
and ligands that possess the indane moiety exhibit high
stereocontrolling abilities. Substitution in the 1,2,4-tria-
zine ring has a crucial impact on chemical yield of the
investigated reaction. From this point of view, the ligands
having a phenyl group at the C5 position of 1,2,4-triazine
are preferred. Structures of 1-Cu complexes so far are not
known, but it can be suggested on the basis of the ligand
crystal structures [4] that the nitrogen atoms of oxazo-
line and amino groups may participate in the complexa-
tion of copper ion. Similar complexation mode of zinc
was observed by Guiry [5]. In the Henry reaction, a base
or counter ion is necessary to abstract the proton from
nitromethane. Our catalytic system works without an
external base, so the nitronate anion must be generated
with the involvement a counter ion or the 1-Cu complex
Received January 3, 2016; accepted February 17, 2016
Abstract: Synthesis and catalytic activity of chiral ligands
5
,6-diphenyl-3-{3-[(4S/R)-4-R/Ar-4,5-dihydro-1,3-oxazol-
2
-yl]pyridin-2-yl}amino-1,2,4-triazines 2 and their analogs
3
possessing an N-oxide function in the pyridine ring are
described. The pivotal step in the synthesis of ligands 2
is the Buchwald-Hartwig Pd-catalyzed cross-coupling
reaction between 3-bromo-5,6-diphenyl-1,2,4-triazine (7a)
and enantiopure 3-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-
2
-amines 6a–d. Aromatic nucleophilic substitution of
chlorine in 3-chloro-5,6-diphenyl-1,2,4-triazine (7b) with
-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-amine 1-oxides 12
3
was investigated as the key reaction in the synthesis of
ligands 3. Two undesired derivatives 13 or 14, resulting
from unexpected reactions of 3, were isolated depending
on reaction conditions. Compounds 2 and 3 as well as the
side products 13 and 14 were screened as chiral ligands in
the copper catalyzed enatioselective nitroaldol reaction.
Keywords: asymmetric catalysis; Buchwald-Hartwig ami- plays the role of a bifunctional catalyst. As an extension of
nation; chiral oxazoline ligands; enantioselective Henry the previous work, now we report the synthesis of chiral
reaction; 1,2,4-triazine.
oxazoline ligands 2 and 3 as analogs of ligands 1 where
the N-phenylamine linkage is replaced with pyridine-
2-amine or 2-aminopyridine 1-oxide moiety (Figure 2). The
presence of the nitrogen atom or N-oxide moiety in the
linkage can change electronic properties of the donating
nitrogen atoms, thus having impact on the complexation
and stereo-controlling abilities of ligands. They can also
act as an additional internal base. On the other hand, the
competition between the new electron pair donors and
the nitrogen atoms of oxazoline and amino groups in com-
plexation with copper ion can take place.
Introduction
According to our interest focusing on the design, synthe-
sis, and applications of chiral oxazoline ligands we have
already described several ligands 1 which combine in their
structure two heterocyclic moieties: chiral oxazoline and
1,2,4-triazine linked by an N-phenylamine unit (Figure 1).
The ligands differ in the type of a substituent in the oxazo-
line ring and in the substitution mode of the 1,2,4-triazine
moiety.
Results and discussion
The 1,2,4-triazine ring is π-electron deficient and, there-
fore, susceptible to nucleophilic attack [6]. Highly active
*
Corresponding author: Ewa Wolińska, Department of Chemistry,
Siedlce University, 3 Maja 54, 08-110 Siedlce, Poland,
e-mail: ewol@uph.edu.pl
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ꢀꢀꢀꢀꢁꢀE. Wolińska: Chiral oxazoline ligands with two azaheteroaromatic rings
R2
N
N
N
N
O
∗
N
R1
R1
N
CN
ZnCl2 (20 mol%)
∗
N
+
R3
Ph
N
N
H
H2N
OH Chlorobenzene
reflux
N
NH2
H
N
NH2
N
O
N
O
5a–d
4
∗
6a–d
31–99%
1
R
1a–k
1m
a: R1 = t-Bu (S)
Pd2dba3 Ph
Xantphos
N
a: R2 = R = Ph, R = t-Bu (S)
3
1
2
3
1
1
N
g: R = H, R = Ph, R = i-Pr (S)
b: R = Ph (S)
2
3
1
2
3
1
1
b: R = R = Ph, R = Ph (S)
h: R = H, R = t-Bu, R = t-Bu (S)
c: R = i-Pr (S)
2
3
1
2
3
1
1
K2CO3
Ph
N
Br
c: R = R = Ph, R = i-Pr (S)
i: R = H, R = t-Bu, R = Ph (S)
d: R = Bn (R)
2
3
1
2
3
1
dioxane
reflux
d: R = R = Ph, R = Bn (R)
j: R = H, R = t-Bu, R = i-Pr (S)
7a
2
3
1
2
3
1
e: R = H, R = Ph, R = t-Bu (S)
f: R = H, R = Ph, R = Ph (S)
k: R = H, R = t-Bu, R = Bn (R)
2
3
1
Ph
Ph
N
Figure 1ꢀPreviously investigated 1,2,4-triazine-oxazoline ligands.
N
N
N
N
H
N
∗
R
O
R2
R3
N
N
R2
O
N
N
N
N
N
N
1
2
a–d
N
R3
N
32–37%
H
H
N
∗
O
N
∗
O
Scheme 1ꢀSynthesis of ligands 2a–d.
1
2
R
3
1
R
Figure 2ꢀChiral oxazoline ligands with six-membered azaheteroaro-
matic rings.
After obtaining amines 6, an attempt to react them
with 3-bromo-5,6-diphenyl-1,2,4-triazine (7a) was under-
taken. To synthesize the ligands 2a–d the application of
3
,3′-dichloro-5,5′-bi-1,2,4-triazine undergoes displace- Buchwald-Hartwig Pd-catalysis was necessary. Thus, the
ment of chlorine atoms after few minutes of stirring aryl aminations between 7a and 6a–d were carried out
with aliphatic amines or aniline in the absence of an using Pd dba , Xantphos, and K CO in boiling dioxane
2
3
2
3
additional base [7]. Reactions of less active 1,2,4-tria- (Scheme 1). This procedure allowed to obtain the ligands
zines require the presence of metal catalyst to replace 2a–d in moderate yields ranging from 32% to 37%.
halogen or other nucleofugal leaving group [1, 8, 9].
Synthesis of ligands of type 3 could not be accom-
Thus, a two-step synthetic route to ligands 2 employs plished by simple oxidation of 2a–d, since 1,2,4-triazine
the Pd-catalyzed Buchwald-Hartwig reaction [10–14] [16] as well as the oxazoline [17] rings are also suscepti-
of enantiopure 3-(4,5-dihydro-1,3-oxazol-2-yl)pyridin- ble to oxidizing conditions. Initial attempt was made to
2
-amines 6 with 3-bromo-5,6-diphenyl-1,2,4-triazine (7a) obtain ligands 3 utilizing amination of 3-halo-1,2,4-triazine
as the key step (Scheme 1). 3-(4,5-Dihydro-1,3-oxazol- with N-protected aminopyridine 1-oxides 9 based on aza-
-yl)pyridin-2-amines 6a–d were obtained by condensa- Smiles rearrangement (Scheme 2) [18].
2
tion of enantiomerically pure aminoalcohols 5a–d with
Analogous protocol described by us previously,
the cyano group of 2-aminopyridine-3-carbonitrile (4). proved to be effective for amination of pyridine and pyrim-
This reaction was conducted in the presence of a cata- idine halides [18, 19]. This approach assumes formation of
lytic amount (20 mol%) of ZnCl as Lewis acid [15]. After intermediary salt 10 in reaction of formamidine protected
2
4
days of heating in boiling chlorobenzene the appro- 2-aminopyridine-3-carbonitrile 1-oxide 9 with 3-chloro-
priate (oxazol-2-yl)pyridin-2-amines 6a–d were isolated 5,6-diphenyl-1,2,4-triazine (7b). Base-induced rearrange-
with 31–99% yield. Our previously described protocol ment of 10 should give derivative 11, the condensation of
of condensation of aminoalcohols with 2-aminobenzo- which with aminoalcohols 5 would produce ligands 3. A
nitrile requires the use of an excess of ZnCl , and after reaction of N-oxide 8 with 3 equivalents of N,N-dimethyl-
2
removal of solvent, stirring the mixture with NaOH formamide dimethyl acetal (DMF-DMA) was carried out at
solution to isolate the product [1]. The use of three- room temperature without any solvent. After 80 h of stir-
fold excess of ZnCl in the reaction between 4 and 5a–d ring, the amidine protected compound 9 was isolated in
2
allowed to shorten the reaction time to 24 h, but isola- 92% yield. To our disappointment, the next step, the prep-
tion of the product from the reaction mixture appeared aration of salt 10 appeared difficult. A typical procedure
difficult.
for amination of pyridine and pyrimidine halides with
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E. Wolińska: Chiral oxazoline ligands with two azaheteroaromatic ringsꢂꢁꢀꢀꢀꢂ3
R1
O
∗
Ph
Ph
N
N
N
N
H2N
OH
O
Ph
Ph
N
N
NC
O
Ph
Ph
N
N
Base
N
5
N
N
N
N+
HN
H
Cl-
N
N
∗
O
H
CN
N
1
3
R
10
11
Ph
Ph
N
N
N
Cl
7b
O
CN
CN
MCPBA
N
DMF-DMA
N
NH2
N
N
N
NH2
CN
O
4
8
9
Scheme 2ꢀProposed synthetic approach to ligands 3.
formamidine protected aminopyridine 1-oxides involving amination of 3-chloro-5,6-diphenyl-1,2,4-triazine (7b) with
stirring of the substrates in dry DMF at room temperature (oxazol-2-yl)pyridin-2-amine 1-oxides 12. Thus, the synthe-
in the case of 1,2,4-triazine halide proved to be ineffective. sis of ligands of type 3 began with preparation of N-oxide
Application of different solvents and changing the reac- 8 by oxidizing 2-aminopyridine-3-carbonitrile (4) with
tion temperature did not result in formation of product 10. m-chloroperbenzoic acid in dichloromethane (Scheme 3).
