Synthesis of a 3,4-Dihydro-1,3-oxazin-2-ones Skeleton via an Intermolecular [4 + 2] Process of N-Acyliminium Ions with Ynamides/Terminal Alkynes

Ynamides/Terminal Alkynes

Article

Synthesis of a 3,4-Dihydro-1,3-oxazin-2-ones Skeleton via an

Intermolecular [4 + 2] Process of N‑Acyliminium Ions with

Xiao-Li Han, Xiao-Di Nie, Zhao-Dan Chen, Chang-Mei Si,* Bang-Guo Wei,* and Guo-Qiang Lin

Cite This: https://dx.doi.org/10.1021/acs.joc.0c01692

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sı Supporting Information

ABSTRACT: An approach to access functionalized 3,4-dihydro-1,3-oxazin-

-ones has been developed by reacting semicyclic N,O-acetals 5 and 6 with

ynamides 7 or terminal alkynes 8 in a one-pot fashion. The reaction went

through a formal [4 + 2] cycloaddition process to generate a number of

functionalized 3,4-dihydro-1,3-oxazin-2-ones 9a−9ak and 10a−10bc in yields

of 34−97%. In addition, the utility of this transformation was demonstrated

by the synthesis of (±)-sedamine 13.

INTRODUCTION

The discovery of an eﬃcient methodology to access privileged

azacycles and corresponding benzo heterocycles is one of the

most important areas in current organic syntheses due to their

Kobayashi’s laboratory in which the nucleophilic addition was

■

applied through the coupling with silyl enol ether to form

linear 1,5-amino alcohol (2a, Figure 2). Recently, we also

achieved 1,4- and 1,5-amino alcohols through the reaction with

existence as unique scaﬀold in a large number of biologically

organozinc reagents (2b, Figure 2). In the past decade,

active compounds and clinic drugs, as well as important

alkynes and ynamides have undoubtedly gained signiﬁcant

17,18

auxiliaries and building blocks in organic synthesis. As a

attention in modern organic synthesis.

Many important

prime instance (Figure 1 ), 1 H -benzo[d][1,3]oxazin-2(4H)-

acyclic and cyclic compounds including benzofurans,

Figure 1. Several structures of privileged azacycles and corresponding

benzo heterocycles.

one 1 and 4H-benzo[d][1,3]oxazin-4-one 2, which are

pharmacologically interesting molecules and the key frame-

work of Efavirenz (a prescription medicine for the treatment of

HIV), have received intensive attention in recent years.

Another example is 1,3-oxazinan-2-one 3, which is also an

interesting scaﬀold within natural products and pharmaceut-

7b 10

9b 9c

icals including anti-HIV, , antidiabetic, , anti-inﬂamma-

Figure 2. Lewis acid-promoted intermolecular reactions of semicyclic

N,O-acetals.

9a 12

tory and anticancer, , bioactive molecules. Although

numerous synthetic approaches have been achieved to access

skeleton 3 in past years, there are very few methods to obtain

substituted 3,4-dihydro-1,3-oxazin-2-one 4, which employed

acid-catalyzed cyclization of Boc-protected aminals with

Received: July 16, 2020

alkynes.

N,O-acetals are widely utilized in organic synthesis. In

particular, semicyclic N,O-acetals 5 and 6 have been

investigated in recent years. The ﬁrst example came from

XXXX American Chemical Society

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

7a,18c

17c,18a

quinolines,

oxazoles, pyridines,

carbolines,

moderate yield of 9a (64%, Table 1, entry 18), while both

DCE and PhMe gave much lower yields of 9a, in 27% and

45%, respectively (Table 1, entries 17 and 19).

18b23

enamides, and amidines,

have been successfully

synthesized from alkynes or ynamides. On the basis of our

continuous eﬀorts in exploring chemical transformations of

Next, we turned to investigate the scope and limitation of

such cyclization of semicyclic N,O-acetal (5 or 6a) with

ynamides 7a−7m (Scheme 1). TsNBn-type ynamides with

16,24

17e

18d25

semicyclic N,O-acetals,

alkynes, and ynamides,

envisioned that the iminium ions derived from the semicyclic

N,O-acetals 5 and 6 could undergo a formal [4 + 2]

cycloaddition process to give substituted 3,4-dihydro-1,3-

oxazin-2-one skeletons 9 and 10, respectively (2c, Figure 2).

Scheme 1. Reactions of Semicyclic N,O-Acetals 5/6a with

a b

Ynamides 7a−7m

RESULTS AND DISCUSSION

■

Our investigation started with the reaction of semicyclic N,O-

acetal 5 with ynamide 7a. The reaction did not aﬀord any

desired product in the absent of Lewis acid (Table 1, entry 1).

Table 1. Optimization of Reaction Conditions

entry

catalyst

solvent

T (°C)

r.t.

−78 ∼ −45

r.t.

−78 ∼ −45

r.t.

−78 ∼ −45

Y (%)

DCM

DCE

SIPrAuCl (0.1 equiv)

AgNTf (0.1 equiv)

AgOTf (0.1 equiv)

Zn(OTf) (0.1 equiv)

Ni(OTf) (0.1 equiv)

Cu(OTf) (0.1 equiv)

complex

Sc(OTf) (0.1 equiv)

ZnCl (1.0 equiv)

CuI (0.1 equiv)

TiCl (1.0 equiv)

BF Et O (1.0 equiv)

TMSOTf (1.0 equiv)

TMSOTf (0.5 equiv)

TMSOTf (2.0 equiv)

TMSOTf (1.0 equiv)

complex

THF

PhMe

The reactions were performed with 5 (0.5 mmol), 7a (0.6 mmol),

and catalyst in a dry solvent (2 mL) at speciﬁed temperature for 2 h.

Isolated yield. When Cu(OTf) was used, the amide enol carbamate

18d

was obtained in 38%.

The screening of various Lewis acids, including catalytic

amounts of SIPrAuCl, AgNTf , and Sc(OTf) , turned out to be

The reactions were performed with N,O-acetal 5/6a (0.5 mmol),

ynamide 7 (0.6 mmol), and TMSOTf (0.5 mmol) in dry DCM (2

fruitless (Table 1, entries 2−10). When TiCl was investigated,

mL) at −78 to −45 °C for 2 h. Isolated yield.

the desired product 9a was obtained in 35% yield (Table 1,

entry 11). BF ·Et O could also aﬀord a small amount of

desired product 9a (8% yield, Table 1, entry 12). Delightfully,

stoichiometric TMSOTf could signiﬁcantly increase the yield

of 9a up to 94% (Table 1, entry 13). It was worth noting that

the complex result was obtained when the reaction was treated

at room temperature (Table 1, entry 14). However, the use of

diﬀerent para-substituted (methyl, methoxyl, n-butyl, and

ﬂuoro) aryls were surveyed under the optimized condition,

as summarized in Scheme 1. In general, all these substituted

aryl TsNBn ynamides (7b−7d, 7l) could smoothly react with

semicyclic N,O-acetals 5 and 6a, aﬀording the desired products

in excellent yields. Aliphatic alkyl-substituted TsNBn ynamides

were also suitable substrates for this cyclization reaction. When

cyclopropyl-substituted TsNBn ynamide 7m and semicyclic

N,O-acetal 6a were treated under the optimized condition, the

desired product 9am was obtained in 63% yield. n-Pentyl-

.5 equiv of TMSOTf led to erosion of yield to 46% (Table 1,

entry 15). When 2.0 equiv of TMSOTf was applied, the yield

of 9a slightly decreased to 83% (Table 1, entry 16). Diﬀerent

solvents were also examined, and the results are summarized in

Table 1 (entries 17−19). Among them, THF led to the

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

substituted TsNBn ynamide 7e could also react with 5 and 6a,

aﬀording the corresponding cyclization products 9e and 9ae in

excellent yields. Heteroaryl-substituted TsNBn ynamide 7f

Scheme 2. Reactions of Semicyclic N,O-Acetals 5/6 with

a b

Substituted Acetylenes 8a−8m

(

with 2-thienyl) was also investigated, the desired products 9f

and 9af were produced in moderate yields. When a Bn group

in ynamides was replaced with diﬀerent aryl and alkyl groups,

the corresponding derivatives 7g−7i were also proved to be

appropriate substrates for this cyclization, aﬀording the desired

products 9g−9i and 9ag−9ai in excellent yields. In addition,

the replacement of the Ts group in ynamides with p-

chlorobenzenesulfonyl and carbamate also gave positive results

under the optimized condition, and the desired products 9j,

k, 9aj, and 9ak were obtained from 7j and 7k in moderate

yields. The chemical structures of 9a−9k and 9aa−9am were

unambiguously conﬁrmed based on the X-ray crystallographic

analysis of compound 9a (see the Supporting Information).

The above cyclization of semicyclic N,O-acetals (5 and 6a)

with ynamides 7a−7m could smoothly produce the 3,4-

dihydro-1,3-oxazin-2-one skeleton, with diﬀerent 6-amino

substitutions. Next, we turn our attention to investigate the

reaction of semicyclic N,O-acetal 5 or 6 with terminal alkynes,

aiming at constructing the 3,4-dihydro-1,3-oxazin-2-one

skeleton with diﬀerent 6-alkyl or 6-aryl substitutions. First,

various Lewis acids were investigated for the reaction of 6a and

8c, and the reactivity of terminal alkynes was shown to be

much lower than that of ynamides (see the Supporting

Information ). In addition, TMSOTf still proved to be an

excellent Lewis acid for this cyclization process. Then, a variety

of terminal alkynes (8a−8m) with diﬀerent substituted aryl

groups were screened under the optimized condition, as

summarized in Scheme 2. In general, the para-, meta-, and

ortho-substituted phenylacetylenes 8b-8f could react with ﬁve-

and six-membered semicyclic N,O-acetals 5 and 6a, giving the

desired [4 + 2] cycloaddition products 10b−10f and 10ab−

10af in moderate yields (34%−84%). Halogen-substituted

phenylacetylenes (8g−8i) could also provide comparable

yields (36%−51%). 2- and 3-Thienylacetylenes 8j and 8k

were also suitable substrates for this reaction, aﬀording the

corresponding products in moderate yields (42%−81%). To

our delight, when ethynylcyclopropane 8m was examined, the

desired product 10am was obtained in 65% yield. N-Methyl

semicyclic N,O-acetal 6b was also investigated, and the desired

products 10bc, 10bj, and 10bm were accordingly produced in

moderate yields (37%−56%). The structures of 10a−10k,

0aa−10ag, 10aj−10am, 10bc, 10bj, and 10bm were

unambiguously conﬁrmed based on the X-ray crystallographic

analysis of compound 10al (see the Supporting Information).

