Spirooxazoline Synthesis by an Oxidative Dearomatizing Cyclization

Article abstract of DOI:10.1002/ejoc.202000840

Spirocyclic compounds are of increasing importance owing to their potential applications in the development of new pharmaceuticals. Herein, we describe a new, rapid access to rarely seen spirooxazolines utilizing an I(I)/I(III) reaction manifold. The scope of the cyclization using phenols and naphthols is described along with the stereoselective functionalization of the spirocycles. The application of this method to the formation of dihydrooxazines is also demonstrated.

Full text of DOI:10.1002/ejoc.202000840

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Spirooxazoline Synthesis by an Oxidative Dearomatizing
Cyclization
Authors: M. Umair Tariq and Wesley James Moran
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000840
Link to VoR: https://doi.org/10.1002/ejoc.202000840
01/2020

10.1002/ejoc.202000840
European Journal of Organic Chemistry
FULL PAPER
Spirooxazoline Synthesis by an Oxidative Dearomatizing
Cyclization
M. Umair Tariq,[a] and Wesley J. Moran*[a]
[a]
Dr M. Umair Tariq, Dr Wesley J. Moran
Department of Chemistry
University of Huddersfield
Queensgate, Huddersfield HD1 3DH, U. K.
E-mail: w.j.moran@hud.ac.uk
Supporting information for this article is given via a link at the end of the document.
Abstract: Spirocyclic compounds are of increasing importance owing
to their potential applications in the development of new
pharmaceuticals. Herein, we describe a new, rapid access to rarely
seen spirooxazolines utilizing an I(I)/I(III) reaction manifold. The scope
of the cyclization using phenols and naphthols is described along with
the stereoselective functionalization of the spirocycles. The
application of this method to the formation of dihydrooxazines is also
demonstrated.
O
O
N
N
O
O
O
O
N
CO2Me
O
H
N
O
N
O
O
H
1a, 1b, spiro-oxazoline
2
, IC50 = 36 nM SKOV-3 cancer cells
alkaloids
Cl
Introduction
O
O
NH
Spirocycles are generally regarded as aesthetically pleasing
molecules to synthetic chemists and their prevalence in the
literature has increased massively over the past decade.[1] Many
spirocycles exhibit useful properties and are of increasing interest
to medicinal chemists. Indeed, several thousand different
spirocyclic molecules are now commercially available.[2] There
are also numerous examples of natural products that contain a
spirocyclic core that have inspired elegant synthetic efforts.[3]
Spirooxazoline compounds are rarely found in nature;
however, there are a few examples, such as 1a and 1b (Figure
1).[4] On the other hand, various spiroheterocycles are prevalent
with commercial suppliers because of the interest in these
compounds by medicinal chemists. Weindel et al. reported that a
simple spirooxazolidine inhibits mineralocorticoid biosynthesis in
z. glomerulosa cells.[5] Li and co-workers reported that
spirotriptolide derivative 2 is an effective anticancer agent.[6]
Researchers at Merck reported a spirooxazolidinone to be a
highly effective calcitonin gene-related peptide receptor (CGRP)
antagonist useful for migraine treatment.[7] Fenspiride 3 is an anti-
inflammatory bronchodilator used in the treatment of respiratory
disorders.[8] Lundbeck researchers reported that spirooxazoline 4
is a potent brain penetrant that displays anxiolytic activity.[9]
H
O
N
N
N
N
Ph
O
3, fenspiride - a
bronchodilator
4
, IC50 = 23 nM mGluR5
allosteric modulator
Figure 1 Examples of oxazaspirocycles.
Despite the substantial interest in the synthesis of
spiroheterocyclic compounds, to the best of our knowledge, there
are only two reported synthetic methods to access spirooxazoline
compounds. Zhu reported
a photochemical cycloaddition
approach which appears to be limited to benzo-fused examples
with the difluoro substitution pattern shown (Scheme 1a).[10]
Lundbeck scientists described a multi-step route which converted
a
ketone into
a
spirooxazolidinone and then into the
spirooxazoline (Scheme 1b).[9]
1
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10.1002/ejoc.202000840
European Journal of Organic Chemistry
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Previous work:
Table 1. Optimization of oxidative dearomatization of phenol 5a.
O
F
TMEDA
"standard conditions"
O
F
N
F
33 W CFI
20 mol% 4-iodotoluene
O
HN
Ph
(a)
+
F
Ph
MTBE, rt
79%
O
O
N
Br
Ph
1.6 equiv m-CPBA
O
OH
N
O
5a
6a
HFIP, rt, 16 hours
Ph
O
Entry
1
Deviation from standard conditions
none
Yield/%
67
O
Ar
N
H
2 steps
O
2 steps
N
O
(b) Z
4
NH
2
40 mol% 4-iodotoluene
67
3
10 mol% 4-iodotoluene
33
This work:
R
H
R
N
4
10 mol% 4-iodotoluene, 48 hours
Oxone instead of m-CPBA
Selectfluor instead of m-CPBA
Peracetic acid instead of m-CPBA
10 mol% 5-iodo-m-xylene
20 mol% 2-iodoanisole
45
N
O
ArI
oxidant
OH
HN
(c)
O
O
I
5
19
R
O
Ar
6
15
L
O
7
33
Scheme 1. Synthetic routes to spirooxazolines.
8
22
9
32
Our approach to spirooxazoline formation is by the
dearomatizing cyclisation of phenols (and naphthols) mediated by
in-situ generated hypervalent iodine(III) species (Scheme 1c). We
envisaged that a pendent amide would cyclize on to the aromatic
ring after activation of the oxygen by a 3-iodane. This concept
was inspired by our previous work on the cyclization of amides
onto alkenes and alkynes.[11,12] Oxidative dearomatization of
phenols is a popular strategy in synthesis, especially using
hypervalent iodine reagents under stoichiometric and catalytic
conditions,[13,14] so it is surprising that this approach has not been
used already to access the spirooxazoline framework.
10
11
20 mol% iodobenzene
67
10 mol% 4-iodotoluene, MeCN
<5
The scope of the cyclization of phenols was investigated with
a range of amides under our optimal reaction conditions (Scheme
2). Accordingly, aryl amides, alkyl amides and heteroaryl amide
derivatives were prepared and these all cyclized in good yields.
Alkyl and methoxy substituted phenyl amides were effective
substrates and led to the formation of spirocycles 6b-d in
moderate yields. Notably, the presence of a fluorine on the phenyl
ring led to higher yields of isolated compounds (6e and 6f) than
all of the other examples tested. The presence of one or two
strongly electron-withdrawing nitro or trifluoromethyl groups was
well tolerated in the cyclization (6g-k). Dibromide 6l, chloride 6m
and dichloride 6n were also readily prepared containing handles
for further functionalization. tert-Butyl amide-derived spirocycle
6o was obtained in moderate yield; however, the corresponding
methyl amide-derived spirocycle could not be isolated as it
decomposed readily during purification attempts. Heteroaromatic
amides were also successfully cyclized with furan (6p), thiophene
(6q), benzothiophene (6r), pyrrole (6s) and pyridine (6t) groups
all tolerated with no unwanted over-oxidation observed.
Results and Discussion
We initiated our study with amide 5a, prepared by acylation of the
commercially available amine, and subjected it to conditions that
would generate hypervalent iodine species in-situ (Table 1).
Gratifyingly, smooth dearomatizing cyclization occurred to furnish
spirocycle 6a in 67% yield using 4-iodotoluene as the precatalyst
in the presence of m-CPBA as oxidant in hexafluoroisopropanol
(HFIP) at room temperature after 16 hours (entry 1). Increasing
the amount of 4-iodotoluene did not lead to any improvement in
yield (entry 2). Whereas reducing the amount of 4-iodotoluene led
to a lower yield of product; however, a longer reaction time led to
an augmented yield (entries 3-4). Changing the oxidant from m-
CPBA to Oxone, Selectfluor or peracetic acid led to diminished
yields (entries 5-7). Substituting 4-iodotoluene for 5-iodo-m-
xylene or 2-iodoanisole was detrimental to the reaction outcome
(entries 8-9) whereas iodobenzene displayed similar efficiency
(entry 10). We decided to continue to use 4-iodotoluene rather
than iodobenzene as the former is a solid and is easier to handle
in small quantities. Changing the solvent from HFIP to MeCN was
also detrimental to the yield (entry 11). Interestingly, only HFIP
was found to be an effective solvent for this cyclization.[15]
2
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10.1002/ejoc.202000840
European Journal of Organic Chemistry
FULL PAPER
ARYL
O
Ph
NH
OH
O
Ph
N
40 mol% 4-iodotoluene
F
O
Ph
(a)
R
O
N
N
N
N
N
1.6 equiv m-CPBA
O
O
O
O
O
HFIP, rt, 16 hours
R
7a
7b
8a
8b
R = H
R = Br
52%
51%
O
O
6b
O
6c
O
6d
O
O
I
O
6a
6e
94%
67%
56%
36%
56%
O
O
MesHN
NHMes
O2N
O2N
F3C
CF3
10 mol%
NO2
(b)
7a
8a
N
N
N
N
N
1.2 equiv m-CPBA, 3:1 CH2Cl2/MeOH
F
36% yield
14% ee
-20 oC, 18 h
O
O
O
O
O
Scheme 3. (a) Oxidative dearomatization of naphthol derivatives. (b) Effect of
a chiral iodoarene on the oxidative dearomatization of 7a. Enantioselectivity
determined by chiral HPLC analysis.
