Organic base effects in NHC promoted O- to C-carboxyl transfer; Chemoselectivity profiles, mechanistic studies and domino catalysis

Article abstract of DOI:10.1039/c1ob05160a

The O- to C-carboxyl transfer of oxazolyl carbonates promoted by triazolinylidenes, generated in situ with NEt₃, shows a markedly different rate and chemoselectivity profile to the same reaction promoted by triazolinylidenes generated using KHM

Full text of DOI:10.1039/c1ob05160a

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PAPER
Organic base effects in NHC promoted O- to C-carboxyl transfer;
chemoselectivity profiles, mechanistic studies and domino catalysis†
Craig D. Campbell, Christopher J. Collett, Jennifer E. Thomson, Alexandra M. Z. Slawin and Andrew D. Smith*
Received 28th January 2011, Accepted 28th February 2011
DOI: 10.1039/c1ob05160a
The O- to C-carboxyl transfer of oxazolyl carbonates promoted by triazolinylidenes, generated in situ
with NEt3, shows a markedly different rate and chemoselectivity profile to the same reaction promoted
by triazolinylidenes generated using KHMDS. The mechanism of these pathways has been probed
through extensive crossover studies to understand this process. The use of NEt3 as a base allows
domino multi-step reaction sequences to be developed, although chiral NHCs only generate modest
levels of asymmetric induction (<15% ee) in these domino reaction processes.
that triazolinylidenes, generated by deprotonation of the cor-
responding triazolium salt 2 with a metallated base (typically
Introduction
KHMDS) can efficiently promote the Steglich rearrangement17,18
of oxazolyl carbonates, a reaction process tolerant of a range of
C(4)-substituents as well as alkyl and aryl carbonates (Fig. 1).19
Cognisant of the elegant work of both Bode et al.20 and Glorious
et al.21 concerning the nature of the base used to generate the
NHC and the divergent fate of homoenolate reactions, we chose
to investigate fully the effect of changing the base from an
organometallic base to a weaker organic or inorganic base in this
rearrangement process. Herein we demonstrate that the choice of
base used to mediate the O- to C-carboxyl transfer promoted
by NHCs affects both the rate of product formation and the
chemoselectivity of this transformation. Additionally, the use of
an organic base allows the inclusion of this O- to C-carboxyl
N-Heterocyclic carbene (NHC) mediated catalysis has developed
rapidly within the last decade to include a range of synthetic
transformations that encompass both organometallic chemistry1
and organocatalysis.2,3 Significant advances in organocatalytic
strategies employing NHCs have been made in recent years,
through the development of a series of efficient umpolung,4
conjugate umpolung5 and redox strategies,6 among a number
of others.7 An alternative reaction manifold, employing the
ability of NHCs to act as Lewis base or nucleophilic catalysts
has also been established. In this arena, Smith et al. first
described the stoichiometric transfer of an alkoxycarbonyl unit
from a 2-alkoxycarbonylimidazolium salt to benzyl alcohol in
the presence of DABCO in 1994.8 Building upon this work,
Nolan and Hedrick independently showed that NHCs catalyse
transesterification processes,9 which has been extended to allow
the kinetic resolution of alcohols with chiral NHCs.10 Movassaghi
and co-workers have also demonstrated that NHCs effectively
catalyse the amidation of esters with amino alcohols, although
an alternative mechanism involving the NHC acting as a Brønsted
base, resulting in nucleophilic activation of the alcohol for an initial
transesterification event, followed by rapid O- to N-acyl transfer,
has been proposed.11,12 Alternatively, Ye and co-workers,13 and
ourselves,14 have recently developed a range of NHC-catalysed
asymmetric transformations that harness the use of azolium
enolates, formed from NHC addition to ketenes, for a number
of formal cycloaddition and other processes.
As part of a programme of research concerned with developing
Lewis-base15 catalysed reactions,16 we have previously shown
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh,
St Andrews, KY16 9ST, UK. E-mail: ads10@st-andrews.ac.uk
† Electronic supplementary information (ESI) available: All spectroscopic
data for novel compounds. CCDC reference numbers 809724–809726. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05160a
Fig. 1 NHC-mediated O- to C-carboxyl transfer of oxazolyl carbonates.
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transfer process into domino multi-step reaction sequences for the
synthesis of C-carboxyazlactones.22,23 Part of this work has been
communicated previously.24
same transformation, which proceeds to completion within 5 min
at significantly lower catalyst loadings (typically <1 mol%).19a,b
These disparate rates were initially proposed to correspond to
the concentration of active NHC generated in these protocols,
with KHMDS effecting quantitative conversion of salt 2 to
the corresponding NHC, and NEt3 generating an equilibrium
concentration of the NHC necessary to promote rearrangement.
In support of this hypothesis, increasing the stoichiometry of NEt3
to 100 mol% resulted in a marked increase in reaction rate, giving
complete conversion to 5 within 5 min (entry 5). Furthermore,
doping of the reaction with NEt3·HCl (1 eq) prior to addition
of NEt3 resulted in a decrease in the rate of rearrangement,
proceeding to only 75% conversion to 5 after 2 h. Control
experiments showed that neither NEt3 nor triazolium salt 2 alone
promote the rearrangement of 4 to 5 (entries 6 and 7), consistent
with the need for in situ NHC generation to promote the desired
O- to C-carboxyl transfer. DBU, proton sponge, K2CO3 and
Cs2CO3 can also be used successfully with triazolium salt 2 in
this process (entries 8–11) although DABCO, 2,6-lutidine or N-
methylmorpholine promoted no rearrangement. Further catalyst
screening showed that N-aryl triazolium salts 9 and 10 bearing
either electron withdrawing or electron donating substituents also
proved competent precatalysts for the rearrangement using NEt3
(entries 12 and 13).25
The generality of the NEt3 promoted process in combination
with precatalyst 2 was next established. Intriguingly, variation
of the carbonate functionality showed that rearrangement under
these reaction conditions is highly chemoselective. Only aryl
oxazolyl carbonates rearrange to their C-carboxyazlactones using
NEt3 as the base, with alkyl oxazolyl carbonates 11–13 inert to
these reaction conditions, returning only starting materials even
after extended reaction times (Table 2). NEt3 can also be used
to promote the rearrangement of 1-naphthyl oxazolyl carbonate
14 as well as aryl oxazolyl carbonates 15 and 16 incorporating
electron withdrawing and electron donating substituents (entries
Results and discussion
Base effects upon NHC-mediated O- to C-carboxyl transfer of
oxazolyl carbonates; reaction rates and chemoselectivity
Initial studies concentrated upon the use of NEt3 as an or-
ganic base for the O- to C-carboxyl transfer rearrangement
protocol. As our previous work has shown that oxazolyl phenyl
carbonates undergo facile NHC promoted O- to C-carboxyl
transfer, the rearrangement of phenyl carbonate 4 to 5 was
chosen for optimization. Addition of NEt3 (9 mol%) to a range
of azolium salts (10 mol%) and subsequent rearrangement was
investigated (Table 1). Employing the imidazolium, imidazolinium
or thiazolium salts 6–8 returned only starting material even
upon extended reaction times (entries 1–3), although triazolium
precatalyst 2 gave complete conversion to 5 in THF within 2 h,
giving 5 in 82% isolated yield (entry 4). The rate of rearrangement
of 4 to 5 employing NEt3 as the base with precatalyst 2 is
notably slowed in comparison to the use of KHMDS for the
Table 1 Organic base promoted NHC-catalysed O- to C-carboxyl
transfer
Table 2 Chemoselective NEt3 promoted NHC-catalysed O- to C-
carboxyl transfer
entry
salt
base (mol%)
product conversiona
1
2
3
4
5
6
7
8
6
NEt3 (9)
NEt3 (9)
NEt3 (9)
NEt3 (9)
NEt3 (100)
NEt3 (9)
—
DBU (9)
K2CO3 (9)
Proton sponge (9)
Cs2CO3 (9)
NEt3 (9)
NEt3 (9)
0%
0%
0%
7
oxazolyl
entry carbonate
8
>95% (82%)b
>95% (82%)b,c
0%
R
ester product conversiona Yieldb
2
2
—
2
1
2
3
4
4
Ph
Me
Bn
5
17
18
>95%
0%
0%
82%
—
—
0%
11
12
13
14
15
16
2
>90%
>95%
>95%
>95%
>95%
>95%
9
2
C(Me)2CCl3 19
1-naphthyl 20
4-MeOC6H4 21
4-FC6H4 22
0%
—
10
11
12
13
2
5
>95%
>95%26
>90%26
85%
40%
31%
2
6c
7c
9
10
a All reaction conversions were judged by 1H NMR spectroscopic analysis
of the crude reaction product after two hours. b Isolated yield of homoge-
neous product after chromatographic purification. c Reaction conditions 2
(10 mol%), NEt3 (100 mol%), THF (0.86 M), rt, 2 h.
a All reaction conversions were judged by 1H NMR spectroscopic analysis
of the crude reaction product. b Isolated yield of homogeneous product
after chromatographic purification. c Reaction time 5 min.
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5–7).26 Importantly, these observations contrast our previous work
using KHMDS as the base with precatalyst 2, which promotes
carboxyl transfer for both aryl and alkyl oxazolyl carbonates.
While a change in concentration of the active NHC in these
reactions may account for the disparate rates of reaction observed
within the NEt3 or KHMDS promoted processes, the change in
chemoselectivity of this reaction is intriguing. We investigated
the possibility that KBF4, generated in situ by deprotonation of
triazolium salt 2 with KHMDS, may act as a mild co-operative
Lewis-acid co-catalyst and aid this rearrangement process. To test
this hypothesis, the formation of C-carboxyl 5 from 4 using NEt3
(9 mol%) and triazolium salt 2 (10 mol%) in the presence of
KBF4 (1 eq) was monitored, resulting in a marked increase in
reaction rate, giving >95% conversion after 60 min. However,
methyl oxazolyl carbonate 11 did not rearrange under these
conditions, consistent with the chemoselectivity of this process
being unaffected by addition of KBF4.
