Nitrosocarbonyl hetero-Diels–Alder cycloaddition with 2-substituted 1,3-butadienes

Article abstract of DOI:10.1016/j.tet.2016.11.046

A study of the reactivity of 2-substituted 1,3-butadienes with nitrosocarbonyl compounds in the 4+2 cycloaddition has been carried out showing that the regioselectivity involves a delicate balance of steric and electronic effects. 2-Aryl 1,3-butadienes fa

Full text of DOI:10.1016/j.tet.2016.11.046

Accepted Manuscript
Nitrosocarbonyl hetero-Diels–Alder cycloaddition with 2-substituted 1,3-butadienes
Robert B. Lewis, Javier Read de Alaniz
PII:
S0040-4020(16)31201-7
10.1016/j.tet.2016.11.046
TET 28260
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 August 2016
Revised Date: 2 November 2016
Accepted Date: 16 November 2016
Please cite this article as: Lewis RB, Read de Alaniz J, Nitrosocarbonyl hetero-Diels–Alder cycloaddition
with 2-substituted 1,3-butadienes, Tetrahedron (2016), doi: 10.1016/j.tet.2016.11.046.
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Nitrosocarbonyl Hetero-Diels–Alder
Cycloaddition with 2-Substituted 1,3-
Butadienes
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Robert B. Lewis and Javier Read de Alaniz*
Department of Chemistry and Biochemistry

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Tetrahedron
journal homepage: www.elsevier.com
Nitrosocarbonyl Hetero-Diels–Alder Cycloaddition with 2-Substituted 1,3,-
Butadienes
Robert B. Lewis and Javier Read de Alaniz
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A study of the reactivity of 2-substituted 1,3-butadienes with nitrosocarbonyl compounds in the
4+2 cycloaddion has been carried out showing that the regioselectivity involves a delicate
balance of steric and electronic effects. 2-Aryl 1,3-butadienes favor the distal isomer with the
magnitude of preference ranging from 4:1 to 15:1 depending on the nature of the nitrosocarbonyl
group. However, when bulky 2-substituted dienes are used the proximal isomer is formed
preferentially. The results obtained, together with previous theoretical calculations and
experimental data, provide further data to aid in synthetic planning.
Available online
Keywords:
Nitrosocarbonyl
Aerobic Oxidation
Hetero-Diels–Alder
Cycloaddition
Oxazine
2009 Elsevier Ltd. All rights reserved
.
———
Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

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Tetrahedron
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Introduction
substrate and more studies are necessary to help facilitate
predictability, specifically for the nitrosocarbonyl Diels–Alder
reaction. In the present article, we wish to report our studies with
a range of both nitrosocarbonyl compounds and 2-substituted
dienes.
Transformations that simultaneously construct carbon–
nitrogen and carbon–oxygen bonds are essential for streamlining
the synthesis of natural products and pharmaceutically relevant
agents.1 In this regard, hetero-Diels–Alder reactions between
nitroso compounds and dienes have played an important role in
organic chemistry since their discovery in 1947.2 The oxazine
scaffold, which results from the [4+2] cycloaddition, serves as a
strategic intermediate for the synthesis of a wide-range of natural
products.3 For example, cleavage of the N–O oxazine bond
results in a skeleton with a 1,4-relationship between the alcohol
and amine substituents, which are valuable for further
elaboration.1,3,4 However, like many heterocycloadditions, the use
of unsymmetrical dienes, such as 2-substituted 1,3-butadiene,
necessitates regiocontrol for this transformation to be truly
synthetically useful because the nitroso [4+2]-cycloaddition can
provide two regioisomers. Figure 1 shows the regiochemical
outcome for 2-substituted dienes. When the 2-substituent is close
to the oxygen heteroatom of the oxazine adduct it is referred to as
the proximal isomer and when the 2-substituent is close to the
nitrogen heteroatom of the oxazine adduct it is referred to as the
distal isomer.
Figure 1. Regioselectivity of nitroso-Diels–Alder reactions with 2-substituted
dienes.
