pubs.acs.

org/joc Article

Ring-Opening Cyclization (ROC) of Aziridines with Propargyl

Alcohols: Synthesis of 3,4-Dihydro‑2H‑1,4-oxazines
Bharat Singh, Manish Kumar, Gaurav Goswami, Indresh Verma, and Manas K. Ghorai*
Cite This: J. Org. Chem. 2023, 88, 4504−4518 Read Online

ACCESS Metrics & More Article Recommendations *

sı Supporting Information
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

ABSTRACT: Activated aziridines react with propargyl alcohols in the presence of

Zn(OTf)2 as the Lewis acid catalyst following an SN2-type ring-opening mechanism
Downloaded via INDIAN INST OF TECH KANPUR on March 30, 2024 at 06:23:36 (UTC).

to furnish the corresponding amino ether derivatives. Those amino ethers further
undergo intramolecular hydroamination via 6-exo-dig cyclization in the presence of
Zn(OTf)2 as the catalyst and tetrabutylammonium triflate salt as an additive under
one-pot two-step reaction conditions. However, for nonracemic examples, ring-
opening and cyclization steps were conducted under two-pot conditions. The
reaction works well without any additional solvents. The final 3,4-dihydro-2H-1,4-
oxazine products were obtained with 13 to 84% yield and 78 to 98% enantiomeric
excess (for nonracemic examples).

■ INTRODUCTION
There are numerous reports on N,O-heterocycles, especially
aromatic ring-fused heterocycles, for their syntheses and
biological activities.1,2 Interestingly, among N,O-heterocycles,
1,4-oxazine frameworks were found in several natural products,
which display important bioactivities.3 Oxazines are the
precursors to substituted morpholines, which are of great
significance in medicinal chemistry and chemical biology. 2,5-
and 2,6-Disubstituted morpholines are of pharmacological and
biological importance, as shown in Figure 1.4,5 Moreover,
morpholine derivatives are used as chiral auxiliaries/templates
for the synthesis of α-hydroxy acids/carboxamide and
oxacycles.6 There are a number of reports for the synthesis
of 3,4-dihydro-2H-1,4-oxazine derivatives via Lewis acid/base-
promoted regioselective 6-exo-dig cyclization of amino
propargyl ethers,7 N-protected alkynyl amino alcohols,8 N-
protected alkynals/alkynones,9 epoxy-ynamides,10 etc. Other
approaches for the synthesis of oxazines include the Pd(II)-
catalyzed aerobic oxidative cyclization of 3-aza-5-alkenols,11
Rh(II)-catalyzed reaction between 1-tosyl-1,2,3-triazoles and
epoxides/glycidols/halohydrins,12 Lewis-acid-mediated gemi-
nal acylation of 2-methoxyoxazolidines with five- or six-
membered acyloins followed by heterocyclization,13 and Ir(I)-
catalyzed intramolecular asymmetric allylic substitution re-
action.14
Nucleophilic ring-opening followed by cyclization from
aziridines provides excellent routes to high-value N-hetero-
cyclic synthetic targets.15−20 There are some interesting reports
for the synthesis of 1,4-oxazines from aziridines via ring-
opening cyclization with α-diazocarbonyl compounds and
propargyl alcohols as well.21 However, most of them have
synthetic limitations, such as the following: strategy cannot
provide enantioenriched products (Scheme 1c),21b studies
were directed toward only alkyl aziridines and aryl propargyl
alcohols (Scheme 1a),21c or the cyclization step was shown to
be endo-selective providing the seven-membered rings
(Scheme 1b).21d

Received: December 29, 2022

Published: March 27, 2023

Figure 1. Bioactive compounds containing substituted morpholine.

© 2023 American Chemical Society https://doi.org/10.1021/acs.joc.2c03093

4504 J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
Scheme 1. Reaction of N-Activated Aziridines with Propargyl Alcohols
Scheme 2. Ring-Opening of (±)-2-Phenyl-N-tosylaziridine (1a) with Propargyl Alcohol (2a) Followed by Zn(OTf)2-Assisted
6-exo-dig Cyclization of 3aa
For almost two decades, our group has been extensively
involved in the synthesis of a wide array of N-heterocycles of
contemporary biological and pharmacological interest via SN2-
type nucleophilic ring-opening of activated aziridines/azeti-
dines followed by cyclization following either ROC or domino
ring-opening cyclization (DROC) strategies.22 Recently, we
have reported Zn(OTf)2-catalyzed stereoselective synthesis of
hexahydroimidazo[1,2-a]quinolones via SN2-type ring-opening
hydroarylation−hydroamination cascade cyclization of acti-
vated aziridines with N-propargylanilines.22a We anticipated
4505
pubs.acs.org/joc Article
that the enantioenriched 3,4-dihydro-2H-1,4-oxazines can
easily be accessed via ROC/DROC of enantiopure aziridines
with propargyl alcohols in the presence of Zn(OTf)2. In
continuation of our research activities in this area, we have
successfully developed a highly regioselective synthetic route to
3,4-dihydro-2H-1,4-oxazines via Lewis-acid catalyzed SN2-type
ring-opening of activated aziridines with propargyl alcohols,
followed by intramolecular hydroamination (6-exo-dig cycliza-
tion) under solvent-free conditions (Scheme 1d); herein, we
report our preliminary results as a full paper.
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry pubs.acs.org/joc Article

■ RESULTS AND DISCUSSION

Our study commenced with the reaction of (±)-2-phenyl-N-
Table 2. Optimization Studied for the Synthesis of (±)-5-
Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-oxazine 4aaa
tosylaziridine (1a) with propargyl alcohol (2a) in the presence
of 10 mol % of Zn(OTf)2 as Lewis acid at room temperature to
furnish the corresponding ring-opening product 3aa as a single
regioisomer in 82% yield (Scheme 2). Next, 3aa was subjected
to 10 mol % of Zn(OTf)2 in dichloroethane (0.5 mL) solvent
at room temperature and no product was observed. The
reaction was studied by increasing the temperature up to 50 °C yield
and then up to 85 °C, and no product was formed in both entry reaction condition (%)b
cases. To our delight, with the addition of 1.0 equiv 1c Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), DCM (1.0 mL), 85 61
Bu4N+OTf− as an additive at 85 °C, product (±)-4aa was °C, Ar, 40 h
obtained in 60% yield as a single regioisomer in 72 h (Scheme 2 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), CH3CN (1.0 mL), 85 70
2). Product 4aa was characterized by spectroscopic data, and °C, Ar, 10 h
the structure was confirmed by X-ray crystallographic analysis 3 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), toluene (1.0 mL), 85 34
°C, Ar, 60 h
(see the SI). 4 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), CCl4 (1.0 mL), 85 °C, 47
To optimize the reaction conditions in terms of better yields, Ar, 6 h
shorter reaction time, and selectivity, a number of Lewis acids, 5 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), dioxane (1.0 mL), 85 -
solvents, additives, and temperatures were screened. First, °C, Ar, 72 h
different Lewis acid catalysts were studied for the nucleophilic 6 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), DMSO (1.0 mL), 85 -
°C, Ar, 72 h
ring-opening of (±)-2-phenyl-N-tosylaziridine with propargyl
7 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), DMF (1.0 mL), 85 -
alcohol (Table 1, entries 1−6). Although similar yields were °C, Ar, 72 h
8 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), 85 °C, Ar, 4h 80
Table 1. Screening of Lewis Acids for the Nucleophilic 9 Zn(OTf)2 (1.0), Bu4N+OTf− (1.0), 85 °C, Ar, 1 h 76
Ring-Opening of Racemic (±)-2-Phenyl-N-tosylaziridine 10 Zn(OTf)2 (0.1), 85 °C, Ar, 84 h 50
(1a) with Propargyl Alcohol (2a)a 11 Bu4N+OTf− (1.0), 85 °C, Ar, 72 h -
12 Zn(OTf)2 (0.1), Bu4N+OTf− (0.1), 85 °C, Ar, 8 h 63
13 Zn(OTf)2 (1.0), Bu4N+OTf− (0.1), 85 °C, Ar, 7 h 53
14 Zn(OTf)2 (0.1), [tBu3PH]+BF4− (1.0), 85 °C, Ar, 42 h -
15 Zn(OTf)2 (0.1), Bu4N+PF6− (1.0), 85 °C, Ar, 42 h -
16 Zn(OTf)2 (0.1), Bu4N+HSO4− (1.0), 85 °C, Ar, 42 h -
17 Zn(OTf)2 (0.1), Bu4N+NO3− (1.0), 85 °C, Ar, 42 h -
s. no. Lewis acid time % yield 18 Zn(OTf)2 (0.1), Et4N+(CH3C6H4SO3)−(1.0), 85 °C, Ar, 33
42 h
1. BF3•OEt2 5 min 78
19 Zn(OTf)2 (0.1), Bu4N+(BF4)− (1.0), 85 °C, Ar, 42 h 55
2. Cu(OTf)2 15 min 73 d
20 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), 85 °C, 42 h 50
3. Zn(OTf)2 20 min 84
21 Zn(OAc)2 (0.1), Bu4N+OTf− (1.0), 85 °C, Ar, 24 h -
4. LiClO4 12 h NR a
5. Yb(OTf)3 10 min 80
Unless otherwise stated, all the reactions were carried out with 0.182
mmol (60 mg, 182 M) of 3a. bYield of the isolated product. cReaction
6. Sc(OTf)3 10 min 80
a
was performed in a sealed tube. dReaction was carried out in the open
Unless otherwise stated, all the ring-opening reactions were carried air.
out with 1.0 equiv (0.183 mmol, 3.66 M) of 1a, 2.0 equiv (0.366
mmol) of 2a, and 10 mol % (0.018 mmol) of Lewis acid in
dichloromethane (50 μL) as the solvent at room temperature.
the best condition in hand, we screened the amount of Zn-salt
and additives (entries 9−13). Generation of 4aa with 50%
yield in the absence of additive in 84 h (entry 10) and no
obtained in all the cases (except LiClO4), because of easy reaction in the absence of Zn-salt (entry 11) indicates that Zn
handling, functional group tolerance, low cost, stability, salt is necessary for the reaction.
nontoxicity,23 and its further use in the cyclization step, We also checked the viability of various ammonium and
Zn(OTf)2 was chosen as the best Lewis acid catalyst (entry 3). phosphonium salts as the additives on our reaction protocol,
We screened different solvents, Zn catalysts, and additives product 4aa was obtained with 33 to 55% yields, in the case of
(Table 2). On changing the solvent from 1,2-dichloroethane to ammonium salts having better-leaving counter anions (entries
dichloromethane, the reaction was completed in 40 h to 18−19), and no reaction was observed in the case of
furnish product 4aa in 61% yield (entry 1). In the case of ammonium salts with poor leaving counter anions (entries
acetonitrile, toluene, and carbon tetrachloride as the solvents, 14−17). Finally, we concluded that Bu4N+OTf− is the best
4aa was obtained in 70, 34, and 47% yields, respectively additive for cyclization. 50% yield of 4aa in the open air (entry
(entries 2−4). However, no product was formed when 1,4- 20) shows that the reaction is not so sensitive to air and
dioxane, dimethyl sulfoxide, and N,N-dimethylformamide were moisture and no reaction was observed in the case of weak
employed as the solvents (entries 5−7). Interestingly, on Lewis acids like Zn(OAc)2 (entry 21). From the above
increasing the concentration of the reaction mixture, a decrease screening, we found that 10 mol % of Zn(OTf)2 and 1.0 equiv
in reaction time and an increase in yield of product 4aa were of Bu4N+OTf− are the best conditions for the intramolecular
observed. This result inspired us to perform the reaction in a hydroamination step (entry 8).
solvent-free condition, and to our delight, 4aa was obtained in The strategy was made more practical as a general
80% yield in 4 h (entry 8). The solvent-free condition being methodology by performing the reaction under one-pot
4506 https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
conditions. (±)-2-Phenyl-N-tosylaziridine was treated with 2.0
equiv propargyl alcohol (2a) in DCM solvent, and after
removal of solvent, the crude was subjected to cyclization
conditions to give product 4aa in 78% overall yield (Scheme
3).
Scheme 3. One-Pot Synthesis of (±)-5-Methyl-2-phenyl-4-
tosyl-3,4-dihydro-2H-1,4-oxazine (4aa)
To investigate the electronic effect of the N-sulfonyl group, a
wide range of racemic (±)-2-phenyl-1-(aryl/alkylsulfonyl)-
aziridines (1b−g) were studied with 2a and the corresponding
2H-1,4-oxazine derivatives 4ba−ga were obtained in moderate
to good yields (Scheme 4). There is not much difference in the
Scheme 4. Substrate Scope for Aziridines Having Various N-
Sulfonyl-Protecting Groups (±)-1b−1g with 2aa
a
Unless otherwise stated, all of the ring-opening steps were carried
out in 1.0 equiv of aziridine 1b−g, 2.0 equiv of propargyl alcohol
(2a), and 10 mol % of Zn(OTf)2 in dichloromethane (50 μL).
ring-opening time whether EDG or EWG is present in the N-
protecting group, but a significant effect on the reaction time
and yield was observed in the hydroamination step. In the case
of 4ca, time and yield are 4 h and 68%, respectively, while for
the 4fa-containing NO2 group, reaction time increases to 48 h
and yield decreases to 37%. Probably EWG decreases the
nucleophilicity of N, and the hydroamination step becomes
slow.
The methodology was further generalized with a variety of
(±)-2-aryl-N-tosylaziridines (1h−u) with 2a (Scheme 5). 2-
Aryl-N-tosylaziridines with electron-donating 4-Me and 4-t-Bu
substituents 1h,i were subjected to ring-opening/cyclization
protocol giving 4ha and 4ia in 51 and 54% yields, respectively.
However, in the case of halo substituents (1j−o), the
corresponding products 4ja−oa were obtained in moderate
to good yields. In the case of o-, m-, and p-Br-substituted
aziridines (1j,k), the corresponding products 4ja, 4ka, and 4la
were obtained in 65, 60, and 75% yields, respectively. On
increasing the electronegativity, o-, p-Cl, and p-F (1m−o), the
corresponding products 4ma, 4na, and 4oa were obtained in
84, 72, and 69% yields, respectively. On further increase in the
electronegativity as in p-CF3 (1p), the corresponding product,
4pa, was isolated in only 57% yield. In the case of a
diastereomeric mixture of 2-methyl-3-phenyl-1-tosylaziridine
(1q), the corresponding products
4qa and 4q′a (cis and trans confirmed by X-ray crystallo-
graphic analysis; see the SI) was obtained in 61% overall yield
with a 2.5:1 diastereomeric ratio. The nucleophilic ring-
4507
pubs.acs.org/joc Article
opening of alkyl aziridines (1t,u) at 50 °C, followed by
cyclization, led to the formation of the corresponding products
4ta and 4ua in 50 and 38% yields, respectively. The reaction of
bulky substituted (±)-2-(naphthalene-2-yl)-1-tosylaziridine
(1v) took place at 50 °C, and after the cyclization, the final
product 4va was obtained only at 40% yield. In the case of
cyclic aziridine 1w, only a trace amount of the product was
obtained (Scheme 5).
In the case of the reaction of (±)-2-phenyl-N-tosyl aziridines
with (±)-but-3-yn-2-ol (2b) and (±)-1-phenylprop-2-yn-1-ol
(2c), the corresponding products 4ab and 4ac were obtained
in 46 and 13% yields, respectively (Scheme 6). In contrast, no
cyclized product was obtained in the case of 2-methyl-but-3-
yn-2-ol as a nucleophile.
The synthetic significance of our methodology was further
demonstrated by the synthesis of nonracemic dihydro-2H-1,4-
oxazines (Scheme 7) by employing enantiopure aziridine as
the starting substrate. We assumed that there would be no
change in enantiomeric excess in the cyclization step because
no chiral center is involved during the cyclization, so we
optimized our protocol in the nucleophilic ring-opening of the
enantiopure aziridine step, as shown in Table 3. From various
screenings (entries 1−23, Table 3), we found that dropwise
addition of a solution of (R)-1a (in DCM) in 5 mol % of
Zn(OTf)2, 1.0 equiv of Bu4N+HSO4− (TBAHS) in DCM
solvent at 0 °C provides ring-opening product (S)-3aa, in 80%
yield with 84% ee, best-optimized condition (entry 5).
The enantiopure (R)-2-phenyl-N-tosylaziridine, (R)-1a
(>99% ee), was reacted with 2a under optimized reaction
conditions (method B), leading to the formation of non-
racemic 3,4-dihydro-2H-1,4-oxazine (S)-4aa in 65% yield and
84% enantiomeric excess. The strategy was generalized with
other aziridines (S)-1m, (S)-1t, and (S)-1u and 2a, and the
corresponding nonracemic 3,4-dihydro-2H-1,4-oxazine deriva-
tives (S)-4ma, (S)-4ta, and (S)-4ua were obtained in 35−80%
yields with 78−98% enantiomeric excess (Scheme 7). A
decrease in enantiomeric excess of the product is probably due
to partial racemization of the starting material in the presence
of Lewis acid during the reaction. On increasing the scale of
the reaction of 1a (2.0 g, 7.317 mmol, 1.0 equiv) with 2a (844
μL, 14.633 mmol, 2.0 equiv) in DCM (500 μL) followed by
cyclization under a one-pot optimized protocol, the final
product 4aa was obtained in 52% (1.253 g, 3.805 mmol) yield.
The plausible mechanistic pathway is shown in Scheme 8.
Based on our experimental observations, we believe that the
ring-opening of N-activated aziridine 1 with propargyl alcohol
(2a) follows the SN2-type pathway established by our group
earlier.4a The Lewis acid Zn(OTf)2 activates aziridine 1 to
generate the adduct 1a′. It undergoes SN2-type nucleophilic
attack with propargyl alcohol (2a) to generate intermediate
3a′, which, after deprotonation, is transformed into the ring-
opening product 3a. We believe that the zinc-coordinated
alkyne species gets further activated in the presence of dipolar
quaternary ammonium salt. The activation of the alkyne π-
system leads to the generation of the intermediate 3b′, which
undergoes intramolecular hydroamination via 6-exo-dig cycliza-
tion to generate intermediate 4a′, which on deprotonation-
protonation followed by exo-endo conversion afforded product
4, and the catalyst is regenerated. Moreover, tetrabutylammo-
nium trifluoromethanesulfonate salts might also participate in
the regeneration of the catalyst system.
Pd-C-catalyzed reduction of (S)-4aa (84% ee) produced the
corresponding morpholine derivative 5a as an inseparable
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry pubs.acs.org/joc Article