The generality of the NEt3 promoted reaction protocol was
investigated through variation of the C(4) substituent of the
oxazolyl carbonate. A range of C(4)-alkyl (R = Me, Et, n-Bu,
i-Bu, CH2CH2SMe, 4-PhOCO2C6H4CH2) and C(4)-aryl (R = Ph)
phenyl oxazolyl carbonates readily rearrange to their C-carboxyl
products (Table 3, entries 1–7). However, structurally challenging
oxazolyl carbonates, such as those bearing a C(4)-a-branched i-Pr
group that rearrange in good yield to the C-carboxyl product using
KHMDS and precatalyst 2, gave only low conversion to product
(<15%), even with excess NEt3.
iments. In addition, we sought to clarify why the NHC derived
from triazolium salt 2 is a better catalyst for this transformation
than those derived from imidazolium or imidazolinium salts 6
and 7 using either NEt3 or KHMDS as the base. Initial crossover
studies showed that treatment of triazolium precatalyst 2 (5 mol%)
with KHMDS (4 mol%) and subsequent addition of a 50 : 50
mixture of oxazolyl carbonates 4 and 37 gave, after 5 min and
at complete reaction conversion, a 23 : 28 : 27 : 23 mixture of the
four possible rearrangement products 38, 5, 30 and 17 respectively
(Scheme 1).27 However, treatment of a 50 : 50 mixture of oxazolyl
carbonates 4 and 37 with precatalyst 2 and NEt3 (1 eq) either in the
presence or absence of KBF4 (1 eq) gave, again after 5 min and at
complete conversion of 4, exclusively 5 and carbonate 37. Further
experiments showed that treatment of a 50 : 50 mixture of either C-
carboxyl 4 and O-carboxyl 38, or a 50 : 50 mixture of C-carboxyl
5 and 38, with the NHC derived from KHMDS and precatalyst 2
both returned 5 and 38 exclusively, consistent with the C–C bond
forming step in this transformation being irreversible.
Table 3 Scope and limitations of the NEt3 promoted NHC-catalysed O-
to C-carboxyl transfer
oxazolyl
entry carbonate
product
R
ester conversiona Yieldb
1
2
3
4
5
6
7
8
4
Bn
5
>95%
>95%
>95%
>95%
>95%
>90%
>90%
<15%
82%
81%
81%
78%
72%
77%
—
23
24
25
26
27
28
29
Me
n-Bu
i-Bu
Ph
30
31
32
33
4-PhOCO2C6H4CH2 34
CH2CH2SMe
i-Pr
35
36
—
Scheme
experiments.
1 NHC-catalysed O- to C-carboxyl transfer: crossover
a All reaction conversions were judged by 1H NMR spectroscopic analysis
of the crude reaction product. b Isolated yield of homogeneous product
after chromatographic purification.
The generation of a near statistical product distribution upon
rearrangement of the mixture of oxazolyl carbonates 4 and 37 with
KHMDS is consistent with an intermolecular step occurring at
some stage within this process. Further experiments were designed
to distinguish between the possibility of crossover occurring
in a pre-equilibrium first stage, resulting in scrambling of the
50 : 50 mixture of oxazolyl carbonates, and/or an intermolecular
pathway between the enolate and a putative carboxyl transfer
intermediate. Monitoring the product distribution formed upon
treatment of a 50 : 50 mixture of oxazolyl carbonates 13 and 37
Mechanistic studies: crossover experiments
The notable differences in reactivity observed in this O- to C-
carboxyl transfer process with a change in base from KHMDS to
NEt3 led us to fundamentally question the reaction mechanisms
and reversibility of these processes, which we decided to probe by
analysis of the product distributions arising from crossover exper-
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with precatalyst 2 (1 mol%) and KHMDS (0.9 mol%) gave, after
5 min, a 43 : 44 : 7 : 6 ratio of exclusively O-carboxyl products
13 : 37 : 39 : 11, that after 30 min gave a mixture of all eight possible
O- and C-carboxyl products in a combined 80 : 20 ratio (Scheme 2).
This product distribution is consistent with an initial reversible
O-transcarboxylation process, followed by a relatively slow C-
carboxylation event. Interestingly, treatment of a 50 : 50 mixture
of 13 and 37 with imidazolium or imidazolinium salts 6 and 7
(10 mol%) respectively and KHMDS (9 mol%) resulted in rapid O-
transcarboxylation to form an equimolar ratio of all four possible
O-carboxyl products 13 : 37 : 39 : 11, with no subsequent formation
of any C-carboxyl products, even after extended reaction times.
This is consistent with the nature of the C-carboxyl intermediate
having a dominant effect upon the viability of the C-carboxylation
process.
was monitored (Scheme 3). Using precatalyst 2 (10 mol%) and
NEt3 (9 mol%) a 25 : 25 : 25 : 25 mixture of C-carboxyl products
5 : 20 : 30 : 42 was observed after 5 min. Adjustment of the reaction
conditions showed that using lower loadings of precatalyst 2
(1 mol%) and NEt3 (0.9 mol%) [2 mM concentration] gave a
mixture of all eight products (arising from O- and C-carboxyl
transfer processes), again consistent with initial rapid transcar-
boxylation to generate a mixture of carbonates, with subsequent
rearrangement to give a mixture of C-carboxyl products.
Scheme 3 NHC-catalysed O- to C-carboxyl transfer: crossover experi-
ments using NEt3.
Taken together, these crossover experiments are consistent with
both KHMDS and NEt3 catalysed O- to C-carboxyl transfer
processes proceeding through a similar mechanistic pathway,
involving an initial reversible O-carboxylation process, followed
by an irreversible C-carboxylation event (Fig. 2). This mechanistic
scheme is consistent with previous crossover studies from Fu using
a planar chiral PPY derivative as an asymmetric catalyst for this
reaction. This mechanistic proposal does not, however, account
for the difference in chemoselectivity noted within this NHC
catalysed process using either KHMDS or NEt3. As Alder and co-
workers have shown that metallated bases such as KHMDS form
complexes with NHCs,28 it may be possible that metal complex-
ation of the carbene upon deprotonation with a metallated base
may lead to enhanced NHC reactivity in this reaction manifold.
Alternatively, ion-pairing of a putative enolate intermediate with
either an ammonium (NEt3H+) or K+ counterion may give rise
to the observed difference in reactivity in these systems; we are
currently investigating the viability of these processes.
Scheme 2 NHC-catalysed O- to C-carboxyl transfer: crossover experi-
ments with triazolium, imidazolinium and imiadazolium precatalysts using
KHMDS.
To probe the NEt3 catalysed reaction pathway, the rearrange-
ment of a 50 : 50 mixture of aryl oxazolyl carbonates 4 and 41
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Fig. 2 Postulated mechanism for the NHC-promoted O- to C-carboxyl
transfer reaction.
Developing a domino two-step rearrangement protocol
Having validated the scope and limitations of employing NEt3 as a
base to promote theO- to C-carboxyltransfer process, the prospect
of using NEt3 to facilitate both the preparation of the oxazolyl
carbonate29 and the in situ generation of an NHC to promote a
one-pot domino rearrangement protocol was investigated. The
suitability of a variety of solvents to promote both oxazolyl
carbonate formation from the corresponding azlactone, and the
rearrangement with precatalyst 2 and NEt3, were separately
evaluated, with THF proving adequate for both stages of the
proposed domino process. Extensive optimisation of this domino
process showed that formation of C-carboxyl 5 from the parent
azlactone required an excess of phenyl chloroformate and NEt3,
as competitive formation of phenyl diethylcarbamate 43 (prepared
from dealkylation of triethylamine with the chloroformate)30
inhibited the formation of the intermediate oxazolyl carbonate. A
simple control experiment showed that excluding triazolium salt 2
from the reaction gave only oxazolyl carbonate 4 and carbamate
43, again consistent with the need to generate an NHC in situ to
promote C-carboxylation. The generality of this two-step domino
process was established, with a range of azlactones giving their
corresponding C-carboxyazlactones in 75–85% isolated yield after
chromatographic purification using either phenyl or 1-naphthyl
chloroformate (Scheme 4).31,32
Scheme 4 Two-step tandem reaction protocol aIsolated yield of homoge-
neous product after chromatographic purification.
Domino poly-step cyclisations
To further extend these domino reaction protocols, the ability to
generate C-carboxyl products directly from N-p-anisoyl amino
acids by incorporating a carboxylate activation and cyclisation
step to generate azlactones in situ, was investigated. Treatment
of N-p-anisoyl phenylalanine with DCC in THF,33 followed
by filtration of the urea by-product after 1 h, and sequential
addition of triazolium salt 2 (5 mol%), NEt3 (1.5 eq) and phenyl
chloroformate (1.3 eq) gave C-carboxyl-5 in 71% yield after
chromatography. This simple process was applied to a number
of derivatives, giving the desired C-carboxyazlactones in 69–84%
isolated yields (Scheme 5).
Scheme 5 DCC promoted cyclisation and domino reaction proto-
col aIsolated yield of homogeneous product after chromatographic
purification.
participate in oxazolyl carbonate formation was attempted.35 An
excess of chloroformate was necessary in order to sequester the
phenolate or naphtholate generated upon azlactone formation in
this reaction cycle, generating the corresponding diaryl carbonate
as a by-product.36 In practice, addition of either phenyl or 1-
naphthyl chloroformate (3 eq) to a solution of a range of N-
acyl amino acids, NEt3 (3.5 eq) and triazolium salt 2 (5 mol%)
As an alternative one-pot procedure for the direct preparation
of C-carboxyazlactones from N-p-anisoyl amino acids,34 the use
of an aryl chloroformate to both promote their cyclisation and
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proceeded to give the corresponding C-carboxyazlactones in 66–
78% isolated yields (Scheme 6).
Scheme 7 Attempted asymmetric domino reaction protocol aIsolated
yield of homogeneous product after chromatographic purification.
bDetermined by HPLC analysis.