Several groups have independently reported on the
regiocontrol of the nitroso-Diels–Alder (NDA) reaction using
both computational and experimental studies.5 As can be seen by
Scheme 1 the regioselectivity for 2-substituted dienes can depend
on a combination of both steric and electronic effects on both the
nitroso and the diene partners. Using FMO and DFT calculations,
as well as experimental data accumulated from the literature,
Houk and co-workers proposed
a general rational for
regiochemical preference for various monosubsubstituted dienes,
including 2-substituted dienes, and nitroso sources (Scheme
1a).6a,5d,6b They showed that the principle interaction is between
the HOMO(diene) and LUMO(nitroso heterodienophile) and that
there is a strong preference for an endo transition state. In
general, for 2-substituted dienes the HOMO should have its
largest coefficient at the C1-position and hence, the distal isomer
is typically expected (Scheme 1b). However, as seen by Scheme
1c using an electron-rich diene in combination with an electron-
poor aryl nitroso compound favors the proximal isomer.5b
Furthermore, Whitting and co-workers recently reported that the
magnitude of preference for the proximal vs. distal isomer can
also depend on the nature of the nitroso group.5h For example, the
reaction of nitrosoformate (Scheme 1d) and nitrosoformamide
(Scheme 1e), generated in situ through a copper-catalyzed
aerobic oxidation, with 2-methyl-1,3-butadiene gave distal and
proximal isomers with a preference for the distal form that varied
from ~1.7:1 to ~4.6:1 depending on the nature of the nitroso
compound. Finally, Boger and co-workers showed that steric
effects are also important in governing regioselectivity (Scheme
2f).5c Because there is a significant unfavorable interaction
between the nitrogen lone pair with the π electrons of the electro-
rich diene, the endo transition state is favored.5d This exo lone
pair effect causes the diene to be in close proximity to the
nitrogen substituent and if the steric interaction is large the
proximal isomer can be favored. It is clear that the regiochemical
preference for the NDA reaction can vary from substrate to
Scheme 1. Literature examples of regiochemical studies for the nitroso-
Diels–Alder reaction with 2-substituted dienes.
Results and Discussion
We chose to study 2-aryl-1,3-butadienes initially as they avoid
the potentially competing nitrosocarbonyl ene reaction due to
their lack of allylic protons.7 To generate the nitrosocarbonyl
compound in situ we employed our previously developed copper-
catalyzed aerobic oxidation conditions (20 mol% CuCl, 5 mol%
pyridine).8a,7f,8b-d Initially a solvent and ligand screen were
conducted using 2-aryl-1,3-butadiene 1 and N-hydroxycarbamate
2 (Table 1) and in all cases we observed a preference for the
distal isomer. The regioselectivity was determined with the aid of
HSQC and 15N HMBC. The reaction solvent and ligand for
copper showed a modest influence on the overall yield of the
NDA reaction, but had little effect on the observed

3
regioselectivity. This is consistent with previous results and
Table 2. Scope of nitrosoformate hetero-Diels–Alder
reaction with a range of 2-substituted 1,3-butadienes.
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supports a transition state with little polar character.5c,5d
Table 1. Optimization screen for NDA reaction.
We next evaluated the electronic effects of the 2-substituent of
the 1,3-butadiene on regioselectivity using N-hydroxycarbamate
2 as the nitroso precursor (Table 2, only major regioisomer
shown). Based on Houk’s model one would predict that the distal
isomer would be preferred as the group at the 2-position
increases in electron density because the interaction between the
HOMO(diene) and LUMO(nitroso heterodienophile) is
maximized.5d This trend was observed in our experimental
results. Electron donating aryl groups give the highest preference
for the distal regioisomer with selectivities up to 15:1, while
electron withdrawing aryl groups show a lower preference for the
distal regioisomer with selectivities dropping to 4:1.
Interestingly, the o-methoxy aryl group (11) resulted in a modest
4:1 selectivity despite being electronically similar to the
p-methoxy aryl group (7). Presumably, the reduced selectivity
results from allyic strain that causes the aryl ring to rotate out of
conjugation with the diene in the reactive s-cis conformation thus
reducing electron density on the alkene and minimizing the
electronic preference for the distal isomer. Consistent with the
literature, 2-methyl-1,3-butadiene gave only a slight preference
for the distal isomer (2:1, distal:proximal) and nitrosocarbonyl
ene adduct was also observed in 38% yield.5h However, in the
case of a bulky 2-substituent the proximal isomer was formed
preferentially (eq. 1). Of note, no nitrosocarbonyl ene reaction
was observed for this example. This highlights that sterics can
override the electronic preference for the distal isomer.
Presumably, the reversal in selectivity is due to unfavorable
interactions between the bulky group of the diene and the
nitrosocarbonyl in the preferred endo transition state. While the
exo transition state would lead to the distal isomer, this is
unlikely due to the exo lone pair effect and hence the proximal
isomer is favored in this case.
To further study the regiochemical outcome of the NDA
reaction, we next evaluated the effects of the N-substituent of the
nitrosocarbonyl compound on the reaction (Table 3). Initially,
using neutral 2-phenyl-1,3-butadiene, which gave average
regioselectivity for the distal isomer (9:1), we evaluated three
different formate groups (Cbz, Troc, and Boc) on the nitrogen
substituent of the nitrosocarbonyl (Table 3, 10, 19, and 20).