Scheme 5. Substrate Scope with Respect to Racemic (±)-2-Aryl-N-tosyl-aziridines with 2aa

a
Unless otherwise stated, the ring-opening step was carried out in 1.0 equiv of 1h−v, 2.0 equiv of 2a, and 10 mol % of Zn(OTf)2 in
dichloromethane (50 μL) solvent at room temperature. Cyclization steps were carried out with 1.0 equiv of Bu4N+OTf−, Ar environment at 85 °C.
b
Isolated yield of the product. cThe regioisomeric ratio was calculated from crude NMR. dRing-opening reaction was carried out at 50 °C in
tetrahydrofuran (50 μL) solvent.

Scheme 6. Substrate Scope with Respect to Propargyl Scheme 7. Synthesis of Enantioenriched Oxazines via ROC
Alcohols with Racemic (±)-2-Phenyl-N-tosyl Aziridines of Enantiopure Aziridines 1 with 2aa

a
Unless otherwise stated, the ring-opening step was carried out in 1.0
equiv of 1a, 2.0 equiv of 2b−d, and 10 mol % of Zn(OTf)2 in
dichloromethane (50 μL) solvent at room temperature. The
cyclization step was carried out with 1.0 equiv of Bu4N+OTf−, Ar
environment at 85 °C.
a
Unless otherwise stated, reactions were carried out with 1.0 equiv of
(1), 0.1 mL of (2a), 5 mol % Zn(OTf)2, and 1.0 equiv of TBAHS in
dry dichloromethane (0.5 mL) at 0 °C. Cyclization steps were carried
mixture of diastereomers (dr 20:1). When 5a was subjected to out with 10 mol % Zn(OTf)2 and 1.0 equiv of Bu4N+OTf− under an
Ar environment. bRing-opening reactions were carried out at 50 °C
Na/C10H8-mediated desulfonylation conditions, the com- temperature in tetrahydrofuran solvent.
pound 5b with free N-H can be isolated in 80% overall yield
as a single diastereomer (Scheme 9).

■ CONCLUSIONS
In conclusion, we have successfully developed an efficient and
simple strategy for the synthesis of 3,4-dihydro-2H-1,4-
oxazines in 13 to 84% yields and excellent enantioselectivity
(ee up to 98%) via Zn(OTf)2-catalyzed ROC of activated
aziridines with propargyl alcohols. We believe that this mild
protocol will be helpful for organic chemists to synthesize
substituted oxazines and morpholines. Further work is in
progress.
4508
■ GENERAL INFORMATION
Compounds were purified by flash column chromatography on
200−400 mesh silica gel using a combination of ethyl acetate
and petroleum ether as the eluent. Analytical thin-layer
chromatography (TLC) was carried out using silica gel 60
F254 pre-coated plates, UV light, and an iodine chamber to
visualize the course of the reactions. Unless noted, all reactions
were carried out in oven-dried glassware under an atmosphere
of argon using anhydrous solvents. All reagents were purified
before use following the Perrin and Armerego24 and Vogel
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry pubs.acs.org/joc Article

Table 3. Optimization Studied for the Nucleophilic Ring- Scheme 8. A Plausible Mechanism for the Synthesis of 3,4-
Opening Enantiopure (R)-1-Phenyl-N-tosylaziridine (1a) Dihydro-2H-1,4-oxazine Derivatives
with Propargyl Alcohol 2aa

entry reaction condition % yield ee %

1 Zn(OTf)2 (5.0 mol %), Bu4N+OTf− (2.0 equiv), 0 86 68
°C, 2 min
2 Zn(OTf)2 (5.0 mol %), Bu4N+OTf− (2.0 equiv), 0 86 67
°C, 5 min
3 Zn(OTf)2 (5.0 mole%), TBAHS (2.0 equiv), 0 °C, 80 79
2 min
4 Zn(OTf)2 (5.0 mole%), TBAHS (2.0 equiv), 80 77
DCM (0.5 mL), 0 °C, 5 min
5b Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), 80 84
DCM (0.5 mL), 0 °C, 20 min
6b Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), 60 84
toluene (0.5 mL), 0 °C, 15 min
7 Zn(OTf)2 (5.0 mol %), Bu4N+OTf− (1.0 equiv), 88 69
DCM (0.5 mL), −10 °C, 8 min guidelines.25 The monosubstituted N-Ts aziridines (1) were
8 Zn(OTf)2 (5.0 mol %), Bu4N+OTf− (2.0 equiv), 90 68 prepared from different styrene derivatives following a reported
DCM (0.5 mL), −10 °C, 6 min procedure.26 Chiral mono-substituted N-Ts aziridines were
9b Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 91 82 prepared from the corresponding amino alcohol following a
(0.5 mL), −10 °C, 24 min
b reported procedure,27 and propargyl alcohols (2) were
10 Zn(OTf)2 (5.0 mol %), TBAHS (0.5 equiv), 78 65
Bu4NOTf (0.5 equiv), DCM (0.5 mL), 0 °C, 27 commercially received from TCI Chemicals. All commercial
min reagents were used as received. The 1H NMR (400 and 500
11 (NH4)2S2O8 (1.0 equiv), DCM (0.5 mL), 0 °C, 5 98 69 MHz) and 13C NMR (100 and 125 MHz) data were recorded
min with CDCl3 as solvent at room temperature unless specified
12b Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), 93 80 otherwise. The chemical shifts (δ) are reported in ppm and
CH3CN (0.5 mL), −10 °C, 10 min
13b,c Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 91 81 coupling constants (J) in Hz. 1H NMR spectra were recorded
(0.5 mL), −10 °C, 50 min with tetramethylsilane (δ = 0.00 ppm) as an internal reference.
13
14 b ,c
Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 89 80 C NMR spectra were recorded with CDCl3 (δ = 77.0 ppm)
(0.5 mL), −20 °C, 72 min as an internal reference. 1H NMR splitting patterns are
15b,c Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 86 83 designated as singlet (s), doublet (d), triplet (t), quartet (q),
(0.5 mL), −30 °C, 2 h
16d Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 65 79
doublet of doublet (dd), multiplet (m), etc. HRMS data were
(0.5 mL), −40 °C, 4.5 h recorded using an ESI mass spectrometer (TOF). IR spectra
17b Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 80 87 were logged in the KBr pallet. Enantiomeric excesses (% ee)
(0.5 mL), −30 °C, 22 min were determined by HPLC using AS-H analytical columns
b
18 Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 70 90 (detection at 254 nm). Melting points were determined using a
(0.5 mL), −40 °C, 35 min
hot-stage apparatus and are uncorrected. Optical rotations
19 LiClO4 (10.0 mol %), TBAHS (1.0 equiv), 88 63
CH3CN (0.5 mL), 85 °C, 30 min were measured using a 6 mL cell with a 50 mm path length and
20b BF3.OEt2 (10 mol %), TBAHS (1.0 equiv), DCM 80 83 are reported as [α]25D (c in gm per 100 mL solvent) at 25 °C.

21e
(0.5 mL), −40 °C, 12 min
BF3.OEt2 (10 mol %), TBAHS (2.0 equiv), DCM
(0.5 mL), −40 °C, 10 min
78
22b Zn(OTf)2 (5.0 mol %), TBAHS (2.0 equiv), THF 76
(0.5 mL), −40 °C, 1.5 h
23b,e Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), 53
toluene (0.5 mL), −40 °C, 60 min
a
Unless noted otherwise, reactions were carried out by taking (R)-1a
(0.183 mmol, 1.0 equiv, 366 M, >99% ee), Lewis acid, ammonium
salt, and 0.1 mL of propargyl alcohol 2a in a single-neck RB and left
for stirring at a given temperature. bSolution of chiral 1a (in 0.5 mL
DCM) was added dropwise in a stirred solution of Zn(OTf)2,
R4N+X−,, and propargyl alcohol. cDuring addition, the solution of
(R)-1a was kept at the reaction mixture temperature. dReaction was
not completed in a given time, and the starting aziridine was
recovered. eLewis acid was added dropwise in a stirred solution of 1a,
R4N+X−, and propargyl alcohol 2 in DCM (0.1 mL). The
enantiomeric excess of 3aa was determined by HPLC (AD-H,
isopropanol/n-hexane = 10/90, 1.0 mL min−1, 720 psi), tR = 19 min,
22 min.
76 ■ EXPERIMENTAL SECTION
General Procedure for the Synthesis of 5-Methyl-2-phenyl-
78 4-tosyl-3,4-dihydro-2H-1,4-oxazine Derivatives. Method A. In a
single-neck RB flask, aziridine 1 (1.0 equiv), propargyl alcohol 2 (2.0
90 equiv), Lewis acid (10 mol %), and DCM (2.0 times of propargyl
alcohol in μL) were taken, and the reaction mixture was stirred for an
appropriate time at an appropriate temperature in an Ar atmosphere.
The progress of the reaction was monitored by TLC using 20% ethyl
acetate in petroleum ether. After completion of the reaction, the
solvent was removed under reduced pressure. After the addition of
tetrabutylammonium triflate in the same pot under an Ar atmosphere,
the reaction mixture was kept for stirring at 85 °C on an oil bath for
an appropriate time. The reaction was monitored by TLC. After
completion, the reaction was quenched with aq. ammonium chloride
and the mixture was extracted with ethyl acetate. The combined
organic layer was dried over anhydrous Na2SO4, and the solvent was
evaporated under reduced pressure. The crude concentrate was
purified by flash column chromatography on a silica gel using 5%
ethyl acetate in petroleum ether as the eluent to afford the pure
product 4.