Difficulties in formation of salt 10 make the selected syn-
thetic strategy unsuccessful.
Condensation of N-oxide 8 with aminoalcohols 5a–e
yielded the desired 3-(oxazol-2-yl)pyridin-2-amine 1-oxides
Searching for another method of synthesis of com- 12a–e in good yields. The reaction time was controlled
pounds 3 we envisaged a more reliable procedure involving to avoid transformation of the products to oxazolines
6
(see Experimental part). The preparation of ligands 3
was first attempted by heating oxides 12a and 12c with
-chloro-5,6-diphenyl-1,2,4-triazine (7b) in dioxane in the
presence of K CO at 95°C. Under these conditions the
R1 ∗
H N
3
O
CN
CN
2
OH
N
MCPBA
CH2Cl2
2
3
5
a–e
unexpected respective products 13a and 13c were gener-
ated (Scheme 4).
N
NH2
H2N
N
NH2
ZnCI2 (20 mol%)
N
∗
R
O
O
4
Chlorobenzene
reflux
The N-oxide function strongly activates the amino
group in compounds 12, so the substitution of the chlo-
rine atom in 7b can proceed under metal-free conditions.
Moreover, the secondary NH group in 3a and 3c is also
active enough to react with a second molecule of 3-chlo-
rotriazine 7b to give compounds 13a and 13c. To inhibit
the reaction of the initially formed compounds 3a and 3c
8
1
1
2a–e
a: R1 = t-Bu (S)
1
62–75%
b: R = Ph (S)
1
c: R = i-Pr (S)
1
d: R = Bn (R)
1
e: R = Bn (S)
Scheme 3ꢀSynthesis of chiral N-oxides 12a–e.
O
N
O
Ph
Ph
N
N
Ph
Ph
N
N
N
N
N
K2CO3
7b
12a or 12c + 7b
N
N
N
dioxane
H
N
9
5°C
N
N O
O
Ph
R1
N
R1
Ph
3a, c
1
3a, 35%
3c, 42%
1
Scheme 4ꢀReaction of N-oxides 12a and 12c with 3-chloro-5,6-diphenyl-1,2,4-triazine (7b).
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4
ꢀꢀꢀꢀꢁꢀE. Wolińska: Chiral oxazoline ligands with two azaheteroaromatic rings
with 3-chlorotriazine, K CO was eliminated from the reac- was shown on the basis of analysis of mass spectra of their
2
3
tion mixture. Under base-free conditions at 95°C product mixtures. The ESI HR mass spectrum of a mixture of 3c
3
a was obtained in 22% yield accompanied by undesired and 14c shows signals at m/z 453.2039 and m/z 489.1804
+
compound 14a isolated in the yield of 54% (Table 1, entry corresponding to the values expected for [3c+H] and
+
1
). When the temperature was lowered to 20°C, no reac- [14c+H] . The mass spectrum of the mixture of 3d and 14d
tion between 12a and 7b occurred (Table 1, entry 2). In indicates the presence of ions of m/z 501.2039 and m/z
+
DMF at 50°C the expected product 3a and unexpected 537.1780 which match the calculated masses of [3d+H]
+
compound 14a were formed in 15% and 48% yield, respec- and [14d+H] . Analogously, ions with m/z 501.2036 and
tively (Table 1, entry 3). Under these conditions, N-oxide m/z 537.1798 are observed for the mixture of 3e and 14e.
1
2b reacted with chlorotriazine 7b giving compounds 3b Their masses are virtually identical with the masses cal-
+
+
and 14b in 10% and 48% respective yields after chroma- culated for [3e+H] and [14e+H] .
tography (Table 1, entry 4). Chemically pure compounds
The cationic activated oxazoline ring-opening
a,b and 14a,b were characterized by several analytical process under an attack of nucleophile gained synthetic
3
1
13
techniques including H NMR, C NMR, IR, HR MS, which importance, for example in the synthesis of polymers
confirmed their structures. [20, 21]. To circumvent the problem with conversion of
Undesirable compounds 14a,b were formed by trans- 3 to 14, the use of organic bases in the reaction of 12
formation of initially formed products 3a,b. Since the with 7b was considered. It was predicted that aliphatic
reaction of (oxazol-2-yl)pyridin-2-amine 1-oxides 12 with amines such as triethylamine or DABCO can form
3
-chloro-5,6-diphenyl-1,2,4-triazine (7b) is conducted in salts with 3-chlorotriazine 7b, as observed previously
the absence of base, evolving hydrochloride protonates [22] and their use was excluded. Therefore, the reac-
the nitrogen atom of the oxazoline ring in 3a,b activating tion of 12b and 7b was repeated with 2 equivalents of
these compounds towards nucleophilic attack of chloride N,N-dimethylaniline, m-nitroaniline or p-nitroaniline.
ion. This leads to opening of the oxazoline ring giving rise Unfortunately, no significant improvement in yield of
to products 14a,b (Scheme 5).
the desired product 3b was achieved. Compound 3b iso-
The observed reactivity was confirmed in the reac- lated in yield 17–24% was still accompanied by its trans-
tions of three other (oxazol-2-yl)pyridin-2-amine 1-oxides formation product 14b (45–52%, Table 1, entry 6, 7, and
1
2c–e with 3-chloro-5,6-diphenyl-1,2,4-triazine (7b). In 8). As can be seen from the results summarized in Table
each case the formation of two products 3c–e and 14c–e 1, in the reaction of 12b and 7b approximately 70% of the
was observed. Attempts to separate the products 3c–e and substrates are initially converted to the desired product
1
4c–e by chromatography failed. They were not isolated 3b but about 50% of the product is transformed to the
in chemically pure form. Formation of 3c–e and 14c–e open-chain compound 14b.
Table 1ꢀReactions of N-oxides 12a,b with 3-chloro-5,6-diphenyl-1,2,4-triazine (7b).
O
O
Ph
Ph
N
N
Ph
Ph
N
N
N
N
N
N
Solvent
+
Temperature
N
12a,b + 7b
N
H
H
Base
N
O
HN
O
R1
a,b
R1
Cl
3
14a,b
ꢁ
Rꢂ
ꢁ
Substrateꢁ
Solvent ꢁꢁ
Base
ꢁ
Temperature °Cꢁ
Yield%
ꢂꢄ
ꢃꢁ
ꢃꢄ
ꢆꢄ
ꢉꢄ
ꢇꢄ
ꢋꢄ
ꢌꢄ
ꢊꢄ
t-Buꢄ
t-Buꢄ
t-Buꢄ
ꢂꢅa
ꢂꢅa
ꢂꢅa
ꢂꢅb
ꢂꢅb
ꢂꢅb
ꢂꢅb
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
Dioxaneꢄ
Dioxaneꢄ
–ꢄ
–ꢄ
–ꢄ
–ꢄ
9ꢅꢄ
ꢆꢈꢄ
ꢅꢈꢄ
ꢅꢈꢄ
ꢅꢈꢄ
ꢅꢈꢄ
ꢅꢈꢄ
ꢆꢆꢄ
–ꢄ
ꢃꢅꢄ
ꢃꢈꢄ
ꢃ9ꢄ
ꢆꢇꢄ
ꢃꢌꢄ
ꢅꢇ
–
ꢇꢊ
ꢇꢊ
ꢅꢃ
ꢇꢅ
ꢅꢆ
DMF
DMF
DMF
DMF
DMF
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
Ph
Ph
Ph
Ph
ꢄ
ꢄ
ꢄ
ꢄ
N,N-dimethylanilineꢄ
m-Nitroaniline
p-Nitroaniline
ꢄ
ꢄ
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E. Wolińska: Chiral oxazoline ligands with two azaheteroaromatic ringsꢂꢁꢀꢀꢀꢂ5
O
Ph
Ph
N
N
Conclusion
A new class of chiral compounds 2 with three differ-
ent heterocyclic rings in their structure have been pre-
pared by employing Pd-catalyzed Buchwald-Hartwig
cross-coupling reaction between the enantiopure
N
N
HCl
3
a,b
14a,b
N
H
H
N+
O
R1
Cl-
Scheme 5ꢀFormation of compounds 14a,b.
3
-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-amines
6
and
3
-bromo-5,6-diphenyl-1,2,4-triazine (7a) as the key step.
