Combination of Enabling Technologies to Improve and Describe the Stereoselectivity of Wolff-Staudinger Cascade Reaction

Article abstract of DOI:10.1055/s-0035-1562579

A new, single-mode bench-top resonator was evaluated for the microwave-assisted flow generation of primary ketenes by thermal decomposition of α-diazoketones at high temperature. A number of amides and β-lactams were obtained by ketene generation in situ and reaction with amines and imines, respectively, in good to excellent yields. The preferential formation of trans-configured β-lactams was observed during the [2+2] Staudinger cycloaddition of a range of ketenes with different imines under controlled reaction conditions. Some insights into the mechanism of this reaction at high temperature are reported, and a new web-based molecular viewer, which takes advantage from Augmented Reality (AR) technology, is also described for a faster interpretation of computed data.

Full text of DOI:10.1055/s-0035-1562579

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–L
paper
A
B. Musio et al.
Paper
Synthesis
Combination of Enabling Technologies to Improve and Describe
the Stereoselectivity of Wolff–Staudinger Cascade Reaction
B. Musioa
F. Mariania,b
E. P. Śliwińskia
M. A. Kabeshova
H. Odajimac
S. V. Ley*a
a University of Cambridge, Department of Chemistry, Lensfield
Road, Cambridge, CB2 1EW, UK
svl1000@cam.ac.uk
b Universitat de Barcelona, Laboratori de Química Orgànica, Fac-
ultat de Farmàcia, Av. Joan XXIII s/n, 08028 Barcelona, Spain
c Saida FDS, 143-10 Itsushiki, Yaizu-shi, Shizuoka Prefecture
4250054, Japan
Received: 11.07.2016
Accepted after revision: 07.08.2016
Published online: 10.08.2016
microwave chemistry suffers from lack of reproducibility
during scale-up, owing to increased heat loss, changes in
absorption, limited penetration depth of the radiation and
additional reflection of the microwaves.12 Since the first-
generation of flow-microwave reactor introduced in 1990,13
great efforts have been made to design modern flow micro-
wave reactors that could be applied to industrial scale.14 In
particular, some of the instruments introduced so far are
defined by high level of control, reproducibility and safety,
thanks to the integration of accurate temperature and pres-
sure monitoring. Nevertheless, further research is needed to
improve the energy efficiency, the capacity, the tempera-
ture and pressure window of operation, and the cost of any
newly introduced microwave flow reactor.
DOI: 10.1055/s-0035-1562579; Art ID: ss-2016-z0490-op
Abstract A new, single-mode bench-top resonator was evaluated for
the microwave-assisted flow generation of primary ketenes by thermal
decomposition of α-diazoketones at high temperature. A number of
amides and β-lactams were obtained by ketene generation in situ and
reaction with amines and imines, respectively, in good to excellent
yields. The preferential formation of trans-configured β-lactams was ob-
served during the [2+2] Staudinger cycloaddition of a range of ketenes
with different imines under controlled reaction conditions. Some in-
sights into the mechanism of this reaction at high temperature are re-
ported, and a new web-based molecular viewer, which takes advantage
from Augmented Reality (AR) technology, is also described for a faster
interpretation of computed data.
Herein, we wish to report a new multidisciplinary ap-
proach to solve a chemical synthesis problem by using a
combined armoury of some new enabling technologies to
achieve sustained high-temperature processes with im-
proved reaction selectivity, which can be mechanistically
rationalised through computational methods and finally vi-
sualised by a new web-based molecular viewer employing
Augmented Reality (AR) technology. While most publica-
tions to date choose to isolate these individual components,
we feel that many synergistic benefits accrue by taking a
more holistic modern approach to a problem.
The well-known and extensively studied Wolff–
Staudinger reactions to afford β-lactams via [2+2] cycload-
dition of ketenes with imines is a case in point. While
achievable under a variety of conditions with a wide sub-
strate scope, stereoselectivity and scale-up can be problem-
atic for this transformation. In particular, the high tempera-
ture and release of gaseous nitrogen as a by-product upon
Wolff rearrangement of α-diazocarbonyl compounds to
produce intermediate ketenes is seen as a hazardous trans-
formation15 despite the value of the final β-lactam cycload-
dition products.
