An Experimental and Computational Approach to Understanding the Reactions of Acyl Nitroso Compounds in [4 + 2] Cycloadditions

Article abstract of DOI:10.1021/acs.joc.5b01470

Catalytic aerobic oxidation of phenyl hydroxycarbamate 1 and 1-hydroxy-3-phenylurea 2 using CuCl₂ and 2-ethyl-2-oxazoline in methanol gave acyl nitroso species in situ, which were trapped in nitroso-Diels-Alder (NDA) reactions with various dienes to afford the corresponding cycloadducts in high yields (90-98%). Competing ene products were also present for dienes containing both alkene π-bonds and allylic σ-bonds, and the ene yields are higher with 1 than with 2. The use of the chiral hydroxamic acid, (R)-1-hydroxy-3-(1-phenylethylurea) 3 (same conditions) gave NDA cycloadducts in high yields (97-99%) with no ene product from 2,3-dimethyl-1,3-butadiene. NDA cycloadducts were not obtained from other hydroxamic acid analogues [RCONHOH (R = PhCH₂ 4; Ph(CH₂)₂ 5; Ph(CH₂)₃ 6; Ph(CH₂)₄ 7; Ph 8; 2-pyridyl 9; 3-pyridyl 10] with various dienes using copper-oxidation but rather were obtained using sodium periodate, resulting in variable NDA yields (13-51%) from hydroxamic acids 1-10 with cyclohexa-1,3-diene and 2,3-dimethyl-1,3-butadiene (several cycloadducts characterized by X-ray crystallography). The NDA and nitroso-ene reaction pathways of nitroso intermediates with dienes were mapped by DFT computations (B3LYP/6-31G), which showed that the acyl nitroso species are super-reactive and that activation energies in the NDA processes are lower than the isomerization barriers between some cis- and trans-butadienes.

Full text of DOI:10.1021/acs.joc.5b01470

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Article
An Experimental and Computational Approach to Understanding
the Reactions of Acyl Nitroso Compounds in [4+2]-Cycloadditions
Duangduan Chaiyaveij, Andrei S. Batsanov, Mark A. Fox, Todd B Marder, and Andrew Whiting
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01470 • Publication Date (Web): 04 Sep 2015
Downloaded from http://pubs.acs.org on September 7, 2015
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An Experimental and Computational Approach to Understanding the Reactions of
Acyl Nitroso Compounds in [4+2]-Cycloadditions
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Duangduan Chaiyaveij,† Andrei S. Batsanov,‡ Mark A. Fox,‡ Todd B. Marder§ and Andrew Whiting‡*
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†Chemistry Department, Faculty of Science and Technology, Thammasat University Rangsit Campus, Khlongluang,
Pathumthani, 12120 Thailand
‡Centre for Sustainable Chemical Processes, Department of Chemistry, Durham University, Science Laboratories, South
Road, Durham, DH1 3LE, U.K. Eꢀmail: andy.whiting@durham.ac.uk
§Institut für Anorganische Chemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg Germany
Abstract
R2
10 mol % CuCl2
R1 R2
O
O
O
R3
R4
O2, rt, MeOH
nitroso-
R3
R4
Ph
Ph
Ph
R1
R6
X
NH
OH
X
X
N
N
O
O
Et
O
Diels-Alder
reaction
R5
6 dienes
R5
R6
20 mol %
N
X = O, NH
90-98 %
1.5 - 6 h
Catalytic aerobic oxidation of phenyl hydroxycarbamate 1 and 1ꢀhydroxyꢀ3ꢀphenylurea 2 using CuCl2
and 2ꢀethylꢀ2ꢀoxazoline in methanol gave acyl nitroso species in situ, which were trapped in nitrosoꢀ
DielsꢀAlder (NDA) reactions with various dienes to afford the corresponding cycloadducts in high
yields (90ꢀ98%). Competing ene products were also present for dienes containing both alkene πꢀbonds
and allylic σꢀbonds, and the ene yields are higher with 1 than with 2. The use of the chiral hydroxamic
acid, (R)ꢀ1ꢀhydroxyꢀ3ꢀ(1ꢀphenylethylurea) 3 (same conditions) gave NDA cycloadducts in high yields
(97ꢀ99%) with no ene product from 2,3ꢀdimethylꢀ1,3ꢀbutadiene. NDA cycloadducts were not obtained
from other hydroxamic acid analogues [RCONHOH (R = PhCH2 4; Ph(CH2)2 5; Ph(CH2)3 6; Ph(CH2)4
7; Ph 8; 2ꢀpyridyl 9; 3ꢀpyridyl 10], with various dienes using the copperꢀoxidation, but were obtained
using sodium periodate, resulting in variable NDA yields (13ꢀ51%) from hydroxamic acids 1ꢀ10 with
cyclohexaꢀ1,3ꢀdiene and 2,3ꢀdimethylꢀ1,3ꢀbutadiene (several cycloadducts characterized by Xꢀray
crystallography). The NDA and nitrosoꢀene reaction pathways of nitroso intermediates with dienes were
mapped by DFT computations (B3LYP/6ꢀ31G*) which showed that the acyl nitroso species are superꢀ
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reactive and activation energies in the NDA processes are lower than the isomerization barriers between
some cisꢀ and transꢀbutadienes.
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Introduction
Nitroso compounds have been widely used and studied in organic chemistry for over a century, with
Baeyer's synthesis of nitroso benzene reported in 1874.1 Since then, not only have the methods of
synthesis improved substantially (Baeyer reacted diphenylmercury with nitroso bromide), but the range
of nitroso species accessible and their range of reactions has increased substantially.2 Indeed, the heteroꢀ
DielsꢀAlder reaction has been widely used not only to derive oxazine systems,2 but also for a wideꢀ
range of synthetic applications,3 including asymmetric synthesis4 and recently in flow chemistry.5
Although nitroso arenes are probably most well known as nitroso dienophiles, many of which are also
commercially available or readily prepared, one of the most useful, and indeed, reactive classes of
nitroso dienophiles are the acyl nitroso (or nitroso carbonyl) species.3 However, unlike their nitroso
arene counterparts, these compounds have not been isolated or characterized, being generated in situ,
generally by the oxidation of hydroxamic acids. The resulting acyl nitroso species are then trapped by
suitable dienes to yield the corresponding [4+2]ꢀcycloaddition products. As part of a program to
develop wider applications of acyl nitroso compounds in synthetic applications, we and others,6 have
been involved in developing cleaner in situ methods for the oxidation of hydroxamic acids, that improve
upon the use of periodates, DMSOꢀbased oxidants and lead(IV)ꢀbased reagents etc.7 Even though
peroxides are less toxic, the yields depend upon the substrate, oxidant and catalyst.7 We recently
reported the use of a Cu(II)ꢀcatalyzed, airꢀbased, in situ hydroxamic acid oxidation reaction, as shown in
Scheme 1,8 which was particularly clean and efficient, and related reactions have been widely used in
synthesis.3,4,9ꢀ11 During these studies, it is clear that both the regiochemistry of nitrosoꢀDielsꢀAlder
(NDA) reactions, and often the chemoselectivity of the acyl nitroso species is not always predictable,
and is difficult to control.8ꢀ11 As a consequence, we undertook to study systematically this reaction both
experimentally and theoretically, in order to develop an understanding of the principles which govern
the reactivity of acyl nitroso compounds of different types with variously substituted dienes, and herein,
we discuss our findings.
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Scheme 1. Reactions of Nꢀ(benzyloxycarbonyl)hydroxylamine with various dienes using the copperꢀ
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oxazoline catalyst and air system.
Results and discussion
Syntheses and Characterizations of Compounds 1-53
The hydroxamic acids 1ꢀ12 listed in Table 1 and were prepared from reactions of hydroxylamine
hydrochloride with appropriate chlorides, isocyanates, carboxylic acids or esters. A new compound 13
was obtained in 13% yield from (R)ꢀ(1ꢀisocyanatoethyl)benzene with hydroxylamine hydrochloride in
the synthesis of (R)ꢀ1ꢀhydroxyꢀ3ꢀ(1ꢀphenylethylurea) 3.
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Table 1. Reactions of cyclohexaꢀ1,3ꢀdiene and 2,3ꢀdimethylꢀ1,3ꢀbutadiene with nitroso compounds prepared in situ from
oxidations of hydroxamic acids, 1ꢀ10.