Two different synthetic routes towards compounds 3 con-
Initial study was focused on the screening of ligands taining N-oxide functionality were investigated: amination
and 3 in the copper catalyzed enatioselective nitroaldol of 3-chloro-5,6-diphenyl-1,2,4-triazine with N-protected
2
reaction. Several aldehydes were treated with nitrometh- aminopyridine 1-oxide 9 based on aza-Smiles rear-
ane in the presence of in situ generated complexes of rangementand and amination of 3-chloro-1,2,4-triazine
ligands 2 and 3 with Cu(OAc) ·H O. The reactions were with enantiopure 3-[4-R/Ar-4,5-dihydro-1,3-oxazol-2-yl]
2
2
carried out in 2-propanol at room temperature and lead pyridine-2-amine 1-oxides 12. The use of the former com-
to β-nitro alcohols with moderate to good chemical yield pound failed due to difficulties in formation of salt 10. The
but no enantioselectivity was observed (Table 2). Enan- second method encountered problems with unexpected
tiopure compounds 13c and 14b were also screened in subsequent reactions of initially formed product 3. Under
the attempted enantioselective addition of nitromethane basic conditions, product 3 acts as good nucleophile and
to m-nitrobenzaldehyde. The β-nitro alcohols formed in undergoes reaction with a second molecule of 7b giving
the respective yields of 42% and 56% and were isolated compounds 13. In the experiments carried out in the
as mixtures of enantiomers, which indicates that the com- absence of a base or in the presence of a weak organic
pounds 13c and 14b are also not good enantiomeric cata- base, initially formed product 3 undergoes the oxazoline
lysts in the nitroaldol reaction (Table 2).
ring opening leading to compound 14. These new classes
of oxazoline ligands 2 and 3 do not exhibit enantio-con-
trolling abilities in the copper catalyzed enantioselective
Henry reaction. This result may indicate a different mode
of copper complexation with ligands 2 and 3 in compari-
son to ligands 1. The nitrogen atom of the pyridine ring or
the oxygen atom of the N-oxide function can be involved
in complexation with the copper ion. The stereogenic
center of the complex may be located at some distance of
the Lewis acid center and does not have any influence on
the stereochemical course of the nitroaldol reaction. This
issue needs further explanation and will be discussed in
due course.
Table 2ꢀScreening of ligands 2, 3, 13c, and 14b in the catalytic
a
enantioselective Henry reaction.
Cu(OAc)2·H2O (5 mol%)
ligand (5 mol%)
O
OH
+
CH3NO2
NO2
R
H
2-propanol, rt
R
1
5a–e
16
17a–e
b
c
ꢁ
R
ꢁ
Aldehydeꢁ Ligandꢁ Productꢁ Yield %ꢁ ee %
ꢃꢄ ꢉ-NO C H
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢂꢆa
ꢂꢆa
ꢂꢆa
ꢂꢆa
ꢂꢆb
ꢂꢆc
ꢂꢆc
ꢂꢆd
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢅa
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢂꢇa
ꢂꢇa
ꢂꢇa
ꢂꢇa
ꢂꢇb
ꢂꢇb
ꢂꢇc
ꢂꢇd
ꢂꢇe
ꢂꢇa
ꢂꢇa
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢋꢌꢄ ꢌ (S)
ꢌꢅꢄ ꢇ (S)
ꢌ9ꢄ rac
ꢌ9ꢄ rac
ꢋꢅꢄ rac
ꢊꢉꢄ rac
ꢌꢌꢄ rac
ꢆ9ꢄ rac
ꢇ9ꢄ rac
ꢇꢆꢄ rac
ꢅꢋꢄ rac
ꢆ
ꢋ
ꢇ
ꢇ
ꢇ
ꢇ
ꢇ
ꢆꢄ ꢉ-NO C H
ꢅc
ꢆ
ꢋ
ꢉꢄ ꢉ-NO C H
ꢅd
ꢃb
ꢃb
ꢃb
ꢃb
ꢃb
ꢃb
ꢂꢃc
ꢂꢄb
ꢆ
ꢋ
ꢇꢄ ꢉ-NO C H
ꢆ
ꢋ
ꢅꢄ ꢇ-NO C H
ꢆ
ꢋ
ꢋꢄ ꢆ-ClC Hꢇ
ꢋ
Experimental
ꢌꢄ ꢆ-BrC Hꢇ
ꢋ
ꢊꢄ ꢉ-MeC Hꢇ
ꢋ
1H and 13C NMR spectra were determined at 400 MHz and 100 MHz,
respectively, on a Varian 400 spectrometer. Chemical shifts (δ) are
reported in part per million from tetramethylsilane with the solvent
resonance as the internal standard. Coupling constants are given
as absolute values expressed in Hertz. Mass spectra were obtained
by using AMD 604 (AMD Intectra GmbH, Germany) and GC/MS QP
5050 Shimadzu (30 mꢀ×ꢀ0.25 mm ID-BPX 5 0.25 mm) spectrometers.
Infrared spectra were obtained by using a Magna FTIR–760 Nico-
let apparatus and Shimadzu FT IR Affinity-1 spectrometer. Elemen-
tal analyzes were obtained with a Elementar Vario EL III CHNS
9
ꢄ
ꢆ-MeOC H ꢄ ꢂꢆe
ꢋ
ꢇ
ꢃꢈꢄ ꢉ-NO C H
ꢄ
ꢄ
ꢂꢆa
ꢂꢆa
ꢆ
ꢋ
ꢇ
ꢃꢃꢄ ꢉ-NO C H
ꢆ
ꢋ
ꢇ
aAll reactions were performed on a 0.5 mmol scale with 5 mol% of
ligand and 5 mol% of Cu(OAc) ·H O in 2 mL of 2-propanol at room
2
2
temperature for ꢍ8 h.
b
Yields of isolated products.
c
Enantiomeric excess was checked by HPLC using Chiracel OD-H
column.
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6
ꢀꢀꢀꢀꢁꢀE. Wolińska: Chiral oxazoline ligands with two azaheteroaromatic rings
analyzer. Optical rotation values were measured at room tempera- 3-[(4S)-4-tert-Butyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine
ture with a Perkin-Elmer polarimeter. The ee values were checked (6a)ꢁCompound was prepared from (S)-2-amino-3,3-dimethylbutan-
by HPLC (Knauer) analysis by using a chiral stationary phase col- 1-ol (176 mg, 1.5 mmol) and 2-aminopyridine-3-carbonitrile after
umn (Chiralcel OD-H), and eluting with 2-propanol–hexanes. Thin 4 days of heating. The product was isolated by silica gel chromatog-
layer chromatography (TLC) was carried out on aluminium sheets raphy (hexane/EtOAc, 5:1) and crystallized from hexanes; yield 69%
coated with silica gel 60 F254 (Merck). Column chromatography (151 mg); mp 69°C; [α]D2 ꢀ=ꢀ +13.9 (c 0.98, CH Cl ); IR (ZnSe): 3336, 3155,
0
2
2
-
1 1
separations were performed by using Merck Kieselgel 60 (0.040- 2953, 1639, 1616, 1467, 1456, 1261, 773 cm ; H NMR (CDCl ): δ 8.12 (dd,
3
0
.060 mm). Solvents were dried and distilled according to standard 1H, J ꢀ=ꢀ 1.8 Hz, J ꢀ=ꢀ 5.2 Hz), 7.90 (dd, 1H, J ꢀ=ꢀ 1.8 Hz, J ꢀ=ꢀ 7.8 Hz), 6.60 (dd,
procedures. 3-Chloro-5,6-diphenyl-1,2,4-triazine [23] and 3-bromo- 1H, J ꢀ=ꢀ 5.2 Hz, J ꢀ=ꢀ 7.8 Hz), 4.29–4.22 (m, 1H), 4.16–4.07 (m, 1H), 2.95 (br
1
3
5
,6-diphenyl-1,2,4-triazine [1] were synthesized according to litera- s, 2H), 0.93 (s, 9H); C NMR (CDCl ) δ: 162.2, 158.2, 151.0, 137.8, 122.2,
3
ture procedures.
104.7, 67.5, 33.8, 25.8. Anal. Calcd for C H N O (219.28): C, 65.73; H,
.81; N, 19.16. Found: C, 65.77; H, 7.75; N, 19.07.
