Oxidative Deconstruction of Azetidinols to α-Amino Ketones

Article abstract of DOI:10.1021/acs.joc.0c00986

A silver-mediated synthesis of α-amino ketones via the oxidative deconstruction of azetidinols has been developed using a readily scalable protocol with isolated yields up to 80percent. The azetidinols are easily synthesized in one step and can act as protecting groups for these pharmaceutically relevant synthons. Furthermore, mechanistic insights are presented and these data have revealed that the transformation is likely to proceed through the β-scission of an alkoxy radical, followed by oxidation and C-N cleavage of the resulting α-amido radical.

Full text of DOI:10.1021/acs.joc.0c00986

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Note
Oxidative Deconstruction of Azetidinols to #-Amino Ketones
Robert-Cristian Raclea, Philipp Natho, Lewis Alexander
Thomas Allen, Andrew J. P. White, and Philip James Parsons
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00986 • Publication Date (Web): 16 Jun 2020
Downloaded from pubs.acs.org on June 17, 2020
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The Journal of Organic Chemistry
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Oxidative Deconstruction of Azetidinols to α-Amino Ketones
Robert-Cristian Raclea, Philipp Natho, Lewis A. T. Allen, Andrew J. P. White & Philip J. Parsons*
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Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, W12 0BZ, London, UK
Supporting Information Placeholder
ABSTRACT: A silver-mediated synthesis of α-amino ketones via the oxidative deconstruction of azetidinols has been developed
using a readily scalable protocol with isolated yields up to 80%. The azetidinols are easily synthesized in one step and can act as
protecting groups for these pharmaceutically relevant synthons. Furthermore, mechanistic insights are presented and these data have
revealed that the transformation is likely to proceed through the β-scission of an alkoxy radical, followed by oxidation and C-N
cleavage of the resulting α-amido radical.
In recent years, cyclobutanols have proven to be promising
substrates for the development of deconstructive
functionalization methodologies. These are achieved through
Scheme 1. Oxidative Ring Opening and Functionalization
of Cyclobutanols (a) and Azetidines (b)
C(sp3)-C(sp3) single bond cleavage and subsequent
diversification, despite the apparent inertness of these bonds.1–7
Their unique reactivity is mainly driven by two thermodynamic
driving forces: the potential to form strong C=O bonds (ca. 179
kcal/mol vs 92 kcal/mol for C-O bonds8) and the release of ring
strain (strain energy of 26.3 kcal/mol).8 In particular, the metal-
mediated generation of alkoxy radicals allows for C(sp3)-C(sp3)
β-scission, which may be followed by radical-radical coupling
to a wide array of functional groups (Scheme 1, a) or ring
expansion. Progress within the field has since led to the
development of significantly milder protocols utilizing photo-
or electrochemical techniques to achieve similar
functionalizations or ring expansions.9–14
The deconstructive functionalization of azetidinols, however, is
less common. Building on earlier observations for the synthesis
of 3,3-disubstituted α-tetralones,15 Murakami reported the ring
expansion of several N-arenesulfonylazetidin-3-ols to
benzosultams in the presence of a Rh(I)-BINAP catalyst via an
alkylrhodium intermediate.16 Later, Gaunt reported an isolated
example of a copper-mediated azetidinol ring expansion via a
semi-pinacol rearrangement,17 and Zuo reported a single
example of azetidinol ring opening using cerium
photocatalysis.18 In addition, Knowles reported the iridium-
mediated ring fragmentation of substituted five- and six-
membered N-heterocyclic alcohols.9,10,13 Finally, Sarpong and
co-workers have shown that the metal-mediated deconstructive
fluorination of azetidines via C(sp3)-N cleavage is possible
through an initial α -oxidation, followed by hemiaminal
formation and decarboxylative fluorination (Scheme 1, b).2 An
alternative mechanism was observed for larger ring sizes. This
involves the conversion of the hemiaminal intermediate to an
alkoxy radical followed by β-scission, yielding N-formylated
amines.
In line with our continuing interest in utilizing small rings as
precursors to pharmacophores,19,20 we recently proposed that a
combination of β-scission (C(sp3)-C(sp3) cleavage) and
demethylation (C(sp3)-N cleavage) of azetidinols under
oxidative conditions would lead to α-amino ketone products
(Scheme 2, a). This would allow azetidinols to function as
stable protecting groups until late-stage conversion is required.
Classically, the synthesis of α-amino ketones relies on the
formation of a carbon-nitrogen bond in the α-position of an
oxygen functionality (e.g. ketone, alcohol).21–30 In contrast, the
use of azetidinols as equivalents of α-amino ketones would
allow for their installation through a carbon-carbon bond
formation, adding a different retrosynthetic approach to the
repertoire of synthetic chemists. The preparation of these high-
value synthons is of continued interest to the pharmaceutical
industry due to their numerous biological applications, such as
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anorectics, antidepressants or stimulants (Scheme 2, b).22,23,27,31–
4), while the use of DCE/H2O gratifyingly doubled the isolated
34
1
yield of 2a (Table 1, entry 5). This solvent system provided an
improved solubility of the starting azetidinol, as well as
reducing the amount of decomposition products when
compared to the experiment in Table 1, entry 1. The drastic
dependence of the reaction outcome on the organic solvent was
attributed to two factors. First, the starting material 1a showed
poor solubility in acetonitrile and DMF, leading to a
heterogenous reaction mixture. Additionally, it is established
that the oxidation potential of silver salts is greatly affected by
the nature of the solvent, which could explain the superior
performance of the oxidant in chlorinated solvents.36
Modification of other reaction parameters, such as an increase
of the reaction temperature to 35 °C (Table 1, entry 6) or
exchanging silver nitrate for silver tetrafluoroborate (Table 1,
entry 7), did not lead to improved results. The replacement of
potassium persulfate with more soluble sodium persulfate
(Table 1, entry 8) resulted in significantly more decomposition
of the starting material, as indicated by the lower mass balance
in comparison with the experiment in Table 1, entry 5.37 In
addition, variation of the reaction concentration had a negative
effect on the yield of the process, returning significantly more
starting material (Table 1, entries 9 & 10). At this stage of the
investigation, it was hypothesized that the incomplete
conversion of 1a is caused by the deactivation of the silver
redox couple, and additional quantities of silver(I) are therefore
required to drive the reaction to completion. This is in line with
Sarpong’s transformation, which required four equivalents of
silver(I) for full conversion.2 In our case, the use of
superstoichiometric quantities of silver(I) with different co-
oxidants did not lead to the desired improvement (Table 1,
entries 11 & 12); instead, it was found that the addition of a
second portion of silver nitrate (0.2 equiv) and co-oxidant (4
equiv) was required after 24 h to achieve full conversion of
azetidinol 1a (Table 1, entry 13). Spectroscopic analysis of the
crude reaction mixture provided no evidence of reaction by-
products, including the intramolecular aromatic substitution
product described for cyclobutanol derivatives under similar
reaction conditions.35 A full disclosure of our optimization
studies is available in the Supporting Information.
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Scheme 2. Proposed Reaction Scheme (a) and Relevant
Examples of Biologically Active α-Amino Ketones (b)
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Our study started with an investigation into reaction conditions
suitable for the proposed transformation by using
benzothiophene-substituted azetidinol 1a as a model substrate
(Table 1). This model was prepared from commercially
available N-Boc-azetidin-3-one and benzothiophene in one
synthetic step. Initially, 1a was treated with AgNO3 and K2S2O8
in DCM/H2O at room temperature, providing the desired α-
amino ketone 2a in 15% yield (Table 1, entry 1). Similar
reaction conditions have previously been employed for the
oxidative ring expansion of cyclobutanols.35 Changing the
protecting group from Boc to N-tosyl had detrimental effect on
the yield (Table 1, entry 2).
Table 1: Optimization of Reaction Conditionsa
entry
variation from
RSMb yield
[%]
[%]
standard conditions
DCM instead of DCE
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15
5
2
DCM instead of DCE, Ts instead of Boc 26
A range of aromatic-substituted azetidinols were prepared in
order to investigate the scope of the transformation (Scheme 3).
To our delight, substrates bearing electronically neutral (1b),
deactivated (1c-f), and activated (1g) aromatic rings provided
the α-amino ketone products in 63-80% yield. While fluorinated
examples (1c-e) were equally successful, the outcome of the
reaction for methoxy-containing substrates (1g-i) was found to
be dependent on the substitution pattern. The reduction in yield
(37-42% vs. 63%) was attributed to competing oxidation of the
unsubstituted para-methoxy positions, leading to quinone side-
products; similar substrates have been reported to undergo this
transformation in the presence of potassium persulfate.38 The
procedure also demonstrated consistent results when the scale
of the reaction was increased: α-amino ketone 2c was obtained
in 80% yield on a 1.2 mmol scale (vs. 80%), and 2i was isolated
in 42% yield on a 4.0 mmol scale (vs. 32%). Unfortunately,
chloro-substituted azetidinol 1l was only partially soluble in the
reaction solvent, leading to a significant recovery of starting
material (43% RSM) and a concomitant reduction in yield.
While mild electronic influences were tolerated well, more
strongly electron-releasing and electron-withdrawing aromatic
rings significantly reduced the rate and yield of the reaction.
After an increased reaction duration of 116 hours,
3
MeCN instead of DCE
DMF instead of DCE
none
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trace
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trace
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35 °C instead of rt
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AgBF4 instead of AgNO3
Na2S2O8 instead of K2S2O8
0.5 mL DCE/H2O
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2 mL DCE/H2O
4 equiv AgNO3 & K2S2O8
4 equiv AgNO3 & (NH4)2S2O8
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48 h, 4 equiv K2S2O8, second portion of trace
oxidant/co-oxidant added after 24 h
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48 h, 4 equiv (NH4)2S2O8, second portion trace
of oxidant/co-oxidant added after 24 h
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a
Standard conditions: 1a (0.30 mmol), AgNO3 (0.2 equiv) and K2S2O8 (3
b
equiv) in 1 mL DCE/H2O (1:1), rt, 24 h. Recovered starting material.
Detailed experimental procedure is available in the Experimental Section.
It was observed that polar solvents, such as acetonitrile and
DMF, led to a drastic reduction in yield (Table 1, entries 3 &
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trifluoromethyl-substituted 2m was obtained in 23% yield, and
only a trace quantity of trimethoxy-substituted 2k was isolated.
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The α-amino ketone functionality could also be obtained on
thiophene (2o) and on the 3-position of benzothiophene (2n)
with no appreciable loss in yield when compared to the model
(2a). The structure of ketone 2a was confirmed by X-ray
crystallography (see Supporting Information). Azetidinol 1p,
bearing tosyl-protected indole as the substituent, underwent the
reaction slowly to yield the α-amino ketone 2p in 37% yield,
together with 14% recovered starting material. Finally, the
benzofuran-containing azetidinol 1q decomposed under the
reaction conditions, with no evidence of the desired ketone
product 2q by NMR spectroscopy.
a
b
Second portion of oxidant/co-oxidant added after 24 h.