A proposed mechanism for the TMSOTf-mediated [4 + 2]

process was illustrated in Figure 3. First, TMSOTf activates

semicyclic N,O-acetal 5 or 6 to form a diene-type N-

acyliminium ion int-2 through the ring-opening of inter-

mediate int-1. Then, the [4 + 2] cycloaddition with the triple

bond in ynamides 7 or terminal alkynes 8 would take place

regioselectively from the less steric side of int-2 to give a six-

membered intermediate int-3 via the transition state TS-1,

which undergoes the cleavage of the t-butyl group to aﬀord the

desired product 9 or 10, along with the generation of 2-

methylprop-1-ene.

The reactions were performed with N,O-acetal 5/6 (0.5 mmol),

terminal alkynes (1.0 mmol), and TMSOTf (0.5 mmol) in dry DCM

(

2 mL) at −78 to −45 °C for 6 h. Isolated yield. 10aa (1.04 g, 42%

yield) was obtained with 6a (10 mmol), 8a (20 mmol), and TMSOTf

10 mmol) in dry DCM (40 mL) at −78 to −45 °C for 6 h.

(

chemistry. Dess−Martin oxidation (DMP) of alcohol 10aa

and subsequent reductive amination (Et SiH/TMSOTf) gave

bicyclic lactone 11 in 75% overall yield. Hydrolysis (KOH) of

11 following protection of the secondary amine (Boc O/TEA)

Finally, we focused on the utility of this intermolecular [4 +

] process of N-acyliminium ions with ynamides/alkynes in the

aﬀorded N-Boc ketone 12a in 78% overall yield. After the

ketone reduction (Li( BuO) AlH) of 12a, the crude secondary

synthesis of biologically active molecules. Scheme 3 shows a

alcohol, without further puriﬁcation, was treated with lithium

facile synthesis of sedamine 13, which was isolated from

aluminum hydride (LiAlH ) to give (+/−)-sedamine (13) in

Sedum species and attracted great interest in synthetic

93% overall yield. The spectroscopic and physical data of the

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J. Org. Chem. XXXX, XXX, XXX−XXX

Article

H NMR and CDCl (77.16 ppm) for C{ H} NMR. The heat

source was an oil bath.

General Procedure for the Synthesis of 7. To a mixture of

an amide (2 mmol), K PO (4 mmol), CuSO ·5H O (0.2 mmol), and

1,10-phenanthroline (0.4 mmol) in toluene under an N atmosphere

was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The

reaction was stirred at 75 °C for 24 h under an N atmosphere. The

reaction mixture was cooled to room temperature, diluted with

EtOAc, and ﬁltered through Celite, and the ﬁltrate was concentrated

in vacuo. The crude products were puriﬁed by ﬂash chromatography

on silica gel to aﬀord the desired ynamide 7. Data for new compounds

of ynamides as following:

-Methoxyethyl Benzyl(phenylethynyl)carbamate (7k). Col-

orless oil (421 mg, 68%); puriﬁed by ﬂash chromatography on silica

gel (PE/EtOAc = 20:1); IR (ﬁlm): ν 2888, 2241, 1727, 1598,

max

−

1 1

(

400, 1294, 1114, 753 cm ; H NMR (400 MHz, CDCl ) δ 7.44−

.40 (m, 2H), 7.39−7.32 (m, 3H), 7.32−7.26 (m, 3H), 7.25−7.22

m, 2H), 4.72 (s, 2H), 4.38−4.35 (m, 2H), 3.68−3.63 (m, 2H), 3.40

13 1

s, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 155.2, 136.0,

31.1, 128.7, 128.3, 128.2, 127.6, 123.4, 70.5, 66.6, 59.3, 54.1 ppm;

HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C H NO ,

10.1438, found 310.1441.

General Procedure for the Syntheses of 9 and 10. To a

Figure 3. Proposed mechanism for the TMSOTf-catalyzed [4 + 2]

process (PH or Me).

solution of 5 or 6 (0.5 mmol) and 7 (0.6 mmol) or 8 (1.0 mmol) in

dry DCM (2 mL) was added dropwise TMSOTf (91 μL, 0.5 mmol)

at −78 °C. The reaction was allowed to warm to −45 °C slowly and

stirred 2 h for compound 9 or 6 h for compound 10 at −45 °C.

Scheme 3. Synthesis of (+/−)-Sedamine 13

Saturated aqueous NaHCO (2 mL) was added to quench the

reaction. The mixture was extracted with DCM (5 mL × 3), and the

combined organic layers were washed with brine. The organic phase

was dried over anhydrous MgSO₄and ﬁltered. The solvent was

evaporated under reduced pressure. The residue was puriﬁed by ﬂash

chromatography on silica gel to obtain 9 or 10.

N-Benzyl-N-(4-(3-hydroxypropyl)-2-oxo-5-phenyl-3,4-dihy-

dro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfonamide (9a).

White solid (232 mg, 94%); mp 149−151 °C; puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν 3280,

max

−

1 1

2929, 1741, 1447, 1351, 1161, 914, 812 cm ; H NMR (400 MHz,

Reagents and conditions: (a) (1) DMP, DCM, r.t., 3 h; (2) Et SiH/

CDCl ) δ 7.78−7.70 (m, 2H), 7.33−7.27 (m, 3H), 7.25−7.20 (m,

TMSOTf, ACN, 0 °C to r.t., 40 min, 75% (2 steps); (b) t-BuOH/

H), 7.17−7.10 (m, 2H), 6.97−6.84 (m, 4H), 6.70 (brs, 1H), 4.22−

toluene (v/v = 1/1), KOH, 85 °C, 30 min, 85%; (c) Boc O/TEA,

4.16 (m, 2H), 4.10−3.98 (m, 1H), 3.62−3.51 (m, 2H), 2.43 (s, 3H),

H O, r.t., 6 h, 92%; (d) (1) Li( BuO) AlH, THF, reﬂux, 4 h; (2)

13 1

.07 (brs, 1H), 1.62−1.43 (m, 4H) ppm; C{ H} NMR (100 MHz,

LiAlH , reﬂux, 4 h, 93% (2 steps).

CDCl ) δ 151.6, 144.5, 137.1, 135.5, 133.7, 132.9, 129.8 (2C), 129.7,

28.8 (2C), 128.6 (2C), 128.4 (2C), 128.3 (2C), 128.2, 128.1 (2C),

19.0, 62.3, 55.3, 51.6, 32.0, 26.8, 21.8 ppm; HRMS (ESI-Orbitrap)

m/z: [M + H] Calcd for C H N O S , 493.1792, found 493.1791.

synthetic (+/−)-sedamine (13) were identical to the reported

27 29

N-Benzyl-N-(4-(3-hydroxypropyl)-2-oxo-5-(p-tolyl)-3,4-dihy-

dro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfonamide (9b).

White solid (225 mg, 89%); mp 150−152 °C; puriﬁed by ﬂash

data.

CONCLUSIONS

In summary, we established a novel and eﬃcient approach for

the synthesis of functionalized 3,4-dihydro-1,3-oxazin-2-ones

■

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν 3261,

max

−

1 1

2918, 1739, 1594, 1400, 1341, 1137, 814 cm ; H NMR (400 MHz,

CDCl ) δ 7.83−7.69 (m, 2H), 7.33−7.30 (m, 2H), 7.25−7.20 (m,

1H), 7.18−7.09 (m, 2H), 7.07−7.04 (m, 2H), 6.98−6.78 (m, 4H),

9a−9am and 10a−10bm. This TMSOTf-mediated one-pot

.57 (brs, 1H), 4.23−4.15 (m, 2H), 4.14−4.01 (m, 1H), 3.62−3.52

process underwent a [4 + 2] cycloaddition from semicyclic

N,O-acetals (5 and 6) with ynamides 7 or terminal alkynes 8.

In addition, the utility of this methodology was demonstrated

by the facile synthesis of natural product (+/−)-sedamine 13.

(

m, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 2.07 (brs, 1H), 1.66−1.41 (m,

H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 151.4, 144.4, 137.9,

37.1, 135.7, 133.8, 129.9, 129.8 (2C), 129.7, 129.0 (2C), 128.7

(

4C), 128.4 (2C), 128.2 (2C), 118.8, 62.5, 55.4, 51.7, 32.2, 26.9, 21.8

1.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

EXPERIMENTAL SECTION

■

C H N O S , 507.1948, found 507.1947.

28 31 2 5

General Considerations. THF was distilled from sodium/

benzophenone, and DCM was distilled from phosphorus pentoxide.

Reactions were monitored by thin-layer chromatography (TLC) on

glass plates coated with silica gel with a ﬂuorescent indicator. Flash

chromatography was performed on silica gel (300−400) with

petroleum/EtOAc or EtOAc/MeOH as the eluent. HRMS was

measured on an LTQ-Orbitrap-XL apparatus. IR spectra were

recorded using a ﬁlm on a Fourier transform infrared spectrometer.

NMR spectra were recorded at 400 or 600 MHz, and chemical shifts

are reported in δ (ppm) referenced to an internal TMS standard for

N-Benzyl-N-(5-(4-ﬂuorophenyl)-4-(3-hydroxypropyl)-2-oxo-

3,4-dihydro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfona-

mide (9c). White solid (209 mg, 82%); mp 149−150 °C; puriﬁed by

ﬂash chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): νmax

−

1 1

3261, 2931, 2359, 1730, 1508, 1353, 1163, 835 cm ; H NMR (400

MHz, CDCl

) δ 7.83−7.71 (m, 2H), 7.35−7.32 (m, 2H), 7.26−7.21

(m, 1H), 7.19−7.11 (m, 2H), 6.95−6.83 (m, 6H), 6.73 (brs, 1H),

4.27−4.21 (m, 1H), 4.20−3.87 (m, 2H), 3.64−3.54 (m, 2H), 2.44 (s,

3H), 2.24 (brs, 1H), 1.68−1.42 (m, 4H) ppm; C{ H} NMR (100

MHz, CDCl ) δ 162.5 (d, J

= 246.3 Hz), 151.3, 144.7, 137.3,

C−F

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

MHz, DMSO-d ) δ 8.21 (brs, 1H), 7.53−7.48 (m, 2H), 7.43−7.39

(m, 4H), 7.38−7.35 (m, 2H), 7.35−7.33 (m, 1H), 4.45 (t, J = 5.0 Hz,

1H), 4.33 (brs, 1H), 3.34−3.29 (m, 2H), 2.77 (s, 3H), 2.39 (s, 3H),

(ESI-Orbitrap) m/z: [M + H] Calcd for C H FN O S , 511.1698,

1.61−1.47 (m, 2H), 1.46−1.27 (m, 2H) ppm; C{ H} NMR (100

found 511.1697.

MHz, DMSO-d ) δ 149.8, 144.0, 139.4, 134.7, 133.6, 129.6 (2C),

N-Benzyl-N-(5-(4-butylphenyl)-4-(3-hydroxypropyl)-2-oxo-

128.4 (2C), 128.3 (2C), 127.9, 127.7 (2C), 115.9, 60.4, 53.6, 35.7,

,4-dihydro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfona-

31.2, 26.4, 21.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd

mide (9d). White solid (239 mg, 87%); mp 151−153 °C; puriﬁed by

for C H N O S , 417.1479, found 417.1483.

