A facile preparation of various N-heterocycles using amides and olefins

Article abstract of DOI:10.1016/j.tetlet.2013.11.054

We herein report a one pot approach for the synthesis of various nitrogen containing heterocycles including: oxazolines, thiazolines, and dihydro dioxazines via the addition of amides to olefins in the presence of N-iodosuccinimide (NIS) and propionitrile

Full text of DOI:10.1016/j.tetlet.2013.11.054

Tetrahedron Letters 55 (2014) 448–452
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile preparation of various N-heterocycles using amides
and olefins
Synthia S. Gratia a, Edward S. Vigneau a, Sumiea Eltayeb b, Kishan Patel a, Terence J. Meyerhoefer a,
Sonia Kershaw a, Victor Huang a, Michael De Castro a,
⇑
a Department of Chemistry, Farmingdale State College-SUNY, 2350-Broadhollow Rd, Farmingdale, NY 11735, USA
b Department of Chemistry and Biochemistry, Seton Hall University, 400-South Orange Ave, NJ 07079, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report a one pot approach for the synthesis of various nitrogen containing heterocycles includ-
ing: oxazolines, thiazolines, and dihydro dioxazines via the addition of amides to olefins in the presence
of N-iodosuccinimide (NIS) and propionitrile at high temperatures. Thus, the reaction of aryl/heteroaryl
amides, thioamides, N-hydroxybenzamide, and phenylurea with various olefins in the presence of NIS
and propionitrile at 45 °C afforded the N-heterocycles in good to moderate yields. Reaction of the electron
Received 29 October 2013
Revised 9 November 2013
Accepted 13 November 2013
Available online 21 November 2013
deficient tri-O-acetyl-D-glucal and tri-O-acetyl-D-galactal with benzamide and thiophene-2-carboxamide
afforded the N-glycooxazolines in good yields. The newly made heterocycles were tested against various
enzymes. Only 3,6-diphenyl-dihydro-1,4,2-dioxazine (1c) was found to moderately inhibit hexokinase II
(hHK2).
Keywords:
Heterocycles
Carbohydrates
Olefins
Oxazolines
Amides
Ó 2013 Elsevier Ltd. All rights reserved.
Introduction
of benzenetellurinyl trifluoroacetate with boron trifluoride.9 Both
methods proceeded with good overall yields and stereoselectivity.
Oxazolines and thiazolines are common functional groups in
many natural products. Allosamidin 1, Trehazolin 2 (insecticides),
Rilmendine 3 (antihypertensive agent), and A289099 4 (tubulin
polymerization inhibitor) are a few examples of biologically active
oxazoline containing compounds (Fig. 1).1
We have previously described the preparation of carbohydrate
fused oxazolines.10 We also successfully prepared N-glycooxazo-
lines and N-glycothiazolines (nitrogen at the anomeric center), in
one step, via the addition of amides and thioamides to benzyl pro-
tected glucal in the presence of NIS and propionitrile at 45 °C.11 We
have extended this methodology to explore the preparation of var-
ious N-heterocycles using alkenes (Scheme 1). Both electron defi-
cient and electron rich alkenes were used in this study.
Therefore, we herein report the direct synthesis of oxazolines,
Oxazolines have also been used as chiral ligands2 and as pro-
tecting groups in natural product synthesis.3,4 Because of their
importance a great deal of effort has been put forward in the devel-
opment of more efficient and cost effective methods for their
chemical synthesis. In general, oxazolines and thiazolines have
been prepared by reacting b-aminoalcohols with acid chlorides,
carboxylic acids, nitriles, and esters.5 More recent methodologies
for the preparation of oxazolines include the reaction of a nitrido-
manganese complex with acid chlorides.6 The direct preparation of
oxazolines has also been accomplished via the addition of aryl and
aliphatic amides to olefins in the presence of tert-butyl hypoiodite
as the source of iodine.7 Other iodinating reagents such as N-iodo-
succinimide (NIS) were explored in the same study but poor yields
were obtained and this chemistry was not further pursued. Other
one-pot procedures for the preparation of oxazolines include the
reaction of alkenes with N-bromosuccinimide (NBS) in the pres-
HO
R2O
HO
OH
CH2OH
HO
CH2OH
HO
R3
O
O
O
O
N
O
R5
N
O
NHAc
HO
R4
NHAc
N
HO
NH
R1
HO
HO
1
O
OH
Allosamidin: R2,R3=H; R4=OH; R1,R5=Me
OH
2
Trehazolin
OCH3
N
H3C N
N
H
O
O
8
OCH3
OCH3
ence of nitriles and Cu(OTf)2 or Zn(OTf)2 as well as the reaction
N
3
4
Rilmendine
A-289099
⇑
Corresponding author. Tel.: +1 631 420 2097; fax: +1 631 420 2759.
