The Easy Approach to N -Hydroxy- N -cycloalkenylamides through Nitrosocarbonyl Ene Reactions to Cycloalkenes: Valuable Compounds for Antiviral Syntheses

Article abstract of DOI:10.1055/s-0037-1610845

An easy approach to N -hydroxy- N -cycloalkenylamides, ene adducts of cyclic alkenes of different sizes, is presented. The products can be obtained both through the thermal generation of the nitrosocarbonyl intermediates and via the photochemical fragment

Full text of DOI:10.1055/s-0037-1610845

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
K. K. Hameed et al.
Paper
Synthesis
The Easy Approach to N-Hydroxy-N-cycloalkenylamides through
Nitrosocarbonyl Ene Reactions to Cycloalkenes: Valuable Com-
pounds for Antiviral Syntheses
Karzan Khaleel Hameeda
O
O
( )n
Ahmed Anwar Amina
Faiq H. S. Hussainb
Misal Giuseppe Memeoc
Mattia Moiolac
Ar
O
O
Ar
Ar
n = 1, 2, 3, 4
H
PCl3
HO
N
N
ene
reaction
N
( )n
( )n
16 examples
Paolo Quadrelli*c
0
0
0
0-0
0
0
1-
5
3
6
9-9
1
4
0
Ar = Ph, Mes
Yields: 42–99%
Quant.
a Salahaddin University – Erbil, Department of Chemistry,
College of Science, Erbil, Iraq
b Research Center-Ishik University, Erbil, Kurdistan Region,
Iraq
c Dipartimento di Chimica, Università degli Studi di Pavia,
Viale Taramelli 12, 27100 – Pavia, Italy
paolo.quadrelli@unipv.it
Received: 06.09.2018
Accepted after revision: 22.10.2018
Published online: 21.11.2018
HO
COR
N
Ar-B(OH)2
COR
N
DOI: 10.1055/s-0037-1610845; Art ID: ss-2018-t0599-op
Ar
Rh(I), base
O
MeOH, 60 °C
1
2
Abstract An easy approach to N-hydroxy-N-cycloalkenylamides, ene
adducts of cyclic alkenes of different sizes, is presented. The products
can be obtained both through the thermal generation of the nitroso-
carbonyl intermediates and via the photochemical fragmentation of the
Wieland heterocycle, this being the mildest way to generate these fleet-
ing species, also affording the best results so far in terms of chemical
yields. The use of the ene reaction for the synthesis of biologically ac-
tive molecules represents an interesting and valuable aspect of modern
organic synthesis, and this is the strategy proposed as a remarkable al-
ternative to current methods.
R'MgX
CuCN
Et2O, r.t.
COR
R'
HO
N
3
CuCl
2-ethyloxazoline
O
OH
N
OTMS
H
N
N
S
O
N
+
R2
HO
R1
Key words nitrosocarbonyl, ene reactions, cycloalkenes, hydroxyl-
amines, amides, antivirals
R1
THF, air, r.t.
S
R2
O
O
O
O
O
4
5
6
Scheme 1 Synthetic approaches to N-hydroxy-N-cycloalkenylamides
and N-hydroxy-β-ketoureas
N-Hydroxy-N-cycloalkenylamides 2 and 3 and N-hy-
droxy-β-ketoureas 6 are structural motifs that can be fre-
quently found in several organic compounds of pivotal in-
terest for different purposes. In recent years rhodium-cata-
lyzed ring-opening reactions of 2-oxa-3-azanorbornenes 1
with arylboronic acids1 furnished a valuable access to com-
pounds of type 2, while compounds of type 3 could be effi-
ciently obtained through reaction with organometallic
compounds such as Grignard reagents to give excellent in-
hibitors against 5-lipoxygenase, an important mediator of
inflammation intimately involved in a number of diseases
(Scheme 1).2 In addition, nitrosocarbonyl ene reactions
have been proposed in their asymmetric version to afford
derivatives 6, valuable α-aminated carbonyl compounds
(Scheme 1).3
the interest of several research groups. Chemler and co-
workers described the stereo- and regioselective synthesis
of heterocycles through Cu(II)-catalyzed addition to
alkenes,4a Helmchen and Qu applied Ir-catalyzed asymmet-
ric allylic substitution for the preparation of nucleosides,4b
while Tambar and Bayeh used chiral catalysts for the allylic
functionalization of unactivated internal alkenes.4c In addi-
tion, allylic alcohols in the presence of nitriles in Pt-cata-
lyzed processes have been proposed by Camp and co-work-
ers5a and a selective method for the synthesis of oxazolines
was suggested by Kokotos and co-workers starting from al-
lylamides.5b
Indeed, allylic amination4 remains a key target in organ-
ic synthesis and the search for mild and efficient methods
for the construction of the C–N bond continues to attract
On pursuing our traditional investigations on the chem-
ical behavior of nitrosocarbonyl intermediates,6 we have re-
cently investigated the ene reactions of nitrosocarbonyl in-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