O
O
6g
O
O
O
6f
6h
6i
6j
86%
60%
Br
50%
70%
63%
F3C
Cl
ALKYL
In order to probe the mechanism of this reaction, 7a was
subjected to the standard reaction conditions but in the presence
of the radical inhibitors TEMPO and galvinoxyl. Product 8a was
isolated in both cases; thus suggesting that this process is not a
radical one but proceeds via a mechanistic pathway similar to that
shown in Scheme 1c.
Cl
CF3
N
N
N
N
N
O
Br
Cl
O
O
O
O
The oxidative dearomatization was also amenable to the
formation of [5.5]-spirocycles by the cyclization of the
homologated compounds 9a and 9b (Scheme 4).
O
O
O
O
O
6k 61%
6l 65%
6m 65%
6n 30%
6o 41%
Ar
HETEROARYL
N
40 mol% 4-iodotoluene
OH
Cl
N
O
NH
Ar
O
1.6 equiv m-CPBA
O
S
S
NH
N
O
HFIP, rt, 16 hours
N
N
N
N
9a
9b
10a
10b
R = Ph
51%
81%
O
O
O
O
O
R = 4-ClC6H4
Scheme 4. Cyclization to form six-membered rings.
O
O
O
O
O
6p 62%
6q 70%
6r 30%
6s 43%
6t 56%
These spirocyclic compounds contain multiple points for
further functionalization. For example, treatment of 6c with MeLi
led to chemoselective addition to the carbonyl group to form 11
as a 5:1 mixture of diastereomers. Attempts to purify 11 by flash
chromatography with silica gel led to rearrangement to phenol 12
(Scheme 5a). Presumably the tertiary doubly allylic alcohol was
protonated and water was lost which generated the stabilized
carbocation. Subsequent [1,2]-rearrangement, aromatization and
opening of the heterocyclic ring led to 12.[17] Treatment of 8a with
MeLi also led to chemoselective addition to the carbon-yl group to
furnish 13 in good yield and similar 5:1 diastereoselectivity
(Scheme 5b). In this case, the spirocycle was stable to
chromatography and the major diastereomer of 13 was isolated
and assigned from the NOESY NMR spectrum (see the SI for
details).
Scheme 2. Cyclization scope with respect to the amide substituent.
Next, we turned our attention to the oxidative dearomatization
of naphthols 7a and 7b. Under the optimized conditions these
amides furnished the expected spirocycles 8a and 8b in moderate
yields (Scheme 3a). These cyclizations were somewhat sluggish
using 20 mol% 4-iodotoluene, therefore 40 mol% was used
instead. We also surveyed a range of chiral iodoarenes in an
attempt to effect the enantioselective dearomatizing cyclization of
7a. After some experimentation, 8a was isolated with 14% ee
using a known Ishihara precatalyst in 10 mol% at -20 oC (Scheme
3b).[16]
3
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10.1002/ejoc.202000840
European Journal of Organic Chemistry
FULL PAPER
was diluted with MeOH (25 mL) and CH2Cl2 (5 mL) then aqueous NaOH
solution (1 M, 18 mL) was added. After stirring for 10 minutes at room
temperature, TLC analysis indicated that any bis-acylated product was
cleaved to give the desired mono-acylated product. Glacial acetic acid was
added to the reaction mixture until it was pH 7 and then the mixture was
concentrated under vacuum. The residue was extracted with CH2Cl2 (50
mL) and washed with brine (50 mL). The organic layers were separated,
dried over MgSO4, filtered and concentrated under reduced pressure. The
organic residue was purified by recrystallisation (MeOH/Petroleum) to give
the desired product as a solid.
Ar
Ar
Ar
N
N
N
O
O
O
SiO2
MeLi, THF
(a)
-78 oC, 1 h
Ar = 2,4,6-Me3C6H2
OH
O
6c
11
5:1 dr
O
HN
Ar
Ar
N
Ar
N
O
O
Procedure B: A solution of acid chloride (2 mmol) in THF (4 mL) was cooled
to 0 oC under nitrogen. Potassium phosphate tribasic (2.5 mmol) was
added in one portion followed by the benzylamine (2 mmol). The mixture
was stirred for 1-2 hour at room temperature then the reaction mixture was
concentrated under reduced pressure. Water (6 mL) and EtOAc (2 mL)
were added, the organic layer separated and then washed with 0.5 N HCl
(5 mL) followed by water (5 mL). The organic layer was dried over MgSO4,
filtered and concentrated under reduced pressure. The crude product was
purified by recrystallisation (EtOAc-hexanes) to give the desired product
as a solid.
HO
12
77%
Ph
Ph
N
N
MeLi, THF
-78 oC, 1 h
O
O
(b)
O
OH
Procedure C: Naphthol (6.94 mmol) and N-(hydroxymethyl)benzamide
(1.05 g, 6.94 mmol) were dissolved in anhydrous ethanol (100 mL).
Concentrated sulfuric acid (10 mL) was added dropwise and the reaction
mixture was stirred for 7 hours at 50 oC. The reaction mixture was cooled
to room temperature and washed with 1 M NaOH solution (50 mL). The
combined organic layers were dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was recrystallised (EtOAc-hexanes)
to afford the desired product as a solid.[18]
8a
13
67% (5:1 dr)
Scheme 5. Functionalization of dearomatized products.
Conclusion
The oxidative cyclization of phenols containing pendent amides to
form spirooxazolines mediated by in-situ generated iodine(III)
species is presented. This process operates with catalytic
quantities of iodoarene and is successful for a wide range of
substrates. The spirooxazoline products can be derivatized in a
diastereoselective manner.
N-(4-Hydroxybenzyl)benzamide 5a. White solid (1.03 g, 55%) using
general procedure A. FT-IR (cm-1): ν = 3397, 3073, 2820, 1614. 1H NMR:
(DMSO-d6, 400 MHz) δ 9.30 (br, s, 1H), 8.95 (br, s, 1H), 7.89 (d, J = 7.1
Hz, 2H), 7.53-7.44 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz,
2H), 4.38 (d, J = 6.0 Hz, 2H). 13C{H} NMR: (DMSO-d6, 100 MHz) δ 166.0,
156.3, 134.5, 131.1, 129.9, 128.6, 128.3, 127.3, 115.0, 42.2. HRMS: m/z
calc’d for C14H13NO2Na [M+Na]+ 250.0838, found 250.0840. Melting Point:
151-153 ℃.
N-(4-Hydroxybenzyl)-3,5-dimethylbenzamide 5b. Beige solid (3.4 g, 63%)
using general procedure B. FT-IR (cm-1): ν = 3260, 2914, 1621, 1515. 1H
NMR: (DMSO-d6, 400 MHz) δ 9.28 (s, 1H), 8.82 (t, J = 5.9 Hz, 1H), 7.49
(s, 2H), 7.14-7.12 (m, 3H), 6.71 (d, J = 8.4 Hz, 2H), 4.34 (d, J = 5.9 Hz,
2H), 2.30 (s, 6H). 13C{H} NMR: (DMSO-d6, 100 MHz) δ 166.2, 156.2, 137.4,
134.5, 132.4, 130.0, 128.6, 125.0, 115.0, 42.1, 20.9. HRMS: m/z calc’d for
Experimental Section
General
C
16H18NO2 [M+H]+ 256.1332, found 256.1339. Melting Point: 165-166 ℃.