ﬂash chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν

261, 2924, 1735, 1455, 1341, 1140, 812, 680 cm ; H NMR (400

max

N-Butyl-N-(4-(3-hydroxypropyl)-2-oxo-5-phenyl-3,4-dihy-

dro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfonamide (9i).

White solid (211 mg, 92%); mp 135−137 °C; puriﬁed by ﬂash

−

1 1

MHz, CDCl ) δ 7.82−7.69 (m, 2H), 7.33−7.30 (m, 2H), 7.23−7.19

(

m, 1H), 7.16−7.08 (m, 2H), 7.06−7.04 (m, 2H), 6.93−6.80 (m,

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν 3253,

max

−

1 1

H), 6.58 (brs, 1H), 4.25−4.19 (m, 1H), 4.19−4.05 (m, 2H), 3.63−

.53 (m, 2H), 2.62−2.59 (m, 2H), 2.44 (s, 3H), 2.07 (brs, 1H),

2922, 1722, 1596, 1445, 1353, 1165, 767 cm ; H NMR (400 MHz,

CDCl ) δ 7.80−7.73 (m, 2H), 7.53−7.49 (m, 2H), 7.43−7.35 (m,

.67−1.57 (m, 5H), 1.44−1.35 (m, 3H), 0.99−0.95 (m, 3H) ppm;

3H), 7.32−7.29 (m, 2H), 6.57 (brs, 1H), 4.45−4.41 (m, 1H), 3.72−

3.61 (m, 2H), 2.97−2.92 (m, 2H), 2.42 (s, 3H), 2.02 (brs, 1H),

1.80−1.69 (m, 4H), 1.24−1.13 (m, 2H), 1.01−0.81 (m, 2H), 0.69−

C{ H} NMR (100 MHz, CDCl ) δ 151.5, 144.4, 142.9, 137.0,

(

35.6, 133.8, 130.0, 129.8 (2C), 129.7, 128.7 (2C), 128.6 (2C), 128.4

2C), 128.3 (2C), 128.1 (2C), 118.9, 62.5, 55.4, 51.7, 35.5, 33.7, 32.2,

0.62 (m, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 151.3,

6.9, 22.6, 21.8, 14.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]

144.2, 138.0, 135.8, 133.3, 129.7 (2C), 128.9 (2C), 128.7 (2C), 128.6

Calcd for C H N O S , 549.2418, found 549.2415.

(2C), 128.5, 118.4, 62.6, 55.6, 48.1, 32.7, 29.7, 27.1, 21.7, 19.9, 13.7

N-Benzyl-N-(4-(3-hydroxypropyl)-2-oxo-5-pentyl-3,4-dihy-

dro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfonamide (9e).

White solid (219 mg, 90%); mp 121−123 °C; puriﬁed by ﬂash

ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

C H N O S , 459.1948, found 459.1953.

N-Benzyl-4-chloro-N-(4-(3-hydroxypropyl)-2-oxo-5-phenyl-

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν 3280,

3,4-dihydro-2H-1,3-oxazin-6-yl)benzenesulfonamide (9j).

White solid (156 mg, 61%); mp 135−137 °C; puriﬁed by ﬂash

max

−

1 1

929, 1737, 1598, 1453, 1353, 1163, 816 cm ; H NMR (400 MHz,

CDCl rotamers) δ 7.82−7.77 (m, 2H), 7.37−7.34 (m, 2H), 7.31−

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν 3382,

max

−

1 1

.28 (m, 5H), 6.50 (brs, 1H), 4.72−4.64 (m, 1H), 4.03−3.93 (m,

H), 3.93−3.83 (m, 1H), 3.72−3.65 (m, 1.45H), 3.49−3.39 (m,

.55H), 2.44 (s, 3H), 2.34−2.22 (m, 2H), 1.93−1.86 (m, 1H), 1.89−

.67 (m, 4H), 1.85−1.79 (m, 0.55H), 1.78−1.70 (m, 1.45H), 1.68−

.62 (m, 1H), 1.43−1.21 (m, 3H), 1.14−0.98 (m, 2H), 0.94−0.88

1739, 1584, 1402, 1357, 1161, 1047, 751 cm ; H NMR (400 MHz,

CDCl ) δ 7.84−7.75 (m, 2H), 7.51−7.47 (m, 2H), 7.33−7.27 (m,

2H), 7.25−7.22 (m, 2H), 7.19−7.11 (m, 2H), 6.98−6.84 (m, 4H),

6.46 (brs, 1H), 4.25−4.17 (m, 2H), 4.13−3.97 (m, 1H), 3.65−3.55

(m, 2H), 1.90 (brs, 1H), 1.62−1.49 (m, 4H) ppm; C{ H} NMR

(

m, 2H), 0.83−0.77 (m, 2.55H), 0.20−0.08 (m, 0.45H) ppm;

(100 MHz, CDCl ) δ 151.0, 140.2, 137.1, 137.0, 133.4, 132.7, 130.1

C{ H} NMR (100 MHz, CDCl , rotamers) δ 151.7, 144.5, 135.8,

(2C), 129.7, 129.5 (2C), 128.8 (2C), 128.6 (2C), 128.44 (2C),

128.39, 128.3 (2C), 119.1, 62.5, 55.4, 52.0, 32.3, 26.9 ppm; HRMS

35.6, 135.4, 135.3, 134.6, 134.3, 130.0, 129.8, 128.7, 128.5, 128.4,

28.0, 118.8, 118.6, 62.5, 62.2, 51.9, 51.7, 50.7, 32.1, 31.8 31.7, 31.0,

7.7, 27.5, 26.8, 26.5, 26.3, 22.6, 21.8, 14.1 ppm; HRMS (ESI-

(ESI-Orbitrap) m/z: [M + H] Calcd for C26

H26ClN O

S , 513.1246,

found 513.1246.

Orbitrap) m/z: [M + H] Calcd for C H N O S , 487.2261, found

2-Methoxyethylbenzyl(4-(3-hydroxypropyl)-2-oxo-5-phe-

nyl-3,4-dihydro-2H-1,3-oxazin-6-yl)carbamate (9k). Colorless

oil (128 mg, 58%); puriﬁed by ﬂash chromatography on silica gel

(PE/EtOAc = 1:2); IR (ﬁlm): νmax 3294, 2947, 1733, 1600, 1445,

87.2268.

N-Benzyl-N-(4-(3-hydroxypropyl)-2-oxo-5-(thiophen-2-yl)-

,4-dihydro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfona-

−1

mide (9f). Pale yellow solid (112 mg, 45%); mp 133−135 °C;

1384, 1131, 702 cm ; H NMR (400 MHz, CDCl rotamers) δ

puriﬁed by ﬂash chromatography on silica gel (PE/EtOAc = 1:2); IR

7.34−7.28 (m, 1H), 7.26−7.24 (m, 2H), 7.19−7.11 (m, 3H), 7.09−

7.07 (m, 0.64H), 7.06−6.90 (m, 4H), 6.80−6.75 (m, 0.36H), 4.58−

4.51 (m, 1H), 4.43−4.40 (m, 0.36H), 4.40−4.35 (m, 0.64H), 4.30−

4.27 (m, 1H), 4.27−4.23 (m, 1.36H), 4.22−4.19 (m, 0.64H), 3.78−

3.64 (m, 1.64H), 3.55−3.50 (m, 2H), 3.44−3.41 (m, 2H), 3.37−3.35

(s, 0.36H), 3.32−3.29 (m, 0.36H), 3.10−2.95 (m, 0.64H), 2.18 (brs,

1H), 1.80−1.62 (m, 2H), 1.57−1.51 (m, 1H), 1.47−1.40 (m, 1H)

−

1 1

(

ﬁlm): ν_m_a_x3180, 2947, 2359, 1741, 1351, 1161, 1051, 814 cm ; H

NMR (400 MHz, CDCl ) δ 7.87−7.84 (m, 2H), 7.39−7.37 (m, 2H),

.32−7.30 (m, 1H), 7.17−7.15 (m, 1H), 7.13−7.07 (m, 5H), 6.98−

.96 (m, 1H), 6.27 (brs, 1H), 4.62−3.87 (m, 3H), 3.65−3.57 (m,

H), 2.47 (s, 3H), 1.78 (brs, 1H), 1.63−1.40 (m, 4H) ppm; C{ H}

NMR (100 MHz, CDCl ) δ 150.9, 144.8, 136.8, 135.1, 134.2, 133.0,

30.1, 129.9 (2C), 128.8 (2C), 128.4 (2C), 128.3 (2C), 126.9, 126.8

ppm; C{ H} NMR (100 MHz, CDCl , rotamers) δ 155.5, 152.2,

(

2C), 114.6, 62.5, 54.3, 52.1, 33.2, 27.2, 21.8 ppm; HRMS (ESI-

139.5, 139.3, 135.4, 133.4, 133.1, 129.7, 128.8, 128.6, 128.3, 128.2,

128.0, 127.7, 113.7, 70.8, 70.6, 65.4, 65.0, 62.4, 59.0, 58.6 54.7, 51.6,

51.2, 32.1, 31.3, 26.9, 26.5 ppm; HRMS (ESI-Orbitrap) m/z: [M +

Orbitrap) m/z: [M + H] Calcd for C H N O S , 499.1356, found

5 2

99.1354.

N-(4-(3-Hydroxypropyl)-2-oxo-5-phenyl-3,4-dihydro-2H-

,3-oxazin-6-yl)-4-methyl-N-phenylbenzenesulfonamide (9g).

H] Calcd for C H N O , 441.2020, found 441.2024.

24 29 2 6

N-Benzyl-N-(4-(4-hydroxybutyl)-2-oxo-5-phenyl-3,4-dihy-

dro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfonamide (9aa).

White solid (238 mg, 94%); mp 152−154 °C; puriﬁed by ﬂash

White solid (160 mg, 67%); mp 124−126 °C; puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν 3355,

max

−

1 1

153, 2941, 1731, 1492, 1357, 1133, 771 cm ; H NMR (400 MHz,

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν 3257,

max

−

1 1

DMSO-d ) δ 8.31 (brs, 1H), 7.48−7.43 (m, 2H), 7.42−7.36 (m, 3H),

2943, 1737, 1496, 1349, 1163, 818, 759 cm ; H NMR (400 MHz,

.36−7.29 (m, 4H), 7.24−7.18 (m, 3H), 6.83−6.68 (m, 2H), 4.44

DMSO-d , rotamers) δ 8.10 (brs, 1H), 7.67−7.61 (m, 2H), 7.41−

(brs, 1H), 4.35−4.29 (m, 1H), 3.33−3.29 (m, 2H), 2.36 (s, 3H),

7.38 (m, 2H), 7.31−7.27 (m, 2H), 7.25−7.23 (m, 2H), 7.22−7.18

(m, 2H), 6.91−6.82 (m, 4H), 4.33 (t, J = 5.0 Hz, 1H), 4.22−4.15 (m,

2H), 4.14−4.07 (m, 1H), 4.06 (brs, 1H), 2.42 (s, 3H), 1.40−1.24 (m,

.57−1.28 (m, 4H) ppm; C{ H} NMR (100 MHz, DMSO-d ) δ

49.7, 144.4, 139.1, 138.4, 134.9, 133.0, 129.5 (2C), 129.2 (2C),

28.4 (4C), 128.2, 128.1 (3C), 126.0 (2C), 117.1, 60.4, 53.7, 31.2,

6.5, 21.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

6H) ppm; C{ H} NMR (100 MHz, DMSO-d , rotamers) δ 149.74,

149.69, 144.1, 136.8, 135.3, 133.8, 133.2, 129.7, 129.2, 128.3, 128.2,

128.0, 127.9, 127.6, 117.8, 60.5, 60.4, 54.1, 54.0, 51.0, 34.0, 32.2, 32.1,

C H N O S , 479.1635, found 479.1639.