1
2
17
3
7
3
-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine
Synthesis of 2-aminopyridine-3-carbonitrile 1-oxide (8)
(
6b)ꢁCompound was prepared from (S)-2-phenylglycinol (105 mg,
1.5 mmol) and 2-aminopyridine-3-carbonitrile after 4 days of heat-
A solution of 2-aminopyridine-3-carbonitrile (4, 950 mg, 8 mmol) in
dichloromethane (30 mL) was cooled to -10°C and treated dropwise
with a solution of m-chloroperbenzoic acid (1656 mg, 9.6 mmol) in
dichloromethane (15 mL). The resulting mixture was stirred at -10°C
for 3 h and then at room temperature for 20 h. The product was fil-
tered off, washed with ethyl ether and dried undera reduced pres-
sure; yield 88% (950 mg); mp 238–239°C; IR (ZnSe): 3271, 3099, 3076,
ing. The product was isolated by silica gel chromatography (hexane/
EtOAc, 3:1) and recrystallized from hexanes; yield 99% (236 mg); mp
20
7
0–71°C; [α]D ꢀ=ꢀ +159.5 (c 1.05, CH Cl ); IR (ZnSe): 3330, 3152, 2950,
2 2
-1
1
1
638, 1614, 1464, 1453, 1260, 771 cm ; H NMR (CDCl ): δ 8.18 (dd, 1H,
3
J ꢀ=ꢀ 1.9 Hz, J ꢀ=ꢀ 4.8 Hz), 7.99 (dd, 1H, J ꢀ=ꢀ 1.9 Hz, J ꢀ=ꢀ 7.6 Hz), 7.39–7.35 (m,
H), 7.32–7.28 (m, 3H), 6.65 (dd, 1H, J ꢀ=ꢀ 4.8 Hz, J ꢀ=ꢀ 7.6 Hz), 5.45 (dd,
H, J ꢀ=ꢀ 8.3 Hz, J ꢀ=ꢀ 10.0 Hz), 4.73 (dd, 1H, J ꢀ=ꢀ 8.3 Hz, J ꢀ=ꢀ 10.0 Hz), 4.17
2
1
-1
1
3
057, 2225, 1620, 1581, 1506, 1446, 1215 cm ; H NMR (CDCl ): δ 8.35
3
(t, 1H, J ꢀ=ꢀ 8.3 Hz), amino group protons were exchanged with deute-
(
dd, 1H, J ꢀ=ꢀ 1.2 Hz, J ꢀ=ꢀ 6.4 Hz), 7.73 (br s, 2H), 7.57 (dd, 1H, J ꢀ=ꢀ 1.2 Hz,
13
rium; C NMR (CDCl ): δ 163.8, 158.3, 151.5, 142.2, 138.2, 128.8, 127.7,
3
13
J ꢀ=ꢀ 8.0 Hz), 6.69 (dd, 1H, J ꢀ=ꢀ 6.4 Hz, J ꢀ=ꢀ 8.0 Hz); C NMR (DMSO-d ): δ
+
6
126.5, 112.3, 104.4, 73.7, 70.1. HRMS (ESI). Calcd for C H N O ([M+H] ):
m/z 240.1131. Found: m/z 240.1131.
1
4
14
3
1
5
52.3, 140.8, 130.9, 115.2, 112.1, 91.3. Anal. Calcd for C H N O (135.12): C,
6 5 3
3.33; H, 3.73; N, 31.10. Found: C, 53.37; H, 3.76; N, 31.16.
3
-[(4S)-4-Isopropyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine
(
6c)ꢁCompound was prepared from (S)-valinol (155 mg, 1.5 mmol)
and 2-aminopyridine-3-carbonitrile after 4 days of heating. The prod-
uct was isolated by silica gel chromatography (hexane/EtOAc, 3:1)
Synthesis of 3-cyano-2-[(dimethylamino)methyleneamino]-
pyridine 1-oxide (9)
and crystallized from hexanes; yield 31% (64 mg); mp 100–101°C;
α]D2 ꢀ=ꢀ -8.5 (c 1.03, CH Cl ); IR (KBr): 3309, 3136, 2954, 2364, 1638,
0
[
1
2
2
2
-Aminopyridine-3-carbonitrile 1-oxide (8, 135 mg, 1 mmol) was
-1 1
577, 1450, 1363, 1258, 1068, 1037 cm ; H NMR (CDCl ): δ 8.11 (dd, 1H,
3
treated with DMF-DMA (0.4 mL, 3 mmol). The mixture was placed in
the ultrasonic bath for 15 min and then stirred at room temperature
J ꢀ=ꢀ 1.9 Hz, J ꢀ=ꢀ 4.9 Hz), 7.90 (dd, 1H, J ꢀ=ꢀ 1.9 Hz, J ꢀ=ꢀ 7.7 Hz), 6.59 (dd, 1H,
J ꢀ=ꢀ 4.9 Hz, J ꢀ=ꢀ 7.7 Hz), 4.34 (dd, 1H, J ꢀ=ꢀ 7.9 Hz, J ꢀ=ꢀ 9.2 Hz), 4.12–4.06
(m, 1H), 4.02 (t, 1H, J ꢀ=ꢀ 7.9 Hz), 1.89 (br s, 2H), 1.81–1.73 (m, 1H), 1.01 (d,
for 80 h. Next, the suspension was dissolved in CCl and the solvent
4
was evaporated. The dissolving-evaporating procedure was repeated
13
3
H, J ꢀ=ꢀ 6.7 Hz), 0.93 (d, 3H, J ꢀ=ꢀ 6.7 Hz); C NMR (CDCl ): δ 162.3, 158.2,
3
five times to obtain analytically pure product 9; yield 92% (175 mg);
1
(
37.8, 112.2, 104.7, 72.9, 69.4, 33.1, 18.9, 18.6. Anal. Calcd for C H N O
11 15 3
-1 1
mp 110–112°C; IR (ZnSe): 2227, 1608, 1570, 1517, 1199, 1109 cm ; H NMR
205.26): C, 64.37; H, 7.37; N, 20.47. Found: C, 64.39; H, 7.31; N, 20.36.
(
CDCl ): δ 10.03 (s, 1H), 8.17 (dd, 1H, J ꢀ=ꢀ 1.6 Hz, J ꢀ=ꢀ 6.8 Hz), 7.41 (dd,
3
1
H, J ꢀ=ꢀ 1.6 Hz, J ꢀ=ꢀ 7.8 Hz), 6.70 (dd, 1H, J ꢀ=ꢀ 6.8 Hz, J ꢀ=ꢀ 7.8 Hz), 3.17 3-[(4R)-4-Benzyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine
s, 3H), 3.15 (s, 3H); 1 C NMR (CDCl ) δ: 156.9, 152.3, 143.1, 131.1, 116.0, (6d)ꢁCompound was prepared from (R)-2-amino-3-phenylpropan-
3
(
3
+
1
15.1, 106.6, 40.9, 33.9. HRMS (ESI). Calcd for C H N O ([M+H] ): m/z 1-ol (227 mg, 1.5 mmol) and 2-aminopyridine-3-carbonitrile after 4
9
11
4
1
91.0927. Found: m/z 191.0928.
days. The product was purified by silica gel chromatography (CH Cl /
2 2
MeOH, 40:1); yield 74% (187 mg), yellow oil; [α]D2 ꢀ=ꢀ -23.9 (c 1.39,
0
CH Cl ); IR (KBr): 3334, 3158, 2949, 1632, 1615, 1459, 1450, 1265, 778
2
2
-
1 1
cm ; H NMR (CDCl ): δ 8.14 (dd, 1H, J ꢀ=ꢀ 1.8 Hz, J ꢀ=ꢀ 4.8 Hz), 7.90 (dd,
General procedure for the synthesis of 3-(4,5-dihydro-
,3-oxazol-2-yl)pyridin-2-amines 6a–d and N-oxides 12a–e
3
1
H, J ꢀ=ꢀ 1.8 Hz, J ꢀ=ꢀ 7.6 Hz), 7.34–7.30 (m, 2H), 7.25–7.21 (m, 3H), 6.60
1
(
dd, 1H, J ꢀ=ꢀ 4.8 Hz, J ꢀ=ꢀ 7.6 Hz), 4.66–4.60 (m, 1H), 4.32 (dd, 1H, J ꢀ=ꢀ 8.0
Hz, J ꢀ=ꢀ 8.8 Hz), 4.06 (dd, 1H, J ꢀ=ꢀ 8.0 Hz, J ꢀ=ꢀ 8.8 Hz), 3.11 (dd, 1H, J ꢀ=ꢀ
An oven dried two-necked flask was filled with argon and charged 7.0 Hz, J ꢀ=ꢀ 13.6 Hz), 2.78 (dd, 1H, J ꢀ=ꢀ 7.0 Hz, J ꢀ=ꢀ 13.6 Hz), amino group
with 2-aminopyridine-3-carbonitrile (4, 119 mg, 1 mmol) or 2-amino- protons were exchanged with deuterium; 13C NMR (CDCl ): δ 162.8,
3
pyridine-3-carbonitrile 1-oxide (8, 135 mg, 1 mmol), the appropriate 158.2, 151.3, 138.0, 137.9, 129.2, 128.5, 126.5, 112.3, 104.6, 70.8, 68.0, 42.1.
amino alcohol (1.5 mmol), and anhydrous chlorobenzene (6 mL). The HRMS (ESI). Calcd for C H N O ([M+H]
): m/z 254.1288. Found: m/z
+
1
5
16
3
mixture was heated to 60°C and freshly flame-dried ZnCl (27 mg, 254.1287.
2
2
0 mol%) was added. The mixture was stirred under reflux for
the indicated period of time. The solvent was then removed under 3-[(4S)-4-tert-Butyl-4,5-dihydro-1, 3-oxazol-2-yl]pyri-
reduced pressure and the product was extracted with dichlorometh- dine-2-amine 1-oxide (12a)ꢁCompound was prepared from
ane and purified as described below.