4509 https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
Scheme 9. Reduction Followed by Desulfonylation of 5-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-oxazine (4aa)
Method B. In a single-neck RB flask, propargyl alcohol 2 (0.1 mL),
Lewis acid (5 mol %), and tetrabutylammonium hydrogensulfate (1.0
equiv) in anhydrous solvent (0.1−0.3 mL) were taken, and the
reaction mixture was stirred at an appropriate temperature for an
appropriate time. Nonracemic aziridine 1 (1.0 equiv) solution in an
appropriate solvent (0.5 mL) was added dropwise within a particular
duration of time (5−20 min). The progress of the reaction was
monitored by TLC using 20% ethyl acetate in petroleum ether. After
completion, the reaction was quenched with aq. ammonium chloride
and the mixture was extracted with ethyl acetate. The combined
organic layer was dried over anhydrous Na2SO4, and the solvent was
evaporated under reduced pressure. The crude concentrate was
purified by flash column chromatography on a silica gel using 8%
ethyl acetate in petroleum ether as the eluent to obtain the pure
product 3. Next, product 3 was treated with Zn(OTf)2 (10 mol %)
and Bu4N+OTf− (1.0 equiv) in an Ar medium at 85 °C on an oil bath
for an appropriate time. The progress of the reaction was monitored
by TLC using 10% ethyl acetate in petroleum ether. After completion
of the reaction and usual workup as mentioned above, the crude
concentrate was purified by flash column chromatography on a silica
gel using 5% ethyl acetate in petroleum ether as the eluent to furnish
the pure product 4.
■ SELECTED SPECTRAL DATA
General Procedure for the Synthesis of (±)-2-Phenyl-
N-tosyl Aziridine (1a). In a double-neck RB flask, anhydrous
chloramine-T (2.762 g, 9.601 mmol, 1.1 equiv) and PTAB
(328 mg, 0.873 mmol, 0.1 equiv) were taken in an Ar
environment, and after the addition of CH3CN (15 mL), the
reaction mixture was stirred for 30 min at room temperature.
Next, styrene (1.0 mL, 8.728 mmol, 1.0 equiv) was added in a
dropwise manner and stirring was continued at the same
temperature for 5 h. After completion, the reaction was
quenched with water and the mixture was extracted with ethyl
acetate. The combined organic layer was dried over anhydrous
Na2SO4, and the solvent was evaporated under reduced
pressure. The crude concentrate was purified by flash column
chromatography on a silica gel using 5% ethyl acetate in
petroleum ether as the eluent to afford the pure product (±)-2-
phenyl-N-tosyl aziridine (1a) as a white crystalline solid (mp
88−89 °C) in 58% (1383 mg, 5.062 mmol) yield. Rf = 0.43 in
20% ethyl acetate in petroleum ether; IR υmax (KBr, cm−1)
3036, 2958, 1667, 1594, 1494, 1458, 1379, 1156; 1H NMR
(500 MHz, CDCl3) δ 7.87 (d, 2H, J = 8.6 Hz), 7.33 (d, 2H, J =
8.0 Hz), 7.29−7.26 (m, 3H), 7.22−7.20 (m, 2H), 3.77 (dd,
1H, J = 7.4, 4.0 Hz), 2.98 (d, 1H, J = 7.4 Hz), 2.43 (s, 3H),
2.38 (d, 1H, J = 4.6 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ
144.7, 135.2, 135.1, 129.8, 128.6, 128.4, 128.0, 126.6, 41.1,
36.0, 21.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C15H16NO2S 274.0897; found 274.0896.
(±)-4-Methyl-N-(2-phenyl-2-(prop-2-yn-1-yloxy)-
ethyl)benzenesulfonamide (3aa). The general method A
described above was followed when racemic (±)-2-phenyl-N-
tosyl aziridine 1a (50 mg, 0.183 mmol, 1.0 equiv) was treated
with propargyl alcohol 2a (21 μL, 0.366 mmol, 2.0 equiv) in
the presence of Zn(OTf)2 (7 mg, 0.018 mmol, 10 mol %) in
DCM (44 μL) at RT for 20 min to get 3aa as a white
4510
pubs.acs.org/joc Article
crystalline solid, mp 51−53 °C in 84% (51 mg, 0.154 mmol)
yield; Rf 0.33 in 20% ethyl acetate in petroleum ether; IR υmax
(KBr, cm−1) 3280, 2923, 2853, 2120, 1597, 1493, 1452, 1326,
1158, 1072, 814; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, 2H, J
= 8.0 Hz), 7.33−7.31 (m, 3H), 7.29 (d, 2H, J = 8.0 Hz), 7.22−
7.20 (m, 2H), 4.97 (d, 1H, J = 8.6 Hz), 4.55 (dd, 1H, J = 9.7,
4.0 Hz), 4.06 (dd, 1H, J = 16.0, 2.9 Hz), 3.81 (dd, 1H, J =
15.5, 2.3 Hz), 3.25−3.20 (m, 1H), 3.06−3.01 (m, 1H), 2.42−
2.41 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 143.4,
137.3, 136.9, 129.7, 128.8, 128.75, 127.1, 126.8, 79.3, 79.0,
74.9, 55.9, 49.0, 21.5; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C18H19NO3SNa 352.0978; found 352.0978.
(±)-5-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-
oxazine (4aa). The general method A described above was
followed when racemic (±)-2-phenyl-N-tosyl aziridine 1a (52
mg, 0.190 mmol, 1.0 equiv) was treated with propargyl alcohol
2a (22 μL, 0.380 mmol, 2.0 equiv) in the presence of
Zn(OTf)2 (7 mg, 0.019 mmol, 10 mol %) in DCM (44 μL) at
RT for 20 min. After completion, the crude was treated with
Bu4N+OTf− (68 mg, 1.0 equiv) as an additive, in an Ar
environment at 85 °C on an oil bath for 6 h to obtain (±)-4aa
as a white solid: mp 116−118 °C in 78% (47 mg, 0.149 mmol)
yield; Rf 0.60 (in 20% ethyl acetate in petroleum ether); IR
υmax (KBr, cm−1) 3065, 2965, 2927, 1660, 1596, 1495, 1453,
1261, 1209, 1167, 1088, 814; 1H NMR (500 MHz, CDCl3) δ
7.72 (d, 2H, J = 8.0 Hz), 7.40 (d, 2H, J = 8.0 Hz), 7.35−7.29
(m, 3H), 7.09−7.06 (m, 2H), 6.17 (s, 1H), 4.11 (dd, 1H, J =
14.3, 2.3 Hz), 3.77 (dd, 1H, J = 10.3, 2.29 Hz), 2.98 (dd, 1H, J
= 14.3, 9.7 Hz), 2.46 (s, 3H), 2.10 (d, 3H, J = 0.8 Hz);
13
C{1H} NMR (125 MHz, CDCl3) δ 144.2, 137.1, 134.8,
132.7, 130.0, 128.6, 128.5, 127.5, 125.8, 111.9, 72.7, 50.7, 21.6,
18.2; HRMS (ESI-TOF) m/z: [M + H] + calcd for
C18H20NO3S 330.1159; found 330.1167.
(±)-4-((4-(tert-Butyl)phenyl)sulfonyl)-5-methyl-2-
phenyl-3,4-dihydro-2H-1,4-oxazine (4ba). The general
method A described above was followed when (±)-1-((4-
(tert-butyl)phenyl)sulfonyl)-2-phenylaziridine 1b (100 mg,
0.317 mmol, 1.0 equiv) was treated with propargyl alcohol
2a (38 μL, 0.634 mmol, 2.0 equiv) in the presence of
Zn(OTf)2 (12 mg, 0.032 mmol, 10 mol %) in DCM (50 μL)
at RT for 23 min. After completion, the crude was treated with
Bu4N+OTf− (124 mg, 0.317 mmol, 1.0 equiv) as an additive, in
an Ar environment at 85 °C on an oil bath for 6 h to obtain
(±)-4ba as a gummy liquid in 66% (78 mg, 0.209 mmol) yield;
Rf 0.52 (in 10% ethyl acetate in petroleum ether); IR υmax
(KBr, cm−1) 3065, 2962, 2924, 2852, 1661, 1594, 1495, 1355,
1265, 1209, 1197, 1170, 1085, 838; 1H NMR (400 MHz,
CDCl3) δ 7.76 (d, 2H, J = 8.5 Hz), 7.60 (d, 2H, J = 8.5 Hz),
7.32−7.28 (m, 2H), 7.07−7.04 (m, 2H), 6.17 (s, 1H), 4.09
(dd, 1H, J = 14.6, 2.4 Hz), 3.77 (dd, 1H, J = 9.8, 2.4 Hz), 2.98
(dd, 1H, J = 14.6, 9.8 Hz), 2.10 (d, 3H, J = 1.2 Hz), 1.35 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.3, 137.2, 135.0,
132.6, 128.7, 128.6, 127.6, 126.4, 125.9, 112.2, 73.1, 50.8, 35.4,
31.2, 18.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C21H26NO3S 372.1628; found 372.1642.
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
(±)-4-((4-Methoxyphenyl)sulfonyl)-5-methyl-2-phe-
nyl-3,4-dihydro-2H-1,4-oxazine (4ca). The general method
A described above was followed when (±)-1-((4-
methoxyphenyl)sulfonyl)-2-phenylaziridine 1c (100 mg,
0.346 mmol, 1.0 equiv) was treated with propargyl alcohol
2a (42 μL, 0.692 mmol, 2.0 equiv) in the presence of
Zn(OTf)2 (13 mg, 0.035 mmol, 10 mol %) in DCM (50 μL)
at RT for 25 min. After completion, the crude was treated with
Bu4N+OTf− (135 mg, 0.346 mmol, 1.0 equiv) as an additive, in
an Ar environment at 85 °C on an oil bath for 4 h to obtain
(±)-4ca as a white solid: mp 78−80 °C in 68% (81 mg, 0.235
mmol) yield; Rf 0.50 (in 10% ethyl acetate in petroleum
ether); IR υmax (KBr, cm−1) 3067, 2928, 2849, 1660, 1595,
1577, 1497, 1352, 1309, 1262, 1208, 1163, 1090, 834; 1H
NMR (400 MHz, CDCl3) δ 7.76 (d, 2H, J = 8.5 Hz), 7.35−
7.29 (m, 3H), 7.10−7.04 (m, 4H), 6.17 (d, 1H, J = 1.2 Hz),
4.09 (dd, 1H, J = 14.6, 2.4 Hz), 3.88 (s, 3H), 3.81 (dd, 1H, J =
9.8, 2.4 Hz), 2.96 (dd, 1H, J = 14.6, 9.8 Hz), 2.09 (d, 3H, J =
1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 163.4, 137.2,
132.8, 129.7, 129.6, 128.7, 128.6, 125.9, 114.6, 112.1, 72.9,
55.8, 50.8, 18.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H20NO4S 346.1108; found 346.1114.
(±)-5-Methyl-2-phenyl-4-(phenylsulfonyl)-3,4-dihy-
dro-2H-1,4-oxazine (4da). The general method A described
above was followed when (±)-2-phenyl-1-(phenylsulfonyl)-
aziridine 1d (100 mg, 0.387 mmol, 1.0 equiv) was treated with
propargyl alcohol 2a (47 μL, 0.774 mmol, 2.0 equiv) in DCM
(50 μL) solvent in the presence of Zn(OTf)2 (14 mg, 0.039
mmol, 10 mol %) at RT for 20 min. After completion, the
crude was treated with Bu4N+OTf− (151 mg, 0.387 mmol, 1.0
equiv) as an additive, in an Ar environment at 85 °C on an oil
bath for 6 h to obtain (±)-4da as a white solid: mp 63−65 °C
in 60% (73 mg, 0.232 mmol) yield; Rf 0.31 (in 10% ethyl
acetate in petroleum ether); IR υmax (KBr, cm−1) 2923, 2853,
1660, 1447, 1352, 1168, 1088, 802; 1H NMR (400 MHz,
CDCl3) δ 7.85−7.82 (m, 2H), 7.65−7.58 (m, 3H), 7.34−7.28
(m, 3H), 7.07−7.05 (m, 2H), 6.17 (d, 1H, J = 1.2 Hz), 4.11
(dd, 1H, J = 14.6, 2.4 Hz), 3.75 (dd, 1H, J = 9.8, 2.4 Hz), 2.99
(dd, 1H, J = 14.6, 9.8 Hz), 2.10 (d, 3H, J = 1.2 Hz); 13C{1H}
NMR (100 MHz, CDCl3) δ 137.9, 137.1, 133.4, 132.9, 129.5,
128.7, 128.6, 127.6, 126.0, 112.0, 73.0, 50.8, 18.2; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C17H18NO3S 316.1002; found
316.1003.
(±)-4-((4-Fluorophenyl)sulfonyl)-5-methyl-2-phenyl-
3,4-dihydro-2H-1,4-oxazine (4ea). The general method A
described above was followed when (±)-1-((4-fluorophenyl)-
sulfonyl)-2-phenylaziridine 1e (109 mg, 0.393 mmol, 1.0
equiv) was treated with propargyl alcohol 2a (47 μL, 0.786
mmol, 2.0 equiv) in the presence of Zn(OTf)2 (14 mg, 0.039
mmol, 10 mol %) in DCM (50 μL) at RT for 20 min. After
completion, the crude was treated with Bu4N+OTf− (154 mg,
0.393 mmol, 1.0 equiv) as an additive, in an Ar environment at
85 °C on an oil bath for 6 h to obtain (±)-4ea as a gummy
liquid in 52% (68 mg, 0.204 mmol) yield; Rf 0.86 (in 20%
ethyl acetate in petroleum ether); IR υmax (KBr, cm−1) 2922,
2851, 1732, 1659, 1590, 1493, 1453, 1356, 1292, 1208, 1168,
1086, 836; 1H NMR (400 MHz, CDCl3) δ 7.86−7.83 (m,
2H), 7.34−7.25 (m, 5H), 7.09−7.07 (m, 2H), 6.19 (s, 1H),
4.10 (dd, 1H, J = 14.6, 2.4 Hz), 3.85 (dd, 1H, J = 10.4, 2.4
Hz), 3.01(dd, 1H, J = 14.6, 10.4 Hz), 2.08 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 165.4 (d, J = 255.9 Hz), 136.9,
134.3 (d, J = 2.9 Hz), 133.1, 130.3 (d, J = 8.6 Hz), 128.8,
125.9, 116.9, 116.7, 111.8, 73.2, 50.7, 18.2; HRMS (ESI-TOF)
4511
pubs.acs.org/joc Article
m/z: [M + H]+ calcd for C17H17FNO3S 334.0908; found
334.0910.
(±)-5-Methyl-4-((4-nitrophenyl)sulfonyl)-2-phenyl-
3,4-dihydro-2H-1,4-oxazine (4fa). The general method A
described above was followed when (±)-1-((4-nitrophenyl)-
sulfonyl)-2-phenylaziridine 1f (100 mg, 0.329 mmol, 1.0
equiv) was treated with propargyl alcohol 2a (40 μL, 0.658
mmol, 2.0 equiv) in the presence of Zn(OTf)2 (12 mg, 0.033
mmol, 10 mol %) in DCM (50 μL) at RT for 18 min. After