N-(4-(3-Hydroxypropyl)-2-oxo-5-phenyl-3,4-dihydro-2H-

,3-oxazin-6-yl)-N,4-dimethylbenzenesulfonamide (9h). White

21.0, 19.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

C H N O S , 507.1948, found 507.1948.

solid (177 mg, 85%); mp 137−139 °C; puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν

N-Benzyl-N-(4-(4-hydroxybutyl)-2-oxo-5-(p-tolyl)-3,4-dihy-

dro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfonamide (9ab).

White solid (247 mg, 95%); mp 121−123 °C; puriﬁed by ﬂash

max

−

1 1

376, 2931, 1739, 1598, 1443, 1345, 1133, 765 cm ; H NMR (400

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν 3271,

52.1, 35.5, 31.9, 21.8, 20.2 ppm; HRMS (ESI-Orbitrap) m/z: [M +

max

−

2924, 1737, 1355, 1161, 1047, 818, 702 cm ; H NMR (400 MHz,

H] Calcd for C H N O S , 513.1512, found 513.1517.

26 29 2 5 2

CDCl ) δ 7.84−7.65 (m, 2H), 7.32−7.29 (m, 2H), 7.25−7.20 (m,

N-(4-(4-Hydroxybutyl)-2-oxo-5-phenyl-3,4-dihydro-2H-1,3-

oxazin-6-yl)-4-methyl-N-phenylbenzenesulfonamide (9ag).

White solid (140 mg, 57%); mp 127−129 °C; puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): νmax 3404,

H), 7.18−7.10 (m, 2H), 7.07−7.04 (m, 2H), 6.94−6.75 (m, 5H),

.21−4.16 (m, 1H), 4.15−3.97 (m, 2H), 3.59−3.55 (m, 2H), 2.43 (s,

H), 2.35 (s, 3H), 2.12 (brs, 1H), 1.49−1.38 (m, 6H) ppm; C{ H}

−

1 1

NMR (100 MHz, CDCl ) δ 151.9, 144.4, 137.9, 137.0, 135.6, 133.8,

2939, 1735, 1594, 1486, 1349, 1131, 763 cm ; H NMR (400 MHz,

29.9, 129.8 (2C), 129.7, 129.0 (2C), 128.6 (4C), 128.4 (2C), 128.2

DMSO-d ) δ 8.30 (brs, 1H), 7.48−7.43 (m, 2H), 7.42−7.36 (m, 3H),

(

2C), 118.8, 62.3, 55.4, 51.7, 34.4, 32.0, 21.7, 21.3, 19.7 ppm; HRMS

ESI-Orbitrap) m/z: [M + H] Calcd for C H N O S , 521.2105,

7.35−7.28 (m, 4H), 7.25−7.18 (m, 3H), 6.86−6.71 (m, 2H), 4.36

(brs, 1H), 4.32−4.27 (m, 1H), 3.33−3.28 (m, 2H), 2.35 (s, 3H),

(

29 33 2 5

found 521.2106.

1.50−1.24 (m, 6H) ppm; C{ H} NMR (100 MHz, DMSO-d ) δ

N-Benzyl-N-(5-(4-ﬂuorophenyl)-4-(4-hydroxybutyl)-2-oxo-

149.7, 144.4, 139.2, 138.5, 134.9, 133.1, 129.5 (2C), 129.2 (2C),

128.4 (4C), 128.2, 128.1 (2C), 128.0, 125.9 (2C), 117.0, 60.6, 53.8₊,

34.2, 32.2, 21.1, 19.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]

,4-dihydro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfona-

mide (9ac). White solid (228 mg, 87%); mp 147−149 °C; puriﬁed

by ﬂash chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm):

Calcd for C H N O S , 493.1792, found 493.1793.

−

1 1

ν_m_a_x3259, 2934, 1729, 1600, 1508, 1355, 1163, 841 cm ; H NMR

N-(4-(4-Hydroxybutyl)-2-oxo-5-phenyl-3,4-dihydro-2H-1,3-

oxazin-6-yl)-N,4-dimethylbenzenesulfonamide (9ah). White

solid (196 mg, 91%); mp 137−139 °C; puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): νmax

(

400 MHz, CDCl ) δ 7.84−7.71 (m, 2H), 7.37−7.33 (m, 2H), 7.26−

.21 (m, 1H), 7.20−7.11 (m, 2H), 6.97−6.81 (m, 6H), 6.38 (brs,

H), 4.31−4.22 (m, 1H), 4.22−3.77 (m, 2H), 3.63−3.58 (m, 2H),

−1 1

.45 (s, 3H), 2.02 (brs, 1H), 1.51−1.38 (m, 6H) ppm; C{ H} NMR

3122, 2935, 2363, 1733, 1596, 1404, 1349, 843 cm ; H NMR (400

MHz, CDCl ) δ 7.68−7.63 (m, 2H), 7.43−7.36 (m, 5H), 7.31−7.26

(

100 MHz, CDCl ) δ 162.5 (d, J

= 246.3 Hz), 151.3, 144.7,

= 8.0 Hz), 129.9, 129.8, 128.8,

C−F

37.4, 135.4, 133.7, 130.7 (d, J

(m, 2H), 6.84 (brs, 1H), 4.41−4.35 (m, 1H), 3.64−3.58 (m, 2H),

2.78 (s, 3H), 2.41 (s, 3H), 2.33 (brs, 1H), 1.63−1.57 (m, 2H), 1.56−

C−F

28.7, 128.5, 128.3, 118.3, 115.3 (d, J

4.5, 32.0, 21.8, 19.7 ppm; F NMR (376 MHz, CDCl ) δ −113.5

= 21.4 Hz), 62.4, 55.5, 51.6,

C−F

1.52 (m, 2H), 1.52−1.47 (m, 2H) ppm; C{ H} NMR (100 MHz,

ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

CDCl ) δ 151.6, 144.3, 140.1, 135.0, 133.2, 129.7 (2C), 128.9 (2C),

C H FN O S , 525.1854, found 525.1853.

128.52 (2C), 128.48, 128.4 (2C), 116.5, 62.3, 55.0, 35.9, 34.7, 32.0,

N-Benzyl-N-(5-(4-butylphenyl)-4-(4-hydroxybutyl)-2-oxo-

21.7, 19.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

,4-dihydro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfona-

C H N O S , 431.1635, found 431.1640.

mide (9ad). White solid (262 mg, 93%); mp 137−139 °C; puriﬁed

N-Butyl-N-(4-(4-hydroxybutyl)-2-oxo-5-phenyl-3,4-dihydro-

by ﬂash chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm):

2H-1,3-oxazin-6-yl)-4-methylbenzenesulfonamide (9ai). White

solid (229 mg, 97%); mp 122−124 °C; puriﬁed by ﬂash

−

1 1

ν_m_a_x3392, 2931, 1731, 1594, 1351, 1163, 1084, 818 cm ; H NMR

400 MHz, CDCl ) δ 7.83−7.67 (m, 2H), 7.33−7.30 (m, 2H), 7.23−

(

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν

3237, 2933, 1737, 1594, 1355, 1165, 1071, 767 cm ; H NMR (400

max

−

1 1

.19 (m, 1H), 7.16−7.09 (m, 2H), 7.06−7.04 (m, 2H), 6.93−6.80

m, 4H), 6.45 (brs, 1H), 4.23−4.19 (m, 1H), 4.13−3.98 (m, 2H),

MHz, CDCl ) δ 7.80−7.73 (m, 2H), 7.52−7.48 (m, 2H), 7.44−7.36

.60−3.57 (m, 2H), 2.63−2.59 (m, 2H), 2.44 (s, 3H), 1.94 (brs, 1H),

(m, 3H), 7.32−7.29 (m, 2H), 6.36 (brs, 1H), 4.41−4.36 (m, 1H),

3.65−3.60 (m, 2H), 2.97−2.91 (m, 2H), 2.42 (s, 3H), 1.97 (brs, 1H),

1.65−1.50 (m, 6H), 1.23−1.12 (m, 2H), 1.01−0.80 (m, 2H), 0.68−

.66−1.58 (m, 3H), 1.45−1.36 (m, 7H), 0.99−0.95 (m, 3H) ppm;

C{ H} NMR (100 MHz, CDCl ) δ 151.7, 144.4, 142.9, 137.0,

35.6, 133.8, 130.0, 129.8 (2C), 129.6, 128.7 (2C), 128.6 (2C), 128.4

0.62 (m, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 151.5,

(2C), 128.3 (2C), 128.2 (2C), 118.8, 62.4, 55.5, 51.7, 35.5, 34.6, 33.7,

144.3, 138.1, 135.8, 133.2, 129.7 (2C), 128.9 (2C), 128.7 (2C), 128.6

(2C), 128.5, 118.2, 62.5, 55.7, 48.1, 34.9, 32.1, 29.7, 21.7, 19.9, 19.7,

2.0, 22.6, 21.8, 19.7, 14.1 ppm; HRMS (ESI-Orbitrap) m/z: [M +

H] Calcd for C H N O S , 563.2574, found 563.2579.

13.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

N-Benzyl-N-(4-(4-hydroxybutyl)-2-oxo-5-pentyl-3,4-dihy-

dro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfonamide (9ae).

White solid (240 mg, 96%); mp 105−107 °C; puriﬁed by ﬂash

S , 473.2105, found 473.2103.

N-Benzyl-4-chloro-N-(4-(4-hydroxybutyl)-2-oxo-5-phenyl-

3,4-dihydro-2H-1,3-oxazin-6-yl)benzenesulfonamide (9aj).