K. K. Hameed et al.
Paper
Synthesis
termediates 7 with trisubstituted methylcycloalkenes.7 Ni-
trosocarbonylbenzene follows a Markovnikov orientation
and abstracts preferentially the twix hydrogens over the
lone ones. With the more sterically demanding nitrosocar-
bonylmesitylene in the presence of five- and six-membered
ring cycloalkenes, the Markovnikov directing effect is re-
lieved and twix and lone abstractions are observed
(Scheme 2). Endocyclic allylic hydrogens on the more con-
gested side of the alkene are exclusively abstracted (the ‘cis
effect’) resembling singlet oxygen behavior.8 We have
demonstrated that the balance between steric and confor-
mational factors as well as the acylnitroso generation con-
ditions dictates the regioselectivity in some cases. Larger
ring cycloalkenes undergo selective twix allylic hydrogen
abstraction. The photochemical generation of nitrosocar-
bonyl is also totally selective according to the Markovnikov
orientation.9
second, the double bond is prone to be further functional-
ized through addition and cycloaddition reactions, intro-
ducing other functional groups for the modulation of the
structure–activity relationship.
For both these reasons, mechanistic and synthetic, we
are still studying the ene reactions with cycloalkenes also
trying to have further insights into the relative reactivities
of cycloalkenes with respect to linear alkenes to find the
best balance between synthetic needs and optimum reac-
tion conditions to achieve the desired targets for our
nucleoside syntheses. Here, we wish to present the results
concerning the ene reactions of five-, six-, seven-, and
eight-membered cycloalkenes and aromatic-substituted ni-
trosocarbonyl intermediates, both thermally and photo-
chemically generated. A discussion of the relative reaction
rates will also complete the investigations.
Addition of N-hydroxybenzimidoyl chloride (11) to a
stirred dichloromethane solution of NMO (1.2 equiv), Et3N
(1.2 equiv), and excess cycloalkenes 13a–d (10 equiv) at
room temperature afforded the ene adducts 14A(a–d) in
good to high yields (42–70%) together with small amounts
of the corresponding 1,3-dipolar cycloadducts 15A(a–d) (2–
5%). In two cases, in the reactions with the cyclohexene
(13b) and cyclooctene (13d) small amounts (10 and 6%, re-
spectively) of O-benzoylbenzhydroxamic acid were isolated
as the product of the dimerization of nitrosocarbonylben-
zene 7A,6 which strongly competes with the ene path
(Scheme 3).
R/Ar
7
O
O
N
twin H
H lone
H
twix
( )n
n = 1, 2, 3
R/Ar
O
O
N
OMs
( )n
N
N
7
N
( )n
( )n
Cl
N
OH
purines
or
pyrimidines
O
N
HO
R/Ar
8
9
10
11
Scheme 2 ‘cis’ Selectivity on ene reactions with methylcycloalkenes
and ene reaction strategy to novel carbocyclic nucleoside analogues
Et3N, NMO
DCM, r.t., 48 h
n
13
a
b
c
d
1
2
3
4
COAr
( )n
Ar
Ar
O
O
N
HO
( )n
Ar = Ph, Mes
From the synthetic point of view, in general cy-
cloalkenes provide valuable mechanistic information on ni-
trosocarbonyl reactivity and this is a key point for their po-
tential synthetic applications. In fact, we are involved in the
preparation of nucleoside analogues derivatives having
small or large carbocyclic rings as a spacer between het-
erobases and hydroxy functionalities (Scheme 2).10 Since
the mesylate derivatives 8 can be easily prepared by litera-
ture protocols11 and functionalized with purine and pyrim-
idine heterobases to afford the cycloalkane compounds 9,
thermal or photochemical generation of suitable nitroso-
carbonyl intermediates will furnish the diastereomeric nu-
cleoside analogues 10 through the ene reaction, and these
products 10 will be evaluated as potential antiviral com-
pounds. Moreover the double bond located on the carbocy-
clic spacer represents a valuable functionality due to its
double role: first, it is able to reduce the conformational
mobility of the spacer fixing the nucleoside structure for a
more ease conformational analysis with suitable receptors;
+
N
N
( )n
14A,B(a–d)
O
7A,B
15A,B(a–d)
NMO
DCM, r.t., 48 h
+
N
_
O
12
Scheme 3 Ene adducts from thermal generation of nitrosocarbonyls
with cycloalkenes 13a–d
The experiments performed with nitrosocarbonylmesi-
tylene 7B and cycloalkenes 13a–d were conducted by add-
ing mesitylenecarbonitrile oxide (12) to a stirred dichloro-
methane solution of NMO (1.2 equiv) and excess cy-
cloalkenes 13a–d (10 equiv) at room temperature. The ene
adducts 14B(a–d) were isolated in high yields (50–99%)
along with small amounts of the corresponding 1,3-dipolar
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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K. K. Hameed et al.