E-mail address: decastm@farmingdale.edu (M. De Castro).
Figure 1. Biologically active oxazoline containing compounds.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.054

S. S. Gratia et al. / Tetrahedron Letters 55 (2014) 448–452
449
R'
in good yields. However, we were only able to produce the known
2, 5-diphenylthiazoline 1e16 in very low yields (results not shown).
When 1-nonene was reacted with benzamide a 1:1 mixture of 5-
heptyl-2-phenyloxazoline 4a and 4-heptyl-2-phenyloxazoline 4a0
were obtained in good yields (Table 1, entry 4). 1H NMR of 5-hep-
NH2COR'
N
1A,1B,1D,2A,2D
3A,3B,3D,4A-A',
4B-B', 4D-D'.
O
NIS/Propionitrile
4Å MS/ 45oC
R
tyl-2-phenyloxazoline gave
a distinct multiplet for H-5 at
Ph
4.72 ppm and a doublet of doublet for H-4 at 4.12 (dd, J = 7.0 Hz,
J = 6.50 Hz, 1H, CHOCH2N) ppm and 3.67 (dd, J = 7.5 Hz,
J = 7.00 Hz, 1H, CHOCH2N) ppm. The regioisomer 4-heptyl-2-phe-
nyloxazoline gave a distinct doublet of doublet at 4.49 (dd,
J = 8.50 Hz, J = 7.50 Hz, 1H, CHNCH2O) ppm and 4.05 (dd,
J = 8.25 Hz, J = 8.00 Hz,1H, CHNCH2O) ppm for H-5 and a multiplet
at 4.28 ppm for H-4 (Scheme 2). The same chemical shift pattern
was observed for the rest of the corresponding 5-heptyl and 4-hep-
tyl substituted oxazolines. Furthermore, 1:1 ratios were also ob-
tained for compounds 4b, 4b0, 4d, 4d0 (Table 1, entry 4). The
regioisomers were easily separated by column chromatography
with the exception of compounds 4d and 4d0 that resulted in an
inseparable mixture. When hydroxybenzamide was used in the
reaction the dihydro-1, 4, 2-dioxazine 4c was obtained as a single
product albeit in low yields. Unfortunately very poor yields were
also obtained with thiobenzamide and the preparation of 4e was
not further pursued.
The use of vinylanisole 2 and vinylpyridine 3 allowed for the for-
mation of the known compounds 2a, 2e, 3a, 3b, 3d, 3e (Table 1, en-
tries 2 and 3).16,17 The yields ranged from good to low, especially for
compounds 2e, 3b, and 3d. During the synthesis of these com-
pounds multiple spots were observed during TLC analysis. The
iodination of mono substituted benzene using NIS and acetoni-
trile18 as well as NIS in the presence of trifluoroacetic acid19 has
been previously reported. It is possible that some of the byproducts
obtained in these reactions may have resulted from the halogena-
tion of the benzene ring via electrophilic aromatic substitution.
We decided to test this hypothesis by mixing vinylanisole with
2.0 equiv of NIS in propionitrile at 45 °C for two hours (Scheme 3).
After column chromatography 1H NMR analysis confirmed the for-
mation of compound 9 only. This result does not surprise us since
the addition of the succinimide ion in the absence of a strong nucle-
ophile has been previously reported using NIS and glucal.20 No sub-
stitution occurred in the benzene ring and compound 9 was never
isolated in any of our reaction trials with alkenes 2 and 3.