White solid (134 mg, 51%); mp 140−142 °C; puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): νmax 3153,

chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν 3282,

max

−

1 1

927, 1737, 1596, 1457, 1351, 1165, 814 cm ; H NMR (400 MHz,

−

1 1

CDCl , rotamers) δ 7.81−7.77 (m, 2H), 7.37−7.34 (m, 2H), 7.31−

2943, 2363, 1745, 1584, 1357, 1163, 751 cm ; H NMR (400 MHz,

CDCl

.28 (m, 5H), 6.09 (brs, 1H), 4.70−4.66 (m, 1H), 4.01−3.88 (m,

.45H), 3.80−3.78 (m, 0.55H), 3.68−3.65 (m, 1.45H), 3.56−3.49

) δ 7.88−7.67 (m, 2H), 7.51−7.46 (m, 2H), 7.31−7.28 (m,

1H), 7.26−7.21 (m, 3H), 7.19−7.11 (m, 2H), 6.99−6.83 (m, 4H),

(

m, 0.55H), 2.44 (s, 3H), 2.30−2.23 (m, 1H), 1.89 (brs, 1H), 1.86−

6.80 (brs, 1H), 4.25−4.13 (m, 2H), 4.12−3.98 (m, 1H), 3.62−3.57

.77 (m, 1.45H), 1.57−1.52 (m, 1H), 1.50−1.46 (m, 0.55H), 1.43−

.35 (m, 1.45H), 1.32−1.22 (m, 2H), 1.15−1.07 (m, 2.45H), 1.03−

.98 (m, 0.55H), 0.95−0.87 (m, 3H), 0.83−0.78 (m, 3H), 0.20−0.08

(m, 2H), 2.35 (brs, 1H), 1.50−1.41 (m, 6H) ppm; C{ H} NMR

(100 MHz, CDCl ) δ 151.5, 140.1, 137.1, 137.0, 133.4, 132.7, 130.1

(2C), 129.7, 129.5 (2C), 128.7 (2C), 128.5 (2C), 128.4 (3C), 128.2

(2C), 119.0, 62.3, 55.4, 52.0, 34.4, 31.9, 19.7 ppm; HRMS (ESI-

(m, 0.55H) ppm; C{ H} NMR (100 MHz, CDCl , rotamers) δ

51.8, 144.4, 135.8, 135.3, 134.6, 130.0, 129.8, 128.7, 128.5, 128.4,

28.3, 128.0, 118.7, 62.5, 62.3, 52.1, 51.8, 51.7, 50.7, 34.6, 32.2, 32.1,

1.7, 29.8, 27.8, 27.5, 26.5, 26.4, 22.6, 21.8, 19.8, 19.5, 14.1 ppm;

Orbitrap) m/z: [M + H] Calcd for C27

28ClN

S , 527.1402,

found 527.1405.

-Methoxyethylbenzyl(4-(4-hydroxybutyl)-2-oxo-5-phenyl-

3,4-dihydro-2H-1,3-oxazin-6-yl) Carbamate (9ak). Colorless oil

159 mg, 70%); puriﬁed by ﬂash chromatography on silica gel (PE/

EtOAc = 1:2); IR (ﬁlm): ν 3302, 2933, 1737, 1602, 1441, 1380,

HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C H N O S ,

(

01.2418, found 501.2419.

N-Benzyl-N-(4-(4-hydroxybutyl)-2-oxo-5-(thiophen-2-yl)-

,4-dihydro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfona-

max

−

1 1

131, 702 cm ; H NMR (400 MHz, CDCl , rotamers) δ 7.34−7.30

mide (9af). Pale yellow solid (136 mg, 53%); mp 93−95 °C; puriﬁed

(m, 1H), 7.26−7.23 (m, 2H), 7.18−7.11 (m, 3H), 7.06−6.97 (m,

3.5H), 6.94 (brs, 1H), 6.79−6.71 (m, 0.5H), 4.56−4.48 (m, 1H),

4.44−4.35 (m, 1H), 4.33−4.27 (m, 1H), 4.26−4.22 (m, 1.5H), 4.21−

4.18 (m, 0.5H), 3.73−3.64 (m, 1.5H), 3.58−3.54 (m, 2H), 3.45−3.41

(m, 2H), 3.38−3.35 (m, 0.5H), 3.33−3.29 (m, 0.5H), 2.89−2.85 (m,

0.5H), 2.17 (brs, 1H), 1.66−1.56 (m, 1H), 1.47−1.37 (m, 5H) ppm;

by ﬂash chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm):

−1 1

ν_m_a_x3347, 2937, 1743, 1592, 1351, 1161, 910, 702 cm ; H NMR

(

400 MHz, CDCl ) δ 7.87−7.83 (m, 2H), 7.39−7.34 (m, 2H), 7.31−

.29 (m, 1H), 7.18−7.03 (m, 6H), 6.98−6.94 (m, 1H), 6.48 (brs,

H), 4.51−4.10 (m, 3H), 3.62−3.54 (m, 2H), 2.45 (s, 3H), 1.99 (brs,

H), 1.56−1.37 (m, 6H) ppm; C{ H} NMR (100 MHz, CDCl ) δ

C{ H} NMR (100 MHz, CDCl , rotamers) δ 155.6, 152.3, 139.4,

51.2, 144.7, 136.9, 135.2, 134.1, 133.0, 130.0, 129.9 (2C), 128.8

139.2, 135.9, 135.5, 133.3, 133.1, 129.7, 128.7, 128.6, 128.3, 128.2,

128.0, 127.6, 113.7, 70.9, 70.5, 65.3, 62.2, 58.9, 54.8, 51.6, 51.2, 34.5,

(2C), 128.4 (2C), 128.3 (2C), 126.9, 126.8 (2C), 114.5, 62.4, 54.4,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

2.3, 19.9, 19.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd

(m, 2H), 1.37−1.31 (m, 2H), 0.99−0.95 (m, 3H) ppm; C{ H}

for C H N O , 455.2177, found 455.2179.

NMR (100 MHz, CDCl ) δ 152.0, 148.3, 144.4, 129.1, 128.6, 124.6,

N-Benzyl-N-(4-(4-hydroxybutyl)-5-(4-methoxyphenyl)-2-

oxo-3,4-dihydro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfo-

namide (9al). White solid (231 mg, 86%); mp 129−131 °C; puriﬁed

by ﬂash chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm):

98.0, 62.2, 51.0, 35.4, 34.8, 33.4, 27.5, 22.3, 13.9 ppm; HRMS (ESI-

Orbitrap) m/z: [M + H] Calcd for C H NO , 290.1751, found

90.1752.

-(3-Hydroxypropyl)-6-(o-tolyl)-3,4-dihydro-2H-1,3-oxazin-

−

1 1

ν_m_a_x3261, 2933, 1735, 1608, 1510, 1349, 1161, 831 cm ; H NMR

400 MHz, CDCl ) δ 7.85−7.72 (m, 2H), 7.34−7.31 (m, 2H), 7.25−

2-one (10e). Colorless oil (54 mg, 44%); puriﬁed by ﬂash

(

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH

.20 (m, 1H), 7.19−7.10 (m, 2H), 6.94−6.83 (m, 3H), 6.81−6.75

= 19:1); IR (ﬁlm): ν 3284, 2941, 1727, 1602, 1404, 1335, 1059,

max

−

1 1

(

m, 3H), 6.71 (brs, 1H), 4.24−3.96 (m, 3H), 3.83 (s, 3H), 3.60−3.56

757 cm ; H NMR (400 MHz, CDCl ) δ 7.34−7.31 (m, 1H), 7.30−

(

m, 2H), 2.44 (s, 3H), 2.02 (brs, 1H), 1.49−1.38 (m, 6H) ppm;

7.28 (m, 1H), 7.27−7.23 (m, 1H), 7.20−7.18 (m, 1H), 7.18−7.14

(m, 1H), 5.11−5.08 (m, 1H), 4.25−4.21 (m, 1H), 3.68−3.64 (m,

C{ H} NMR (100 MHz, CDCl ) δ 159.4, 151.8, 144.5, 137.0,

35.6, 133.8, 130.0 (3C), 129.8 (2C), 129.6, 128.6 (2C), 128.4 (2C),

2H), 3.30 (brs, 1H), 2.40 (s, 3H), 1.76−1.66 (m, 4H) ppm; C{ H}

28.2, 125.0, 118.6, 113.7 (2C), 62.3, 55.4, 51.7, 34.5, 32.0, 21.8, 19.7

NMR (100 MHz, CDCl ) δ 152.3, 149.6, 136.6, 132.7, 130.7, 129.5,

ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

C H N O S , 537.2054, found 537.2054.

129.0, 125.8, 103.2, 62.1, 51.2, 34.6, 27.4, 20.4 ppm; HRMS (ESI-

Orbitrap) m/z: [M + H] Calcd for C H NO , 248.1281, found

14 18 3

N-Benzyl-N-(5-cyclopropyl-4-(4-hydroxybutyl)-2-oxo-3,4-di-

hydro-2H-1,3-oxazin-6-yl)-4-methylbenzenesulfonamide

9am). White solid (148 mg, 63%); mp 146−147 °C; puriﬁed by

ﬂash chromatography on silica gel (PE/EtOAc = 1:2); IR (ﬁlm): ν

248.1278.

4-(3-Hydroxypropyl)-6-(m-tolyl)-3,4-dihydro-2H-1,3-oxazin-

2-one (10f). Colorless oil (62 mg, 50%); puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH

(

max

−

1 1

280, 2937, 1733, 1596, 1349, 1161, 1033, 702 cm ; H NMR (400

= 19:1); IR (ﬁlm): ν 3276, 2933, 1724, 1402, 1259, 1186, 1061,

max

−

1 1

MHz, CDCl , rotamers) δ 7.84−7.80 (m, 2H), 7.37−7.34 (m, 2H),

784 cm ; H NMR (400 MHz, CDCl ) δ 7.45−7.43 (m, 1H), 7.42−

(

.32−7.27 (m, 5H), 6.33 (brs, 1H), 4.77−4.58 (m, 1H), 4.15−3.96

m, 1H), 3.70−3.53 (m, 2H), 3.44−3.33 (m, 0.4H), 3.27−3.16 (m,

.6H), 2.45 (s, 3H), 2.13 (brs, 1H), 1.72−1.52 (m, 4H), 1.51−1.38

m, 2H), 1.16−1.01 (m, 1H), 0.84−0.53 (m, 2H), 0.48−0.36 (m,

7.38 (m, 1H), 7.26−7.21 (m, 1H), 7.18−7.13 (m, 2H), 5.52−5.49

(m, 1H), 4.29−4.24 (m, 1H), 3.73−3.68 (m, 2H), 2.84 (brs, 1H)

2.36 (s, 3H), 1.83−1.67 (m, 4H) ppm; C{ H} NMR (100 MHz,

(

CDCl ) δ 152.1, 148.4, 138.3, 131.7, 130.2, 128.5, 125.4, 121.9, 98.9,

.6H), 0.22−0.16 (m, 1H), −0.14 to −0.21 (m, 0.4H) ppm; C{ H}

62.3, 51.1, 34.8, 27.6, 21.5 ppm; HRMS (ESI-Orbitrap) m/z: [M +

NMR (100 MHz, CDCl rotamers) δ 152.3, 144.4, 135.8, 134.3,

H] Calcd for C H NO , 248.1281, found 248.1279.