NMR spectra were recorded at room temperature in the solvent and at the
frequencies stated in each case. Chemical shifts are reported in parts per
million (ppm) relative to the residual solvent peaks. Infrared (IR) spectra
(cm–1) were recorded on a Nicolet 380 spectrum spotlight system,
equipped with a diamond probe ATR attachment. High-resolution mass
spectra (m/z) were obtained in the electrospray (ESI) mode. All reagents
and solvents were purchased from commercial sources and used without
further purification except THF (dried over 3 Å molecular sieves and then
freshly distilled from Na/benzophenone under nitrogen). Flash
chromatographic separations were performed on SigmaAldrich silica gel
60 (35-70 μm).
N-(4-Hydroxybenzyl)-2,4,6-trimethylbenzamide 5c. Pale yellow solid (0.81
g, 46%) using general procedure B. FT-IR (cm-1): ν = 3373, 3163, 2917,
1620. 1H NMR: (DMSO-d6, 400 MHz) δ 9.26 (s, 1H), 8.58 (t, J = 6.0 Hz,
1H), 7.14 (d, J = 8.5 Hz, 2H), 6.82 (s, 2H), 6.70 (d, J = 6.0 Hz, 2H), 4.30
(d, J = 6.0 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 6H). 13C{H} NMR: (DMSO-d6, 100
MHz) δ 168.9, 156.2, 136.9, 135.8, 133.5, 129.9, 128.8, 127.6, 114.9, 41.8,
20.6, 18.8. HRMS: m/z calc’d for C17H20NO2 [M+H]+ 270.1489, found
270.1496. Melting Point: 150-151 ℃.
N-(4-Hydroxybenzyl)-4-methoxybenzamide 5d. Off-white crystalline solid
(1.29 g, 61%) using general procedure B. FT-IR (cm-1): ν = 3257, 3009,
2971, 2936, 2836, 1604. 1H NMR: (DMSO-d6, 300 MHz) δ 9.29 (s, 1H),
8.79 (t, J = 5.9 Hz, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H),
6.98 (d, J = 8.9 Hz, 2H), 6.70 (d, J = 8.5 Hz, 2H), 4.33 (d, J = 6.0 Hz, 2H),
3.80 (s, 3H). 13C{H} NMR: (DMSO-d6, 75 MHz) δ 165.3, 161.3, 155.9,
129.9, 128.9, 128.4, 126.5, 114.8, 113.3, 55.1, 41.9. HRMS: m/z calc’d for
C15H16NO3 [M+H]+ 258.1125, found 258.1126. Melting Point: 155-156 ℃.
General Syntheses of Benzamide Starting Materials
Procedure A: To a solution of the benzylamine (2.44 mmol, 1 equiv) and
triethylamine (2.44 mmol) in CH2Cl2 (12 mL) at 0 oC was added the acid
chloride (2.44 mmol) and this was left to stir at room temperature for 1-2
hours. The reaction mixture was diluted with CH2Cl2 (50 mL), quenched
with saturated aqueous NaHCO3 solution (25 mL) and the organic layer
was separated and concentrated under vacuum. The obtained residue
3-Fluoro-N-(4-hydroxybenzyl)-4-methylbenzamide 5e. Pink solid (1.78 g,
53%) using general procedure B. FT-IR (cm-1): ν = 3314, 3012, 1630. 1H
4
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10.1002/ejoc.202000840
European Journal of Organic Chemistry
FULL PAPER
NMR: (DMSO-d6, 300 MHz) δ 9.29 (s, 1H), 8.95 (t, J = 5.8 Hz, 1H), 7.66-
7.61 (m, 2H), 7.41-7.35 (m, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.71 (d, J= 8.4
Hz, 2H), 4.35 (d, J = 5.9 Hz, 2H), 2.28 (s, 3H). 13C{H} NMR: (DMSO-d6, 75
MHz) δ 164.3 (d, J = 2.3 Hz), 160.0 (d, J = 241 Hz), 156.0, 133.9 (d, J =
7.0 Hz), 131.3 (d, J = 5.1 Hz), 129.4, 128.4, 127.5 (d, J = 17.1 Hz), 122.9
(d, J = 3.5 Hz), 114.7, 113.4 (d, J = 23.3 Hz), 41.9, 13.9 (d, J = 3.0 Hz).
HRMS: m/z calc’d for C15H15FNO2 [M+H]+ 260.1081, found 260.1086.
Melting Point: 131-132 ℃.
1510, 1310, 1225. 1H NMR (DMSO-d6, 400 MHz) δ: 9.31 (s, 1H), 8.93 (t,
J = 5.7 Hz, 1H), 7.61-7.53 (m, 3H), 7.16 (d, J = 8.3 Hz, 2H), 6.72 (d, J =
8.3 Hz, 2H), 4.31 (d, J = 5.8 Hz, 2H). 13C{H} NMR: (DMSO-d6, 100 MHz)
δ 165.6, 156.3, 140.9, 134.7, 133.5, 131.2, 128.9, 128.7, 120.5, 118.2,
115.0, 42.1. HRMS: m/z calc’d for C14H12Br2NO2 [M+H]+ 383.9229, found
385.9231. Melting Point: 187-188 ℃.
4-Chloro-N-(4-hydroxybenzyl)benzamide 5m.[19] Off-white solid (1.03 g,
49%) using general procedure A. FT-IR (cm-1): ν = 3353, 3176, 2921, 1630.
1H NMR: (DMSO-d6, 400 MHz) δ 9.29 (s, 1H), 9.01 (t, J = 5.9 Hz, 1H), 7.89
(d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 6.70
(d, J = 8.5 Hz, 2H), 4.35 (d, J = 6.0 Hz, 2H). 13C{H} NMR: (DMSO-d6, 75
MHz) δ 164.9, 156.3, 136.0, 133.2, 129.6, 129.2, 128.7, 128.4, 115.0, 42.4.
HRMS: m/z calc’d for C14H13ClNO2 [M+H]+ 262.0629, found 262.0631.
Melting Point: 195-196 ℃ (lit: 196-197 ℃).
2-Fluoro-N-(4-hydroxybenzyl)benzamide 5f. Beige coloured solid (1.40 g,
54%) using general procedure B. FT-IR (cm-1): ν = 3400, 3224, 3078, 1614.
1H NMR: (DMSO-d6, 300 MHz) δ 9.30 (s, 1H), 8.75 (t, J = 6.3 Hz, 1H),
7.64-7.58 (m, 1H), 7.55-7.48 (m, 1H), 7.31-7.24 (m, 2H), 7.13 (d, J = 8.5
Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H), 4.34 (d, J = 6.3 Hz, 2H). 13C{H} NMR:
(DMSO-d6, 75 MHz) δ 163.6, 159.2 (d, J = 248 Hz), 156.3, 132.3 (d, J =
8.4 Hz), 130.0 (d, J = 3.1 Hz), 129.4, 128.5, 124.4 (d, J = 3.3 Hz), 124.3
(d, J = 14.6 Hz), 116.1 (d, J = 22.4 Hz), 115.0, 42.2. HRMS: m/z calc’d for
2,3-Dichloro-N-(4-hydroxybenzyl)benzamide 5n. White solid (1.3 g, 68%)
using general procedure B. FT-IR (cm-1): ν = 3331, 3066, 1624, 772. 1H
NMR: (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 8.93 (t, J = 5.6 Hz, 1H), 7.70-
7.68 (m, 1H), 7.43-7.38 (m, 2H), 7.15 (d, J = 8.2 Hz, 2H), 6.73 (d, J = 8.2
Hz, 2H), 4.33 (d, J = 5.8 Hz, 2H). 13C{H} NMR: (DMSO-d6, 100 MHz) δ
165.5, 156.3, 139.4, 131.9, 130.9, 129.0, 128.6, 128.5, 128.0, 127.3, 115.0,
42.0. HRMS: m/z calc’d for C14H12Cl2NO2 [M+H]+ 296.0240, found
296.0250. Melting Point: 161-163 ℃.
C
14H13FNO2 [M+H]+ 246.0925, found 246.0928. Melting Point: 129-130 ℃.
N-(4-Hydroxybenzyl)-3-nitrobenzamide 5g. Beige powder (2.0 g, 45%) by
general method A. FT-IR (cm-1): ν = 3080, 3022, 1634, 1530, 1344, 1223.