Recovered starting material.
A series of control experiments were performed in order to gain
insight into the mechanism of this transformation. First,
azetidinol 1a was reacted with potassium persulfate in the
absence of silver nitrate (Scheme 5, a); no conversion was
observed, demonstrating that potassium persulfate alone cannot
trigger this reaction. Since the reaction between silver(I) and
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2-
S2O8 is known to generate silver(II)-species in situ,39 the
Ag(II)/Ag(I) redox couple appears to be required for the
transformation to proceed. Next, we found that reaction of
substrate 1c is completely inhibited in the presence of TEMPO,
indicating radical-mediated steps in the pathway (Scheme 5, b).
Additionally, ether 5 was treated with our optimized reaction
conditions (Scheme 5, c), but no conversion of the starting
material was detected. This suggests that the initiation of this
reaction involves a single-electron oxidation of the alcohol
moiety, rather than an α-oxidation process (cf. Scheme 1, b).
Scheme 3. Substrate Scope of the Oxidative Deconstruction
of Azetidinolsa
We decided to probe the fate of this putative alkoxy radical. In
line with our proposed role of silver(II) in this process, substrate
1a was treated with silver(II) fluoride (Scheme 5, d). The main
product of this transformation was determined to be the dimer
6, which is likely to have formed through the radical-radical
coupling of two α-amido radical species. The generation of
these intermediates can be explained by a -scission process
from the alkoxy radical.7,40,41
Scheme 5: Mechanistic Experiments
a
Conditions: azetidinol (0.30 mmol), AgNO3 (0.2 equiv) and
K2S2O8 (4 equiv) in 1 mL DCE/H2O (1:1), rt. b Second portion of
oxidant/co-oxidant added after 24 h. c Third portion of oxidant/co-
oxidant added after 48 h. d Recovered starting material.
In addition, aryl-substituted pyrrolidinol 3 was subjected to the
optimized protocol (Scheme 4). While the desired -amino
ketone 4 was formed in 29% yield, significant quantities of
unreacted starting material were also isolated (53% RSM). As
such, it was concluded that the release of ring strain is a key
driving force for this transformation.
a Second portion of AgF2 added after 24 h.
A plausible reaction mechanism can be envisioned based on the
above results (Scheme 6). The proposed mechanism
commences with conversion of azetidinol 1 to alkoxy radical 7,
either by single-electron transfer (SET) to Ag(II) or hydrogen
Scheme 4. Oxidative Deconstruction of Pyrrolidinol 3 to -
- 39
Amino Ketone 4a
atom abstraction (HAT) by the radical anion SO4 . Alkoxy
radical 7 subsequently undergoes a facile -scission to give α-
amido radical 8, which converts to iminium 9 through a second
Ag(II)-mediated SET process.1,41–43Alternatively, persulfate
sources are known to facilitate this latter oxidation.44 Iminium
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9 is trapped by water to form hemiaminal 10, which is unstable
General Procedures
(A) Synthesis of azetidinols via metal-halogen exchange.49
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under the acidic reaction conditions (pH ≈ 2), generating the α-
amino ketone product 2 and formaldehyde. The energetic cost
of breaking the C-N bond is outweighed by the enthalpic benefit
gained from the formation of a carbonyl bond and an increase
in the system’s entropy.45 Further oxidation of formaldehyde to
either formic acid or CO2 drives this equilibrium process.46
A
solution of aryl bromide (3.25 mmol) in THF (10 mL) was
cooled to −78 °C and n-butyllithium (2.30 M in hexanes, 1.41
mL, 3.25 mmol) was added over five minutes, maintaining the
internal temperature below −60 °C, followed by stirring for 30
minutes. tert-Butyl 3-oxoazetidine-1-carboxylate (13) (0.428 g,
2.50 mmol) was slowly added as a solution in THF (1.5 mL),
after which the reaction was stirred at −78 °C for a further 10
minutes and then allowed to warm to room temperature. The
mixture was quenched with sat. aq. NH4Cl (10 mL) and
partitioned between water (15 mL) and EtOAc (15 mL), then
the aqueous phase was re-extracted with EtOAc (3 x 15 mL).
The combined organic fraction was washed with sat. aq. sodium
chloride solution (75 mL), dried over Na2SO4 and concentrated
under reduced pressure. The crude mixture was purified by
flash column chromatography (EtOAc in pentane) to yield the
pure product.
Scheme 6: Proposed Reaction Mechanism
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(B) Oxidative deconstruction of azetidinols. Azetidinol (0.30
mmol), silver nitrate (0.010 g, 0.059 mmol) and potassium
persulfate (0.32 g, 1.2 mmol) were added to a flask, which was
subsequently evacuated and backfilled with nitrogen three
times. DCE (0.50 mL) and degassed deionized water (0.50 mL)
were added via syringe, after which the flask was sealed and the
reaction was stirred for 24 h. If conversion was deemed
incomplete by TLC, silver nitrate (0.010 g, 0.059 mmol) and
potassium persulfate (0.32 g, 1.2 mmol) were added to the flask
under a positive pressure of nitrogen and the reaction mixture
was stirred for a further 24 h. For substrates where conversion
was particularly slow, additional portions of silver nitrate
(0.010 g, 0.059 mmol) and potassium persulfate (0.32 g, 1.2
mmol) were added after 48 h and the reaction was stirred for a
total of 116 h. The mixture was then partitioned between water
(10 mL) and DCM (10 mL) and the aqueous phase was re-
extracted with DCM (3 x 10 mL). The combined organic
fraction was washed with sat. aq. sodium chloride solution (40
mL), dried over MgSO4 and concentrated under reduced
pressure. The crude mixture was purified by flash column
chromatography (EtOAc in pentane) to yield the pure product.
In summary, a deconstructive protocol for the conversion of
azetidinols to α-amino ketones has been disclosed. This scalable
procedure uses relatively inexpensive oxidants and shows good
tolerance for a wide range of aryl and heteroaryl substituents.
Our mechanistic studies give weight to a radical-based
mechanism featuring a sequence of C-C and C-N bond
cleavages. Applications of this novel protecting group strategy
to the synthesis of bioactive scaffolds are currently under
investigation.
EXPERIMENTAL SECTION
General Methods
All reaction glassware was oven-dried at 100 °C overnight
before use. All reagents and solvents were purchased from
commercial suppliers and used without further purification.
Reactions were carried out under nitrogen unless otherwise
stated. Deionized water was purged with nitrogen for at least 15
minutes prior to use. The concentration of n-butyllithium
solution was determined via titration with diphenylacetic acid.
1-[(4-Methylphenyl)sulfonyl]-3-azetidinone
(11),
3-
bromobenzo[b]thiophene and 1-Tosyl-1H-indole (12) were
obtained using literature protocols.16,47,48 Removal of volatiles
was achieved using a Büchi R-114 rotary evaporator under
reduced pressure (68 mbar) using bath temperatures of 25-40
°C. TLC analysis was performed using Mercksilica gel 60 F₂₅₄
plates, followed by visualization using a Mineralight Multiband
UV 254/365 nm lamp and staining with an ethanolic vanillin
solution. Silica gel (40-63 m, WVR) was used for flash
column chromatography and head pressure was supplied via the
use of bellows. Solvents for chromatography were used as
received from commercial suppliers. NMR spectra were
recorded in chloroform-d using a Bruker AV-400 spectrometer
(400 MHz for 1H NMR, 101 MHz for 13C NMR and 377 MHz
Synthesis and Characterization
tert-Butyl
3-(benzo[b]thiophen-2-yl)-3-hydroxyazetidine-1-
carboxylate, 1a. A solution of benzo[b]thiophene (0.366 g, 2.73
mmol) in THF (4 mL) was cooled to −78 °C and n-butyllithium
(2.25 M in hexanes, 1.30 mL, 2.93 mmol) was added as drops,
maintaining the internal temperature below −60 °C, followed
by stirring for one hour. 13 (0.514 g, 3.00 mmol) was then
slowly added as a solution in THF (4 mL). The mixture was
stirred at −78 °C for two more hours, then allowed to warm to
room temperature and quenched with sat. aq. NH4Cl (10 mL).
After partitioning the mixture between water (15 mL) and
EtOAc (15 mL), the aqueous phase was re-extracted with
EtOAc (2 x 15 mL). The combined organic fraction was washed
with sat. aq. sodium chloride solution (50 mL), dried over
MgSO4 and concentrated under reduced pressure to give the
crude title compound (0.709 g, 2.32 mmol, 85%) as a light
orange solid, which was used without further purification.
1H NMR (400 MHz, Chloroform-d) δ 7.81 (ddd, J = 7.4, 1.7,
0.7 Hz, 1H), 7.77 – 7.70 (m, 1H), 7.40 – 7.30 (m, 2H), 7.30 (s,
1H), 4.32 (d, J = 9.3 Hz, 2H), 4.23 (dd, J = 9.3, 1.0 Hz), 3.40
(s, 1H), 1.46 (s, 9H); 13C{1H} NMR (101 MHz, Chloroform-d)
δ 156.6, 148.3, 139.7, 139.6, 124.7 (app. d, J = 2.3 Hz), 123.9,
122.6, 120.2, 80.4, 70.2, 64.8 (br), 28.5; IR (neat, v cm-1) =
1
for 19F NMR). H and 13C shifts are referenced against the
residual CHCl3 peak (7.26 ppm for 1H NMR and 77.2 ppm for
13C NMR). Apparent multiplets that correspond to 2 distinct
signals in close proximity are annotated as “app.”. IR spectra
were recorded using an Agilent Cary 630 Fourier Transform
Infrared Spectrometer and samples were loaded neat. HRMS
analysis was performed on Micromass AutoSpec Premier and
Waters LCT Premier instruments, using either electrospray
ionization (ESI) or chemical ionization (CI). Uncorrected
melting point values were collected using an SRS MPA100
Optimelt system.
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2H), 2.87 (s, 1H), 1.45 (s, 9H). 13C{1H} NMR (101 MHz,
3311, 2973, 1653, 1418, 1367, 1213, 1107; HRMS (ESI) m/z:
calcd for C16H20NO3S [M+H]+, 306.1164; found, 306.1161.