14 18 3

30.0, 128.5, 128.4, 128.3, 128.2, 119.3, 62.4, 51.4, 35.6, 32.0, 29.8,

6-(4-Fluorophenyl)-4-(3-hydroxypropyl)-3,4-dihydro-2H-

1,3-oxazin-2-one (10g). White solid (64 mg, 51%); mp 83−85 °C;

puriﬁed by ﬂash chromatography on silica gel (PE/EtOAc = 1:3 to

1.8, 20.2, 9.3, 6.0, 4.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]

Calcd for C H N O S , 471.1948, found 471.1952.

-(3-Hydroxypropyl)-6-phenyl-3,4-dihydro-2H-1,3-oxazin-

-one (10a). Colorless oil (62 mg, 53%); puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH

19:1); IR (ﬁlm): ν 3292, 2935, 1724, 1402, 1255, 1133, 1055,

EtOAc/MeOH = 19:1); IR (ﬁlm): ν 3312, 2916, 1724, 1508, 1400,

max

−

1 1

1233, 1057, 753 cm ; H NMR (400 MHz, CDCl ) δ 7.63−7.58 (m,

2H), 7.10−7.04 (m, 2H), 6.65 (brs, 1H), 5.48−5.45 (m, 1H), 4.30−

4.25 (m, 1H), 3.76−3.71 (m, 2H), 2.17 (brs, 1H), 1.85−1.76 (m,

max

−

53 cm ; H NMR (400 MHz, CD OD) δ 7.69−7.65 (m, 2H),

2H), 1.73−1.65 (m, 2H) ppm; C{ H} NMR (100 MHz, CDCl ) δ

.43−7.38 (m, 3H), 5.80 (d, J = 4.0 Hz, 1H), 4.28−4.23 (m, 1H),

163.5 (d, J

= 247.9 Hz), 151.4, 147.7, 128.0 (d, J

= 8.2 Hz), 115.7 (d, J

35.1, 27.7 ppm; F NMR (376 MHz, CD OD) δ −111.5 ppm;

HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C H FNO ,

= 1.2 Hz),

C−F

.65−3.60 (m, 2H), 1.78−1.71 (m, 2H), 1.70−1.62 (m, 2H) ppm;

126.8 (d, J

= 21.7 Hz), 98.7, 62.5, 51.3,

C−F

C{ H} NMR (100 MHz, CD OD) δ 153.5, 149.3, 133.2, 130.3,

29.6, 125.5, 100.4, 62.6, 52.0, 35.0, 28.2 ppm; HRMS (ESI-Orbitrap)

m/z: [M + H] Calcd for C H NO , 234.1125, found 234.1121.

13 15 3

252.1031, found 252.1031.

-(3-Hydroxypropyl)-6-(p-tolyl)-3,4-dihydro-2H-1,3-oxazin-

-one (10b). Colorless oil (82 mg, 66%); puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH

19:1); IR (ﬁlm): ν 3280, 2922, 2861, 1722, 1402, 1259, 1057,

6-(4-Chlorophenyl)-4-(3-hydroxypropyl)-3,4-dihydro-2H-

1,3-oxazin-2-one (10h). Foamed solid (55 mg, 41%); puriﬁed by

ﬂash chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/

MeOH = 19:1); IR (ﬁlm): ν 3337, 2929, 1722, 1492, 1396, 1257,

max

−

−1

55 cm ; H NMR (400 MHz, CDCl ) δ 7.50−7.46 (m, 2H), 7.23

1090, 755 cm ; H NMR (400 MHz, CD OD) δ 7.68−7.64 (m,

(

brs, 1H), 7.19−7.15 (m, 2H), 5.46−5.43 (m, 1H), 4.26−4.22 (m,

2H), 7.45−7.41 (m, 2H), 5.85 (d, J = 4.0 Hz, 1H), 4.27−4.23 (m,

H), 3.71−3.66 (m, 2H), 3.45−3.13 (brs, 1H), 2.34 (s, 3H), 1.79−

1H), 3.64−3.60 (m, 2H), 1.77−1.71 (m, 2H), 1.69−1.64 (m, 2H)

.64 (m, 4H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 152.2,

ppm; C{ H} NMR (100 MHz, CD OD) δ 153.2, 148.3, 136.1,

48.3, 139.4, 129.3, 129.0, 124.6, 98.2, 62.2, 51.1, 34.7, 27.5, 21.3

ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C H NO ,

132.0, 129.8, 127.1, 101.1, 62.6, 52.1, 35.0, 28.2 ppm; HRMS (ESI-

Orbitrap) m/z: [M + H] Calcd for C H ClNO , 268.0735, found

13 15 3

48.1281, found 248.1281.

-(4-Ethoxyphenyl)-4-(3-hydroxypropyl)-3,4-dihydro-2H-

,3-oxazin-2-one (10c). Foamed solid (103 mg, 74%); puriﬁed by

268.0735.

6-(4-Bromophenyl)-4-(3-hydroxypropyl)-3,4-dihydro-2H-

1,3-oxazin-2-one (10i). Pale yellow oil (56 mg, 36%); puriﬁed by

ﬂash chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/

MeOH = 19:1); IR (ﬁlm): ν 3298, 2941, 1722, 1604, 1512, 1247,

MeOH = 19:1); IR (ﬁlm): ν 3288, 2927, 1729, 1396, 1257, 1006,

max

−

−1 1

176, 757 cm ; H NMR (400 MHz, CD OD) δ 7.60−7.56 (m,

835, 755 cm ; H NMR (400 MHz, CD OD) δ 7.59−7.55 (m, 4H),

H), 6.97−6.93 (m, 2H), 5.64 (d, J = 3.2 Hz, 1H), 4.26−4.20 (m,

5.84 (d, J = 4.0 Hz, 1H), 4.27−4.22 (m, 1H), 3.65−3.60 (m, 2H),

H), 4.10−4.05 (m, 2H), 3.65−3.60 (m, 2H), 1.75−1.64 (m, 4H),

1.78−1.71 (m, 2H), 1.70−1.64 (m, 2H) ppm; C{ H} NMR (100

.44−1.40 (m, 3H) ppm; C{ H} NMR (100 MHz, CD OD) δ

MHz, CD OD) δ 153.1, 148.4, 132.8, 132.3, 127.3, 124.2, 101.2, 62.6,

61.3, 153.7, 149.3, 127.0, 125.6, 115.5, 98.3, 64.6, 62.6, 52.0, 35.2,

8.2, 15.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

52.1, 34.9, 28.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd

for C H BrNO , 312.0230, found 312.0229.

C H NO , 278.1387, found 278.1385.

4-(3-Hydroxypropyl)-6-(thiophen-2-yl)-3,4-dihydro-2H-1,3-

oxazin-2-one (10j). Colorless oil (74 mg, 62%); puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH =

-(4-Butylphenyl)-4-(3-hydroxypropyl)-3,4-dihydro-2H-1,3-

oxazin-2-one (10d). Colorless oil (75 mg, 52%); puriﬁed by ﬂash

19:1); IR (ﬁlm): ν 3300, 2939, 1729, 1520, 1410, 1243, 1059, 753

max

−

1 1

cm ; H NMR (400 MHz, CDCl ) δ 7.32−7.30 (m, 1H), 7.28−7.26

(m, 1H), 7.14 (brs, 1H), 7.02−6.99 (m, 1H), 5.40 (dd, J = 3.6, 1.6

Hz, 1H), 4.26−4.23 (m, 1H), 3.71−3.68 (m, 2H), 2.95 (brs, 1H),

1.79−1.66 (m, 4H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 150.5,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

43.1, 134.2, 126.7, 125.1, 124.0, 97.1, 61.2, 50.1, 33.6, 26.5 ppm;

ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C H NO ,

15 20 3

262.1438, found 262.1436.

HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C H NO S ,

40.0689, found 240.0686.

4-(4-Hydroxybutyl)-6-(m-tolyl)-3,4-dihydro-2H-1,3-oxazin-

2-one (10af). Colorless oil (57 mg, 44%); puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH

= 19:1); IR (ﬁlm): νmax 3280, 2933, 1729, 1657, 1400, 1265, 1073,

-(3-Hydroxypropyl)-6-(thiophen-3-yl)-3,4-dihydro-2H-1,3-

oxazin-2-one (10k). White solid (50 mg, 42%); mp 130−132 °C;

puriﬁed by ﬂash chromatography on silica gel (PE/EtOAc = 1:3 to

EtOAc/MeOH = 19:1); IR (ﬁlm): ν 3290, 2935, 1722, 1398, 1261,

−

1 1

784 cm ; H NMR (400 MHz, CDCl ) δ 7.46−7.43 (m, 1H), 7.42−

max

−

1 1

184, 1061, 755 cm ; H NMR (400 MHz, CD OD) δ 7.62−7.58

7.39 (m, 1H), 7.26−7.23 (m, 1H), 7.17−7.14 (m, 1H), 5.52−5.49

(m, 1H), 4.23−4.17 (m, 1H), 3.68−3.63 (m, 2H), 2.36 (s, 3H),

1.71−1.64 (m, 2H), 1.63−1.57 (m, 2H), 1.56−1.49 (m, 2H) ppm;

(

m, 1H), 7.46−7.43 (m, 1H), 7.34−7.31 (m, 1H), 5.66 (d, J = 3.6 Hz,

H), 4.21 (dd, J = 9.0, 4.6 Hz, 1H), 3.63−3.56 (m, 2H), 1.76−1.67

(

m, 2H), 1.66−1.59 (m, 2H) ppm; C{ H} NMR (100 MHz,

C{ H} NMR (100 MHz, CDCl ) δ 152.2, 148.2, 138.2, 131.6,

CD OD) δ 153.4, 146.4, 135.3, 127.7, 125.3, 123.1, 99.7, 62.6, 51.9,

130.1, 128.4, 125.2, 121.8, 98.8, 62.2, 51.0, 37.4, 32.1, 21.4, 20.6 ppm;

5.0, 28.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C15

20NO

C H NO S , 240.0689, found 240.0686.

262.1438, found 262.1436.