While N-Troc protected hydroxylamine gave comparable degrees
of regioselectivity to N-Cbz (8:1 and 9:1, respectively), switching
to the bulky N-Boc group caused a significant drop in selectivity
from 9:1 to 3:1. These results show that steric effects of the
nitrosocarbonyl compound influence the regioselectivity and
should be considered at the design stage. In this case, we
speculate that the drop in selectivity is due to unfavorable
interactions of the O-tert-butyl group of the nitrosocarbonyl and
the phenyl substituent of the diene in the preferred endo
transition state. Next, we investigated the use of
nitrosoformamide derivatives, which provided the highest
selectivity for Whiting and co-workers with 2-methyl-1,3-
butadiene (Scheme 1e vs. Scheme 1d).5h In the presence of
electron rich p-methoxy aryl group, mixed results were observed
with the preference for the distal isomer varying from 20:1 (19),
which was an improvement compared to Cbz-nitrosoformate (7,
15:1), to 9:1 (20). Switching the methoxy group on the aryl ring
to the meta-position decreased the selectivity from 9:1 to as low
as 4:1 compared to the analogous nitrosoformate (8 vs. 21–23).
However, with electron deficient p-CF3-aryl group a notable
increase in selectivity was observed with the formation of 24,
while adduct 25 was isolated in with a similar distal preference as
the corresponding N-Cbz adduct 10. When 2-methyl 1,3-

4
Tetrahedron
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butadiene was employed improved regioselectivity was
preferentially. The factors governing the regioselectivity depend
observed (26 and 27), which is consistent with Whiting and co-
workers results. Finally, the use of bulky 2-substituted 1,3-dienes
were studied with Cbz, Troc, and Boc nitrogen protected
nitrosocarbonyl compounds (14, 28, and 29). Similar to our
previous results, these reactions were highly selective for the
proximal isomer with selectivities up to 1:17. However, unlike
the 2-aryl substituted dienes, the selectivity was improved when
bulky N-Boc group was used.
on the both the steric and electronic effects of both the diene and
nitroso reagent. With aryl groups at the 2-position, the distal
isomer is always favored but the ratio can vary depending on the
sterics of the formate group appended to the nitrosocarbonyl. In
this case, N-Boc gave the lowest selectivity. While
nitrosoformamides consistently afforded oxazine adducts with a
preference for the distal isomer, the factors governing the
selectivity was less predictable. This work also showed that the
proximal isomer is favored when a bulky 2-substituted 1,3-
butadiene is used. In general, the results can be rationalized using
Houk’s model where there is a strong preference for the endo
path and the regioselectivities of 2-substituted dienes involves the
delicate balance of stereoelectronic effects. The results presented
will help aid in synthetic planning and provide further examples
to strengthen the predicted outcome of the nitrosocarbonyl
hetero-Diels–Alder reaction.
Table 3. Scope of nitrosocarbonyl hetero-Diels–Alder
reaction with a range of 2-substituted 1,3-butadienes.
Experimental section
General Procedure: To a stirred solution of hydroxamic acid
(1 equiv) and 2-substituted-1,3-butadiene (1.2 equiv) in THF (0.1
M) was added 20 mol % CuCl and 5 mol % pyridine. The
reaction was stirred at room temperature open to the air until
complete by TLC. Upon completion, the reaction was quenched
with EDTA (0.5 M, pH 7.0), diluted with ethyl acetate and stirred
until color no longer persisted in organic layer (approx. 30 min).
The reaction was extracted with ethyl acetate three times and the
combined organic layers were dried over MgSO4. The product
was filtered and then concentrated in vacuo. The residue was
purified by column chromatography to afford the corresponding
oxazine product.
Benzyl 4-(4-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazine-2-
carboxylate (7):
According to the general procedure, oxazine products 7 and
7a were isolated as a mixture (28 mg, 90%, 15:1). 1H NMR (600
MHz, CDCl3) δ 7.42 – 7.25 (m, 7H), 6.91 – 6.84 (m, 2H), 6.09 –
6.04 (m, 1H), 5.24 (s, 2H), 4.61 – 4.56 (m, 2H), 4.51 – 4.46 (m,
2H), 3.80 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 159.6, 155.6,
135.9, 132.3, 129.5, 128.5, 128.3, 128.2, 126.0, 118.1, 114.0,
68.8, 67.8, 55.3, 46.3; IR (thin film) 3041, 2933, 1706, 1608,
1515, 1455, 1346, 1283, 1246, 1182, 1095, 1032 cm-1; MS (ESI)
m/z 348.13 (348.12 calculated for C19H19NO4Na [M+Na]+).
Benzyl 4-(3-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazine-2-
carboxylate (8): According to the general procedure, oxazine
products 8 and 8a were isolated as a mixture (24 mg, 78%, 9:1).
