Unexpected Rearrangement of N-Allyl-2-phenyl-4,5-Dihydrooxazole-4-Carboxamides to Construct Aza-Quaternary Carbon Centers

Article abstract of DOI:10.3390/molecules24244495

The unexpected rearrangement of N-allyl-2-phenyl-4,5-dihydrooxazole-4-carboxamides in the presence of LiHMDS has been found. The key features are: (1) the net reaction consisted of 1,3-migration of the N-allyl group, (2) the rearrangement produced a congested aza-quaternary carbon center, (3) both cyclic and acyclic substrates underwent the unexpected rearrangement to afford products in moderate to high yields, and (4) the reaction seemed to be highly stereoselective. In addition, a plausible mechanism has been discussed.

Full text of DOI:10.3390/molecules24244495

molecules
Article
Unexpected Rearrangement of
N-Allyl-2-phenyl-4,5-Dihydrooxazole-4-Carboxamides
to Construct Aza-Quaternary Carbon Centers
1
1
1
1
2
Goyeong Choi , Seoyoung Jo , Juyeon Mun , Yonguk Jeong , Seok-Ho Kim
1
,
and Jong-Wha Jung *
1
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University,
Daegu 41566, Korea; qlgudtmfkqmf@naver.com (G.C.); tjdud117@naver.com (S.J.);
wndus2604@naver.com (J.M.); nemo946@naver.com (Y.J.)
Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University,
Gyeonggi-do 11160, Korea; ksh3410@cha.ac.kr
2
*
Correspondence: jungj@knu.ac.kr; Tel.: +82-53-950-8578
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Narciso M. Garrido
Received: 19 November 2019; Accepted: 6 December 2019; Published: 8 December 2019
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: The unexpected rearrangement of N-allyl-2-phenyl-4,5-dihydrooxazole-4-carboxamides
in the presence of LiHMDS has been found. The key features are: (1) the net reaction consisted
of 1,3-migration of the N-allyl group, (2) the rearrangement produced a congested aza-quaternary
carbon center, (3) both cyclic and acyclic substrates underwent the unexpected rearrangement to
afford products in moderate to high yields, and (4) the reaction seemed to be highly stereoselective.
In addition, a plausible mechanism has been discussed.
Keywords: rearrangement; aza-quaternary carbon center; ring expansion
1
. Introduction
Rearrangements are highly defined and reliable chemical transformations in terms of efficiency
and atom economy. Unlike other chemical reactions, rearrangement involves structural reorganization.
This facilitates the construction of congested carbon centers in a highly stereo-controlled fashion.
Numerous methods, protocols, and applications have been developed for rearrangement reactions,
[3,3]-sigmatropic rearrangement being a textbook example [1–4]. Among the driving forces that have
been discovered or developed to facilitate such rearrangements, the accelerating effects of various
substituents continue to attract attention [5–8].
In our research on the synthesis of bioactive alkaloids and small molecules, we became interested
in the accelerating effects of substituents in an aza-Claisen rearrangement (ACR) [
2]. Much of
the effort in the development of ACR has focused on cationic or zwitterionic ACR [
9
]. Anionic
ACR is relatively unexplored, possibly because its activation energy is large [10]. Rate acceleration
with the ionic involvement of a neighboring functional group could be utilized to overcome the
activation energy barrier of anionic ACR [2]. For instance, Tsunoda et al. [11
,12] employed glycinamide
for amide-enolate-induced ACR using an acyclic precursor, while Suh et al. [13
–
15] did so with
a cyclic precursor (Figure 1A). Rearrangement acceleration in those cases could be attributed to
an electronic effect, a chelation effect, or both [11]. Interestingly, those methods have not been
expanded for the construction of congested aza-quaternary carbon centers, even though a great deal
of effort has been devoted to constructing nitrogen-bearing quaternary centers through molecular
rearrangement [16]. We thus became interested in the synthesis of compounds with aza-quaternary
carbon centers by accelerating such rearrangements. During our research program, we observed
Molecules 2019, 24, 4495; doi:10.3390/molecules24244495
www.mdpi.com/journal/molecules