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Synthesis
Table 1 Physical and Spectroscopic Data of Ene Adducts 14A,B(a–d) from the Reactions of Nitrosocarbonyls 7A,B with Cycloalkenes 13a–d
a
Ene adduct
Yield (%)
Mp (°C) (solvent)
IRa (cm–1
)
1H NMR (DMSO-d6)
νOH, νC=O
HC–Nb
CH=CHc
OHd
14Aa
14Ab
14Ac
14Ad
14Ba
14Bb
14Bc
14Bd
70
42
50
53
99
50
74
74
135–136 (EtOH)
2930, 1652
3109, 1768
3144, 1678
3121, 1672
3062, 1624
3130, 1654
3071, 1655
3065, 1656
5.49
4.93
5.04
5.25
4.47
5.15
5.24
5.50
5.69, 6.02
5.60, 5.89
5.84
9.46
9.51
9.72
9.72
9.16
9.22
9.44
9.41
132–134 (cyclohexane/benzene)
99–102 (benzene)
100–103 (hexane/benzene)
117–119 (PE/benzene)
131–133 (hexane/benzene)
198–200 (i-Pr2O/EtOH)
203–205 (i-Pr2O/EtOH)
5.75
5.66, 6.04
5.55, 5.91
5.81
5.70
a Nujol mull.
b Broad signals.
c Multiplets.
d Singlets.
cycloadducts 15B(b–d) (2–9%). In the case of the reaction
with cycloalkene 13b (cyclohexene), small amounts (4%) of
mesitoic anhydride were isolated as the product competing
dimerization of nitrosocarbonylmesitylene 7B (Scheme 3).6
The structure of ene compounds 14A,B(a–d) relies upon
the analytical and spectroscopic analyses collected and the
most relevant and diagnostic data are gathered in Table 1.
All the products are solids and in the IR spectra showed the
bands corresponding to the OH and C=O groups in the ex-
1
pected regions. In H NMR spectra (DMSO-d6), besides the
signals corresponding to the protons of the aromatic por-
tions of the molecules, the CH–N protons are represented
by broad signals around δ = 5 while the CH=CH protons are
coupled with the adjacent protons giving rise to multiplets
in the expected range. Finally, the acidic OH proton signals
are found in the range δ = 9.2–9.8 as singlets. As a general
comment on the spectroscopic data, it is worth noting that
in the case of the products derived from the reactions of ni-
trosocarbonylmesitylene 7B, the 1H NMR spectra appear as
mixtures of rotamers due to the hindered rotation around
the amide bond, furtherly slowed down by the presence of
the mesityl substituent. In Table 1 the chemical shifts for
compounds 14B(a–d) refer to the major rotamer (see ex-
perimental section for complete assignments).
To complete the structure assignment, we were able to
obtain for one of the synthetized products compound 14Aa
the X-ray crystal structure; the ORTEP view of 14Aa is
shown in Figure 1.
As nitrosocarbonyl intermediates can be efficiently gen-
erated through photocycloreversion of 1,2,4-oxadiazole 4-
oxides,6 this being the softest and cleanest method for their
generation, we investigated the ene reactions in the pres-
ence of the cycloalkenes 13a–d starting from 3,5-diphenyl-
1,2,4-oxadiazole 4-oxide (16) and 3,5-dimesityl-1,2,4-oxa-
diazole 4-oxide (17).
Figure 1 ORTEP view of compound 14Aa
The reactions were conducted in a simple Pyrex flask by
dissolving the Wieland heterocycles12 16 or 17 in methanol
and adding 10 equivalents of the desired cycloalkene 13.
Ph
O_
+
N
N
Ph
O
16
hν
MeOH, r.t., 5 h
n
13
a
b
c
d
COAr 14A Y (%) 14B Y (%)
1
2
3
4
Ar
O
O
a
b
c
d
94
96
91
92
a
b
c
d
94
92
93
91
( )n
N
HO
Ar = Ph, Mes
N
( )n
14A,B(a–d)
7A,B
hν
Ar-CN
MeOH, r.t., 10 h
_
O
Mes
+
N
N
Mes
O
17
Scheme 4 Ene adducts from photochemical generation of nitrosocar-
bonyls with cycloalkenes 13a–d
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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K. K. Hameed et al.
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Synthesis
The solutions were exposed to sunlight under stirring and
the consumption of the starting heterocycle was monitored
by TLC (Scheme 4).
From the photochemical cleavage of the oxadiazole
rings, the nitrosocarbonyls 7A,B were generated along with
benzonitrile and mesitylenecarbonitrile as byproducts. The
workup procedure is extremely simple; upon evaporation
at reduced pressure the reaction products were collected
and purified by simple recrystallization leaving the desired
ene adducts 14A,B(a–d) in excellent yields.
An easy implementation of molecular diversity aiming
to have more scaffolds for the synthesis of analogues of an-
tiviral compounds is represented by the dehydroxylation
reaction of the ene adducts 14A,B(a–d), also contributing to
a structural confirmation of previous assignments.