completion, the crude was treated with Bu4N+OTf− (129 mg,
0.329 mmol, 1.0 equiv) as an additive, in an Ar environment at
85 °C on an oil bath for 48 h to obtain (±)-4fa as a yellow
semi solid in 37% (44 mg, 0.122 mmol) yield; Rf 0.32 (in 10%
ethyl acetate in petroleum ether); IR υmax (KBr, cm−1) 3071,
3032, 2925, 2851, 1661, 1494, 1454, 1404, 1358, 1209, 1170,
1087, 837; 1H NMR (400 MHz, CDCl3) δ 8.44−8.41 (m,
2H), 7.98−8.01 (m, 2H), 7.37−7.31 (m, 3H), 7.10−7.08 (m,
2H), 6.20 (d, 1H, J = 1.2 Hz), 4.17 (dd, 1H, J = 14.5, 2.4 Hz),
3.97 (dd, 1H, J = 9.8, 2.4 Hz), 3.10 (dd, 1H, J = 14.5, 9.8 Hz),
2.08 (d, 3H, J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ
150.3, 144.1, 136.5, 133.4, 128.9, 128.8, 128.7, 125.8, 124.7,
111.3, 73.7, 50.7, 18.0; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C17H17N2O5S 361.0853; found 361.0852.
(±)-5-Methyl-4-(methylsulfonyl)-2-phenyl-3,4-dihy-
dro-2H-1,4-oxazine (4ga). The general method A described
above was followed when (±)-1-(methylsulfonyl)-2-phenyl-
aziridine 1g (100 mg, 0.506 mmol, 1.0 equiv) was treated with
propargyl alcohol 2a (61 μL, 1.012 mmol, 2.0 equiv) in the
presence of Zn(OTf)2 (18 mg, 0.051 mmol, 10 mol %) in
DCM (50 μL) at RT for 12 h. After completion, the crude was
treated with Bu4N+OTf− (198 mg, 0.506 mmol, 1.0 equiv) as
an additive, in an Ar environment at 85 °C on an oil bath for
3.5 h to obtain (±)-4ga as a gummy liquid in 60% (76 mg,
0.304 mmol) yield; Rf 0.39 (in 20% ethyl acetate in petroleum
ether); IR υmax (KBr, cm−1) 3312, 3064, 3030, 2956, 2926,
2854, 1667, 1497, 1454, 1343, 1158, 1087, 832; 1H NMR (400
MHz, CDCl3) δ 7.40−7.31 (m, 5H), 6.22 (s, 1H), 4.84 (dd,
1H, J = 9.2, 2.4 Hz), 4.16 (dd, 1H, J = 14.0, 2.4 Hz), 3.18 (dd,
1H, J = 14.6, 9.2 Hz), 2.89 (s, 3H), 1.99 (d, 3H, J = 1.2 Hz);
13
C{1H} NMR (100 MHz, CDCl3) δ 137.2, 131.6, 128.8,
128.7, 126.1, 112.0, 75.0, 50.3, 40.4, 17.4; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C12H16NO3S 254.0846; found
254.0844.
(±)-5-Methyl-2-(p-tolyl)-4-tosyl-3,4-dihydro-2H-1,4-
oxazine (4ha). The general method A described above was
followed when (±)-2-(p-tolyl)-1-tosylaziridine 1h (100 mg,
0.348 mmol, 1.0 equiv) was treated with propargyl alcohol 2a
(42 μL, 0.696 mmol, 2.0 equiv) in the presence of Zn(OTf)2
(13 mg, 0.035 mmol, 10 mol %) in DCM (50 μL) at RT for 15
min. After completion, the crude was treated with Bu4N+OTf−
(136 mg, 0.348 mmol, 1.0 equiv) as an additive, in an Ar
environment at 85 °C on an oil bath for 3 h to obtain (±)-4ha
as a gummy liquid in 52% (62 mg, 0.181 mmol) yield; Rf 0.43
(in 10% ethyl acetate in petroleum ether); IR υmax (KBr, cm−1)
2923, 2852, 1659, 1597, 1516, 1494, 1355, 1305, 1206, 1168,
1088, 813; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 2H, J = 7.9
Hz), 7.38 (d, 2H, J = 8.5 Hz), 7.12 (d, 2H, J = 7.9 Hz), 6.95
(d, 2H, J = 7.9 Hz), 6.15 (s, 1H), 4.08 (dd, 1H, J = 14.6, 2.4
Hz), 3.73 (d, 1H, J = 9.7 Hz), 2.96 (dd, 1H, J = 14.6, 9.8 Hz),
2.45 (s, 3H), 2.32 (s, 3H), 2.09 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 144.2, 138.5, 135.0, 134.2, 132.8, 130.1, 129.4,
127.6, 125.8, 112.0, 72.8, 50.8, 21.7, 21.2, 18.3; HRMS (ESI-
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
TOF) m/z: [M + Na]+ calcd for C19H21NNaO3S 366.1135;
found 366.1140.
(±)-2-(4-(tert-Butyl)phenyl)-5-methyl-4-tosyl-3,4-di-
hydro-2H-1,4-oxazine (4ia). The general method A
described above was followed when (±)-2-(p-tolyl)-1-
tosylaziridine 1i (100 mg, 0.303 mmol, 1.0 equiv) was treated
with propargyl alcohol 2a (37 μL, 0.607 mmol, 2.0 equiv) in
the presence of Zn(OTf)2 (11 mg, 0.030 mmol, 10 mol %) in
DCM (50 μL) at RT for 20 min. After completion, the crude
was treated with Bu4N+OTf− (119 mg, 0.303 mmol, 1.0 equiv)
as an additive, in an Ar environment at 85 °C on an oil bath for
5.5 h to obtain (±)-4ia as a gummy liquid in 54% (63 mg,
0.164 mmol) yield; Rf 0.36 (in 10% ethyl acetate in petroleum
ether); IR υmax (KBr, cm−1) 2962, 2927, 2868, 1659, 1597,
1515, 1493, 1461, 1355, 1214, 1167, 1088, 814; 1H NMR (400
MHz, CDCl3) δ 7.70 (d, 2H, J = 7.9 Hz), 7.36 (dd, 4H, J =
15.3, 7.9 Hz), 7.00 (d, 2H, J = 7.9 Hz), 6.15 (s, 1H), 4.10 (dd,
1H, J = 14.6, 1.8 Hz), 3.72 (d, 1H, J = 8.5 Hz), 2.98 (dd, 1H, J
= 14.6, 9.8 Hz), 2.45 (s, 3H), 2.09 (s, 3H), 1.28 (s, 9H);
13
C{1H} NMR (100 MHz, CDCl3) δ 151.7, 144.2, 135.0,
134.2, 132.9, 130.0, 127.7, 125.6, 112.0, 72.7, 50.7, 34.7, 31.3,
21.7, 18.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C22H28NO3S 386.1785; found 386.1793.
(±)-2-(2-Bromophenyl)-5-methyl-4-tosyl-3,4-dihy-
dro-2H-1,4-oxazine (4ja). The general method A described
above was followed when (±)-2-(2-bromophenyl)-1-tosylazir-
idine 1j (100 mg, 0.285 mmol, 1.0 equiv) was treated with
propargyl alcohol 2a (34 μL, 0.570 mmol, 2.0 equiv) in the
presence of Zn(OTf)2 (10 mg, 0.028 mmol, 10 mol %) in
DCM (50 μL) at RT for 1 h. After completion, the crude was
treated with Bu4N+OTf− (112 mg, 0.285 mmol, 1.0 equiv) as
an additive in an Ar environment at 85 °C on an oil bath for 8
h to obtain (±)-4ja as a solid: mp 94−96 °C in 65% (76 mg,
0.184 mmol) yield; Rf 0.27 (in 10% ethyl acetate in petroleum
ether); IR υmax (KBr, cm−1) 3061, 2921, 2850, 1666, 1597,
1568, 1494, 1437, 1350, 1265, 1162, 1091, 814, 690; 1H NMR
(400 MHz, CDCl3) δ 7.78 (d, 2H, J = 8.5 Hz), 7.49 (d, 1H, J =
7.9 Hz), 7.33−7.27 (m, 4H), 7.17−7.13 (m, 1H), 6.18 (d, 1H,
J = 1.2 Hz), 4.53 (dd, 1H, J = 9.8, 2.4 Hz), 4.38 (dd, 1H, J =
14.6, 2.4 Hz), 2.86 (dd, 1H, J = 14.0, 9.8 Hz), 2.42 (s, 3H),
2.10 (d, 3H, J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ
144.0, 136.6, 135.8, 132.9, 132.2, 130.0, 129.0, 128.0, 127.9,
127.8, 121.6, 112.2, 72.6, 48.9, 21.7, 18.2; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H19BrNO3S 408.0264; found
408.0274.
(±)-2-(3-Bromophenyl)-5-methyl-4-tosyl-3,4-dihy-
dro-2H-1,4-oxazine (4ka). The general method A described
above was followed when (±)-2-(3-bromophenyl)-1-tosylazir-
idine 1k (100 mg, 0.285 mmol, 1.0 equiv) was treated with
propargyl alcohol 2a (34 μL ml, 0.570 mmol, 2.0 equiv) in the
presence of Zn(OTf)2 (10 mg, 0.028 mmol, 10 mol %) in
DCM (50 μL) at RT for 35 min. After completion, the crude
was treated with Bu4N+OTf− (112 mg, 0.285 mmol, 1.0 equiv)
as an additive in an Ar environment at 85 °C on an oil bath for
5 h to obtain (±)-4ka as a semi-solid 60% (70 mg, 0.170
mmol) yield; Rf 0.25 (in 10% ethyl acetate in petroleum
ether); IR υmax (KBr, cm−1) 2923, 2853, 1732, 1660, 1596,
1569, 1493, 1461, 1354, 1167, 1088, 813, 696; 1H NMR (400
MHz, CDCl3) δ 7.70 (d, 2H), 7.43−7.38 (m, 3H), 7.19 (t, 1H,
J = 7.8 Hz), 7.00 (d, 1H, J = 7.8 Hz), 6.15 (s, 1H), 4.09 (dd,
1H, J = 14.2, 2.3 Hz), 3.77 (dd, 1H, J = 10.0, 2.3 Hz), 2.93
(dd, 1H, J = 14.6, 10.1 Hz), 2.45 (s, 3H), 2.08 (s, 3H);
13
C{1H} NMR (100 MHz, CDCl3) δ 144.4, 139.5, 135.0,
4512
pubs.acs.org/joc Article
132.4, 131.7, 130.3, 130.1, 129.0, 127.6, 124.5, 122.9, 112.4,
72.2, 50.7, 21.7, 18.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C18H19BrNO3S 408.0264; found 408.0267.
(±)-2-(4-Bromophenyl)-5-methyl-4-tosyl-3,4-dihy-
dro-2H-1,4-oxazine (4la). The general method A described
above was followed when (±)-2-(4-bromophenyl)-1-tosylazir-
idine 1l (100 mg, 0.285 mmol, 1.0 equiv) was treated with
propargyl alcohol 2a (34 μL, 0.570 mmol, 2.0 equiv) in the
presence of Zn(OTf)2 (10 mg, 0.028 mmol, 10 mol %) in
DCM (50 μL) at RT for 25 min. After completion, the crude
was treated with Bu4N+OTf− (56 mg, 0.285 mmol, 1.0 equiv)
as an additive in an Ar environment at 85 °C on an oil bath for
5 h to obtain (±)-4la as a white solid: mp 58−60 °C in 75%
(86 mg, 0.212 mmol) yield; Rf 0.24 (in 10% ethyl acetate in
petroleum ether); IR υmax (KBr, cm−1) 2965, 2926, 2852,
1660, 1596, 1490, 1443, 1354, 1208, 1167, 1089, 815, 687; 1H
NMR (400 MHz, CDCl3) δ 7.69 (d, 2H, J = 7.9 Hz), 7.45 (d,
2H, J = 7.9 Hz), 7.38 (d, 2H, J = 7.3 Hz), 6.96 (d, 2H, J = 7.9
Hz), 6.14 (s, 1H), 4.07 (d, 1H, J = 14.6 Hz), 3.77 (d, 1H, J =
9.8 Hz), 2.92 (dd, 1H, J = 14.6, 9.8 Hz), 2.45 (s, 3H), 2.08 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3) δ 144.4, 136.3, 135.1,
132.4, 131.9, 130.1, 127.6, 127.5, 122.6, 112.4, 72.4, 50.6, 21.7,
18.2; HRMS (ESI-TOF) m/z: [M + H] + calcd for
C18H19BrNO3S 408.0264; found 408.0268.
(±)-2-(2-Chlorophenyl)-5-methyl-4-tosyl-3,4-dihy-
dro-2H-1,4-oxazine (4ma). The general method A described
above was followed when (±)-2-(2-chlorophenyl)-1-tosylazir-
idine 1m (100 mg, 0.326 mmol, 1.0 equiv) was treated with
propargyl alcohol 2a (39 μL, 0.651 mmol, 2.0 equiv) in the
presence of Zn(OTf)2 (12 mg, 0.033 mmol, 10 mol %) in
DCM (50 μL) at RT for 50 min. After completion, the crude
was treated with Bu4N+OTf− (128 mg, 0.326 mmol, 1.0 equiv)
as an additive in an Ar environment at 85 °C on an oil bath for
6.5 h to obtain (±)-4ma as a solid: mp 100−102 °C in 84%
(99 mg, 0.274 mmol) yield; Rf 0.38 (in 10% ethyl acetate in
petroleum ether); IR υmax (KBr, cm−1) 2924, 2853, 1732,
1665, 1597, 1494, 1443, 1352, 1166, 1089, 812, 579; 1H NMR
(400 MHz, CDCl3) δ 7.75 (d, 2H, J = 8.5 Hz), 7.33 (d, 2H, J =
8.5 Hz), 7.30−7.20 (m, 4H), 6.18 (s, 1H), 4.46 (dd, 1H, J =
9.8, 2.4 Hz), 4.36 (dd, 1H, J = 14.6, 2.4 Hz), 2.86 (dd, 1H, J =
14.0, 9.8 Hz), 2.42 (s, 1H), 2.11 (d, 1H, J = 1.2 Hz); 13C{1H}
NMR (100 MHz, CDCl3) δ 144.0, 135.5, 135.0, 132.3, 131.8,
129.9, 129.6, 127.8, 127.7, 127.4, 112.2, 70.2, 48.9, 21.7, 18.3;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H19ClNO3S
364.0769; found 364.0785.
(±)-2-(4-Chlorophenyl)-5-methyl-4-tosyl-3,4-dihy-
dro-2H-1,4-oxazine (4na). The general method A described
above was followed when (±)-2-(4-chlorophenyl)-1-tosylazir-
idine 1n (100 mg, 0.326 mmol, 1.0 equiv) was treated with
propargyl alcohol 2a (39 μL, 0.651 mmol, 2.0 equiv) in the
presence of Zn(OTf)2 (12 mg, 0.033 mmol, 10 mol %) in
DCM (48 μL) at RT for 20 min. After completion, the crude
was treated with Bu4N+OTf− (76 mg, 0.326 mmol, 1.0 equiv)
as an additive in an Ar environment at 85 °C on an oil bath for
5 h to obtain (±)-4na as a solid: mp 98−100 °C in 72% (85
mg, 0.234 mmol) yield; Rf 0.52 (in 10% ethyl acetate in
petroleum ether); IR υmax (KBr, cm−1) 2923, 2852, 1657,
1597, 1492, 1456, 1353, 1260, 1166, 1087, 813, 578; 1H NMR
(400 MHz, CDCl3) δ 7.70 (d, 2H, J = 7.9 Hz), 7.38 (d, 2H, J =
7.9 Hz), 7.30−7.28 (m, 2H), 7.01 (d, 2H, J = 8.5 Hz), 6.14 (s,
1H), 4.07 (dd, 1H, J = 14.0, 1.8 Hz), 3.78 (dd, 1H, J = 9.8, 2.4
Hz), 2.93 (dd, 1H, J = 14.0, 9.8 Hz), 2.45 (s, 3H), 2.08 (d, 3H,
J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 144.4, 135.7,
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
135.0, 134.4, 132.5, 130.1, 128.9, 127.6, 127.2, 112.3, 72.3,
50.7, 21.7, 18.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H19ClNO3S 364.0769; found 364.0759.
(±)-2-(4-Fluorophenyl)-5-methyl-4-tosyl-3,4-dihydro-
2H-1,4-oxazine (4oa). The general method A described
above was followed when (±)-2-(4-fluorophenyl)-1-tosylazir-
idine 1o (100 mg, 0.343 mmol, 1.0 equiv) was treated with