Experimental section
General experimental
1H NMR Spectra were recorded using a Bruker Avance 400
spectrometer and Bruker Avance 300 spectrometer at 400 MHz
and 300 MHz respectively, using residual protonated solvent as a
reference for internal lock. The chemical shift information (dH) for
each resonance signal are given in units of parts per million (ppm)
relative to tetramethylsilane (TMS) where dH TMS = 0.00 ppm,
or to residual (protonated) solvent. The number of protons (n)
for a reported resonance signal are indicated by nH from their
integral value and their multiplicity is reported with their coupling
constants (J) quoted in Hz. Coupling constants are determined
Scheme 6 The development of domino multi-step reaction protocols
R
R
by analysis using iNMRꢀ and Topspinꢀ.
aIsolated yield of homogeneous product after chromatographic purifica-
13C NMR Spectra were recorded using a Bruker Avance 300
and Bruker Avance 400 spectrometer using the PENDANT
sequence at 75.5 MHz and 100 MHz respectively with internal
deuterated solvent lock. The chemical shift information (dC) for
each resonance signal is given in units of parts per million (ppm)
relative to tetramethylsilane (TMS) where dC TMS = 0.00 ppm, or
to the relevant solvent.
b
tion. Reaction conditions employed NEt3 (5.5 eq), PhOCOCl (5 eq) or
1-NapOCOCl (5 eq), salt 2 (10 mol%), THF, rt.
Domino asymmetric catalysis
After demonstrating the feasibility of this domino reaction process
in the racemic series, the ability of chiral NHCs to promote an
asymmetric version of this process was investigated. Screening
of a range of chiral azolium salts 47–49 identified a number of
NHCs that proved catalytically active in this process, but all gave
disappointing levels of asymmetric induction (Scheme 7).
19F NMR Spectra were recorded using a Bruker Avance 400
spectrometer at 282 MHz. The chemical shift information (dF) for
each resonance signal are given in units of parts per million (ppm)
relative to trichlorofluoromethane (CFCl3) where dF = 0.00.
Mass spectrometric (m/z) data were acquired by electrospray
ionisation (ESI), electron impact (EI) or chemical ionisation (CI),
either at the University of St Andrews Mass Spectrometry facility
([A] quoted) or at the EPSRC National Mass Spectrometry Service
Centre, Swansea ([A]+ or [A]- quoted). At the University of St
Andrews, low and high resolution ESI MS was carried out on
a Micromass LCT spectrometer and low and high resolution EI
and CI MS was carried out on a Micromass GCT spectrometer.
At the EPSRC National Mass Spectrometry Service Centre, low
resolution ESI MS was carried out on a Waters Micromass
ZQ4000 spectrometer and low resolution EI and CI MS was
carried out on a Micromass Quattro II spectrometer. High
resolution ESI and ESI MS was carried out on a Finnigan MAT
900 XLT or a Finnigan MAT 95 XP; a Thermofisher LTQ Orbitrap
Conclusion
In conclusion, the NHC generated from triazolium salt 2 with
NEt3 promotes the chemoselective rearrangement of aryl oxa-
zolyl carbonates to their corresponding C-aryloxyazlactones. The
mechanism of this transformation has been probed through a se-
ries of crossover experiments. The NEt3 promoted NHC mediated
rearrangement protocol can be incorporated into domino reaction
sequences, although chiral NHCs only promote this reaction with
low levels of enantioselectivity. Current investigations from this
laboratory are focused upon developing alternative applications
of NHCs in asymmetric catalysis.
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XL spectrometer was also used to obtain high resolution ESI MS
for accurate mass determination but also provided fragmentation
data for the characterisation of samples. Values are quoted as a
ratio of mass to charge in Daltons.
Melting points were determined using an Electrothermal 9100
melting point apparatus and are uncorrected.
General procedure C (one-pot). To a mixture of azolium salt
(x mol%) and carbonate (1 equiv) in THF or toluene (~1 mL per
100 mg of carbonate) was added a solution of base in solvent
(0.9x mol%). The mixture was stirred for y min then concentrated
in vacuo and, if necessary, the residue was purified by silica
chromatography.
Optical rotations were determined using a PerkinElmer Model
341 Polarimeter, at 20.0 ◦C using a Na/Hal lamp tuned to 589 nm.
Chiral HPLC was performed on either a Varian ProStar or
Gilson apparatus, using a CHIRALPAK OD-H, AD-H or AS-H
silica column, 0.46 cm f ¥ 25 cm, using hexane and isopropanol
as eluents.
Analytical thin layer chromatography (tlc) was carried out on
pre-coated 0.20 mm Machery-Nagel Polygram SIL G/UV254 silica
plates. Visualisation was carried out by absorption of ultraviolet
light or thermal decomposition after dipping in either an ethanolic
solution of phosphomolybdic acid or an aqueous solution of
potassium permanganate/sodium hydroxide.
For crossover experiments, 0.5 equiv of both carbonate sub-
strates were combined in the relevant solvent, and following the
aforementioned general procedure B, a sample of the product mix-
ture was concentrated in vacuo then examined spectroscopically to
determine the product distributions.
General procedure D (two-step domino cascade). To a mixture
of azlactone (1 equiv) and triazolium salt (5 mol%) in THF (~1 mL
per 100 mg of azlactone) was added Et3N (1.5 equiv) followed
by the requisite aryl chloroformate (1.3 equiv). The mixture was
stirred at ambient temperature, then Et3N·HCl was removed by fil-
tration and the filtrate concentrated in vacuo. Purification by silica
chromatography (EtOAc/petrol, Et2O/petrol or CH2Cl2/petrol)
gave the desired product.
Chromatography was performed using Merck Ltd. silica gel 40–
63 mm, eluting with solvents supplied under a positive pressure of
compressed air.
General procedure E (multi-step domino cascade with DCC).
A mixture of N-(p-anisoyl) amino acid (1 equiv) and DCC
(1.01 equiv) were stirred in THF for 2 h then filtered (to
remove dicyclohexylurea), followed by addition of triazolium salt
2 (5 mol%), Et3N (1.5 equiv) and then phenyl chloroformate
(1.3 equiv). The mixture was stirred at ambient temperature, then
Et3N·HCl was removed by filtration and the filtrate concentrated
in vacuo. Purification by silica chromatography (Et2O/petrol) gave
the desired product.
Anhydrous solvents were obtained from the MBraun SPS-800
solvent purification system.
Chemicals were purchased from Acros UK, Sigma-Aldrich UK,
Alfa Aeasar UK, Fisher UK or Merck. Brine refers to a saturated
aqueous solution of sodium chloride.
Reactions involving moisture sensitive reagents were performed
under an atmosphere of N2 or Ar using standard vacuum line
techniques and with freshly distilled solvents. All glassware was
flame-dried and allowed to cool under vacuum.
For known compounds, where certain elements of analytical
data are not described in the literature, these data have been
reported and are marked §.
General procedure F (multi-step domino cascade with aryl chlo-
roformates). To a mixture of N-(p-anisoyl) amino acid (1 equiv)
and triazolium salt 2 (5–10 mol%) in THF was added Et3N
(3.5 equiv) followed by phenyl chloroformate (3 equiv), with
significant exotherm and effervescence observed. The mixture was
stirred at ambient temperature for 5–60 min, then Et3N·HCl was
removed by filtration and the filtrate concentrated in vacuo. Purifi-
cation by silica chromatography (Et2O/petrol or CH2Cl2/petrol)
gave the desired product.
General procedures
General procedure A (preparation of oxazolyl carbonates from
azlactones). Based upon a procedure by Fu and co-workers,18a
Et3N (1.1–1.5 equiv) was added to a stirred solution of the desired
azlactone (1 equiv) in THF at 0 ◦C, followed by addition of
the desired chloroformate (1.06 equiv). The mixture was stirred
at 0 ◦C for 30 min before warming to ambient temperature
and stirring over 16 h. The resulting solution was poured into
H2O and the aqueous phase extracted with Et2O (¥ 3). The
organic extracts were combined, washed with 0.1 M HCl(aq),
sat NaHCO3(aq) solution, brine, dried (MgSO4), filtered and
concentrated in vacuo. Purification by recrystallisation or silica
chromatography (Et2O/petrol) gave the desired product.
Known substrates and rearrangement products. Known
azlactone precursors, carbonate substrates and their C-
carboxyazlactone isomers were prepared following literature pro-
cedures with physical and spectroscopic data in agreement with
the literature (for 4 and 5 see ref. 18a; for 11, 12, 17, 18, 24, 25,
26, 28, 29, 31, 32, 33, 35, 36, 37, 38, 39 and 40 see ref. 19b; for 13
and 19 see ref. 16a; for 23 and 30 see ref. 18b. Spectroscopic data
of purified materials were used to identify product distributions in
crossover experiments.
Literature procedures were used for the preparation of com-
pounds 2,19b 6,19b 7,19b 9,19b 10,19b 4714a and 48,37 giving analytical
and spectroscopic data in accordance with the literature.
Procedures for Steglich rearrangement
General procedure B (standard protocol). To a mixture of
azolium salt (x mol%) in solvent (typically THF, ~1 mL per
100 mg of carbonate) was added a solution of base in solvent
(0.9x mol%). The mixture was stirred for 20 min then a solution of
carbonate (1 equiv) in solvent (typically THF, ~1 mL per 100 mg
of carbonate) was added via cannula. The mixture was stirred
for y min (typically <60 min) then concentrated in vacuo and, if
necessary, the residue was purified by silica chromatography.
(R)- and (RS)-Phenyl 4-benzyl-5-oxo-2-(4-methoxyphenyl)-4,5-
dihydrooxazole-4-carboxylate 5
Using catalytic base. Following general procedure C, car-
bonate 4 (100 mg, 0.249 mmol), triazolium salt 2 (6.80 mg,
0.0249 mmol), THF (1 mL) and Et3N (3.12 mL, 0.0224 mmol)
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gave, after 120 min and chromatography (10% EtOAc : petrol),
ester ( )-5 as a colourless oil (82.0 mg, 82%).