Key words microwave, Wolff, Staudinger, flow, Augmented Reality,
molecular visualisation
There is a considerable interest in developing more en-
ergy efficient, safer and more flexible chemical processes,
which meet competitive sustainability challenges.1 Micro-
reactor technology and flow chemistry can be considered
under the umbrella of strategies for process intensification,2
as demonstrated by their popularity both in academia and
in industry.3 More importantly, the possibility of combining
continuous-flow technology with other enabling technolo-
gies leads to autonomous processes and increased through-
put.4 There is now a plethora of examples describing the ad-
vantages arising from the combination of flow chemistry
with heterogeneous catalysis,5 photochemistry,6 electro-
chemistry,7 ultrasound,8 etc.
In particular, high temperature and high pressure chem-
ical transformations can be derived from the synergic bene-
fits of microwave irradiation9 and continuous-flow technol-
ogy,10 as demonstrated by several applications reported
during the last decade.11 Indeed, the traditional batch-type
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B. Musio et al.
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Synthesis
In the first phase of the program we examined the heat-
ing efficiency of a recently developed single-mode bench-
top continuous-flow microwave apparatus16 for the im-
proved generation of primary ketenes from α-diazoketones
by Wolff rearrangement at high temperature. We tested the
reproducibility of the equipment to function over an ex-
tended period of time, monitoring some crucial parameters
in real time. A good ratio between the irradiating power
and the reflecting power was observed, showing a good ef-
ficiency of the system in maintaining constant field
strength (Figure 1a).17
Pressure regulators installed in front and back-end of
the flow borosilicate glass reactor allowed an accurate con-
trol of the pressure inside the system (Figure 1b). The mon-
itoring of the temperature under classical sealed-vessel
microwave conditions is often not easy, because classical
direct temperature sensors such as thermometers or
thermocouples can interfere with the electromagnetic
field.18 In our flow microwave set-up, the temperature in-
side the reactor could be continuously monitored by using a
thermocouple installed at the exit of the coil, without af-
fecting the uniformity of the electromagnetic field. Once
the steady state was reached, an impressive stability of the
temperature was recorded (Figure 1c). The maximum tem-
perature reached was dependent on the irradiating power
and on the residence time of the solution inside the irradi-
ating cavity. The steady state was reached faster at higher
flow rate, thus at low residence time (Figure 1d). This is in
accordance with the reported studies on the efficiency of
energy transfer of the microwave irradiation into heat,
which can be affected by the additional reflection of the
microwaves inside the irradiation cavity.17 To assess the re-
liability of the temperature measurement by the thermo-
couple, a sequence of thermal images were captured over
the time. For this purpose, a thermal camera was directed
at a slit positioned on one wall of the microwave cavity,
containing the reactor tube. A uniform temperature distri-
bution was reached after a few minutes throughout the bo-
rosilicate glass reactor (for more details see the Supporting
Information).
Figure 1 (a) Irradiating power and reflecting power over 1 h. Solvent: acetonitrile; flow rate: 1.0 mL/min; back pressure regulator (BPR): 20 bar. (b) Inlet
pressure and outlet pressure over 1 h. Solvent: acetonitrile; flow rate: 1.0 mL/min; back pressure regulator (BPR): 20 bar. (c) Temperature measured by
a thermocouple at the exit of the reactor over 1 h. Solvent: acetonitrile; flow rate: 1.0 mL/min; back pressure regulator (BPR): 20 bar. (d) Temperature
measured by a thermocouple at the exit of the reactor at different flow rate (0.5, 1.0, 1.5, 2.0 and 3.0 mL/min). Solvent: acetonitrile; back pressure
regulator (BPR): 20 bar.
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B. Musio et al.
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Synthesis
ticularly with regard to the stereoselective outcome. A
number of differently substituted α-diazoketones and
imines were reacted under the above optimised reaction
conditions for the synthesis of amides (solvent: MeCN; flow
rate 0.5 mL/min per pump; irradiating power: 80 W; tem-
perature: 165 °C).
When aliphatic, aryl and heteroaryl α-diazoketones 1e–
i were reacted with N-benzylidene benzylamine (E)-5a, a
range of β-lactams 6a–e were obtained in good yields (up to
85%) and with high comparable diastereoselectivity
(Scheme 2).
[3a–f]
O
20 bar
O
R1
A
NHBn
N2
R1
80 W, 165 °C
1a–f
4a, R1 = (4-CF3)C6H4, 65%
4b, R1 = 4-FC6H4, 92%
4c, R1 = Naph, 80%
4d, R1 = Ph, 81%
4e, R1 = (4-MeO)C6H4, 99%
4f, R1 = Me, 99%
T
R 7.0 min
B
0.06 M in MeCN
0.5 ml/min
BnNH2
2
0.125 M in MeCN
0.5 ml/min
Scheme 1 Continuous-flow microwave-assisted Wolff rearrangement
of α-diazoketones 1a–f and trapping of ketene 3a–f in situ with benzyl-
amine 2.