propargyl alcohol 2a (42 μL, 686 mmol, 2.0 equiv) in the
presence of Zn(OTf)2 (12 mg, 0.034 mmol, 10 mol %) in
DCM (50 μL) at RT for 18 min. After completion, the crude
was treated with Bu4N+OTf− (134 mg, 0.343 mmol, 1.0 equiv)
as an additive in an Ar environment at 85 °C on an oil bath for
4 h to obtain (±)-4oa as a white fine crystalline solid: mp
130−132 °C in 69% (82 mg, 0.237 mmol) yield; Rf 0.37 (in
10% ethyl acetate in petroleum ether); IR υmax (KBr, cm−1)
2927, 2852, 1660, 1512, 1494, 1414, 1354, 1284, 1224, 1169,
814; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 2H, J = 7.9 Hz),
7.38 (d, 2H, J = 7.9 Hz), 7.06−6.98 (m, 4H), 6.14 (d, 1H, J =
1.2 Hz), 4.07 (dd, 1H, J = 14.6, 2.4 Hz), 3.78 (dd, 1H, J = 9.8,
2.4 Hz), 2.94 (dd, 1H, J = 14.6, 9.8 Hz), 2.45 (s, 3H), 2.08 (d,
3H, J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8
(d, J = 247.2 Hz), 144.3, 135.0, 133.0 (d, J = 3.8 Hz), 132.6,
130.1, 127.6 (d, J = 11.5 Hz), 115.8, 115.6, 112.2, 72.4, 50.8,
21.7, 18.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H19FNO3S 348.1064; found 348.1056.
(±)-5-Methyl-4-tosyl-2-(4-(trifluoromethyl)phenyl)-
3,4-dihydro-2H-1,4-oxazine (4pa). The general method A
described above was followed when (±)-1-tosyl-2-(4-
(trifluoromethyl)phenyl)aziridine 1p (100 mg, 0.293 mmol,
1.0 equiv) was treated with propargyl alcohol 2a (35 μL, 0.586
mmol, 2.0 equiv) in the presence of Zn(OTf)2 (11 mg, 0.029
mmol, 10 mol %) in DCM (50 μL) at RT for 10 h. After
completion, the crude was treated with Bu4N+OTf− (115 mg,
0.293 mmol, 1.0 equiv) as an additive in an Ar environment at
85 °C on an oil bath for 3 h to obtain (±)-4pa as a white solid:
mp 120−122 °C in 57% (66 mg, 0.167 mmol) yield; Rf 0.46
(in 10% ethyl acetate in petroleum ether); IR υmax (KBr, cm−1)
2930, 1661, 1598, 1420, 1355, 1325, 1167, 1089, 814; 1H
NMR (400 MHz, CDCl3) δ 7.71 (d, 2H, J = 7.9 Hz), 7.59 (d,
2H, J = 7.9 Hz), 7.39 (d, 2H, J = 7.9 Hz), 7.22 (d, 2H, J = 7.9
Hz), 6.17 (d, 1H, J = 1.2 Hz), 4.11 (dd, 1H, J = 14.6, 2.4 Hz),
3.87 (dd, 1H, J = 10.4, 1.8 Hz), 2.94 (dd, 1H, J = 14.6, 10.3
Hz), 2.45 (s, 3H), 2.10 (d, 3H, J = 1.2 Hz); 13C{1H} NMR
(100 MHz, CDCl3) δ 144.5, 141.5, 141.1, 135.0, 132.3, 130.8
(d, J = 32.6 Hz), 127.6, 130.2, 125.7 (d, J = 3.8 Hz), 124.0 (d, J
= 272 Hz), 112.5, 72.4, 50.6, 21.7, 18.2; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C19H19F3NO3S 398.1033; found
398.1016.
3,5-Dimethyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-
oxazine (4qa) and 2,5-Dimethyl-3-phenyl-4-tosyl-3,4-
dihydro-2H-1,4-oxazine (4q′a). The general method A
described above was followed when 2-methyl-3-phenyl-1-
tosylaziridine 1q (100 mg, 0.348 mmol, 1.0 equiv) was treated
with propargyl alcohol 2a (42 μL, 0.697 mmol, 2.0 equiv) in
the presence of Zn(OTf)2 (13 mg, 0.035 mmol, 10 mol %) in
DCM (50 μL) at RT for 2 h. After completion, the crude was
treated with Bu4N+OTf− (136 mg, 0.348 mmol, 1.0 equiv) as
an additive in an Ar environment at 85 °C on an oil bath for 16
h to obtain 4qa (white crystalline solid) and 4q′a (white
crystalline solid) as pure solid compounds: mp 68−70 °C and
95−97 °C in 61% overall yield (73 mg, 0.212 mmol, 5:2 in
diastereomeric ratio) yield; Rf 0.29 and 0.17, respectively (in
10% diethyl ether in petroleum ether); (4qa, cis) IR υmax (KBr,
4513
pubs.acs.org/joc Article
cm−1) 3064, 3030, 2983, 2930, 1736, 1661, 1597, 1495, 1451,
1352, 1240, 1169, 1087, 814; 1H NMR (500 MHz, CDCl3) δ
7.74 (d, 2H, J = 8.0 Hz), 7.38 (d, 2H, J = 8.0 Hz), 7.32−7.29
(m, 2H), 7.25−7.23 (m, 1H), 7.08 (d, 2H, J = 7.4 Hz), 6.12
(d, 1H, J = 1.2 Hz), 4.24−4.19 (m, 1H), 3.81 (d, 1H, J = 2.3
Hz), 2.41 (s, 3H), 2.11 (d, 3H, J = 1.2 Hz), 0.84 (d, 3H, J =
6.9 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ 144.0, 137.3,
134.8, 131.3, 129.9, 128.3, 127.7, 127.4, 125.3, 109.8, 74.6,
53.3, 21.5, 18.6, 10.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C19H22NO3S 344.1315; found 344.1316.
(4q′a, trans) IR υmax (KBr, cm−1) 2955, 2926, 2869, 1671,
1494, 1458, 1346, 1209, 1166, 1086, 813; 1H NMR (500
MHz, CDCl3) δ 7.19−7.18 (m, 3H), 7.15−7.13 (m, 2H), 7.06
(d, 2H, J = 8.6 Hz), 6.92 (d, 2H, J = 8.0 Hz), 5.91 (d, 1H, J =
1.1 Hz), 5.01 (d, 1H, J = 1.7 Hz), 4.74−4.70 (m,1H), 2.26 (s,
3H), 1.73 (d, 3H, J = 1.1 Hz), 1.40 (d, 3H, J = 6.9 Hz);
13
C{1H} NMR (125 MHz, CDCl3) δ 142.7, 139.1, 138.6,
129.4, 128.4, 127.4, 126.8, 126.6, 125.3, 111.6, 79.2, 53.6, 21.4,
18.3, 17.1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C19H21NO3SNa 366.1135; found 366.1134.
3-Ethyl-5-methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-
1,4-oxazine (4ra) and 2-Ethyl-5-methyl-3-phenyl-4-
tosyl-3,4-dihydro-2H-1,4-oxazine (4r′a). The general
method A described above was followed when 2-ethyl-3-
phenyl-1-tosylaziridine 1r (100 mg, 0.332 mmol, 1.0 equiv)
was treated with propargyl alcohol 2a (40 μL, 0.664 mmol, 2.0
equiv) in the presence of Zn(OTf)2 (12 mg, 0.033 mmol, 10
mol %) in DCM (50 μL) at RT for 6 h. After completion, the
crude was treated with Bu4N+OTf− (130 mg, 0.332 mmol, 1.0
equiv) as an additive in an Ar environment at 85 °C on an oil
bath for 16 h to obtain (±)-4ra as gummy liquid and (±)-4r′a
as white crystalline solid: (mp 65−67 °C of 4r′a) in 58%
overall yield (69 mg, 0.192 mmol, 2:1 in diastereomeric ratio);
Rf 0.26 and 0.09, respectively, (in 10% diethyl ether in
petroleum ether); (4ra, cis) IR υmax (KBr, cm−1) 3065, 3030,
2969, 2931, 2876, 1661, 1597, 1496, 1452, 1352, 1261, 1208,
1089, 814; 1H NMR (500 MHz, CDCl3) δ 7.75 (d, 2H, J = 8.0
Hz), 7.38 (d, 2H, J = 8.0 Hz), 7.31 (t, 2H, J = 7.4 Hz), 7.26−
7.23 (m, 1H), 7.09 (d, 2H, J = 7.4 Hz), 6.12 (s, 1H), 3.99−
3.96 (m, 1H), 3.85 (d, 1H, J = 2.3 Hz), 2.42 (s, 3H), 2.13 (d,
3H, J = 1.5 Hz), 1.30−1.22 (m, 1H), 1.02−0.97 (m, 1H), 0.86
(t, 3H, J = 6.9 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ
144.0, 137.3, 134.8, 131.9, 129.9, 128.3, 127.6, 127.5, 125.3,
109.6, 74.7, 59.2, 21.6, 18.6, 16.4, 10.6; HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C20H23NO3SNa 380.1291; found
380.1289.
(4r′a, trans) IR υmax (KBr, cm−1) 3064, 3030, 2968, 2931,
2877, 1672, 1598, 1495, 1450, 1347, 1206, 1166, 1090, 814;
1
H NMR (500 MHz, CDCl3) δ 7.25−7.20 (m, 3H), 7.18−7.17
(m, 2H), 6.99 (d, 2H, J = 8.6 Hz), 6.93 (d, 2H, J = 8.6 Hz),
5.97 (d, 1H, J = 1.2 Hz), 5.23 (s, 1H), 4.61−4.58 (m, 1H),
2.31 (s, 3H), 1.87−1.74 (m, 6H), 1.13 (t, 3H, J = 8.3 Hz);
13
C{1H} NMR (125 MHz, CDCl3) δ 142.5, 139.3, 138.3,
129.3, 128.4, 127.3, 127.0, 126.9, 125.2, 111.3, 77.2, 59.6, 24.8,
21.4, 17.4, 11.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H24NO3S 358.1472, found 358.1480.
5-Methyl-2-phenyl-3-propyl-4-tosyl-3,4-dihydro-2H-
1,4-oxazine (4sa) and 5-Methyl-3-phenyl-2-propyl-4-
tosyl-3,4-dihydro-2H-1,4-oxazine (4s′a). The general
method A described above was followed when 2-phenyl-3-
propyl-1-tosylaziridine 1s (100 mg, 0.317 mmol, 1.0 equiv)
was treated with propargyl alcohol 2a (38 μL, 0.635 mmol, 2.0
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
equiv) in the presence of Zn(OTf)2 (12 mg, 0.032 mmol, 10
mol %) in DCM (50 μL) at RT for 8 h. After completion, the
crude was treated with Bu4N+OTf− (124 mg, 0.317 mmol, 1.0
equiv) as an additive in an Ar environment at 85 °C on an oil
bath for 42 h to obtain (±)-4sa as semi-solid and (±)-4s′a as
white solid: (mp 94−96 °C of 4s′a) in 48% overall yield (56
mg, 0.152 mmol, 16:9 in diastereomeric ratio); Rf 0.27 and
0.10, respectively (in 10% diethyl ether in petroleum ether);
(4sa, cis) IR υmax (KBr, cm−1) 3064, 3029, 2960, 2930, 2872,
1660, 1597, 1495, 1451, 1353, 1204, 1168, 1089, 814; 1H
NMR (400 MHz, CDCl3) δ 7.74 (d, 2H, J = 8.5 Hz), 7.37 (d,
2H, J = 7.9 Hz), 7.33−7.29 (m, 2H), 7.26−7.22 (m, 1H), 7.08
(d, 2H, J = 7.3 Hz), 6.13 (d, 1H, J = 1.2 Hz), 4.08−4.04 (m,
1H), 3.82 (d, 1H, J = 2.4 Hz), 2.41 (s, 3H), 2.12 (d, 3H, J =
1.2 Hz), 1.47−1.40 (m, 1H), 1.30−1.20 (m, 2H), 0.89−0.82
(m, 1H), 0.78 (t, 3H, J = 7.3 Hz); 13C{1H} NMR (125 MHz,
CDCl3) δ 144.0, 137.3, 134.8, 132.0, 129.9, 128.3, 127.6,
127.5, 125.2, 109.6, 74.6, 57.6, 25.4, 21.6, 19.1, 18.6, 13.7;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H25NO3SNa
394.1448; found 394.1446.
(4s′a, trans) IR υmax (KBr, cm−1) 2958, 2928, 2872, 1672,
1598, 1495, 1450, 1378, 1203, 1165, 813; 1H NMR (500
MHz, CDCl3) δ 7.25−7.20 (m, 3H), 7.18−7.17 (m, 2H), 6.99
(d, 2H, J = 8.0 Hz), 6.93 (d, 2H, J = 8.6 Hz), 5.97 (s, 1H),
5.21 (s, 1H), 4.69−4.66 (m, 1H), 2.32 (s, 3H), 1.83 (s, 3H),
1.80−1.76 (m, 1H), 1.73−1.68 (m, 1H), 1.61−1.56 (m, 2H),
1.04 (t, 3H, J = 7.4 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ
142.5, 139.3, 138.3, 129.3, 128.4, 127.3, 127.0, 126.9, 125.2,
111.3, 77.4, 58.0, 34.0, 21.4, 19.8, 17.4, 14.0; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C21H26NO3S 372.1628; found
372.1635.
(±)-3,5-Dimethyl-4-tosyl-3,4-dihydro-2H-1,4-oxazine
(4ta). The general method A described above was followed
when (±)-2-methyl-1-tosylaziridine 1t (100 mg, 0.473 mmol,
1.0 equiv) was treated with propargyl alcohol 2a (57 μL, 0.947
mmol, 2.0 equiv) in the presence of Zn(OTf)2 (17 mg, 0.047
mmol, 10 mol %) in THF (50 μL) at 50 °C for 12 h. After
completion, the crude was treated with Bu4N+OTf− (185 mg,
0.473 mmol, 1.0 equiv) as an additive in an Ar environment at
85 °C on an oil bath for 5 h to obtain (±)-4ta as a sticky liquid
in 50% (63 mg, 0.236 mmol) yield; Rf 0.76 (in 10% ethyl
acetate in petroleum ether). IR υmax (KBr, cm−1) 2964, 2926,
2853, 1659, 1598, 1494, 1449, 1350, 1211, 1167, 1088, 813;
1
H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H, J = 8.5 Hz), 7.30
(d, 2H, J = 8.5 Hz), 5.92 (s, 1H), 3.96 (dd, 1H, J = 14.0, 2.4
Hz), 3.03−3.11 (m, 1H), 2.81 (dd, 1H, J = 14.0, 9.8 Hz), 2.42
(s, 3H), 1.99 (d, 3H, J = 1.2 Hz), 1.06 (d, 3H, J = 6.7 Hz);
13
C{1H} NMR (125 MHz, CDCl3) δ 143, 135.5, 132.0, 129.8,
127.2, 111.4, 67.6, 50.1, 21.6, 17.9, 17.8; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C13H18NO3S 268.1002; found
268.1007.
(±)-3-Isopropyl-5-methyl-4-tosyl-3,4-dihydro-2H-1,4-
oxazine (4ua). The general method A described above was
followed when (±)-2-isopropyl-1-tosylaziridine 1u (100 mg,
0.418 mmol, 1.0 equiv) was treated with propargyl alcohol 2a
(51 μL, 0.836 mmol, 2.0 equiv) in the presence of Zn(OTf)2
(15 mg, 0.042 mmol, 10 mol %) in THF (50 μL) at 50 °C for
2 h. After completion, the crude was treated with Bu4N+OTf−
(164 mg, 0.418 mmol, 1.0 equiv) as an additive in an Ar
environment at 85 °C on an oil bath for 4 h to obtain (±)-4ua
as a sticky liquid in 38% (47 mg, 0.159 mmol) yield; Rf 0.76
(in 10% ethyl acetate in petroleum ether). IR υmax (KBr, cm−1)
2961, 2925, 1658, 1599, 1495, 1463, 1328, 1235, 1160, 1093,
4514
pubs.acs.org/joc Article
815; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, 2H, J = 8.6 Hz),
7.25 (d, 2H, J = 8.0 Hz), 5.89 (d, 1H, J = 1.2 Hz), 3.96 (dd,
1H, J = 14.3, 2.3 Hz), 2.78 (dd, 1H, J = 14.3, 9.7 Hz), 2.49−
2.46 (m, 1H), 2.7 (s, 3H), 1.95 (d, 3H, J = 1.2 Hz), 1.52−1.59
(m, 1H), 0.74 (dd, 6H, J = 6.9, 2.3 Hz); 13C{1H} NMR (125