Chloroform-d) δ 162.4 (d, J = 247.1 Hz), 156.6, 139.2 (d, J =
2.5 Hz), 126.6 (d, J = 8.3 Hz), 115.6 (d, J = 21.6 Hz), 80.2, 71.1,
64.7 (br), 28.5; 19F NMR (377 MHz, Chloroform-d) δ -114.48
(p, J = 7.5 Hz); IR (neat, v cm-1) = 3389, 3327, 2969, 2876,
1659, 1427, 1368, 1227, 1157, 1116; HRMS (ESI) m/z: calcd
for C14H19NO3F [M+H]+, 268.1349; found, 268.1358.
1
2
3
4
5
3-(Benzo[b]thiophen-2-yl)-1-tosylazetidin-3-ol. It was obtained
through the same procedure as 1a (11 used instead of 13) as a
white solid (0.499 g, 1.39 mmol, 45%). Purification was
achieved via flash column chromatography (20-40% EtOAc in
pentane).
6
tert-Butyl
3-(3-fluorophenyl)-3-hydroxyazetidine-1-
1H NMR (400 MHz, Chloroform-d) δ 7.82 – 7.72 (m, 3H), 7.70
– 7.62 (m, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.33 (td, J = 7.0, 1.5
Hz, 2H), 7.02 (d, J = 0.7 Hz, 1H), 4.19 – 4.13 (m, 2H), 4.09 –
4.03 (m, 2H), 3.01 (s, 1H), 2.47 (s, 3H); 13C{1H} NMR (101
MHz, Chloroform-d) δ 146.8, 144.7, 139.5 (app. d, J = 8.2 Hz),
131.2, 130.1, 128.7, 124.9, 124.8, 123.9, 122.5, 120.6, 69.3,
65.6, 21.8; IR (neat, v cm-1) = 3532, 1595, 1457, 1330, 1154,
1283, 1088; HRMS (ESI) m/z: calcd for C18H18NO3S2 [M+H]+,
360.0728; found, 360.0733.
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8
9
carboxylate, 1d. It was obtained through general procedure (A)
(Et2O used instead of THF) as a pale green solid (0.343 g, 1.28
mmol, 51%). Purification was achieved via flash column
chromatography (20-30% EtOAc in pentane).
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60
1H NMR (400 MHz, Chloroform-d) δ 7.36 (td, J = 7.9, 5.8 Hz,
1H), 7.28 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.23 (ddd, J = 10.1,
2.7, 1.7 Hz, 1H), 7.00 (tdd, J = 8.2, 2.6, 1.1 Hz, 1H), 4.19 (d, J
= 9.2 Hz, 2H), 4.16 (d, J = 9.2 Hz, 2H), 3.31 (s, 1H), 1.45 (s,
9H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 163.1 (d, J =
246.4 Hz), 156.6, 146.2 (d, J = 6.9 Hz), 130.4 (d, J = 8.0 Hz),
120.3 (d, J = 2.9 Hz), 114.8 (d, J = 21.0 Hz), 112.1 (d, J = 22.7
Hz), 80.4, 70.9, 64.8 (br), 28.5; 19F NMR (377 MHz,
Chloroform-d) δ -112.29 (q, J = 8.5 Hz); IR (neat, v cm-1) =
3294, 2973, 2876, 1653, 1420, 1366, 1251, 1160, 1116; HRMS
(CI) m/z: calcd for C14H18FNO3Cl [M+Cl]-, 302.0954; found,
302.0964.
tert-Butyl 3-hydroxy-3-phenylazetidine-1-carboxylate, 1b. A
solution of bromobenzene (0.640 mL, 6.00 mmol) THF (10 mL)
was cooled to −78 °C and n-Butyllithium (2.30 M in hexanes,
2.61 mL, 6.00 mmol) was added as drops, maintaining the
internal temperature below −60 °C, followed by stirring for one
hour. 13 (0.342 g, 2.00 mmol) was then slowly added as a
solution in THF (1.5 mL). The reaction was stirred at −78 °C
for three hours, then allowed to warm to room temperature and
subsequently cooled on an ice-water bath for 10 minutes. The
mixture was quenched with sat. aq. NH4Cl (10 mL) and
partitioned between water (15 mL) and Et2O (15 mL), then the
aqueous phase was re-extracted with Et2O (3 x 15 mL). The
combined organic fraction was washed with sat. aq. sodium
chloride solution (75 mL), dried over MgSO4 and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography (20-30% EtOAc in pentane) to yield
the pure title compound (0.281 g, 1.13 mmol, 57%) as a white
solid.
1H NMR (400 MHz, Chloroform-d) δ 7.53 – 7.46 (m, 2H), 7.43
– 7.37 (m, 2H), 7.35 – 7.28 (m, 1H), 4.26 (d, J = 9.3 Hz, 2H),
4.16 (dd, J = 9.2, 1.0 Hz, 2H), 2.89 (s, 1H), 1.46 (s, 9H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 156.6, 143.3, 128.8,
128.0, 124.7, 80.1, 71.5, 64.5 (br), 28.5; IR (neat, v cm-1) =
3408, 3321, 2973, 1654, 1420, 1365, 1231, 1116; HRMS (ESI)
m/z: calcd for C14H20NO3 [M+H]+, 250.1443; found, 250.1437;
1H NMR data are consistent with reported literature.50
tert-Butyl
3-(2-fluorophenyl)-3-hydroxyazetidine-1-
carboxylate, 1e. It was obtained through general procedure (A)
(Et2O used instead of THF) as a white solid (0.406 g, 1.52
mmol, 61%). Purification was achieved via flash column
chromatography (15-25% EtOAc in pentane).
1H NMR (400 MHz, Chloroform-d) δ 7.38 (td, J = 7.8, 1.8 Hz,
1H), 7.32 (dddd, J = 8.2, 7.2, 5.2, 1.8 Hz, 1H), 7.16 (td, J = 7.6,
1.2 Hz, 1H), 7.09 (ddd, J = 11.2, 8.2, 1.2 Hz, 1H), 4.42 (dt, J =
9.6, 1.3 Hz, 2H), 4.16 (dt, J = 9.7, 1.1 Hz, 2H), 3.01 (d, J = 1.5
Hz, 1H), 1.44 (s, 9H); 13C{1H} NMR (101 MHz, Chloroform-
d) δ 160.8 (d, J = 247.4 Hz), 156.7, 130.4 (d, J = 8.5 Hz), 129.4
(d, J = 13.0 Hz), 127.3 (d, J = 4.1 Hz), 124.4 (d, J = 3.5 Hz),
116.4 (d, J = 21.5 Hz), 80.0, 70.1, 62.7 (br), 28.5; 19F NMR (377
MHz, Chloroform-d) δ -115.78 (dt, J = 11.8, 6.0 Hz); IR (neat,
v cm-1) = 3411, 2969, 2935, 2878, 1660, 1429, 1367, 1213,
1161, 1113; HRMS (ESI) m/z: calcd for C14H19NO3F [M+H]+,
268.1349; found, 268.1347.
tert-Butyl
3-(2,6-difluorophenyl)-3-hydroxyazetidine-1-
tert-Butyl
3-(4-fluorophenyl)-3-hydroxyazetidine-1-
carboxylate, 1f. It was obtained through general procedure (A)
as a white solid (0.578 g, 2.03 mmol, 81%). Purification was
achieved via flash column chromatography (15-25% EtOAc in
pentane).
1H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.19 (m, 1H), 6.96
– 6.85 (m, 2H), 4.52 – 4.44 (m, 2H), 4.25 – 4.17 (m, 2H), 2.98
(s, 1H), 1.43 (s, 9H); 13C NMR (101 MHz, Chloroform-d) δ
160.9 (dd, J = 250.3, 8.4 Hz), 156.6, 130.6 (t, J = 10.8 Hz),
117.8 (t, J = 17.6 Hz), 112.2 (dd, J = 19.2, 5.8 Hz), 80.0, 68.2,
62.9 (br), 28.5; 19F NMR (377 MHz, Chloroform-d) δ -113.53
(t, J = 7.3 Hz); IR (neat, v cm-1) = 3290, 2973, 1670, 1466, 1437,
1368, 1116, 1101; HRMS (ESI) m/z: calcd for C14H18NO3F2
[M+H]+, 286.1255; found, 286.1255.
carboxylate, 1c. A solution of 4-fluorobromobenzene (0.659
mL, 6.00 mmol) in THF (10 mL) was cooled to −78 °C and n-
butyllithium (2.30 M in hexanes, 2.61 mL, 6.00 mmol) was
added as drops, maintaining the internal temperature below −60
°C, followed by stirring for one hour. 13 (0.342 g, 2.00 mmol)
was then slowly added as a solution in THF (1.5 mL). The
reaction was stirred at −78 °C for three hours, then allowed to
warm to room temperature and subsequently cooled on an ice-
water bath for 10 minutes. After quenching with sat. aq. NH4Cl
(10 mL), the mixture was partitioned between water (15 mL)
and Et2O (15 mL) and the aqueous phase was re-extracted with
Et2O (3 x 15 mL). The combined organic fraction was washed
with sat. aq. sodium chloride solution (75 mL), dried over
MgSO4 and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (20-30%
EtOAc in pentane) to yield the pure title compound (0.305 g,
1.14 mmol, 57%) as a pale yellow solid.
tert-Butyl
3-hydroxy-3-(4-methoxyphenyl)azetidine-1-
carboxylate, 1g. It was obtained through general procedure (A)
as a white solid (0.421 g, 1.51 mmol, 60%). Purification was
achieved via flash column chromatography (20-30% EtOAc in
pentane).
1H NMR (400 MHz, Chloroform-d) δ 7.45 – 7.36 (m, 2H), 6.96
– 6.88 (m, 2H), 4.24 (d, J = 9.2 Hz, 2H), 4.14 (dd, J = 9.2, 1.0
1H NMR (400 MHz, Chloroform-d) δ 7.53 – 7.43 (m, 2H), 7.07
(t, J = 8.7 Hz, 2H), 4.22 (d, J = 9.3 Hz, 2H), 4.16 (d, J = 9.2 Hz,
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Page 6 of 12
Hz, 2H), 3.81 (s, 3H), 2.72 (s, 1H), 1.45 (s, 9H); 13C{1H} NMR
as a white solid (0.509 g, 1.79 mmol, 72%). Purification was
achieved via flash column chromatography (20-30% EtOAc in
pentane).