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Hydroxamic Acid Entry
Cycloadduct from
cyclohexaꢀ1,3ꢀdiene
GP1a GP2b GP3c
Yield Yield Yield
Entry
11
Product(s) from 2,3ꢀdimethylꢀ1,3ꢀbutadiene GP1a GP2b GP3c
Yield Yield Yield
1
51
98
ꢀ
47
95
ꢀ
14d,e
1
24
34
24:34 Ratio 1:0 from GP1; 6:1 from GP2
2
49
98
ꢀ
12
45
90
ꢀ
15e,f
2e
25e,g
35g
25:35 Ratio 1:0 from GP1; 9:1 from GP2
3
42
48
49
32
97
0
ꢀ
13
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15
16
13
99
0
ꢀ
16e
17e
18
3e
26
27
4
61
65
73
42h
37h
40h
0
0
0
4
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0
0
5
28
29
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0
0
6
19
7
38
53
42
0
0
0
78
49
0
17
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41h
46
0
0
0
0
0
0
7
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30
8
21e,i
8
31
9
21
9e
32e
22
10
31
0
0
20
18
0
0
10
23
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aGP1: MeOH (30 mL), diene (2 equivalent), NaIO4(0.83 mmol), hydroxamic acid (0.83 mmol), stirred at rt, 2ꢀ4 h. At completion, the solvent evaporated
and the product was purified by silica gel chromatography. Isolated yields quoted after purification bGP2: MeOH(5 mL), diene (2 equivalent), CuCl
(0.06
mmol), 2ꢀethylꢀ2ꢀoxazoline (0.12 mmol),hydroxamic acid (0.63 mmol), stirred at rt in air 2ꢀ6 h. At completion, the solvent evaporated and the product was
purified by silica gel chromatography. Isolated yields quoted after purification. cGP3: Toluene (5 mL), diene (2 equivalent), CuCl2 (0.14 mmol), 2ꢀethylꢀ2ꢀ
oxazoline (0.28 mmol),, hydroxamic acid (1.40 mmol), heated under reflux and stirred in air, 4ꢀ20 h. At completion, the solvent evaporated and the product
was purified by silica gel chromatography. Isolated yields quoted after purification. dReference 12. eXꢀray structure obtained in this study. fReference 9.
gReference 13. hEne and methanolysis products also observed. iReferences 14 and 15. Note: All chiral cycloadducts are racemic.
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Initially, in situ oxidations of the hydroxamic acids 1ꢀ12 with sodium periodate in the presence of
cyclohexaꢀ1,3ꢀdiene or 2,3ꢀdimethylꢀ1,3ꢀbutadiene were employed to establish whether cycloadducts
can be formed (Table 1, Entries 1ꢀ20, method GP1). The reactions were complete in 4 hours with low to
moderate yields of 13ꢀ53% of the desired cycloadducts 14ꢀ33 from hydroxamic acids 1ꢀ10. However,
two hydroxamic acids, Nꢀhydroxyꢀ2ꢀ(pyridinꢀ2ꢀyl)acetamide 11 and 2ꢀaminoꢀNꢀhydroxybenzamide 12,
gave only black tars after oxidation.
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The aerobic oxidation procedure (method GP2), successfully used on Nꢀ(benzyloxycarbonyl)ꢀ
hydroxylamine (Scheme 1), with 10 mol% CuCl2 and 20 mol% 2ꢀethylꢀ2ꢀoxazoline at room temperature
in methanol was then applied to hydroxamic acids 1ꢀ10 (Table 1). Only three hydroxamic acids 1ꢀ3
gave the expected cycloadducts 14ꢀ16 from cyclohexaꢀ1,3ꢀdiene (Table 1, Entries 1ꢀ3, GP2) and
cycloadducts 24ꢀ26 from 2,3ꢀdimethylꢀ1,3ꢀbutadiene (Table 1, Entries 11ꢀ13, GP2). Nevertheless, the
cycloadduct yields from this method of 90ꢀ99% were remarkably high compared to 13ꢀ51% yields with
the periodate method for the three hydroxamic acids 1ꢀ3.
Nitroso ene products were also present from the copperꢀcatalyzed oxidations of acids 1 and 2 with
dimethylꢀ1,3ꢀbutadiene (Table 1, Entries 11 and 12, GP2). The NDA:ene ratios were 6:1 (24:34) and
9:1 (25:35) from 1 and 2, respectively, indicating that the nitroso intermediate from 2 was more
selective than the nitroso species from 1. Despite several attempts, the ene products 34 and 35 could not
be isolated as pure compounds. These ene products were not observed with the periodate method (GP1)
here and elsewhere,12 suggesting that the copper method promoted the nitrosoꢀene process. Curiously,
the chiral hydroxamic acid 3 did not give an ene product using the copper procedure (Table 1, Entry
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13), which might be interpreted by the accessibility of several conformations, all of which are reactive
with no major conformation having an ability to control facial reactivity effectively.
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A third aerobic oxidation method (GP3) was applied to hydroxamic acids 4ꢀ10 using refluxing toluene
instead of methanol at room temperature to facilitate the generation of the nitroso intermediates. The
expected cycloadducts were formed in 49ꢀ78% yields from cyclohexaꢀ1,3ꢀdiene with hydroxamic acids
4ꢀ8 (Table 1, Entries 4ꢀ8, GP3) but no cycloadducts were obtained from 2,3ꢀdimethylꢀ1,3ꢀbutadiene
with the same acids (Table 1, Entries 14ꢀ18, GP3). This suggested that cyclohexaꢀ1,3ꢀdiene was a much
more efficient reagent than 2,3ꢀdimethylꢀ1,3ꢀbutadiene in the nitrosoꢀDielsꢀAlder process under these
reaction conditions.16
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No cycloadducts were obtained from the hydroxamic acids containing pyridyl groups, 9 and 10, (Table
1, Entries 9, 10, 19, 20) or from hydroxamic acids 11 and 12 (Chart 1) when the copperꢀcatalyzed
oxidation methods (GP2 and GP3) were used. It appeared that chelation takes place between the pyridyl
or amine group and the copper complex preventing the oxidation process, as indicated by the rapid
formation of an insoluble light blue precipitate which did not dissolve even after several days and no
further reaction occurred.
The hydroxamic acids, phenyl hydroxycarbamate 1 and 1ꢀhydroxyꢀ3ꢀphenylurea 2, gave high yields of
the cycloadducts with cyclohexaꢀ1,3ꢀdiene and 2,3ꢀdimethylꢀ1,3ꢀbutadiene using the room temperature
copper catalyst method (GP2), hence, this method was examined further on 1 and 2 with six dienes,
cyclopentadiene, dimethylanthracene (DMA), 1,4ꢀdimethylꢀ1,3ꢀbutadiene, 1,4ꢀdiphenylꢀ1,3ꢀbutadiene,
1ꢀhydroxymethylꢀ4ꢀmethylꢀ1,3ꢀbutadiene and 2ꢀmethylꢀ1,3ꢀbutadiene (Table 2). The yields of the
cycloadducts from these dienes were also high (90ꢀ99 %), except for the reactions with DMA and 1,4ꢀ
diphenylꢀ1,3ꢀbutadiene. These latter reactions required longer times of 24ꢀ48 hours, yet were still not
complete, giving lower yields of the cycloadducts (30ꢀ82%). The known cycloadduct 46 from 2 and
DMA undergoes cycloꢀreversion on standing,17 and thus a 10% yield was estimated here (Table 2, Entry
8).
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Table 2. Reactions of various dienes with nitroso compounds prepared in situ from copperꢀcatalyzed oxidations of
3
4
hydroxamic acids, 1 and 2.
R2
5
6
7
8
R1 R2
O
O
O
10 mol % CuCl2
R3
R4
Nitroso-
R3
R4
Ph
Ph
Ph
R1
R6
X
NH
OH
X
X
N
N
O
O
O2, rt, MeOH
Diels-Alder
reaction
R5
R5
R6
9
Et
O
1 X = O,
2 X = NH
Nitroso
intermediate
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90-98 % yields with 6 dienes
N
20 mol %
1.5 - 6 h
R4
R1 = R2 = H, R3 = Me
Nitroso-ene reaction
O
Ph
R5
X
N
R6
OH
Diene
Entrya
Product(s) from 1
Yieldb
99
Entrya
Product(s) from 2
Yieldb
96
1
7
8
45d
36c
O
2
80e
(10)f, g
Ph
O
N
O
46h
37
O
Ph
N
N
O
3
4
93
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97
H
47
38
82e
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30f
39
48
5
6
93
90
11
12
90
40 proximal
41 distal
49 proximal
50 distal
40:41 Ratio 1 : 1
49:50 Ratio 1.5 : 1.0
95
42 distal
43 proximal
51 distal
52 proximal
44
53
51:52:53 Ratio 7.4 : 1.6 : 1.0
42:43:44 Ratio 1.9 : 1.1 : 1.0
a For reactions of 1 and 2 with two other dienes see Entries 1, 2, 11 and 12 in Table 1. b From GP2 – see Table 1 for details. Isolated yields quoted after
purification. cXꢀray structure determined in this study. d Reference 12. e After 24 h. f After 48 h. g Yield not accurately obtained due to cycloꢀreversion
process of the cycloadduct. h Reference 17. Note: All chiral cycloadducts are racemic.