The only detectably secondary products were, in some
cases, the 3,5-diphenyl- and the 3,5-dimesityl-1,2,4-oxadi-
azoles (2–4%), derived from the deoxygenation process of
the starting reagents 16 and 17, respectively. As stated
above, the photochemical process is the cleanest method
for nitrosocarbonyl generation and allowed the ene adducts
to be obtained in very high yields in the absence of signifi-
cant byproducts. The reactions were simply conducted by
addition of PCl3 to a benzene solution of the ene adduct
14A,B(a–d) and leaving the mixture at room temperature
for one day (Scheme 5).13 Simple solvent evaporation at re-
duced pressure and crystallization allowed the unsaturated
amides 18A,B(a–d) to be obtained. The amide derivatives
are known compounds; however some spectroscopic analy-
ses were conducted to corroborate their structures and
those of the starting ene adducts (see experimental section
for references). The yields are nearly quantitative and the
corresponding IR spectra clearly showed, besides the bands
of the carbonyl groups in the range 1628–1638 cm–1, the
presence of the new sharp bands relative to the NH groups
at 3281–3314 cm–1. The 1H NMR spectra of the amides
18A(a–d) maintained the same general appearance of the
proton spectra of the ene adducts with the diagnostic pres-
ence of the NH proton signals in the range δ = 6.13–6.35 (in
CDCl3). The chemical shifts in the 1H NMR spectra of amides
18B(a–d) are slightly different, although maintaining the
same general aspects of the proton spectra of 18A(a–d); the
diagnostic NH proton signals were at δ = 5.35–6.01 (in
CDCl3), reasonably because of shielding effects of the steri-
cally demanding mesitylene ring.
COAr
COAr
18A Y (%) 18B Y (%)
N
N
H
HO
PCl3
a
b
c
d
90
96
95
97
a
b
c
d
90
97
98
96
benzene
r.t., 24 h
( )n
18A,B(a–d)
( )n
14A,B(a–d)
Scheme 5 Dehydroxylation of ene adducts 14A,B(a–d)
The described syntheses are robust, reliable, and afford
a variety of valuable compounds, and we completed the
study from the reactivity point of view by performing com-
petition ene reactions between pairs of linear and cyclic
alkenes to determine the relative rates of different types of
alkenes in the reaction with nitrosocarbonylbenzene 7A,
generated in situ from the corresponding N-hydroxybenz-
imidoyl chloride (11). Pairs of linear and cyclic alkenes were
used in excess (5 equiv + 5 equiv) in the presence of 1.1
equivalents of NMO and 1.1 equivalents of Et3N (Scheme 6).
Cl
N
OH
Et3N, NMO
( )n
Ph
O
O
R
ene adduct
from olefin 1 from olefin 2
ene adduct
+
olefin 1 (5 equiv)
+
olefin 2 (5 equiv)
N
DCM, r.t., 48 h
11
7A
R = Me, Ph
n = 1, 2, 3, 4
Scheme 6 Competition experiments for the determination of relative
rates in ene reactions between nitrosocarbonylbenzene 7A and linear
and cyclic alkenes
After 48 hours at room temperature, the mixtures were
submitted to the usual workup procedure and the crude
residues, from evaporation of the organic phases, were ex-
1
amined by H NMR. The relative rates were calculated by
using the integral values of the hydroxyl protons that in
DMSO-d6 appear as sharp singlets. Figure 2 reports the rela-
tive rates of the evaluated cycloalkenes towards nitrosocar-
bonylbenzene 7A generated as reported in Scheme 6.
Tetramethylethylene shows the highest reactivity as ex-
pected for the prevailing HOMO(alkene)–LUMO(nitrosocarbonyl) in-
teraction. Second comes trimethylethylene, which has the
same rate as α-methylstyrene. Then, cycloalkenes follow
with a neat prevalence of large size rings with respect to
five- or six-membered rings. Methyl substitution on cyclic
cycloalkenes somewhat reduces, presumably for steric rea-
sons, the rates. Large rings seem to resemble linear alkenes,
being more reactive than cyclopentene or cyclohexene by
two or three times. Typically for nitrosocarbonyl intermedi-
ates, the relative reactivities span a remarkably narrow
Ph
1.00 0.80 0.80
0.71
0.64
0.49
0.43
0.20 0.10
0.05
Figure 2 Relative rates of cycloalkenes towards nitrosocarbonylbenzene 7A
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

E
K. K. Hameed et al.
Paper
Synthesis
range;14 this is particularly clear by comparing the values
for the same alkenes in the reactions with N-phenyltriazo-
linedione (Ph-TAD) and singlet oxygen (1O2).15 In fact, te-
tramethylethylene is 2000 times more reactive than trans-
hex-3-ene in the reaction with Ph-TAD and 2900 times
more reactive than trans-hex-3-ene in the reaction with
1O2.