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3
4
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7
8
(101 MHz, Chloroform-d) δ 159.3, 156.6, 135.5, 126.1, 114.1,
80.0, 71.4, 64.3 (br), 55.5, 28.5; IR (neat, v cm-1) = 3408, 3299,
2971, 2874, 1661, 1428, 1366, 1244, 1162, 1103; HRMS (ESI)
m/z: calcd for C15H22NO4 [M+H]+, 280.1549; found, 280.1560;
All data are consistent with reported literature.49
1H NMR (400 MHz, Chloroform-d) δ 7.47 – 7.42 (m, 2H), 7.38
– 7.33 (m, 2H), 4.22 – 4.12 (m, 4H), 3.15 (s, 1H), 1.45 (s, 9H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 156.6, 142.0, 133.8,
128.9, 126.2, 80.3, 71.0, 64.7 (br), 28.5; IR (neat, v cm-1) =
3414, 3302, 2969, 2944, 2875, 1663, 1425, 1366, 1230, 1159,
1117, 1093; HRMS (CI) m/z: calcd for C9H11ONCl [M-
Boc+2H]+, 184.0529; found, 184.0523; NMR and IR data are
consistent with reported literature.51
tert-Butyl
3-hydroxy-3-(3-methoxyphenyl)azetidine-1-
carboxylate, 1h. It was obtained through general procedure (A)
as a white solid (0.366 g, 1.31 mmol, 52%). Purification was
achieved via flash column chromatography (20-30% EtOAc in
pentane).
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15
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60
1H NMR (400 MHz, Chloroform-d) δ 7.31 (t, J = 7.9 Hz, 1H),
7.07 (ddd, J = 7.7, 1.8, 0.9 Hz, 1H), 7.04 (t, J = 2.1 Hz, 1H),
6.85 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 4.24 (d, J = 9.3 Hz, 2H),
4.14 (dd, J = 9.3, 1.0 Hz, 2H), 3.82 (s, 3H), 2.95 (s, 1H), 1.45
(s, 9H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 160.0,
156.6, 145.0, 129.9, 117.0, 113.3, 110.7, 80.1, 71.4, 64.5 (br),
55.5, 28.5; IR (neat, v cm-1) = 3401, 2976, 2933, 1670, 1602,
1425, 1258, 1154, 1116; HRMS (CI) m/z: calcd for C15H22NO4
[M+H]+, 280.1549; found, 280.1541.
tert-Butyl 3-hydroxy-3-(4-(trifluoromethyl)phenyl)azetidine-1-
carboxylate, 1m. It was obtained through general procedure (A)
as a white solid (0.537 g, 1.69 mmol, 68%). Purification was
achieved via flash column chromatography (20-30% EtOAc in
pentane).
1H NMR (400 MHz, Chloroform-d) δ 7.65 (s, 4H), 4.25 – 4.16
(m, 4H), 3.17 (s, 1H), 1.46 (s, 9H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 156.6, 147.3, 130.2 (q, J = 33.0 Hz), 125.7 (q,
J = 3.9 Hz), 125.1, 124.4 (q, J = 271.8 Hz), 80.5, 71.0, 64.9 (br),
28.5; 19F NMR (377 MHz, Chloroform-d) δ -62.58; IR (neat, v
cm-1) = 3381, 2977, 2943, 1679, 1438, 1322, 1160, 1106, 1066;
HRMS (ESI) m/z: calcd for C16H19NO5F3 [M-H+HCO2H]-,
362.1215; found, 362.1224.
tert-Butyl
3-(3,4-dimethoxyphenyl)-3-hydroxyazetidine-1-
carboxylate, 1i. It was obtained through general procedure (A)
as a pale yellow solid (0.552 g, 1.78 mmol, 71%). Purification
was achieved via flash column chromatography (35-45%
EtOAc in pentane).
1H NMR (400 MHz, Chloroform-d) δ 7.04 – 6.98 (m, 2H), 6.86
(d, J = 8.0 Hz, 1H), 4.25 (d, J = 9.2 Hz, 2H), 4.15 (dd, J = 9.2,
0.9 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 2.81 (s, 1H), 1.45 (s,
9H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 156.7, 149.2,
148.8, 135.9, 117.0, 111.1, 108.2, 80.1, 71.5, 64.4 (br), 56.1,
28.5; IR (neat, v cm-1) = 3418, 2980, 2968, 2936, 1666, 1518,
1412, 1366, 1252, 1224, 1150, 1107, 1029; HRMS (CI) m/z:
calcd for C11H16NO3 [M-Boc+2H]+, 210.1130; found,
210.1123.
tert-Butyl
3-(benzo[b]thiophen-3-yl)-3-hydroxyazetidine-1-
carboxylate, 1n. It was obtained through general procedure (A)
(Et2O used instead of THF) as an off-white solid (0.430 g, 1.41
mmol, 56%). Purification was achieved via flash column
chromatography (30% EtOAc in pentane).
1H NMR (400 MHz, Chloroform-d) δ 7.90 – 7.85 (m, 1H), 7.85
– 7.81 (m, 1H), 7.41 (s, 1H), 7.41 – 7.37 (m, 2H), 4.45 (d, J =
9.4 Hz, 2H), 4.28 (d, J = 9.3 Hz, 2H), 2.96 (s, 1H), 1.44 (s, 9H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 156.6, 141.3, 137.4,
136.6, 124.9, 124.6, 123.6, 123.3, 123.0, 80.1, 69.8, 62.6 (br),
28.5; IR (neat, v cm-1) = 3354, 2973, 2878, 1663, 1390, 1364,
1154, 1088; HRMS (ESI) m/z: calcd for C16H20NO3S [M+H]+,
306.1164; found, 306.1154.
tert-Butyl
3-hydroxy-3-(2-methoxyphenyl)azetidine-1-
carboxylate, 1j. It was obtained through general procedure (A)
as a white solid (0.423 g, 1.51 mmol, 60%). Purification was
achieved via flash column chromatography (20-30% EtOAc in
pentane).
1H NMR (400 MHz, Chloroform-d) δ 7.34 – 7.24 (m, 2H), 6.98
(td, J = 7.5, 1.0 Hz, 1H), 6.92 (dd, J = 8.2, 1.0 Hz, 1H), 4.34 (d,
J = 9.5 Hz, 2H), 4.12 (dd, J = 9.5, 1.1 Hz, 2H), 3.88 (s, 3H),
3.42 (s, 1H), 1.43 (s, 9H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 157.0, 156.7, 130.0, 129.8, 126.2, 120.9,
111.1, 79.6, 71.2, 62.4, 61.3, 55.6, 28.5; IR (neat, v cm-1) =
3368, 2974, 2943, 1663, 1409, 1364, 1250, 1123, 1094; HRMS
(ESI) m/z: calcd for C15H22NO4 [M+H]+, 280.1549; found,
280.1545.
tert-Butyl 3-hydroxy-3-(thiophen-2-yl)azetidine-1-carboxylate,
1o. A solution of thiophene (0.260 mL, 3.25 mmol) in THF (10
mL) was cooled to −78 °C and n-butyllithium (2.30 M in
hexanes, 1.41 mL, 3.25 mmol) was added as drops, maintaining
the internal temperature below −60 °C, followed by stirring for
one hour. 13 (0.428 g, 2.50 mmol) was then slowly added as a
solution in THF (1.5 mL). The reaction was stirred at −78 °C
for 10 minutes, then allowed to warm to room temperature and
stirred for one hour. The mixture was then quenched with sat.
aq. NH4Cl (10 mL) and partitioned between water (15 mL) and
EtOAc (15 mL), then the aqueous phase was re-extracted with
EtOAc (3 x 15 mL). The combined organic fraction was washed
with sat. aq. sodium chloride solution (75 mL), dried over
MgSO4 and concentrated under reduced pressure to give the
crude product. This was purified by column chromatography
(15-25% EtOAc in pentane) to yield the pure title compound
(0.356 g, 1.39 mmol, 56%) as a white solid.
1H NMR (400 MHz, Chloroform-d) δ 7.28 (dd, J = 5.1, 1.2 Hz,
1H), 7.09 (dd, J = 3.6, 1.2 Hz, 1H), 7.00 (dd, J = 5.1, 3.6 Hz,
1H), 4.25 (d, J = 9.3 Hz, 2H), 4.19 (dd, J = 9.3, 1.0 Hz, 2H),
3.14 (s, 1H), 1.45 (s, 9H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 156.6, 147.9, 127.3, 125.5, 123.7, 80.2, 70.0,
65.0 (br), 28.5; IR (neat, v cm-1) = 3354, 2971, 2934, 2870,
1648, 1437, 1392, 1366, 1235, 1211, 1153, 1105; HRMS (ESI)
m/z: calcd for C12H18NO3S [M+H]+,256.1007; found, 256.1007.
tert-Butyl 3-hydroxy-3-(3,4,5-trimethoxyphenyl)azetidine-1-
carboxylate, 1k. It was obtained through general procedure (A)
as a white solid (0.469 g, 1.38 mmol, 55%). Purification was
achieved via flash column chromatography (35-45% EtOAc in
pentane).
1H NMR (400 MHz, Chloroform-d) δ 6.69 (s, 2H), 4.25 (d, J =
9.4 Hz, 2H), 4.15 (d, J = 9.2 Hz, 2H), 3.87 (s, 6H), 3.84 (s, 3H),
2.83 (s, 1H), 1.46 (s, 9H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 156.7, 153.5, 139.0, 137.6, 102.0, 80.2, 71.7,
64.3 (br), 61.0, 56.3, 28.5; IR (neat, v cm-1) = 3418, 2971, 2934,
2875, 1680, 1590, 1419, 1367, 1324, 1221, 1116; HRMS (ESI)
m/z: calcd for C17H26NO6 [M+H]+, 340.1760; found, 340.1772.
tert-Butyl
3-(4-chlorophenyl)-3-hydroxyazetidine-1-
carboxylate, 1l. It was obtained through general procedure (A)
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The Journal of Organic Chemistry
3-hydroxy-3-(1-tosyl-1H-indol-2-yl)azetidine-1- Some peaks are doubled due to minor quantities of hydrogen-
tert-Butyl
1
carboxylate, 1p. A solution of 12 (1.63 g, 6.01 mmol) in THF
(20 mL) was cooled to −78 °C and n-butyllithium (2.30 M in
hexanes, 2.61 mL, 6.00 mmol) was added as drops, maintaining
the internal temperature below −60 °C, followed by stirring for
two hours. 13 (0.514 g, 3.00 mmol) was then slowly added as a
solution in THF (1.5 mL). The reaction was stirred at −78 °C
for 20 minutes, then allowed to warm to room temperature and
stirred for another 20 minutes. The mixture was quenched with
sat. aq. NH4Cl (10 mL) and partitioned between water (20 mL)
and EtOAc (20 mL), then the aqueous phase was re-extracted
with EtOAc (3 x 20 mL). The combined organic fraction was
washed with sat. aq. sodium chloride solution (100 mL), dried
over MgSO4 and concentrated under reduced to give the crude
product. This was purified by column chromatography (20-35%
EtOAc in pentane) to yield the pure title compound as a white
solid (0.984 g, 2.22 mmol, 74%).
bonded isomer.