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an unexpected rearrangement reaction of N-allyl-2-phenyl-4,5-dihydrooxazole-4-carboxamides to
construct aza-quaternary carbon centers (Figure 1B). Herein we report the rearrangement reaction,
including its scope and limitations.
Figure 1. (A) Anionic aza-Claisen rearrangement (ACR) of glycinamides; (B) this work.
2
. Results and Discussion
2
.1. Substrate Screening and Optimization of Reaction Conditions
We envisioned employing amide-enolate-induced ACR for the construction of congested
aza-quaternary carbon centers using glycinamide substrates. We initially evaluated glycinamides as
potential substrates for ACR (Table 1, Entries 1–5). Unfortunately, our attempts with glycinamide
1
a
, which had a free amine functional group, did not produce the desired ACR product (
2). Unlike
the results reported by Tsunoda et al. and Suh et al. [11 15], our substrate (1a) decomposed to
–
unidentified compounds over time (Table 1, Entries 1 and 2). We also tried protecting the glycinamide
with various protecting groups (1b–e), including Fmoc (Table 1, Entry 3), Boc (Table 1, Entry 4),
Cbz (Table 1, Entry 5), and phthalimide (Table 1, Entry 6). However, these attempts failed to provide
the desired ACR product (
-phenyl-4,5-dihydrooxazole-4-carboxamide (1f, Entries 7–10). To our satisfaction, a product was
obtained under the standard amide-enolate-induced ACR conditions [ ] in a reasonable yield (Table 1,
2) again. We continued our experiment using a serinamide derivative,
2
2
Entry 7). The reaction was even successful at room temperature (Table 1, Entry 8). We initially thought
1
we obtained the desired ACR product (
2
). To our surprise, H NMR spectroscopy revealed terminal
vinyl protons instead of the expected internal olefin protons. After carefully analyzing the spectral
data, the compound was found to be an unexpected rearrangement product (
3
) rather than the ACR
1
product (
2). After careful analysis of H NMR spectrum, the rearrangement product (
3) appeared to be
a single diastereomer in a view of relative stereochemistry, even though it could not be determined.
To the best of our knowledge, this type of rearrangement has never been reported. After evaluating a

Molecules 2019, 24, 4495
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different solvent (Table 1, Entries 8 and 9) and base (Table 1, Entries 9 and 10), we had our optimized
condition (Table 1, Entry 9).
Table 1. Optimization of the Reaction a.
O
1
2
N(R )(R )
N
R3
H
O
2
1
2
N(R )(R )
expected aza-Claisen
rearrangement product
N
R3
O
O
N
H
1
2
N(R )(R )
R3
N
1
2
H
N(R )(R )
1
R3
3
unexpected
rearrangement product
Yield 3 (%) b
Entry
1
Substrate
Conditions
Time (h)
Yield 2 (%)
O
NH2
Me
N
LiHMDS
toluene
reflux
4
-
ND c
1a
O
NH2
Me
N
iPrMgCl
benzene
reflux
2
3
4
5
4
4
4
4
-
-
-
-
ND c
ND c
ND c
ND c
1a
LiHMDS
toluene
reflux
LiHMDS
toluene
reflux
LiHMDS
toluene
reflux
LiHMDS
toluene
reflux
6
4
-
ND c

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Table 1. Cont.
O
1
2
N(R )(R )
N
H
R3
O
2
1
2
N(R )(R )
expected aza-Claisen
rearrangement product
N
R3
O
O
N
H
1
2
N(R )(R )
R3
N
1
2
H
N(R )(R )
1
R3
3
unexpected
rearrangement product
Yield 3 (%) b
Entry
7
Substrate
Conditions
Time (h)
Yield 2 (%)
LiHMDS
toluene
reflux
72 d
1
-
LiHMDS
toluene
rt
92 d
96 d
84 d
8
9
1
1
1
-
-
-
LiHMDS
benzene
rt
iPrMgCl
benzene
rt
1
0
a
Reaction conditions: Three equivalents of either lithium bis(trimethylsilyl)amide (LiHMDS) or isopropylmagnesium
chloride (iPrMgCl) were added dropwise to the given substrate in solution and either refluxed or reacted at room
temperature (rt). Isolated yields. c Not detected. d Single diastereomer, not determined.
b
2
.2. Preparation of Substrates
Next, we explored the scope of the reaction using various substrates to determine whether
the unexpected rearrangement could be generalized. The requisite serinamide derivatives were
prepared as shown in Scheme 1. Seven- to nine-membered vinyl azacycles (1g–i) were synthesized
from the corresponding lactams (4g–i) as previously reported [17]. Briefly, partial reduction of
the Boc-protected lactams (5g–i) and consecutive trimethylsilyl (TMS) trapping yielded N,O-acetal
TMS ethers (6g–i). The N-acyliminium ion precursors (6g–i) were treated with vinyl Grignard
reagent and copper salt in the presence of BF as a Lewis acid to give vinyl azacycles (7g-i),
3
which were then treated with trifluoroacetic acid (TFA) for deprotection. Finally, the resulting
TFA salts (8g–i) were cross-coupled with sodium carboxylate (9) to afford the desired serinamides

