Efficient oxidative conversion of aldehydes to 2-substituted oxazolines and oxazines using (diacetoxyiodo)benzene

Article abstract of DOI:10.1055/s-2007-982571

An efficient synthesis of 2-substituted oxazolines from aldehydes and 2-amino alcohol using (diacetoxyiodo)benzene as an oxidant, is reported. (Diacetoxyiodo)benzene acts as a mild dehydrogenating agent to convert the initially formed oxazolidine from ald

Full text of DOI:10.1055/s-2007-982571

LETTER
1921
Efficient Oxidative Conversion of Aldehydes to 2-Substituted Oxazolines and
Oxazines Using (Diacetoxyiodo)benzene
Conversion of
Ald
a
e
hydes to
2
n
-Substitute
d
d
O
xazoline
s
a
k
nd
O
xazine
s
ishor N. Karade,* Girdharilal B. Tiwari, Sumit V. Gampawar
School of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded 431606, Maharashtra, India
Fax +91(2462)229245; E-mail: nnkarade2007@rediffmail.com
Received 29 March 2007
hydes with rather less readily available 2-azido alcohols in
Abstract: An efficient synthesis of 2-substituted oxazolines from
aldehydes and 2-amino alcohol using (diacetoxyiodo)benzene as an
oxidant, is reported. (Diacetoxyiodo)benzene acts as a mild dehy-
drogenating agent to convert the initially formed oxazolidine from
presence of BF3·OEt2 gives 2-substituted oxazolines in
good yields.12 However, the reaction outcome of 2-azido-
ethanol and aliphatic aldehyde is found to be dependent
aldehyde and 2-amino alcohol to furnish 2-substituted oxazoline. on the catalyst and the structure of the azido alcohol.13
Recently, the N-bromosuccinimide14 and pyridinium
Similarly, 3-aminopropanol and aldehydes gives the corresponding
2-substituted oxazines.
hydrobromide perbromide15 have been reported for the
Key-words: hypervalent iodine, oxazolines, oxazines, oxidation,
aldehydes
oxidative conversion of aldehydes to corresponding 2-
substituted oxazolines. Although all of these methods
afford 2-oxazolines in good yields, some of them suffer
from drawbacks such as difficulty in multistep mani-
The substructural units of oxazoline heterocycle exist in a pulation,9,10 utilization of toxic reagents,6 high reaction
variety of naturally occurring iron chelators,1a cytotoxic temperature (200–220 °C),6c more than stoichiometric use
cyclic peptides1b and antimitotic1c and neuroprotective of reagents,12,15 and stringent reaction parameters with
agents.1d They also contribute to the flavors of a variety of occasional low yields of the products. Thus, there is still a
foods.2 The 2-substituted oxazolines can also be used as a need for the development of new, mild, and effective
robust protecting group for carboxylic acids resisting the methods for the synthesis of 2-oxazoline compounds from
attack of nucleophiles, bases ,and radicals.3 In synthetic a readily available precursor such as aldehyde.
chemistry, Meyers and others have found that 2-aryl-2-
Recently, hypervalent iodine reagents are gaining increas-
oxazolines can be used as highly regio- and enantioselec-
ing popularity as versatile oxidizing agents in modern
tive directing groups for the ortho lithiation of aryl rings.4
organic synthesis.16 (Diacetoxyiodo)benzene (DIB) is the
most extensively utilized parent hypervalent iodine(III)
In addition, the recent intense study of chiral oxazolines as
ligands in enantioselective Lewis acid catalysis is particu-
reagent which is easy to handle, nontoxic, commercially
larly significant area of research within heterocyclic
available, and similar in reactivity to heavy metal reagents
chemistry and organic synthesis in general.5
and anodic oxidations.17 In continuation of our interest in
There are several synthetic methods for the preparation of hypervalent iodine reagents,18 we wish to report herein a
2-substituted oxazolines mainly from carboxylic acids6 mild and facile synthesis of 2-substituted oxazolines and
using different reagents such as SOCl2,6a,b PPh3/DEAD,6c oxazines from aldehydes using DIB as an oxidant
DAST6d and Burgess reagent.6e Other starting materials (Scheme 1).