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3
4
5
6
7
8
9
1H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.90 (app.
ddd, J = 9.6, 8.0, 1.2 Hz, 2H), 7.49 (ddd, J = 8.2, 7.1, 1.4 Hz,
1H), 7.43 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 5.45 (s, 1H), 5.07 (s,
0.2H), 4.70 (d, J = 4.8 Hz, 2H), 1.52 (s, 0.7H), 1.48 (s, 9H);
13C{1H} NMR (101 MHz, Chloroform-d): δ 189.4, 155.8,
142.5, 140.5, 139.0, 129.5, 128.0, 126.3, 125.4, 123.1, 80.2,
47.8, 28.5, 28.1; IR (neat, v cm-1) = 3421, 3087, 3068, 2974,
2919, 1712, 1662, 1508, 1359, 1233, 1147; HRMS (ESI) m/z:
calcd for C15H18NO3S [M+H]+, 292.1007; found, 292.1014;
m.p. 164.9 °C (decomposition).
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N-(2-(Benzo[b]thiophen-2-yl)-2-oxoethyl)-4-
methylbenzenesulfonamide. It was obtained through general
procedure (B) (DCM used instead of DCE, 24 h reaction time)
as a light pink solid (0.0050 g, 0.014 mmol, 5%). Purification
was achieved via flash column chromatography (15-30%
EtOAc in pentane). Unreacted starting material (0.028 g, 0.078
mmol, 26%) was also recovered.
1H NMR (400 MHz, Chloroform-d) δ 7.84 (dd, J = 8.5, 1.0 Hz,
1H), 7.68 – 7.61 (m, 2H), 7.54 – 7.48 (m, 1H), 7.30 – 7.22 (m,
2H), 7.22 – 7.17 (m, 2H), 6.79 (d, J = 0.8 Hz, 1H), 4.49 – 4.40
(m, 3H), 4.27 (dd, J = 9.6, 1.0 Hz, 2H), 2.33 (s, 3H), 1.44 (s,
9H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 156.4, 145.5,
142.0, 137.2, 135.5, 130.1, 128.4, 126.6, 125.8, 124.2, 121.7,
114.7, 111.1, 80.0, 67.9, 62.5 (br), 28.5, 21.7; IR (neat, v cm-1)
= 3501, 2974, 1670, 1406, 1365, 1251, 1171, 1064; HRMS
(ESI) m/z: calcd for C25H29N3O5SNa [M+MeCN+Na]+,
506.1726; found, 506.1717.
1H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.88 (dd, J
= 12.1, 8.1 Hz, 2H), 7.82 – 7.75 (m, 2H), 7.50 (t, J = 7.6 Hz,
1H), 7.43 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.9 Hz, 2H), 5.55 (t,
J = 4.7 Hz, 1H), 4.50 (dd, J = 4.6, 1.4 Hz, 2H), 2.39 (s, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 187.2, 144.1, 142.7,
139.5, 138.8, 136.1, 130.1, 130.0, 128.3, 127.3, 126.4, 125.6,
123.1, 49.0, 21.7; IR (neat, v cm-1) = 3275, 3066, 2958, 2851,
1672, 1594, 1344, 1320, 1156, 1256, 1090; HRMS (ESI) m/z:
calcd for C17H16NO3S2 [M+H]+, 346.0572; found, 346.0565.
tert-Butyl
3-(benzofuran-2-yl)-3-hydroxyazetidine-1-
carboxylate, 1q. A solution of benzofuran (0.771 mL, 7.00
mmol) in THF (20 mL) was cooled to −78 °C and n-
butyllithium (2.30 M in hexanes, 3.04 mL, 7.00 mmol) was
added as drops, maintaining the internal temperature below −60
°C, followed by stirring for 10 minutes. The solution was
allowed to warm to room temperature and stirred for two hours.
After cooling to −78 °C again, tert-Butyl 3-oxoazetidine-1-
carboxylate (1.09 g, 6.36 mmol) was slowly added as a solution
in THF (2 mL). The reaction was stirred at −78 °C for one hour,
then allowed to warm to room temperature, followed by
quenching with sat. aq. NH4Cl (20 mL). After partitioning the
mixture between water (30 mL) and EtOAc (30 mL), the
aqueous phase was re-extracted with EtOAc (2 x 30 mL). The
combined organic fraction was washed with sat. aq. sodium
chloride solution (80 mL), dried over MgSO4 and concentrated
under reduced pressure to give the crude product, which was
triturated with pentane (10 mL) to give the title compound (1.06
g, 3.66 mmol, 58%) as a pale yellow solid.
1H NMR (400 MHz, Chloroform-d) δ 7.60 – 7.54 (m, 1H), 7.49
(m, 1H), 7.32 (ddd, J = 8.2, 7.2, 1.5 Hz, 1H), 7.26 (td, J = 7.4,
1.1 Hz, 1H), 6.75 (d, J = 1.0 Hz, 1H), 4.41 (d, J = 9.3 Hz, 2H),
4.19 (dd, J = 9.3, 1.0 Hz, 2H), 3.73 (s, 1H), 1.48 (s, 9H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 157.4, 156.6, 155.1,
128.0, 124.8, 123.2, 121.4, 111.5, 103.1, 80.3, 67.9, 62.1 (br),
28.5; IR (neat, v cm-1) = 3400, 2975, 2937, 2876, 1663, 1437,
1367, 1248, 1156, 1114, 1105; HRMS (CI) m/z: calcd for
C11H12O2N [M-Boc+2H]+, 190.0863; found, 190.0856.
tert-Butyl (2-oxo-2-phenylethyl)carbamate, 2b. It was obtained
through general procedure (B) (24 h reaction time) as a
colorless oil (0.045 g, 0.19 mmol, 63%). Purification was
achieved via flash column chromatography (15% EtOAc in
pentane).
Some peaks are doubled due to minor quantities of non-
hydrogen-bonded isomer.
1H NMR (400 MHz, Chloroform-d) δ 9.32 (s, 1H), 8.01 – 7.92
(m, 2H), 7.67 – 7.56 (m, 1H), 7.50 (dd, J = 8.4, 7.1 Hz, 2H),
5.03 (s, 2H), 4.66 (d, J = 4.5 Hz, 0.1H), 1.52 (s, 9H), 1.48 (s,
0.5H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 191.9, 162.8,
134.8, 134.0, 129.0, 128.1, 84.8, 46.6, 28.5, 28.1; IR (neat, v
cm-1) = 2978, 2939, 1741, 1685, 1359, 1328, 1224, 1145;
HRMS: molecular ion not identified via ESI or CI analysis;
NMR and IR data are consistent with reported literature.52
tert-Butyl (2-(4-fluorophenyl)-2-oxoethyl)carbamate, 2c. It was
obtained through general procedure (B) (48 h reaction time) as
a colorless oil (0.060 g, 0.24 mmol, 80%). Purification was
achieved via flash column chromatography (15% EtOAc in
pentane).
Some peaks are doubled due to minor quantities of non-
hydrogen-bonded isomer.
1H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 8.08 – 7.92
(m, 2H), 7.22 – 7.11 (m, 2H), 4.99 (s, 2H), 4.62 (d, J = 4.6 Hz,
0.1H), 1.51 (s, 9H), 1.47 (s, 0.7H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 190.4, 166.2 (d, J = 256.0 Hz), 162.7, 151.9,
131.2 (d, J = 3.1 Hz), 130.8 (d, J = 9.5 Hz), 116.2 (d, J = 22.0
Hz), 84.9, 47.5, 46.4, 28.5, 28.1; 19F NMR (377 MHz,
Chloroform-d) δ -103.39, -103.61; IR (neat, v cm-1) = 2979,
2939, 1741, 1685, 1597, 1359, 1329, 1224, 1145; HRMS (CI)
m/z: calcd for C8H9ONF [M-Boc+2H]+, 154.0668; found,
154.0660; 1H-NMR data are consistent with reported
literature.53
tert-Butyl (2-(benzo[b]thiophen-2-yl)-2-oxoethyl)carbamate,
2a. It was obtained through general procedure (B) (48 h reaction
time) as a crystalline solid (0.036 g, 0.12 mmol, 40%).
Purification was achieved via flash column chromatography
(15% EtOAc in pentane). A crystalline sample suitable for X-
ray crystallography was obtained via recrystallization from
chloroform.
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Page 8 of 12
Scale-up procedure: 1c (0.321 g, 1.20 mmol), silver nitrate 162.5, 160.8 (dd, J = 256.5, 6.9 Hz), 151.9, 133.9 (t, J = 10.8
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(0.0414 g, 0.244 mmol) and potassium persulfate (1.30 g, 4.81
mmol) were added to a flask which was subsequently evacuated
and backfilled with nitrogen three times. DCE (2.0 mL) and
degassed deionized water (2.0 mL) were added via syringe,
after which the flask was sealed and the reaction was stirred for
24 h. The mixture was then partitioned between water (25 mL)
and DCM (25 mL) and the aqueous phase was re-extracted with
DCM (3 x 25 mL). The combined organic fraction was then
washed with sat. aq. sodium chloride solution (100 mL), dried
over MgSO4 and concentrated. The crude mixture was purified
by column chromatography (15% EtOAc in pentane) to yield
the pure title compound (0.244 g, 0.963 mmol, 80%) as a white
solid.
Hz), 115.1 (t, J = 18.1 Hz), 112.8 – 112.3 (m), 84.9, 50.7 (d, J
= 5.6 Hz), 28.0; 19F NMR (377 MHz, Chloroform-d) δ -110.20,
-110.62; IR (neat, v cm-1) = 2984, 2945, 1723, 1675, 1623,
1464, 1392, 1359, 1319, 1206, 1148, 1131; HRMS (CI) m/z:
calcd for C8H8ONF2 [M-Boc+2H]+, 172.0574; found, 172.0565.
tert-Butyl (2-(4-methoxyphenyl)-2-oxoethyl)carbamate, 2g. It
was obtained through general procedure (B) (48 h reaction time)
as a pale yellow oil (0.045 g, 0.19 mmol, 63%). Purification was
achieved via flash column chromatography (15% EtOAc in
pentane).
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Some peaks are doubled, as 2g was obtained as a ca. 2:3
mixture of hydrogen-bonded/non-hydrogen-bonded isomers.