In parallel, we measured the relative rates towards a re-
duced number of alkenes by generating the nitrosocarbon-
ylbenzene 7A through the photochemical method using the
Wieland heterocycle 16 in methanol as solvent, as this is
best method for conducting these photochemical reactions
(Scheme 7). The reactions were conducted in a quartz tube,
degassing the solutions with pure nitrogen gas for 15 min-
utes and irradiating them with 2 × 15 W lamps (310 nm) for
5 hours. The reactions mixtures were then simply concen-
trated to dryness and analyzed by 1H NMR (as above).
in a range of 0.1–0.15. These results did not add much to
the entire view of the relative reactivities of the alkenes in
the ene reaction with nitrosocarbonyl 7A and for these rea-
sons only a limited number of cases were tested with the
photochemical generation methodology.
The reactivity clustering effect of alkenes towards nitro-
socarbonyl intermediates is even more pronounced in the
case of nitrosocarbonylmesitylene 7B, both thermally or
photochemically generated.
In conclusion we have reported the easy approach to
ene adducts to cyclic alkene of different size that can be ob-
tained both through the thermal generation of the nitroso-
carbonyl intermediates and via the photochemical frag-
mentation of the Wieland heterocycle, this being the mild-
est way for the generation of these fleeting species, also
affording the best results ever in terms of chemical yields.
Having these results in hand, we can now consider the use
of the ene reactions for the synthesis of biologically active
molecules. Scheme 8 shows the strategy we are planning to
apply: a variety of aliphatic,16 aromatic,17 and heterocyclic18
nitrosocarbonyl intermediates of type 7, belonging to our
‘portfolio’ of highly reactive nitroso derivatives,6 are prone
to be installed on a carbon skeleton (cyclic or acyclic) to
prepare a variety of N-hydroxyamides of type 19 and am-
ides of type 20.
Ph
O_
( )n
olefin 1
(5 equiv)
+
Ph
O
O
+
N
hν
R
ene adduct
from olefin 1 from olefin 2
ene adduct
+
N
N
MeOH
r.t., 5 h
Ph
O
16
7A
olefin 2
(5 equiv)
R = Me, Ph
n = 1, 2
Furthermore, the possibility to correctly functionalize
these types of alkenes with suitable heterobases bearing
the purine and pyrimidine skeleton 9 will allow compounds
of type 10 to be furnished that we have demonstrated to
deserve attention in terms of antiviral activities.10
Scheme 7 Competition experiments for relative rates determination in
ene reactions between nitrosocarbonylbenzene 7A and linear and cyclic
alkenes
The results shown in Figure 3 demonstrate the narrow-
ing of the relative rates on a shorter scale, where tetrameth-
ylethylene remains the best alkene and the other reported
cases hardly reaching 0.5 in the reactivity scale.
Figure 3 reports the relative rates of the evaluated
alkenes towards nitrosocarbonylbenzene 7A generated as
reported in Scheme 7.
O
O
( )n
R/Ar/Het
R/Ar/Het PCl3
R
H
R
HO
R
N
N
ene
reaction
( )n
( )n
19
20
Het/Ar/R
O
O
N
N
( )3
N
Ph
7
( )n
( )n
1.00
0.63
0.42
0.11
0.03
0.008
9
10
O
N
ene
reaction
HO
R/Ar/Het
Figure 3 Relative rates of alkenes towards nitrosocarbonylbenzene 7A,
generated photochemically
Scheme 8 Synthetic strategy for the application of ene reactions be-
tween nitrosocarbonyl intermediates of type 7 and linear alkenes, cy-
cloalkenes, and heterobase-functionalized alkenes for the preparation
of bioactive molecules
These data were collected by the photochemical genera-
tion of the intermediate 7A in a different solvent with re-
spect to the cases reported in Figure 2. Here, methanol was
chosen since it is the best solvent for the photochemical
fragmentation of the Wieland heterocycle 16. On the basis
of these results, we also performed analogous competition
experiments in dichloromethane and acetonitrile with the
photochemical generation protocol. The results indicated a
clustering of the reactivity rates at the top of the scale with-
On pursuing our investigation on antiviral compounds
and bioactive molecules in general, we will select specific
biological targets where the available structures through
the proposed synthetic methodology could help in a short-
cut synthesis of valuable compounds and to investigate the
relative structure–activity relationship.
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K. K. Hameed et al.
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1H NMR (CDCl3, 300 MHz): δ = 9.72 (s, 1 H, N-OH), 7.60 (m, 2 H, Ph),
7.43 (m, 3 H, Ph), 5.84 (m, 2 H, CH=CH), 5.04 (br, 1 H, CH-N), 2.17 (m,
1 H, CH2), 1.98 (m, 2 H, CH2), 1.80 (m, 2 H, CH2), 1.68 (m, 1 H, CH2),
1.59 (br, 1 H, CH2), 1.25 (m, 1 H, CH2).
13C NMR (CDCl3, 75 MHz): δ = 168.4 (C=O), 135.3, 133.8, 131.0, 129.9
(arom), 128.1, 127.7 (CH=CH), 57.8 (CH-N), 31.7, 28.15, 28.1, 26.1
(CH2).