161.7 (MeOArC-1), 155.7 (ArC), 150.2 (ArC), 146.6 (ArC), 145.9
(ArC), 137.6 (ArC), 134.8 (ArC), 129.1 (ArCH), 128.8 (ArCH),
128.3 (ArCH), 128.0 (ArCH), 127.2 (ArCH), 127.2 (ArCH), 127.1
(ArCH), 126.9 (ArCH), 126.1 (ArC), 125.4 (ArCH), 123.5 (ArC),
120.9 (ArCH), 119.9 (ArC), 117.3 (ArCH), 114.4 (ArCH), 55.6
(OCH3) and 31.9 (CH2); m/z MS (ESI+) 469 (100, [M + NH4]+),
Using stoichiometric base. Following general procedure C,
carbonate 4 (100 mg, 0.249 mmol), triazolium salt 2 (6.80 mg,
0.0249 mmol), THF (1 mL) and Et3N (34.7 mL, 0.249 mmol) gave,
after 5 min and chromatography (10% EtOAc:petrol), ester ( )-5
as a colourless oil (82.1 mg, 82%).
HRMS (ESI+) C28H25N2O5 ([M + NH4]+) requires 469.1758,
+
found 469.1758 (+0.0 ppm); IR nmax (KBr)/cm-1 3052 (Ar C–
H), 3027, 2970, 2913, 2835, 1792 (C O), 1667 (Ar C C), 1617
(C N), 1603 (Ar C C), 1459, 1502, 1455, 1434, 1393, 1307, 1258
(C–O), 1213 (C–O) and 1180 (C–O).
Two-step domino cascade. Following general procedure D,
azlactone (200 mg, 0.711 mmol), triazolium salt 2 (9.70 mg,
0.0355 mmol), THF (2 mL), Et3N (128 mL, 0.924 mmol) and
phenyl chloroformate (88.0 mL, 0.782 mmol) gave, after chro-
matography (10% EtOAc : petrol), ester ( )-5 as a colourless oil
(231 mg, 81%).
Naphthalen-1-yl 4-benzyl-2-(4-methoxyphenyl)-5-oxo-4,5-
dihydrooxazole-4-carboxylate 20
Multi-step domino cascade with DCC. Following general pro-
cedure E, N-p-anisoyl-DL-phenylalanine (300 mg, 1.00 mmol),
DCC (208 mg, 1.01 mmol), triazolium salt 2 (13.7 mg,
0.0500 mmol), THF (3 mL), Et3N (182 mL, 1.30 mmol), and phenyl
chloroformate (123 mL, 1.10 mmol) gave, after chromatography
(20% Et2O/petrol), ester ( )-5 as a colourless oil (285 mg, 71%).
Following general procedure C, carbonate 14 (100 mg,
0.221 mmol), triazolium salt 2 (6.05 mg, 0.0221 mmol), THF
(1 mL) and Et3N (2.77 mL, 0.0199 mmol) gave, after 120 min and
chromatography (10% EtOAc : petrol), ester ( )-20 as a colourless
oil (84.9 mg, 85%).
Following general procedure D, azlactone (200 mg,
0.711 mmol), triazolium salt 2 (9.70 mg, 0.0355 mmol), THF
(2 mL), Et3N (128 mL, 0.924 mmol) and 1-naphthyl chlorofor-
mate (127 mL, 0.782 mmol) gave, after chromatography (10%
EtOAc:petrol), ester ( )-20 as a colourless oil (273 mg, 85%).
Following general procedure E, N-p-anisoyl-DL-phenylalanine
(300 mg, 1.00 mmol), DCC (208 mg, 1.01 mmol), triazolium salt 2
(13.7 mg, 0.0500 mmol), THF (3 mL), Et3N (182 mL, 1.30 mmol),
and 1-naphthyl chloroformate (0.179 mL, 1.10 mmol) gave, after
chromatography (20% Et2O : petrol), ester ( )-20 as a colourless
oil (361 mg, 80%).
Multi-step domino cascade with phenyl chloroformate. Follow-
ing general procedure F, N-p-anisoyl-DL-phenylalanine (300 mg,
1.00 mmol), Et3N (0.487 mL, 3.51 mmol), triazolium salt 2
(13.7 mg, 0.0500 mmol), THF (3 mL) and phenyl chlorofor-
mate (0.340 mL, 3.01 mmol) gave, after chromatography (20%
Et2O : petrol), ester ( )-5 as a colourless oil (286 mg, 71%).
dH (300 MHz, CDCl3) 7.92–7.87 (2H, m, MeOArH-2,6), 7.43–
7.37 (2H, m, PhH), 7.30–7.19 (6H, m, PhH), 7.15–7.10 (2H, m,
PhH), 6.98–6.94 (2H, m, MeOArH-2,6), 3.88 (3H, s, ArOCH3),
3.75 (1H, ABd, J 13.7, CHAHBPh) and 3.61 (1H, ABd, J
13.7, CHAHBPh). Spectroscopic data are in accordance with the
literature.19b
Following general procedure F, N-p-anisoyl-DL-phenylalanine
(200 mg, 0.668 mmol), 1-naphthyl chloroformate (0.325 mL,
2.00 mmol), Et3N (0.325 mL, 2.34 mmol), triazolium salt 2
(9.12 mg, 33.4 mmol) and THF (2 mL), gave, after chromatographic
purification (20% EtOAc : petrol), the product as a colourless oil
(232 mg, 70%).
Asymmetric multi-step domino cascades. Following general
procedure E, N-p-anisoyl-DL-phenylalanine (150 mg, 0.500 mmol),
Et3N (0.243 mL, 1.75 mmol), chiral triazolium salt 47–49
(0.0250 mmol), THF (1.5 mL) and phenyl chloroformate
(0.170 mL, 1.50 mmol) gave, after chromatography (20%
Et2O : petrol), ester (R)-5 as a colourless oil:
Using triazolium salt 47, 60% isolated yield, 10% ee.
Using triazolium salt 48, 85% isolated yield, 14% ee.
Using triazolium salt 49, 70% isolated yield, <5% ee.
Enantiomeric excesses were determined byHPLC withChiralcel
OD-H column (5% i-PrOH : hexane, flow rate = 1.0 mL min-1),
tR(R) 13.8 min and tR(S) 18.9 min.
dH (400 MHz, CDCl3) 7.96–7.90 (2H, m, MeOArH-3,5), 7.88–
7.83 (2H, m, NapH), 7.76 (1H, br d, J 8.1, ArH), 7.54–7.48
(2H, m, ArH), 7.45 (1H, t, J 8.2, ArH), 7.33–7.17 (6H, m,
ArH), 6.97–6.63 (2H, m, MeOArH-2,6), 3.86 (3H, s, OCH3),
3.81 (1H, ABd, J 13.7, PhCHAHB) and 3.68 (1H, ABd, J 13.7,
PhCHAHB); dC (100 MHz, CDCl3) 174.0 (C-2), 164.6 (MeOArC-
1), 163.7 (COOAr), 163.5 (ArC), 151.9 (ArC), 146.0 (ArC), 134.6
(ArC), 132.8 (ArC), 130.5 (ArCH), 130.3 (ArCH), 128.4 (ArCH),
128.0 (ArCH), 127.7 (ArCH), 126.9 (ArCH), 126.8 (ArCH), 126.7
(ArCH), 126.3 (ArCH), 125.2 (ArCH), 121.0 (ArCH), 117.1
(ArC), 114.3 (MeOArC-2,6), 77.9 (C-4), 55.6 (OCH3) and 40.1
(CH2); m/z MS (ESI+) 451 (42, [M + H]+), 407 (100, [M + MeOH
- Ph]+); HRMS (ESI+) C23H22O2N ([M + H]+) requires 344.1645,
found 344.1647 (+0.4 ppm); IR nmax (KBr)/cm-1 3063, 3033, 2965,
2937, 2841, 1822 (C O), 1770 (C O), 1645 (C N), 1606 (Ar
4-Benzyl-2-(4-methoxyphenyl)oxazol-5-yl naphthalen-1-yl
carbonate 14
Following general procedure A, Et3N (0.594 mL, 4.27 mmol),
phenylalanine-derived azlactone (1.00 g, 3.56 mmol), CH2Cl2
(10 mL) and 1-naphthyl chloroformate (0.660 mL, 4.09 mmol),
C
C), 1575, 1512, 1495 (Ar C C), 1442, 1426, 1390, 1307, 1263
gave the crude product as
a yellow oil. Crystallisation
(C–O), 1212 (C–O) and 1173 (C–O).
(Et2O : hexane) gave the product as a colourless solid (828 mg,
51%). mp 86–88 ◦C; dH (400 MHz, CDCl3) 7.95–7.89 (4H, m,
MeOArH-3,5 and NapH), 7.80 (1H, d, J 8.3, NapH), 7.57 (2H,
dt, 6.7, 3.0, ArH), 7.49 (1H, t, J 8.0, ArH), 7.39–7.31 (5H, m,
ArH), 7.27–7.24 (1H, m, ArH), 6.95 (2H, d, J 8.8, MeOArH-2,6),
3.97 (2H, s, PhCH2) and 3.85 (3H, s, OCH3); dC (100 MHz, CDCl3)
4-Benzyl-2-(4-methoxyphenyl)oxazol-5-yl (4-methoxyphenyl)
carbonate 15
Following general procedure A, Et3N (0.920 mL, 6.60 mmol),
phenylalanine-derived azlactone (1.16 g, 4.12 mmol), THF
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(20 mL) and 4-methoxyphenyl chloroformate (1.84 mL,
12.4 mmol) gave the crude product as a yellow oil. Crystallisation
(Et2O : petrol) gave the product as a colourless solid (1.44 g, 81%).
mp 86–87 ◦C; dH (400 MHz, CDCl3) 7.81–7.77 (2H, m, MeOArH-
3,5), 7.24–7.06 (4H, m, ArH), 6.99–6.96 (2H, m, MeOArH-2,6),
6.84–6.78 (5H, ArH), 3.74 (2H, s, PhCH2), 3.74 (3H, s, OCH3) and
3.70 (3H, s, ArOCH3). dC (100 MHz, CDCl3) 161.6 (MeOArC),
158.0 (MeOArC), 155.6 (ArC), 150.5 (ArC), 147.5 (ArC), 144.4
(ArC), 137.6 (ArC), 129.1 (ArCH), 128.7 (ArCH), 127.9 (ArCH),
126.8 (ArC), 123.4 (ArCH), 121.5 (ArC), 119.9 (ArC), 114.7
(ArCH), 114.3 (ArCH), 55.8 (OCH3), 55.6 (OCH3) and 31.8
(CH2); m/z MS (NSI+) 376 (100, [M + H]+), HRMS (NSI+)
C
1167.