1H NMR (600 MHz, CDCl3) δ 7.41 – 7.22 (m, 6H), 6.96 – 6.91
(m, 1H), 6.89 – 6.82 (m, 2H), 6.19 – 6.11 (m, 1H), 5.24 (s, 2H),
4.62 – 4.57 (m, 2H), 4.52 – 4.48 (m, 2H), 3.80 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 159.8, 155.6, 138.4, 135.9, 132.9, 129.7,
128.6, 128.3, 128.2, 120.2, 117.3, 113.4, 110.9, 68.7, 67.8, 55.2,
46.3; IR (thin film) 3064, 2941, 2839, 1706, 1600, 1580, 1430,
1346, 1289, 1211, 1171, 1098, 1050 cm-1; HRMS (ESI) m/z
348.1248 (348.1212 calculated for C19H19NO4Na [M+Na]+).
Benzyl 4-phenyl-3,6-dihydro-2H-1,2-oxazine-2-carboxylate
(9): According to the general procedure, oxazine products 9 and
1
9a were isolated as a mixture (25 mg, 82%, 9:1). H NMR (500
MHz, CDCl3) δ 7.45 – 7.25 (m, 10H), 6.23 – 6.18 (m, 1H), 5.27
(s, 2H), 4.65 – 4.60 (m, 2H), 4.57 – 4.52 (m, 2H); 13C NMR (150
MHz, CDCl3) δ 155.6, 136.9, 135.9, 133.0, 128.7, 128.6, 128.3,
128.2, 128.2, 124.9, 119.9, 68.8, 67.9, 46.3; IR (thin film) 3033,
2906, 2849, 1704, 1497, 1408, 1347, 1221, 1096 cm-1; MS (ESI)
m/z 318.12 (318.11 calculated for C18H17NO3Na [M+Na]+).
Conclusion
In conclusion, this study revealed that the hetero-Diels–Alder
cycloaddition of nitrosocarbonyl compounds and 2-substituted
1,3-butadienes can afford either the distal or proximal isomer

5
Benzyl
4-(4-(trifluoromethyl)phenyl)-3,6-dihydro-2H-1,2-
13C NMR (150 MHz, CDCl3) δ 155.0, 155.0, 137.2, 136.6,
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oxazine-2-carboxylate (10): According to the general procedure,
oxazine products 10 and 10a were isolated as a mixture (30 mg,
88%, 4:1). H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz,
134.6, 133.2, 128.7, 128.6, 128.0, 124.8, 124.8, 120.1, 118.5,
81.8, 81.8, 69.3, 68.2, 46.4, 45.2, 28.3, 28.3, 27.6; IR (thin film)
3058, 2978, 2849, 1702, 1496, 1367, 1235, 1164, 1099 cm-1; MS
1
2H), 7.45 (d, J = 8.0 Hz, 2H), 7.42 – 7.30 (m, 5H), 6.30 – 6.26
(m, 1H), 5.25 (s, 2H), 4.64 – 4.60 (m, 2H), 4.54 – 4.50 (m, 2H);
Mixture 13C NMR (150 MHz, CDCl3) δ 155.5, 155.5, 140.3,
139.9, 135.8, 133.8, 132.1, 130.1 (q, J = 32.7 Hz), 128.6, 128.4,
128.2, 128.2, 125.6 (q, J = 3.7 Hz), 125.1, 123.9 (q, J = 272.2
Hz), 122.2, 120.5, 69.6, 68.6, 68.0, 68.0, 46.1, 45.1; IR (thin
film) 3035, 2922, 2850, 1708, 1616, 1414, 1327, 1167, 1117,
1071 cm-1; HRMS (ESI) m/z 386.1095 (100%), 387.1143 (21%),
388.1161 (3%) (386.0980, 387.1014, 388.1047 calculated for
C19H16F3NO3Na [M+Na]+).
(ESI) m/z 284.13 (284.13 calculated for C15H19NO3Na [M+Na]+
).
4-(4-Methoxyphenyl)-3,6-dihydro-2H-1,2-oxazine-2-
carboxamide (19): According to the general procedure, oxazine
products 19 and 19a were isolated as a mixture (25 mg, 86%,
20:1). H NMR (600 MHz, CD3OD) δ 7.39 – 7.33 (m, 2H), 6.93
– 6.87 (m, 2H), 6.19 – 6.14 (m, 1H), 4.60 – 4.55 (m, 2H), 4.37 –
4.33 (m, 2H), 3.78 (s, 3H); 13C NMR (150 MHz, CD3OD) δ
161.8, 161.1, 133.8, 131.0, 127.0, 119.3, 115.1, 70.1, 55.7, 46.1;
IR (thin film) 3453, 3221, 2905, 1677, 1607, 1518, 1446, 1281,
1241, 1031 cm-1; HRMS (ESI) m/z 257.0966 (257.0902
calculated for C12H14N2O3Na [M+Na]+).