All melting points (mp) are uncorrected. Elemental analyses were
performed on a Carlo Erba NA-1500. 1H and 13C NMR spectra were re-
corded on a 300 MHz spectrometer (solvents specified) referenced to
internal TMS. IR spectra (Nujol mulls) were recorded on a Perkin
Elmer RX-1 spectrophotometer. Column chromatography and TLC:
silica gel H60 and GF254, respectively; eluants: cyclohexane/EtOAc
(9:1) to pure EtOAc; MPLC Biotage Flash Master Personal; eluants: cy-
clohexane/EtOAc (9:1) to pure EtOAc.
Anal. Calcd for C14H17NO2 (231.30): C, 72.70; H, 7.41; N, 6.06. Found:
C, 72.69; H, 7.43; N, 6.05.
N-Hydroxybenzimidoyl chloride (11) and mesitylenecarbonitrile ox-
ide (12) were prepared by reported literature procedures.19 3,5-Di-
phenyl-1,2,4-oxadiazole 4-oxide (16) and 3,5-dimesityl-1,2,4-oxadi-
azole 4-oxide (17) were prepared according to the reported synthe-
ses.12,20 Cycloalkenes 13a–d were purchased from chemical suppliers.
Other reagents and solvents were purchased from chemical suppliers
and used without any further purification.
N-(Cyclooct-2-en-1-yl)-N-hydroxybenzamide (14Ad)
White crystals; yield: 1.29 g (53%); mp 100–103 °C (hexane/benzene).
IR: 3121 (OH), 1672 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): δ = 9.72 (s, 1 H, N-OH), 7.57 (m, 2 H, Ph),
7.45 (m, 3 H, Ph), 5.75 (m, 2 H, CH=CH), 5.25 (br, 1 H, CH-N), 1.18–
2.18 (m, 10 H, CH2).
Ene Reactions of N-Hydroxybenzimidoyl Chloride (11) with
13C NMR (CDCl3, 75 MHz): δ = 168.3 (C=O), 135.4, 133.8, 129.9, 129.4,
(arom), 128.3, 127.8 (CH=CH), 54.3 (CH-N), 32.8, 28.5, 26.1, 26.0, 23.8
(CH2).
Cycloalkenes 13a–d; General Procedure
To a solution of cycloalkene 13a–d (0.1 mol) in DCM (100 mL) was
added NMO (0.012 mol) and distilled Et3N (0.012 mol). N-Hydroxy-
benzimidoyl chloride (11; 0.01 mol) was then dissolved in DCM (50
mL) and the solution added dropwise to the solution of cycloalkene
with stirring at r.t. and the mixture was stirred for a further 48 h.
Then, the mixture was washed with water (2 × 30 mL) and the organic
phase was dried (anhyd Na2SO4). The solvent was evaporated and the
residue was submitted to chromatographic separation for isolation
and purification of the products.
Anal. Calcd for C15H19NO2 (243.14): C, 73.44; H, 7.81; N, 5.74. Found:
C, 73.45; H, 7.83; N, 5.75.
Ene Reactions of Mesitylenecarbonitrile Oxide (12) with
Cycloalkenes 13a–d; General Procedure
To a solution of cycloalkene 13a–d (0.1 mol) in DCM (100 mL) was
added NMO (0.012 mol). Mesitylenecarbonitrile oxide (12; 0.01 mol)
was then dissolved in DCM (50 mL) and the solution added dropwise
to the cycloalkene solution with stirring at r.t. and stirring was con-
tinued for 48 h. The mixture was washed with water (2 × 30 mL) and
the organic phase was dried (anhyd Na2SO4). The solvent was evapo-
rated and the residue was submitted to chromatographic separation
for isolation and purification of the products.
N-(Cyclopent-2-en-1-yl)-N-hydroxybenzamide (14Aa)
White crystals; yield: 1.42 g (70%); mp 135–136 °C (EtOH).
IR: 2930 (OH), 1652 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): δ = 9.46 (s, 1 H, N-OH), 7.62 (m, 2 H, Ph),
7.43 (m, 3 H, Ph), 6.02 (m, 1 H, =CH), 5.69 (m, 1 H, =CH), 5.49 (br, 1 H,
CH-N), 2.42 (m, 1 H, H-CH), 2.28 (m, 1 H, HC-H), 2.01 (m, 1 H, H-CH),
1.95 (m, 1 H, HC-H).
N-(Cyclopent-2-en-1-yl)-N-hydroxy-2,4,6-trimethylbenzamide
(14Ba)
13C NMR (CDCl3, 75 MHz): δ = 168.4 (C=O), 135.4, 135.1, 129.9, 129.2
White crystals; yield: 2.41 g (99%); mp 117–119 °C (PE/benzene).