such as carboxylic esters,7 nitriles,8 imidates,9 amido alco-
To study this process, we have examined the model reac-
hols,10 and olefins11 can also be used for the synthesis of
tion of 4-tolualdehyde (1.0 mmol) with 2-aminoethanol
2-substituted oxazolines. The literature survey has re-
(1.0 mmol) in acetonitrile (15 mL). This reaction mixture
vealed that there are fewer methods for the direct one-pot
was stirred for four hours and then (diacetoxyiodo)ben-
conversion of aldehydes to 2-substituted oxazolines. In
zene (1.2 mmol) was added consecutively. The resulting
one report, it has been shown that the reaction of alde-
mixture was again stirred at room temperature for another
H
H2N
HO
N
O
PhI(OAc)2
r.t., stirring
MeCN
N
R
RCHO
+
r.t., stirring
R
n
n
n
O
n = 1 or 2
Scheme 1
SYNLETT 2007, No. 12, pp 1921–1924
2
4
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982571; Art ID: D09507ST
© Georg Thieme Verlag Stuttgart · New York

1922
N. N. Karade et al.
LETTER
H
N
three hours. After completion of reaction, the correspond-
ing 2-(4-tolyl)-4,5-dihydrooxazole was established as the
final product, mp 143–144 °C (lit.8d 144–145 °C) in 72%
yield.19
N
..
NH2
R
R
RCHO
+ HO
– H2O
AcO
O
HO
..
2
1
4
3
Ph
Apart from (diacetoxyiodo)benzene, we have also exam-
ined different sources of electrophilic iodine as oxidizing
agents such as I2 and I2/K2CO3 and the results are summa-
rized in Table 1 with respect to the formation of 2-(4-
tolyl)-4,5-dihydrooxazole. It follows from Table 1 that
the molecular iodine with moderate oxidizing capacity
was insufficient to produce 3d in any appreciable quanti-
ty. The combination of I2 and K2CO3 only resulted in the
formation of 3d in a poor yield. The electrophilic DIB
was, however, found to be, above all, an excellent oxidiz-
ing agent to yield 3d in reasonably good yield under very
mild conditions.
I
N
N
O
PhI(OAc)2
4
+
R
H
– AcOH
– PhI
– AcOH
O
R
5
7
6
Scheme 2
the applications of chiral oxazolines as chiral ligands have
been recently increasing. Thus, the aromatic (Table 2, en-
try i) and aliphatic aldehydes (Table 2, entry j) afforded
the corresponding chiral oxazolines in high yields. Having
succeeded with 2-oxazoline formation, we then attempted
the reaction of 3-aminopropanol with 4-methoxybenz-
aldehyde using (diacetoxyiodo)benzene under similar re-
action conditions to afford 2-(4-methoxyphenyl)-5,6-
dihydro-4H-1,3-oxazine in 67% yield. Thus the present
protocol also permits the one-pot oxidative conversion of
aldehydes directly to 2-substituted oxazines (Table 2,
entries k–m).
Table 1 Study of Different Iodine Related Oxidizing Agents for the
Formation of 2-(4-Tolyl)-4,5-dihydrooxazole
N
CHO
HO
oxidant
MeCN
O
+
H2N
Me
Me
3d
Entry Oxidizing
agent
Quantity of Reaction time
the catalyst and conditions
(equiv)
Yield of
In conclusion, we have developed a transition-metal-free
protocol for the oxidative conversion of aldehydes to 2-
substituted oxazolines and oxazines using DIB as an oxi-
dant. This reaction is a useful entry in demonstrating the
role of DIB as a versatile dehydrogenating reagent. The
other advantages of the present reaction are mild reaction
conditions, short reaction time, easy work-up, and high
yields of the products.
3d (%)a
1
2
3
I2
1
24 h and reflux
10 h and reflux
7 h and r.t. stirring
0
18
72
I2/K2CO3
PhI(OAc)2
1:1
1.2
a Isolated yields.
Acknowledgment
A possible mechanism for the reaction is depicted in
Scheme 2. Reaction of aldehyde with 2-amino alcohol
gives open-chain imine 3 which can exist in equilibrium
with oxazolidines 4.20 In support of this fact, we have iso-
lated the intermediate 2-styryloxazolidine resulting from
the reaction of cinnamaldehyde and 2-amino-2-methyl-1-
propanol and analyzed by LCMS analysis (M +
1 = 204).21 Ligand-exchange reaction between electro-
philic DIB and 4 will generate the putative intermediate 6.