1
Benzyl 4-(2-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazine-2-
carboxylate (11): According to the general procedure, oxazine
products 11 and 11a were isolated as a mixture (29 mg, 92%,
4-(3-Methoxyphenyl)-3,6-dihydro-2H-1,2-oxazine-2-
carboxamide (21): According to the general procedure, oxazine
products 21 and 21a were isolated as a mixture (24 mg, 82%,
4:1). H NMR (600 MHz, CD3OD) δ 7.25 (t, J = 8.0 Hz, 1H),
7.01 – 6.82 (m, 3H), 6.29 – 6.26 (m, 1H), 4.61 – 4.56 (m, 2H),
4.38 – 4.34 (m, 2H), 3.79 (s, 3H); 13C NMR (150 MHz, CD3OD)
δ 160.3, 160.0, 138.6, 132.9, 129.3, 120.1, 116.8, 113.1, 110.2,
68.6, 54.2, 44.7; IR (thin film) 3469, 3331, 2924, 1676, 1580,
1430, 1288, 1210, 1050 cm-1; HRMS (ESI) m/z 257.0966
(257.0902 calculated for C12H14N2O3Na [M+Na]+).
1
4:1). H NMR (600 MHz, CDCl3) δ 7.43 – 7.25 (m, 6H), 7.19 –
7.14 (m, 1H), 6.96 – 6.84 (m, 2H), 5.95 – 5.91 (m, 1H), 5.23 (s,
2H), 4.63 – 4.58 (m, 2H), 4.55 – 4.51 (m, 2H), 3.77 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 156.9, 155.6, 136.1, 133.8, 129.5,
129.4, 128.6, 128.3, 128.2, 121.9, 120.9, 110.9, 77.2, 68.8, 67.7,
55.4, 47.5; IR (thin film) 3064, 3033, 2943, 2838, 1727, 1706,
1597, 1490, 1455, 1343, 1215, 1094 cm-1; HRMS (ESI) m/z
348.1326 (348.1212 calculated for C19H19NO4Na [M+Na]+).
1
Benzyl 4-methyl-3,6-dihydro-2H-1,2-oxazine-2-carboxylate
(12) and benzyl hydroxy(2-methylenebut-3-en-1-yl)carbamate
(S-6): According to the general procedure, oxazine products 12
and 12a were isolated as a mixture (62 mg, 48%, 2:1) separate
N-Benzyl-4-(3-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazine-
2-carboxamide (22): According to the general procedure,
oxazine products 22 and 22a were isolated as a mixture (31 mg,
1
77%, 7:1). H NMR (600 MHz, CDCl3) δ 7.38 – 7.23 (m, 6H),
1
from carbamate product S-6 (49 mg, 38%). (12): H NMR (600
7.03 – 6.82 (m, 3H), 6.19 – 6.15 (m, 1H), 4.59 – 4.56 (m, 2H),
4.49 (d, J = 5.8 Hz, 2H), 4.47 – 4.44 (m, 2H), 3.81 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 159.8, 158.6, 138.7, 138.7, 133.8,
129.6, 128.7, 127.7, 127.4, 119.9, 117.5, 113.5, 110.8, 69.3, 55.3,
46.3, 44.0; IR (thin film) 3341, 3033, 2933, 2837, 1670, 1523,
1431, 1288, 1209, 1049 cm-1; HRMS (ESI) m/z 347.1475
(347.1372 calculated for C19H20N2O3Na [M+Na]+).
MHz, CDCl3) δ 7.40 – 7.27 (m, 5H), 5.54 – 5.47 (m, 1H), 5.20 (s,
2H), 4.40 – 4.34 (m, 2H), 4.02 – 3.98 (m, 2H), 1.72 (s, 3H);
(12a): 1H NMR (600 MHz, CDCl3) δ 7.40 – 7.27 (m, 5H), 5.54 –
5.47 (m, 1H), 5.20 (s, 2H), 4.28 – 4.24 (m, 2H), 4.12 – 4.06 (m,
2H), 1.64 (s, 3H); Mixture: 13C NMR (150 MHz, CDCl3) δ 155.6,
155.5, 136.0, 136.0, 131.5, 130.1, 128.5, 128.5, 128.2, 128.1,
128.1, 118.0, 116.2, 71.6, 68.5, 67.7, 67.7, 48.5, 44.7, 19.7, 18.3.
4-(3-Methoxyphenyl)-N-phenyl-3,6-dihydro-2H-1,2-oxazine-
2-carboxamide (23): According to the general procedure, oxazine
products 23 and 23a were isolated as a mixture (25 mg, 64%,
4:1). 1H NMR (600 MHz, CDCl3) δ 7.73 (s, 1H), 7.55 – 7.26 (m,
5H), 7.11 – 6.81 (m, 4H), 6.22 – 6.19 (m, 1H), 4.72 – 4.67 (m,
2H), 4.53 – 4.49 (m, 2H), 3.82 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 160.0, 155.7, 138.7, 138.0, 133.9, 129.9, 129.8, 129.2,
123.7, 119.8, 119.5, 117.7, 113.8, 111.0, 77.2, 69.9, 55.5, 45.9;
IR (thin film) 3321, 3063, 2920, 2837, 1675, 1531, 1446, 1288,
1208, 1050 cm-1; HRMS (ESI) m/z 333.1364 (333.1215
calculated for C18H18N2O3Na [M+Na]+).