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The unsymmetric diene, 1ꢀhydroxymethylꢀ4ꢀmethylꢀ1,3ꢀbutadiene, upon reaction with the oxidation
product of acid 1, gave two cycloadducts 40 and 41 in equal amounts indicating no preference for one
adduct over the other (Table 2, Entry 5). However, a preference of one cycloadduct 49 over adduct 50
was observed when the oxidation product of acid 2 was employed, with a proximal:distal ratio of 3:2
showing some selectivity (Table 2, Entry 11). The identities of 40, 41, 49 and 50 were determined with
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1
the aid of 2D H NOESY spectra. The product selectivities increased when 2ꢀmethylꢀ1,3ꢀbutadiene is
used with ratios of 1.7:1 for distal:proximal adducts 42:43 from 1 (Table 2, Entry 6), and 4.5:1 for
distal:proximal adducts 51:52 obtained from 2 (Table 2, Entry 12). In addition, there was an increase in
selectivity of the adducts over the ene products (44 and 53) observed in the reactions with a 3:1
NDA:ene ratio for 1 and 9:1 NDA:ene ratio for 2. Despite attempts, the cycloadduct 50 and the eneꢀ
products 44 and 53 could not be isolated as pure substances. The identities of 42, 43, 51 and 52 were
determined on the basis of similar cycloadducts reported elsewhere.8
The cycloadducts reported herein were all characterized by 1H NMR, C NMR, IR spectroscopies and
13
mass spectrometry (Figures S14ꢀS45 for NMR spectra). While most adducts showed only one
conformer in solution from NMR studies at ambient temperature, the bicyclic oxazaoctene 22 existed as
a pair of rotamers (Figure 1). NMR observations of a pair of rotamers have been reported previously for
21 at lower temperatures.9,15
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Figure 1. Comparison of observed and computed (GIAO) 1H and 13C NMR spectra for the two rotamers
of 22. Peaks with asterisks correspond to chloroform as solvent.
Crystal Structures
Xꢀray crystal determinations were carried out on three hydroxamic acids (2, 3 and 9), five adducts from
the cyclohexadiene nitrosoꢀDielsꢀAlder (NDA) reactions (14ꢀ17 and 21), two from 2,3ꢀdimethylꢀ1,3ꢀ
butadiene NDA reactions (25 and 32) and one from the cyclopentadiene NDA reaction (36) (Figures
S46ꢀ48 and Table S1). The cyclohexadiene NDA adducts may contain four distinct bicyclic
oxaazaoctene geometries AꢀD (Figure 2). Compound 14 has conformer B, where the carbonyl C=O
bond is orientated syn to the NꢀO bond, and the C=O group located adjacent to the C=C double bond in
the bicycle whereas adducts 15-17 and 21 were of conformer A type, with the carbonyl C=O bond
orientated anti to the NꢀO bond (Figure 3).
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The bicyclic oxaazaoctene geometries structurally characterized previously included two examples of
conformer B with a ꢀCOOR group (R = cyclohexyl containing ꢀMe and ꢀCMe2ꢀnaphthyl substituents)18
and a ꢀCOPh group19 at the bicyclic nitrogen atom. Four reported geometries were of conformer A with
ꢀCOOCH2Ph groups,8,20 a ꢀCOꢀcamphoryl21 and a ꢀCOCH(OH)Ph22 group at the bicyclic nitrogen. For
bicyclic oxaazaoctenes structurally characterized to date, the ꢀCOOR and ꢀCOPh groups at the bicyclic
nitrogen atom adopted the antiꢀconformer A or the synꢀconformer B whereas others, with ꢀCOR groups
at the bicyclic nitrogen atom, adopted the anti conformer A. All of these bicyclic oxaazaoctenes, 14ꢀ17
and 21, contained the C=O group located adjacent to the C=C double bond in the bicycle. Conformers C
and D have not been reported for these systems and were assumed to be less favorable.
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The dimethylbutadiene NDA adducts, 25 and 32, contain the carbonyl C=O bond oriented anti to the Nꢀ
O bond with ꢀCONHPh and ꢀCOPy groups at the oxazine nitrogen atom. Many antiꢀconformer
geometries have been determined with a ꢀCOR group at the oxazine nitrogen atom.23 There have been
reported oxazine structures where the carbonyl C=O bonds were oriented syn to the NꢀO bond with ꢀ
t
COOR (R = Bu, PhCH2) groups at the cyclic nitrogen atom.24 There seems to be little preference for
either the syn- or antiꢀgeometry in oxazines with ꢀCOR groups at the nitrogen atom except for ꢀ
CONHR, for which the anti geometry is expected, with a distance of 2.183 Å found for the favorable Nꢀ
H..O interaction in 25.
The cyclopentadiene NDA adduct 36 contained a COOPh group at the nitrogen atom of the bicyclic
oxaazaheptene skeleton where the C=O bond was syn to the NꢀO bond. The only published bicyclic
oxaazaheptene with a ꢀCOR group at the nitrogen atom is the anti conformer for R = ꢀ
CHMeNHOCOCH2Ph.25
Table 3. Conformers AꢀD and calculated relative and rotation barrier energies (kcal molꢀ1) for 14, 15, 21 and 22.
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O3
C9
O1
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C9
C4
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N3
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N-O anti to C=O
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Figure 2. Views of the substituents at N3 with respect to the bicyclic framework in molecular structures of 14, 15 and 21.
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Computations on NDA Cycloadducts
Geometry optimizations were carried out via DFT calculations in the gasꢀphase at the B3LYP/6ꢀ31G*
level on 14, 15 and 21 to compare with their solidꢀstate geometries as determined by Xꢀray diffraction,
and also to estimate the relative energies of the syn and anti conformers AꢀD. Comparison between the
bond lengths of Xꢀray and computed geometries revealed a very good agreement with differences not
exceeding 0.011 Å, except for the NꢀC bonds between NꢀO and C=O, which are computed to be longer
by 0.017ꢀ0.034 Å than observed experimentally (Table S2). The latter differences may have been due to
an overestimation of the lone pair contribution from the nitrogen donor atom and the electronꢀpoor
carbonyl carbon atom with the B3LYP functional. Similar NꢀC bond length overestimations (0.014ꢀ
0.027 Å) were found for optimized geometries of 14, 15 and 21 using the larger 6ꢀ311++G** versus 6ꢀ
31G* basis set.
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Relative energies for the conformers AꢀD of 14, 15 and 21 showed a preference for the anti conformer
A (Table 3). While the preference was in accord with observed experimental geometries for 15 and 21,
the experimental geometry in 14 is the syn conformer B. Conformer B was only 0.8 kcal molꢀ1 higher in
energy than conformer A for 14. As two rotamers of 22 were observed by NMR spectra at room
temperature (Figure 1), conformers AꢀD for 22 were also examined computationally with the syn
conformer B calculated to be lower in energy than the antiꢀconformer A by only 0.1 kcal molꢀ1 in
energy.
The rotational energy barriers between anti and syn conformers A and B of 14, 15, 21 and 22 were
estimated computationally (Figure 1). The calculated value of 14.1 kcal molꢀ1 was in good agreement
with the reported14 experimental value of 13.8 kcal molꢀ1 for 21. The lower energy barrier of 13.8 kcal
molꢀ1 for 14 suggested that 14 was fluxional in solution between the two conformers at room
temperature as observed for 21. While the rotational energy barrier of 17.4 kcal molꢀ1 for 15 suggested
that two conformers were present in the NMR spectra, the strong preference for the anti conformer A
over the syn form B was reflected by an energy difference of 8.8 kcal molꢀ1. This indicated that only the
anti conformer for 15 was observed experimentally in solution and likely to be due to the favorable
intramolecular hydrogen interaction between the hydrogen atom at N1 and the oxygen atom O2 in the
bicycle with an experimentally determined distance of 2.136 Å with the hydrogen atom in a calculated
position (Figure 2).
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The NMR spectra of 22 showed both conformers at room temperature (Figure 1) as the anti and syn
conformers were very similar in energies and the rotational energy barrier between these conformers in
22 were slightly higher than in 14 and 21 (Figure 2). The syn conformer was the major component
based on comparison of observed NMR chemical shifts with computed GIAOꢀNMR chemical shifts
where the computed peak intensities assumed a 3:1 syn:anti conformer ratio. The agreement between
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observed and computed H NMR shifts was not expected to be very good as H NMR chemical shifts
are strongly influenced by the nature of the solvent. Nevertheless, the agreement between observed and
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computed C NMR shifts for 22 was very good when the different observed peak intensities expected
from different types of carbon groups were taken into account which were not modeled
computationally.
Reaction Pathway Computations
There have only been three computational studies on intermolecular nitrosoꢀDielsꢀAlder (NDA)
reactions of nitroso species with dienes.26,27 The excellent 2001 study by Leach and Houk looked at the
transition states for reactions of several nitroso species (RNO where R = H, alkyl, Ph, s-trans CHO and
s-cis CHO) with butadiene and substituted butadienes with MeO, Me and CN as substituents.26 They
showed that the endoꢀNDA pathway was the favored one over the exoꢀNDA and nitrosoꢀene pathways
for all reactions.
