Synthesis of 2-aminooxazolines and spiro-2-aminooxazolines by using a convenient two-step INCO-mediated reaction

Article abstract of DOI:10.1055/s-0033-1339652

A two-step reaction sequence yielding 2-aminooxazolines under mild conditions was developed. Both electron-rich and electron-deficient styrenes as well as functionalized primary and secondary amides could be used in the reaction to afford 2-aminooxazolines in reasonable yields. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339652

2140▌
LETTER
lSetyternthesis of 2-Aminooxazolines and Spiro-2-aminooxazolines by Using a Con-
venient Two-Step INCO-Mediated Reaction
2-Aminooxazolines and Spiro-2-aminooxazolines
Corey D. Anderson, Dean M. Wilson, Long Mao,1a Michele Ramirez-Weinhouse,1a Daniel D. Long,1b
Christine M. Crane,1a Catherine Jolivet,1a Dewey Fanning, Valentina Molteni,1c Andreas Termin*
Vertex Pharmaceuticals, San Diego, 11010 Torreyana Rd., San Diego, CA 92121, USA
Fax +1(858)4046726; E-mail: Andreas_Termin@vrtx.com
Received: 31.05.2013; Accepted after revision: 25.07.2013
by reaction of the α-iodoisocyanates 2 with amine nucleo-
Abstract: A two-step reaction sequence yielding 2-aminooxazo-
philes.8 This approach was better suited to our require-
lines under mild conditions was developed. Both electron-rich and
ments than other known syntheses, which are either
electron-deficient styrenes as well as functionalized primary and
longer, have fewer commercially available starting mate-
rials or require reagents that are poorly suited to parallel
synthesis.9 We felt that if we defined some general condi-
tions for the use of α-iodoisocyanates to produce 2-ami-
noozazolines, that this method could be suitable for
parallel and automated synthesis. Herein, we report the
successful development of an INCO-mediated reaction
that provides convenient access to 2-aminooxazolines.
secondary amides could be used in the reaction to afford 2-amino-
oxazolines in reasonable yields.
Key words: isocyanate, library generation , styrene, heterocycles,
multicomponent reactions
As part of a medicinal chemistry research program fo-
cused on the parallel synthesis of heterocyclic com-
pounds, we required a synthesis of 2-aminooxazolines
that was amenable to high throughput synthesis. Such
compounds have shown anorectant and CNS stimulant ac-
tivities in rodents,2 α-adrenergic receptor antagonism3 and
agonism,4 and the known drug rilmenidine (Figure 1) is
useful as a antihypertensive agent.5
The conversion of olefins 1 into α-iodoisocyanates 2 was
initially evaluated in several solvents. Preparation of io-
dine isocyanate in situ was achieved by stoichiometric re-
action of iodine with silver cyanate (Scheme 1; silver
cyanate is known to be light sensitive, therefore reactions
were conducted in subdued light when possible10). It has
been reported that extended reaction times (12–48 h) were
necessary in diethyl ether, whereas use of dichlorometh-
ane resulted in complete conversion into α-iodoisocyanate
intermediate 2 in less than one hour.7 We investigated the
reaction sequence in tetrahydrofuran, thereby providing a
suitable solvent for both the formation of the α-iodoisocy-
anate intermediate and subsequent reaction with amines.
Furthermore, the use of tetrahydrofuran allows the appli-
cation of automated liquid handling. The addition of sty-
renes or olefins to the INCO solution in tetrahydrofuran
readily formed α-iodoisocyanates 2 in less than 16 hours.
The preferred regiochemical outcome, as expected, result-
N
N
O
H
Figure 1 Rilmenidine
In general, 2-aminooxazolines are prepared by the reac-
tion of an amino alcohol with an isocyanate followed by
conversion of the urea into a chlorourea and subsequent
ring closure. Although a reliable procedure, the limited
availability of amino alcohols and the inability to install
disubstituted amines restricts this approach. Unsubstitut-
ed 2-aminooxazolines can be synthesized from alkenes by
treatment with urea or cyanamide in the presence of N-
bromosuccinimide (NBS), with the latter reagent requir-
ing subsequent acid hydrolysis followed by ring closure to
form the desired heterocycle.6
O
C
R2
N
AgOCN, I2
R3
R3
R1
R2
R1
1
I
2
R
R
R
1 = aryl
Styrenes and olefins are readily converted into α-iodoiso-
cyanates 2 with iodine isocyanate (INCO). Subsequent re-
action of the resulting intermediate with methanol has
been shown to give α-iodocarbamates, which can be con-
verted into aziridines, oxazolidinones or dehalogenated
carbamates.7 It has been demonstrated that 2-aminooxa-
zolines 3 could be synthesized in an analogous sequence
R4
R5
2 = H, alkyl
3 = H, alkyl
N
H
R1–R2 = cycloalkyl
R4
N
R5
N
O
R2
R1
R3
SYNLETT 2013, 24, 2140–2142
Advanced online publication: 28.08.2013
DOI: 10.1055/s-0033-1339652; Art ID: ST-2013-R0506-L
© Georg Thieme Verlag Stuttgart · New York
3
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Scheme 1 Preparation of 2-aminooxazolines