The specific substitution pattern of the imine was also
evaluated by reacting imines (E)-5a–m with one specific α-
diazoketone 1e, affording β-lactams 6a and 6g–r (13 exam-
ples, Scheme 2). A preferential formation of trans-config-
ured β-lactams was observed in all these cases, with the ex-
ception of 6j (dr trans/cis 1:16.4), 6k (dr trans/cis 1.1:1) and
6r (dr trans/cis 1:1). The size of the substituent at the nitro-
gen atom of the imine likely affected the stereochemical
outcome of the [2+2] Staudinger cycloaddition. The prefer-
ential formation of trans-configured β-lactams was ob-
served for 6g (R2 = Me) and 6h (R2 = n-Bu). When imine (E)-
5d (R2 = i-Pr, R3 = Ph) was reacted with ketene 1e, β-lactam
6i was formed as a mixture of trans- and cis-configured
products (dr trans/cis 3.2:1). Interestingly, when the imine
(E)-5e (R2 = t-Bu, R3 = Ph), containing a bigger substituent at
the nitrogen atom, was reacted with 1e, the formation of
the β-lactam 6j proceeded stereoselectively in favour of the
cis-configured product (dr trans/cis 1:16.4). Similar effect of
the size of the substituent at the nitrogen of the imine was
observed during the formation of N-benzyl β-lactams 6a
and 6r. The [2+2] Staudinger cycloaddition reaction pro-
ceeded stereoselectively (dr trans/cis 24:1) and in high
yields (85%) for 1e (R1 = (4-MeO)C6H4) with (E)-5a (R2 = Bn,
R3 = Ph), giving 6a. In contrast, β-lactam 6r was obtained in
poor yield (30%) and with no diastereoselectivity (dr
trans/cis 1:1) by reaction of 1e [R1 = (4-MeO)C6H4] with
(E)-5m (R2 = CHPh2, R3 = Ph).
The new equipment was applied to the generation of
ketene from α-diazoketone followed by trapping in situ
with benzylamine (Scheme 1). The solvent, the reagent
concentration, the irradiation power and the flow rate were
accurately adjusted to reduce collateral reactions arising
from the extremely high reactivity of the heated ketenes.19
The best results were observed when the reaction mixture
in acetonitrile was passed through the reactor at 1.0
mL/min and heated at 165 °C by irradiating with a power of
80 W. Thus a solution (0.06 M in acetonitrile) of different α-
diazoketones 1a–f was pumped and then mixed with a
solution of benzylamine 2 (0.125 M in acetonitrile) before
passing through the helical tubular borosilicate glass reac-
tor contained in the microwave cavity. The resulting amides
4a–f were isolated in good yields (65–99%) after passing
through the reactor at 1 mL/min (residence time = 7 min-
utes) and heated at 165 °C by 80 W irradiation.
The safety and the reliability of the system during the
reaction scale-up were evaluated by attempting a continu-
ous multigram synthesis of amide 4f. The crucial parame-
ters (temperature and pressure) were stable over the reac-
tion time, and the preparation of 4f was accomplished in 7
h, with no need for further purification (15 mmol, 2.4 g).