From the 2001 investigation, the transition state enthalpies from the acyl nitroso HCONO species and
butadiene to the nitrosoꢀDielsꢀAlder adduct (III) are only 3.6 and 4.9 kcal molꢀ1 above the starting
butadiene and the nitroso species s-trans HCONO and s-cis HCONO, respectively. These values were
confirmed here if the starting geometries were assumed to be the trans-butadiene and s-transꢀHCONO
(I in Figure 3, Tables S3 and S4). However, the cisꢀbutadiene geometry was clearly the precursor along
with s-transꢀHCONO (II in Figure 3) to the endo NDA transition state (TSꢀII,III) so the transitionꢀstate
enthalpy was calculated as a negative(!) value at ꢀ0.1 kcal molꢀ1 instead of the reported value of 3.6 kcal
molꢀ1. Obviously, there must be a local minimum (LM) between cis-butadiene and s-trans HCONO that
is lower in energy than the NDA transition state and such a local minimum II(LM) (Figures 3 and 4)
was found with an energy of 1.8 kcal molꢀ1 lower than the energy of the NDA transition state (TSꢀII,III).
The intriguing aspect of the acyl nitrosoꢀbutadiene pathway is that the transitionꢀstate energy of the
geometry located (TSꢀI,II in Figure 3) in the s-trans and s-cis butadiene conversion was higher than the
transitionꢀstate energy of the NDA adduct formation irrespective of whether local minima (LM) are
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located (Figure 3). This view indicated that acyl nitroso species are superꢀreactive species, as noted
elsewhere.28
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O
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TS-I,II
N
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O
Relative Energy
kcalmol-1
+7.6
(+7.1)
O
N
TS-II,III
O
+3.9
(+3.7)
+1.6
O
(+3.6)
0.0
N
O
O
II
O
N
O
ꢀ51.3
N
O
(ꢀ45.1)
I
III
O
TS-I,II(LM)
N
O
O
+7.9
Relative Energy
kcalmol-1
N
O
TS-II,III
(+7.3)
+4.0
(+5.2)
+2.2
(+2.5)
0.0
O
N
O
O
O
ꢀ48.9
N
O
N
O
(ꢀ43.4)
II(LM)
III
I(LM)
Figure 3. Reaction pathways (top) without local minima of starting molecules and (bottom) with local minima of the starting
molecules. Energies in parentheses are based on computed enthalpy values and are in agreement with those reported in
reference 26.
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Figure 4. Geometries of butadieneꢀacylnitroso association complex local minima.
The pathways of the reactions carried out experimentally in this study were explored computationally
using MeOCONO and MeNHCONO as models for PhOCONO and PhNHCONO species generated
from oxidations of the hydroxamic acids 1 and 2, respectively. While the s-transꢀform was much more
stable than the s-cisꢀform by 3.3 kcal molꢀ1 in HCONO, the energy differences between s-trans and s-cis
forms were much smaller in MeOCONO and MeNHCONO being only 0.8 and 0.1 kcal molꢀ1,
respectively, with the most stable forms being s-cis and s-trans for MeOCONO and MeNHCONO,
respectively (Table S5). Both conformations were considered in all NDA reaction pathways
investigated here. The s-transꢀforms were the preferred reagents in all computed NDA reaction
pathways containing the lowest transition energies overall.
The relative energies of the local minima (LM), transition states (TS) and products are shown in Figure
5 and Tables S6 and S7 with cyclohexaꢀ1,3ꢀdiene, 2,3ꢀdimethylbutadiene, 1,4ꢀdiphenylbutadiene and
9,10ꢀdimethylanthracene (DMA) as the dienes in reaction pathways with MeOCONO and
MeNHCONO. The cyclohexaꢀ1,3ꢀdiene ꢀ acyl nitroso pathway was clearly very favorable with: i) NDA
transition state energies of only 2.4ꢀ2.8 kcal molꢀ1 higher than the energies of the local minima of the
reactants; and ii) the energies of adducts being lower by over ꢀ30 kcal molꢀ1 than the energies of the
local minima of the starting reactants. The DMA ꢀ acyl nitroso pathway was less favorable with higher
energy barrier of 5.9 kcal molꢀ1 for MeOCONO which explained the need for a longer reaction time to
obtain a high yield of the cycloadduct 37. The energy of the MeNHCONO cycloadduct at ꢀ15.4 kcal
molꢀ1, relative to the starting nitroso species and DMA, shows that it was susceptible to cycloꢀreversion
thus the corresponding known17adduct 46 could not be obtained in high yield experimentally.
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III
I(LM)
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III
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Ph
Ph
Ph
R
R
R
N
R
R
R
N
N
O
N
N
O
N
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O
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O
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TS
III
II(LM)
III
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+7.6
-15.4
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H
Figure 5. Relative energies (kcal molꢀ1) for computed nitrosoꢀDielsꢀAlder model pathways.
For the acyclic dienes, the energy barriers for isomerization from the s-trans to s-cis diene geometries
are higher than the energies of the NDA transition states in all cases except for 2,3ꢀdimethylbutadiene
and MeNHCONO as shown in Figure 6. The experimental s-trans- to s-cis diene rotational
interconversion barriers for 2,3ꢀdimethylbutadiene and 2ꢀmethylꢀ1,3ꢀbutadiene were estimated at 3.4
and 3.9 kcal molꢀ1 respectively, which were lower than our computed ‘gasꢀphase’ values of 4.8 and 6.7
,
kcal molꢀ1.29 As discussed for the simple model HNO + butadiene reaction, there were competing
energy barriers between the s-trans and s-cis diene rotational interconversion and the NDA adduct
formation. The longer reaction time required for a high yield of the cycloadduct 39 from 1,4ꢀ
diphenylbutadiene was due to the comparatively high energy s-trans to s-cis diene conformation barrier
of 10.0 kcal molꢀ1, and the s-trans diene was more stable than the s-cis diene by 6.2 kcal molꢀ1. The
NDA adduct from 1,4ꢀdiphenylbutadiene and MeNHCONO was only ꢀ16.5 kcal molꢀ1 lower in energy
compared to the combined energy of the starting reactants thus cycloꢀreversion would be expected in
48.
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Figure 6. Relative energies (kcal molꢀ1) for computed acyclic diene and nitrosoꢀDielsꢀAlder model
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pathways.
The observed NDA products from in situ oxidations of 1 and 2 in the presence of 2ꢀmethylꢀ1,3ꢀ
butadiene gave distal and proximal isomers with a preference for the distal form, particularly from urea
2 (Table S7). The computed reaction pathways showed a preference for the proximal form with
MeOCONO but distal form with MeNHCONO and transition state energy differences of only 0.7 and
0.4 kcal molꢀ1 respectively. Such small differences were reflected in both proximal and distal forms
,
being observed experimentally. The reported19 reaction of MeOCONO with 2ꢀ[(tert-
butyldimethylsilyl)oxy]methylꢀ1,3ꢀbutadiene gave the proximal form as the major isomer, hence, the
isomer ratio would depend on whether MeOCONO or PhOCONO was used.
The presence of ene products, 34, 35, 44 and 53, from 2,3ꢀdimethylbutadiene and 2ꢀmethylbutadiene
with 1 and 2 suggested that ene reaction pathways from these dienes with MeOCONO and
MeNHCONO are competing with NDA pathways. By computing the pathways with s-cis or s-trans
dienes as starting reactants, we located transition states with energies at least 5 kcal molꢀ1 higher than
the corresponding endo NDA transition state energies (Figure 7 and Table S8). Attempts to establish
complete ene reaction pathways with diradical species were unsuccessful. The ene products observed
were assumed to form from reaction pathways involving the copper complex as: i) the predicted
transition state energies for the ene pathways were too high to compete with the NDA pathways; and ii)
the copperꢀfree periodate method (GP1) did not give ene products from 1 and 2.
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Figure 7. Nitrosoꢀene pathways with relative energies in kcal molꢀ1.
Unlike intramolecular NDA pathways where predictions of relative transition energies are
straightforward,30 intermolecular NDA pathways are difficult to model given that there are many
possible starting points, different conformers and local minima of the two reactant molecules. This
difficulty is compounded by superꢀreactive acyl nitroso species, such as MeOCONO and MeNHCONO,
where the endoꢀNDA transition state can be only 2.0 kcal molꢀ1 higher than the starting diene and
nitroso species. Nevertheless, the computations here showed that the preferred reaction pathway was via
the endoꢀNDA transitionꢀstate, over both the exoꢀNDA and ene transitionꢀstates (Table S9), as also
reported elsewhere.26 The data also showed that the endoꢀNDA transitionꢀstates can be lower in energy
than the transition states involved in the s-trans to s-cis diene isomerization processes for acyclic dienes.