N
NH2CSPh
1E,3E.
S
R
R
NIS/Propionitrile
4Å MS/ 45oC
R= 1)C6H5
N
Ph
2)p-CH3OC6H4
O
3)C5H4N
1C,2C,3C,4C.
HONHCOPh
4)CH3(CH2)6
O
R
R'=Ph,NHPh,C4H3S
NIS/Propionitrile
4Å MS/ 45oC
Scheme 1. Targeted N-heterocycles.
thiazolines, and the less abundant dihydro dioxazine via the addi-
tion of amides and N-hydroxyamides to alkenes and unsaturated
sugars in the presence of NIS and propionitrile at 45 °C. In this
study we show that access to oxazolines and other heterocycles
is possible using alkenes and an excess of both NIS and the amide
at 45 °C. The overall yields and stereoselectivity obtained for the
formation of oxazolines when using electron rich alkenes are com-
parable with currently published one-pot procedures. Previously
we attempted to use the electron deficient glycals, tri-O-acetyl-
glucal and tri-O-acetyl- -galactal in a two-step iodoamidation/
cyclization to form the oxazolines. Yields were poor and mixtures
of products were obtained.10 When tri-O-acetyl-
-glucal, tri-O-
acetyl- -galactal, and tri-O-methyl- -glucal were employed in the
new one-pot reaction the N-glycooxazolines were obtained exclu-
sively. Compounds 1a, 1c, 2a, 2d, 2e, 3c were selected to be
screened against a panel of enzymes as part of Eli-Lilly’s open inno-
vation drug discovery program. All of the compounds were inactive
with the exception of 1c which exhibited moderate inhibition
against hexokinase II (hHK2) with a 70% inhibition and IC50
D-
D
D
D
D
>20 lM.
Results and discussion
Based on these results one can envision the formation of the
oxazolines and thiazolines via the addition of the nitrogen of the
amide to the benzylic carbon of aryl alkenes. Migration of the
nitrogen via an acyl aziridine followed by O-alkylation will lead
to ring closure and formation of the 2,5-disubstituted oxazoline/
thiazoline. While a free radical mechanism is possible it is not
likely to occur in this case since reaction yields were not affected
when conducted in the presence of light. However, the migration
of amides through an aziridine intermediate is well documented.21
Therefore we hypothesized that the formation of the dihydro
dioxazine will follow a similar pathway through the initial forma-
tion of intermediate 11 (Scheme 4). Displacement of the iodine fol-
lowed by O-alkylation will lead to ring closure and formation of our
target compound 13 exclusively. The electron deficient 5,6-dihydro-
2H-pyran-2-one and trimethyl silyl acrylate were also used in this
study but gave very sluggish results and their use was discontinued.
As part of our program aimed at the synthesis of novel glycosi-
dase inhibitors we decided to revisit the direct preparation of the
Compounds 1a–e (Table 1, entry 1) were prepared by reacting
benzamide,
thiophene-2-carboxamide,
thiobenzamide,
N-
hydroxybenzamide, and phenylurea with styrene in the presence
of N-iodosuccinimide (NIS).12 Hence, styrene (1 equiv) was mixed
in freshly distilled propionitrile (4.0 mL) followed by the addition
of the amide (3 equiv). The mixture was heated to 45 °C until the
reaction became homogenous. Pre-activated 4 Å molecular sieves
powder was added to the reaction mixture to avoid inadvertent
addition of water across the double bond and formation of halo-
hydrins. Finally, NIS (2 equiv) was added to the reaction mixture.