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(1g–i) as diastereomeric mixtures. It was worth noting that after screening a series of coupling agents,
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
(HATU) was the most efficient reagent in terms of chemical yield. The required sodium carboxylate (9)
was prepared from L-serine methyl ester according to a reported procedure [18].
Scheme 1. Preparation of serinamides 1g–i.
To synthesize the acyclic serinamide derivatives (1j–n), secondary amines with allyl or substituted
allyl groups were first prepared from commercially available benzyl amine and the corresponding alkyl
bromides (10, Scheme 2). The resulting secondary amines (11j–n) were cross-coupled with sodium
carboxylate (9) to afford the desired serinamide derivatives (1j–n) in moderate to high yields.
Scheme 2. Preparation of serinamides 1j–n.
2
.3. Reaction Scope
Reacting the seven- to nine-membered cyclic substrates (1g–i) in the presence of LiHMDS afforded
the expected rearrangement products (3g–i) in moderate to high yields at room temperature (Table 2,
1
Entries 2–4). All of the products (3g–i) appeared to be single diastereomers in the H NMR spectra.
An acyclic substrate with a terminal olefin (1j) also provided the expected product (3j) within a very
short period of time (Table 2, Entry 5). Unlike the reactions that generated the cyclic substrates (3f–i),
ACR could not be ruled out as a plausible mechanism in this case. We next performed the reactions
with acyclic substrates using substituted olefins. However, the reaction between the acyclic substrate
and the phenyl-substituted olefin 1k was slower. Only trace amounts of unidentified products were
obtained after many hours at room temperature. We thus tried reacting 1k–n by refluxing them in the
solvent, which effectively generated the expected rearrangement products (3k–n) after 12 h (Table 2,
1
Entries 7–10). In this case, the H NMR spectrum of each product (3k–n) clearly showed a pair of
internal olefin protons. It was noted that the internal olefin geometry was conserved after the reactions

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(Table 2, Entries 8 and 9). A larger substituent reduced the chemical yield, possibly through steric
interactions. Based on the results of reacting acyclic substrates with substituted olefins, we concluded
that the reaction between acyclic substrates and terminal olefins might proceed by the same mechanism
as the others rather than ACR.
Table 2. Scope of the reaction a.
Yield (%) b
Entry
1
Substrate
Product
Time
1 h
96 c
2
3
4
5
6
1 h
1 h
71 c
76 c
77 c
95
1 h
5 min
12 h d
70

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Table 2. Cont.
Yield (%) b
Entry
7
Substrate
Product
Time
12 h d
84
12 h d
8
75
74
O
Bn
N
N
Ph
12 h d
9
O
Et
1n
a
Reactions were performed with three equivalents of LiHMDS, at room temperature unless otherwise noted.
Isolated yields. c Single diastereomer, not determined. d Refluxed.
b
2
.4. Proposed Mechanism
Plausible mechanism for the unexpected rearrangement is shown in Figure 2. One mechanism
(Route A) is 1,3-migration of the N-allyl group (Route A), while the other involves tandem reactions
(Route B). To investigate the direct 1,3-migration mechanism which is similar to 1,2-migration of
Stevens rearrangement [19–22] we performed the reaction with substrates bearing N-propyl (saturated)
or N-benzyl groups. This failed to provide the expected products, so rearrangement more likely
occurred through tandem reactions even though we could not isolate any of the possible intermediates
of tandem reactions. Since the geometry of the internal olefins was conserved (Table 2, Entries 8 and 9),
the tandem reactions appeared to be highly stereo-controlled. Further studies are needed to confirm
the unexpected reaction mechanism.