C), 1503, 1454, 1261 (C–O), 1218 (C–O), 1187 (C–O) and
4-Fluorophenyl 4-benzyl-2-(4-methoxyphenyl)-5-oxo-4,5-
dihydrooxazole-4-carboxylate 22
Following general procedure C, carbonate 16 (100 mg,
0.231 mmol), triazolium salt 2 (6.5 mg, 0.0238 mmol), THF
(1 mL) and Et3N (33.2 ml, 0.238 mmol gave, after 120 min and
chromatography (20% Et2O : petrol) ester ( )-22 as a colourless
oil (31.4 mg, 31%). dH (300 MHz, CDCl3) 7.91–7.89 (2H, m,
MeOArH-3,5), 7.29–7.21 (5H, m, PhH), 7.11–7.08 (4H, m,
pFArH), 6.97–6.95, (2H, m, MeOArH-2,6), 3.88 (3H, s, OCH3),
3.73 (1H, ABd, J 13.7, PhCHAHB) and 3.61 (1H, ABd, J 13.7,
PhCHAHB); dC (100 MHz, CDCl3) 173.7 (MeOArC), 164.8 (ArC),
163.8 (ArC), 163.3 (ArC), 160.7 (d, J 245.4, pFArC), 146.1 (d, J
2.7, pFArC), 132.8 (ArC), 130.6 (ArCH), 130.3 (ArCH), 128.5
(ArCH), 127.8 (ArCH), 122.8 (d, J 8.6, pFArC), 117.2 (ArC),
116.4 (d, J 23.7, pFArC), 114.4 (ArCH), 77.6 (ArC), 55.7 (OCH3)
and 40.4 (CH2); dF (282 MHz, CDCl3) 116.2; m/z MS (NSI+) 452
(100, [M + H + CH3OH]+), HRMS (NSI+) C25H23FNO6+ requires
452.1504 found 452.1498, (-1.3 ppm); IR nmax (thin film)/cm-1
2966 (Ar C–H), 2842, 1823, 1770 (C O), 1645 (Ar C C), 1607
(C N), 1504 (Ar C C), 1456, 1456, 1262 (C–O) and 1178 (C–O).
+
C22H18NO5 requires 375.3741, found 375.3737, (-1.1 ppm); IR
nmax (KBr)/cm-1 2961 (Ar C–H), 2837, 1785 (C O), 1672 (Ar
C
C), 1614 (C N), 1601 (Ar C C), 1498, 1460, 1254 (C–O),
1220 (C–O) and 1170 (C–O).
4-Methoxyphenyl 4-benzyl-2-(4-methoxyphenyl)-5-oxo-4,5-
dihydrooxazole-4-carboxylate 21
Following general procedure C, carbonate 15 (100 mg,
0.231 mmol), triazolium salt 2 (6.50 mg, 0.0231 mmol), THF
(1 mL) and Et3N (32.2 mL, 0.231 mmol) gave, after 120 min and
chromatography (10% Et2O : petrol), ester ( )-21 as a colourless
oil (40.1 mg, 40%). dH (300 MHz, CDCl3) 7.89–7.86 (2H, m,
MeOArH-3,5), 7.27–7.19 (5H, m, PhH), 7.04–7.01 (2H, m,
MeOArH), 6.95–6.93 (2H, m, MeOArH), 6.88–6.86, (2H, m,
MeOArH), 3.86 (3H, s, ArOCH3), 3.79 (3H, s, OCH3), 3.72 (1H,
ABd, J 13.7, PhCHAHB) and 3.59 (1H, ABd, J 13.7, PhCHAHB);
dC (100 MHz, CDCl3) 174.1 (MeOArC), 165.3 (MeOArC), 164.1
(ArC), 163.5 (ArC), 158.1 (ArC), 144.2 (ArC), 133.3 (ArC),
130.9 (ArCH), 130.6 (ArCH), 128.7 (ArCH), 128.1 (ArC), 122.4
(ArCH), 122.2 (ArC), 117.7 (ArC), 114.9 (ArCH), 114.7 (ArCH),
56.0 (OCH3), 55.9 (OCH3) and 40.7 (CH2); m/z MS (NSI+) 432
(RS)-Phenyl methyl-5-oxo-2-(4-methoxyphenyl)-4,5-dihydro-
oxazole-4-carboxylate 30
Following general procedure C, carbonate 23 (100 mg,
0.307 mmol), triazolium salt 2 (8.39 mg, 0.0307 mmol), THF
(1 mL) and Et3N (3.85 mL, 0.0276 mmol) gave, after 120 min and
chromatography (10% EtOAc : petrol), ester ( )-30 as a colourless
oil (81.0 mg, 81%).
Following general procedure D, alanine-derived azlactone
(300 mg, 1.46 mmol), triazolium salt 2 (39.9 mg, 0.146 mmol),
THF (3 mL), Et3N (305 mL, 2.19 mmol) and phenyl chloro-
formate (214 mL, 1.90 mmol) gave, after chromatography (10%
EtOAc : petrol), ester ( )-30 as a colourless oil (385 mg, 81%).
Following general procedure E, N-p-anisoyl-DL-alanine
(200 mg, 0.896 mmol), DCC (187 mg, 0.905 mmol), triazolium
salt 2 (12.2 mg, 0.0448 mmol), THF (2 mL), Et3N (186 mL,
1.34 mmol), and phenyl chloroformate (132 mL, 1.17 mmol)
gave, after chromatography (20% Et2O : petrol), ester ( )-30 as
a colourless oil (201 mg, 69%).
Following general procedure F, N-p-anisoyl-DL-alanine
(500 mg, 2.24 mmol), Et3N (1.09 mL, 7.84 mmol), triazolium
salt 2 (30.5 mg, 0.112 mmol), THF (4 mL) and phenyl chloro-
formate (760 mL, 6.72 mmol) gave, after chromatography (20%
Et2O : petrol), ester ( )-30 as a colourless oil (568 mg, 78%).
dH (300 MHz, CDCl3) 7.97–7.92 (2H, m, MeOArH-3,5),
7.34–7.25 (2H, m, PhH-2,6), 7.19–7.13 (1H, m, PhH-4), 7.05–
6.99 (2H, m, PhH-3,5), 6.95–6.90 (2H, m, MeOArH-2,6), 3.81
(3H, s, OCH3) and 1.80 (3H, s, CH3). Spectroscopic data are in
accordance with the literature.19b
(100, [M + H]+), HRMS (NSI+) C25H22NO6 requires 432.1442,
+
found 432.1440, (-0.4 ppm); IR nmax (thin film)/cm-1 2965 (Ar
C–H), 2840, 1785 (C O), 1670 (Ar C C), 1614 (C N), 1508
(Ar C C), 1494, 1459, 1225 (C–O), 1217 (C–O) and 1170 (C–O).
4-Benzyl-2-(4-methoxyphenyl)oxazol-5-yl (4-fluorophenyl)
carbonate 16
Following general procedure A, Et3N (0.920 mL, 6.60 mmol),
phenylalanine-derived azlactone (1.16 g, 4.12 mmol), THF
(20 mL) and 4-fluorophenyl chloroformate (1.62 mL, 12.4 mmol)
gave the crude product as
a yellow oil. Crystallisation
(Et2O : petrol) gave the product as a colourless solid (1.56 g, 90%).
mp 81–83 ◦C; dH (300 MHz, CDCl3) 7.82–7.77 (2H, m, MeOArH-
3,5), 7.22–7.14 (5H, m, ArH), 7.06–6.94 (4H, ArH), 6.85–6.80
(2H, m, MeOArH-2,6), 3.82 (2H, s, CH2Ph) and 3.73 (3H, s,
OCH3); dC (75 MHz, CDCl3) 161.5 (MeOArC), 160.7 (d, J 246.0,
pFArC), 155.5 (ArC), 150.1 (ArC), 146.5 (d, J 2.8, pFArC), 145.6
(ArC), 137.4 (ArC), 129.0 (ArCH), 128.6 (ArCH), 127.8 (ArCH),
126.7 (ArC), 123.4 (ArCH), 122.1 (d, J 8.7, pFArC), 119.8 (ArC),
116.4 (d, J 23.8, pFArC), 114.2 (ArCH), 55.4 (OCH3), and 31.8
(CH2); dF (282 MHz, CDCl3) 115.6; m/z MS (NSI+) 420 (100, [M
Phenyl 4-butyl-2-(4-methoxyphenyl)-5-oxo-4,5-dihydrooxazole-4-
carboxylate 31
+ H]+), HRMS (NSI+) C24H19FNO5 requires 420.1242, found
+
420.1242, (-0.9 ppm); IR nmax (KBr)/cm-1 3075, 2944 (Ar C–
Following general procedure C, carbonate 24 (100 mg,
0.272 mmol), triazolium salt 2 (7.43 mg, 0.0272 mmol), THF
H), 2839, 1787 (C O), 1670 (Ar C C), 1615 (C N), 1589 (Ar
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(1 mL) and Et3N (3.41 mL, 0.0245 mmol) gave, after 120 min and
chromatography (10% Et2O : petrol), ester ( )-31 as a colourless
oil (81.0 mg, 81%).