(S)-2-amino-3,3-dimethylbutan-1-ol (176 mg, 1.5 mmol) and
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E. Wolińska: Chiral oxazoline ligands with two azaheteroaromatic ringsꢂꢁꢀꢀꢀꢂ7
2
-aminopyridine-3-carbonitrile 1-oxide after 60 h of heating. The chromatography (CH Cl /MeOH, 30:1) and crystallized from a mixture
2 2
2
0
product was isolated by silica gel chromatography (CH Cl /MeOH, of hexanes and EtOAc; yield 72% (194 mg); mp 134–136°C; [α]D ꢀ=ꢀ
2
2
1
1
1
1
1
4
0:1) and crystallized from hexanes; yield 75% (176 mg); mp 128– +76.8 (c 0.52, CH Cl ); IR (KBr): 3385, 3251, 3034, 2893, 1641, 1548,
2 2
2
0
-1 1
29°C; [α]D ꢀ=ꢀ +41.8 (c 1.02, CH Cl ); IR (KBr): 3320, 3220, 2952, 2870, 1454, 1193 cm ; H NMR (CDCl ): δ 8.72 (br s, 2H), 8.15 (d, 1H, J ꢀ=ꢀ 6.9
2
2
3
-1 1
620, 1611, 1446, 1210 cm ; H NMR (CDCl ): δ 8.86 (br s, 2H), 8.20 (dd, Hz), 7.53 (d, 1H, J ꢀ=ꢀ 6.9 Hz), 7.28–7.17 (m, 5H), 6.51 (t, 1H, J ꢀ=ꢀ 6.9 Hz),
H, J ꢀ=ꢀ 1.6 Hz, J ꢀ=ꢀ 6.4 Hz), 7.62 (dd, 1H, J ꢀ=ꢀ 1.2 Hz, J ꢀ=ꢀ 8.0 Hz), 6.57 (dd, 4.63–4.56 (m, 1H), 4.31 (t, 1H, J ꢀ=ꢀ 9.2 Hz), 4.06 (t, 1H, J ꢀ=ꢀ 8.0 Hz), 3.04
H, J ꢀ=ꢀ 6.4 Hz, J ꢀ=ꢀ 7.6 Hz), 4.32 (dd, 1H, J ꢀ=ꢀ 8.4 Hz, J ꢀ=ꢀ 9.6 Hz), 4.21– (dd, 1H, J ꢀ=ꢀ 6.8 Hz, J ꢀ=ꢀ 13.6 Hz), 2.77 (dd, 1H, J ꢀ=ꢀ 6.8 Hz, J ꢀ=ꢀ 13.6 Hz);
3
.11 (m, 2H), 0.94 (s, 9H); 1 C NMR (CDCl ): δ 161.0, 150.8, 139.0, 128.4,
3
13
C NMR (CDCl ): δ 161.4, 150.4, 138.8, 137.3, 129.0, 128.4, 127.9, 126.4,
3
3
+
1
6
10.2, 106.9, 76.3, 68.1, 33.8, 25.8. Anal. Calcd for C H N O (235.28): C, 110.2, 106.5, 71.0, 67.7, 41.6. HRMS (ESI). Calcd for C H N O ([M+H] ):
12
17
3
2
15 16
3
2
1.26; H, 7.28; N, 17.86. Found: C, 61.28; H, 7.11; N, 17.83.
m/z 270.1237. Found: m/z 270.1236.
3
-[(4S)-4-Phenyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine
1
-oxide (12b)ꢁCompound was prepared from (S)-2-phenylglicinol General procedure for the preparation of ligands 2a–d
105 mg, 1.5 mmol) and 2-aminopyridine-3-carbonitrile 1-oxide after
4 h of heating. The product was isolated by silica gel chromatogra-
phy (CH Cl /MeOH, 30:1) and recrystallized from the mixture of hex-
(
2
An oven-dried three-necked flask was filled with argon and charged
with Pd dba (45.8 mg, 10 mol%), Xantphos (57.8 mg, 20 mol%),
2
2
2
0
2
3
anes and EtOAc; yield 73% (186 mg); mp 108–109°C; [α]D ꢀ=ꢀ +257.5
3
-(oxazol-2-yl)pyridine-2-amine 6a–d (0.6 mmol), 3-bromo-5,6-diphe-
-1
1
(
c 1.04, CH Cl ); IR (KBr): 3250, 1620, 1540, 1446, 1220 cm ; H NMR
2 2
nyl-1,2,4-triazine (7a, 156 mg, 0.5 mmol) and K CO (1.38 g, 10 mmol).
2
3
(
CDCl ): δ 8.76 (br s, 2H), 8.23 (dd, 1H, J ꢀ=ꢀ 1.2 Hz, J ꢀ=ꢀ 6.4 Hz), 7.70 (dd,
3
Then, the flask was evacuated and backfilled with argon. Dioxane (10
mL) was added trough a septum and the mixture was heated under
reflux for the indicated period of time. After cooling, the solid mate-
rial was filtered off and washed with CH Cl . The solvent was evapo-
1
H, J ꢀ=ꢀ 1.2 Hz, J ꢀ=ꢀ 8.0 Hz), 7.40–7.27 (m, 5H), 6.61 (dd, 1H, J ꢀ=ꢀ 6.4 Hz,
J ꢀ=ꢀ 8.0 Hz), 5.49 (dd, 1H, J ꢀ=ꢀ 8.4 Hz, J ꢀ=ꢀ 10.0 Hz), 4.78 (dd, 1H, J ꢀ=ꢀ 8.4
13
Hz, J ꢀ=ꢀ 10.0 Hz), 4.22 (t, 1H, J ꢀ=ꢀ 8.4 Hz); C NMR (CDCl ): δ 162.6, 150.9,
3
2
2
1
41.6, 139.1, 128.9, 128.0, 127.9, 126.5, 110.4, 106.4, 74.1, 70.2. Anal. Calcd
rated, and the resulting crude product was purified as described
below.
for C H N O (255.27): C, 65.87; H, 5.13; N, 16.46. Found: C, 65.93; H,
14
13
3
2
5
.12; N, 16.36.
5
,6-Diphenyl-3-{3-[(4S)-4-tert-butyl- 4,5-dihydro-1,3-oxazol-2-yl]
3
-[(4S)-4-Isopropyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-
-amine 1-oxide (12c)ꢁCompound was prepared from (S)-valinol
pyridin-2-yl}amino-1,2,4-triazine (2a)ꢁThe product was obtained
from 3-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine
2
(
155 mg, 1.5 mmol) and 2-aminopyridine-3-carbonitrile 1-oxide after
(
6a) after 24 h of heating as a yellow solid, purified by column chro-
4
0 h of heating. The product was isolated by silica gel chromatogra-
matography (CH Cl /MeOH, 30:1) and crystallized from ethanol; yield
2
2
phy (CH Cl /MeOH, 30:1) and crystallized from hexanes; yield 62%
(
3
20
2
2
36% (81 mg); mp 204–206°C; [α]D ꢀ=ꢀ –1.7 (c 0.54, CH Cl ); IR (ZnSe):
2 2
2
0
137 mg); mp 130–131°C; [α]D ꢀ=ꢀ +22.0 (c 1.01, CH Cl ); IR (KBr): 3346,
228, 2958, 2873, 1643, 1614, 1548, 1446, 1192 cm ; H NMR (CDCl ): δ
-1
1
2
2
3057, 2958, 1631, 1610, 1506, 1435, 1390, 1053, 759, 696 cm ; H NMR
-
1 1
3
(CDCl ): δ 12.74 (s, 1H), 8.60 (dd, 1H, J ꢀ=ꢀ 1.6 Hz, J ꢀ=ꢀ 4.8 Hz), 8.13 (dd,
3
8
.80 (br s, 2H), 8.18 (dd, 1H, J ꢀ=ꢀ 1.6 Hz, J ꢀ=ꢀ 6.4 Hz), 7.60 (dd, 1H, J ꢀ=ꢀ 1.6
1
H, J ꢀ=ꢀ 2.0 Hz, J ꢀ=ꢀ 7.6 Hz), 7.65–7.63 (m, 2H), 7.58–7.54 (m, 2H), 7.40–7.29
Hz, J ꢀ=ꢀ 8.0 Hz), 6.56 (dd, 1H, J ꢀ=ꢀ 6.8 Hz, J ꢀ=ꢀ 8.0 Hz), 4.39 (dd, 1H, J ꢀ=ꢀ
(
m, 6H), 6.99 (dd, 1H, J ꢀ=ꢀ 5.2 Hz, J ꢀ=ꢀ 8.0 Hz), 4.41–4.36 (m, 1H), 4.27–
7
.6 Hz, J ꢀ=ꢀ 9.2 Hz), 4.18–4.06 (m, 2H), 1.87–1.77 (m, 1H), 1.02 (d, 3H, J ꢀ=ꢀ
13
4
.22 (m, 2H), 1.03 (s, 9H); C NMR (CDCl ): δ 161.9, 158.0, 155.8, 152.3,
3
.8 Hz), 0.94 (d, 3H, J ꢀ=ꢀ 6.8 Hz); 1 C NMR (CDCl ): δ 161.1, 150.7, 138.9,
3
6
3
151.9, 151.0, 137.7, 136.0, 135.9, 130.5, 129.9, 129.3, 128.7, 128.4, 128.3,
116.4, 108.6, 76.2, 68.1, 34.0, 25.9. Anal. Calcd for C H N O (450.53):
C, 71.98; H, 5.82; N, 18.65. Found: C, 71.81; H, 5.79; N, 18.61.