-(4-Hydroxybutyl)-6-phenyl-3,4-dihydro-2H-1,3-oxazin-2-

6-(4-Fluorophenyl)-4-(4-hydroxybutyl)-3,4-dihydro-2H-1,3-

oxazin-2-one (10ag). White solid (48 mg, 36%); mp 88−90 °C;

puriﬁed by ﬂash chromatography on silica gel (PE/EtOAc = 1:3 to

one (10aa). Colorless oil (49 mg, 40%); puriﬁed by ﬂash

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH

19:1); IR (ﬁlm): ν 3278, 2939, 2861, 1729, 1400, 1257, 1022,

EtOAc/MeOH = 19:1); IR (ﬁlm): ν 3284, 2935, 1727, 1600, 1506,

max

−

1 1

−

1 1

(

406, 1069, 755 cm ; H NMR (400 MHz, CD OD) δ 7.71−7.66

57 cm ; H NMR (400 MHz, CDCl ) δ 7.63−7.58 (m, 2H), 7.38−

m, 2H), 7.17−7.11 (m, 2H), 5.75 (d, J = 3.6 Hz, 1H), 4.23−4.18 (m,

.33 (m, 3H), 5.53−5.50 (m, 1H), 4.23−4.17 (m, 1H), 3.67−3.62

1H), 3.61−3.57 (m, 2H), 1.72−1.65 (m, 2H), 1.63−1.57 (m, 2H),

(

m, 2H), 1.71−1.63 (m, 2H), 1.61−1.50 (m, 4H) ppm; C{ H}

.55−1.48 (m, 2H) ppm; C{ H} NMR (100 MHz, CD OD) δ

NMR (100 MHz, CDCl ) δ 152.1, 148.2, 131.8, 129.4, 128.6, 124.7,

63.2 (d, J

= 246.2 Hz), 151.9, 147.0, 128.2 (d, J

= 2.9 Hz),

[

9.0, 62.3, 51.2, 37.5, 32.2, 20.7 ppm; HRMS (ESI-Orbitrap) m/z:

M + H] Calcd for C H NO , 248.1281, found: 248.1278.

C−F

126.3 (d, J

= 8.7 Hz), 115.0 (d, J

= 22.0 Hz), 98.9, 61.3, 50.8,

C−F

6.9, 32.0, 20.2 ppm; F NMR (376 MHz, CD OD) δ −114.0 ppm;

HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C H FNO ,

-(4-Hydroxybutyl)-6-(p-tolyl)-3,4-dihydro-2H-1,3-oxazin-2-

one (10ab). Colorless oil (85 mg, 65%); puriﬁed by ﬂash

14 17

66.1187, found 266.1185.

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH

19:1); IR (ﬁlm): ν 3324, 2937, 1730, 1606, 1404, 1261, 1130,

-(4-Hydroxybutyl)-6-(thiophen-2-yl)-3,4-dihydro-2H-1,3-

max

−

oxazin-2-one (10aj). Colorless oil (103 mg, 81%); puriﬁed by ﬂash

57 cm ; H NMR (400 MHz, CDCl ) δ 7.52−7.48 (m, 2H), 7.19−

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH =

.15 (m, 2H), 6.94 (brs, 1H), 5.48−5.45 (m, 1H), 4.23−4.17 (m,

H), 3.69−3.63 (m, 2H), 2.35 (s, 3H), 1.72−1.64 (m, 2H), 1.63−

−

9:1); IR (ﬁlm): ν_m_a_x3280, 2937, 1733, 1402, 1237, 1059, 702 cm ;

H NMR (400 MHz, CDCl

H), 7.21 (brs, 1H), 7.02−6.98 (m, 1H), 5.41−5.38 (m, 1H), 4.21−

4.16 (m, 1H), 3.67−3.62 (m, 2H), 2.96 (brs, 1H), 1.70−1.62 (m,

) δ 7.33−7.30 (m, 1H), 7.29−7.25 (m,

.58 (m, 2H), 1.56−1.49 (m, 2H) ppm; C{ H} NMR (100 MHz,

CDCl ) δ 152.2, 148.3, 139.5, 129.3, 129.0, 124.6, 98.1, 62.3, 51.2,

7.6, 32.2, 21.4, 20.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]

Calcd for C H NO , 262.1438, found 262.1435.

2H), 1.61−1.55 (m, 2H), 1.54−1.47 (m, 2H) ppm; C{ H} NMR

100 MHz, CDCl ) δ 151.6, 144.0, 135.2, 127.6, 126.0, 125.0, 98.1,

(

-(4-Ethoxyphenyl)-4-(4-hydroxybutyl)-3,4-dihydro-2H-1,3-

2.2, 51.1, 37.4, 32.1, 20.6 ppm; HRMS (ESI-Orbitrap) m/z: [M +

oxazin-2-one (10ac). White solid (122 mg, 84%); mp 130−132 °C;

H] Calcd for C H NO S , 254.0845, found 254.0843.

puriﬁed by ﬂash chromatography on silica gel (PE/EtOAc = 1:3 to

12 16

-(4-Hydroxybutyl)-6-(thiophen-3-yl)-3,4-dihydro-2H-1,3-

EtOAc/MeOH = 19:1); IR (ﬁlm): ν 2939, 1731, 1606, 1510, 1404,

max

−

oxazin-2-one (10ak). White solid (75 mg, 59%); mp 89−91 °C;

(

269, 1043, 755 cm ; H NMR (400 MHz, CD OD) δ 7.56−7.53

puriﬁed by ﬂash chromatography on silica gel (PE/EtOAc = 1:3 to

m, 2H), 6.92−6.89 (m, 2H), 5.59 (d, J = 3.6 Hz, 1H), 4.18−4.13 (m,

EtOAc/MeOH = 19:1); IR (ﬁlm): ν 3306, 2935, 1729, 1655, 1414,

max

H), 4.06−4.00 (m, 2H), 3.58−3.54 (m, 2H), 1.67−1.61 (m, 2H),

−

1 1

(

259, 1051, 757 cm ; H NMR (400 MHz, CDCl ) δ 7.60−7.57 (m,

.59−1.53 (m, 2H), 1.51−1.44 (m, 2H), 1.40−1.36 (m, 3H) ppm;

H), 7.32−7.29 (m, 1H), 7.22−7.19 (m, 1H), 7.00 (brs, 1H), 5.39

C{ H} NMR (100 MHz, CD OD) δ 161.2, 153.7, 149.1, 126.9,

dd, J = 3.2, 1.6 Hz, 1H), 4.22−4.18 (m, 1H), 3.68−3.63 (m, 2H),

(

25.5, 115.4, 98.3, 64.6, 62.7, 52.1, 38.5, 33.4, 21.5, 15.1 ppm; HRMS

ESI-Orbitrap) m/z: [M + H] Calcd for C H NO , 292.1543,

.63 (brs, 1H), 1.71−1.63 (m, 2H), 1.62−1.57 (m, 2H), 1.55−1.48

13 1

(

m, 2H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 151.9, 145.1,

found 292.1544.

33.8, 126.6, 124.1, 122.7, 98.4, 62.3, 51.0, 37.5, 32.1, 20.7 ppm;

-(4-Butylphenyl)-4-(4-hydroxybutyl)-3,4-dihydro-2H-1,3-

HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C H NO S ,

oxazin-2-one (10ad). Colorless oil (85 mg, 56%); puriﬁed by ﬂash

54.0845, found 254.0843.

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH =

-([1,1′-Biphenyl]-4-yl)-4-(4-hydroxybutyl)-3,4-dihydro-2H-

9:1); IR (ﬁlm): ν 3304, 2929, 2859, 1733, 1661, 1514, 1257, 759

max

1,3-oxazin-2-one (10al). White solid (86 mg, 53%); mp 137−139

°C; puriﬁed by ﬂash chromatography on silica gel (PE/EtOAc = 1:3

to EtOAc/MeOH = 19:1); IR (ﬁlm): ν 3147, 2933, 1714, 1486,

−

1 1

cm ; H NMR (400 MHz, CDCl ) δ 7.54−7.51 (m, 2H), 7.19−7.16

(

m, 2H), 7.04 (brs, 1H), 5.48−5.46 (m, 1H), 4.23−4.18 (m, 1H),

max

.68−3.63 (m, 2H), 2.84 (brs, 1H), 2.63−2.58 (m, 2H), 1.72−1.64

−1 1

400, 1276, 1067, 765 cm ; H NMR (400 MHz, CD OD) δ 7.77−

m, 2H), 1.63−1.59 (m, 2H), 1.58−1.47 (m, 4H), 1.37−1.31 (m,

.74 (m, 2H), 7.71−7.65 (m, 4H), 7.49−7.44 (m, 2H), 7.40−7.35

H), 0.94−0.90 (m, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ

(m, 1H), 5.86 (d, J = 4.0 Hz, 1H), 4.25 (dd, J = 9.2, 5.2 Hz, 1H),

52.3, 148.3, 144.5, 129.2, 128.6, 124.6, 98.1, 62.3, 51.1, 37.6, 35.5,

.63−3.59 (m, 2H), 1.75−1.69 (m, 2H), 1.66−1.60 (m, 2H), 1.57−

13 1

3.5, 32.2, 22.4, 20.7, 14.0 ppm; HRMS (ESI-Orbitrap) m/z: [M +

.51 (m, 2H) ppm; C{ H} NMR (100 MHz, CD OD) δ 153.5,

H] Calcd for C H NO , 304.1907, found 304.1906.

149.0, 143.2, 141.5, 132.1, 130.0, 128.7, 128.1, 127.9, 126.0, 100.5,

-(4-Hydroxybutyl)-6-(o-tolyl)-3,4-dihydro-2H-1,3-oxazin-2-

2.7, 52.2, 38.4, 33.4, 21.6 ppm; HRMS (ESI-Orbitrap) m/z: [M +

one (10ae). Colorless oil (44 mg, 34%); puriﬁed by ﬂash

H] Calcd for C H NO , 324.1594, found 324.1591.

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH

19:1); IR (ﬁlm): ν 3280, 2933, 1727, 1663, 1400, 1249, 1022,

59 cm ; H NMR (400 MHz, CDCl ) δ 7.35−7.32 (m, 1H), 7.30−

.25 (m, 1H), 7.22−7.20 (m, 1H), 7.19−7.16 (m, 1H), 6.97 (brs,

H), 5.13−5.11 (m, 1H), 4.23−4.19 (m, 1H), 3.67−3.62 (m, 2H),

.42 (s, 3H), 2.14 (brs, 1H), 1.71−1.65 (m, 2H), 1.61−1.52 (m, 4H)

ppm; C{ H} NMR (100 MHz, CDCl ) δ 152.2, 149.8, 136.7, 132.7,

30.7, 129.5, 129.0, 125.8, 103.1, 62.3, 51.3, 37.5, 32.1, 20.6, 20.5

-Cyclopropyl-4-(4-hydroxybutyl)-3,4-dihydro-2H-1,3-oxa-

zin-2-one (10am). Colorless oil (69 mg, 65%); puriﬁed by ﬂash

max

−

1 1

chromatography on silica gel (PE/EtOAc = 1:3 to EtOAc/MeOH =

19:1); IR (ﬁlm): ν 3285, 2934, 2863, 1729, 1410, 1263, 1069, 759

max

−

1 1

cm ; H NMR (400 MHz, CDCl ) δ 7.11 (brs, 1H), 4.81 (dd, J =

3.0, 1.4 Hz, 1H), 4.02−3.96 (m, 1H), 3.65−3.60 (m, 2H), 3.22 (brs,

1H), 1.60−1.51 (m, 4H), 1.49−1.41 (m, 3H), 0.79−0.73 (m, 2H),

0.71−0.65 (m, 2H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 152.2,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.0c01692.