Following general procedure E, N-p-anisoyl-DL-norleucine
(300 mg, 1.13 mmol), DCC (236 mg, 1.14 mmol), triazolium
salt 2 (15.5 mg, 0.0568 mmol), THF (3 mL), Et3N (236 mL,
1.70 mmol), and phenyl chloroformate (166 mL, 1.47 mmol)
gave, after chromatography (10% Et2O : petrol), ester ( )-31 as
a colourless oil (303 mg, 73%).
Following general procedure F, N-p-anisoyl-DL-norleucine
(900 mg, 3.39 mmol), Et3N (1.65 mL, 11.9 mmol), triazolium salt
2 (46.3 mg, 0.170 mmol), THF (9 mL) and phenyl chloroformate
(1.14 mL, 10.2 mmol) gave, after chromatographic purification
(3% → 20% Et2O : petrol), ester ( )-31 as a colourless oil (934 mg,
75%).
dH (400 MHz, CDCl3) 8.06–8.02 (2H, m, MeOArH-3,5),
7.69–7.34 (2H, m, PhH-3,5), 7.26–7.22 (1H, m, PhH-4), 7.13–
7.10 (2H, m, PhH-2,6), 7.03–6.99 (2H, m, MeOArH-2,6), 3.88
(3H, s, OCH3), 2.45–2.38 (1H, m, C(4)HAHB), 2.34–2.28 (1H, m,
C(4)HAHB), 1.44–1.35 (3H, m, CH3CH2CHAHB), 1.31–1.21 (1H,
m, CH3CH2CHAHB) and 0.91 (3H, t, J 7.1, CH3); dC (100 MHz,
CDCl3) 174.5 (COOCR2), 164.8 (COOPh), 163.9 and 163.3
(MeOArC-1 and C N), 150.4 (OPhC-1), 130.5 (MeOArCH-3,5),
129.6 (OPhCH-3,5), 126.6 (OPhCH-4), 121.2 (OPhCH-2,6), 117.4
(MeOArC-4), 114.5 (MeOArCH-2,6), 76.8 (C-4), 55.7 (OCH3),
34.3 (CH2), 25.5 (CH2), 22.6 (CH2CH3) and 13.9 (CH3); m/z MS
(ESI+) 386 (100, [M + H]), 248 (72, [M - COOPh + H]) and
135 (38, ArC O); HRMS (ESI+) C21H22NO5 ([M + H]) requires
368.1489, found 368.1498 (-2.4 ppm); IR nmax (thin film)/cm-1
2961, 2934, 2874, 1823 (C O), 1771 (C O), 1653 (C N), 1609,
1513, 1308, 1262 (C–O) and 1173 (C–O).
Phenyl 2-(4-methoxyphenyl)-5-oxo-4-phenyl-4,5-dihydrooxazole-
4-carboxylate 33
Following general procedure C, carbonate 26 (100 mg,
0.258 mmol), triazolium salt 2 (7.04 mg, 0.0258 mmol), THF
(1 mL) and Et3N (3.24 mL, 0.0232 mmol) gave, after 120 min and
chromatography (15% Et2O : petrol), ester ( )-33 as a colourless
oil (72.2 mg, 72%).
Following general procedure D, phenylglycine-derived azlac-
tone (200 mg, 0.748 mmol), triazolium salt 9 (10 mg, 0.0374 mmol),
THF (2 mL), Et3N (135 mL, 0.972 mmol) and phenyl chlorofor-
mate (93.0 mL, 0.823 mmol) gave, after chromatography (20%
Et2O : petrol), ester ( )-33 as a colourless oil (217 mg, 75%).
dH (400 MHz, CDCl3) 8.15–8.12 (2H, m, MeOArH-3,5), 7.86–
7.84 (2H, m, PhH), 7.49–7.42 (3H, m, PhH), 7.38–7.33 (2H, m,
PhH), 7.23 (1H, tt, J 7.4, 1.4, PhH-4), 7.11–7.09 (2H, m, PhH-
2,6), 7.05–7.02 (2H, m, MeOArH-2,6) and 3.90 (3H, s, OCH3).
Spectroscopic data are in accordance with the literature.19b
Phenyl 2-(4-methoxyphenyl)-5-oxo-4-(4-phenoxycarbonyloxy)-
benzyl-4,5-dihydrooxazole-4-carboxylate 34
Following general procedure C, carbonate 27 (100 mg,
0.186 mmol), triazolium salt 2 (5.08 mg, 0.0186 mmol), THF
(1 mL) and Et3N (2.33 mL, 0.0167 mmol) gave, after 120 min and
chromatography (10% Et2O : petrol), ester ( )-34 as a colourless
oil (77.0 mg, 77%).
Following a stoichiometric modification to general procedure
F, N-p-anisoyl-DL-tyrosine (250 mg, 0.793 mmol), Et3N (661 mL,
4.76 mmol), triazolium salt 2 (10.8 mg, 0.0397 mmol), THF
(2.5 mL) and phenyl chloroformate (493 mL, 4.36 mmol) gave,
after chromatographic purification (20% Et2O : petrol), ester ( )-
34 as a colourless oil (281 mg, 66%).
dH (300 MHz, CDCl3) 7.91–7.86 (2H, m, MeOArH-3,5), 7.43–
7.32 (5H, m, ArH), 7.32–7.27 (2H, m, ArH), 7.26–7.22 (3H, m,
ArH), 7.21–7.08 (4H, m, ArH), 6.97–6.92 (2H, m, MeOArH-
2,6), 3.86 (3H, s, OCH3), 3.74 (1H, ABd, J 13.8, ArCHAHB) and
3.59 (1H, ABd, J 13.8, ArCHaHB); dC (75 MHz, CDCl3) 173.8
(COOCR2), 164.6 (COOPh), 164.0 and 163.6 (MeOArC-1 and
Phenyl isobutyl-2-(4-methoxyphenyl)-5-oxo-4,5-dihydrooxazole-4-
carboxylate 32
Following general procedure C, carbonate 25 (100 mg,
0.272 mmol), triazolium salt 2 (7.43 mg, 0.0272 mmol), THF
(1 mL) and Et3N (3.41 mL, 0.0245 mmol) gave, after 120 min and
chromatography (10% Et2O : petrol), ester ( )-32 as a colourless
oil (77.8 mg, 78%).
Following general procedure D, leucine-derived azlactone
(200 mg, 0.809 mmol), triazolium salt 9 (11.1 mg, 0.0405 mmol),
THF (2 mL), Et3N (157 mL, 1.13 mmol) and phenyl chlo-
roformate (119 mL, 1.05 mmol) gave, after chromatography
(15% Et2O : petrol), ester ( )-32 as a colourless oil (252 mg,
85%).
Following general procedure E, N-p-anisoyl-DL-leucine
(300 mg, 1.13 mmol), DCC (236 mg, 1.14 mmol), triazolium
salt 2 (15.1 mg, 0.0552 mmol), THF (3 mL), Et3N (236 mL,
1.70 mmol) and phenyl chloroformate (166 mL, 1.47 mmol)
gave, after chromatography (15% Et2O : petrol), ester ( )-32 as
a colourless oil (290 mg, 70%).
C
N), 152.0 (ArC), 151.2 (ArC), 150.7 (ArC), 150.5 (ArC),
132.0 (ArCH), 131.3 (ArCH), 130.5 (ArCH), 129.8 (ArCH),
126.8 (ArCH), 126.6 (MeOArC-4), 121.4 (ArCH), 121.2 (ArCH),
121.1 (ArCH), 121.0 (ArCH), 117.2 (PhOC(O)OArC-4), 114.6
(OArCH-2,6), 77.6 (C-3), 55.8 (OCH3) and 39.7 (CH2); m/z MS
(ESI+) 538 (100, [M + H]+); HRMS (ESI+) C31H24NO8 ([M +
H]) requires 538.1501, found 538.1502 (-0.2 ppm); IR nmax (thin
film)/cm-1 2934 (CH), 2824 (CH), 2360 (CH), 1823 (C O), 1773
(C O), 1771 (C O), 1646 (C N), 1608, 1513, 1493, 1259, 1236
(C–O), 1185, 1161, 980, 841, 742 and 687.