1H NMR: (DMSO-d6, 300 MHz) δ 9.32 (s, 2H), 8.71 (t, J = 1.9 Hz, 1H),
8.39-8.31 (m, 2H), 7.77 (t, J = 8.1 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.72
(d, J = 8.4 Hz, 2H), 4.40 (d, J = 5.7 Hz, 2H). 13C{H} NMR: (DMSO-d6, 75
MHz) δ 163.9, 156.4, 147.8, 135.9, 133.8, 130.1, 129.3, 128.8, 125.9,
122.0, 115.1, 42.5. HRMS: m/z calc’d for C14H13N2O4 [M+H]+ 273.0870,
found 273.0874. Melting Point: 168-169 ℃.
N-(4-Hydroxybenzyl)pivalamide 5o. Brown solid (0.8 g, 48%) using
general method B. FT-IR (cm-1): ν = 3418, 3121, 2963, 2932, 1627. 1H
NMR: (DMSO-d6, 400 MHz) δ 9.24 (s, 1H), 7.93 (t, J = 5.9 Hz, 1H), 7.00
(d, J = 8.5 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 4.13 (d, J = 6.0 Hz, 2H), 1.11
(s, 9H). 13C{H} NMR: (DMSO-d6, 100 MHz) δ 177.2, 156.0, 130.3, 128.0,
114.9, 41.6, 38.0, 27.5. HRMS: m/z calc’d for C12H18NO2 [M+H]+ 208.1332,
found 208.1337. Melting Point: 135-136 ℃.
N-(4-Hydroxybenzyl)-3,5-dinitrobenzamide 5h. Yellow solid (2.1 g, 45%)
using general procedure B. FT-IR (cm-1): ν = 3435, 3107, 1644, 1530, 1350.
1H NMR: (DMSO-d6, 400 MHz) δ 9.63 (t, J = 5.3 Hz, 1H), 9.34 (s, 1H), 9.10
(d, J = 1.8 Hz, 2H), 8.94 (t, J = 2.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.72
(d, J = 8.4 Hz, 2H), 4.43 (d, J = 5.6 Hz, 2H). 13C{H} NMR: (DMSO-d6, 100
MHz) δ 161.9, 156.5, 148.2, 136.9, 129.0, 128.8, 127.6, 120.8, 115.1, 42.8.
HRMS: m/z calc’d for C14H12N3O6 [M+H]+ 318.0721, found 318.0717.
Melting Point: 204-205 ℃.
N-(4-Hydroxybenzyl)furan-2-carboxamide 5p. Pink solid (1.15 g, 65%)
using general procedure B. FT-IR (cm-1): ν = 3119, 2815, 1633, 1591, 1513,
1221, 1184, 1038. 1H NMR: (DMSO-d6, 400 MHz) δ 9.28 (s, 1H), 8.80 (t,
J = 6.0 Hz, 1H), 7.82 (s, 1H), 7.11-7.09 (m, 3H), 6.70 (d, J = 8.4 Hz, 2H),
6.61-6.60 (m, 1H), 4.29 (d, J = 6.1 Hz, 2H). 13C NMR: (DMSO-d6, 100 MHz)
δ 157.6, 156.3, 148.0, 145.0, 129.7, 128.7, 115.0, 113.3, 111.8, 41.4.
HRMS: m/z calc’d for C12H12NO3 [M+H]+ 218.0812, found 218.0815.
Melting Point: 162-163 ℃.
N-(4-Hydroxybenzyl)-4-(trifluoromethyl)benzamide 5i. White solid (1.5 g,
78%) using general procedure A. FT-IR (cm-1): ν = 3355, 3193, 1635, 1190.
1H NMR: (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 9.17 (t, J = 5.8 Hz, 1H), 8.06
(d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.14-7.12 (m, 2H), 6.73-6.70
(m, 2H), 4.38 (d, J = 5.7 Hz, 2H). 13C{H} NMR: (DMSO-d6, 100 MHz) δ
164.9, 156.3, 138.2, 131.1 (q, 32 Hz), 129.5, 128.7, 128.2, 125.3 (q, 3.8
Hz), 122.6 (q, J = 274 Hz), 115.1, 42.3. HRMS: m/z calc’d for C15H13F3NO2
[M+H]+ 296.0893, found 296.0896. Melting Point: 155-156 ℃.
N-(4-Hydroxybenzyl)thiophene-2-carboxamide 5q. Light brown solid (0.97
g, 51%) using general procedure B. FT-IR (cm-1): ν = 3073, 2827, 1613,
1548, 1510, 1239. 1H NMR: (DMSO-d6, 400 MHz) δ 9.28 (s, 1H), 8.92 (t,
J = 5.8 Hz, 1H), 7.79 (d, J = 3.7 Hz, 1H), 7.74 (d, J = 5.0 Hz, 1H), 7.15-
7.11 (m, 3H), 6.72 (d, J = 8.4 Hz, 2H), 4.33 (d, J = 6.0 Hz, 2H). 13C{H}
NMR: (DMSO-d6, 100 MHz) δ 160.9, 156.3, 140.1, 130.7, 129.6, 128.6,
128.0, 127.9, 115.0, 42.0. HRMS: m/z calc’d for C12H12NO2S [M+H]+
234.0583, found 234.0587. Melting Point: 191-192 ℃.
N-(4-Hydroxybenzyl)-3-(trifluoromethyl)benzamide 5j. Light pink solid (1.2
g, 63%) using general procedure A. FT-IR (cm-1): ν = 3307, 3139, 1632,
1441. 1H NMR: (DMSO-d6, 400 MHz) δ 9.34 (s, 1H), 9.21 (t, J = 5.7 Hz,
1H), 8.23 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.72 (t,
J = 7.8 Hz, 1H), 7.14 (d, J= 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 4.39 (d,
J = 5.8 Hz, 2H). 13C{H} NMR: (DMSO-d6, 100 MHz) δ 164.5, 156.4, 135.3,
131.4, 130.1, 129.7, 129.4, 129.3, 129.0, 127.8 (q, J = 32 Hz), 124.1 (q, J
= 272 Hz), 123.9 (q, J = 4.0 Hz), 115.1, 42.4. HRMS: m/z calc’d for
3-Chloro-N-(4-hydroxybenzyl)benzo[b]thiophene-2-carboxamide 5r. Light
brown crystalline solid (0.2 g, 78%) using general procedure B. FT-IR (cm-
1): ν = 3242, 3062, 2357, 1606, 1519, 1268, 1239. 1H NMR: (DMSO-d6,
400 MHz) δ 9.33 (s, 1H), 8.88 (t, J = 5.8 Hz, 1H), 8.11-8.09 (m, 1H), 7.90-
7.88 (m, 1H), 7.60-7.56 (m, 2H), 7.17 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.3
Hz, 2H), 4.39 (d, J = 5.9 Hz, 2H). 13C{H} NMR: (DMSO-d6, 100 MHz) δ
159.8, 156.1, 136.3, 135.7, 132.1, 128.7, 128.4, 127.1, 125.7, 123.1, 122.2,
118.4, 114.8, 42.3. HRMS: m/z calc’d for C16H13ClNO2S [M+H]+ 318.0350,
found 318.0350. Melting Point: 200-201 ℃.
C
15H13F3NO2 [M+H]+ 296.0893, found 296.0898. Melting Point: 154-155 ℃.
N-(4-Hydroxybenzyl)-3,5-bis(trifluoromethyl)benzamide 5k. Pink solid (2.4
g, 68%) using general procedure A. FT-IR (cm-1): ν = 3272, 3140, 1642,
1286, 1142. 1H NMR: (DMSO-d6, 300 MHz) δ 9.41 (t, J = 5.6 Hz, 1H), 9.33
(s, 1H), 8.53 (s, 2H), 8.31 (s, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4
Hz, 2H), 4.41 (d, J = 5.7 Hz, 2H). 13C{H} NMR: (DMSO-d6, 75 MHz) δ 162.7,
156.3, 136.0, 130.2 (q, J = 33 Hz), 128.7, 128.3, 127.9 (q, J = 2.8 Hz),
124.5 (q, J = 3.5 Hz), 123.0 (q, J = 273 Hz), 114.8, 42.4. HRMS: m/z calc’d
for C16H12F6NO2 [M+H]+ 364.0772, found 364.0770. Melting Point: 176-
177 ℃.