Article

50.9, 97.1, 62.1, 50.8, 37.6, 32.1, 20.5, 12.4, 4.5, 4.4 ppm; HRMS

128.8, 128.4, 79.7, 48.3, 39.3, 28.4, 25.4, 19.0 ppm; HRMS (ESI-

(

ESI-Orbitrap) m/z: [M + H] Calcd for C H NO , 212.1281,

Orbitrap) m/z: [M + H] Calcd for C H NO , 304.1907, found

18 26 3

found 212.1281.

304.1904.

2-(1-Methylpiperidin-2-yl)-1-phenylethan-1-ol (13).

-(4-Ethoxyphenyl)-4-(4-hydroxybutyl)-3-methyl-3,4-dihy-

dro-2H-1,3-oxazin-2-one (10bc). White solid (86 mg, 56%); mp

10−112 °C; puriﬁed by ﬂash chromatography on silica gel (PE/

EtOAc = 1:2 to EtOAc/MeOH = 49:1); IR (ﬁlm): ν 3449, 2933,

White solid (202 mg, 93%, 2 steps); mp 77−79 °C; IR (ﬁlm): ν

max

−

1 1

2931, 2855, 2792, 1453, 1371, 1063, 751, 700 cm ; H NMR (400

max

MHz, CDCl ) δ 7.39−7.36 (m, 2H), 7.35−7.30 (m, 2H), 7.26−7.21

−

712, 1604, 1512, 1239, 1176, 754 cm ; H NMR (400 MHz,

(m, 1H), 4.88 (dd, J = 10.4, 2.4 Hz, 1H), 3.10−3.02 (m, 1H), 2.88−

2.80 (m, 1H), 2.58−2.50 (m, 1H), 2.48 (s, 3H), 2.16−2.03 (m, 1H),

1.79−1.71 (m, 1H), 1.69−1.56 (m, 2H), 1.55−1.48 (m, 1H), 1.48−

CDCl ) δ 7.55−7.52 (m, 2H), 6.88−6.85 (m, 2H), 5.40 (d, J = 4.4

Hz, 1H), 4.06−4.02 (m, 2H), 4.01−3.98 (m, 1H), 3.64−3.60 (m,

H), 3.02 (s, 3H), 2.19 (brs, 1H), 1.79−1.71 (m, 1H), 1.69−1.62 (m,

1.45 (m, 1H), 1.44−1.41 (m, 1H), 1.36−1.30 (m, 1H) ppm; C{ H}

H), 1.61−1.56 (m, 2H), 1.46−1.42 (m, 1H), 1.41−1.39 (m, 3H),

NMR (100 MHz, CDCl ) δ 145.8, 128.4, 127.1, 125.7, 74.7, 61.0,

.38−1.36 (m, 1H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 159.8,

51.4, 148.4, 126.1, 124.1, 114.4, 96.5, 63.6, 62.4, 57.5, 34.2, 33.9,

2.5, 19.8, 14.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd

51.5, 40.1, 39.9, 26.0, 22.5, 20.7 ppm; HRMS (ESI-Orbitrap) m/z:

[M + H] Calcd for C14H22NO , 220.1696, found 220.1691.

for C H NO , 306.1700, found 306.1700.

ASSOCIATED CONTENT

sı Supporting Information

■

-(4-Hydroxybutyl)-3-methyl-6-(thiophen-3-yl)-3,4-dihy-

dro-2H-1,3-oxazin-2-One (10bj). Pale yellow solid (71 mg, 53%);

mp 90−92 °C; puriﬁed by ﬂash chromatography on silica gel (PE/

The Supporting Information is available free of charge at

EtOAc = 1:2 to EtOAc/MeOH = 49:1); IR (ﬁlm): ν 3133, 2935,

max

−

712, 1404, 1231, 1192, 1112, 790 cm ; H NMR (400 MHz,

Optimization of reaction conditions for the synthesis of

CDCl ) δ 7.62−7.59 (m, 1H), 7.33−7.29 (m, 1H), 7.21−7.18 (m,

compound 10; copies of H, C{ H}, and F NMR

spectra; X-ray structural data (CIF) (9a ; 10al); and

HPLC reports of 9aa, 9e, 9k, and 9ak (PDF )

H), 5.40 (d, J = 4.8 Hz, 1H), 4.05−4.01 (m, 1H), 3.67−3.63 (m,

H), 3.04 (s, 3H), 1.83−1.77 (m, 1H), 1.71−1.62 (m, 3H), 1.46−

.41 (m, 2H), ppm; C{ H} NMR (100 MHz, CDCl ) δ 151.1,

45.7, 133.8, 126.6, 124.2, 122.8, 97.9, 62.7, 57.4, 34.4, 33.9, 32.6,

9.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

Accession Codes

C H NO S , 268.1002, found 268.1001.

CCDC 2013028 (9a) and 2013029 (10al) contain the

supplementary 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:

-Cyclopropyl-4-(4-hydroxybutyl)-3-methyl-3,4-dihydro-

H-1,3-oxazin-2-one (10bm). Colorless oil (42 mg, 37%); puriﬁed

by ﬂash chromatography on silica gel (PE/EtOAc = 1/2 to EtOAc/

MeOH = 49/1); IR (ﬁlm): ν 3424, 2939, 1720, 1602, 1453, 1237,

max

−

1 1

067, 755 cm ; H NMR (400 MHz, CDCl ) δ 4.83 (d, J = 4.4 Hz,

H), 3.85−3.81 (m, 1H), 3.66−3.62 (m, 2H), 2.96 (s, 3H), 2.13 (brs,

H), 1.71−1.64 (m, 1H), 1.64−1.57 (m, 2H), 1.56−1.50 (m, 1H),

.48−1.41 (m, 1H), 1.39−1.30 (m, 2H), 0.82−0.73 (m, 2H), 0.72−

441223 336033.

.66 (m, 2H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 151.6,

AUTHOR INFORMATION

■

51.4, 96.7, 62.5, 57.3, 34.2, 33.9, 32.5, 19.6, 12.3, 4.7, 4.5 ppm;

Corresponding Authors

HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C H NO ,

Chang-Mei Si − Institutes of Biomedical Sciences and School of

Pharmacy, Fudan University, Shanghai 200433, China;

Email: sicm@fudan.edu.cn

26.1438, found 226.1434.

-Phenyl-4a,5,7,8-tetrahydro-1H,6H-pyrido[1,2-c][1,3]-

oxazin-1-one (11).

Colorless oil (344 mg, 75%, 2 steps); puriﬁed

by ﬂash chromatography on silica gel (PE/EtOAc = 5/1); IR (ﬁlm):

ν_m_a_x2937, 2853, 1720, 1496, 1447, 1222, 765 cm ; H NMR (400

Bang-Guo Wei − Institutes of Biomedical Sciences and School of

Pharmacy, Fudan University, Shanghai 200433, China;

orcid.org/0000-0003-3470-6741; Email: bgwei1974@

fudan.edu.cn

−

1 1

MHz, CDCl ) δ 7.64−7.58 (m, 2H), 7.38−7.32 (m, 3H), 5.43−5.40

(

m, 1H), 4.50 (d, J = 13.6 Hz, 1H), 4.02−3.96 (m, 1H), 2.79−2.71

m, 1H), 1.96−1.91 (m, 1H), 1.84−1.80 (m, 1H), 1.75−1.70 (m,

H), 1.60−1.46 (m, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ

Authors

49.7, 147.3, 131.9, 129.3, 128.5, 124.7, 98.9, 55.4, 45.3, 34.0, 25.1,

4.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for

Xiao-Li Han − Institutes of Biomedical Sciences and School of

Pharmacy, Fudan University, Shanghai 200433, China

Xiao-Di Nie − Institutes of Biomedical Sciences and School of

Pharmacy, Fudan University, Shanghai 200433, China

Zhao-Dan Chen − Institutes of Biomedical Sciences and School

of Pharmacy, Fudan University, Shanghai 200433, China

Guo-Qiang Lin − Shanghai Institute of Organic Chemistry,

Chinese Academy of Sciences, Shanghai 200032, China

C H NO , 230.1176, found 230.1174.

1-Phenyl-2-(piperidin-2-yl)ethan1-one (12).

Colorless oil

(

864 mg, 85%); puriﬁed by ﬂash chromatography on silica gel

(EtOAc/MeOH = 2/1, 0.2% TEA); IR (ﬁlm): ν 3335, 2931, 1682,

max

−

1 1

596, 1447, 1290, 1008, 749 cm ; H NMR (400 MHz, CDCl ) δ

.98−7.92 (m, 2H), 7.58−7.52 (m, 1H), 7.49−7.41 (m, 2H), 3.15−

.10 (m, 1H), 3.06−3.01 (m, 3H), 2.75−2.67 (m, 1H), 2.46 (brs,

H), 1.83−1.77 (m, 1H), 1.69−1.60 (m, 2H), 1.50−1.38 (m, 2H),

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c01692

.34−1.24 (m, 1H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 199.6,

37.1, 133.2, 128.6, 128.1, 52.9, 46.9, 45.7, 32.8, 26.1, 24.8 ppm;

HRMS (ESI-Orbitrap) m/z: [M + H] Calcd for C H NO ,

Notes

04.1383, found 204.1381.

tert-Butyl 2-(2-oxo-2-phenylethyl)piperidine-1-carboxylate

The authors declare no competing ﬁnancial interest.

17d

(12a). Colorless oil (1.1 g, 92%); puriﬁed by ﬂash chromatography

on silica gel (PE/EtOAc = 5/1); IR (ﬁlm): ν 3341, 2939, 1684,

max

ACKNOWLEDGMENTS

−

■

(

596, 1410, 1276, 1161, 753 cm ; H NMR (400 MHz, CDCl ) δ

.01−7.97 (m, 2H), 7.59−7.54 (m, 1H), 7.50−7.45 (m, 2H), 4.86−

.79 (m, 1H), 4.14−3.96 (m, 1H), 3.26−3.19 (m, 1H), 3.18−3.12

We thank the National Natural Science Foundation of China

21772027 to B.-G.W.) and (21702032 to C.-M.S) and the

Open Research Fund Program of Beijing Key Lab of Plant

Resource Research and Development, BTBU (no. PRRD-

(m, 1H), 2.93−2.84 (m, 1H), 1.69−1.58 (m, 6H), 1.36 (s, 9H) ppm;

C{ H} NMR (100 MHz, CDCl ) δ 198.5, 154.8, 136.9, 133.2,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

018-ZD1) for ﬁnancial support. The authors also thank Dr.

Huang, N.-Y.; Yan, J.-Y.; Hu, W.-M.; Liu, M.-G.; Ding, M.-W.

Article

Catalytic aza-Wittig Reaction of Acid Anhydride for the Synthesis of

H-Benzo[d][1,3]oxazin-4-ones and 4-Benzylidene-2-aryloxazol-

Han-Qing Dong (Arvinas, Inc.) for helpful suggestions.

(4H)-one. ACS Catal. 2016 , 6 , 4010 −4016. (d) Hao, W.; Xu, Z.;

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