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Figure 2. Plausible mechanism for the unexpected rearrangement.
. Materials and Methods
3
3
.1. General Information
Unless noted otherwise, all starting materials and solvents were used as obtained from commercial
suppliers (Aldrich, Yongin, Korea) without further purification. Organic solvents used in this study
were dried over appropriate drying agents and distilled prior to use. Thin layer chromatography was
carried out using Merck silica gel 60 F254 plates, and flash chromatography was performed automatically
with Biotage Isolera or manually using Merck silica gel 60 (0.040–0.063 mm, 230–400 mesh, Seoul,
1
13
Korea). H and C NMR spectra were recorded using JEOL-500 and BRUKER (Seongnam, Korea)
1
13
AVANCE-500. H and C NMR chemical shifts are reported in parts per million (ppm) relative to TMS,
with the residual solvent peak used as an internal reference. Low and high resolution mass spectra
were obtained with JEOL JMS-700 instrument (Seoul, Korea) and Agilent Q TOF 6530 (Seoul, Korea).
1
H NMR data were reported in the order of chemical shift, multiplicity (br, broad signal; s, singlet;
d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet and/or multiple resonances), number of
1
13
protons, and coupling constant in hertz (Hz). H and C NMR spectra of compounds 1f-n and 3f-n
are available in Supplementary Materials.
3
.2. Experimental
3
.2.1. Representative Procedure: Synthesis of Compound 1g
TFA (0.383 mL, 5.00 mmol) was added to a solution of compound 7g (113 mg, 0.502 mmol) [17
]
in CH Cl (2.5 mL). The reaction mixture was stirred till completion. Then, volatiles were removed
2
2
in vacuo to afford crude compound 8g. Compound 8g was used for next reaction without further
purification. To a stirred solution of the above compound 8g in CH Cl (2.5 mL), compound (148 mg,
.751 mmol) [18], HATU (285 mg, 0.751 mmol) and Et N (0.139 mL, 1.00 mmol) were added. The reaction
9
2
2
0
3
mixture was stirred overnight. The resulting mixture was quenched with water, and extracted with
CH Cl . The organic extracts were dried over anhydrous MgSO . After filtration, the filtrate was
2
2
4
concentrated under reduced pressure. The residue was purified by SiO chromatography to afford the
2
desired product 1g (118 mg, 0.396 mmol).
3
.2.2. (2-Phenyl-4,5-dihydrooxazol-4-yl)(2-vinylpiperidin-1-yl)methanone (1f)
1
Yield 95% for 2 steps, a colorless oil; H NMR (300 MHz, CDCl )
5
δ 7.96–7.89 (m, 2H), 7.49-7.30 (m, 3H),
3
13
.96–5.76 (m, 1H), 5.40–4.88 (m, 5H), 4.49–4.40 (m, 2H), 3.25 and 2.75 (m, 1H), 2.04–1.43 (m, 6H);
C