The overwhelming tendency of iodobenzene for reductive
elimination from the intermediate 6 will promote the
concomitant oxidation of the oxazolidine 4 to yield 2-sub-
stituted oxazolines 7.
The authors are thankful to Department of Science and Technology,
New Delhi, India, for the financial support (No. SR/FTP/CS-77/
2005).
References and Notes
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Noyori, R.; Trost, B. M., Eds.; Georg Thieme Verlag:
New York, 1994.
In order to assess the generality of the methodology, we
synthesized several 2-substituted oxazolines from a range
of aldehydes and appropriate amino alcohols (Table 2). In
all the reactions, good to excellent yields of the products
were observed with 1.2 equivalents of DIB as the mild
oxidant. Aliphatic aldehydes were also transformed to the
respective oxazolines with good yields. The yields of re-
actions were relatively less dependent on the substituents
present on the aromatic rings. The use of (R)-2-amino-1-
butanol in place of 2-aminoethanol was also studied, since
Synlett 2007, No. 12, 1921–1924 © Thieme Stuttgart · New York

LETTER
Conversion of Aldehydes to 2-Substituted Oxazolines and Oxazines
1923
Table 2 Formation of 2-Substituted Oxazolines and Oxazines from Aldehydes and Amino Alcohol Using (Diacetoxyiodo)benzene in
Acetonitrile at Room-Temperature Stirring
Entry
Aldehyde
1
Amino alcohol
2
Product
3
Reaction time
(h)
Yield
(%)a
N
a
7
7
63
CHO
HO
HO
NH2
NH2
O
N
b
70
69
MeO
CHO
CHO
MeO
MeO
MeO
MeO
O
MeO
MeO
N
c
9
HO
NH2
O
MeO
N
d
e
f
7
8
72
65
52
70
62
Me
Cl
CHO
Me
Cl
HO
HO
HO
HO
HO
NH2
NH2
NH2
NH2
NH2
O
N
CHO
O
N
9
O2N
CHO
O2N
Ph
O
N
g
h
PhCH2CHO
9
O
N
Me(CH2)5CHO
10
O
N
i
j
8
8
68
65
MeO
CHO
MeO
HO
NH2
NH2
O
N
PhCH2CHO
PhCH2
MeO
HO
HO
O
N
k
l
7
7
8
67
71
69
MeO
CHO
NH2
NH2
NH2
O
N
O2N
l
O2N
CHO
HO
HO
O
N
O
m
PhCH2CHO
PhCH2
a Isolated yields.
(4) (a) Meyers, A. I.; Lutomski, K. A. J. Am. Chem. Soc. 1982,
104, 879. (b) Meyers, A. I.; Hangan, M. A.; Trefonas, L. M.;
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D. R. Org. Lett. 2000, 2, 1165. (e) Wipf, P.; Miller, C. P.
Tetrahedron Lett. 1992, 33, 907.
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Synlett 2007, No. 12, 1921–1924 © Thieme Stuttgart · New York

1924
N. N. Karade et al.
LETTER
(8) (a) Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T. Chem.
Ber. 1991, 124, 1173. (b) Clarke, D. S.; Wood, R. Synth.
Commun. 1996, 26, 1335. (c) Jnaneshwara, G. K.;
Deshpande, V. H.; Lalithambika, M.; Ravindranathan, T.;
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A.; Hell, Z.; Hegedüs, A.; Finta, Z.; Horvath, Z. Tetrahedron
Lett. 2002, 43, 3985. (e) Mohammadpoor-Baltork, I.;
Khosropour, A. R.; Hojati, H. S. Synlett 2005, 2747.
(9) (a) Neilson, D. G. In The Chemistry of Amidines and
Imidates; Patai, S., Ed.; Wiley: London, 1975, 389.
(b) Hoppe, D.; Schöllkopf, U. Angew. Chem., Int. Ed. Engl.
1970, 9, 300.
2964, 2891, 1724, 1638, 1590, 1474, 1280, 1073, 933, 824,
763 cm–1. 1H NMR (CDCl3): d = 3.72 (t, J = 9.4 Hz, 2 H),
3.97 (t, J = 9.4 Hz, 2 H), 7.40 (d, J = 7.9 Hz, 2 H), 7.68 (d,
J = 7.9 Hz, 2 H). LCMS [M + 1]: m/z = 182.