1
27.7, 110.3, 106.8, 72.9, 69.9, 33.0, 18.8, 18.5. Anal. Calcd for C H N O
11 15 3 2
2
7
26
6
(
221.25): C, 59.71; H, 6.83; N, 18.99. Found: C, 59.82; H, 6.87; N, 18.93.
3
-[(4R)-4-Benzyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine 5,6-Diphenyl-3-{3-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]
1
-oxide (12d)ꢁCompound was prepared from (R)-2-amino-3-phenyl- pyridin-2-yl}amino-1,2,4-triazine (2b)ꢁThe product was obtained
propan-1-ol (227 mg, 1.5 mmol) and 2-aminopyridine-3-carbonitrile from 3-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine
-oxide after 42 h of heating. The product was isolated by silica gel (6b) after 22 h of heating as a yellow solid, purified by column chro-
chromatography (CH Cl /MeOH, 20:1) and crystallized from a mixture matography (CH Cl /MeOH, 30:1) and crystallized from ethanol; yield
1
2
2
2
2
2
0
20
of hexanes and EtOAc; yield 73% (196 mg); mp 134–135°C; [α]D ꢀ=ꢀ 32% (75 mg); mp 104–105°C; [α]D ꢀ=ꢀ +212.9 (c 0.51, CH Cl ); IR (ZnSe):
2
2
-
1
77.5 (c 1.02, CH Cl ); IR (KBr): 3379, 3250, 3040, 2884, 1642, 1614, 1546, 3026, 2887, 1614, 1504, 1442, 1413, 1350, 1128, 1041, 958, 763, 694 cm-1
;
2
2
-1
1
1
455, 1194 cm ; H NMR (CDCl ): δ 8.75 (br s, 2H), 8.20 (dd, 1H, J ꢀ=ꢀ 1.2
H NMR (CDCl ): δ 12.38 (s, 1H), 8.62 (dd, 1H, J ꢀ=ꢀ 1.8 Hz, J ꢀ=ꢀ 4.8 Hz),
3
3
Hz, J ꢀ=ꢀ 6.4 Hz), 7.58 (dd, 1H, J ꢀ=ꢀ 1.2 Hz, J ꢀ=ꢀ 8.0 Hz), 7.33–7.22 (m, 5H), 8.22 (dd, 1H, J ꢀ=ꢀ 1.8 Hz, J ꢀ=ꢀ 7.8 Hz), 7.62–7.60 (m, 2H), 7.56–7.41 (m, 2H),
6
.56 (dd, 1H, J ꢀ=ꢀ 6.4 Hz, J ꢀ=ꢀ 8.0 Hz), 4.67–4.62 (m, 1H), 4.37 (t, 1H, J ꢀ=ꢀ 7.40–7.29 (m, 11H), 7.04 (dd, 1H, J ꢀ=ꢀ 4.8 Hz, J ꢀ=ꢀ 7.8 Hz), 5.61 (dd, 1H, J ꢀ=ꢀ
8
.4 Hz), 4.11 (dd, 1H, J ꢀ=ꢀ 7.6 Hz, J ꢀ=ꢀ 8.4 Hz), 3.10 (dd, 1H, J ꢀ=ꢀ 6.4 Hz, J ꢀ=ꢀ 8.4 Hz, J ꢀ=ꢀ 10.0 Hz), 4.84 (dd, 1H, J ꢀ=ꢀ 8.4 Hz, J ꢀ=ꢀ 10.0 Hz), 4.29 (t, 1H,
3.6 Hz), 2.83 (dd, 1H, J ꢀ=ꢀ 7.6 Hz, J ꢀ=ꢀ 14.0 Hz); 1 C NMR (CDCl ): δ 161.7, J ꢀ=ꢀ 8.4 Hz); C NMR (CDCl ): δ 163.2, 158.0, 155.9, 152.4, 152.1, 151.3, 141.
3
13
1
1
3
3
50.7, 139.0, 137.5, 129.2, 128.6, 127.8, 126.7, 110.3, 106.6, 71.3, 68.0, 41.8. 6, 138.1, 135.9, 130.4, 130.0, 129.3, 128.8, 128.7, 128.4, 128.3, 127.7, 126.4,
): m/z
Anal. Calcd for C H N O (269.30): C, 66.90; H, 5.61; N, 15.60. Found: 116.6, 108.5, 73.9, 69.9. HRMS (ESI). Calcd for C H N O ([M+H]
+
1
5
15
3
2
29 23
6
C, 66.91; H, 5.64; N, 15.52.
471.1928. Found: m/z 471.1921.
3
-[(4S)-4-Benzyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine 5,6-Diphenyl-3-{3-[(4S)-4-isopropyl- 4,5-dihydro-1,3-oxazol-2-yl)
-oxide (12e)ꢁCompound was prepared from (S)-2-amino-3-phenyl- pyridin-2-yl]amino-1,2,4-triazine (2c)ꢁThe product was obtained
propan-1-ol (227 mg, 1.5 mmol) and 2-aminopyridine-3-carbonitrile from 3-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine
-oxide after 47 h of heating. The product was isolated by silica gel (6c) after 21 h of heating as a yellow solid, purified by column
1
1
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8
ꢀꢀꢀꢀꢁꢀE. Wolińska: Chiral oxazoline ligands with two azaheteroaromatic rings
chromatography (CH Cl /MeOH, 30:1) and crystallized from ethanol; 2-[Bis(5,6-diphenyl-1,2,4-triazin-3-yl)amino]-3-[(4S)-4-isopropyl-
2
2
2
0
yield 35% (76 mg); mp 158–160°C; [α]D ꢀ=ꢀ +1.5 (c 0.52, CH Cl ); IR 4,5-dihydro-1,3-oxazol-2-yl]pyridine 1-oxide (13c)ꢁCompound
2
2
(
ZnSe): 2.960, 2926, 2899, 2881, 1643, 1627, 1516, 1442, 1396, 1049, 765, was prepared from 3-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]
-1 1
6
94 cm ; H NMR (CDCl ): δ 12.65 (s, 1H), 8.59 (dd, 1H, J ꢀ=ꢀ 1.9 Hz, J ꢀ=ꢀ pyridine-2-amine 1-oxide (12c) (243 mg, 1.1 mmol), purified by silica
3
4
.8 Hz), 8.13 (dd, 1H, J ꢀ=ꢀ 1.9 Hz, J ꢀ=ꢀ 7.7 Hz), 7.62–7.64 (m, 2H), 7.54–7.56 gel chromatography (CH Cl /MeOH, 30:1) and crystallized from hex-
2 2
2
0
(
(
m, 2H), 7.40–7.29 (m, 6H), 7.00 (dd, 1H, J ꢀ=ꢀ 4.8 Hz, J ꢀ=ꢀ 7.7 Hz), 4.46 anes/EtOAc; yield 42% (143 mg); mp 142–144°C; [α]D ꢀ=ꢀ -21.8 (c 0.61,
dd, 1H, J ꢀ=ꢀ 8.2 Hz, J ꢀ=ꢀ 9.3 Hz), 4.26–4.20 (m, 1H), 4.13 (t, 1H, J ꢀ=ꢀ 8.1 CH Cl ); IR (KBr): 3057, 2958, 1651, 1519, 1489, 1398, 1367, 1282, 1064,
2
2
-1 1
Hz), 1.90–1.82 (m, 1H), 1.14 (d, 3H, J ꢀ=ꢀ 6.7 Hz), 1.01 (d, 3H, J ꢀ=ꢀ 6.7 Hz); 759, 696 cm ; H NMR (CDCl ): δ 8.43 (dd, 1H, J ꢀ=ꢀ 1.2 Hz, J ꢀ=ꢀ 6.8 Hz),
3
13
C NMR (CDCl ): δ 162.7, 158.8, 156.6, 153.0, 152.7, 151.7, 138.4, 136.7, 7.95 (dd, 1H, J ꢀ=ꢀ 1.2 Hz, J ꢀ=ꢀ 8.8 Hz), 7.54–7.47 (m, 9H), 7.40–7.33 (m,
3
1
1
36.6, 131.1, 130.6, 129.9, 129.4, 129.0, 128.9, 117.0, 109.2, 73.2, 70.5, 33.5, 10H), 7.24–7.20 (m, 2H), 4.19 (t, 1H, J ꢀ=ꢀ 7.6 Hz), 3.94–3.85 (m, 2H), 1.52–
1
3
9.0, 18.9. Anal. Calcd for C H N O (436.51): C, 71.54; H, 5.54; N, 19.25. 145 (m, 1H), 0.64 (d, 3H, J ꢀ=ꢀ 6.8 Hz), 0.60 (d, 3H, J ꢀ=ꢀ 6.8 Hz); C NMR
2
6
24
6
Found: C, 71.51; H, 5.61; N, 19.18.
(CDCl ): δ 159.0, 158.9, 158.3, 156.7, 156.6, 153.9, 153.8, 145.7, 141.2, 135.6,
35.5, 135.4, 130.5, 130.4, 130.1, 130.0, 129.4, 129.3, 129.2, 129.1, 128.4,
,6-Diphenyl-3-{3-[(4R)-4-benzyl-4,5-dihydro-1,3-oxazol-2-yl] 128.2, 128.1, 127.2, 126.8, 123.9, 72.9, 70.0, 32.4, 18.3, 18.0. HRMS (ESI).