2-(4-Methoxyphenyl)-4-methyloxazol-5-yl naphthalen-1-yl
carbonate 41
dH (400 MHz, CDCl3) 8.07–8.04 (2H, m, MeOArH-3,5), 7.45–
7.09 (5H, m, PhH), 7.05–6.99 (2H, m, MeOArH-2,6), 3.90 (3H, s,
OCH3), 2.48 (1H, ABX, JAB 14.1, JAX 6.0, CHAHBCH(CH3)2),
2.17 (1H, ABX, JBA 14.1, JBX 7.2, CHAHBCH(CH3)2), 1.83 (1H,
app sept, J 6.6, CH(CH3)2), 1.01 (3H, d, J 6.6, CH(CH3)2) and 0.97
(3H, d, J 6.6, CH(CH3)2). Spectroscopic data are in accordance
with the literature.19b
Following general procedure A, Et3N (0.81 mL, 5.84 mmol),
alanine derived azlactone (1.00 g, 5.84 mmol), THF (15 mL)
and 1-naphthyl chloroformate (0.94 mL, 5.60 mmol) gave the
crude product as a yellow oil. Crystallisation (Et2O : petrol) g◦ave
the product as a colourless solid (1.21 g, 66%). mp 120–122 C;
dH (400 MHz, CDCl3) 8.07–8.04 (1H, m, ArH), 7.94–7.91 (3H,
m, ArH), 7.84–7.80 (1H, m, ArH), 7.64–7.55 (2H, m, ArH),
4214 | Org. Biomol. Chem., 2011, 9, 4205–4218
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7.51–7.50 (2H, m, ArH), 6.97–6.94 (2H, m, MeOArH-2,6), 3.85
(3H, s, OCH3) and 2.23 (3H, s, CH3); dC (100 MHz, CDCl3)
161.5 (MeOArC), 155.3 (ArC), 150.3 (ArC), 146.6 (ArC), 145.6
(ArC), 134.8 (ArC), 128.3 (ArCH), 127.7 (ArCH), 127.2 (ArCH),
127.1 (ArCH), 127.0 (ArCH), 126.1 (ArC), 125.4 (ArCH), 120.6
(ArCH), 120.4 (ArC), 119.9 (ArC), 117.3 (ArC), 114.3 (ArCH),
55.5 (OCH3) and 10.6 (CH3); m/z MS (NSI+) 432 (100, [M + H]+),
C
N), 158.4 (BnOArC-1), 150.4 (OPhC-1), 137.0 (CH2PhC-1),
131.8 (ArCH), 130.4 (ArCH), 129.7 (ArCH), 128.7 (ArCH), 128.1
(ArCH), 127.6 (ArCH), 126.7 (ArCH), 125.2 (MeOArC-4), 121.3
(ArCH), 117.4 (BnOArC-4), 114.8 (OArCH-2,6), 114.5 (OArCH-
2,6), 77.8 (C-3), 70.0 (OCH2), 55.7 (OCH3) and 39.7 (BnOAr–
CH2); m/z MS (ESI+) 508 (10, [M + H]+), 135 (38, ArC O+) and
95 (100); HRMS (ESI+) C31H26NO6 ([M + H]+) requires 508.1763,
found 508.1760 (+0.6 ppm); IR nmax (thin film)/cm-1 3064 (CH),
3035 (CH), 2935 (CH), 2841 (CH), 1823 (C O), 1766 (C O),
1647, 1609, 1512, 1493, 1325, 1307 and 1262 (C–O).
+
HRMS (NSI+) C25H22NO6 requires 432.1442, found 432.1434,
(-1.8 ppm); IR nmax (KBr)/cm-1 1784 (C O), 1670 (Ar C C),
1615 (C N), 1498, 1467, 1396, 1255 (C–O), 1224 (C–O) and 1173
(C–O).
Naphthalen-1-yl 2-(4-methoxyphenyl)-4-(4-((naphthalen-1-yloxy)-
carbonyloxy)benzyl)-5-oxo-4,5-dihydrooxazole-4-carboxylate 46
Naphthalen-1-yl 2-(4-methoxyphenyl)-4-methyl-5-oxo-4,5-
dihydrooxazole-4-carboxylate 42
Following a stoichiometric modification to general procedure F,
N-p-anisoyl-DL-tyrosine (284 mg, 0.900 mmol), 1-naphthyl chlo-
roformate (0.730 mL, 4.50 mmol), Et3N (0.690 mL, 4.95 mmol),
triazolium salt 2 (12.3 mg, 0.045 mmol) and THF (4 mL), gave,
after chromatographic purification (20% EtOAc : petrol), the ester
( )-46 as a colourless oil (373 mg, 65%). dH (300 MHz, CDCl3)
8.09–8.06 (1H, m, ArH), 7.94–7.88 (2H, m, MeOArH-3,5), 7.83–
7.78 (2H, m, ArH), 7.63–7.41 (10H, m, ArH) 7.34–7.26 (3H,
m, ArH), 7.00–6.95 (2H, m, MeOArH-2,6), 3.88 (1H, ABd, J
13.8, ArCHAHB), 3.87 (3H, s, OCH3) and 3.74 (1H, ABd, J
13.7, ArCHAHB); dC (75 MHz, CDCl3) 174.0 (COOCR2), 164.6
(MeOArC-1), 163.9 (COOAr), 163.8 (ArC), 151.9 (ArC), 150.7
(ArC), 146.8, (ArC), 134.7 (ArC), 131.9 (ArCH), 131.2 (ArC),
130.4 (ArCH), 128.14 (ArCH), 128.07 (ArCH), 127.1 (ArCH),
126.9 (ArCH), 126.8 (ArCH), 126.6 (ArCH), 126.5 (ArCH), 126.5
(ArC), 126.4 (ArC), 125.4 (ArCH), 125.3 (ArCH), 121.0 (ArCH),
120.9 (ArCH), 117.9 (ArCH), 117.5 (ArC), 117.1 (ArC), 114.5
(MeOArC-2,6), 77.7 (C–N), 55.6 (OCH3) and 39.4 (Ar–CH2);
m/z MS (CI+) 638.2 (100, [M + H]+); HRMS (ESI+) C39H28O8N+
([M + H]+) requires 638.1809, found 638.1807 (-0.4 ppm); IR nmax
(KBr)/cm-1 3058, 3011, 2937, 2841, 1822 (C O), 1776 (C O),
1742 (C O), 1654 (C N), 1605 (Ar C C), 1574, 1508, 1495 (Ar
Following general procedure F, N-p-anisoyl-DL-alanine (200 mg,
0.896 mmol), Et3N (0.436 mL, 3.14 mmol), 1-naphthyl chlorofor-
mate (0.436 mL, 2.69 mmol), triazolium salt 2 (12.2 mg, 44.8 mmol)
and THF (2 mL) gave, after chromatographic purification (20%
Et2O : petrol), ester ( )-42 as a colourless oil (235 mg, 70%). dH
(400 MHz, CDCl3) 8.10–8.06 (2H, m, MeOArH-3,5), 7.88–7.83
(2H, m, NapH-5,8), 7.75 (1H, br d, J 8.3, NapH-4), 7.52–7.48
(2H, m, NapH-6,7), 7.44 (1H, t, J 7.9, NapH-3), 7.28 (1H, dd, J
7.6, 1.0, NapH-2), 7.04–7.01 (2H, m, MeOArH-2,6), 3.90 (3H, s,
OCH3) and 1.95 (3H, s, CH3); dC (100 MHz, CDCl3) 175.5
(COOCR2), 165.0 (COOAr), 164.0 and 163.8 (MeOArC-1 and
C
N), 146.1 (NapC-1), 134.7 (NapC-4a), 130.5 (MeOArCH-
3,5), 128.1 (NapCH-5), 127.0 (NapCH), 126.9 (NapCH), 126.8
(NapCH), 126.4 (NapC-8a), 125.3 (NapCH-3), 121.0 (NapCH-
8), 117.9 (NapCH-2), 117.5 (MeOArC-4), 114.6 (MeOArCH-2,6),
73.2 (MeC(COOAr)), 55.7 (OCH3) and 20.6 (CH3); m/z MS
(ESI+) 408 (100, [M + MeOH - H]+); HRMS (ESI+) C23H22NO6
+
([M + MeOH + H]+) requires 408.1442, found 408.1440 (-0.5
ppm); IR nmax (thin film)/cm-1 3057, 3009, 2937, 2842, 1826
(C O), 1772 (C O), 1645 (C N), 1608, 1308, 1262 (C–O) and
1221 (C–O).
C
C), 1442, 1391, 1302, 1263 (C–O), 1229 (C–O), 1202 (C–O)
and 1154 (C–O).
Phenyl 4-(4-benzyloxyphenyl)-2-(4-methoxyphenyl)-5-oxo-4,5-
dihydrooxazole-4-carboxylate 45
(S)-5-Benzyl-2-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[3,4-
c][1,4]oxazin-2-ium tetrafluoroborate 49
Following general procedure E, N-p-anisoyl-DL-(O-benzyl)-
tyrosine (200 mg, 0.493 mmol), DCC (103 mg, 0.498 mmol),
triazolium salt 2 (7.04 mg, 0.0258 mmol), THF (2 mL), Et3N
(104 mL, 0.747 mmol), and phenyl chloroformate (72.0 mL,
0.641 mmol) gave, after chromatography (20% Et2O : petrol), ester
( )-45 as a colourless oil (210 mg, 84%).
Following general procedure F, N-p-anisoyl-DL-(O-benzyl)-
tyrosine (200 mg, 0.493 mmol), Et3N (0.241 mL, 1.73 mmol),
triazolium salt 2 (6.73 mg, 0.0247 mmol), THF (2 mL) and
phenyl chloroformate (0.165 mL, 1.48 mmol) gave, after chro-
matography (10% Et2O : petrol), ester ( )-45 as a colourless oil
(210 mg, 84%).
dH (300 MHz, CDCl3) 7.84–7.78 (2H, m, MeOArH-3,5), 7.33–
7.21 (7H, m, ArH), 7.20–7.14 (1H, m, ArH), 7.14–7.07 (2H, m,
ArH), 7.04–7.00 (2H, m, ArH), 6.89–6.84 (2H, m, MeOArH-
2,6), 6.77–6.71 (2H, m, BnOArH-2,6), 4.89 (2H, s, PhCH2), 3.78
(3H, s, OCH3), 3.59 (1H, ABd, J 13.8, BnOArCHAHB) and 3.47
(1H, ABd, J 13.8, BnOArCHAHB); dC (100 MHz, CDCl3) 173.8
(COOCR2), 164.7 (COOPh), 163.8 and 163.3 (MeOArC-1 and
To a mixture of sodium borohydride (2.60 g, 68.8 mmol) in THF
(80 mL) was added L-phenylalanine (5.00 g, 30.2 mmol). The
mixture was cooled to 0 ◦C and a solution of iodine (7.67 g,
30.2 mmol) in THF (20 mL) was added dropwise over 40 min.