2-(4-Methoxyphenyl)-4,5-dihydrooxazole
Mp 138–139 °C. IR (KBr): 2958, 2849, 1711, 1620, 1505,
1255, 1158, 1024, 842, 775 cm–1. 1H NMR (CDCl3):
d = 3.71 (s, 3 H), 3.76 (t, J = 9.2 Hz, 2 H), 3.91 (t, J = 9.2 Hz,
2 H), 7.49 (d, J = 7.6 Hz, 2 H), 6.87 (d, J = 7.6 Hz, 2 H).
LCMS [M + 1]: m/z = 178.
2-(3,4,5-Trimethoxyphenyl)-4,5-dihydrooxazole
Mp 83–85 °C. IR (KBr): 2940, 2849, 1711, 1638, 1584,
1407, 1225, 1128, 988, 769 cm–1. 1H NMR (CDCl3):
d = 3.89 (m, 9 H), 4.07 (t, J = 9.3 Hz, 2 H), 4.43 (t, J = 9.3
Hz, 2 H), 6.97 (s, 1 H), 7.13 (s, 1 H). LCMS [M + 1]: m/z =
238.
(10) (a) Wuts, P. G. M.; Northuis, J. M.; Kwan, T. A. J. Org.
Chem. 2000, 65, 9223. (b) Wipf, P.; Venkatraman, S.
Tetrahedron Lett. 1996, 37, 4659. (c) Lafargue, P.; Guenot,
P.; Lellouche, J. P. Heterocycles 1995, 41, 497.
(11) Minakata, S.; Nishimura, M.; Takahashi, T.; Oderaotoshi,
Y.; Komatsu, M. Tetrahedron Lett. 2001, 42, 9019.
(12) Badiang, J. G.; Aube, J. J. Org. Chem. 1996, 61, 2484.
(13) Chakraborty, R.; Franz, V.; Bez, G.; Vasadia, D.; Popuri, C.;
Zhao, C.-G. Org. Lett. 2005, 19, 4145.
(14) Schwekendiek, K.; Glorius, F. Synthesis 2006, 2996.
(15) Sayama, S. Synlett 2006, 1479.
(16) (a) Wirth, T. Angew. Chem. Int. Ed. 2005, 44, 3656.
(b) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893.
(c) Stang, P. J. J. Org. Chem. 2003, 68, 2997. (d)Zhdankin,
V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523.
(e) Moriarty, R. M.; Prakash, O. Org. React. 2002, 57, 327.
(17) Varvoglis, A. Hypervalent Iodine in Organic Synthesis;
Academic Press: London, 1997, Chap. 3, 19.
(18) (a) Karade, N. N.; Tiwari, G. B.; Huple, D. B. Synlett 2005,
2039. (b) Karade, N. N.; Shirodkar, S. G.; Dhoot, B. M.;
Waghmare, P. B. J. Chem. Res., Synop. 2005, 274.
(c) Karade, N. N.; Tiwari, G. B.; Shirodkar, S. G.; Dhoot, B.
M. Synth. Commun. 2005, 35, 1197. (d) Karade, N. N.;
Budhewar, V. H.; Katkar, A. N.; Tiwari, G. B. ARKIVOC
2006, (xi), 162.
2-(4-Tolyl)-4,5-dihydrooxazole
Mp 143–144 °C (lit.8d mp 144–145 °C). IR (KBr): 2928,
2879, 2855, 1650, 1596, 1389, 1286, 1055, 969, 811 cm–1.
1H NMR (CDCl3): d = 2.46 (s, 3 H), 3.75 (t, J = 9.3 Hz, 2 H),
3.91 (t, J = 9.3 Hz, 2 H), 7.63 (d, J = 7.4 Hz, 2 H), 7.22 (d,
J = 7.6 Hz, 2 H). LCMS [M + 1]: m/z = 162.