Interestingly, similar results were not observed when
the same reaction was performed under standard sealed
vessel microwave conditions. Attempts to generate the
ketenes through more conventional conductive heating in
flow were also performed. The reagent mixture was passed
continuously through a stainless steel coil under different
reaction conditions (solvent, temperature, flow rate). In all
the cases, both lower conversion and poorer selectivity
were observed, thereby further demonstrating the efficien-
cy of the new microwave flow set-up. Our group recently
reported on the flow reaction of imines with mono-alkyl
and phenyl ketenes, generated by zinc-mediated dehaloge-
nation of α-bromo acyl bromides at room temperature, to
provide β-lactams. The final products were obtained in
good yields but with variable diastereomeric ratios.20 In an
attempt to demonstrate the beneficial effect of a rapid mi-
crowave-assisted heating of the reagents, we decided to ap-
ply the above protocol of the Wolff generated ketenes in
combination with a Staudinger cycloaddition reaction par-
The effect of the substitution at the sp2 carbon of the
imine was also considered, reacting diazoketone 1e with
different N-benzylideneimines (E)-5g–j under our
conditions. When the electron-rich imine (E)-5i (R2 = Ph,
R3 = (4-MeO)C6H4) was reacted with 1e, β-lactam 6m was
obtained in good yield (61%) and high diastereomeric ratio
(dr trans/cis 9:1). However, when electron-poor imines
(E)-5g (R2 = Ph, R3 = pyridin-2-yl) and (E)-5j [R2 = Ph,
R3 = (4-FC3)C6H4] were employed under the same reaction
conditions, the resulting β-lactams 6l and 6o were formed
in lower yields (respectively 56% and 47%) and lower diaste-
reomeric ratio (respectively dr trans/cis 3.8:1 for 6l and 5:1
for 6o). To demonstrate the additive effect of the substitu-
tion at the nitrogen atom and the substituent at the sp2 car-
bon of the imine, ketene 1e was reacted with imine (E)-5f
(R2 = i-Pr, R3 = pyridin-2-yl). The resulting β-lactam 6k was
obtained with low diastereoselectivity (dr trans/cis 1.1:1),
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D
B. Musio et al.
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Synthesis
O
1e, R1 = (4-MeO)C6H4
N2
1f, R1 = Me
R1
A
B
R2
R3
O
1g, R1 = t-Bu
0.06 M MeCN
0.5 ml/min
N
20 bar
1h, R1 = benzofuran-2-yl
1i, R1 = pyridin-3-yl
R1
N
R3
80 W, 165 °C
6a–r
R2
0.125 M MeCN
0.5 ml/min
(E)-5a, R2 = Bn, R3 = Ph
(E)-5h, R2 = Ph, R3 = Ph
(E)-5b, R2 = Me, R3 = Ph
(E)-5i, R2 = Ph, R3 = (4-MeO)C6H4
(E)-5j, R2 = Ph, R3 = (4-F3C)C6H4
(E)-5c, R2 = n-Bu, R3 = Ph
(E)-5d, R2 = i-Pr, R3 = Ph
(E)-5e, R2 = t-Bu, R3 = Ph
(E)-5f, R2 = i-Pr, R3 = pyridin-2-yl
(E)-5g, R2 = Ph, R3 = pyridin-2-yl
(E)-5k, R2 = (4-MeO)C6H4, R3 = (4-Cl)C6H4
(E)-5l, R2 = Naph, R3 = Ph
(E)-5m, R2 = (CH)Ph2, R3 = Ph
Bn
Ph
O
Bn
O
Bn
Ph
O
Bn
Ph
O
Bn
Ph
O
i-Pr
O
N
N
N
N
N
N
O
PMP
Ph
t-Bu
Ph
N
6a
6b
6c
6d
6e
6f
trans/cis 24:1
trans/cis 3:1
trans/cis 11.6:1
trans/cis 15.7:1
trans/cis 19:1
trans/cis 8:1
85%
61%
84%
61%
43%
65%
i-Pr
O
Me
Ph
O
n-Bu
O
i-Pr
O
t-Bu
O
Ph
O
N
N
N
N
N
N
N
N
PMP
PMP
Ph
PMP
Ph
PMP
Ph
PMP
PMP
6g
6h
6i
6j
6k
6l
trans/cis 24.8:1
trans/cis 6.9:1
trans/cis 3.2:1
trans/cis 1:16.4
trans/cis 1.1:1
trans/cis 3.8:1
63%
65%
68%
43%
77%
56%
Naph
Ph
O
Ph2HC
Ph
O
Ph
O
N
PMP
O
Ph
Ph
O
Ph
O
N
N
N
N
N
PMP
PMP
PMP
PMP
4-ClC6H4
6p
PMP
PMP
(4-F3C)C6H4
PMP
6o
6m
6n
6q
6r
trans/cis 5:1
trans/cis 9:1
trans/cis 19:1
trans/cis 9:1
trans/cis 13.3:1
trans/cis 1:1
47%
61%
77%
70%
32%
30%
Scheme 2 Microwave-assisted Wolff–Staudinger strategy with formation of β-lactams 6a–r in situ (PMP = p-methoxyphenyl).
confirming the crucial role of the substitution pattern of
the imine in controlling the stereochemical outcome of this
transformation.