MHz, CDCl3) δ 143.8, 135.1, 132.3, 129.8, 127.4, 111.5, 75.6,
46.7, 30.1, 21.5, 18.1, 17.80, 17.77; HRMS (ESI-TOF) m/z:
[M − H]+ calcd for C15H20NO3S 294.1159; found 294.1160.
(±)-5-Methyl-2-(naphthalen-2-yl)-4-tosyl-3,4-dihy-
dro-2H-1,4-oxazine (4va). The general method A described
above was followed when (±)-2-(naphthalen-2-yl)-1-tosylazir-
idine 1v (100 mg, 0.305 mmol, 1.0 equiv) was treated with
propargyl alcohol 2a (37 μL, 0.610 mmol, 2.0 equiv) in the
presence of Zn(OTf)2 (11 mg, 0.030 mmol, 10 mol %) in THF
(50 μL) at 50 °C on an oil bath for 5 h. After completion, the
crude was treated with Bu4N+OTf− (119 mg, 0.305 mmol, 1.0
equiv) as an additive in an Ar environment at 85 °C on an oil
bath for 6 h to obtain (±)-4va as a solid: mp 112−114 °C in
40% (46 mg, 0.122 mmol) yield; Rf 0.40 (in 10% ethyl acetate
in petroleum ether); IR υmax (KBr, cm−1) 2924, 2852, 1659,
1597, 1493, 1443, 1352, 1262, 1166, 1088, 815; 1H NMR (400
MHz, CDCl3) δ 7.82−7.80 (m, 3H), 7.75 (d, 2H, J = 7.9 Hz),
7.57 (s, 1H), 7.49−7.47 (m, 2H), 7.41 (d, 2H, J = 7.9 Hz),
7.17 (d, 1H, J = 7.9 Hz), 6.22 (s, 1H), 4.2 (dd, 1H, J = 14.6,
2.4 Hz), 3.99 (d, 1H, J = 9.7 Hz), 3.06 (dd, 1H, J = 14.0, 9.8
Hz), 2.46 (s, 3H), 2.12 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 144.3, 135.1, 134.6, 133.3, 133.2, 132.8, 130.1,
128.6, 128.1, 127.8, 127.6, 126.6, 126.5, 125.1, 123.4, 112.2,
73.0, 50.8, 21.8, 18.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C22H22NO3S 380.1315; found 380.1329.
(±)-5,6-Dimethyl-2-phenyl-4-tosyl-3,4-dihydro-2H-
1,4-oxazine (4ab). The general method A described above
was followed when (±)-2-phenyl-1-tosylaziridine 1a (100 mg,
0.366 mmol, 1.0 equiv) was treated with propargyl alcohol
(±)-2b (58 μL, 0.732 mmol, 2.0 equiv) in the presence of
Zn(OTf)2 (13 mg, 10 mol %) in DCM (50 μL) at RT for 30
min. After completion, the crude was treated with Bu4N+OTf−
(143 mg, 0.366 mmol, 1.0 equiv) as an additive in an Ar
environment at 85 °C on an oil bath for 8 h to obtain (±)-4ab
as a gummy liquid in 46% (58 mg, 0.168 mmol) yield; Rf 0.40
(in 10% ethyl acetate in petroleum ether); IR υmax (KBr, cm−1)
2926, 2856, 1664, 1596, 1493, 1454, 1351, 1209, 1166, 1088,
814; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, 2H), 7.36 (d,
2H, J = 7.9 Hz), 3.34−7.27 (m, 3H), 7.10−7.08 (m, 2H), 4.06
(dd, 1H, J = 14.0, 3.0 Hz), 3.95 (dd, 1H, J = 10.3, 3.0 Hz),
2.88 (dd, 1H, J = 14.6, 10.3 Hz), 2.44 (s, 3H), 2.14 (s, 3H),
1.90 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 144.0,
140.4, 137.6, 135.5, 129.9, 128.6, 128.4, 127.6, 125.7, 105.8,
73.2, 50.6, 21.6, 17.7, 17.1; HRMS (ESI-TOF) m/z: [M +
H]+calcd for C19H22NO3S 344.1315; found 344.1317.
(±)-5-Methyl-2,6-diphenyl-4-tosyl-3,4-dihydro-2H-
1,4-oxazine (4ac). The general method A described above
was followed when (±)-2-phenyl-1-tosylaziridine 1a (100 mg,
0.366 mmol, 1.0 equiv) was treated with propargyl alcohol
(±)-2c (89 μL, 0.732 mmol, 2.0 equiv) in the presence of
Zn(OTf)2 (13 mg, 0.037 mmol, 10 mol %) in DCM (50 μL)
at RT for 45 min. After completion, the crude was treated with
Bu4N+OTf− (143 mg, 0.366 mmol, 1.0 equiv) as an additive in
an Ar environment at 85 °C on an oil bath for 10 h to (±)-4ac
as a white solid: mp 152−156 °C in 13% (19 mg, 0.048 mmol)
yield; Rf 0.40 (in 10% ethyl acetate in petroleum ether); IR
υmax (KBr, cm−1) 2923, 2853, 1640, 1597, 1493, 1455, 1358,
1227, 1165, 1088, 801; 1H NMR (500 MHz, CDCl3) δ 7.55
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
(d, 2H, J = 8.0 Hz), 7.39−7.21 (m, 12H), 4.37−4.31 (m, 2H),
3.07 (dd, 1H, J = 14.3, 10.3 Hz), 2.42 (s, 3H), 1.91 (s, 3H);
13
C{1H} NMR (125 MHz, CDCl3) δ 143.9, 143.2, 137.5,
137.0, 135.7, 130.0, 129.7, 128.8, 128.6, 127.9, 127.7, 127.0,
126.0, 112.3, 74.8, 50.7, 21.7, 18.0; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C24H24NO3S 406.1472; found 406.1468.
(S)-5-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-ox-
azine ((S)-4aa). The general method B described above was
followed when dry DCM (0.5 mL) solution of (R)-2-phenyl-
N-tosyl aziridine 1a (50 mg, 0.183 mmol, 1.0 equiv, >99% ee)
was treated with a reaction mixture of propargyl alcohol 2a
(0.1 mL), Zn(OTf)2 (3 mg, 0.009 mmol, 5 mol %), and
Bu4N+HSO4− (62 mg, 0.183 mmol, 1.0 equiv) at 0 °C for 20
min in a dropwise manner. After completion, the reaction was
quenched with NH4+Cl−, and after the workup, the crude was
purified by flash column chromatography to obtain (S)-3aa in
80% yield (48 mg, 0.146 mmol). Next, (S)-3aa (48 mg, 0.146
mmol, 1.0 equiv) was treated with Zn(OTf)2 (5 mg, 0.015
mmol, 10 mol %) as the catalyst and Bu4N+OTf− (57 mg,
0.146 mmol, 1.0 equiv) as an additive in an Ar environment at
85 °C on an oil bath for 4 h to obtain (S)-4aa as a white solid:
mp 116−118 °C in 81% (39 mg, 0.118 mmol) yield (65%
overall yield). [α]25D −242.96 (c 0.150 in C2H4Cl2) for a >
84% ee sample. Optical purity was determined by chiral HPLC
(AS-H, isopropanol/n-hexane = 1/99, flow rate = 1.0 mL/
min) tR = 28.88 min (major), 65.88 min (minor), Rf 0.60 (in
20% ethyl acetate in petroleum ether); IR υmax (KBr, cm−1)
3280, 2923, 2853, 2120, 1597, 1493, 1452, 1326, 1158, 1088,
814; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, 2H, J = 8.0 Hz),
7.40 (d, 2H, J = 8.0 Hz), 7.35−7.29 (m, 3H), 7.09−7.06 (m,
2H), 6.17 (s, 1H), 4.11 (dd, 1H, J = 14.3 Hz, 2.29 Hz), 3.77
(dd, 1H, J = 10.3, 2.29 Hz), 2.98 (dd, 1H, J = 14.3, 9.7 Hz),
2.46 (s, 3H), 2.10 (d, 3H, J = 0.8 Hz); 13C{1H} NMR (125
MHz, CDCl3) δ 144.2, 137.1, 134.8, 132.7, 130.0, 128.6, 128.5,
127.5, 125.8, 111.9, 72.7, 50.7, 21.6, 18.2; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H20NO3S 330.1159; found
330.1167.
(R)-2-(2-Chlorophenyl)-5-methyl-4-tosyl-3,4-dihydro-
2H-1,4-oxazine ((R)-4ma). The general method B described
above was followed when dry DCM (0.5 mL) solution of (S)-
2-(2-chlorophenyl)-1-tosylaziridine 1m (50 mg, 0.162 mmol,
1.0 equiv, >82% ee) was treated with a reaction mixture of
propargyl alcohol 2a (0.1 mL), Zn(OTf)2 (3 mg, 0.008 mmol,
5 mol %) and Bu4N+HSO4− (55 mg, 0.162 mmol, 1.0 equiv) at
0 °C for 60 min in a dropwise manner. After completion, the
reaction was quenched with NH4+Cl−, and after the workup,
the crude was purified by flash column chromatography to
furnish (R)-3ma in 97% yield (57 mg, 0.157 mmol). Next,
(R)-3ma (57 mg, 0.157 mmol, 1.0 equiv) was treated with
Zn(OTf)2 (6 mg, 0.016 mmol, 10 mol %) as the catalyst and
Bu4N+OTf− (61 mg, 0.157 mmol, 1.0 equiv) as an additive in
an Ar environment at 85 °C on an oil bath for 5 h to obtain
(R)-4ma as a white solid (mp 100−102 °C) in 80% yield (47
mg, 0.129 mmol). [α]25D −202.78 (c 0.360 in C2H4Cl2) for a >
77% ee sample. Optical purity was determined by chiral HPLC
(AS-H, isopropanol/n-hexane = 1/99, flow rate = 1.0 mL/min,
l = 254 nm) tR = 29.51 min (major), 65.94 min (minor), Rf
0.38 (in 10% ethyl acetate in petroleum ether); IR υmax (KBr,
cm−1) 2924, 2853, 1665, 1597, 1494, 1476, 1443, 1352, 1205,
1166, 1089, 812; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, 2H, J
= 8.5 Hz), 7.33 (d, 2H, J = 8.5 Hz), 7.30−7.20 (m, 4H), 6.18
(s, 1H), 4.46 (dd, 1H, J = 9.8, 2.4 Hz), 4.36 (dd, 1H, J = 14.6,
2.4 Hz), 2.86 (dd, 1H, J = 14.0, 9.8 Hz), 2.42 (s, 1H), 2.11 (d,
4515
pubs.acs.org/joc Article
1H, J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 144.0,
135.5, 135.0, 132.3, 131.8, 129.9, 129.6, 127.8, 127.7, 127.4,
112.2, 70.2, 48.9, 21.7, 18.3; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C18H19ClNO3S 364.0769; found 364.0785.
(S)-3,5-Dimethyl-4-tosyl-3,4-dihydro-2H-1,4-oxazine
((S)-4ta). The general method B described above was followed
when (S)-2-methyl-1-tosylaziridine 1t (50 mg, 0.237 mmol, 1.0
equiv, >99% ee) was treated with propargyl alcohol 2a (0.1
mL), Zn(OTf)2 (4 mg, 0.012 mmol, 5 mol %), and
Bu4N+HSO4− (80 mg, 0.237 mmol, 1.0 equiv) in dry THF
(0.5 mL) at 50 °C for 2 h. After completion, the reaction was
quenched with NH4+Cl−, and after the workup, the crude was
purified by flash column chromatography to obtain (S)-3ta in
48% yield (30 mg, 0.112 mmol). Next, (S)-3ta (30 mg, 0.112
mmol, 1.0 equiv) was treated with Zn(OTf)2 (4 mg, 0.012
mmol, 10 mol %) as the catalyst and Bu4N+OTf− (44 mg,
0.112 mmol, 1.0 equiv) as an additive in an Ar environment at
85 °C on an oil bath for 5 h to obtain (S)-4ta as a gummy
liquid in 74% (22 mg, 0.083 mmol) yield (35% overall yield).
[α]25D +150.0 (c 0.140 in C2H4Cl2) for a >98% ee sample. The
optical purity was determined by chiral HPLC (AS-H,
isopropanol/n-hexane = 1/99, flow rate = 1.0 mL/min, l =
254 nm) tR = 15.41 min (minor), 18.62 min (major); Rf 0.76
(in 10% ethyl acetate in petroleum ether). IR υmax (KBr, cm−1)
2964, 2926, 2853, 1659, 1598, 1494, 1449, 1350, 1211, 1167,
1088, 813; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H, J = 8.5
Hz), 7.30 (d, 2H, J = 8.5 Hz), 5.92 (s, 1H), 3.96 (dd, 1H, J =
14.0, 2.4 Hz), 3.11−3.03 (m, 1H), 2.81 (dd, 1H, J = 14.0, 9.8
Hz), 2.42 (s, 3H), 1.99 (d, 3H, J = 1.2 Hz), 1.06 (d, 3H, J =
6.7 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ 143, 135.5,
132.0, 129.8, 127.2, 111.4, 67.6, 50.1, 21.6, 17.9, 17.8; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C13H18NO3S 268.1002;
found 268.1007.
(S)-3-Isopropyl-5-methyl-4-tosyl-3,4-dihydro-2H-1,4-
oxazine ((S)-4ua). The general method B described above
was followed when (S)-2-isopropyl-1-tosylaziridine 1u (50 mg,
0.209 mmol, 1.0 equiv, >94% ee) was treated with propargyl
alcohol 2a (0.1 mL), Zn(OTf)2 (4 mg, 0.010 mmol, 5 mol %),
and Bu4N+HSO4− (71 mg, 0.209 mmol, 1.0 equiv) in dry THF
(0.5 mL) at 50 °C on an oil bath for 2 h. After completion, the
reaction was quenched with NH4+Cl− and purified by flash
column chromatography to obtain (S)-3ua in 51% yield (31
mg, 0.106 mmol). Next, (S)-3ua (31 mg, 0.106 mmol, 1.0
equiv) was treated with Zn(OTf)2 (4.0 mg, 0.011 mmol, 10
mol %) as the catalyst and Bu4N+OTf− (42 mg, 0.106 mmol,
1.0 equiv) as an additive in an Ar environment at 85 °C on an
oil bath for 4 h to obtain 4ua as a gummy liquid in 70% (22
mg, 0.074 mmol) yield (36% overall yield). [α]25D +61.429 (c
0.140 in C2H4Cl2) for a >92% ee sample. Optical purity was
determined by chiral HPLC analysis (AS-H, isopropanol/n-
hexane = 1/99, flow rate = 1.0 mL/min, l = 254 nm) tR = 09.91
min (major), 15.14 min (minor); Rf 0.76 (in 10% ethyl acetate
in petroleum ether). IR υmax (KBr, cm−1) 2961, 2925, 1658,
1599, 1495, 1463, 1328, 1235, 1160, 1093, 815; 1H NMR (500
MHz, CDCl3) δ 7.55 (d, 2H, J = 8.6 Hz), 7.25 (d, 2H, J = 8.0
Hz), 5.89 (d, 1H, J = 1.2 Hz), 3.96 (dd, 1H, J = 14.3, 2.3 Hz),
2.78 (dd, 1H, J = 14.3, 9.7 Hz), 2.49−2.46 (m, 1H), 2.7 (s,
3H), 1.95 (d, 3H, J = 1.2 Hz), 1.59−1.52 (m, 1H), 0.74 (dd,
6H, J = 6.9, 2.3 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ
143.8, 135.1, 132.3, 129.8, 127.4, 111.5, 75.6, 46.7, 30.1, 21.5,
18.1, 17.80, 17.77; HRMS (ESI-TOF) m/z: [M − H]+ calcd
for C15H20NO3S 294.1159; found 294.1160.
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
5-Methyl-2-phenylmorpholine (5b). (1) In a double-