1H NMR (400 MHz, Chloroform-d) δ 9.31 (s, 0.3H), 8.10 – 7.76
(m, 2H), 7.09 – 6.69 (m, 2H), 5.57 (s, 0.6H), 4.98 (s, 0.8H), 4.60
(d, J = 4.5 Hz, 1.3H), 3.87 (app. d, J = 1.4 Hz, 3H), 1.50 (s,
3.5H), 1.47 (s, 5.5H); 13C{1H} NMR (101 MHz, Chloroform-d)
δ 192.9, 190.2, 164.2, 164.1, 162.8, 155.9, 130.4, 130.2, 127.8,
127.7, 114.2, 114.1, 84.6, 79.8, 55.6, 47.2, 46.3, 28.5, 28.1; IR
(neat, v cm-1) = 3420, 2975, 2933, 1680, 1598, 1510, 1358,
1230, 1148: HRMS (CI) m/z: calcd for C14H20NO4 [M+H]+,
266.1387; found, 266.1386; NMR data are consistent with
reported literature.54
tert-Butyl (2-(3-fluorophenyl)-2-oxoethyl)carbamate, 2d. It
was obtained through general procedure (B) (24 h reaction time)
as a colorless oil (0.056 g, 0.22 mmol, 73%). Purification was
achieved via flash column chromatography (15% EtOAc in
pentane).
Some peaks are doubled due to minor quantities of non-
hydrogen-bonded isomer.
1H NMR (400 MHz, Chloroform-d) δ 9.29 (s, 1H), 7.73 (dt, J =
7.7, 1.3 Hz, 1H), 7.63 (ddd, J = 9.2, 2.6, 1.5 Hz, 1H), 7.48 (td,
J = 8.0, 5.4 Hz, 1H), 7.31 (tdd, J = 8.3, 2.6, 1.0 Hz, 1H), 4.99
(s, 2H), 4.63 (d, J = 4.7 Hz, 0.1H), 1.51 (s, 9H), 1.47 (s, 0.5H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 190.9, 163.0 (d, J =
248.8 Hz), 162.6, 151.9, 136.8 (d, J = 6.3 Hz), 130.7 (d, J = 7.8
Hz), 123.8 (d, J = 3.1 Hz), 121.0 (d, J = 21.3 Hz), 114.9 (d, J =
22.4 Hz), 84.9, 47.8, 46.7, 28.5, 28.1; 19F NMR (377 MHz,
Chloroform-d) δ -111.07; IR (neat, v cm-1) = 2979, 2939, 1743,
1685, 1589, 1359, 1327, 1252, 1144; HRMS (CI) m/z: calcd for
C8H9ONF [M-Boc+2H]+, 154.0668; found, 154.0660.
tert-Butyl (2-(3-methoxyphenyl)-2-oxoethyl)carbamate, 2h. It
The title compound was obtained through general procedure (B)
(24 h reaction time) as a colorless oil (0.030 g, 0.11 mmol,
37%). Purification was achieved via flash column
chromatography (15% EtOAc in pentane).
Some peaks are doubled due to minor quantities of hydrogen-
bonded isomer.
1H NMR (400 MHz, Chloroform-d) δ 7.53 – 7.49 (m, 1H), 7.46
(dd, J = 2.7, 1.5 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.14 (ddd, J
= 8.2, 2.7, 1.0 Hz, 1H), 5.54 (s, 1H), 5.00 (s, 0.2H), 4.64 (d, J =
4.6 Hz, 2H), 3.84 (s, 3H), 1.51 (s, 0.7H), 1.47 (s, 9H); 13C{1H}
NMR (101 MHz, Chloroform-d) δ 194.4, 162.7, 160.1, 155.9,
135.9, 130.0, 120.7, 120.4, 112.3, 112.2, 80.0, 55.6, 47.7, 46.7,
28.5, 28.1; IR (neat, v cm-1) = 3422, 2974, 2932, 1685, 1582,
1487, 1363, 1258, 1156; HRMS (CI) m/z: calcd for C14H20NO4
[M+H]+, 266.1387; found, 266.1387.
tert-butyl (2-(2-fluorophenyl)-2-oxoethyl)carbamate, 2e. It was
obtained through general procedure (B) (48 h reaction time) as
a pale yellow oil (0.057 g, 0.23 mmol, 77%). Purification was
achieved via flash column chromatography (15% EtOAc in
pentane).
Some peaks are doubled due to minor quantities of non-
hydrogen-bonded isomer.
1H NMR (400 MHz, Chloroform-d) δ 9.29 (s, 1H), 8.00 – 7.86
(m, 1H), 7.57 (dddd, J = 8.4, 7.1, 5.1, 1.9 Hz, 1H), 7.25 (td, J =
7.5, 1.1 Hz, 1H), 7.16 (ddd, J = 11.3, 8.4, 1.1 Hz, 1H), 4.95 (d,
J = 3.5 Hz, 2H), 4.58 (dd, J = 5.0, 3.2 Hz, 0.3H), 1.51 (s, 9H),
1.46 (s, 1.4H);13C{1H} NMR (101 MHz, Chloroform-d) δ 190.2
(d, J = 4.5 Hz), 162.7, 162.5 (d, J = 254.9 Hz), 152.0, 135.7 (d,
J = 9.1 Hz), 131.0 (d, J = 3.0 Hz), 130.8 (d, J = 2.4 Hz), 124.9
(d, J = 3.4 Hz), 123.0 (d, J = 14.0 Hz), 116.8 (d, J = 23.6 Hz),
84.6, 79.9, 51.6 (d, J = 13.1 Hz), 50.3 (d, J = 13.6 Hz), 28.4,
28.0; 19F NMR (377 MHz, Chloroform-d) δ -107.66, -107.80;
IR (neat, v cm-1) = 2978, 1743, 1689, 1480, 1453, 1359, 1328,
1273, 1252, 1146; HRMS (CI) m/z: calcd for C15H19N2O3NaF
[M+CH3CN+Na]+, 317.1277; found, 317.1263.
tert-Butyl (2-(3,4-dimethoxyphenyl)-2-oxoethyl)carbamate, 2i.
It was obtained through general procedure (B) (24 h reaction
time) as a colorless oil (0.028 g, 0.095 mmol, 32%). Purification
was achieved via flash column chromatography (25% EtOAc in
pentane).
Some peaks are doubled due to minor quantities of hydrogen-
bonded isomer.
1H NMR (400 MHz, Chloroform-d) δ 7.57 (dd, J = 8.5, 2.0 Hz,
1H), 7.49 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.56 (t,
J = 4.6 Hz, 1H), 4.99 (s, 0.1H), 4.62 (d, J = 4.5 Hz, 2H), 3.94
(s, 3H), 3.92 (s, 3H), 1.51 (s, 0.4H), 1.47 (s, 9H); 13C{1H} NMR
(101 MHz, Chloroform-d) δ 193.0, 155.9, 154.0, 149.3, 127.8,
122.5, 110.4, 110.0, 79.9, 56.2 (app. d, J = 9.6 Hz), 47.2, 28.5,
28.1; IR (neat, v cm-1) = 3384, 2973, 2932, 1709, 1675, 1585,
1512, 1417, 1363, 1261, 1244, 1144, 1018; HRMS (ESI) m/z:
calcd for C17H24N2O5Na [M+CH3CN+Na]+, 359.1583; found,
359.1594.
tert-Butyl (2-(2,6-difluorophenyl)-2-oxoethyl)carbamate, 2f. It
was obtained through general procedure (B) (48 h reaction time)
as a white solid (0.060 g, 0.22 mmol, 73%). Purification was
achieved via flash column chromatography (15% EtOAc in
pentane).
Scale-up procedure: 1i (1.24 g, 4.01 mmol), silver nitrate (0.136
g, 0.801 mmol) and potassium persulfate (4.33 g, 16.0 mmol)
were added to a flask which was subsequently evacuated and
backfilled with nitrogen three times. DCE (6.7 mL) and
degassed deionized water (6.7 mL) were added via syringe and
Some peaks are doubled due to minor quantities of non-
hydrogen-bonded isomer.
1H NMR (400 MHz, Chloroform-d) δ 9.28 (s, 1H), 7.47 (tt, J =
8.4, 6.2 Hz, 1H), 7.03 – 6.95 (m, 2H), 4.84 (t, J = 1.3 Hz, 2H),
1.51 (s, 9H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 189.3,
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The Journal of Organic Chemistry
the reaction was stirred for 24 h under nitrogen. The mixture Some peaks are doubled due to minor quantities of non-
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was then partitioned between water (100 mL) and DCM (100
mL) and the aqueous phase was re-extracted with DCM (3 x
100 mL). The combined organic fraction was then washed with
brine (400 mL), dried over MgSO4 and concentrated. The crude
mixture was purified by column chromatography (25% EtOAc
in pentane) to yield the pure title compound (0.498 g, 1.69
mmol, 42%) as a pale yellow foam.
hydrogen-bonded isomer.
1H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 8.06 (d, J =
8.1 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 5.03 (s, 2H), 4.68 (d, J =
4.7 Hz, 0.2H), 1.52 (s, 9H), 1.48 (s, 0.8H); 13C{1H} NMR (101
MHz, Chloroform-d) δ 191.3, 162.6, 151.8, 137.5, 135.2 (d, J =
33.1 Hz), 128.5, 128.4, 126.1 (q, J = 3.8 Hz), 123.6 (q, J = 272.9
Hz), 85.1, 48.0, 46.8 , 28.5, 28.1; 19F NMR (377 MHz,
Chloroform-d) δ -63.24, -63.25; IR (neat, v cm-1) = 2981, 2939,
1744, 1686, 1409, 1320, 1224, 1126, 1064; HRMS (CI) m/z:
calcd for C9H9F3NO[M-Boc+2H]+, 204.0636; found, 204.0630.
tert-Butyl (2-(2-methoxyphenyl)-2-oxoethyl)carbamate (non-
hydrogen-bonded), 2j. It was obtained through general
procedure (B) (24 h reaction time) as a colorless oil (0.019 g,
0.094 mmol, 31%). Purification was achieved via flash column
chromatography (15% EtOAc in pentane). It was obtained
alongside hydrogen-bonded isomer 2j’, which was isolated and
characterized separately.
1H NMR (400 MHz, Chloroform-d) δ 7.94 (dd, J = 7.8, 1.8 Hz,
1H), 7.51 (ddd, J = 8.8, 7.3, 1.9 Hz, 1H), 7.05 – 7.00 (m, 1H),
6.98 (d, J = 8.4 Hz, 1H), 5.63 (s, 1H), 4.61 (d, J = 4.8 Hz, 2H),
3.93 (s, 3H), 1.46 (s, 9H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 195.4, 159.8, 156.0, 135.0, 131.1, 124.6,
120.9, 111.8, 79.6, 55.7, 52.3, 28.5; IR (neat, v cm-1) = 3424,
2974, 2931, 1707, 1670, 1597, 1484, 1363, 1241, 1158: HRMS
(ESI) m/z: calcd for C16H22N2O4Na [M+CH3CN+Na]+,
329.1477; found, 329.1477.