N-(4-Hydroxybenzyl)-1H-pyrrole-2-carboxamide 6s. Brick red powder
(1.37 g, 39%) using general procedure B. FT-IR (cm-1): ν = 3417, 3115,
2838, 1650, 1526, 1513, 1334, 1188. 1H NMR: (DMSO-d6, 400 MHz) δ
11.43 (s, 1H), 9.26 (s, 1H), 8.40 (t, J = 6.0 Hz, 1H), 7.09 (d, J = 8.4 Hz,
2H), 6.84-6.78 (m, 2H), 6.70 (d, J = 8.4 Hz, 2H), 6.08-6.06 (m, 1H), 4.31
(d, J = 6.0 Hz, 2H). 13C{H} NMR: (DMSO-d6, 100 MHz) δ 160.5, 156.1,
130.2, 128.5, 126.3, 121.2, 114.9, 109.9, 108.5, 41.4. HRMS: m/z calc’d
2,5-Dibromo-N-(4-hydroxybenzyl)benzamide 5l. Dark brown solid (1.93 g,
34%) using general procedure B. FT-IR (cm-1): ν = 3290, 3076, 1628, 1580,
5
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10.1002/ejoc.202000840
European Journal of Organic Chemistry
FULL PAPER
for C12H13N2O2 [M+H]+ 217.0972, found 217.0976. Melting Point: 175-
176 ℃.
128.8, 128.1, 128.0, 127.0, 79.0, 63.6. HRMS: m/z calc’d for C14H12NO2
[M+H]+ 226.0863, found 226.0866.
N-(4-Hydroxybenzyl)picolinamide 5t. Brown solid (1.16 g, 61%) using
general procedure B. FT-IR (cm-1): ν = 3175, 2850, 1632, 1531, 1514,
1231. 1H NMR: (DMSO-d6, 400 MHz) δ 9.27 (s, 1H), 9.14 (t, J = 5.8 Hz,
1H), 8.63-8.62 (m, 1H), 8.06-7.96 (m, 2H), 7.60-7.57 (m, 1H), 7.14 (d, J =
8.2 Hz, 2H), 6.70 (d, J = 8.2 Hz, 2H), 4.38 (d, J = 6.2 Hz, 2H). 13C{H} NMR:
(DMSO-d6, 100 MHz) δ 163.5, 156.1, 149.9, 148.3, 137.6, 129.6, 128.7,
126.3, 121.8, 114.9, 41.8. HRMS: m/z calc’d for m/z calc’d for C13H13N2O2
[M+H]+ 229.0972, found 229.0975. Melting Point: 182-184 ℃.
2-(3,5-Dimethylphenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one 6b.
Yellow oil (56 mg, 56%). FT-IR (cm-1): ν = 3102, 1672, 1652, 1634, 1601,
1209. 1H NMR: (CDCl3, 300 MHz) δ 7.57 (s, 2H), 7.16 (s, 1H), 6.94 (d, J =
10.0 Hz, 2H), 6.30 (d, J = 10.0 Hz, 2H), 4.11 (s, 2H), 2.35 (s, 6H). 13C{H}
NMR: (CDCl3, 100 MHz) δ 184.8, 163.9, 146.2, 138.4, 133.8, 128.9, 126.5,
126.3, 79.2, 64.6, 21.3. HRMS: m/z calc’d for [M+H]+ C16H16NO2 254.1176,
found 254.1180.
2-Mesityl-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one 6c. Pale yellow oil
(36 mg, 36 %). FT-IR (cm-1): ν = 3040, 2921, 2830, 1716, 1671, 1635,
1611, 1574, 1429, 1248. 1H NMR: (CDCl3, 400 MHz) δ 6.92 (d, J = 10.0
Hz, 2H), 6.83 (s, 2H), 6.22 (d, J = 10.0 Hz, 2H), 4.09 (s, 2H), 2.31 (s, 6H),
2.23 (s, 3H). 13C{H} NMR: (CDCl3, 100 MHz) δ 184.4, 163.7, 145.9, 139.7,
136.8, 128.6, 128.3, 124.3, 78.6, 64.4, 21.1, 19.7. HRMS: m/z calc’d for
N-((2-Hydroxynaphthalen-1-yl)methyl)benzamide 7a.17 Light brown solid
(2.74 g, 71%) using general procedure C. FT-IR (cm-1): ν = 3265, 3130,
1660, 1650. 1H NMR: (DMSO-d6, 400 MHz) δ 10.28 (s, 1H), 9.11 (t, J =
5.1 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.90-7.88 (m, 2H), 7.81-7.76 (m, 2H),
7.53-7.41 (m, 4H), 7.30 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 8.9 Hz, 1H), 4.88
(d, J = 5.2 Hz, 2H). 13C{H} NMR: (DMSO-d6, 100 MHz) δ 167.4, 153.8,
133.6, 133.4, 131.4, 129.4, 128.2, 127.5, 126.5, 122.8, 122.6, 119.0, 115.7,
34.5. HRMS: m/z calc’d for C18H16NO2 [M+H]+ 278.1176, found 278.1181.
Melting Point: 177-178 ℃.
C
17H18NO2 [M+H]+ 268.1332, found 268.1341.
2-(4-Methoxyphenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one
6d.
Colorless oil (28 mg, 56%). FT-IR (cm-1): ν = 3080, 2925, 1666, 1648, 1632,
1608, 1253. 1H NMR: (CDCl3, 400 MHz) δ 7.88 (d, J = 8.8 Hz, 2H), 6.95-
6.91 (m, 4H), 6.27 (d, J = 9.9 Hz, 2H), 4.09 (s, 2H), 3.85 (s, 3H). 13C{H}
NMR: (CDCl3, 100 MHz) δ 184.9, 163.4, 162.7, 146.4, 130.4, 128.9, 119.2,
114.0, 79.2, 64.6, 55.6. HRMS: m/z calc’d for C15H14NO3 [M+H]+ 256.0968,
found 256.0970.
N-((6-Bromo-2-hydroxynaphthalen-1-yl)methyl)benzamide
7b.
Pale
yellow solid (0.95 g, 59%) using general procedure C. FT-IR (cm-1): ν =
3462, 3425, 3148, 1624, 1572, 1501, 1293. 1H NMR: (DMSO-d6, 400 MHz)
δ 10.37 (s, 1H), 9.04 (t, J = 5.1 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 8.01 (d,
J = 9.1 Hz, 1H), 7.86-7.84 (m, 2H), 7.75 (d, J = 8.9 Hz, 1H), 7.56 (dd, J1=
9.1 Hz, J2 = 2.2 Hz, 1H), 7.51-7.47 (m, 1H), 7.45-7.40 (m, 2H), 7.22 (d, J =
9.0 Hz, 1H), 4.82 (d, J = 5.2 Hz, 2H). 13C{H} NMR: (DMSO-d6, 100 MHz)
δ 167.2, 154.3, 133.6, 132.0, 131.4, 130.0, 129.5, 129.2, 128.6, 128.2,
127.4, 125.3, 120.1, 116.0, 115.5, 34.2. HRMS: m/z calc’d for
2-(3-Fluoro-4-methylphenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one
6e. Light brown oil (75 mg, 94%). FT-IR (cm-1): ν = 3056, 2961, 1678, 1632,
1602, 1389, 1283, 1252. 1H NMR: (CDCl3, 300 MHz) δ 7.64-7.56 (m, 2H),
7.28-7.22 (m, 1H), 6.93 (d, J = 10.1 Hz, 2H), 6.29 (d, J = 10.1 Hz, 2H),
4.11 (s, 2H), 2.33 (d, J = 1.6 Hz, 3H). 13C{H} NMR: (CDCl3, 75 MHz) δ
184.7, 162.7, 161.0 (d, J = 245 Hz), 146.0, 131.8 (d, J = 5.3 Hz), 129.7 (d,
J = 17.5 Hz), 129.0, 126.2 (d, J = 9.0 Hz), 124.0 (d, J = 3.8 Hz), 115.2 (d,
J = 25 Hz), 79.5, 64.7, 14.9 (d, J = 3.6 Hz). HRMS: m/z calc’d for
C
18H15BrNO2 [M+H]+ 356.0281, found 356.0282. Melting Point: 211-212 ℃.