LETTER
2-Aminooxazolines and Spiro-2-aminooxazolines
2141
ed from Markovnikov addition of the cyanate nucleophile
to the iodonium intermediate.
Table 2 Amine Substrates
R2
R3
N
O
Filtration to remove the resulting silver iodide gave a so-
lution of α-iodoisocyanate 2, which could be reacted di-
rectly with amine nucleophiles in the presence of two
equivalents of Hünig’s base to give the desired 2-amino-
oxazolines 3. Final products were then purified by prepar-
ative HPLC with mass-triggered fractionation.11
1) I2, AgOCN
THF
N
2) amine, DIPEA
R1
R1
Entry Amine
R1
H
Yield
(%)a
Since steric and electronic effects are known to attenuate
both iodonium ion formation and subsequent isocyanate
addition,10,12 the scope of the reaction was explored with
styrenes bearing a variety of aromatic substituents (Table
1). Compared to styrene itself, 2-chloro, 3-chloro, and 4-
chloro analogues performed similarly (Table 1, entries 1–
4). In general, yields were higher for alkyl substituted sty-
renes (Table 1, entries 6 and 7). 3-Nitro substitution was
also tolerated, but 4-nitro variants failed uniformly (Table
1, entry 9). Analysis of the reaction mixture from 4-nitro-
styrene (Table 1, entry 4) showed only unreacted styrene
starting material after mixing for 24 hours with iodine iso-
cyanate. These results are consistent with electronic re-
quirements of the reaction, in which formation and
stabilization of the cationic iodonium intermediate is fa-
vored with electron-rich styrenes. Both primary and sec-
ondary amine nucleophiles were employed in this reaction
with alcohol, ether, tertiary amine, and ester substituents
being tolerated (Table 2).
1
2
morpholine
41
morpholine
CH3 43
55
3
(R)-2-amino-2-phenylethanol
(R)-2-amino-2-phenylethanol
isopropylamine
H
4
CH3 49
CH3 52
CH3 50
5
6
methoxyethylamine
7
N-ethylbenzylamine
H
H
H
H
H
H
H
H
53
47
43
23
77
36
39
51
8
ethyl 2-(benzylamino)acetate
dipropylamine
9
10
11
12
13
14
N,N-dibutylethane-1,2-diamine
2-(3,4-dimethoxyphenyl)-N-methylethanamine
(R)-1-(naphthalen-6-yl)ethanamine
(R)-1-(4-methoxyphenyl)ethanamine
N-methyl-2-phenyl ethanamine
Table 1 Styrene Substrates
1) I2, AgOCN
THF
a Isolated yield.
N
N
Ar
Ar
2) (n-Pr)2NH
DIPEA
O
This methodology was also used for the manual synthesis
of 10–50 membered focused libraries.14
Entry
Styrene derivative
Yield (%)a
Exocyclic alkylidine cycloalkanes could also be convert-
ed into the corresponding spiro-cycloalkyl-2-aminooxa-
zolines (Scheme 2). A competing side reaction was
formation of the unsaturated urea, presumably through
regioisomeric adduct formation followed by dehydro-
halogenation.15
1
2
styrene
34
27
27
28
52
42
44
40
15
0
2-chlorostyrene
3-chlorostyrene
4-chlorostyrene
2,5-dichlorostyrene
3-methylstyrene
3
4
NMR experiments, including heteronuclear multiple bond
correlation (HMBC) and heteronuclear multiple quantum
coherence (HMQC), were used to confirm the identity of
the desired spiro-oxazolines and the urea byproducts;
such mixtures were separable by HPLC. The sequence
was used to successfully prepare five-, six-, and seven-
membered spiro variants, including the hindered 2,6-di-
methylmethylidine cyclohexane 7a–c. Although the over-
all yields were low (generally 10–30%), the facile
assembly of such complex structures is noteworthy.
5
6
7
2,4,6-trimethylstyrene
4-tert-butoxystyrene
3-nitrostyrene
8
9
10
4-nitrostyrene
a Isolated yield.
In conclusion, an efficient and convenient process has
been developed to prepare 2-aminooxazolines under mild
conditions. The procedure was successful with a variety
of reactants, including substituted olefins and alkylidine
cycloalkanes. The sequence has proven amenable to par-
Using this reaction sequence and automated liquid
handling techniques, a solution-phase parallel library of
575 substituted 2-aminooxazolines was synthesized from
a variety of commercially available amines and styrenes.13
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2140–2142