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NMR (500 MHz, CDCl3)
δ
167.8, 164.5, 137.05, 136.4, 131.4, 128.4, 128.2, 127.5, 117.2, 116.2, 69.3, 69.2,
6
9.1, 67.6, 67.2, 54.4, 50.8, 42.0, 38.2, 29.8, 29.3, 28.4, 26.3, 25.8, 25.2, 19.7, 19.6; HRMS (EI+) calcd for
+
C H N O [M] : 284.1525, found: 284.1526.
17
20
2
2
3
.2.3. (2-Phenyl-4,5-dihydrooxazol-4-yl)(2-vinylazepan-1-yl)methanone (1g)
1
Yield 79% for 2 steps, a colorless oil; H NMR (500 MHz, CDCl )
δ 7.93–7.92 (m, 2H), 7.48–7.44 (m,
3
1
2
1
H), 7.40–7.37 (m, 2H), 5.75–5.69 (m, 1H), 5.31–4.90 (m, 5H), 4.59–4.14 (m, 2H), 3.14 and 2.75 (m, 1H),
.42–1.22 (m, 8H); 13C NMR (500 MHz, CDCl3)
169.0, 168.6, 138.9, 133.1, 131.3, 128.5, 128.5, 128.4,
28.4, 114.1, 114.0, 59.2, 42.6, 34.3, 33.7, 29.7, 27.1, 26.6, 25.6, 24.6; HRMS (EI+) calcd for C H N O
δ
18
22
2
2
+
[M] : 298.1681, found: 298.1684.
3
.2.4. (2-Phenyl-4,5-dihydrooxazol-4-yl)(2-vinylazocan-1-yl)methanone (1h)
1
Yield 70% for 2 steps, a colorless oil; H NMR (500 MHz, CDCl )
δ 7.92–7.90 (m, 2H), 7.47 (t, J = 3.0 Hz,
3
1
2
H), 7.41–7.38 (m, 2H), 5.83–5.77 (m, 1H), 5.32–4.92 (m, 6H), 4.48–4.38 (m, 1H), 3.94–3.79 (m, 2H),
13
.93–2.87 (m, 1H), 2.05–1.25 (m, 10H); C-NMR(500 MHz, CDCl3)
δ 168.9, 138.9, 137.9, 131.5, 128.5,
1
28.4, 128.4, 128.3, 128.3, 128.2, 114.0, 68.9, 67.4, 58.7, 42.5, 29.7, 27.0, 26.6, 26.1, 26.0, 25.6, 24.5; HRMS
+
(EI+) calcd for C H N O [M] : 312.1838, found: 312.1841.
19 24 2 2
3
.2.5. (2-Phenyl-4,5-dihydrooxazol-4-yl)(2-vinylazonan-1-yl)methanone (1i)
1
Yield 72% for 2 steps, a colorless oil; H NMR (500 MHz, CDCl )
δ 7.92–7.90 (m, 2H), 7.46–7.43 (m, 1H),
3
7
(
.39–7.36 (m, 2H), 5.78–5.71(m, 1H), 5.37–5.24 (m, 3H), 4.98–4.93 (m, 1H), 4.47–4.39 (m, 1H), 3.87–3.83
m, 1H), 2.80–2.75 (m, 2H), 2.15–1.20 (m, 14H); 13C NMR (500 MHz, CDCl3)
169.7, 164.4, 139.0, 131.5,
29.8, 128.5, 128.4, 128.3, 128.3, 127.6, 114.7, 114.4, 77.6, 69.1, 67.8, 59.4, 44.7, 32.0, 30.2, 29.7, 29.7, 29.4,
δ
1
2
+
7.6, 26.9, 26.0, 25.7, 23.5, 22.7, 14.1; HRMS (EI+) calcd for C H N O [M] : 326.1994, found: 326.1998.
20
26
2
2
3
.2.6. N-allyl-N-benzyl-2-phenyl-4,5-dihydrooxazole-4-carboxamide (1j)
1
Yield 85%, a colorless sticky oil; H NMR 300 MHz, CDCl )
δ 7.90–7.81 (m, 2H), 7.42–7.17 (m, 8H), 5.87
3
(
m, 1H), 5.20–4.93 (m, 4H), 4.79 (d, J = 15.8 Hz, 1H), 4.55 (m, 1H), 4.40 (d, J = 15.2 Hz, 2H), 4.10 (m, 1H);
1
3
C NMR (500 MHz, CDCl3)
δ 169.4, 169.2, 164.6, 164.5, 137.0, 133.5, 132.3, 131.3, 128.5, 128.3, 128.2,
1
28.0, 127.8, 127.2, 127.0, 126.8, 117.2, 116.8, 69.0, 67.4, 67.1, 49.8, 49.0, 48.3, 48.0; HRMS (EI+) calcd for
+
C H N O [M] : 320.1525, found: 320.1528.
20
20
2
2
3
.2.7. (E)-N-benzyl-N-cinnamyl-2-phenyl-4,5-dihydrooxazole-4-carboxamide (1k)
1
Yield 75%, a colorless sticky oil; H NMR (500 MHz, CDCl )
7
δ 8.01–7.99 (m, 1H), 7.96–7.94 (m, 1H),
3
13
.54–7.24 (m, 13H), 6.56–6.46 (m, 1H), 6.35–6.17 (m, 1H), 5.29–4.03 (m, 5H); C NMR (500 MHz, CDCl3)
169.7, 169.6,165.0,164.9, 137.2,136.6, 136.4, 133.2, 132.2, 131.6, 131.6, 128.8, 128.7, 128.6, 128.5, 128.3,
δ
1
5
28.3, 128.2, 127.9, 127.7, 127.5, 127.5, 127.4, 127.4, 127.0, 126.5, 126.4, 125.1, 124.1, 69.3, 69.3, 67.7, 67.6,
0.1, 48.9, 48.7, 47.9; HRMS (EI+) calcd for C H N O [M] : 396.1838, found: 396.1838.
26 24 2 2
+
3
.2.8. (E)-N-benzyl-N-(but-2-en-1-yl)-2-phenyl-4,5-dihydrooxazole-4-carboxamide (1l)
1
Yield 70%, a colorless sticky oil; H NMR (500 MHz, CDCl )
δ 7.99 (d, J. = 11.5 Hz 1H), 7.91 (d, J =
3
7
.8 Hz 1H), 7.50–7.20 (m, 8H), 5.66–5.20 (m, 2H), 5.18–4.95 (m, 2H), 4.51–4.41 (m, 2H), 4.11–4.01 (m, 1H),
1
1
1
1
.68–1.54 (m, 3H); 13C NMR (125 MHz, CDCl3)
δ
169.5, 169.4, 164.9, 137.4, 137.3, 131.5, 129.3, 129.0,
28.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.6, 127.5, 127.3, 127.1, 127.0, 126.4, 126.3,
25.4, 125.2, 69.4, 69.3, 67.7, 67.5, 67.4, 50.2, 49.8, 48.7, 48.3, 47.7, 43.8, 42.3, 30.9, 29.7, 17.8, 17.7, 13.1,
2.9; HRMS (EI+) calcd for C H N O [M] : 334.1681, found: 334.1677.
+
20
18
2
2