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tert-Butyl (2-(benzo[b]thiophen-3-yl)-2-oxoethyl)carbamate,
2n. It was obtained through general procedure (B) (48 h reaction
time) as a crystalline solid (0.034 g, 0.12 mmol, 40%).
Unreacted starting material (0.0060 g, 0.020 mmol, 7%) was
also recovered. Purification was achieved via flash column
chromatography (15% EtOAc in pentane).
Some peaks are doubled, as 2n was obtained as a ca. 1:3
mixture of hydrogen-bonded/non-hydrogen-bonded isomers.
1H NMR (400 MHz, Chloroform-d) δ 9.35 (s, 0.2H), 8.71 (ddd,
J = 8.1, 1.3, 0.7 Hz, 0.7H), 8.68 (ddd, J = 8.1, 1.4, 0.8 Hz, 0.2H),
8.36 (s, 0.2H), 8.35 (s, 0.8H), 7.93 – 7.84 (m, 1H), 7.50 (dtd, J
= 8.3, 7.1, 1.3 Hz, 1H), 7.43 (ddt, J = 9.0, 7.2, 1.6 Hz, 1H), 5.57
(s, 1H), 5.04 (s, 0.5H), 4.65 (d, J = 4.8 Hz, 1.5H), 1.52 (app. d,
J = 1.6 Hz, 2.7H), 1.49 (s, 7.3H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 189.4, 186.5, 162.5, 155.6, 139.5, 139.4,
136.7, 136.3 (app. d, J = 6.4 Hz), 136.2, 132.4, 125.9, 125.8,
125.6, 125.5, 125.3, 125.2, 122.1, 122.0, 84.5, 79.7, 47.8, 46.7,
28.2, 27.8; IR (neat, v cm-1) = 3387, 3101, 2974, 1740, 1674,
1517, 1493, 1364, 1270, 1252, 1144, 1047; HRMS (ESI) m/z:
calcd for C15H18NO3S [M+H]+, 292.1007; found, 292.0996;
m.p. 141.3 °C (decomposition).
tert-Butyl
(2-(2-methoxyphenyl)-2-oxoethyl)carbamate
(hydrogen-bonded), 2j’. It was obtained through general
procedure (B) (24 h reaction time) as a colorless oil (0.0050 g,
0.025 mmol, 8%). Purification was achieved via flash column
chromatography (15% EtOAc in pentane). It was obtained
alongside non-hydrogen-bonded isomer 2j, which was isolated
and characterized separately.
1H NMR (400 MHz, Chloroform-d) δ 9.31 (s, 1H), 7.89 (dd, J
= 7.7, 1.9 Hz, 1H), 7.52 (ddd, J = 8.4, 7.3, 1.8 Hz, 1H), 7.13 –
6.91 (m, 2H), 4.97 (s, 2H), 3.95 (s, 3H), 1.51 (s, 9H); 13C{1H}
NMR (101 MHz, Chloroform-d) δ 192.9, 163.0, 159.6, 134.9,
131.3, 125.0, 121.0, 111.7, 84.3, 55.7, 51.0, 28.1; IR (neat, v
cm-1) = 2976, 2937, 1740, 1681, 1597, 1484, 1325, 1204, 1146;
HRMS (CI) m/z: calcd for C9H12O2N [M-Boc+2H]+, 166.0868;
found, 166.0863.
tert-Butyl (2-oxo-2-(thiophen-2-yl)ethyl)carbamate, 2o. It was
obtained through general procedure (B) (48 h reaction time) as
a colorless oil (0.029 g, 0.12 mmol, 40%). Purification was
achieved via flash column chromatography (15% EtOAc in
pentane).
Some peaks are doubled, as 2o was obtained as a ca. 1:3
mixture of hydrogen-bonded/non-hydrogen-bonded isomers.
tert-Butyl (2-(4-chlorophenyl)-2-oxoethyl)carbamate, 2l. It was
obtained through general procedure (B) (48 h reaction time) as
a colorless oil (0.019 g, 0.070 mmol, 23%). Purification was
achieved via flash column chromatography (15% EtOAc in
pentane). Unreacted starting material (0.032 g, 0.13 mmol,
43%) was also recovered.
1H NMR (400 MHz, Chloroform-d) δ 9.29 (s, 0.3H), 7.78 (dd,
J = 3.9, 1.1 Hz, 0.3H), 7.76 (dd, J = 3.8, 1.1 Hz, 0.7H), 7.69 (dd,
J = 5.0, 1.1 Hz, 0.3H), 7.68 (dd, J = 5.0, 1.1 Hz, 0.7H), 7.15 (m,
1H), 5.44 (s, 0.7H), 4.95 (s, 0.6H), 4.57 (d, J = 4.8 Hz, 1.5H),
1.50 (s, 2.8H), 1.46 (s, 7H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 187.8, 184.9, 162.6, 155.8, 141.1, 141.0,
134.4, 132.2 (app. d, J = 4.6 Hz), 128.5, 128.4, 84.9, 80.1, 47.6,
46.5, 28.5, 28.0; IR (neat, v cm-1) = 3382, 3089, 2975, 2930,
1744, 1670, 1498, 1413, 1363, 1328, 1228, 1148, 1048; HRMS
(ESI) m/z: calcd for C13H18N2O3NaS [M+CH3CN+Na]+,
305.0936; found, 305.0924.
Some peaks are doubled due to minor quantities of non-
hydrogen-bonded isomer.
1H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 7.96 – 7.84
(m, 2H), 7.53 – 7.42 (m, 2H), 4.99 (s, 2H), 4.62 (d, J = 4.6 Hz,
0.1H), 1.52 (s, 9H), 1.47 (s, 0.5H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 190.7, 162.6, 151.8, 140.4, 133.0, 129.4,
129.2, 84.8, 47.5, 46.4, 28.4, 28.0; IR (neat, v cm-1) = 2977,
2937, 1744, 1686, 1588, 1359, 1329, 1224, 1148, 1092; HRMS
(CI) m/z: calcd for C13H14NO3Cl [M-2H]-, 267.0662; found,
267.0657.
tert-Butyl
(2-oxo-2-(1-tosyl-1H-indol-2-yl)ethyl)carbamate,
2p. It was obtained through general procedure (B) (116 h
reaction time) as a pale yellow film (0.045 g, 0.11 mmol, 37%).
Unreacted starting material (0.018 g, 0.041 mmol, 14%) was
also recovered. Purification was achieved via flash column
chromatography (15% EtOAc in pentane).
tert-Butyl
(2-oxo-2-(4-
(trifluoromethyl)phenyl)ethyl)carbamate, 2m. It was obtained
through general procedure (B) (116 h reaction time) as a
colorless oil (0.021 g, 0.069 mmol, 23%). Purification was
achieved via flash column chromatography (15% EtOAc in
pentane).
Some peaks are doubled, as 2p was obtained as a ca. 1:4
mixture of hydrogen-bonded/non-hydrogen-bonded isomers.
1H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 0.2H), 8.18 – 8.09
(m, 1H), 7.90 – 7.86 (m, 0.4H), 7.86 – 7.81 (m, 1.6H), 7.63 –
7.53 (m, 1H), 7.50 – 7.43 (m, 1H), 7.29 (m, 1H), 7.26 – 7.21
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(m, 2H), 7.18 (s, 1H), 5.38 (s, 0.7H), 4.99 (s, 0.4H), 4.54 (d, J
1H NMR (400 MHz, Chloroform-d) δ 9.17 (s, 1H), 8.03 – 7.90
= 5.3 Hz, 1.6H), 2.36 (s, 3H), 1.55 (s, 2H), 1.43 (s, 8H); 13C{1H}
NMR (101 MHz, Chloroform-d) δ 190.6, 162.7, 155.9, 145.3,
145.2, 139.0, 138.7, 137.0, 136.8, 135.2, 135.1, 129.7 (app. d, J
= 3.9 Hz), 128.5, 128.3, 128.0, 127.9, 127.7, 127.5, 124.6,
124.5, 123.1, 118.0, 117.4, 115.8, 115.6, 85.0, 80.0, 50.0, 48.7,
28.4, 28.0, 21.8; IR (neat, v cm-1) = 3405, 2974, 2932, 1741,
1696, 1595, 1496, 1363, 1251, 1171; HRMS (ESI) m/z: calcd
for C22H24N2O5NaS [M+Na]+, 451.1304; found, 451.1297.
(m, 2H), 7.19 – 7.08 (m, 2H), 4.07 – 3.98 (m, 2H), 3.24 – 3.15
(m, 2H), 1.53 (s, 9H), 1.52 (s, 0.6H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 196.2, 166.0 (d, J = 254.9 Hz), 163.1, 152.2,
133.1 (d, J = 2.2 Hz), 130.8 (d, J = 9.5 Hz), 115.9 (d, J = 21.9
Hz), 84.6, 37.0, 36.7, 28.2 ; 19F NMR (377 MHz, Chloroform-
d) δ -104.64 – -104.92 (m); IR (neat, v cm-1) = 3407, 2960, 2890,
1663, 1605, 1509, 1420, 1388, 1366, 1342, 1222, 1134, 1093,
HRMS (CI) m/z: calcd for C10H9FNO2 [M-tBuOH-H]-,
192.0460; found, 192.0459; NMR data are consistent with
reported literature.55
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tert-Butyl
3-(4-fluorophenyl)-3-hydroxypyrrolidine-1-
9
carboxylate, 3. A solution of 4-fluorobromobenzene (0.357 mL,
3.25 mmol) in THF (10 mL) was cooled to −78 °C and n-
butyllithium (2.30 M in hexanes, 1.41 mL, 3.25 mmol) was
added over five minutes, maintaining the internal temperature
below −60 °C, followed by stirring for 30 minutes. tert-Butyl
3-oxopyrrolidine-1-carboxylate (0.463 g, 2.50 mmol) was
slowly added as a solution in THF (1.5 mL), after which the
reaction was stirred at −78 °C for 10 minutes and then allowed
to warm to room temperature. After stirring for 30 minutes, the
mixture was quenched with sat. aq. NH4Cl (10 mL) and
partitioned between water (15 mL) and EtOAc (15 mL), then
the aqueous phase was re-extracted with EtOAc (3 x 15 mL).
The combined organic fraction was washed with sat. aq. sodium
chloride solution (75 mL), dried over Na2SO4 and concentrated
under reduced pressure. The crude mixture was purified by
flash column chromatography (25% EtOAc in pentane) to yield
the pure title compound (0.185 g, 0.658 mmol, 26%) as a white
solid.