The low yields of cycloadducts 46 and 48 from urea 2 and 9,10ꢀdimethylanthracene and 1,4ꢀ
diphenylbutadiene (Table 2, entries 8 and 10) can be understood by the fact that the calculated energies
of the cycloadducts were close in energies to the combined energies of their corresponding diene and
nitroso species, and thus were susceptible to cycloreversion processes. As the ene reaction pathways
show considerably higher energy barriers than the NDA pathways for 2,3ꢀdimethylbutadiene and 2ꢀ
methylbutadiene with nitroso species, we suggest here that the copper complex present in solution is
involved in the ene pathways and thus, the copperꢀmediated ene pathways compete with the NDA
pathways. This assumption is supported by a reported10 copperꢀmediated procedure specific for
reactions of acylnitroso species with alkenes to give ene products in high yields at ambient
temperatures.
Summary and conclusions
From the work shown here, we conclude that: 1) the copperꢀoxazoline complex is an excellent catalyst
for the aerobic oxidation of acyl hydroxamic acid to generate the corresponding acyl nitroso species; 2)
this system can only be used with a hydroxamic acid containing a heteroꢀatom between the aryl and
carbonyl group; 3) the nitroso species generated in situ can be trapped by most dienes resulting in the
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corresponding cycloadducts; 4) the yield of the products varied from high to moderate, depending upon
the reaction time because there is competitive decomposition of the nitroso species, reducing the yield
of the NDA adduct. The longer the trapping time (slower NDA reaction), the lower the yield, generally;
5) the chemoselectivity of this system depends upon the reactivity of the hydroxamic acid ꢀ the higher
the reactivity, the lower the chemoselectivity. Overall, the catalytic aerobic oxidation is a particularly
efficient, mild, clean, simple and environmentally benign method for generating acyl nitroso species in
situ and trapping them via a NDA reaction. When these types of reactions are examined by DFT
calculations, the preference for endo transitionꢀstates, over exo and ene transition states, was confirmed.
Interestingly, for the super reactive acyl nitroso species, diene rotational conformational interconversion
between s-cis and s-trans forms, can be slower than the nitrosoꢀDA reaction, since the transitionꢀstate
energies are lower for the DA reaction via the endo transitionꢀstate. This could explain variable yields in
some cases, because the acyl nitroso compounds were inherently unstable and decomposition could
compete on this basis. In addition, the inherent reversibility in these reactions also likely played a major
role in reaction yields. Calculated energies confirm the greater reversibility of certain diene ꢀ nitroso
species combinations, again, providing time for nitroso species decomposition. The reversibility has
also likely to impact upon observed both regioꢀ and stereoꢀcontrol in these reactions. This issue has not
been addressed to a major extent in the literature, but the prediction of considerable reversibility in these
reactions means that a detailed examination of kinetic versus thermodynamic effects on the reaction
outcome would shed further light upon the selectivity in the nitrosoꢀDA reactions.
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Experimental Section
General
All reactions were performed in the presence of air, unless otherwise stated. All reagents were
purchased from commercial sources and were used as received without further purification unless
1
otherwise stated. Solvents (AR grade) were used as received. H NMR spectra were recorded at 400,
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500, 600 or 700 MHz and C{1H} spectra were recorded at 101, 125, 150, or 176 MHz, in CDCl3 or
1
DMSOꢀd6 as solvents. H NMR chemical shifts are reported with reference to TMS using residual
proton on non deuterated solvent (CDCl3: 7.26 ppm; DMSOꢀd6: 2.50 ppm; 3.33 ppm for water present
in DMSOꢀd6) whereas 13C NMR spectra are reported with reference to TMS using the carbon signals of
the deuterated solvent (CDCl3: 77.23 ppm; DMSOꢀd6: 39.52 ppm). All chromatography was carried out
using 40ꢀ63 ꢁm silica gel. The removal of solvent was performed on a rotary evaporator under vacuum.
Melting points were determined using a melting point apparatus and are uncorrected. Low resolution
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mass spectrometry was carried out on a TQD equipped with a UPLC and an electrospray ion source,
and high resolution mass spectrometry was carried out on a TOFꢀMS equipped with an electrospray ion
source.
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Hydroxamic acid syntheses
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Compounds 1ꢀ12 have been reported elsewhere31ꢀ42 using different procedures to those described here.
Phenyl hydroxycarbamate 31 1
A solution of phenyl chloroformate (5.32 g, 34.0 mmol) in ether was added dropwise in 30 min to a
stirred solution of hydroxylamide hydrochloride (2.36 g, 34.0 mmol) and potassium carbonate (5.17 g,
37.4 mmol) in 30 mL of ether and 5 mL of water at 5 °C. After the addition, the reaction was stirred at
room temperature for 4 h. The organic layer was separated and dried over MgSO4. The solvent was
evaporated in vacuo to yield a white solid product 1 (3.10 g, 59%) this compound was used in the next
1
experiment without purification; m.p. 98 – 101 °C; H NMR (400 MHz, DMSOꢀd6) δ 10.33 (s, 1H),
13
9.08 (s, 1H), 7.42 – 7.36 (m, 2H), 7.25 – 7.19 (m, 1H), 7.13 – 7.07 (m, 2H), C{1H} NMR (101 MHz,
DMSOꢀd6) δ 155.5, 150.7, 129.4, 125.1, 121.5; FTIR (thin film) inter alia 3299, 1687 (C=O), 1511,
1492, 1284, 1201, 1105, 795, 687; LRMS (ESI+) m/z 176.1 (M+ +Na); HRMS (ESI+) m/z Calcd for
C7H7NO3Na 176.0324 found 176.0333.
1ꢀHydroxyꢀ3ꢀphenylurea32,33
2
A solution of phenylisocyanate (4.00 g, 33.6 mmol) in 10 mL of DCM was added dropwise over 30 min
to a solution of sodium hydroxide (1.34 g, 33.6 mmol) and hydroxylamine hydrochloride (2.33 g, 33.6
mmol) in 5 mL of water and 60 mL of DCM at 0 °C. After the addition, the reaction was warmed to the
room temperature and stirred for 3 h to yield a white solid. The reaction was washed by 20 mL of water
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and 20 mL of DCM. The precipitate was collected by filtration and recrystalized from ethyl acetate to
give the product 2 as a white solid (2.53 g, 50 %); m.p. 148 – 150 °C; 1H NMR (400 MHz, DMSOꢀd6) δ
8.96 (s, 1H), 8.81 (s, 1H), 8.75 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.23 (t, J = 7.9 Hz, 2H), 6.95 (t, J = 7.3
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Hz, 1H); C{1H} NMR (101 MHz, DMSOꢀd6) δ 159.0, 139.8, 128.9, 122.6, 119.6; FTIR (thin film)
inter alia 3221, 2951, 2894, 1630, 1595, 1537, 1501, 1449, 1074, 755, 688 cmꢀ1; LRMS (ESI+) m/z
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175.1 (M+ +Na); HRMS (ESI+) m/z Calcd for C7H8N2O2Na 175.0483 found 175.0483.
(R)ꢀ1ꢀHydroxyꢀ3ꢀ(1ꢀphenylethyl)urea32,34 3 and NꢀHydroxyꢀN’ꢀ[(R)ꢀ1ꢀPhenylethyl]ꢀNꢀ[(R)ꢀ1ꢀ
Phenylethylcarbamoyl]urea 13
A solution of (R)ꢀ(1ꢀisocyanatoethyl)benzene (1.00 g, 6.79 mmol) in 10 mL of DCM was added
dropwise over 30 min to a solution of sodium hydroxide (0.27 g, 6.79 mmol) and hydroxylamine
hydrochloride (0.47 g, 6.79 mmol) in 1 mL of water and 20 mL of DCM at 0 °C. After the addition, the
reaction was warmed to the room temperature and stirred for 3 h. The reaction was washed by 20 mL of
water and 20 mL of DCM. The organic phase was separated and dried over MgSO4. The removal of
solvent gave a colorless oil which then was separated by column chromatography (ethyl acetate as
eluent) to yield 0.60 g (49%) of product 3; m.p. 106ꢀ108 °C ; 1H NMR (400 MHz, DMSOꢀd6) δ 8.67 (d,
J = 0.8 Hz, 1H), 8.40 (s, 1H), 7.42 – 7.34 (m, 4H), 7.30 – 7.24 (m, 1H), 7.00 (d, J = 8.7 Hz, 1H), 4.94ꢀ
13
4.86 (m, 1H), 1.45 (d, J = 7.1 Hz, 3H); C{1H} NMR (101 MHz, DMSOꢀd6) δ 161.0, 145.8, 128.6,
126.9, 126.5, 48.6, 23.1; FTIR (thin film) inter alia 3311, 2931, 1649 (C=O), 1514, 766, 698 cmꢀ1;
LRMS (ESI+) m/z 203.5 (M+ +Na); HRMS (ESI+) m/z Calcd for C9H12N2O2Na 203.0796 found
1
203.0796 and an orange oil side product 13 (0.31 g, 13%); H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H),
7.32 – 7.08 (m, 12H), 4.87 (s, 2H), 1.45 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 153.1, 142.0,
127.7, 126.4, 124.9, 49.2, 21.7; FTIR (thin film) inter alia 3270, 3029, 2971, 1691 (C=O), 1658 (C=O),
1491, 1209, 696 cmꢀ1; LRMS (ESI+) m/z 350.7 (M+ +Na); HRMS (ESI+) m/z Calcd for C18H21N3O3Na
350. 1481 found 350.1472.