Benzyl 4-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3,6-dihydro-
2H-1,2-oxazine-2-carboxylate (14): According to the general
procedure, oxazine products 14 and 14a were isolated as a
1
mixture (95 mg, 77%, 1:13). H NMR (600 MHz, CDCl3) δ 7.39
– 7.27 (m, 5H), 5.67 – 5.62 (m, 1H), 5.20 (s, 2H), 4.46 – 4.39 (m,
2H), 4.25 (q, J = 6.6 Hz, 1H), 4.14 – 4.10 (m, 2H), 1.19 (d, J =
6.5 Hz, 3H), 0.86 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 155.5, 139.8, 136.0, 128.5, 128.2, 128.1,
115.0, 69.3, 68.4, 67.7, 44.6, 25.7, 23.2, 18.1, -4.8, -4.9; IR (thin
film) 3066, 2955, 2856, 1712, 1343, 1214, 1088 cm-1; MS (ESI)
m/z 400.21 (400.19 calculated for C20H31NO4SiNa [M+Na]+).
4-(4-(Trifluoromethyl)phenyl)-3,6-dihydro-2H-1,2-oxazine-2-
carboxamide (24): According to the general procedure, oxazine
products 24 and 24a were isolated as a mixture (109 mg, 72%,
15:1). 1H NMR (600 MHz, CD3OD) δ 7.67 (d, J = 8.5 Hz, 2H),
7.64 (d, J = 8.5 Hz, 2H), 6.50 – 6.46 (m, 1H), 4.67 – 4.62 (m,
2H), 4.46 – 4.41 (m, 2H); 13C NMR (150 MHz, CD3OD) δ
160.3, 140.9, 131.9, 129.45 (q, J = 32.3 Hz), 125.20 (q, J = 3.8
Hz), 125.0, 122.6, 121.0, 68.6, 44.5; IR (thin film) 3420, 3192,
2959, 2846, 1638, 1592, 1326, 1171, 1128, 1070 cm-1; MS (ESI)
m/z 295.06 (100%), 296.07 (25%), 297.07 (6%) (295.07, 296.07,
297.08 calculated for C12H11F3N2O2Na [M+Na]+).
2,2,2-Trichloroethyl 4-phenyl-3,6-dihydro-2H-1,2-oxazine-2-
carboxylate (17): According to the general procedure, oxazine
products 17 and 17a were isolated as a mixture (94 mg, 81%,
1
8:1). H NMR (600 MHz, CDCl3) δ 7.38 – 7.28 (m, 5H), 6.22 –
6.18 (m, 1H), 4.84 (s, 2H), 4.69 – 4.65 (m, 2H), 4.61 – 4.57 (m,
2H); 13C NMR (150 MHz, CDCl3) δ 153.6, 136.7, 132.8, 128.8,
128.3, 124.9, 119.7, 95.1, 75.1, 68.9, 46.2; IR (thin film) 3059,
2955, 2851, 1745, 1720, 1496, 1436, 1347, 1229, 1114 cm-1;. MS
(ESI) m/z 357.99 (100%), 359.99 (95%), 361.98 (33%) (357.98,
359.98, 361.97 calculated for C13H12Cl3NO3Na [M+Na]+).
tert-Butyl 4-phenyl-3,6-dihydro-2H-1,2-oxazine-2-carboxylate
N-Benzyl-4-(4-(trifluoromethyl)phenyl)-3,6-dihydro-2H-
1,2-oxazine-2-carboxamide (25): According to the general
procedure, oxazine products 25 and 25a were isolated as a
mixture (118 mg, 58%, 4:1). 1H NMR (600 MHz, CDCl3) δ 7.61
(d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.40 – 7.25 (m, 5H),
(18): According to the general procedure, oxazine products 18
1
and 18a were isolated as a mixture (70 mg, 77%, 3:1). H NMR
(600 MHz, CDCl3) δ 7.38 – 7.23 (m, 5H), 6.19 – 6.15 (m, 1H),
4.60 – 4.55 (m, 2H), 4.46 – 4.42 (m, 2H), 1.51 (s, 9H); Mixture

6
Tetrahedron
ACCEPTED MANUSCRIPT
2010, 352, 945; (f) Wang, T.; Huang, X.-L.; Ye, S. Org.
Biomol. Chem. 2010, 8, 5007.