quantum chemistry calculations have been used to describe
the system at high temperature. Therefore, we decided to
perform a computational analysis taking into account the
experimental conditions. According to the reported mecha-
nism of this transformation,22 the initial nucleophilic addi-
tion of imine 5 to ketene 3 would lead to the formation of a
zwitterionic intermediate, ZW, which, in the subsequent
cycloaddition step, would provide the final β-lactam 6
(Scheme 3). Firstly, the computational analysis aimed to
evaluate Gibbs activation energies of the nucleophilic addi-
tion of the two isomeric imines, (E)-5h and (Z)-5h
(R2 = R3 = Ph), to ketene 3e (R1 = (4-MeO)C6H4) in endo- and
exo-fashion at high temperature (165 °C). Irrespective of
the imine configuration, the exo-addition was found to have
These experimental results demonstrated that high di-
astereoselectivity in the Staudinger reaction can be
achieved under high-temperature conditions for a wide
range of α-diazoketones with appropriate imines. Further-
more, the high temperature reached in the flow-microwave
reactor, as recorded in our experiments, appears to be a
crucial parameter for the stereoselectivity of the reaction.21
To suggest a mechanistic model and ultimately to ra-
tionalise and predict the stereochemical outcome of the
[2+2] ketene-imine cycloaddition reaction at high tempera-
ture, computational studies at the Density Functional Theo-
ry (DFT) level were performed. A number of experimental
mechanistic studies22 of the [2+2] ketene-imine cycloaddi-
tion together with DFT level calculations23 were previously
reported. Nevertheless, to our knowledge, none of the
a
lower energy barrier than the endo-counterpart
(ΔG1# = 20.8 and ΔG3# = 20.4 kcal mol–1 vs. ΔG5# = 23.2 and
ΔG7# = 24.3 mol–1; Scheme 3). The subsequent conrotatory
ring-closure step was characterised with significantly high-
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Synthesis
ΔG‡6 = 38.9
Ph
Ar
Ph
N
kcal mol–1
trans-6m
–O
H
6m-ZW3
ΔG‡5 = 23.2
3e
endo
Ph
kcal mol–1
Ph
ΔG‡2 = 28.9
Ph
O
Ph
Ar
3e
N
kcal mol–1
Ph
N
H
Ph
exo
N
-O
Ar
(E)-5h
ΔG‡1 = 20.8
ΔG‡is = 19.9
kcal mol–1
6m-ZW1
cis-6m
kcal mol–1
Ph
ΔG‡9 = 41.9
kcal mol–1
Ph
N
Ph
3e
exo
Ph
O
Ph
Ar
N
N
Ph
H
ΔG‡3 = 20.4
ΔG‡4 = 27.5
(Z)-5h
kcal mol–1
–O
Ar
kcal mol–1
ΔG‡7 = 24.3
3e
endo
trans-6m
kcal mol–1
6m-ZW2
Ph
ΔG‡8 = 34.0
Ph
N
Ar
H
kcal mol–1
cis-6m
–O
6m-ZW4
Scheme 3 Possible reaction pathways for the formation of cis- and trans-lactams 6m by [2+2] imine-ketene cycloaddition reaction (Ar = (4-MeO)C6H4);
the Gibbs energies shown are Gibbs energies of activation where (E)-5h+3e is set as the ground state; barriers ΔG≠1, ΔG≠2, ΔG≠3, ΔG≠4, ΔG≠is, ΔG≠5, ΔG≠
,
6
ΔG≠7, ΔG≠8, ΔG≠9 correspond to the transition states 6m-TS1, 6m-TS2, 6m-TS3, 6m-TS4, 5h-TS, 6m-TS1-endo, 6m-TS2-endo, 6m-TS3-endo, 6m-TS4-endo,
6m-ZW-is; see the Supporting Information for 3D structures).
er energy barriers for the endo-addition paths than for the
exo-counterparts (ΔG6# = 38.9 kcal mol–1 for 6m-ZW3 and
ΔG8# = 34.0 kcal mol–1 for 6m-ZW4 vs. ΔG2# = 28.9 and
ΔG4# = 27.5 mol–1, respectively, for 6m-ZW1 and 6m-ZW2;
Scheme 3). Based on these results, the endo-addition path-
ways were discarded from further studies for other imines.