Molecules 2019, 24, 4495
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3
.2.9. (E)-N-benzyl-N-(pent-2-en-1-yl)-2-phenyl-4,5-dihydrooxazole-4-carboxamide (1m)
1
Yield 72%, a colorless oil; H NMR (500 MHz, CDCl )
δ 7.97 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H),
3
7
.49–7.44 (m, 1H), 7.41–7.35(m, 3H), 7.30–77.22 (m, 4H), 5.68–5.39 (m, 2H), 5.19–5.01 (m, 2H), 4.86–4.73
13
(
m, 1H), 4.51–4.41 (m, 2H), 4.12–3.83 (m, 1H), 2.11–2.00 (m, 2H), 1.02–0.94 (m, 3H); C NMR (125 MHz,
CDCl3) 206.8, 169.6, 164.9, 137.4, 136.4, 135.7, 131.5, 128.7, 128.5, 128.3, 128.1, 127.6, 127.5, 127.4, 127.2,
27.0, 124.0, 124.1, 123.1, 69.3, 67.7, 67.4, 49.8, 48.7, 48.4, 47.7, 30.9, 25.3, 13.4; HRMS (EI+) calcd for
δ
1
+
C H N O [M] : 348.1838, found: 348.1835.
22
24
2
2
3
.2.10. (Z)-N-benzyl-N-(pent-2-en-1-yl)-2-phenyl-4,5-dihydrooxazole-4-carboxamide (1n)
1
Yield 72%, a colorless sticky oil; H NMR (500 MHz, CDCl )
7
δ 7.98–7.97 (m, 1H), 7.92–7.90 (m, 1H),
3
13
.50–7.26 (m, 8H), 5.22–4.41 (m, 7H), 4.13–3.99 (m, 1H), 2.10–1.94 (m, 2H), 1.00–0.91 (m, 3H); C NMR
(
125 MHz, CDCl3) 169.5, 169.4, 164.9, 164.8, 137.3,137.3,135.8, 135.6, 131.5,131.5, 128.7, 128.6, 128.5,
δ
1
1
28.3, 128.3, 128.1, 127.6, 127.5, 127.3, 127.0, 124.7, 123.6, 67.3, 67.7, 67.5, 50.1, 48.6, 44.0, 42.5, 20.8, 20.6,
+
4.1; HRMS (EI+) calcd for C H N O [M] : 348.1838, found: 348.1835.
22
24
2
2
3
.2.11. Representative Procedure: Synthesis of Compound 3f
To stirred solution of 1f (292 mg, 1.02 mmol) in benzene (5 mL) was added LHMDS (3.06 mL, 1M in
hexane) and stirred for 1 h. The reaction mixture was quenched with aq. NH Cl solution, and extracted
4
with EtOAc. The organic extracts were dried over anhydrous MgSO . After filtration, the filtrate was
4
concentrated under reduced pressure. The residue was purified by SiO chromatography to afford the
2
desired product 3f (280 mg, 0.98 mmol).
3
.2.12. 2-Phenyl-12-vinyl-3-oxa-1,7-diazaspiro[4.7]dodec-1-en-6-one (3f)
1
Yield 96%, a colorless oil; H NMR (300 MHz, CDCl )
δ
8.19 (s, 1H), 7.84–7.78 (m, 2H), 7.45–7.33 (m,
3
3
H), 6.15 (s, 1H), 5.90–5.79 (m, 1H), 5.34–5.10 (m, 4H), 4.27 (d, J = 14.7 Hz, 1H), 3.03 (t, J = 12.3 Hz, 1H),