6.28 – 6.24 (m, 1H), 6.18 – 6.13 (br, 1H), 4.62 – 4.56 (m, 2H),
4.51 – 4.48 (m, 2H), 4.47 – 4.44 (m, 2H); 13C NMR (150 MHz,
CD3OD) δ 159.4, 140.9, 139.4, 131.9, 129.34 (q, J = 32.2 Hz),
128.0, 126.9, 126.7, 125.19 (q, J = 3.7 Hz), 125.0, 122.6, 68.7,
45.3, 43.0; IR (thin film) 3435, 3342, 3032, 2891, 2844, 1674,
1525, 1326, 1166, 1116, 1071 cm-1; MS (ESI) m/z 386.11
(100%), 387.12 (24%), 388.12 (7%) (385.11, 386.12, 387.12
calculated for C19H17F3N2O2Na [M+Na]+).
2. Baeyer, A. Ber. Dtsch. Chem. Ges. 1874, 7, 1638.
3. For select reviews, see: (a) Streith, J.; Defoin, A. Synthesis
1994, 1107; (b) Kibayashi, C.; Aoyagi, S. Synlett 1995,
873; (c) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54,
1317; (d) Iwasa, S.; Fakhruddin, A.; Nishiyama, H. Mini -
Rev. Org. Chem. 2005, 2, 157; (e) Yamamoto, Y.;
Yamamoto, H. Eur. J. Org. Chem. 2006, 2031; (f) Bodnar,
B. S.; Miller, M. J. Angew. Chem. Int. Ed. 2011, 50, 5630.
4. For select examples, see: (a) Aoyagi, S.; Tanaka, R.;
Naruse, M.; Kibayashi, C. J. Org. Chem. 1998, 63, 8397;
(b) Keck, G. E.; Wager, T. T.; McHardy, S. F. Tetrahedron
1999, 55, 11755; (c) Li, F.; Brogan, J. B.; Gage, J. L.;
Zhang, D.; Miller, M. J. J. Org. Chem. 2004, 69, 4538; (d)
Jana, C. K.; Studer, A. Chem. Eur. J. 2008, 14, 6326; (e)
Huang, J.; Chen, Z.; Yuan, J.; Peng, Y. Asian J. Org.
Chem. 2016, 5, 951.
4-Methyl-3,6-dihydro-2H-1,2-oxazine-2-carboxamide
and 1-hydroxy-1-(2-methylenebut-3-en-1-yl)urea
(26)
(S-12):
According to the general procedure, oxazine products 26 and 26a
were isolated as a mixture (34 mg, 20%, 4:1) separate from urea
product S-12 (20 mg, 10%). 1H NMR (600 MHz, CD3OD) δ 5.60
– 5.53 (m, 1H), 4.39 – 4.33 (m, 2H), 3.89 – 3.85 (m, 2H), 1.74 (s,
3H); 13C NMR (150 MHz, CD3OD) δ 160.2, 130.2, 117.7, 68.2,
46.8, 18.4; IR (thin film) 3335, 2853, 1668, 1584, 1440, 1102 cm-
1; MS (ESI) m/z 165.06 (165.06 calculated for C6H10N2O2Na
[M+Na]+).
5. For exmaples of regioselective nitroso Diels–Alder
reactions, see: (a) Sasaki, T.; Eguchi, S.; Ishii, T.; Yamada,
H. J. Org. Chem. 1970, 35, 4273; (b) Taylor, E. C.;
McDaniel, K.; Skotnicki, J. S. J. Org. Chem. 1984, 49,
2500; (c) Boger, D. L.; Patel, M.; Takusagawa, F. J. Org.
Chem. 1985, 50, 1911; (d) Leach, A. G.; Houk, K. N. J.
Org. Chem. 2001, 66, 5192; (e) Galvani, G.; Lett, R.;
Kouklovsky, C. Chem. Eur. J. 2013, 19, 15604; (f)
Tripoteau, F.; Eberlin, L.; Fox, M. A.; Carboni, B.;
Whiting, A. Chem. Commun. 2013, 49, 5414; (g) Tran, A.
T.; Liu, P.; Houk, K. N.; Nicholas, K. M. J. Org. Chem.
2014, 79, 5617; (h) Chaiyaveij, D.; Batsanov, A. S.; Fox,
M. A.; Marder, T. B.; Whiting, A. J. Org. Chem. 2015, 80,
9518; (i) Pous, J.; Courant, T.; Bernadat, G.; Iorga, B. I.;
Blanchard, F.; Masson, G. J. Am. Chem. Soc. 2015, 137,
11950.