neck RB, 4aa (100 mg, 0.304 mmol, 1.0 equiv) and Pd-C (10%
Pd) (32 mg, 0.030 mmol, 10 mol %) were introduced in an
inert environment and 5.0 mL of dry ethanol was added to it,
and the reaction mixture was stirred at RT. After 5 min, H2-gas
was purged with the help of a balloon and stirring was
continued at RT for 36 h. The reaction was monitored by
TLC. After completion, the reaction mixture product was
filtered out with the help of a celite pad. After the usual
workup, the crude concentrate was used for the next step. The
1 Manish Kumar − Department of Chemistry, Indian Institute of
H NMR of the crude reaction mixture indicated that the
product (Rf 0.33 in 5% ethyl acetate in petroleum ether) was a
mixture of diastereomers (dr 20:1).
(2) In a double-neck RB, Na (3.04 mmol, 10 equiv) was
taken in Ar environment and a solution of naphthalene (3.04
mmol, 10 equiv in 5 mL of THF) was added to it. The reaction
mixture was kept for stirring at room temperature. After 5 min,
the color of the reaction mixture started to change from
colorless to green color, indicating the beginning of the
generation of naphthyl radicals. After 1 h, the solution became
dark green and then the reaction mixture was transferred to
−78 °C; after 10 min a solution of the crude product
(obtained from the first step) in THF (5 mL) was added
dropwise and the reaction was monitored by TLC. The
reaction was completed in 1 h, quenched by a saturated
solution of NH4Cl, and left for stirring for 10 min at the same
temperature. After ethyl acetate and water workup, the
combined organic layer was washed with 50% NaOH solution
(10 mL) three times. The crude product was purified on
neutral alumina using 25% ethyl acetate in petroleum ether to
afford pure 5b as a single diastereomer as a light-yellow liquid
in 80% yield (43 mg, 0.243 mmol). IR υmax (KBr, cm−1) 3305,
2924, 2854, 1645, 1495, 1452, 1381, 1262, 1102; 1H NMR
(500 MHz, CDCl3) δ 7.40−7.34 (m, 4H), 7.30−7.27 (m, 1H),
4.51 (dd, 1H, J = 8.6, 2.9 Hz), 3.84 (dd, 1H, J = 10.9, 2.9 Hz),
3.70 (dd, 1H, J = 11.5, 2.9 Hz), 3.18 (dd, 1H, J = 12.6, 8.6
Hz), 3.08−3.04 (m, 1H), 2.93 (dd, 1H, J = 12.6, 2.9 Hz), 2.00
(bs, 1H), 1.30 (d, 3H, J = 6.9 Hz); 13C{1H} NMR (125 MHz,
CDCl3) δ 140.5, 128.5, 127.6, 126.3, 78.2, 71.4, 47.4, 46.9,
16.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H16NO
178.1227; found 178.1236.
■ ASSOCIATED CONTENT
Data Availability Statement
The data underlying this study are available in the published
article and its Supporting Information.
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.2c03093.
Copies of 1H and 13C{1H} NMR spectra of the
compounds, HPLC chromatograms for the enantiomeric
excess determination, and details of single-crystal X-ray
analysis of the compounds (PDF)
Accession Codes
CCDC 2113282 and 2202229−2202231 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
4516
pubs.acs.org/joc Article
■ AUTHOR INFORMATION
Corresponding Author
Manas K. Ghorai − Department of Chemistry, Indian Institute
of Technology, Kanpur 208016, India; orcid.org/0000-
0002-0472-4757; Phone: (+91)-512-2597518;
Email: mkghorai@iitk.ac.in; Fax: (+91)-512-2596806
Authors
Bharat Singh − Department of Chemistry, Indian Institute of
Technology, Kanpur 208016, India
Technology, Kanpur 208016, India
Gaurav Goswami − Department of Chemistry, Indian Institute
of Technology, Kanpur 208016, India
Indresh Verma − Department of Chemistry, Indian Institute of
Technology, Kanpur 208016, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.2c03093
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
M.K.G. is grateful to IIT Kanpur and SERB (DST/
CHM2019478), India, for the financial support. B.S. thanks
CSIR, and M.K., G.G., and I.V. thank IIT Kanpur, India, for
the research fellowships.
■ REFERENCES
(1) (a) Witt, J. O.; McCollum, A. L.; Hurtado, M. A.; Huseman, E.
D.; Jeffries, D. E.; Temple, K. J.; Plumley, H. C.; Blobaum, A. L.;
Lindsley, C. W.; Hopkins, C. R. Synthesis and characterization of a
series of chiral alkoxymethyl morpholine analogs as dopamine
receptor 4 (D4R) antagonists. Bioorg. Med. Chem. Lett. 2016, 26,
2481−2488. (b) Roughley, S. D.; Jordan, A. M. The Medicinal
Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of
Drug Candidates. J. Med. Chem. 2011, 54, 3451−3479. (c) Wijtmans,
R.; Vink, M. K. S.; Schoemaker, H. E.; Van Delft, F. L.; Blaauw, R. H.;
Rutjes, F. P. J. T. Biological relevance, and synthesis of C-substituted
morpholine derivatives. Synthesis 2004, 5, 641−662.
(2) (a) Fang, Y.; Zhang, S.; Li, M.; Xiong, L.; Tu, L.; Xie, S.; Jin, Y.;
Liu, Y.; Yang, Z.; Liu, R. Optimisation of novel 4, 8-disubstituted
dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119
agonists. J. Enzyme Inhib. Med. Chem. 2020, 35, 50−58. (b) Shao, X.;
Pak, S.; Velagapudi, U. K.; Gobbooru, S.; Kommaraju, S. S.; Low, W.-
K.; Subramaniam, G.; Pathak, S. K.; Talele, T. T. Synthesis of 2,3-
dihydrobenzo[b][1,4]dioxine-5-carboxamide and 3-oxo-3,4-
dihydrobenzo[b][1,4]oxazine-8-carboxamide derivatives as PARP1
inhibitors. Bioorg. Chem. 2020, 102, 104075−107589. (c) Mal, A.;
Wani, I. A.; Goswami, G.; Ghorai, M. K. Synthesis of Nonracemic 1,4-
Benzoxazines via Ring-Opening/Cyclization of Activated Aziridines
with 2-Halophenols: Formal Synthesis of Levofloxacin. J. Org. Chem.
2018, 83, 7907−7918.
(3) (a) Ko, Y. O.; Jeon, H. J.; Jung, D. J.; Kim, U. B.; Lee, S.-G.
Rh(II)/Mg(OtBu)2-Catalyzed Tandem One-Pot Synthesis of 1,4-
Oxazepines and 1,4-Oxazines from N-Sulfonyl-1,2,3-triazoles and
Glycidols. Org. Lett. 2016, 18, 6432−6435. (b) Asahina, Y.; Takei, M.;
Kimura, T.; Fukuda, Y. Synthesis and Antibacterial Activity of Novel
Pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic Acid Derivatives Car-
rying the 3-Cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl
Group as a C-10 Substituent. J. Med. Chem. 2008, 51, 3238−3249.
(c) Croom, K. F.; Goa, K. L. Levofloxacin. Drugs 2003, 63, 2769−
2802.
(4) (a) Ghorai, M. K.; Shukla, D.; Bhattacharyya, A. Syntheses of
Chiral β- and γ-Amino Ethers, Morpholines, and Their Homologues
via Nucleophilic Ring-Opening of Chiral Activated Aziridines and
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
Azetidines. J. Org. Chem. 2012, 77, 3740−3753. (b) Gharpure, S. J.;
Prasad, J. V. K. Stereoselective Synthesis of C-Substituted Morpholine
Derivatives using Reductive Etherification Reaction: Total Synthesis
of Chelonin C. J. Org. Chem. 2011, 76, 10325−10331. (c) Ghorai, M.
K.; Shukla, D.; Das, K. Enantioselective Syntheses of Morpholines and
Their Homologues via SN2-Type Ring Opening of Aziridines and
Azetidines with Haloalcohols J. Org. Chem. 2009, 74, 7013−7022.
(5) (a) Hajós, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown, M.
T.; Wong, E. H. F. The Selective Norepinephrine Reuptake Inhibitor
Antidepressant Reboxetine: Pharmacological and Clinical Profile.
CNS Drug Rev. 2004, 10, 23−44. (b) Georgopapadakou, N. H.;
Walsh, T. J. Antifungal Agents: Chemotherapeutic Targets and
Immunologic Strategies. Antimicrob. Agents Chemother. 1996, 40,
279−291. (c) Baloch, R. I.; Mercer, E. I. Inhibition of sterol Δ8 → Δ7-
isomerase and Δ14-reductase by fenpropimorph tridemorph and
fenpropidin in cell-free enzyme systems from Saccharomyces cerevisiae.
Phytochemistry 1987, 26, 663−668.
(6) (a) Pansare, S. V.; Adsool, V. A. A Concise, Enantioselective
Approach to (−)-Quinic Acid. Org. Lett. 2006, 8, 2035−2037.
(b) Pansare, S. V.; Adsool, V. A. Enantioselective Synthesis of
Functionalized Medium-Sized Oxacycles. Org. Lett. 2006, 8, 5897−
5899. (c) Pansare, S. V.; Jain, R. P. Enantioselective Synthesis of (S)-
(+)-Pantolactone. Org. Lett. 2000, 2, 175−177.
(7) Zulys, A.; Dochnahl, M.; Hollmann, D.; Lohnwitz, K.;
Herrmann, J.-S.; Roesky, P. W.; Blechert, S. Intramolecular Hydro-
amination of Functionalized Alkenes and Alkynes with a Homoge-
nous Zinc Catalyst. Angew. Chem., Int. Ed. 2005, 44, 7794−7798.
(8) (a) Yao, L.-F.; Wang, Y.; Huang, K.-W. Synthesis of morpholine
or piperazine derivatives through gold-catalyzed cyclization reactions
of alkynylamines or alkynylalcohols. Org. Chem. Front. 2015, 2, 721−
725. (b) Vandavasi, J. K.; Hu, W.-P.; Chen, H.-Y.; Senadi, G. C.;
Chen, C.-Y.; Wang, J.-J. A New Approach to 1,4-Oxazines and 1,4-
Oxazepines via Base-Promoted Exo Mode Cyclization of Alkynyl
Alcohols: Mechanism and DFT Studies. Org. Lett. 2012, 14, 3134−
3137.
(9) Cambeiro, F.; López, S.; Varela, J. A.; Saá, C. Vinyl
Dihydropyrans and Dihydrooxazines: Cyclizations of Catalytic
Ruthenium Carbenes Derived from Alkynals and Alkynones. Angew.
Chem., Int. Ed. 2014, 53, 5959−5963.
(10) (a) Anitha, M.; Shankar, M.; Kumara Swamy, K. C. Reactivity
of epoxy-ynamides with metal halides: nucleophile (Br/Cl/OH)-
assisted tandem intramolecular 5-exo-dig or 6-endo-dig cyclisation and
AgF2-promoted oxidation. Org. Chem. Front. 2019, 6, 1133−1139.
(b) Kumari, A. L. S.; Reddy, A. S.; Kumara Swamy, K. C. Transition
Metal-Free Cascade Cyclization of Epoxy-Ynamides: To Go for 1,3-
Oxazines or 1,4-Oxazines? Org. Lett. 2016, 18, 5752−5755.
(c) Maheswara, M.; Lee, Y. Y.; Kang, E. J. AgOTf-Catalyzed
Cycloisomerization of Alkynyl Oxiranes for Dihydro-1,4-oxazine
Synthesis. Synlett 2012, 23, 2481−2484.
(11) Broggini, G.; Beccalli, E. M.; Borsini, E.; Fasana, A.; Zecchi, G.
Intramolecular Oxidative Pd (II)-Catalyzed Alkoxylation of 3-Aza-5-
alkenols with O2 as Sole Oxidant: Mild Conditions for the Synthesis
of 1,4-Oxazine Derivatives. Synlett 2011, 2, 227−230.
(12) (a) Jones, K. D.; Nutt, M. J.; Comninos, E.; Sobolev, A. N.;
Moggach, S. A.; Miura, T.; Murakami, M.; Stewart, S. G. A One-Pot
Reaction of α-Imino Rhodium Carbenoids and Halohydrins: Access
to 2,6-Substituted Dihydro-2H-1,4-oxazines. Org. Lett. 2020, 22,
3490−3494. (b) Ko, Y. O.; Jeon, H. J.; Jung, D. J.; Kim, U. B.; Lee, S.-
G. Rh(II)/Mg(OtBu)2-Catalyzed Tandem One-Pot Synthesis of 1,4-
Oxazepines and 1,4-Oxazines from N-Sulfonyl-1,2,3-triazoles and
Glycidols. Org. Lett. 2016, 18, 6432−6435. (c) Ma, X.; Pan, S.; Wang,
H.; Chen, W. Rhodium-Catalyzed Transannulation of N-Sulfonyl-
1,2,3-triazoles and Epoxides: Regioselective Synthesis of Substituted
3,4-Dihydro-2H-1,4-oxazines. Org. Lett. 2014, 16, 4554−4557.
(13) Moulins, J. R.; Hughes, J. A.; Doyle, L. E.; Cameron, T. S.;
Burnell, D. J. Two Rearrangement Pathways in the Geminal Acylation
of 2-Methoxyoxazolidines Leading to Substituted 1,4-Oxazines. Eur. J.
Org. Chem. 2015, 1325−1332.
4517
pubs.acs.org/joc Article
(14) Wang, Y.; Zhang, W.-Y.; You, S.-L. Ketones and Aldehydes as
O-Nucleophiles in Iridium-Catalyzed Intramolecular Asymmetric
Allylic Substitution Reaction. J. Am. Chem. Soc. 2019, 141, 2228−
2232.
(15) (a) Takeda, Y.; Sameera, W. M. C.; Minakata, S. Palladium-
Catalyzed Regioselective and Stereospecific Ring-Opening Cross-
Coupling of Aziridines: Experimental and Computational Studies. Acc.
Chem. Res. 2020, 53, 1686−1702. (b) Li, D.; Wang, L.; Zhu, H.; Bai,
L.; Yang, Y.; Zhang, M.; Yang, D.; Wang, R. Catalytic Asymmetric