2142
C. D. Anderson et al.
LETTER
(6) (a) Hewlett, N. M.; Tepe, J. J. Org. Lett. 2011, 13, 2011.
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(7) Hassner, A.; Lorber, M. E.; Heathcock, C. J. Org. Chem.
1967, 32, 540.
O
O
R1
C
C
I
AgOCN
I2
N
N
I
+
R1
R1
n
(8) (a) Chiang C. G., Stevenson T. M., Thieu T. V., Gebreysus
C., Yatsko C.; 219th National ACS Meeting Poster No.
ORGN 615, March 28th, 2000. (b) Huang, H.; La, D. S.;
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Dineen, T. A.; Epstein, O.; Graceffa, R.; Hickman, D.;
Kiang, Y. H.; Louie, S.; Luo, Y.; Wahl, R. C.; Wen, P. H.;
Wood, S.; Fremeau, R. T. Jr. J. Med. Chem. 2012, 55, 9156.
(9) (a) Pitha, J.; Jonas, J.; Kovar, J.; Blaha, K. Collect. Czech.
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Ortiz Mellet, C.; Pradera Adrian, M. A.; Fuentes Mota, J.
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Lacoste, J.-M.; Descombes, J.-J.; Courchay, C.; Vanhoutte,
P. M.; Laubie, M.; Verbeuren, T. J. J. Med. Chem. 1995, 38,
4056. (d) Tiecco, M.; Testaferri, L.; Marini, F.; Temperini,
A.; Bagnoli, L.; Santi, C. Synth. Commun. 1997, 27, 4131.
(10) Hassner, A. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L., Ed.; John Wiley & Sons: New York,
1995, 2808.
4
n
n
5
6
R2R3NH
DIPEA
R2
R3
N
O
O
R2
N
HN
N
+
R3
R1
R1
n
n
7
8
examples (isolated yield)
N
N
O
N
(11) (a) Zeng, L.; Kassel, D. B. Anal. Chem. 1998, 70, 4380.
(b) Zeng, L.; Wang, X.; Wang, T.; Kassel, D. B. Comb.
Chem. High Throughput Screening 1998, 1, 101. (c) Zeng,
L.; Burton, L.; Yung, K.; Shushan, B.; Kassel, D. B. J.
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N
N
N
O
O
7a
(28%)
7b
7c
(12) Hassner, A.; Lorber, M. E.; Heathcock, C. J. Org. Chem.
1967, 32, 540.
(19%)
(15%)
(13) Of the 575 reactions, 311 of the products were recovered in
milligram quantities and >85% pure (by LC/MS) after
HPLC purification.
Scheme 2 Synthesis of spirocyclic 2-aminooxazolidines
(14) Synthesis of 5-[4-(tert-butoxy)phenyl]-N,N-di-n-propyl-
4,5-dihydrooxazol-2-amine (Table 1, entry 8); Typical
Procedure: To a solution of iodine (38 mg, 0.15 mmol) in
THF (0.3 mL) in an amber vial (wrapped in foil to exclude
light), was added silver cyanate (29 mg, 0.195 mmol) and the
mixture was stirred vigorously under subdued light for
30 min. 4-tert-Butoxystyrene (0.028 mL, 0.15 mmol) in
THF (0.1 mL) was added and the reaction mixture was
stirred vigorously for 16 h at room temperature under
subdued light. The suspension was filtered through a
0.45 μm filter, under subdued light, to remove silver salts.
Di-n-propylamine (0.021 mL, 0.15 mmol) and DIPEA (0.05
mL, 0.3 mmol) in THF (0.1 mL) were added to the INCO
intermediate and the reaction mixture was stirred for 16 h at
room temperature. Evaporation of the reaction mixture
followed by HPLC purification gave the title compound as a
red oil. Yield: 18 mg (40%). 1H NMR (400 MHz, CDCl3): δ
= 7.18 (d, J = 8.6 Hz, 2 H), 6.95 (d, J = 8.5 Hz, 2 H), 5.11–
5.02 (m, 1 H), 4.58 (t, J = 8.5 Hz, 1 H), 4.01 (t, J = 7.3 Hz,
1 H), 3.43–3.16 (m, 4 H), 1.80–1.64 (m, 4 H), 1.34 (s, 9 H),
0.94 (t, J = 7.4 Hz, 6 H). 13C NMR (101 MHz, CDCl3): δ =
162.48, 154.36, 126.92, 124.30, 78.22, 77.22, 75.47, 67.42,
50.04, 28.82, 21.44, 11.23. IR (neat): 1647, 1504, 1233,
1158, 895 cm–1. LC/MS (ESI): tR = 1.36 min (XIC
maximum, 3 min run; m/z [M + H]+ found: 319.3). HRMS
(ESI): m/z [MH]+ calcd for C19H31N2O2: 319.2386; found:
319.2393.
allel synthesis and automation, making it useful for the
preparation of 2-aminooxazolines libraries.
Acknowledgment
We thank George Trainor, Mark Suto, Peter Myers, and Robyn
Rourick for their support, technical assistance, and helpful discus-
sions.
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Synlett 2013, 24, 2140–2142
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