1
1
.80-1.49 (m, 6H); 13C NMR (125 MHz, CDCl3)
δ
167.4, 165.8, 136.2, 135.5, 133.7, 131.7, 128.4, 127.2,116.8,
+
03.6, 29.1, 25.6, 19.8; HRMS (EI+) calcd for C H N O [M] : 284.1525, found: 284.1528.
17
20
2
2
3
.2.13. 2-Phenyl-13-vinyl-3-oxa-1,7-diazaspiro[4.8]tridec-1-en-6-one (3g)
1
Yield 71%, a colorless oil; H NMR (500 MHz, CDCl )
δ
8.06 (s, 1H), 7.82–7.80 (m, 2H), 7.54–7.51 (m,
3
1
1
1
4
2
H), 7.46–7.44 (m, 2H) 6.16 (s, 1H), 5.86–5.79 (m, 1H), 5.25 (s, 1H), 5.18 (d, J = 10.5 Hz, 1H), 5.10 (d, J =
7.0 Hz, 1H), 4.75 (s, 1H), 4.13–4.10 (m, 1H), 2.82 (d, J =12.5, 1H) 2.20–2.16 (m, 1H), 1.84–1.73 (m, 3H)
.55–1.24 (m, 5H); 13C NMR (125 MHz, CDCl3)
2.9, 34.9, 30.0, 29.7, 29.4, 26.9, 24.3, 22.7; HRMS (EI+) calcd for C H N O [M] : 298.1681, found:
δ
166.0, 138.4, 134.3, 132.0, 128.7, 127.1, 114.3, 103.9, 60.4,
+
18
22
2
2
98.1679.
3
.2.14. 2-Phenyl-14-vinyl-3-oxa-1,7-diazaspiro[4.9]tetradec-1-en-6-one (3h)
1
Yield 76%, a colorless oil; H NMR (500 MHz, CDCl )
δ 7.92 (s, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.52–7.49
3
(
2
m, 1H), 7.44 (t, J = 7.5 Hz, 2H), 6.29 (s, 1H), 5.75–5.63 (m, 1H), 5.13–4.87 (m, 5H), 3.96–3.90 (m, 1H),
.94–2.88 (m, 1H), 2.15–1.45 (m, 9H), 1.25–1.22 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 171.3, 167.9,
1
4
66.2, 166.1, 138.7, 137.2, 135.0, 132.0, 128.8, 128.8, 127.0, 127.0, 115.3, 115.2, 104.0, 103.3, 61.2, 60.4, 58.4,
2.8, 40.7, 34.3, 30.3, 30.0, 29.2, 26.6, 26.3, 26.1, 26.0, 25.8, 24.2, 24.1, 21.1, 14.2; HRMS (EI+) calcd for
+
C H N O [M] : 312.1838, found: 312.1842.
19
24
2
2
3
.2.15. 2-Phenyl-15-vinyl-3-oxa-1,7-diazaspiro[4.10]pentadec-1-en-6-one (3i)
1
Yield 77%, a colorless oil; H NMR (500 MHz, CDCl )
δ
7.92 (s, 1H), 7.79 (t, J = 7.5 Hz, 2H), 7.55–7.53
3
(
m, 1H), 7.47–7.44 (m, 2H), 6.32 (s, 1H), 5.78–5.70 (m, 2H), 5.18–5.14 (m 2H), 5.06–4.93 (m, 3H), 3.93–3.85
m, 2H), 2.90–2.80 (m, 1H) 2.09–1.88 (m, 3H), 1.77–1.70 (m, 4H), 1.47–1.42 (m, 3H), 1.27–1.25 (m, 1H);
(
1
3
C NMR (125 MHz, CDCl3)
δ 168.6, 166.1, 138.7, 134.4, 132.0, 128.9, 127.0, 115.7, 103.4, 61.9, 60.4, 44.4,