General procedure of hydroxamic acid synthesis from esters (GPHA)35
Four equivalents of sodium hydroxide were dissolved in water followed by two equivalents of
hydroxylamine hydrochloride. Then, this solution was added dropwise to the appropriate ester in
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methanol. The reaction was stirred at room temperature for 4 h and monitored by TLC. When the
reaction was finished, the solution was acidified with 5% HCl to pH 5.5. The solvent was removed in
vacuo to yield a mixture of product and sodium chloride, which was then redissolved in methanol. The
sodium chloride was removed by filtration. The methanol was removed in vacuo to give the
corresponding product, which then recrystallized from hot water to give the pure product.
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NꢀHydroxyꢀ2ꢀphenylacetamide36 4
The reaction was performed according to GPHA, using methylphenylacetate (10.2 g, 67.9 mmol) in 200
mL of methanol, sodium hydroxide (10.9 g, 272 mmol), hydroxylamine hydrochloride (9.4 g, 135
mmol) in 200 mL of water. The product 4 was isolated as an offꢀwhite solid (5.6 g, 54%); m.p. 139–
142 °C; 1H NMR (400 MHz, DMSOꢀd6) δ 10.67 (s, 1H), 8.84 (s, 1H), 7.32 – 7.19 (m, 5H), 3.28 (s, 2H);
13C{1H} NMR (101 MHz, DMSOꢀd6) δ 167.0, 136.1, 128.9, 128.1, 126.4, 39.4; FTIR (thin film) inter
alia 3186, 3002, 2902, 1631 (C=O), 1548, 1495, 1455, 1054, 978, 715; LRMS (ESIꢀ) m/z 150.2 (M+ ꢀ
H); HRMS (ESI+) m/z Calcd for C8H8NO2 150.0555 found 150.0555.
NꢀHydroxyꢀ3ꢀphenylpropanamide36 5
The reaction was performed according to GPHA, using ethylhydrocinnamate (9.4 g, 52.7 mmol) in 200
mL of methanol, sodium hydroxide (8.4 g, 210 mmol), hydroxylamine hydrochloride (7.3 g, 105 mmol)
in 200 mL of water. The product 5 was isolated as a white solid (4.9 g, 56%); m.p. 75 – 77 °C; 1H NMR
(400 MHz, CDCl3) δ 9.20 (s, 2H), 7.25 – 7.20 (m, 2H), 7.18 – 7.10 (m, 3H), 2.87 (t, J = 8 Hz, 2H), 2.38
13
(t, J = 8 Hz, 2H); C{1H} NMR (101 MHz, CDCl3) δ 171.1, 140.2, 128.6, 128.3, 126.4, 34.6, 31.3;
FTIR (thin film) inter alia 3296, 3062, 2782, 1662 (C=O), 1626, 1557, 1496, 1455, 1062, 995, 695;
LRMS (ESI+) m/z 188.2 (M+ +Na); HRMS (ESI+) m/z Calcd for C9H11NO2Na 188.0687 found
188.0689.
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4ꢀPhenylbutyric acid (7.4 g, 45.1 mmol), NMM (5.0 g, 50.5 mmol), DMAP (0.06 g, 0.05 mmol) and
hydroxylamine hydrochloride (3.5 g, 50.5 mmol) were dissolved in 150 mL of DCM. The mixture was
stirred and cooled to 0 °C. Then cyanuric chloride (2.5 g, 15.0 mmol) was added to the solution and the
mixture was warmed to room temperature. The reaction was stirred for 24 h. After completion, the
solution was filtered through Celite, then washed with 45 mL of 1 M HCl (3X). The organic layer was
separated and dried over MgSO4. The solvent was evaporated in vacuo to yield a white solid product,
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which was then purified by silica gel column chromatography (EtOAc as eluent) to give product
6
1
(2.00 g, 25%); m.p. 71 – 74 °C; H NMR (400 MHz, DMSOꢀd6) δ 10.36 (s, 1H), 8.71 (s, 1H), 7.28 –
7.23 (m, 2H), 7.18 – 7.14 (m, 3H), 2.54 (t, J = 8.0 Hz, 2H), 1.95 (t, J = 8.0 Hz, 2H), 1.82 – 1.71 (m,
13
2H); C{1H} NMR (101 MHz, DMSOꢀd6) δ 168.8, 141.6, 128.3, 128.3, 125.7, 34.6, 31.8, 27.0; FTIR
(thin film) inter alia 3170, 3024, 2908, 1622 (C=O), 1542, 1495, 1459, 1065, 1016, 742, 694; LRMS
(ESI+) m/z 202.2 (M+ +Na); HRMS (ESI+) m/z Calcd for C10H13NO2Na 202.0844 found 202.0849.
NꢀHydroxyꢀ5ꢀphenylpentanamide38
7
Hydrogen chloride gas, generated from dropping 36% HCl into 98% H2SO4, was bubbled into a
solution of 5ꢀphenylvaleric acid (5.0 g, 28.1 mmol) in 150 mL of methanol at room temperature for 15
min. Then sodium hydroxide (4.5 g, 112 mmol), and hydroxylamine hydrochloride (3.9 g, 56.2 mmol)
in 100 mL of water were added dropwise to the solution. The reaction was stirred for 24 h and then
acidified to pH 5.5 using 10% HCl. The solvents were removed under vacuum. The residue was
redissolved in methanol and the sodium chloride was removed by filtration. The solvent then removed
to yield a yellow oil, which was recrystalized from ether to yield a white solid product 7 (3.60 g, 67%);
m.p. 68 – 71 °C; 1H NMR (400 MHz, DMSOꢀd6) δ 10.32 (s, 1H), 8.67 (s, 1H), 7.27 (t, J = 7.5 Hz, 2H),
13
7.20 – 7.14 (m, 3H) 2.56 (t, J = 6.7 Hz, 2H), 1.97 (t, J = 6.8 Hz, 2H), 1.63 – 1.39 (m, 4H); C{1H}
NMR (101 MHz, DMSOꢀd6) δ 169.0, 142.0, 128.2, 128.2, 125.6, 34.8, 32.1, 30.5, 24.8; FTIR (thin
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film) inter alia 3186, 3038, 2910, 1618 (C=O), 1434, 1085, 992, 962, 749, 698; LRMS (ESI+) m/z
216.2 (M+ +Na); HRMS (ESI+) m/z Calcd for C11H15NO2Na 216.1000 found 216.1007.
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NꢀHydroxybenzamide36 8
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The reaction was performed according to GPHA, using methylbenzoate (5.30 g, 38.9 mmol) in 100 mL
of methanol, sodium hydroxide (6.23 g, 156 mmol), and hydroxylamine hydrochloride (5.41 g, 77.9
mmol) in 100 mL of water. The product 8 was isolated as a white solid (3.4 g, 64%); m.p. 121 – 123 °C;
1H NMR (400 MHz, DMSOꢀd6) δ 11.22 (s, 1H), 9.05 (s, 1H), 7.82 – 7.68 (m, 2H), 7.54 – 7.48 (m, 1H),
13
7.48 – 7.36 (m, 2H); C{1H} NMR (101 MHz, DMSOꢀd6) δ 164.7, 133.3, 131.6, 128.8, 127.3; FTIR
(thin film) inter alia 3292, 3062, 2746, 1644, 1602, 1557, 1490, 1316, 1163, 1022, 897, 787, 689;
LRMS (ESI+) m/z 138.2 (M+ +H); HRMS (ESI+) m/z Calcd for C7H8NO2 138.0555 found 138.055.
2ꢀPyridinehydroxamic acid39 9
The reaction was performed according to GPHA, using ethylꢀ2ꢀpicolinate (5.00 g, 33 mmol) in 100 mL
of methanol, sodium hydroxide (5.29 g, 132 mmol), and hydroxylamine hydrochloride (4.60 g, 66
mmol) in 100 mL of water. The product 9 was isolated as a white solid (3.00 g, 66%); m.p. 119 – 120
°C; 1H NMR (400 MHz, DMSOꢀd6) δ 11.46 (s, 1H), 9.24 (s, 1H), 8.63 (dt, J = 4.8, 1.3 Hz, 1H), 8.04 –
13
7.97 (m, 2H), 7.64 – 7.57 (m, 1H); C{1H} NMR (101 MHz, DMSOꢀd6) δ 162.2, 151.0, 149.4, 138.5,
127.2, 122.7.; FTIR (thin film) inter alia 3264 (broad), 2778 (broad), 1662 (C=O), 1592, 1570, 1516,
1475, 1177, 1030, 816; LRMS (ESIꢀ) m/z 161.4 (M+ Na); HRMS (ESI+) m/z Calcd for C6H6N2O2Na
161.0327 found 161.0323.