After gas evolution had ceased, the reaction was heated at reflux
(80 ◦C) for 18 h. When the reaction had cooled to ambient
temperature, MeOH was added slowly until the solution became
clear and the mixture was stirred for a further 30 min. The mixture
was concentrated in vacuo to afford a colourless paste, which
was redissolved in KOH(aq) (20% w/v, 100 mL) with stirring
over 4 h. The mixture was extracted with CH2Cl2 (150 mL ¥
2), the organics layers were combined, dried (Na2SO4), filtered
and concentrated in vacuo to afford the crude product as a
colourless solid. Recrystallisation from Et2O gave the product
(S)-phenylalaninol◦as a colourless solid (2.49 g, 55%). mp 88–
◦
90 C, lit.38 86–88 C; [a]D20 -22.3 (c 1.01, CHCl3), lit.38 -21.7 (c
1.0, CHCl3); dH (400 MHz, CDCl3) 7.36–7.18 (5H, m, PhH), 3.66
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(1H, ABX, JAB 10.6, JAX 3.9, CHAHBOH), 3.41 (1H, ABX, JBA
10.6, JBX 7.2, CHAHBOH), 3.18–3.11 (1H, m, CHNH2), 2.82 (1H,
ABX, JAB 13.5, JAX 5.2, PhCHAHB), 2.55 (1H, ABX, JBA 13.5, JBX
8.6, PhCHAHB) and 1.79 (2H, br s, NH2). Data are in accordance
with the literature.38
2969, 1585 (C N), 1536, 1497 (Ar C C), 1469, 1118 (C–O) and
1054 (br).
Acknowledgements
To a cooled (0 ◦C) solution of (S)-phenylalaninol (500 mg,
3.31 mmol) and Et3N (1.38 mL, 9.92 mmol) in CH2Cl2 (10 mL)
was added chloroacetyl chloride (0.28 mL, 3.47 mmol) dropwise.
The mixture was warmed to ambient temperature over 16 h then
sat NaHCO3(aq) (10 mL) added and the mixture extracted with
CH2Cl2 (20 mL ¥ 3). The organics were combined and washed
with 1 M H2SO4(aq) (10 mL), H2O (10 mL) and brine (10 mL),
then dried (Na2SO4), filtered and concentrated in vacuo to afford
the crude amide intermediate as a brown oil which was used
immediately in the subsequent step. The product was redissolved
in THF (10 mL) and cooled to 0 ◦C before addition of potassium
tert-butoxide (405 mg, 3.61 mmol). The mixture was warmed to
ambient temperature over 90 min then concentrated in vacuo
then partitioned between EtOAc (10 mL) and brine (10 mL).
The aqueous fraction was extracted with EtOAc (10 mL ¥ 2),
then the combined organic fractions was dried (MgSO4), filtered
and concentrated in vacuo to afford the crude morpholinone
product. Chromatographic purification (40% EtOAc : petrol) gave
the◦morpholinone as a colourless solid (420 mg, 66%). mp 85–
The authors would like to thank the Royal Society for a Uni-
versity Research Fellowship (ADS), The Carnegie Trust for the
Universities of Scotland for a scholarship (CDC), The EPSRC
(CJC), EaStCHEM and the University of St Andrews (JET) for
funding, and the EPSRC National Mass Spectrometry Service
Centre (Swansea).
Notes and references
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Bertrand, Chem. Rev., 2000, 100, 39–92; W. A. Herrmann, Angew.
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Nolan, Eur. J. Inorg. Chem., 2005, 10, 1815–1828.
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Angew. Chem., Int. Ed., 2001, 40, 3726–3748; P. I. Dalko and L. Moisan,
Angew. Chem., Int. Ed., 2004, 43, 5138–5178; A. M. Walji and D. W. C.
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S. L. Riches and V. K. Aggarwal, Chem. Rev., 2007, 107, 5841–5883.
3 For select reviews of NHCs in organocatalysis see D. Enders, O.
Niemeier and A. A. Henseler, Chem. Rev., 2007, 107, 5606–5655;
N. Marion, S. D´ıez-Gonza´lez and S. P. Nolan, Angew. Chem., Int.
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Chemistry, Vol. 291 (Ed.: B. List), Springer, Berlin, 2009, pp. 77–144;
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in Transition Metal Catalysis and Organocatalysis, Catalysis by Metal
Complexes 32 (Ed.: C. S. J. Cazin), Springer, Berlin, 2010, pp. 263–297.
4 For select examples see (a) J. H. Teles, J.-P. Melder, K. Ebel, R.
Schneider, E. Gehrer, W. Harder, S. Brode, D. Enders, K. Breuer and
G. Raabe, Helv. Chim. Acta, 1996, 79, 61–83; (b) M. S. Kerr, J. Read
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◦
87 C, lit.39 86–87 C; [a]2D0 +4.2 (c 1.0, MeOH), lit.39 +4.0 (c
0.66 MeOH); dH (400 MHz, CDCl3) 7.33–7.16 (5H, m, PhH),
5.89 (1H, br s, NH), 4.22 (1H, ABq, J 17.8, OCHAHBCO), 4.19
(1H, ABq, J 17.8, OCHAHBCO), 3.88 (1H, ABX, JAB 11.5, JAX
3.8, OCHAHBCH), 3.77 (1H, ddd, J 9.2, 5.8, 3.8, NHCH), 3.46
(1H, ABX, JBA 11.5, JBX 5.8, OCHAHBCH), 2.85 (1H, ABX, JAB
13.5, JAX 5.8, CHAHBPh) and 2.70 (1H, ABX, JBA 13.5, JBX 9.2,
CHAHBPh). Data are in accordance with the literature.39 To a
solution of lactam (400 mg, 2.09 mmol) in CH2Cl2 (12 mL) was
added trimethyloxonium tetrafluoroborate (337 mg, 2.28 mmol)
and the mixture was stirred for 16 h. To the mixture was then added
phenylhydrazine (0.206 mL, 2.09 mmol) and the mixture was
stirred for 20 h. The mixture was then concentrated in vacuo and
redissolved in MeOH (1.5 mL) and triethyl orthoformate (4.5 mL).
The mixture was heated at reflux (110 ◦C) for 16 h then cooled
to ambient temperature, whereby the product had precipitated
(in the event of no precipitation, the mixture was concentrated in
vacuo, redissolved in EtOAc (5 mL), then Et2O (1 drop) was added
to induce precipitation). The product was collected by filtration
and washed with cold (-78 ◦C) EtOAc (~5 mL) to afford the
triazolium salt 49 as a pale peach solid (230 mg, 29%). mp 190–
◦
195 C; [a]2D0 -18.1 (c 0.8, MeOH); dH (400 MHz, d6-DMSO)
10.91 (1H, s, NCHN), 7.90–7.88 (2H, m, PhH), 7.76–7.71 (2H,
m, PhH), 7.71–7.65 (1H, m, PhH-4), 7.43–7.40 (2H, m, NPhH-2),
7.36–7.32 (3H, m, NPhH), 5.23 (1H, ABq, J 16.2, OCHAHB),
5.15 (1H, ABq, J 16.2, OCHAHB), 4.85 (1H, app dq, J 9.7,
5.9, BnCH), 4.01–3.93 (2H, m, OCH2CHBn), 3.50 (1H, ABX,
JAB 13.6, JAX 5.9, PhCHAHB) and 3.18 (1H, ABX, JBA 13.6, JBX
9.7, PhCHAHB); dC (100 MHz, d6-DMSO) 149.9 (NCHN), 135.1
(N C), 134.9 (NArC-1), 134.9 (CH2PhC-1), 130.8 (ArCH-4),
130.4 (ArCH), 129.5 (ArCH), 129.0 (ArCH), 127.5 (ArCH), 120.7
(ArCH), 65.1 (OCH2), 61.5 (OCH2), 56.3 (NCH) and 37.5 (Ph-
CH2); m/z MS (ESI+) 292 (100, [M - BF4]+); HRMS (ESI+)
C18H18ON3+ ([M - BF4]+) requires 292.1444, found 292.1443 (-0.4
ppm); IR nmax (KBr)/cm-1 3337, 3141, 3060 (Ar C–H), 3026, 2987,
5 For examples see (a) C. Burstein and F. Glorius, Angew. Chem., Int. Ed.,
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15 For an excellent recent review of Lewis-base mediated reaction
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16 For Lewis-base catalysed processes using isothioureas see (a) C.
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18 For asymmetric versions of this reaction see (a) J. C. Ruble and G. C. Fu,
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20 S. S. Sohn and J. W. Bode, Org. Lett., 2005, 7, 3873–3876; J.
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22 Peris and Vedejs have recently demonstrated a related diastereoselective
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this transformation as it is employed both as a base and nucleophilic
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23 For other examples of a related procedure involving stoichiometric
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8 C. Bakhtiar and E. H. Smith, J. Chem. Soc., Perkin Trans. 1, 1994,
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25 The Supporting Information contains the X-ray crystal structures of
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Centre as supplementary publication numbers CCDC 809724, CCDC
809725 and CCDC 809726.
26 Rearrangement of 15 and 16 using 2 (10 mol%) and NEt3 (100 mol%)
gave, at >95% and ~90% conversion, a 75 : 25 and 66 : 34 mixture of
carbonate to the corresponding azlactone respectively.
observed. This reaction profile is consistent with oxazolyl carbonate 4
being an intermediate in this reaction pathway rather than direct C-
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27 Within experimental error this product distribution (as determined
1
by H NMR spectroscopic analysis of the crude reaction product) is
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28 R. W. Alder, M. E. Blake, C. Bortolotti, S. Bufali, C. P. Butts, E.
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30 An authentic sample of carbamate 43 was prepared by treatment of
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36 Attempts to use diphenyl carbonate as an alternative to phenyl
chloroformate to generate oxazolyl carbonates from azlactones in the
presence of NEt3 only returned starting material.
31 In each case, the crude reaction product contained ~10% of either
diethyl phenyl or diethyl 1-naphthyl carbamate 43 or 44.
32 Monitoring the progress of this two-step domino reaction sequence
37 M. S. Kerr, J. Read de Alaniz and T. Rovis, J. Am. Chem. Soc., 2002,
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1
by H NMR spectroscopic analysis commencing from phenylalanine
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derived azlactone indicated full conversion to oxazolyl carbonate 4 as
the sole reaction product after short reaction times (1 to 15 min), with
subsequent slow rearrangement of carbonate 4 to give C-carboxyl-5
39 J. Hlavacek, J. Marik, J. Konvalink, B. Bennetova and R. Tykua, Amino
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