Molecules 2019, 24, 4495
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+
3
1.0, 29.7, 29.4, 26.6, 26.1, 25.6, 25.1, 24.0, 22.7, 21.1, 14.2, 14.1; HRMS (EI+) calcd for C H N O [M] :
20
26
2
2
3
26.1994, found: 326.1996.
3
.2.16. 4-Allyl-N-benzyl-2-phenyl-4,5-dihydrooxazole-4-carboxamide (3j)
1
Yield 84%, a colorless sticky oil; H NMR (300 MHz, CDCl )
δ 8.56 (s, 1H), 7.80 (d, J = 7.1 Hz, 2H),
3
7
2
.50–7.24 (m, 8H), 6.01 (s, 1H), 5.88–5.79 (m, 1H), 5.29–5.19 (m, 2H), 5.10 (s, 1H), 4.73 (s, 2H), 4.08 (s,
H), 1.41–0.72 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ
168.5, 165.9, 136.4, 135.0, 133.9, 131.9, 128.8, 128.6,
+
1
27.5, 127.2, 118.3, 104.4; HRMS (EI+) calcd for C H N O [M] : 320.1525, found: 320.1527.
20
20
2
2
3
.2.17. N-benzyl-4-cinnamyl-2-phenyl-4,5-dihydrooxazole-4-carboxamide (3k)
1
Yield 70%, a colorless sticky oil; H NMR (500 MHz, CDCl )
δ 8.32 (s, 1H), 7.84–7.81 (m, 2H), 7.53–7.50
3
(
4
1
m, 1H), 7.54–7.42 (m, 2H), 7.37–7.28 (m, 9H), 6.50 (d, J = 15.9 Hz, 1H), 6.19–6.18 (m, 2H), 5.20 (s, 1H),
.9 (s, 1H), 4.25 (s, 1H); 13C NMR (125 MHz, CDCl3)
δ
168.4, 166.0, 136.4, 136.3, 134.7, 134.1, 132.0, 128.9,
+
28.7, 128.7, 128.0, 127.7, 127.4, 127.2, 126.5, 104.5, 30.9, 34.4; HRMS (EI+) calcd for C H N O [M] :
26
24
2
2
3
96.1838, found: 396.1840.
3
.2.18. (E)-N-benzyl-4-(but-2-en-1-yl)-2-phenyl-4,5-dihydrooxazole-4-carboxamide (3l)
1
Yield 70%, colorless sticky oil; H NMR (500 MHz, CDCl )
(
δ
8.63 (s, 1H), 7.84–7.81 (m, 2H), 7.38–7.14
3
13
m, 10H), 5.87(s, 1H), 5.50–5.35 (m, 2H), 4.94 (s,1H), 4.60 (s, 2H), 3.90 (s, 2H); C NMR (125 MHz,
CDCl3)
δ
168.4, 166.0, 137.1, 136.7, 134.8, 134.1, 134.0, 131.9, 128.8, 128.7, 128.6, 127.4, 127.1, 104.3, 60.4,
+
3
0.3, 25.3, 21.1, 14.2, 13.4; HRMS (EI+) calcd for C H N O [M] : 334.1682, found: 334.1681.
21
22
2
2
3
.2.19. (E)-N-benzyl-4-(pent-2-en-1-yl)-2-phenyl-4,5-dihydrooxazole-4-carboxamide (3m)
1
Yield 74%, colorless oil; H NMR (500 MHz, CDCl )
δ
8.35 (s, 1H), 7.83–7.82 (t, J = 7.2 Hz, 2H), 7.54–7.50
3
(m, 1H), 7.46–7.43 (m, 2H), 7.37–7.35 (t, J = 7.2 Hz, 2H), 7.30–7.26 (m, 3H), 6.17 (s, 1H), 5.65–5.59 (m,
1
H), 5.45-5.40 (m, 1H), 5.13 (s, 1H), 4.73 (s, 2H), 4.13–4.10 (m, 2H), 1.94–1.89 (m, 2H), 0.93–0.90 (m, 3H);
1
3
C NMR (125 MHz, CDCl3)
δ 168.3, 166.0, 137.1, 136.7, 134.8., 134.1, 131.9, 128.8, 128.6, 127.5, 127.2,
+
1
04.4, 60.4, 30.9, 21.1, 14.2, 13.4; HRMS (EI+) calcd for C H N O [M] : 348.1838, found: 348.1841.
22
24
2
2
3
.2.20. (Z)-N-benzyl-4-(pent-2-en-1-yl)-2-phenyl-4,5-dihydrooxazole-4-carboxamide (3n)
1
Yield 75%, colorless sticky oil; H NMR (500 MHz, CDCl )
δ 8.49 (s, 1H), 7.82 (d, J = 5.0 Hz, 2H),
3
7
5
.51–7.50 (m, 1H), 7.49–7.48 (m, 2H), 7.34–7.40 (m, 2H), 7.28–7.25 (m, 3H), 6.12 (s, 1H), 5.64–5.60 (m, 1H)
13
.45–5.42 (m, 1H), 5.14 (s, 1H), 4.71 (s, 2H), 4.03 (s, 2H) 2.06 (t, J = 7.0 Hz), 0.98 (t, J = 7.5 Hz); C NMR
168.3, 166.0, 137.1, 136.7, 134.8, 134.1, 131.9, 128.8, 128.6, 127.5, 127.2, 104.4, 60.4,
(
125 MHz, CDCl3)
δ
+
3
0.9, 25.3, 21.1, 14.2, 13.4; HRMS (EI+) calcd for C H N O [M] : 348.1838, found: 348.1836.
22 24 2 2
4
. Conclusions
The unexpected rearrangement of N-allyl-2-phenyl-4,5-dihydrooxazole-4-carboxamides in the
presence of LiHMDS was discovered. Several key features were noted: (1) The net reaction consisted
of 1,3-migration of the N-allyl group. (2) The rearrangement produced a congested aza-quaternary
carbon center. (3) Both cyclic and acyclic substrates underwent the unexpected rearrangement to afford
products in moderate to high yields. (4) The reaction seemed to be highly stereoselective. Although
the reaction mechanism has not yet been confirmed, the method might be useful for the synthesis of
challenging targets that possess aza-quaternary carbon centers. These centers are found in a variety of
bioactive alkaloids and small molecules.
Supplementary Materials: The following are available online. H and 13C NMR spectra of 1f-n and 3f-n.
1
Author Contributions: Conceptualization, J.-W.J.; Experimental work, G.C., S.J., J.M., Y.J. and S.-H.K.;
Writing—original draft, G.C. and J.-W.J.; Writing—review & editing, S.-H.K. and J.-W.J.; Supervision, project
administration and funding acquisition, J.-W.J.

Molecules 2019, 24, 4495
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Funding: This research was funded by Ministry of Science and ICT and the Ministry of Education through the
National Research Foundation of Korea grant number NRF-2015M3A9E7029176, NRF-2017R1D1A1B03032798,
and NRF-2018M3A9A8055212.
Acknowledgments: We thank Seung-Yong Seo and Jaebong Jang for invaluable comments and suggestions.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 3f-n are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).