N-(4-Hydroxyphenethyl)benzamide 9a. Off-white solid (2.0 g, 63%) using
general procedure B. FT-IR (cm-1): ν = 3323, 3025, 1636, 1538, 1511,
1250. 1H NMR: (DMSO-d6, 300 MHz) δ 9.18 (s, 1H), 8.52 (t, J = 5.7 Hz,
1H), 7.81 (d, J = 7.3 Hz, 2H), 7.51 7.42 (m, 3H), 7.01 (d, J = 8.3 Hz, 2H),
6.68 (d, J = 8.3 Hz, 2H), 3.44-3.37 (m, 2H), 2.71 (t, J = 7.5 Hz, 2H). 13C{H}
NMR: (DMSO-d6, 75 MHz) δ 166.0, 155.6, 134.6, 131.0, 129.5, 129.4,
128.2, 127.0, 115.1, 41.2, 34.3. HRMS: m/z calc’d for C15H16NO2 [M+H]+
242.1176, found 242.1180. Melting Point: 158-159 ℃.
C
15H13FNO2 [M+H]+ 258.0925, found 258.0929.
2-(2-Fluorophenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one 6f. Light
brown oil (51 mg, 86%). FT-IR (cm-1): ν = 3115, 2936, 2856, 1654, 1641,
1536, 1066, 978, 756, 695. 1H NMR: (CDCl3, 300 MHz) δ 7.90-7.84 (m,
1H), 7.54-7.46 (m, 1H), 7.23-7.14 (m, 2H), 6.95 (d, J = 10.1 Hz, 2H), 6.30
(d, J = 10.1 Hz, 2H), 4.17 (s, 2H). 13C{H} NMR: (CDCl3, 75 MHz) δ 184.7,
161.5 (d, J = 259 Hz), 159.8, 145.9, 133.8 (d, J = 8.9 Hz), 131.2, 129.1,
124.3 (d, J = 3.7 Hz), 117.0 (d, J = 21.7 Hz), 115.1 (d, J = 10.1 Hz), 78.8,
65.0. HRMS: m/z calc’d for Cl4H11FNO2 [M+H]+ 244.0768, found 244.0770.
4-Chloro-N-(4-hydroxyphenethyl)benzamide 9b. White solid (2.4 g, 68%)
using general procedure B. FT-IR (cm-1): ν = 3307, 2871, 2797, 1650, 1592,
1511, 1240. 1H NMR: (DMSO-d6, 300 MHz) δ 9.19 (s, 1H), 8.62 (t, J = 5.5
Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.4
Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 3.44-3.37 (m, 2H), 2.71 (t, J = 7.5 Hz,
2H). 13C{H} NMR: (DMSO-d6, 75 MHz) δ 165.0, 155.6, 135.8, 133.3, 129.5,
129.4, 129.0, 128.3, 115.1, 41.3, 34.2. HRMS: m/z calc’d for C15H15ClNO2
[M+H]+ 276.0786, found 276.0790. Melting Point: 178-179 ℃.
2-(3-Nitrophenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one 6g. Pale
yellow oil (30 mg, 60%). FT-IR (cm-1): ν = 3059, 2976, 2871, 1695, 1645,
1635, 1579, 1449, 1347, 1265, 1212. 1H NMR: (CDCl3, 400 MHz) δ 8.78
(t, J = 1.93 Hz, 1H), 8.40-8.37 (m, 1H), 8.30-8.28 (m, 1H), 7.65 (t, J = 8.20
Hz, 1H), 6.93 (d, J = 10.1 Hz, 2H), 6.32 (d, J = 10.1 Hz, 2H), 4.18 (s, 2H).
13C{H} NMR: (CDCl3, 100 MHz) δ 184.5, 161.5, 145.4, 134.2, 129.9, 129.3,
128.7, 126.6, 123.7, 80.1, 64.9. HRMS: m/z calc’d for C14H11N2O4 [M+H]+
271.0713, found 271.0719.
Synthesis of Spirocycles
Representative Procedure for Oxidative Cyclization of Benzamides and
Naphthol Amides: Synthesis of 2-phenyl-1-oxa-3-azaspiro[4.5]deca-2,6,9-
trien-8-one 6a. To a stirred solution of amide 5a (227 mg, 1.0 mmol) in
HFIP (6 mL) was added m-CPBA (~75% purity, 380 mg, 1.6 mmol) and 4-
iodotoluene (43.6 mg, 0.20 mmol). The resulting mixture was stirred
overnight at room temperature and then a saturated aqueous solution of
NaHCO3 (6 mL) was added to the reaction mixture followed by water (6
mL). The organic layer was extracted with ethyl acetate (10 mL x 3), dried
over MgSO4, filtered and concentrated under vacuum. The residue was
purified by flash chromatography (3:1 petroleum ether/EtOAc) to afford 2-
phenyl-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one 6a as a brown oil (158
mg, 67%). FT-IR (cm-1): ν = 3160, 2991, 1668, 1650, 1630, 1251. 1H NMR:
(DMSO, 400 MHz) δ 7.89 (d, J = 7.4 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.51
(t, J = 7.6 Hz, 2H), 7.22 (d, J = 9.9 Hz, 2H), 6.26 (d, J = 9.9 Hz, 2H), 4.12
(s, 2H). 13C{H} NMR: (DMSO, 100 MHz) δ 184.5, 161.6, 147.3, 132.0,
2-(3,5-Dinitrophenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one
6h.
Yellow oil (50 mg, 50%). FT-IR (cm-1): ν = 3069, 1664, 1632, 1538, 1342,
1281, 1251. 1H NMR: (CDCl3, 400 MHz) δ 9.19-9.18 (m, 1H), 9.10-9.09 (m,
2H), 6.93 (d, J = 9.9 Hz, 2H), 6.36 (d, J = 9.9 Hz, 2H), 4.24 (s, 2H). 13C{H}
NMR: (CDCl3, 100 MHz) δ 184.2, 159.7, 148.8, 144.6, 130.5, 129.6, 128.5,
121.5, 80.8, 65.0. HRMS: m/z calc’d for C14H10N3O6 [M+H]+ 316.0564,
found 316.0564.
2-(4-(Trifluoromethyl)phenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one
6i. Pale yellow oil (70 mg, 70%). FT-IR (cm-1): ν = 3048, 2934, 2850, 1715,
1673, 1635, 1620, 1575, 1412, 1320, 1249. 1H NMR: (CDCl3, 400 MHz) δ
8.06 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 10.0 Hz, 2H),
6
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10.1002/ejoc.202000840
European Journal of Organic Chemistry
FULL PAPER
6.32 (d, J = 10.0 Hz, 2H), 4.15 (s, 2H). 13C{H} NMR: (CDCl3, 100 MHz) δ
184.6, 162.3, 145.7, 133.6 (q, J = 32.7 Hz), 130.1, 129.1, 128.9, 125.3 (q,
J = 3.7 Hz), 123.7 (q, J = 272 Hz), 79.7, 64.7. HRMS: m/z calc’d for
C15H11F3NO2 [M+H]+ 294.0736, found 294.0741.
= 1.1 Hz, 1H), 7.53 (dd, J1 = 3.7 Hz, J2 = 1.1 Hz, 1H), 7.11 (dd, J1 = 5.0 Hz,
J2 = 3.7 Hz, 1H), 6.95 (d, J = 10.1 Hz, 2H), 6.30 (d, J = 10.1 Hz, 2H), 4.11
(s, 2H). 13C{H} NMR: (CDCl3, 100 MHz) δ 184.7, 159.3, 145.8, 131.4,
131.0, 129.1, 129.1, 128.0, 79.9, 64.6. HRMS: m/z calc’d for C12H10NO2S
[M+H]+ 232.0427, found 232.0429.
2-(3-(Trifluoromethyl)phenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one
6j. Yellow oil (50 mg, 63%). FT-IR (cm-1): ν = 3046, 2936, 2836, 1714,
1670, 1635, 1626, 1571, 1409, 1320, 1250. 1H NMR: (CDCl3, 300 MHz) δ
8.21 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.58 (t, J =
7.8 Hz, 1H), 6.93 (d, J = 10.1 Hz, 2H), 6.30 (d, J = 10.1 Hz, 2H), 4.15 (s,
2H). 13C{H} NMR: (CDCl3, 75 MHz) δ 184.7, 162.3, 145.7, 131.6, 131.7 (q,
J = 33 Hz), 129.3, 129.1, 128.6 (q, J = 3.8 Hz), 127.6, 125.5 (q, J = 3.7 Hz),
123.8 (q, J = 273.3 Hz), 79.8, 64.7. HRMS: m/z calc’d for C15H11F3NO2
[M+H]+ 294.0736, found 294.0741.