IR: 3062 (OH), 1624 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): δ = 9.16 [9.46]* (s, 1 H, N-OH), 6.81 [6.90]*
(s, 2 H, Mes), 6.04 [5.93]* (m, 1 H, =CH), 5.66 [5.53]* (m, 1 H, =CH),
4.47 [5.72]* (br, 1 H, CH-N), 2.29 (m, 2 H, CH2), 2.22 [2.24]* (s, 3 H,
CH3), 2.16 [2.19]* (s, 3 H, CH3), 2.14 [2.18]* (s, 3 H, CH3), 1.92 (m, 2 H,
CH2); * minor rotamer.
(arom), 128.1, 127.7 (CH=CH), 66.9 (CH-N), 31.3, 26.0 (CH2).
Anal. Calcd for C12H13NO2 (203.14): C, 70.92; H, 6.45; N, 6.89. Found:
C, 70.93; H, 6.43; N, 6.87.
N-(Cyclohex-2-en-1-yl)-N-hydroxybenzamide (14Ab)
White crystals; yield: 0.92 g (42%); mp 132–134 °C (cyclohex-
ane/benzene).
13C NMR (CDCl3, 75 MHz): δ = 169.6 [164.2]* (C=O), 136.5 [137.6]*,
135.2 [133.4]*, 135.0 [133.3]*, 133.1, 129.0, 128.0, (arom), 127.3,
127.2 (CH=CH), 61.1 [65.5]* (CH-N), 31.1 [31.3]*, 25.6 [26.3]*, 20.6,
18.6 (CH2); * minor rotamer.
IR: 3109 (OH), 1768 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): δ = 9.51 (s, 1 H, N-OH), 7.61 (m, 2 H, Ph),
7.43 (m, 3 H, Ph), 5.89 (m, 1 H, =CH), 5.60 (m, 1 H, =CH), 4.93 (br, 1 H,
CH-N), 1.97 (m, 1 H, H-CH), 1.81 (m, 3 H, CH2), 1.48–1.67 (m, 2 H,
CH2).
13C NMR (CDCl3, 75 MHz): δ = 168.7 (C=O), 130.7, 129.9, 129.5, 129.2,
128.7, 128.3, 128.1 (arom), 127.7, 127.5 (CH=CH), 53.1 (CH-N), 25.4,
24.0, 20.7 (CH2).
Anal. Calcd for C15H19NO2 (243.32): C, 73.44; H, 7.81; N, 5.71. Found:
C, 73.43; H, 7.83; N, 5.72.
N-(Cyclohex-2-en-1-yl)-N-hydroxy-2,4,6-trimethylbenzamide
(14Bb)
Anal. Calcd for C13H15NO2 (217.27): C, 71.87; H, 6.96; N, 6.45. Found:
C, 71.85; H, 6.97; N, 6.47.
White crystals; yield: 1.30 g (50%); mp 131–133 °C (hexane/benzene).
IR: 3130 (OH), 1654 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): δ = 9.22 (s, 1 H, N-OH), 6.81 (s, 2 H, Mes),
5.91 (m, 1 H, =CH), 5.55 (m, 1 H, =CH), 5.15 (br, 1 H, CH-N), 2.18 (s, 3
H, CH3), 2.16 (s, 3 H, CH3), 2.13 (s, 3 H, CH3), 1.70–2.07 (m, 6 H, CH2).
N-(Cyclohept-2-en-1-yl)-N-hydroxybenzamide (14Ac)
White crystals; yield: 1.16 g (50%); mp 99–102 °C (benzene).
IR: 3144 (OH), 1678 cm–1 (C=O).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

G
K. K. Hameed et al.
Paper
Synthesis
13C NMR (CDCl3, 75 MHz): δ = 169.6 (C=O), 136.5, 134.4, 133.1, 133.0,
130.8, 127.5 (arom), 127.3, 127.2 (CH=CH), 51.4 (CH-N), 25.3, 24.0,
20.7, 20.6, 18.6 (CH2).
the organic phase was dried (anhyd Na2SO4). The solvent was evapo-
rated and the residue was crystallized for purification to give
18A,B(a–d) which were characterized and found identical with com-
pounds reported in literature.13,21–27 The corresponding spectroscopic
data are reported in the Supporting Information.
Anal. Calcd for C16H21NO2 (259.35): C, 74.10; H, 8.16; N, 5.40. Found:
C, 74.11; H, 8.13; N, 5.42.
Ene Reaction Competitions for Relative Reaction Rate Determina-
tions
N-(Cyclohept-2-en-1-yl)-N-hydroxy-2,4,6-trimethylbenzamide
(14Bc)
Method A: N-Hydroxybenzimidoyl chloride (11; 16 mg) was added to
a degassed (pure and dry N2 stream) solution of pairs of alkenes (5 + 5
equiv) in DCM (10 mL) in the presence of NMO (1.1 equiv) and Et3N
(1.1 equiv) and the mixture was allowed to react for 48 h at r.t. The
mixture was washed with water and the organic phases dried (anhyd
Na2SO4). The relative rates were calculated by using the integrals of
the hydroxy protons that in DMSO-d6 appear as sharp singlets in 1H
NMR spectra. Figure 2 reports the relative rates of the evaluated
alkenes towards the nitrosocarbonylbenzene 7A generated as report-
ed in Scheme 6.