Among other possible pathways that may explain the for-
mation of stereoisomeric lactams 6m, the E/Z isomerisation
of the zwitterionic intermediates 6m-ZW1, and 6m-ZW2
was considered. This possibility was also disregarded be-
cause it would involve a rotation around the C=N bond,
which would require a high energy barrier (ΔG9# = 41.9 kcal
mol–1; Scheme 3). The C=N double bonds in the range of
imines and zwitterionic intermediates were characterised
with similar bond lengths (differences are within 1.5%; see
Table 1 in the Supporting Information). This evidence sug-
gested that they all have similar double bond character and
therefore similar rotation barriers.24
Gibbs energies of different (E)- and (Z)-imines (5b, 5d,
5e, 5h, 5l and 5m with R3 = Ph, R2 = Me, i-Pr, t-Bu, Ph, Naph,
and (CH)Ph2, respectively; 5f and 5g with R3 = Pyridin-2-yl,
R2 = i-Pr and Ph, respectively), were calculated at 165 °C,
finding the (E)-imines to be significantly more stable than
their (Z)-counterparts for all six cases. Two alternative
pathways were initially considered for the E/Z imine isom-
erisation: (1) through nucleophilic attack to the carbon of
the iminium double bond, followed by rotation and elimi-
nation; (2) through nitrogen inversion in the starting imine.
Given that the reaction was performed in acid- and metal-
free conditions using anhydrous aprotic solvent (acetoni-
trile), the first hypothesis was not comprehensively evalu-
ated. The second hypothetic pathway was studied deeper
and the transition state 5-TS with the linear configuration
of the C=N-R moiety was characterised for the most repre-
sentative cases.25
As expected, due to stabilisation of the linear configura-
tion by the aromatic system,26 the isomerisation of the
imines 5h, 5g and 5l were characterised with lower energy
barriers (ΔGis≠ 19.9, 23.2 and 18.5 kcal mol–1; Table 1) than
≠
other N-alkyl imines (ΔGis 28.2, 28.6, 25.8, 27.9, 27.0 for
5b, 5d, 5e, 5f and 5m, respectively; Table 1; for more details
see the Supporting Information).
The possibility of the trans–cis isomerisation of the
β-lactams through either retro-Staudinger cycloaddition27
or enolisation reactions was also considered. To verify
whether this side reaction occurs experimentally, a mixture
of 6r in acetonitrile (dr trans/cis 50:50) was treated under
our reaction conditions (power 80 W, temperature 165 °C).
1
The reaction mixture then was analysed by H NMR spec-
troscopy, revealing that the diastereomeric ratio of the
product mixture was unchanged with regard to the starting
β-lactams mixture. The fact that the ratio of the two prod-
ucts cis- and trans-6r remained the same could be ex-
plained either by assuming an established thermodynamic
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of zwitterionic intermediates (ΔG≠2 and ΔG≠4 for 6-ZW1 and
6-ZW2); E/Z imine 5 isomerisation (ΔG≠is; Table 1). These
values were used to choose the mechanistic model applica-
ble for the prediction of the diastereomeric ratios of the fi-
nal products 6. It was found that in all computed cases the
conrotatory ring closure of both zwitterionic intermediates
6-ZW1 and 6-ZW2 was characterised with significantly
higher barrier than the nucleophilic addition of the corre-
R3
R2
O
R3
R1
ΔG‡
R2
N
H
+ 3
– 3
1
ΔG‡
2
N
R2
N
R3
–O
R1
(E)-5
cis-6
6-ZW1
R3
N
ΔG‡
is
R2
R3
R1
ΔG‡
R3
ΔG‡
+ 3
– 3
3
N
R2
H
4
R2
sponding imine 5 to the ketene 3 (compare both ΔG≠ and
N
2
O
–O
6-ZW2
R1
ΔG≠4 against ΔG≠1 and ΔG≠ , accordingly; Table 1). Moreover,
3
(Z)-5
trans-6
the computed barrier for the ring closure of intermediate 6-
ZW1 derived from imine (E)-5 (ΔG≠ ; Table 1) was found to
Scheme 4 Suggested operational mechanism for the formation of cis-
and trans-lactams 6 by [2+2] imine–ketene cycloaddition reaction.
2
be either higher (Table 1, entries 1, 4, and 6–9) or similar
(Table 1, entries 2, 3, and 5) to the imine (E)-5 isomerisation
barrier (ΔG≠is; Table 1). Taking into account the low concen-
tration of ketene intermediate 3 in the reaction media, the
first-order trans–cis isomerisation of imines 5 is expected
to be much faster than the second-order [2+2] Staudinger
reaction between isomeric imines 5 and ketene 3. The Cur-
tin–Hammett principle29 could be applied and the expected
trans/cis ratios of β-lactams 6 could be calculated from
ΔΔG# of conrotatory ring closure steps. To confirm that the
Curtin–Hammett principle can be successfully applied to
predict trans/cis ratios for all studied cases, the diastereo-
meric ratios of the products 6 for the cases where imine
isomerisation and the lactam ring closure had similar reac-
tion barriers (compare ΔG2# and ΔGis# for Table 1, entries 2,
3, 5) were recalculated by using the differential rate law30
and the activation Gibbs energy of the ketene 3e formation
from the diazocompound 1e equal to 32.2 kcal mol–1 at
165 °C (see the Supporting Information for details). It was
found that both approaches give the same values for
trans/cis ratios, providing a good agreement with the ex-
perimental results.