3ꢀPyridinehydroxamic acid40 10
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The reaction was performed according to GPHA, using ethyl nicotinate (5.00 g, 33 mmol) in 100 mL of
methanol, sodium hydroxide (5.29 g, 132 mmol), and hydroxylamine hydrochloride (4.60 g, 66 mmol)
in 100 mL of water. The product 10 was isolated as a white solid (2.70 g, 59%): m.p. 160 – 161 °C; 1H
NMR (400 MHz, DMSOꢀd6) δ 11.37 (s, 1H), 9.59 – 8.99 (m, 1H), 8.89 (dt, J = 20.8, 10.4 Hz, 1H), 8.74
9
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– 8.61 (m, 1H), 8.18 – 8.00 (m, 1H), 7.49 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H); C{1H} NMR (101 MHz,
DMSOꢀd6) δ 162.9, 152.3, 148.3, 135.1, 128.9, 124.0; FTIR (thin film) inter alia 1634 (C=O), 1594,
1495, 1472, 1422, 1305, 1024, 700; LRMS (ESIꢀ) m/z 137.1 (M+ ꢀH); HRMS (ESIꢀ) m/z Calcd for
C6H5N2O2 137.0351 found 137.0332.
NꢀHydroxyꢀ2ꢀ(pyridinꢀ2ꢀyl)acetamide41 11
The reaction was performed according to GPHA, using ethyl 2ꢀpyridylacetate (2.00 g, 12.1 mmol) in
50mL of methanol, sodium hydroxide (1.94 g, 48.4 mmol), and hydroxylamine hydrochloride (1.68 g,
24.2 mmol) in 50 mL of water. The product 11 was isolated as a white solid (0.93g, 50%), which was
used in the next experiment without purification: m.p. 159 – 161 °C; 1H NMR (600 MHz, DMSOꢀd6) δ
10.93 (s, 1H), 8.97 (s, 1H), 8.57 (d, J = 4.3 Hz, 1H), 7.96 (dd, J = 7.6, 6.4 Hz, 1H), 7.52 (d, J = 7.8 Hz,
1H), 7.47 – 7.41 (m, 1H), 3.64 (s, 2H); 13C{1H} NMR (151 MHz, DMSOꢀd6) δ 165.3, 154.5, 146.7,
139.1, 124.9, 122.8, 40.5; FTIR (thin film) inter alia 1677 (C=O), 1645, 1600, 1546, 1442, 1044, 1012,
797, 764, 616; LRMS (ESI+) m/z 175.4 (M+ Na); HRMS (ESI+) m/z Calcd for C7H8N2O2Na 175.0483
found 175.0473.
2ꢀAminoꢀNꢀhydroxybenzamide42 12
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The reaction was performed according to GPHA, using methyl 2ꢀaminobenzoate (10.00 g, 66.2 mmol)
in 200 mL of methanol, sodium hydroxide (10.60 g, 265 mmol), and hydroxylamine hydrochloride
(9.20 g, 132 mmol) in 200 mL of water. The product 12 was isolated as a pale yellow solid (6.10 g,
1
60%): m.p. 143ꢀ145 °C; H NMR (400 MHz, DMSOꢀd6) δ 10.91 (s, 1H), 8.89 (s, 1H), 7.30 (dd, J =
9
13.1, 6.5 Hz, 1H), 7.12 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 6.69 (dd, J = 8.2, 1.0 Hz, 1H), 6.51 – 6.44 (m,
1H), 6.22 (s, 2H); 13C{1H} NMR (101 MHz, DMSOꢀd6) δ 166.8, 149.2, 131.5, 127.5, 116.2, 114.7,
113.2; FTIR (thin film) inter alia 3163, 2950, 2856, 1618, 1560, 1493, 1449, 1348, 1249, 1021, 741,
671; LRMS (ESI+) m/z 175.1 (M+ +Na); HRMS (ESI+) m/z Calcd for C7H8N2O2Na 175.0483 found
175.0473.
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Nitroso-Diels-Alder reactions
General Procedure 1, GP1: General procedure for the formation of acyl cycloadducts using sodium
periodate oxidation of hydroxamic acids
Hydroxamic acid dissolved in methanol (10 mL) was added dropwise to a solution of diene, and sodium
periodate in methanol (20 mL) at room temperature. The reaction mixture was stirred for 4 h and was
monitored by TLC. Then the solvent was removed under vacuum. The crude product was purified by
silica gel chromatography (6:1 v/v, hexane/EtOAc).
General Procedure 2, GP2: General procedure for the formation acyl cycloadducts using copper-
oxazoline catalyzed oxidation of hydroxamic acids in methanol
To a methanol (5 ml) solution of 2 equivalents of diene, 10 mol% CuCl2 and 20 mol% 2ꢀethylꢀ2ꢀ
oxazoline was added the hydroxamic acid. The resulting solution was stirred and monitored by TLC.
The completion of the reaction was confirmed by the disappearance of the starting material. The solvent
was removed by evaporation and the crude product was purified by silica gel chromatography
(hexane:ethyl acetate, 6:1 v/v, as eluent).
General Procedure 3, GP3: General procedure for the formation of acyl cycloadducts using copper-
oxazoline catalyzed oxidation of hydroxamic acids in refluxing toluene
To a toluene (5 ml) solution of 2 equivalents of diene, 10 mol% CuCl2 and 20 mol% 2ꢀethylꢀ2ꢀ
oxazoline was added the hydroxamic acid. The resulting solution was heated under reflux with stirring,
and the reaction was monitored by TLC. The completion of the reaction was confirmed by the
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disappearance of the starting material. The solvent was removed by evaporation and the crude product
was purified by silica gel chromatography (hexane:ethyl acetate, 6:1 v/v, as eluent).
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Reactions of hydroxamic acids with 1,3-cyclohexadiene
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Entry 1, Table 1: Phenyl-2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxylate 14
A) The reaction was performed according to GP1, using phenyl hydroxycarbamate 1 (128 mg, 0.83
mmol), 1,3ꢀcyclohexadiene (134 mg, 1.68 mmol), and sodium periodate (179 mg, 0.83 mmol). The
reaction mixture was stirred for 2 h. The product 14 was obtained as a white solid (99 mg, 51 %); m.p.
1
127–129 °C; H NMR (400 MHz, CDCl3) δ 7.37 – 7.28 (m, 2H), 7.21 – 7.15 (m, 1H), 7.14 – 7.06 (m,
2H), 6.73 – 6.64 (m, 1H), 6.63 – 6.57 (m, 1H), 4.99 – 4.90 (m, 1H), 4.88 – 4.80 (m, 1H), 2.31 – 2.17 (m,
2H), 1.59 – 1.52 (m, 1H), 1.48 – 1.40 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 155.9, 150.9, 132.0,
131.8, 129.3, 125.6, 121.5, 71.4, 50.3, 23.4, 20.7; FTIR (thin film) inter alia 1716 (C=O), 1389, 1196,
1067, 994, 750, 691 cmꢀ1; LRMS (ESI+) m/z 254.2 (M+ + Na); HRMS (ESI+) m/z Calcd for C13H13Nꢀ
O3Na 254.0793 found 254.0800.
B) The reaction was performed according to GP2 using phenyl hydroxycarbamate 1 (103 mg, 0.67
mmol), 1,3ꢀcyclohexadiene (66 mg, 0.80 mmol), CuCl2 (9 mg, 0.07 mmol) and 2ꢀethylꢀ2ꢀoxazoline (13
mg, 0.13 mmol), the reaction was complete in 2 h giving 14 (152 mg, 98 %) as a white solid.
Entry 2, Table 1: N-Phenyl-2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxamide 15
A) The reaction was performed according to GP1, using 1ꢀhydroxyꢀ3ꢀphenylurea 2 (131 mg, 0.86
mmol), 1,3ꢀcyclohexadiene (138 mg, 1.72 mmol), and sodium periodate (184 mg, 0.86 mmol). The
reaction mixture was stirred for 2 h. The product 15 was obtained as a white solid (97 mg, 49%); m.p.
102 – 104 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.44 (dd, J = 8.6, 1.0 Hz, 2H), 7.28 (dd, J =
10.9, 5.4 Hz, 2H), 7.10 – 7.01 (m, 1H), 6.62 – 6.56 (m, 1H), 6.55 – 6.47 (m, 1H), 5.06 – 4.98 (m, 1H),
4.83 – 4.75 (m, 1H), 2.25 – 2.13 (m, 2H), 1.61 – 1.53 (m, 1H), 1.43 – 1.36 (m, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 159.3, 137.7, 132.7, 130.4, 128.9, 123.5, 119.3, 71.2, 50.0, 23.9, 20.0; FTIR (thin film)
inter alia 1667 (C=O), 1594, 1531, 1445, 1228, 907, 767, 701 cmꢀ1; LRMS (ESI+) m/z 253.2 (M+ +
Na); HRMS (ESI+) m/z Calcd for C13H14N2O2Na 253.0953 found 253.0958.