N-Benzyl-4-methyl-3,6-dihydro-2H-1,2-oxazine-2-
carboxamide (27) and 3-benzyl-1-hydroxy-1-(2-methylenebut-3-
en-1-yl)urea (S-13): According to the general procedure, oxazine
products 27 and 27a were isolated as a mixture (46 mg, 33%, 5:1)
1
separate from urea product S-13 (16 mg, 12%). (27): H NMR
(600 MHz, CD3OD) δ 7.61 – 7.56 (br, 1H), 7.31 – 7.24 (m, 5H),
5.58 – 5.52 (m, 1H), 4.35 (s, 2H), 4.35 – 4.33 (m, 2H), 3.89 –
3.85 (m, 2H), 1.73 (s, 3H); (27a): 1H NMR (600 MHz, CD3OD) δ
7.61 – 7.56 (m, 1H), 7.24 – 7.16 (m, 5H), 5.58 – 5.52 (m, 1H),
4.36 (s, 2H), 4.30 – 4.23 (m, 2H), 3.95 – 3.90 (m, 2H), 1.65 (s,
3H); Mixture: 13C NMR (150 MHz, CD3OD) δ 159.4, 159.3,
139.6, 139.5, 131.6, 130.3, 128.0, 126.8, 126.8, 126.6, 126.6,
117.8, 116.3, 71.5, 68.3, 47.6, 43.9, 43.0, 42.9, 18.5, 16.8; IR
(thin film) 3444, 3030, 2914, 1658, 1524, 1496, 1452, 1206,
1105, 1059, 1027 cm-1; MS (ESI) m/z 255.11 (255.11 calculated
for C13H16N2O2Na [M+Na]+).
6. For computational work, see: (a) McCarrick, M. A.; Wu,
Y. D.; Houk, K. N. J. Org. Chem. 1993, 58, 3330; (b)
Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 1243
and reference 5d.
2,2,2-Trichloroethyl 4-(1-((tert-butyldimethylsilyl)oxy)ethyl)-
3,6-dihydro-2H-1,2-oxazine-2-carboxylate (28): According to the
general procedure, oxazine products 28 and 28a were isolated as
7. For examples of the nitroso ene reactions, see: (a) Keck, G.
E.; Webb, R. R. J. Org. Chem. 1982, 47, 1302; (b) Kirby,
G. W.; McGuigan, H.; McLean, D. J. Chem. Soc., Perkin
Trans. 1 1985, 1961; (c) Adam, W.; Bottke, N.; Krebs, O.;
Saha-Möller, C. R. Eur. J. Org. Chem. 1999, 1999, 1963;
(d) Adam, W.; Degen, H.-G.; Krebs, O.; Saha-Möller, C.
R. J. Am. Chem. Soc. 2002, 124, 12938; (e) Adam, W.;
Krebs, O. Chem. Rev. 2003, 103, 4131; (f) Frazier, C. P.;
Engelking, J. R.; Read de Alaniz, J. J. Am. Chem. Soc.
2011, 133, 10430; (g) Baidya, M.; Yamamoto, H.
Synthesis 2013, 45, 1931.
8. For aerobic oxidation conditions to generate
nitrosocarbonyl compounds in situ, see: (a) Chaiyaveij, D.;
Cleary, L.; Batsanov, A. S.; Marder, T. B.; Shea, K. J.;
Whiting, A. Org. Lett. 2011, 13, 3442; (b) Frazier, C. P.;
Bugarin, A.; Engelking, J. R.; Read de Alaniz, J. Org. Lett.
2012, 14, 3620; (c) Sandoval, D.; Frazier, C. P.; Bugarin,
A.; Read de Alaniz, J. J. Am. Chem. Soc. 2012, 134,
18948; (d) Frazier, C. P.; Sandoval, D.; Palmer, L. I.; Read
de Alaniz, J. Chem. Sci. 2013, 4, 3857.
1
a mixture (69 mg, 88%, 1:13). H NMR (600 MHz, CDCl3) δ
5.71 – 5.66 (m, 1H), 4.81 (d, J = 3.3 Hz, 2H), 4.52 – 4.50 (m,
2H), 4.28 (q, J = 6.4 Hz, 1H), 4.23 – 4.18 (m, 2H), 1.22 (d, J =
6.4 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 153.5, 139.8, 120.5, 114.6, 75.0, 69.3, 68.6,
25.7, 23.2, 18.1, -4.8, -4.9; IR (thin film) 2956, 2857, 1724, 1440,
1213, 1112 cm-1; MS (ESI) m/z 440.07 (99%), 442.07 (100%),
444.07 (36%) (440.06, 442.06, 444.05 calculated for
C15H26Cl3NO4SiNa [M+Na]+).
Acknowledgments
This work was supported by UCSB.
References and notes
1. For select examples, see: a) Frederickson, M. Tetrahedron
1997, 53, 403; (b) Gothelf, K. V.; Jørgensen, K. A. Chem.
Rev. 1998, 98, 863; (c) Young, I. S.; Kerr, M. A. Org. Lett.
2004, 6, 139; (d) Dochnahl, M.; Fu, G. C. Angew. Chem.
Int. Ed. 2009, 48, 2391; (e) Chatterjee, I.; Jana, C. K.;
Steinmetz, M.; Grimme, S.; Studer, A. Adv. Synth. Catal.
Supplementary Material
Experimental procedures and characterization data for all
compounds (PDF) is available.