Reactions of α-Isocyanoacetates and meso-Aziridines Mediated by an
in-Situ-Generated Magnesium Catalytic Method. Org. Lett. 2019, 21,
4717−4720. (c) Suzuki, S.; Asako, T.; Itami, K.; Yamaguchi, J.
Modular synthesis of heptaarylindole. Org. Biomol. Chem. 2018, 16,
3771−3776. (d) Lin, T. Y.; Wu, H.-H.; Feng, J.-J.; Zhang, J. Transfer
of Chirality in the Rhodium-Catalyzed Chemoselective and
Regioselective Allylic Alkylation of Hydroxyarenes with Vinyl
Aziridines. Org. Lett. 2017, 19, 2897−2900.
(16) (a) Xing, S.; Wang, C.; Gao, T.; Wang, Y.; Wang, H.; Wang, H.;
Wang, K.; Zhu, B. Construction of 4-spiroannulated tetrahydroiso-
quinoline skeletons via a sequential ring opening of aziridines and
Pictet−Spengler reaction. New J. Chem. 2022, 46, 2553−2558.
(b) Wani, I. A.; Goswami, G.; SK, S.; Mal, A.; Sayyad, M.; Ghorai,
M. K. A synthetic route to 1,4-disubstituted tetrahydro-β-carbolines
and tetrahydropyranoindoles via ring-opening/Pictet-Spengler reac-
tion of aziridines and epoxides with indoles/aldehydes. Org. Biomol.
Chem. 2020, 18, 272−287. (c) Das, B. K.; Pradhan, S.;
Punniyamurthy, T. Stereospecific Ring-Opening and Cycloisomeriza-
tion of Aziridines with Propargylamines: Synthesis of Functionalized
Piperazines and Tetrahydropyrazines. Org. Lett. 2018, 20, 4444−
4448. (d) Liao, Y.; Zhou, B.; Xia, Y.; Liu, X.; Lin, L.; Feng, X.
Asymmetric [3 + 2] Cycloaddition of 2,2′-Diester Aziridines to
Synthesize Pyrrolidine Derivatives. ACS Catal. 2017, 7, 3934−3939.
(e) Sayyad, M.; Mal, A.; Wani, I. A.; Ghorai, M. K. A Synthetic Route
to Chiral Tetrahydropyrroloindoles via Ring-Opening of Activated
Aziridines with 2-Bromoindoles Followed by Copper-Catalyzed C-N
Cyclization. J. Org. Chem. 2016, 81, 6424−6432. (f) Xing, S.; Ren, J.;
Wang, K.; Cui, H.; Li, W.; Yan, H. Lewis acid promoted three-
component reactions of aziridines, arenes and aldehydes: an efficient
and diastereoselective synthesis of cis-1,4-disubstituted tetrahydroiso-
quinolines. Tetrahedron 2015, 71, 6290−6299. (g) Yang, D.; Wang,
L.; Han, F.; Li, D.; Zhao, D.; Cao, Y.; Ma, Y.; Kong, W.; Sun, Q.;
Wang, R. Highly Enantioselective Ring-Opening Reactions of
Aziridines with Indole and Its Application in the Building of C3-
Halogenated Pyrroloindolines. Chem. − Eur. J. 2014, 20, 16478−
16483.
(17) (a) Nicastri, K. A.; Zappia, S. A.; Pratt, J. C.; Duncan, J. M.;
Guzei, I. A.; Fernández, I.; Schomaker, J. M. Tunable Aziridinium
Ylide Reactivity: Noncovalent Interactions Enable Divergent Product
Outcomes. ACS Catal. 2022, 12, 1572−1580. (b) Coin, G.; Montal,
O. D. F. D.; Dubourdeaux, P.; Latour, J.-M. Expedient Synthesis of 2-
Iminothiazolidines via Telescoping Reactions Including Iron-Cata-
lyzed Nitrene Transfer and Domino Ring-Opening Cyclization
(DROC). Eur. J. Org. Chem. 2021, 443−448. (c) Zuo, Q.; Shi, Z.;
Zhan, F.; Wang, Z.; Lin, J.-S.; Jiang, Y. TfOH-catalyzed formal [3+2]
cycloaddition of N-tosylaziridine dicarboxylates and nitriles: Synthesis
of tetrafunctionalized 2-imidazolines. Tetrahedron Lett. 2020, 61,
151576−151580. (d) Hajra, S.; Bhosale, S. S.; Hazra, A.; Kanaujia, N.
The one pot asymmetric synthesis of 3,3′-pyrrolidonyl spiroxindoles
via a regio- and stereoselective domino reaction. Org. Biomol. Chem.
2019, 17, 8140−8148. (e) Tu, L.; Li, Z.; Feng, T.; Yu, S.; Huang, R.;
Li, J.; Wang, W.; Zheng, Y.; Liu, J. Access to Imidazolidines via 1,3-
Dipolar Cycloadditions of 1,3,5-Triazinanes with Aziridines. J. Org.
Chem. 2019, 84, 11161−11169. (f) Hajra, S.; Saleh, S. K. A.; Hazra,
A.; Singh, M. S. Organocatalytic Domino Reaction of Spiroaziridine
Oxindoles and Malononitrile for the Enantiopure Synthesis of
Spiro[dihydropyrrole-3,3′-oxindoles]. J. Org. Chem. 2019, 84,
8194−8201. (g) Bhattacharyya, A.; Shahi, C. K.; Pradhan, S.;
Ghorai, M. K. Stereospecific Synthesis of 1,4,5,6-Tetrahydropyrimi-
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry
dines via Domino Ring-Opening Cyclization of Activated Aziridines
with α-Acidic Isocyanides. Org. Lett. 2018, 20, 2925−2928.
(18) (a) Lee, S. G.; Kim, S.-G. Electrochemical Oxidation with
Lewis-Acid Catalysis Leads to Trifluoromethylative Difunctionaliza-
tion of Alkenes Using CF3SO2Na. Tetrahedron Lett. 2018, 74, 3671−
3678. (i) Mal, A.; Sayyad, M.; Wani, I. A.; Ghorai, M. K. Domino
Ring-Opening Cyclization of Activated Aziridines with Indoles:
Synthesis of Chiral Hexahydropyrroloindoles. J. Org. Chem. 2017,
82, 4−11. (b) Wang, B.; Liang, M.; Tang, J.; Deng, Y.; Zhao, J.; Sun,
H.; Tung, C. H.; Jia, J.; Xu, Z. Gold/Lewis Acid Catalyzed
Cycloisomerization/Diastereoselective [3+2] Cycloaddition Cascade:
Synthesis of Diverse Nitrogen-Containing Spiro Heterocycles. Org.
Lett. 2016, 18, 4614−4617. (c) Kaicharla, T.; Jacob, A.; Gonnade, R.
G.; Biju, A. T. AgOTf-catalyzed dehydrative [3+2] annulation of
aziridines with 2-naphthols. Chem. Commun. 2017, 53, 8219−8222.
(d) Xing, S.; Ren, J.; Wang, K.; Cui, H.; Xia, T.; Zhang, M.; Wang, D.
Facile, Efficient and Diastereoselective Construction of Indane-Fused
Pyrrolidin-2-ones via a Potassium Hydroxide-Catalyzed Domino
Reaction. Adv. Synth. Catal. 2016, 358, 3093−3099.
(19) (a) Xing, S.; Wang, Y.; Jin, C.; Shi, S.; Zhang, Y.; Liao, Z.;
Wang, K.; Zhu, B. Construction of Bridged Aza- and Oxa-[n.2.1]
Skeletons via an Intramolecular Formal [3+2] Cycloaddition of
Aziridines and Epoxides with Electron-Deficient Alkenes. J. Org.
Chem. 2022, 87, 6426−6431. (b) Eshon, J.; Nicastri, K. A.; Schmid, S.
C.; Raskopt, W. T.; Guzei, I. A.; Fernández, I.; Schomaker, J. M.
Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-
dines through the intermediacy of aziridinium ylides Nat. Commun.
2020, 11, 1273−1280. (c) Elwrfalli, F.; Esvan, Y. J.; Robertson, C. M.;
Aïssa, C. Regioselective cycloaddition of potassium alkynyltrifluor-
oborates with 3-azetidinones and 3-oxetanone by nickel-catalysed C-C
bond activation. Chem. Commun. 2019, 55, 497−500. (d) Lin, T.-Y.;
Wu, H.-H.; Feng, J. J.; Zhang, J. Chirality Transfer in Rhodium(I)-
Catalyzed [3 + 2]-Cycloaddition of Vinyl Aziridines and Oxime
Ethers: Atom-Economical Synthesis of Chiral Imidazolidines. Org.
Lett. 2018, 20, 3587−3590. (e) Xing, S.; Gu, N.; Wang, X.; Liu, J.;
Xing, C.; Wang, K.; Zhu, B. Substitution-Controlled Selective
Formation of Hexahydrobenz[e]isoindoles and 3-Benzazepines via
In(OTf)3-Catalyzed Tandem Annulations. Org. Lett. 2018, 20, 5680−
5683. (f) Pazos, M.; González, B.; Suescun, L.; Seoane, G.; Carrera, I.
Production of enantiopure β-amino-γ-hydroxyesters from benzoic
acid by a selective formal aminohydroxylation. Tetrahedron Lett. 2017,
58, 2182−2185. (g) Xing, S.; Cui, H.; Gu, N.; Li, Y.; Wang, K.; Tian,
D.; Qin, J.; Liu, Q. AgOTf-catalyzed sequential synthesis of 4-
isoquinolones via oxidative ring opening of aziridines and aza-Michael
addition. Org. Biomol. Chem. 2017, 15, 8308−8312.
(20) (a) Dolfen, J.; Vervisch, K.; Kimpe, N. D.; D’hooghe, M.
LiAlH4-Induced Selective Ring Rearrangement of 2-(2-Cyanoethyl)-
aziridines toward 2-(Aminomethyl)pyrrolidines and 3-Aminopiper-
idines as Eligible Heterocyclic Building Blocks. Chem. − Eur. J. 2016,
22, 4945−4951. (b) Xing, S.; Ren, J.; Wang, K.; Cui, H.; Yan, H.; Li,
W. Diastereoselective Synthesis of Substituted Tetrahydroisoquino-
lines and Isoindolines via a Silver(I) Triflate-Promoted Tandem
Reaction. Adv. Synth. Catal. 2016, 358, 532−538. (c) Ji, M.-K.;
Hertsen, D.; Yoon, D.-H.; Eum, H.; Goossens, H.; Waroquier, M.;
Speybroeck, V. V.; D’Hooghe, M.; Kimpe, N. D.; Ha, H.-J.
Nucleophile-Dependent Regio- and Stereoselective Ring Opening of
1-Azoniabicyclo[3.1.0]hexane Tosylate. Chem. − Asian J. 2014, 9,
1060−1067. (d) Dolfen, J.; Kenis, S.; Hecke, K. V.; Kimpe, N. D.;
D’hooghe, M. Selective Synthesis of Functionalized Trifluoromethy-
lated Pyrrolidines, Piperidines, and Azepanes Starting from 1-Tosyl-2-
(trifluoromethyl)aziridine. Chem. − Eur. J. 2014, 20, 10650−10653.
(e) Sun, H.; Huang, B.; Lin, R.; Yang, C.; Xia, W. Metal-free one-pot
synthesis of 2-substituted and 2,3-disubstituted morpholines from
aziridines. Beilstein J. Org. Chem. 2015, 11, 524−529.
(21) (a) Fang, S.; Zhao, Y.; Li, H.; Zheng, Y.; Lian, P.; Wan, X.
[3+3]-Cycloaddition of α-Diazocarbonyl Compounds and N-
Tosylaziridines: Synthesis of Polysubstituted 2H-1,4-Oxazines
through Synergetic Catalysis of AgOTf/Cu(OAc)2. Org. Lett. 2019,
21, 2356−2359. (b) Zhang, S.; Shan, C.; Zhang, S.; Yuan, L.; Wang,
4518
pubs.acs.org/joc Article
J.; Tung, C.-H.; Xing, L.-B.; Xu, Z. Breaking aziridines to construct
morpholines with a gold (I)-catalyzed tandem ring-opening and
cycloisomerization reaction. Org. Biomol. Chem. 2016, 14, 10973−
10980. (c) Wang, L.; Liu, Q.-B.; Wang, D.-S.; Li, X.; Han, X.-W.;
Xiao, W.-J.; Zhou, Y.-G. Tandem Ring-Opening/Closing Reactions of
N-Ts Aziridines and Aryl Propargyl Alcohols Promoted by t-BuOK.
Org. Lett. 2009, 11, 1119−1122. (d) Bera, M.; Roy, S. Silver(I)-
Catalyzed Dual Activation of Propargylic Alcohol and Aziridine/
Azetidine: Triggering Ring-Opening and Endo-Selective Ring-Closing
in a Cascade. J. Org. Chem. 2009, 74, 8814−8817.
(22) (a) Pradhan, S.; Chauhan, N.; Shahi, C. K.; Bhattacharyya, A.;
Ghorai, M. K. Stereoselective Synthesis of Hexahydroimidazo[1,2-
a]quinolines via SN2-Type Ring-Opening Hydroarylation-Hydro-
amination Cascade Cyclization of Activated Aziridines with N-
Propargylanilines. Org. Lett. 2020, 22, 7903−7908. (b) Tarannum, S.;
Sk, S.; Das, S.; Wani, I. A.; Ghorai, M. K. Stereoselective Syntheses of
Highly Functionalized Imidazolidines and Oxazolidines via Ring-
Opening Cyclization of Activated Aziridines and Epoxides with
Amines and Aldehydes. J. Org. Chem. 2020, 85, 367−379.
(23) (a) Lühl, A.; Nayek, H. P.; Blechert, S.; Roesky, P. W. Zinc−
zinc bonded decamethyldizincocene Zn2(η5-C5Me5)2 as catalyst for
the inter- and intramolecular hydroamination reaction. Chem.
Commun. 2011, 47, 8280−8282. (b) Mukherjee, A.; Sen, T. K.;
Ghorai, P. K.; Samuel, P. P.; Schulzke, C.; Mandal, S. K. Phenalenyl-
Based Organozinc Catalysts for Intramolecular Hydroamination
Reactions: A Combined Catalytic, Kinetic, and Mechanistic
Investigation of the Catalytic Cycle. Chem. − Eur. J. 2012, 18,
10530−10545. (c) Nisa, R. U.; Ayub, K. Mechanism of Zn(OTf)2
catalyzed hydroamination-hydrogenation of alkynes with amines:
insight from theory. New J. Chem. 2017, 41, 5082−5090.
(24) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, 1988.
(25) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.
Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longman
Group, U.K. Ltd., 1989.
(26) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
Bromine-Catalyzed Aziridination of Olefins. A Rare Example of
Atom-Transfer Redox Catalysis by a Main Group Element. J. Am.
Chem. Soc. 1998, 120, 6844−6845.
(27) Groeper, J. A.; Eagles, J. B.; Hitchcock, S. R. A facile, one-pot
synthesis of Ephedra-based aziridines. Tetrahedron: Asymmetry 2009,
20, 1969−1974.
https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518