3
1
5
+
pyridin-2-yl}amino-1,2,4-triazine (2d)ꢁThe product was obtained Calcd for C H N O ([M+H] ): m/z 684.2830. Found: m/z 684.2836.
41
34
9
2
from 3-[(4R)-4-benzyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine
6d) after 18 h of heating as a yellow solid, purified by column chro-
matography (CH Cl /MeOH, 30:1) and crystallized from ethanol; yield
(
2
2
Procedure for the reaction of 3-chloro-5,6-diphenyl-
,2,4-triazine (7b) with (4,5-dihydro-1,3-oxazol-2-yl)
pyridine-2-amine 1-oxides in the absence of K CO
2
0
3
7% (89 mg); mp 168–170°C; [α]D ꢀ=ꢀ -24.6 (c 0.53, CH Cl ); IR (ZnSe):
2 2
1
-1
1
3
061, 2887, 1643, 1604, 1496, 1440, 1411, 1346, 1047, 767, 694 cm ; H
NMR (CDCl ): δ 12.38 (s, 1H), 8.58 (dd, 1H, J ꢀ=ꢀ 1.8 Hz, J ꢀ=ꢀ 5.0 Hz), 8.12
2
3
3
(
dd, 1H, J ꢀ=ꢀ 1.8 Hz, J ꢀ=ꢀ 7.8 Hz), 7.63–7.58 (m, 2H), 7.57–7.56 (m, 2H),
7
.44–7.24 (m, 9H), 7.21–7.17 (m, 2H), 7.00 (dd, 1H, J ꢀ=ꢀ 5.0 Hz, J ꢀ=ꢀ 7.6 Hz), The mixture of 3-chloro-5,6-diphenyl-1,2,4-triazine (7b, 267 mg,
4
.79–4.71 (m, 1H), 4.41 (t, 1H, J ꢀ=ꢀ 8.2 Hz), 4.16 (t, 1H, J ꢀ=ꢀ 8.2 Hz), 3.25 1 mmol) and 3-[(4S)-4-alkyl/aryl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-
(
dd, 1H, J ꢀ=ꢀ 6.8 Hz, J ꢀ=ꢀ 14.0 Hz), 2.87 (dd, 1H, J ꢀ=ꢀ 6.8 Hz, J ꢀ=ꢀ 14.0 Hz); 2-amine 1-oxide (12a or 12b, 1.1 mmol) in DMF (7 mL) was heated at
13
C NMR (CDCl ): δ 162.4, 158.0, 156.0, 152.3, 152.1, 151.1, 137.9, 137.5, 50°C for 24 h. The solvent was evaporated under vacuum and the pro-
3
1
36.0, 135.9, 130.4, 130.0, 129.3, 128.8, 128.6, 128.4, 128.3, 126.6, 116.6, ducts were isolated by silica gel chromatography (CH Cl /MeOH, 30:1).
2
2
+
1
08.6, 71.1, 67.9, 41.7. HRMS (ESI). Calcd for C H N O ([M+H] ): m/z
3
0
25
6
4
85.2084. Found: m/z 485.2088.
2-(5,6-Diphenyl-1,2,4-triazin-3-ylamino)-3-[(4S)-4-tert-butyl-
4
,5-dihydrooxazol-2-yl]pyridine 1-oxide (3a)ꢁCompound was
prepared from 3-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]pyri-
dine-2-amine 1-oxide (12a, 259 mg, 1.1 mmol); yield 15% (105 mg); mp
Procedure for the reaction of 3-chloro-5,6-diphenyl-
,2,4-triazine (7b) with (4,5-dihydro-1,3-oxazol-2-yl)
pyridine-2-amine 1-oxides in the presence of K CO
0
9
8–100°C; [α]D2 ꢀ=ꢀ -30.1 (c 1.27, CH Cl ); IR (SnZe): 3061, 2955, 1645,
2
2
1
-1
1
1
504, 1360, 1190, 1058, 696 cm ; H NMR (CDCl ): δ 10.59 (br s, 1H),
3
2
3
8.40 (dd, 1H, J ꢀ=ꢀ 1.2 Hz, J ꢀ=ꢀ 6.4 Hz), 7.81 (dd, 1H, J ꢀ=ꢀ 1.2 Hz, J ꢀ=ꢀ 8.0
Hz), 7.55–7.51 (m, 4H), 7.40–7.29 (m, 6H), 7.08 (dd, 1H, J ꢀ=ꢀ 6.4 Hz, J ꢀ=ꢀ
1
3
A mixture of 3-chloro-5,6-diphenyl-1,2,4-triazine (7b, 267 mg, 1 8.0 Hz), 4.05–4.03 (m, 2H), 3.75 (t, 1H, J ꢀ=ꢀ 9.4 Hz), 0.83 (s, 9H);
mmol), appropriate [4,5-dihydro-1,3-oxazol-2-yl]pyridine-2-amine NMR (CDCl ): δ 160.1, 156.8, 155.7, 152.6, 144.7, 139.9, 135.5, 135.3, 130.6,
C
3
1
-oxide (1.1 mmol), and K CO (415 mg, 3 mmol) were placed in 129.9, 129.3, 128.9, 128.4, 128.3, 127.6, 118.1, 117.1, 75.8, 68.9, 33.6, 25.8.
2 3
+
round-bottom flask. Then, freshly dried dioxane (16 mL) was added HRMS (ESI). Calcd for C H N O ([M+H] ): m/z 467.2190. Found m/z
2
7
27
6
2
and the mixture was heated at 95°C for 24 h. After cooling, the 467.2190.
solid material was filtered off and washed with CH Cl . The solvent
was evaporated, and the resulting crude product was purified as 2-(5,6-Diphenyl-1,2,4-triazin-3-ylamino)-3-[(4S)-4-phenyl-
described below.
2
2
4,5-dihydrooxazol-2-yl]pyridine 1-oxide (3b)ꢁCompound was
prepared from 3-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-
2
-[Bis(5,6-diphenyl-1,2,4-triazin-3-yl)amino]-3-[(4S)-4-tert-butyl- 2-amine 1-oxide (12b, 279 mg, 1.1 mmol); yield 10% (29 mg); mp 114–
,5-dihydro-1,3-oxazol-2-yl]pyridine 1-oxide (13a)ꢁCompound 115°C; [α]D2 ꢀ=ꢀ -16.2 (c 0.49, CH Cl ); IR (SnZe): 3059, 2918, 1643, 1600,
0
4
2
2
-1 1
was prepared from 3-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl] 1579, 1487, 1390, 1193, 1060, 694 cm ; H NMR (DMSO-d ): δ 10.01 (br
6
pyridine-2-amine 1-oxide (12a, 259 mg, 1.1 mmol), purified by silica s, 1H), 8.59 (dd, 1H, J ꢀ=ꢀ 1.4 Hz, J ꢀ=ꢀ 6.4 Hz), 7.85 (dd, 1H, J ꢀ=ꢀ 1.4 Hz, 8.0
gel chromatography (dichloromethane/methanol, 30:1) and crystal- Hz), 7.46–7.36 (m, 7H), 7.33–7.32 (m, 4H), 7.24–7.21 (m, 3H), 7.11–7.09 (m,
lized from hexanes/EtOAc; yield 35% (61 mg); mp 134–136°C; [α]D2 ꢀ=ꢀ 2H), 5.22 (dd, 1H, J ꢀ=ꢀ 8.8 Hz, J ꢀ=ꢀ 10.4 Hz), 4.61 (dd, 1H, J ꢀ=ꢀ 8.8 Hz, J ꢀ=ꢀ
0
1
3
-
1 7.0 ( c 0.61, CH Cl ); IR (KBr): 3059, 2956, 2868, 1651, 1517, 1490, 1398, 10.4 Hz), 3.76 (t, 1H, J ꢀ=ꢀ 8.8 Hz); C NMR (CDCl ): δ 161.8, 156.8, 156.0,
2
2
3
-1
1
1
1
365, 1280, 1062, 769, 696 cm ; H NMR (CDCl ): δ 8.43 (dd, 1H, J ꢀ=ꢀ 152.9, 144.3, 141.1, 139.5, 135.3, 135.1, 130.8, 129.8, 129.3, 129.1, 128.7,
3
.6 Hz, J ꢀ=ꢀ 6.8 Hz), 7.95 (dd, 1H, J ꢀ=ꢀ 1.6 Hz, J ꢀ=ꢀ 4.8 Hz), 7.54–7.47 (m, 128.4, 128.3, 128.1, 127.6, 126.4, 118.0, 74.5, 69.8. HRMS (ESI). Calcd for
+
9
H), 7.41–7.32 (m, 10H), 7.24–7.19 (m, 2H), 4.15 (dd, 1H, J ꢀ=ꢀ 8.6 Hz, J ꢀ=ꢀ C H N O ([M+H] ): m/z 487.1877. Found: m/z 487.1880.