The reaction was kept at 45 °C and after 2 h TLC analysis showed
complete disappearance of the starting material. The mixture
was quenched with deionized water and diluted in dichlorometh-
ane (50 mL). The crude was filtered to remove the molecular sieves
and subsequently washed with saturated Na2S2O3 (100 mL) and
distilled water (3 ꢀ 100 mL). Reactions were conducted in the
presence and absence of light and no changes were observed in
product yields. The best overall yields were obtained when 1-non-
ene 4 and styrene 1 were used in the reaction (Table 1, entries 1
and 4). Our NMR data for compounds 1a13 and 1d14 matched the
data previously reported confirming the formation of the 2, 5-
diphenyloxazoline 1a and N, 5-diphenyl-4, 5-dihydrooxazol-2-
amine 1d. The known compounds 1b15 and 1c were also obtained
N-glycooxazolines using the electron deficient tri-O-acetyl-
D-glu-
cal 5 and tri-O-acetyl- -galactal 6 (Table 1, entry 6). Acetate pro-
D
tecting groups are easily removed under basic conditions making
them a very desirable protecting group in carbohydrate synthesis.
When benzamide was used in the reaction the N-glycooxazolines
5a, 6a were obtained exclusively in fair yields. Similar results were
obtained when thiophene-2-carboxamide was employed in the

450
S. S. Gratia et al. / Tetrahedron Letters 55 (2014) 448–452
Table 1
Cyclization products
O
O
O
O
S
S
S
Entry
Alkene
H2N
H2N
HOHN
H2N
H2N
Ph
N
H
Ph
N
N
Ph
NHPh
N
Ph
N
O
O
O
S
O
Ph
O
1
1PAh (60%)
N
1C (68%)
Ph
Ph
1D (61%)
1E (15%)
1B (65%)
Ph
N
N
Ph
NHPh
N
Ph
N
O
O
O
S
O
O
N
2
3
NR
O
O
O
O
2C (69%)
2A (68%)
2D (65%)
2E (56%)
Ph
N
Ph
NHPh
Ph
S
O
O
S
O
O
N
N
N
N
N
O
N
N
N
N
3D (10%)
3E (58%)
3A (70%)
3C (65%)
3B (12%)
R
R
R
R
R
R
R
O
N
N
O
O
N
O
N
+
+
+
6
O
N
O
N
N
O
O
Ph 1:1
Ph
NH1P:1h
NHPh
1:1
C4H3S
C4H3S
Ph
4
5
6
7
NR
4A (42%)
4B (54%)
4D, 4D’ (90%)
4C (25%)
4A’ (55%)
R = HEPTYL
4B’(45%)
R = HEPTYL
AcO
R = HEPTYL
R = HEPTYL
AcO
AcO
O
AcO
AcO
AcO
AcO
AcO
O
O
AcO
N
N
O
O
NR
NR
NR
NR
NR
NR
NR
S
Ph
5A (45%)
5B (40%)
OAc
AcO
OAc
AcO
AcO
OAc
OAc
O
O
O
AcO
AcO
N
S
N
O
NR
O
Ph
6A (41%)
6B (43%)
MeO
MeO
MeO
MeO
MeO
MeO
MeO
O
MeO
O
N
O
MeO
N
O
O
NR
S
Ph
7B (85%)
7A (80%)
4.49 ppm, 4.05 ppm
5
O
4.12 ppm, 3.67 ppm
4.72 ppm
4.28 ppm
N
4
4
5
N 3
2
I
1
O
2
NIS/Propionitrile
4a' N
O
O
4a
3
1
Ph
Ph
4Å MS/ 45oC
89%
Scheme 2. Proton chemical shifts for compounds 4a and 4a0.
OCH3
8
OCH3
9
reaction resulting in compounds 5b and 6b (Table 1, entries 5 and
6). The formation of the N-glycooxazolines was easily confirmed
using 1H NMR and 13C NMR where the characteristic doublet of
doublet at 6.07 ppm for the anomeric proton and 94.33 ppm for
the anomeric carbon was observed.10,11 We were only successful
in the addition and cyclization of these two amides. We turned
Scheme 3. Addition of succinamide to vinylanisole.
our attention to the methyl protected glucal. Methyl ethers have
been used as permanent protecting groups in the chemical synthe-

S. S. Gratia et al. / Tetrahedron Letters 55 (2014) 448–452
451
O
H
N
H
Ph
N
O
Ph
Ph
N
O
N
O
O
O
NIS
O
O
R
R
HONHCOPh
R
R
11
10
13
I
12
Scheme 4. Possible mechanism for the formation of dihydro dioxazines using NIS.