equilibrium between the two species, or by the absence of
product interconversion. If the system was at thermody-
namic equilibrium, according to the DFT calculations, the
trans-configured product would be the prevailing compo-
nent in the reaction mixture (trans/cis ratio of 3:1, calculat-
ed from ΔGf (trans) = –15.8 and ΔGf (cis) = –14.6 kcal mol–1,
respectively). This theoretical finding, contradicting the ex-
perimental result (trans/cis ratio of 1:1), could be used to
rule out the trans/cis isomerisation of the lactams 6r as a
factor affecting the stereochemical outcome of the [2+2]
Staudinger cycloaddition reaction. The elementary reaction
steps of the [2+2] Staudinger cycloaddition28 were comput-
ed to elucidate the operational mechanism (Scheme 4).
The steady-state approximation29 could be applied to
describe the transformations of zwitterionic intermediates
6-ZW1 and 6-ZW2. The activation Gibbs energies of the key
elementary steps were computed for a number of cases ex-
hibiting different stereochemical outcome (Table 1): nucleo-
philic exo-addition of E/Z imines 5 to the ketene 3e (ΔG≠
1
and ΔG≠ for (E)- and (Z)-imines); conrotatory ring closure
3
Table 1 Predicted and Experimental Stereoselectivity of the [2+2] Staudinger Reaction (T = 165 °C)a
R1
R2
R3
ΔGis
ΔG1
ΔG2
ΔG3
ΔG4
ΔΔG≠b
trans/cis
trans/cis
≠
≠
≠
≠
≠
Entry
Comd
(calc.)c
(exp.)d
1
2
3
4
5
6
7
8
9
6f
Me
i-Pr
Ph
28.6
28.2
28.6
25.8
27.9
23.2
19.9
18.5
27.0
21.1
17.3
20.4
21.3
20.3
25.2
20.8
22.2
21.1
31.8
27.7
28.9
28.0
27.3
33.2
28.9
31.5
29.4
26.4
20.0
22.3
25.5
24.3
25.2
20.4
21.7
24.6
30.0
24.3
27.1
30.2
27.7
32.7
27.5
28.3
29.9
–1.8 (–1.8)
–3.4 (–2.8)
–1.8 (–1.0)
+2.2 (+2.4)
+0.4 (0.0)
8:1
8:1
6g
6i
(4-MeO)C6H4
(4-MeO)C6H4
(4-MeO)C6H4
(4-MeO)C6H4
(4-MeO)C6H4
(4-MeO)C6H4
(4-MeO)C6H4
(4-MeO)C6H4
Me
Ph
49:1
8:1
25:1
3:1
i-Pr
Ph
6j
t-Bu
i-Pr
Ph
1:12
1:2
1:16
1:1
6k
6l
py-2-yle
py-2-yl
Ph
Ph
–0.5 (–1.2)
–1.4 (–1.9)
–3.2 (–2.3)
+0.5 (0.0)
2:1
4:1
6m
6q
6r
Ph
5:1
9:1
Naph
(CH)Ph2
Ph
40:1
1:2
13:1
1:1
Ph
a The Gibbs energies shown are Gibbs energies of activation (expressed in kcal mol–1), where (E)-5+3 is set as the ground state; barriers ΔG≠1, ΔG≠2, ΔG≠3, ΔG≠
,
4
ΔG≠is correspond to the transition states 6-TS1, 6-TS2, 6-TS3, 6-TS4, 5-TS, respectively, in all computed cases; see the Supporting Information for 3D structures.
b Calculated by using the following formula: ΔΔG# = ΔG4# – ΔG2#. The values derived from experimental ratios are given in brackets.
c Calculated at T = 438 K (165 °C).
d Determined by 1H NMR spectroscopic analysis of the reaction crude mixture.
e Pyridin-2-yl is abbreviated py-2-yl.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

G
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Synthesis
Figure 2 Reaction coordinates for the formation of cis- and trans-lactams 6 by [2+2] cycloaddition Staudinger reaction. Link to the animated 3D
representation of the reaction pathways for the [2+2] Staudinger cycloaddition reactions between 5h and 3e, at 165 °C:
https://leyscigateway.ch.cam.ac.uk/staudinger/
It can be concluded from the computational studies that
the conrotatory ring closure step was the stereochemistry
determining step. For a number of the computed cases, the
ring closure of the zwitterion ZW2, derived from the imine
Our web-application allows the reader to quickly gain
access to specific structural data with molecular
visualisation among the large number of computed
structures reported in the current account. For each com-
puted structure the reader is directed to an HTML
document by scanning a QR code or via a URL link32
(https://leyscigateway.ch.cam.ac.uk/staudinger/viewer.html).