29
23
6
2
1
0.0 Hz), 3.98 (t, 1H, J ꢀ=ꢀ 8.6 Hz), 3.85 (dd, 1H, J ꢀ=ꢀ 8.6 Hz, J ꢀ=ꢀ 10.0 Hz),
1
3
0
.61 (s, 9H); C NMR (CDCl ): δ 159.0, 158.9, 158.1, 156.7, 156.6, 153.9, 3-[(2S)-1-Chloro-3,3-dimethylbutan-2-ylcarbamoyl]-2-(5,6-diphe-
3
1
45.8, 141.1, 135.7, 135.6, 135.5, 135.4, 130.5, 130.4, 130.1, 130.0, 129.4, nyl-1,2,4-triazin-3-ylamino)pyridine 1-oxide (14a)ꢁCompound
1
29.1, 129.0, 128.4, 128.1, 127.2, 126.9, 124.0, 76.8, 33.6, 25.6. HRMS (ESI). was prepared from 3-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]
+
Calcd for C H N O ([M+H] ): m/z 698.2986. Found: m/z 698.2995.
pyridine-2-amine 1-oxide (12a, 259 mg, 1.1 mmol); yield 48% (255 mg);
42
36
9
2
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E. Wolińska: Chiral oxazoline ligands with two azaheteroaromatic ringsꢂꢁꢀꢀꢀꢂ9
mp 128–130°C; [α]D20 ꢀ=ꢀ +11.9 (c 0.65, CH Cl ); IR (SnZe): 3059, 2964,
[5] Coeffard, V.; Müller-Bunz, H.; Guiry, P. J. The synthesis of new
oxazoline-containing bifunctional catalysts and their applica-
tion in the addition of diethylzinc to aldehydes. Org. Biomol.
Chem. 2009, 7, 1723–1734.
[6] Charushin, V. N.; Alekxeev, S. G.; Chupakhin, O. N.;
Van der Plas, H. C. Behavior of monocyclic 1,2,4-triazines in
reactions with C-, N-, O-, and S-nucleophiles. In Advances in
Heterocyclic Chemistry. Katritzky, A. R., Ed. Academic Press,
Inc.: New York, 1ꢍ8ꢍ; Vol. 46, pp 73–142.
2
2
-1 1
1
660, 1573, 1504, 1479, 1242, 1060, 696 cm ; H NMR (CDCl ): δ 9.89 (br
3
s, 1H), 8.36 (d, 1H, J ꢀ=ꢀ 6.4 Hz), 7.76 (d, 1H, J ꢀ=ꢀ 7.6 Hz), 7.52–7.51 (m, 2H),
.40–7.27 (m, 8H), 7.13–7.09 (m, 2H), 4.16–4.03 (m, 1H), 3.65 (dd, 1H,
7
J ꢀ=ꢀ 3.6 Hz, J ꢀ=ꢀ 11.6 Hz), 3.46 (dd, 1H, J ꢀ=ꢀ 4.8 Hz, 12.0 Hz), 0.84 (s, 9H);
1
3
C NMR (CDCl ): δ 157.7, 157.6, 153.3, 142.4, 138.9, 135.4, 134.9, 130.9,
3
1
30.0, 129.2, 129.1, 128.6, 128.4, 128.3, 128.3, 119.7, 58.4, 45.1, 35.1, 26.9.
+
HRMS (ESI). Calcd for C H N O Cl ([M+H] ): m/z 503.1957. Found:
2
7
28
6
2
m/z 503.1952.
[
7] Wolińska, E. A convenient method of preparation of
3
-[(S)-2-Chloro-1-phenylethylcarbamoyl]-2-(5,6-diphenyl-
,2,4-triazin-3-ylamino)pyridine 1-oxide (14b)ꢁCompound was
prepared from 3-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]pyridine-
3
,3′-dichloro-5,5′-bi-1,2,4-triazine and its synthetic application.
1
Heterocycles 2009, 78, 623–633.
[
8] Nyffenegger, C.; Fournet, G.; Joseph, B. Synthesis of 3-amino-
2
-amine 1-oxide (12b, 279 mg, 1.1 mmol); yield 48% (260 mg); mp
5
H-pyrrolo[2,3-e]-1,2,4-triazines by Sonogashira/copper(I)-
20
1
57–158°C; [α] ꢀ=ꢀ +31.5 (c 0.5, CH Cl ); IR (SnZe): 3059, 1651, 1575,
D
2
2
catalyzed heteroannulation. Tetrahedron Lett. 2007, 48,
506ꢍ–5072.
ꢍ] Pellegatti, L.; Vedrenne, E.; Leger, J.-M.; Jarry, C.; Routier, S.
First efficient palladium-catalyzed aminations of pyrimidines,
-1 1
1
504, 1483, 1386, 1244, 1062, 694 cm ; H NMR (DMSO-d ): δ 9.98 (br
6
s, 1H), 9.15 (d, 1H, J ꢀ=ꢀ 8.8 Hz), 8.56 (dd, 1H, J ꢀ=ꢀ 1.6 Hz, J ꢀ=ꢀ 6.4 Hz),
[
7
.57 (dd, 1H, J ꢀ=ꢀ 1.6 Hz, J ꢀ=ꢀ 8.0 Hz), 7.43–7.34 (m, 9H), 7.33–7.27 (m,
1
3
4
H), 7.21–7.15 (m, 3H), 5.18–5.07 (m, 1H), 3.71–3.69 (m, 2H); C NMR
1
,2,4-triazines and tetrazines by original methyl sulfur release.
(CDCl ): δ 164.1, 157.2, 157.1, 153.5, 142.5, 138.8, 137.9, 135.3, 134.7, 131.0,
3
Synlett 2009, 2137–2142.
1
30.0, 129.4, 129.2, 128.8, 128.7, 128.4, 128.3, 128.2, 126.6, 126.4, 119.0,
[
[
[
[
[
[
10] Yang, B. H.; Buchwald, S. L. Palladium-catalyzed amination of
+
5
4.5, 47.2. HRMS (ESI). Calcd for C H N O Cl ([M+H] ): m/z 523.1643.
2
9
24
6
2
aryl halides and sulfonates. J. Organomet. Chem. 1999, 576,
Found: m/z 523.1642.
1
25–146.
11] Hartwig, J. F. Discovery and understanding of transition-metal-
catalyzed aromatic substitution reactions. Synlett 2006, 17,
General procedure for the catalytic enantioselective
Henry reaction
1
283–12ꢍ4.
12] Hartwig, J. F. Evolution of a fourth generation catalyst for the
amination and thioetherification of aryl halides. Acc. Chem.
Res. 2008, 41, 1534–1544.
A mixture of Cu(OAc) ·H O (5 mg, 0.025 mmol, 5 mol%) and ligand
2
2
13] Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in
palladium-catalyzed amination. Angew. Chem., Int. Ed. 2008,
(
0.025 mmol, 5 mol%) in anhydrous 2-propanol (2 mL) was stirred at
room temperature for 4 h under argon atmosphere to give a red-brown
47, 6338–6361.
solution. The aldehyde (0.5 mmol) and the nitromethane (270 μL,
5
14] Surry, D. S.; Buchwald, S. L. Dialkylbiaryl phosphines
mmol) were added and the mixture was stirred at room temperature
in Pd-catalyzed amination: a user’s guide. Chem. Sci. 2011, 2,
for 4 days. Than the solvent was evaporated under reduced pressure
and the product was isolated by column chromatography. All spec-
troscopic data of the nitroaldol adducts were in good agreement with
those reported previously [1].
2
7–50.
15] Fujisawa, T.; Ichiyanagi, T.; Shimizu, M. Enantioselective
Diels-Alder reaction using chiral Lewis acid prepared from
Grignard reagent and a chiral 2-(2-p-toluenesulfonylamino)
phenyl-4-phenyloxazoline. Tetrahedron Lett. 1995, 36,
5031–5034.
Acknowledgments: The Author is grateful to Prof. Andrzej
Rykowski for helpful discussions.
[16] Radel, R. J.; Keen, B. T.; Wong, C.; Paudler, W. W. Syntheses,
carbon-13 and proton nuclear magnetic resonance spectra of
some 1,2,4-triazine 1- and 2-oxides. J. Org. Chem. 1977, 42,
5
46–550.
References
[
17] Gant, T. G.; Meyers, A. I. The chemistry of 2-oxazolines. Tetra-
herdon 1994, 50, 22ꢍ7–2360.
[
1] Wolińska, E. Chiral oxazoline ligands containing a 1,2,4-triazine
ring and their application in the Cu-catalyzed asymmetric Henry
reaction. Tetrahedron 2013, 69, 726ꢍ–7278.
[18] Wolińska, E. Sequential amination of heteroaromatic halides
with aminopyridine 1-oxides and their N-protected derivatives
based on novel aza-Smiles rearrangement. Heterocycl. Com-
mun. 2012, 18, 227–232.
[
2] Wolińska, E. Asymmetric Henry reactions catalyzed by copper(II)
complexes of chiral 1,2,4-triazine-oxazoline ligands: the impact
of substitution in the oxazoline ring on ligand activity. Tetrahe-
dron: Asymmetry 2014, 25, 1122–1128.
[1ꢍ] Wolińska, E.; Pucko, W. Diversity of reactions of isomeric
aminopyridine N-oxides with chloronitropyridines: an experi-
mental and theoretical study. J. Heterocyclic Chem., 2013, 50,
5ꢍ0–5ꢍ8.
[
[
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1
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