White crystals; yield: 2.02 g (74%); mp 198–200 °C (i-Pr2O/EtOH).
IR: 3071 (OH), 1655 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): δ = 9.44 (s, 1 H, N-OH), 6.82 (s, 2 H, Mes),
5.81 (m, 2 H, CH=CH), 5.24 (br, 1 H, CH-N), 2.23 (s, 3 H, CH3), 2.14 (s, 6
H, CH3), 1.03–2.05 (m, 8 H, CH2).
13C NMR (CDCl3, 75 MHz): δ = 168.8 (C=O), 136.6, 134.4, 133.2, 133.1,
131.3 (arom), 130.8, 127.3 (CH=CH), 56.1 (CH-N), 31.7, 28.2, 28.1,
26.2, 20.6, 18.6 (CH2).
Anal. Calcd for C17H23NO2 (273.38): C, 74.69; H, 8.48; N, 5.12. Found:
C, 74.67; H, 8.49; N, 5.12.
Method B: Wieland heterocycle 16 (15 mg) was added to a degassed
(pure and dry N2 stream) solution of pairs of alkenes (5 + 5 equiv) in
MeOH (10 mL) contained in quartz tubes. Degassing was conducted
for 15 min and the resulting mixtures were irradiated with 2 × 15 W
lamps (310 nm) for 5 h. The mixture was then simply concentrated to
N-(Cyclooct-2-en-1-yl)-N-hydroxy-2,4,6-trimethylbenzamide
(14Bd)
White crystals; yield: 2.13 g (74%); mp 203–205 °C (i-Pr2O/EtOH).
IR: 3065 (OH), 1656 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): δ = 9.41 [9.71]* (s, 1 H, N-OH), 6.81 [6.88
and 6.94]* (s, 2 H, Mes), 5.70 (m, 2 H, CH=CH), 5.50 [4.26]* (br, 1 H,
CH-N), 2.22 [2.25]* (s, 3 H, CH3), 2.15 [2.21]* (s, 3 H, CH3), 2.10 [2.07]*
(s, 3 H, CH3), 0.82–1.98 (m, 10 H, CH2); * minor rotamer.
1
dryness and analyzed by H NMR. The relative rates were calculated
by using the integrals of the hydroxy protons that in DMSO-d6 appear
as sharp singlets. Figure 3 reports the relative rates of the evaluated
alkenes towards the nitrosocarbonylbenzene 7A generated as report-
ed in Scheme 7.
13C NMR (CDCl3, 75 MHz): δ = 169.2 [164.4]* (C=O), 136.5 [137.6]*,
133.3 [133.7]*, 133.1 [134.5]*, 129.5 [129.4]* (arom), 127.8 [127.9]*,
127.3 [127.4]* (CH=CH), 52.6 [56.6]* (CH-N), 32.8 [33.5]*, 28.4, 26.0
[26.4]*, 26.0 [25.8]*, 23.7 [23.6, 20.6 [20.7]*, 18.6 [18.8]*, 18.6 [18.7]*
(CH2); * minor rotamer.
Funding Information
Financial support: University of Pavia, MIUR (PRIN 2011, CUP:
F11J12000210001) and COST Action CM1004. We also thank ‘VIPCAT
– Value Added Innovative Protocols for Catalytic Transformations’
Anal. Calcd for C18H25NO2 (287.40): C, 75.22; H, 8.77; N, 4.87. Found:
C, 75.23; H, 8.79; N, 4.85.
project (CUP: E46D17000110009) for valuable financial support.
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Acknowledgment
Photochemical Ene Reactions with Cycloalkenes 13a–d; General
Procedure
University of Pavia is gratefully acknowledged for supporting the re-
search activities and the reported results. We also thank warmly the
Salahaddin University of Erbil (Iraq) for supporting the research activ-
ity and co-authorship. We thank Prof. B. Bovio for X-ray data collec-
tion.
To a solution of 3,5-diphenyl-1,2,4-oxadiazole 4-oxide (16; 23.8 mg,
100 mmol) in MeOH (50 mL) in a Pyrex glass flask was added excess
cycloalkene 13a–d (10 equiv). The solution was exposed to sunlight
with stirring until consumption of the starting heterocycle (TLC mon-
itoring: 4–6 h). The mixture was then simply concentrated to dryness
and the residue submitted to chromatographic separation for isola-
tion and purification of the products 14A(a–d).
Supporting Information
Similarly, to a solution of 3,5-dimesityl-1,2,4-oxadiazole 4-oxide (17;
32.2 mg, 100 mmol) in MeOH (50 mL) in a Pyrex glass flask was added
excess cycloalkene 13a–d (10 equiv). The solution was exposed to
sunlight with stirring for until consumption of the starting heterocy-
cle (TLC monitoring: 10 h). The mixture was then simply concentrat-
ed to dryness and the residue submitted to chromatographic separa-
tion for isolation and purification of the products 14B(a–d).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610845.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H