B) The reaction was performed according to GP2, using 1ꢀhydroxyꢀ3ꢀphenylurea 2 (105 mg, 0.69
mmol), 1,3ꢀcyclohexadiene (68 mg, 0.83 mmol), CuCl2 (9 mg, 0.07 mmol) and 2ꢀethylꢀ2ꢀoxazoline (14
mg, 0.14 mmol), the reaction complete in 4 h giving 15 (156 mg, 98%) as a white solid.
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Entry 3, Table 1: N-[(R)-1-Phenylethyl]-2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxamide 16
A) The reaction was performed according to GP1, using (R)ꢀ1ꢀhydroxyꢀ3ꢀ(1ꢀphenylethyl)urea 3 (125
mg, 0.70 mmol), 1,3ꢀcyclohexadiene (112 mg, 1.39 mmol), and sodium periodate (149 mg, 0.70 mmol).
The reaction mixture was stirred for 2 h. The product 16 was obtained as a white solid (76 mg, 42%);
m.p. 92ꢀ94 °C; 1H NMR (700 MHz, CDCl3) δ 7.33 – 7.22 (m, 3H), 7.22 – 7.17 (m, 2H), 6.54 – 6.40 (m,
2H), 5.99 (dd, J = 22.7, 7.1 Hz, 1H), 4.96 – 4.84 (m, 2H), 4.64 (d, J = 2.1 Hz, 1H), 2.16 – 2.03 (m, 2H),
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60
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1.52 – 1.45 (m, 1H), 1.41 (dd, J = 12.6, 6.9 Hz, 3H), 1.34 – 1.28 (m, 1H); C{1H} NMR (176 MHz,
CDCl3) δ 161.5, 161.4, 143.7, 143.5, 132.2, 132.1, 130.2, 130.2, 128.5, 128.4, 127.1, 127.0, 126.0,
125.9, 70.5, 50.3, 50.1, 49.1, 49.1, 23.9, 23.9, 22.4, 22.3, 20.1, 20.0. FTIR (thin film) inter alia 1651,
1515, 1494, 1230, 906, 766, 699, 667 cmꢀ1; LRMS (ESI+) m/z 281.2 (M+ + Na); HRMS (ESI+) m/z
Calcd for C15H18N2O2Na 281.1266 found 281.1268.
B) The reaction was performed according to GP2, using (R)ꢀ1ꢀhydroxyꢀ3ꢀ(1ꢀphenylethyl)urea 3 (99 mg,
0.55 mmol), 1,3ꢀcyclohexadiene (53 mg, 0.66 mmol), CuCl2 (7 mg, 0.05 mmol) and 2ꢀethylꢀ2ꢀoxazoline
(11 mg, 0.11 mmol), the reaction was complete in 4 h giving 16 (141 mg, 97%) as a white solid.
Entry 4, Table 1: 2-Oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-2-phenyl-ethanone 17
A) The reaction was performed according to GP1, using Nꢀhydroxyꢀ2ꢀphenylacetamide 4 (290 mg, 1.92
mmol), 1,3ꢀcyclohexadiene (307 mg, 3.84 mmol), and sodium periodate (410 mg, 1.92 mmol). The
reaction mixture was stirred for 4 h. The product 17 was obtained as an offꢀwhite solid (275 mg, 48 %);
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m.p. 74 ꢀ76 °C; H NMR (400 MHz, CDCl3) δ 7.37 – 7.19 (m, 5H), 6.66 – 6.56 (m, 1H), 6.50 – 6.42
(m, 1H), 5.33 – 5.22 (m, 1H), 4.80 – 4.70 (m, 1H), 3.70 – 3.57 (m, 2H), 2.17 – 1.99 (m, 2H), 1.50 – 1.39
(m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.5, 134.8, 132.9, 131.3, 129.5, 128.2, 126.5, 71.9,
46.6, 40.1, 23.4, 21.0; FTIR (thin film) inter alia 1640 (C=O), 1412, 1086, 955, 900, 828, 734, 698 cmꢀ
1; LRMS (ESI+) m/z 252.3 (M+ + Na); HRMS (ESI+) m/z Calcd for C14H15NO2 Na 252.1000 found
252.1010.
B) The reaction was performed according to GP3, using Nꢀhydroxyꢀ2ꢀphenylacetamide 4 (208 mg, 1.38
mmol), 1,3ꢀcyclohexadiene (220 mg, 2.75 mmol), CuCl2 (19 mg, 0.14 mmol) and 2ꢀethylꢀ2ꢀoxazoline
(27 mg, 0.28 mmol), the reaction was heated at reflux and was complete in 10 h to yield the product as
an offꢀwhite solid 16 (192 mg, 61 %).
Entry 5, Table 1: 2-Oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-3-phenylpropan-1-one 18
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A) The reaction was performed according to GP1, using Nꢀhydroxyꢀ3ꢀphenylpropanamide 5 (171 mg,
1.03 mmol), 1,3ꢀcyclohexadiene (166 mg, 2.06 mmol), and sodium periodate (221 mg, 1.03 mmol). The
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reaction mixture was stirred for 4 h. The product 18 was obtained as colorless oil (123 mg, 49 %); H
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NMR (400 MHz, CDCl3) δ 7.30 – 7.26 (m, 2H), 7.24 – 7.18 (m, 3H), 6.69 – 6.59 (m, 1H), 6.53 – 6.48
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(m, 1H), 5.30 (s, 1H), 4.74 (s, 1H), 2.91 (t, J = 8.0 Hz, 2H), 2.70 – 2.62 (m, 1H), 2.59 – 2.51 (m, 1H),
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2.19 – 2.12 (m, 1H), 2.12 – 2.05 (m, 1H), 1.52 – 1.45 (m, 2H); C{1H} NMR (101 MHz, CDCl3) δ
171.1, 140.4, 132.0, 130.3, 127.4, 127.3, 124.9, 70.8, 45.4, 33.9, 29.3, 22.5, 20.1; FTIR (thin film) inter
alia 1644 (C=O), 1453, 1166, 954, 902, 748, 699 cmꢀ1; LRMS (ESI+) m/z 266.3 (M+ + Na); HRMS
(ESI+) m/z Calcd for C15H17NO2 Na 266.1157 found 266.1169.
B) The reaction was performed according to GP3, using Nꢀhydroxyꢀ3ꢀphenylpropanamide 5 (189 mg,
1.14 mmol), 1,3ꢀcyclohexadiene (183 mg, 2.29 mmol), CuCl2 (15 mg, 0.11 mmol) and 2ꢀethylꢀ2ꢀ
oxazoline (23 mg, 0.23 mmol), the reaction was heated at reflux and was complete in 5 h. The product
was obtained as colorless oil (181 mg, 65 %).
Entry 6, Table 1: 2-Oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-4-phenylbutan-1-one 19
A) The reaction was performed according to GP1, using Nꢀhydroxyꢀ4ꢀphenylbutanamide 6 (153 mg,
0.85 mmol), 1,3ꢀcyclohexadiene (137 mg, 1.70 mmol), and sodium periodate (183 mg, 0.85 mmol). The
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reaction mixture was stirred for 4 h. The product 19 was obtained as colorless oil (70 mg, 32 %); H
NMR (400 MHz, CDCl3) δ 7.24 – 7.16 (m, 2H), 7.14 – 7.06 (m, 3H), 6.55 (t, J = 6.6 Hz, 1H), 6.42 (t, J
= 6.6 Hz, 1H), 5.20 (s, 1H), 4.66 (s, 1H), 2.60 – 2.51 (m, 2H), 2.31 – 2.17 (m, 2H), 2.13 – 1.94 (m, 2H),
1.88 – 1.77 (m, 2H), 1.47 – 1.35 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.9, 141.0, 132.1,
130.2, 127.5, 127.3, 124.8, 70.8, 45.4, 34.4, 31.7, 24.8, 22.6, 20.1; FTIR (thin film) inter alia 1644
(C=O), 1453, 955, 902, 833, 746, 699 cmꢀ1; LRMS (ESI+) m/z 280.3 (M+ + Na); HRMS (ESI+) m/z
Calcd for C16H19NO2 Na 280.1313 found 280.1314.
B) The reaction was performed according to GP3, using Nꢀhydroxyꢀ4ꢀphenylbutanamide (200 mg, 1.12
mmol), 1,3ꢀcyclohexadiene (179 mg, 2.23 mmol), CuCl2 (15 mg, 0.11 mmol) and 2ꢀethylꢀ2ꢀoxazoline
(22 mg, 0.22 mmol), the reaction was heated at reflux and was complete in 3 h. The product was
obtained as colorless oil (210 mg, 73 %)
Entry 7, Table 1: 2-Oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-5-phenylpentan-1-one 20
A) The reaction was performed according to GP1, using Nꢀhydroxyꢀ5ꢀphenylpentanamide 7 (225 mg,
1.16 mmol), 1,3ꢀcyclohexadiene (187 mg, 2.32 mmol), and sodium periodate (249 mg, 1.16 mmol). The
1
reaction mixture was stirred for 4 h. The product 20 was obtained as colorless oil (120 mg, 38 %); H
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