4-Ethyl-4,5-dihydro-2-(4-methoxyphenyl)oxazole
Liquid. IR (KBr): 3068, 2964, 2873, 2855, 1645, 1489,
1268, 1085, 818 cm–1. 1H NMR (CDCl3): d = 0.92 (t, J = 9.1
Hz, 3 H), 1.36 (m, 2 H), 3.86 (s, 3 H), 3.97 (d, J = 9.2 Hz, 2
H), 4.14 (m, 1 H), 6.91 (d, J = 7.5 Hz, 2 H), 7.49 (d, J = 7.6
Hz, 2 H). LCMS [M + 1]: m/z = 206.
2-(4-Methoxyphenyl)-5,6-dihydro-4H-[1,3]-oxazine
Liquid. IR (KBr): 3012, 2958, 1637, 1602, 1510, 1358,
1307, 1283, 1273, 1256 cm–1. 1H NMR (CDCl3): d = 1.96
(quin, J = 5.8 Hz, 2 H), 3.58 (t, J = 5.4 Hz, 2 H), 3.81 (s, 3
H), 4.37 (t, J = 5.4 Hz, 2 H), 6.89 (d, J = 9.4 Hz, 2 H), 7.87
(d, J = 9.4 Hz, 2 H). LCMS [M + 1]: m/z = 192.
2-(4-Nitrophenyl)-5,6-dihydro-4H-[1,3]-oxazine
Mp 143–144 °C (lit.22 mp 145–146 °C). 1H NMR (CDCl3):
d = 1.99 (quin, J = 5.8 Hz, 2 H), 3.66 (t, J = 5.6 Hz, 2 H),
4.37 (t, J = 5.6 Hz, 2 H), 8.07 (d, J = 9.2 Hz, 2 H), 8.22 (d,
J = 9.3 Hz, 2 H). LCMS [M + 1]: m/z = 207.
(19) Typical Experimental Procedure
A mixture of an aldehyde (1.0 mmol) and an appropriate 2-
amino alcohol (1.0 mmol) was stirred for 4 h at r.t.
(Diacetoxyiodo)benzene (1.2 mmol) was then added to the
above mixture and the resulting reaction mixture was again
subjected for stirring for another 3–6 h. The progress of the
reaction was monitored by TLC. After the completion of the
reaction, H2O (15 mL) was added and the mixture extracted
with CH2Cl2 (2 × 15 mL). The combined organic extracts
were dried over anhyd Na2SO4, concentrated in vacuo, and
chromatographed to give 2-substituted oxazolines/oxazines.
Spectroscopic Data of Selected Products
(20) (a) Snieckus, V. Chem. Rev. 1990, 90, 879. (b) Martinek,
T.; Lazar, L.; Fulop, F.; Riddell, F. G. Tetrahedron 1998, 54,
12887. (c) Agami, C.; Comesse, S.; Kadouri-Puchot, C.
J. Org. Chem. 2002, 67, 1496.
(21) When the reaction mixture of cinnamaldehyde and 2-amino-
2-methyl-1-propanol was stirred in the absence of DIB, the
immediate precipitation of 2-styryloxazolidine was
observed. This product was recrystallized from PE and
subjected to LCMS analysis which showed a molecular ion
peak [M + 1] at 204 corresponding to the formation of 4,4-
dimethyl-2-styryloxazolidine. The reaction of 4,4-dimethyl-
2-styryloxazolidine (1 mmol) with DIB (1.2 mmol) in CHCl3
(10 mL) was independently carried out at r.t. stirring for
another 3 h. After usual reaction workup, the formation of
4,5-dihydro-4,4-dimethyl-2-styryloxazole was realized in
38% yield.
2-(4-Nitrophenyl)-4,5-dihydrooxazole
Mp 157–159 °C. IR (KBr): 3028, 2971, 2894, 1649, 1602,
1528, 1464, 1349, 1268, 1092, 952, 861, 710 cm–1. 1H NMR
(CDCl3): d = 4.12 (t, J = 9.6 Hz, 2 H), 4.50 (t, J = 9.6 Hz, 2
H), 8.14 (d, J = 8.3 Hz, 2 H), 8.24 (d, J = 8.3 Hz, 2 H).
LCMS [M + 1]: m/z = 193.
2-(4-Chlorophenyl)-4,5-dihydrooxazole
(22) Katritzky, A. R.; Cai, C.; Suzuki, K.; Singh, S. K. J. Org.
Chem. 2004, 69, 811.
Mp 116–118 °C (lit.8d mp 118–119 °C). IR (KBr): 3062,
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