2-(3-Chlorobenzo[b]thiophen-2-yl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-
8-one 6r. Pale yellow oil (15 mg, 30%). FT-IR (cm-1): ν = 3148, 3051, 2838,
2741, 1671, 1643, 1633, 1517, 1228. 1H NMR: (CDCl3, 400 MHz) δ 7.96-
7.94 (m, 1H), 7.84-7.82 (m, 1H), 7.53-7.50 (m, 2H), 6.99 (d, J1 = 10.1 Hz,
2H), 6.32 (d, J = 10.1 Hz, 2H), 4.20 (s, 2H). 13C{H} NMR: (CDCl3, 100 MHz)
δ 184.6, 158.4, 145.6, 138.3, 137.1, 129.3, 128.0, 125.7, 125.3, 123.6,
122.8, 122.2, 79.9, 64.7. HRMS: m/z calc’d for C16H11ClNO2S [M+H]+
316.0194, found 316.0195.
2-(3,5-Bis(trifluoromethyl)phenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-
8-one 6k. Blood red oil (61 mg, 61%) using general procedure D. FT-IR
(cm-1): ν = 3078, 2980, 1674, 1636, 1602, 1396, 1280, 1250. 1H NMR:
(CDCl3, 300 MHz) δ 8.40 (s, 2H), 8.01 (s, 1H), 6.94 (d, J = 10.0 Hz, 2H),
6.32 (d, J = 10.0 Hz, 2H), 4.18 (s, 2H). 13C{H} NMR: (CDCl3, 75 MHz) δ
184.1, 161.0, 145.1, 132.4 (q, J = 34.4 Hz), 129.3, 129.0, 128.6 (q, J = 3.8
Hz), 125.4 (q, J = 3.7 Hz), 122.8 (q, J = 272.8 Hz), 80.2, 64.8. HRMS: m/z
calc’d for C16H10F6NO2 [M+H]+ 362.0610, found 362.0540.
2-(1H-Pyrrol-2-yl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one
6s.
Reddish oil (43 mg, 43%). FT-IR (cm-1): ν = 3100, 2942, 2830, 1671, 1635,
1620, 1448, 1270. 1H NMR: (CDCl3, 400 MHz) δ 10.71 (s, 1H), 6.96-6.91
(m, 3H), 6.80 (s, 1H), 6.29-6.25 (m, 3H), 4.07 (s, 2H). 13C{H} NMR: (CDCl3,
100 MHz) δ 184.7, 158.5, 145.9, 129.0, 123.2, 118.7, 114.3, 110.2, 79.2,
63.6. HRMS: m/z calc’d for C12H11N2O2 [M+H]+ 215.0815, found 215.0821.
2-(Pyridin-2-yl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one
6t.
Pale
yellow oil (28 mg, 56%). FT-IR (cm-1): ν = 3054, 2851, 2760, 1671, 1633,
1522, 1483, 1345, 1265. 1H NMR: (CDCl3, 300 MHz) δ 8.76-8.74 (m, 1H),
8.07-8.04 (m, 1H), 7.84 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.48-7.43 (m,
1H), 6.98 (d, J = 10.2 Hz, 2H), 6.30 (d, J = 10.2 Hz, 2H), 4.20 (s, 2H).
13C{H} NMR: (CDCl3, 75 MHz) δ 184.7, 150.2, 145.8, 137.0, 129.1, 126.3,
124.3, 80.1, 64.8. HRMS: m/z calc’d for C13H11N2O2 [M+H]+ 227.0815,
found 227.0818.
2-(2,5-Dibromophenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one
6l.
Light brown oil (32.5 mg, 65%). FT-IR (cm-1): ν = 3063, 2920, 2841, 1718,
1670, 1634, 1576, 1455, 1238. 1H NMR: (CDCl3, 400 MHz) δ 7.89 (d, J =
2.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.46 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz,
1H), 6.99 (d, J = 10.0 Hz, 2H), 6.31 (d, J = 10.0 Hz, 2H), 4.18 (s, 2H).
13C{H} NMR: (CDCl3, 100 MHz) δ 184.6, 161.5, 145.5, 135.7, 135.4, 134.4,
129.9, 129.2, 121.3, 120.9, 79.8, 64.8. HRMS: m/z calc’d for C14H10Br2NO2
[M+H]+ 381.9073, found 381.9070.
2'-Phenyl-2H,4'H-spiro[naphthalene-1,5'-oxazol]-2-one 8a. Pale yellow oil
(26 mg, 52%). FT-IR (cm-1): ν = 3160, 3053, 2869, 1715, 1673, 1652, 1603,
1569, 1547, 1367, 1338, 1283, 770. 1H NMR: (CDCl3, 400 MHz) δ 8.08-
8.06 (m, 2H), 7.56-7.35 (m, 8H), 6.21 (d, J = 10.0 Hz, 1H), 4.48 (d, J = 15.4
Hz, 1H), 4.01 (d, J = 15.4 Hz, 1H). 13C{H} NMR: (CDCl3 100 MHz) δ 197.8,
164.3, 145.8, 142.3, 132.0, 131.0, 129.7, 129.0, 128.9, 128.8, 128.6, 127.0,
125.7, 123.7, 86.6, 69.8. HRMS: m/z calc’d for C18H14NO2 [M+H]+
276.1019, found 276.1019. Chiralpak IB, 254 nm, hexane/IPA gradient
(100:0 to 90:10 over 35 min), 1 mL/min, retention times 12.9 & 15.1
minutes.
2-(4-Chlorophenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one
6m.
Brown solid (33 mg, 65%). FT-IR (cm-1): ν = 3052, 2920, 2870, 1714, 1672,
1653, 1635, 1596, 1490, 1337, 1261. 1H NMR: [CDCl3, 400 MHz)] δ 7.88
(d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 10.0 Hz, 2H), 6.30
(d, J = 10.0 Hz, 2H), 4.12 (s, 2H). 13C{H} NMR: [CDCl3, 100 MHz) δ 184.6,
162.8, 145.8, 138.5, 129.9, 129.0, 128.9, 125.1, 79.6, 64.4. HRMS: m/z
calc’d for C14H11ClNO2 [M+H]+ 260.0473, found 260.0477.
2-(2,3-Dichlorophenyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one 6n.
Colorless oil (30 mg, 30%). FT-IR (cm-1): ν = 3060, 2991, 1667, 1634, 1414,
1195. 1H NMR: (CDCl3, 400 MHz) δ 7.70-7.67 (m, 1H), 7.63-7.60 (m, 1H),
7.31-7.27 (m, 1H), 7.00 (d, J = 10.0 Hz, 2H), 6.32 (d, J = 10.0 Hz, 2H),
4.19 (s, 2H). 13C{H} NMR: (CDCl3, 100 MHz) δ 184.6, 161.7, 145.6, 134.7,
133.2, 132.1, 129.7, 129.2, 128.6, 127.4, 79.7, 64.9. HRMS: m/z calc’d for
6-Bromo-2'-phenyl-2H,4'H-spiro[naphthalene-1,5'-oxazol]-2-one 8b. Pale
yellow oil (25.5 mg, 51%). FT-IR (cm-1): ν = 3273, 3060, 2922, 2869, 1718,
1679, 1655, 1602, 1579, 1556, 1483, 1367, 1338, 1283, 1246. 1H NMR:
(CDCl3, 400 MHz) δ 8.06-8.04 (m, 2H), 7.56-7.40 (m, 6H), 7.32-7.30 (m,
1H), 6.30 (d, J = 10.0 Hz, 1H), 4.47 (d, J = 15.0 Hz, 1H), 4.00 (d, J = 15.0
Hz, 1H). 13C{H} NMR: (CDCl3, 100 MHz) δ 197.0, 164.3, 144.1, 141.0,
133.7, 132.3, 132.1, 131.0, 128.9, 128.7, 127.4, 126.8, 125.0, 123.0, 86.3,
69.7. HRMS: m/z calc’d for C18H1381BrNO2 [M+H]+ 356.0104, found
356.0111.
C
14H10Cl2NO2 [M+H]+ 294.0083, found 294.0080.
2-(tert-Butyl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one 6o. Colorless oil
(196 mg, 41%). FT-IR (cm-1): ν = 2972, 2872, 1663, 1633, 1609, 1480,
1395, 1267, 1129. 1H NMR: (CDCl3, 300 MHz) δ 6.82 (d, J = 10.1 Hz, 2H),
6.23 (d, J = 10.1 Hz, 2H), 3.88 (s, 2H), 1.26 (s, 9H). 13C{H} NMR: (CDCl3,
75 MHz) δ 184.9, 174.0, 146.3, 128.7, 79.0, 64.1, 33.6, 27.8. HRMS: m/z
calc’d for C12H16NO2 [M+H]+ 206.1176, found 206.1178.