sis of carbohydrate based natural products.22 This eliminates a final
deprotection step and is the reason why we pursued the prepara-
tion of N-glycooxazolines using this protecting group. When tri-O-
thiazolines, and dioxazines. The reaction proceeded with a great
degree of stereoselectivity when electron rich alkenes were used
in the reaction with the exception of 1-nonene. The yields obtained
for the preparation of oxazolines are comparable to those reported
in earlier one-pot procedures. When the electron deficient tri-O-
methyl-D-glucal 7 was used in the reaction with benzamide and
thiophene-2-carboxamide the N-glycooxazolines 7a and 7b (Ta-
ble 1, entry 7) were obtained exclusively. Once again we failed to
produce any carbohydrate-based heterocycles using thiobenza-
mide, phenylurea, or N-hydroxybenzamide.
acetyl-D-glucal and D-galactal were reacted with benzamide and
thiophene-2-carboxamide the N-glycooxazoline was obtained
exclusively. Higher yields were obtained with tri-O-methyl-D-
Compounds 1a, 1c, 2a, 2d, 2e, 3c were screened against a panel
of enzymes including hexokinase II (hHK2) as part of Eli-Lilly Phar-
maceutical’s open innovation drug discovery program. Hexokinase
type II isoform has been shown to play a crucial role in initiating
and maintaining the high glucose catabolic rate observed in malig-
nant tumors.23 Inhibitors of this enzyme have emerged as potential
chemotherapeutic agents for the treatment of cancer.24 Compound
1c showed moderate activity against hHK2 with a 70% inhibition
glucal.
Conclusions
The addition and cyclization of amides and amide derivatives to
electron rich olefins such as: styrene, vinyl anisole, vinyl pyridine
as well as 1-nonene in the presence of NIS at 45 °C are a viable
alternative for the preparation of substituted oxazolines and other
N-heterocycles. This reaction takes place in one step in a very short
period of time with good overall yields. The addition and cycliza-
and IC50 > 20
lM (Fig. 2). The synthesis of 5,6-dihydro-1,4,2-diox-
azines has been previously reported using hydroxyamides and
a
-
bromoesters25 as well as nitrosocarbonyl compounds with cyclic
dienes.26 The method reported in this Letter will allow for the rapid
generation of small libraries of dihydro dioxazine analogues of 1c
and further test their inhibitory properties against hexokinase II.
The optimization of compound 1c is currently underway and the re-
sults will be disclosed in future publications. The % inhibition ob-
tion of amides using the electron deficient tri-O-acetyl-
D-glucal,
D-galactal, and tri-O-methyl- -glucal lead to the formation of the
D
N-glycooxazolines in good yields. Optimization of compound 1c
is currently underway in our laboratory and results will be dis-
closed in future publications.
tained for concentrations at 20
mentioned above is shown in (Fig. 2). Compound 3c showed a
0.5% inhibition at 20 M. Compounds 1a and 2a exhibited negative
inhibition (ꢁ100% and ꢁ40%) respectively. These results are indic-
ative of stimulation rather than inhibition. We intend to investigate
the regioisomers of 1a and 2a for hexokinase II activity. Our labora-
tory is currently working on the chemical synthesis of such com-
pounds using alternative procedures and the results will be
reported in due time.
In summary we have achieved the direct addition and cycliza-
tion of amides and amide derivatives to aryl, heteroaryl, and ali-
phatic alkenes using NIS and propionitrile at 45 °C. This one pot
procedure allowed for the formation of substituted oxazolines,
lM for all the compounds
Acknowledgments
l
The authors will like to thank the Farmingdale-CSTEP program
for financial support. The authors thank Dr. Cecilia Marzabadi-Se-
ton Hall University, Dr. Nanette Wachter and Dr. Ling Huang-Hof-
stra University for their help with the acquisition of the NMR
spectra.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.11.
054.
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