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tert-Butyl
3-(4-fluorophenyl)-3-methoxyazetidine-1-
carboxylate, 5. A solution of 1c (0.19 g, 0.71 mmol) in THF
(1.4 mL) was cooled down to 0 °C. Sodium hydride (60%
suspension in mineral oil, 0.036 g, 0.90 mmol) was added in
one portion, after which the mixture was allowed to warm to
room temperature and stirred for one hour. Methyl iodide (0.060
mL, 0.96 mmol) was added and the reaction was stirred for a
further two hours. After quenching with methanol (10 mL), the
mixture was concentrated under reduced pressure and the crude
product was immediately purified by column chromatography
(10-15% EtOAc in pentane) to yield the pure title compound
(0.18 g, 0.64 mmol, 90%) as a white solid.
1H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.33 (m, 2H), 7.12
– 7.05 (m, 2H), 4.16 (d, J = 8.9 Hz, 2H), 4.12 (d, J = 8.9 Hz,
2H), 3.07 (s, 3H), 1.45 (s, 9H); 13C{1H} NMR (101 MHz,
Chloroform-d) δ 162.5 (d, J = 247.3 Hz), 156.7, 135.9 (d, J =
3.3 Hz), 128.1 (d, J = 8.2 Hz), 115.7 (d, J = 21.6 Hz), 80.0, 76.3,
59.3 (br), 51.7, 28.5; 19F NMR (377 MHz, Chloroform-d) δ -
107.44 – -121.61 (m); IR (neat, v cm-1) = 2974, 2882, 2825,
1696, 1605, 1510, 1388, 1364, 1224, 1156, 1098, 1068; HRMS
(CI) m/z: calcd for C10H13NOF [M-Boc+2H]+, 182.0976; found,
182.0967.
Some peaks are doubled or distorted due to proposed five-
membered ring conformational isomerism.
1H NMR (400 MHz, Chloroform-d) δ 7.54 – 7.42 (m, 2H), 7.12
– 7.02 (m, 2H), 3.83 – 3.48 (m, 4H), 2.40 – 2.10 (m, 3H), 1.49
(app. d, J = 6.2 Hz, 9H); 13C{1H} NMR (101 MHz, Chloroform-
d) δ 162.4 (d, J = 246.6 Hz), 154.9, 154.7, 138.7 (d, J = 8.3 Hz),
127.2 (d, J = 8.2 Hz), 115.5 (d, J = 21.3 Hz), 80.4, 79.8, 79.6,
59.7, 58.9, 45.1, 44.7, 39.8, 39.0, 28.7; 19F NMR (377 MHz,
Chloroform-d) δ -114.60 – -114.91 (m); IR (neat, v cm-1) =
3407, 2960, 2890, 1663, 1605, 1509, 1420, 1388, 1366, 1342,
1222, 1134, 1093; HRMS (CI) m/z: calcd for C15H20FNO2Cl
[M+Cl]-, 316.1110; found, 316.1120.
di-tert-Butyl ethane-1,2-diylbis((2-(benzo[b]thiophen-2-yl)-2-
oxoethyl)carbamate), 6. Azetidinol 1a (0.092 g, 0.30 mmol)
and silver (II) fluoride (0.044 g, 0.30 mmol) were added to a
flask which was subsequently evacuated and backfilled with
nitrogen three times. DCE (1 mL) was then added, after which
the flask was sealed and covered in aluminum foil. After stirring
for 24 h, additional silver (II) fluoride (0.13 g, 0.90 mmol) was
added to the flask under a nitrogen funnel and the reaction was
allowed to run for a further 24 h. The mixture was then diluted
with DCM (25 mL), filtered through Celite® and concentrated
under reduced pressure. The crude product was purified by
column chromatography (15% EtOAc in pentane) to yield the
pure title compound (0.018 g, 0.030 mmol, 20%) as a white
solid.
tert-Butyl (3-(4-fluorophenyl)-3-oxopropyl)carbamate, 4. 3
(0.084 g, 0.30 mmol), silver nitrate (0.010 g, 0.059 mmol) and
potassium persulfate (0.32 g, 1.2 mmol) were added to a flask
which was subsequently evacuated and backfilled with nitrogen
three times. DCE (0.50 mL) and degassed deionized water (0.50
mL) were added via syringe, after which the flask was sealed
and the reaction was stirred for 24 h. Silver nitrate (0.010 g,
0.059 mmol) and potassium persulfate (0.32 g, 1.2 mmol) were
added to the flask under positive nitrogen pressure and the
reaction mixture was stirred for a further 24 h. The mixture was
then partitioned between water (10 mL) and DCM (10 mL) and
the aqueous phase was re-extracted with DCM (3 x 10 mL). The
combined organic fraction was then washed with sat. aq.
sodium chloride solution (40 mL), dried over MgSO4 and
concentrated under reduced pressure. The crude mixture was
purified by flash column chromatography (15% EtOAc in
pentane) to yield the pure title compound (0.023 g, 0.086 mmol,
29%) as a colorless oil. Unreacted starting material (0.045 g,
0.16 mmol, 53%) was also recovered.
Some peaks appear as multiplets or are distorted due to
proposed conformational isomerism.
1H NMR (400 MHz, Chloroform-d) δ 8.04 – 7.94 (m, 2H), 7.92
– 7.76 (m, 4H), 7.52 – 7.36 (m, 4H), 5.00 – 4.89 (m, 4H), 4.86
– 4.66 (m, 4H), 1.52 (s, 7H), 1.35 (s, 11H); 13C{1H} NMR (101
MHz, Chloroform-d) δ 190.1 – 188.8 (m), 155.7 – 154.5 (m),
142.4 (app. d, J = 5.7 Hz), 141.6 – 140.6 (m), 139.4 – 139.0
(m), 129.5 – 128.7 (m), 127.9 – 127.3 (m), 126.1, 125.6 – 124.9
(m), 123.1, 82.1 – 81.0 (m), 76.6 – 76.0 (m), 54.6 – 51.8 (m),
28.4, 28.2; IR (neat, v cm-1) = 2974, 2929, 1702, 1681, 1514,
1428, 1392, 1366, 1254, 1227, 1159; HRMS (ESI) m/z: calcd
for C32H36N2O6S2K [M+K]+, 647.1652; found, 647.1641.
Some peaks are doubled due to minor quantities of non-
hydrogen-bonded isomer.
ASSOCIATED CONTENT
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The Journal of Organic Chemistry
(11) Wang, D.; Mao, J.; Zhu, C. Visible Light-Promoted Ring-
Opening Functionalization of Unstrained Cycloalkanols via Inert C–C
Bond Scission. Chem. Sci. 2018, 9 (26), 5805–5809.
Supporting Information
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The Supporting Information is available free of charge on the ACS
Publications website.
(12) Guo, J. J.; Hu, A.; Chen, Y.; Sun, J.; Tang, H.; Zuo, Z.
Photocatalytic C−C Bond Cleavage and Amination of Cycloalkanols
by Cerium(III) Chloride Complex. Angew. Chemie - Int. Ed. 2016, 55
(49), 15319–15322.
(13) Zhao, K.; Yamashita, K.; Carpenter, J. E.; Sherwood, T. C.;
Ewing, W. R.; Cheng, P. T. W.; Knowles, R. R. Catalytic Ring
Expansions of Cyclic Alcohols Enabled by Proton-Coupled Electron
Transfer. J. Am. Chem. Soc. 2019, 141 (22), 8752–8757.
(14) Allen, B. D. W.; Hareram, M. D.; Seastram, A. C.; McBride,
T.; Wirth, T.; Browne, D. L.; Morrill, L. C. Manganese-Catalyzed
Electrochemical Deconstructive Chlorination of Cycloalkanols via
Alkoxy Radicals. Org. Lett. 2019, 21 (22), 9241–9246.
1H NMR Features of α-Amino Ketones 2a-p, full optimization
studies, 1H NMR, 13C NMR, and 19F NMR spectra (PDF)
X-Ray Crystallographic Information (PDF)
AUTHOR INFORMATION
Corresponding Author
* Philip J. Parsons
E-mail: p.parsons@imperial.ac.uk
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(15) Ishida, N.; Sawano, S.; Murakami, M. Synthesis of 3,3-
Disubstituted α-Tetralones by Rhodium-Catalysed Reaction of 1-(2-
Haloaryl)Cyclobutanols. Chem. Commun. 2012, 48 (14), 1973–1975.
(16) Ishida, N.; Shimamoto, Y.; Yano, T.; Murakami, M. 1,5-
Rhodium Shift in Rearrangement of N -Arenesulfonylazetidin-3-Ols
into Benzosultams. J. Am. Chem. Soc. 2013, 135 (51), 19103–19106.
(17) Lukamto, D. H.; Gaunt, M. J. Enantioselective Copper-
Catalyzed Arylation-Driven Semipinacol Rearrangement of Tertiary
Allylic Alcohols with Diaryliodonium Salts. J. Am. Chem. Soc. 2017,
139 (27), 9160–9163.
(18) Hu, A.; Chen, Y.; Guo, J. J.; Yu, N.; An, Q.; Zuo, Z. Cerium-
Catalyzed Formal Cycloaddition of Cycloalkanols with Alkenes
through Dual Photoexcitation. J. Am. Chem. Soc. 2018, 140 (42),
13580–13585.
(19) Natho, P.; Kapun, M.; Allen, L. A. T.; Parsons, P. J.
Regioselective Transition-Metal-Free Oxidative Cyclobutanol Ring
Expansion to 4-Tetralones. Org. Lett. 2018, 20 (24), 8030–8034.
(20) Natho, P.; Allen, L. A. T.; White, A. J. P.; Parsons, P. J.
Transition-Metal-Free Access to Heteroaromatic-Fused 4-Tetralones
by the Oxidative Ring Expansion of the Cyclobutanol Moiety. J. Org.
Chem. 2019, 84 (15), 9611–9626.
ORCID
Philip J. Parsons: 0000-0002-9158-4034
Robert-Cristian Raclea: 0000-0001-7008-069X
Notes
The authors declare no competing interests.
ACKNOWLEDGMENT
The authors gratefully acknowledge the receipt of an EPSRC
Imperial College London President’s Scholarship (to P.N.).
Additional generous funding from Dr Isabel Bader and her late
husband Dr Alfred Bader (to P.J.P.) is gratefully recognized. We
thank Pete Haycock (Imperial College London) and Dr Lisa Haigh
(Imperial College London) for NMR and mass spectrometric
analysis, respectively. This paper is dedicated to the late
philanthropist Dr Alfred Bader and also in memory of the late
Oxana Bennett.
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For Table of Contents Only
NBoc
OH
NHBoc
AgNO3, K2S2O8
R
R
DCE/H2O, rt
16 examples
O
(hetero)aryl-azetidinols
▪
▪
▪
Scalable protocol
Azetidinols act as
Mechanistic insights
with yields up to 80%
masked α-amino ketones
presented
ACS Paragon Plus Environment