2-Phenyl-1-oxa-3-azaspiro[5.5]undeca-2,7,10-trien-9-one
10a.
Pale
yellow oil (51 mg, 51%). FT-IR (cm-1): ν = 3067, 2925, 2867, 2761, 1672,
1655, 1653, 1536, 1346, 1279, 1219. 1H NMR: (CDCl3, 400 MHz) δ 7.90
(d, J = 7.3 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.38(t, J = 7.4 Hz, 2H), 6.97
(d, J = 10.2 Hz, 2H), 6.30 (d, J = 10.2 Hz, 2H), 3.76 (t, J = 6.1 Hz, 2H),
2.00 (t, J = 6.1 Hz, 2H). 13C{H} NMR: (CDCl3, 100 MHz) δ 184.7, 154.3,
146.7, 133.2, 131.0, 129.1, 128.3, 127.2, 71.7, 40.3, 30.5. HRMS: m/z
calc’d for C15H14NO2 [M+H]+ 240.1019, found 240.1019.
2-(Furan-2-yl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one 6p. Colorless
oil (31 mg, 62%). FT-IR (cm-1): ν = 3128, 2872, 2779, 1715, 1672, 1635,
1560, 1479, 1399, 1266. 1H NMR: (CDCl3, 400 MHz) δ 7.60-7.59 (m, 1H),
7.02 (d, J = 3.5 Hz, 1H), 6.93 (d, J = 10.1 Hz, 2H), 6.54-6.53 (m, 1H), 6.30
(d, J = 10.1 Hz, 2H), 4.13 (s, 2H). 13C{H} NMR: (CDCl3, 100 MHz) δ 184.6,
155.7, 146.1, 145.6, 142.0, 129.2, 115.7, 111.9, 79.6, 64.6. HRMS: m/z
calc’d for C12H10NO3 [M+H]+ 216.0655, found 216.0655.
2-(4-Chlorophenyl)-1-oxa-3-azaspiro[5.5]undeca-2,7,10-trien-9-one 10b.
Pale yellow oil (81 mg, 81%). FT-IR (cm-1): ν = 3053, 2867, 2740, 1673,
1656, 1638, 1596, 1536, 1486, 1398, 1346, 1278. 1H NMR: (CDCl3, 300
MHz) δ 7.83 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 10.2
Hz, 2H), 6.30 (d, J = 10.2 Hz, 2H), 3.73 (t, J = 6.2 Hz, 2H), 2.00 (t, J = 6.2
Hz, 2H). 13C{H} NMR: (CDCl3, 75 MHz) δ 184.6, 153.4, 146.4, 137.1, 131.7,
2-(Thiophen-2-yl)-1-oxa-3-azaspiro[4.5]deca-2,6,9-trien-8-one 6q. Pale
yellow oil (35 mg, 70%). FT-IR (cm-1): ν = 3090, 2861, 2760, 1667, 1648,
1633, 1428, 1250. 1H NMR: (CDCl3, 400 MHz) δ 7.63 (dd, J1 = 3.7 Hz, J2
7
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10.1002/ejoc.202000840
European Journal of Organic Chemistry
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129.2, 128.6, 128.5, 71.8, 40.2, 30.4. HRMS: m/z calc’d for C15H13ClNO2
[M+H]+ 274.0629, found 274.0629.
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H. Zhou, S. W. Topiol, M. Grenon, H. N. Jimenez, M. A. Uberti, D. G.
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1677.
Methylation of Spirocycles: To a solution of spirocycle (0.32 mmol, 1 equiv)
in dry THF (5 mL) at ˗78 °C under a nitrogen atmosphere, was added MeLi
(1.2 equiv, 1.6 M in hexane) dropwise over 5 minutes. The reaction mixture
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°
was stirred at ˗78 C for 1 hour, then quenched with saturated aqueous
°
NH4Cl solution (5 mL) at ˗78 C. The aqueous layer was extracted with
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Mowdawalla, Org. Biomol. Chem. 2019, 17, 7822-7848; b) F. V. Singh,
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ethyl acetate (2 x 5 mL) and the combined organic layers were washed
with brine, dried over MgSO4, filtered and concentrated under vacuum.
The residue was purified by flash chromatography (petroleum ether/ethyl
acetate (4:1 then 2:1)) to yield the corresponding product.
N-(2-Hydroxy-4-methylbenzyl)-2,4,6-trimethylbenzamide 12. Colorless oil
(70 mg, 77%). FT-IR (cm-1): ν = 3268, 2969, 2720, 1602, 1542, 1506, 1458,
1378, 1268. 1H NMR: (CDCl3, 400 MHz) δ 7.06 (s, 1H), 6.98 (d, J = 8.5 Hz,
1H), 6.80 (s, 2H), 6.68 (d, J = 8.5 Hz, 1H), 6.30 (s, 1H), 5.90 (t, J = 5.5 Hz,
1H), 4.49 (d, J = 5.5 Hz, 2H), 2.26 (s, 9H), 2.19 (s, 3H). 13C{H} NMR:
(CDCl3, 100 MHz) δ 170.8, 154.1, 138.7, 134.6, 134.3, 131.0, 129.4, 128.3,
126.8, 124.6, 115.3, 43.7, 21.2, 19.2, 16.0. HRMS: m/z calc’d for
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Synthesis 2019, 51, 3675-3682; b) M. Ogasawara, H. Sasa, H. Hu, Y.
Amano, H. Nakajima, N. Takenaga, K. Nakajima, Y. Kita, T. Takahashi,
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L.-Z. Gong, Chem. Eur. J. 2015, 21, 10314-10317; d) T. Dohi, N.
Takenaga, T. Nakae, Y. Toyoda, M. Yamasaki, M. Shiro, H. Fujioka, A.
Maruyama, Y. Kita, J. Am. Chem. Soc. 2013, 135, 4558–4566; e) T. Dohi,
N. Takenaga, K.-I Fukushima, T. Uchiyama, D. Kato, S. Motoo, H.
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Maruyama, Y. Minamitsuji, N. Takenaga, Y. Kita, Chem. Commun. 2007,
1224–1226.
C
18H22NO2 [M+H]+ 284.1645, found 2844.1645
2-Methyl-2'-phenyl-2H,4'H-spiro[naphthalene-1,5'-oxazol]-2-ol 13. The
crude reaction mixture contained a 5:1 ratio of diastereomers. The major
diastereomer was obtained as
a colorless oil (60 mg, 67%).
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Rev. Chem. 2017, 1, 0088.
Characterization data for the major diastereomer is provided only. FT-IR
(cm-1): ν = 3241, 2975, 2851, 2700, 1606, 1523, 1501, 1478, 1346, 1285,
1220. 1H NMR: (CDCl3, 400 MHz) δ 7.97-7.95 (m, 2H), 7.49-7.13 (m, 8H),
6.51 (d, J = 9.8 Hz, 1H), 6.00 (d, J = 9.8 Hz, 1H), 4.43 (d, J = 15.4 Hz, 1H),
4.08 (d, J = 15.4 Hz, 1H), 2.66 (s, 1H), 1.32 (s, 3H). 13C{H} NMR: (CDCl3,
100 MHz) δ 163.2, 137.0, 134.5, 131.6, 131.4, 130.0, 128.6, 128.4, 128.4,
127.5, 127.5, 124.8, 90.9, 72.5, 60.5, 21.3. HRMS: m/z calc’d for
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Angew. Chem. Int. Ed. 2010, 49, 2175-2177.
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C
19H18NO2 [M+H]+ 292.1332, found 292.1336.
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Acknowledgements
We thank the University of Huddersfield for a postgraduate
scholarship (MUT) and Lukas Jokubauskas (University of
Huddersfield) for experimental assistance.
Keywords: spirocycle • oxazoline • dearomatization • iodine •
cyclization
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8
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European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
N
20-40 mol% 4-iodotoluene
HN
R
>20 examples
O
1.6 equiv m-CPBA
R
O
OH
O
HFIP, rt, 16 hours
The oxidative spirocyclization of phenols and naphthols containing pendent amides is described that grants access to unusual
spirooxazoline compounds. These rare spirocycles are prepared by an iodine(I)/(III) catalytic cycle.
Researcher Twitter usernames: @DrWesleyMoran; @iUmyrr
Homepage: https://pure.hud.ac.uk/en/persons/wesley-moran
Key topic: Hypervalent Iodine
9
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