The HTML document displays a 3D molecular representa-
tion of the structure, with the possibility for the reader to
zoom, pan or rotate the 3D interactive structure, to hide the
hydrogen atoms, to monitor structural parameters such as a
single atom coordinates, interatomic distances, angles and
dihedral angles, to export atoms coordinates as an XYZ file,
or to access the 3D representation of other computed struc-
tures (Figure 3a). Finally, if the device is equipped with a
camera and allows the MediaStream request,33 the video
stream is displayed on a canvas element and the reader is
invited to scan a 2D fiducial marker associated with the
structure. As soon as the Hamming type marker34 is identi-
fied by the web application, it is overlaid with the 3D struc-
ture of the molecule (Figure 3b; for details see the Support-
ing Information). The resulting Augmented Reality experi-
ence allows the reader to quickly load, visualise and
interact with multiple molecular structures simultaneously
within the web interface by scanning the multiple associat-
ed 2D markers (for a maximum of 1023 different markers).
Finally, our web-based viewer was also successfully em-
ployed for the semi-automatic animation of reaction path-
≠
(Z)-5, was characterised by a lower barrier (ΔG4 ; Table 1)
than the counterpart ZW1, derived from the imine (E)-5
≠
(ΔG2 ; Table 1).
This could explain the trans-stereoselectivity observed
experimentally during the [2+2] Staudinger cycloaddition
reaction. However, introducing sterically large substituents
(R2) on the imine nitrogen, or electron-poor substituents
(R3) into the imine structure, diminished the difference be-
tween the rates of conrotatory closure steps of the zwitteri-
ons ZW1 and ZW2. This resulted in deteriorated (Table 1, en-
tries 3, 5, 6 and 9) or reversed (Table 1, entry 4) stereoselec-
tivity of the [2+2] Staudinger reaction. In the last phase of
this investigation and to facilitate the interpretation of
computational data,16 we studied the enhancement of the
approach using a web-based Augmented Reality (AR) tech-
nology developed from open-source components (for tech-
nical details see the Supporting Information). Within the
context of chemical applications, several AR initiatives were
previously reported, mainly for educational purposes.31
Nevertheless, to the best of our knowledge, there is no re-
ported use of web-based AR in a chemical research pro-
gram.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

H
B. Musio et al.
Paper
Synthesis
Figure 3 (a) Screen capture of the web application showing available features. (b) Screen capture of AR controls in operation.
ways by linear interpolation of each atom location between
consecutive reaction points on the pathway. An application
is the animated 3D representation of the reaction coordi-
nates for the [2+2] Staudinger cycloaddition reactions be-
tween 5h and 3e, at 165 °C (Figure 2, for more details see
the Supporting Information).
spectrometer with complete proton decoupling. Chemical shifts are
reported in ppm with the solvent resonance as the internal standard
(CDCl3: δ = 77.0 ppm). Data are reported as follows: chemical shift
δ/ppm, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
br = broad, m = multiplet or combinations thereof; 13C signals are sin-
glets unless otherwise stated), coupling constants are reported in Hz,
integration (1H only). 1H NMR signals are reported to two decimal
places and 13C signals to one decimal place unless rounding would
produce a value identical to another signal; in this case, an additional
decimal place is reported for both signals concerned. 19F NMR signals
are reported to two decimal places and trifluorotoluene was used as
internal standard (δ = –63.72 ppm). High-resolution mass spectrome-
try (HRMS) was performed with a Waters Micromass LCT spectrome-
ter using electrospray ionisation, time-of-flight analysis and Micro-
mass MS software HRMS signals are reported to four decimal places
and are within ±5 ppm of theoretical values. IR spectra were recorded
neat as thin films with a Perkin–Elmer Spectrum One FTIR spectrom-
eter; only selected peaks are reported. Melting points were collected
with a Stanford Research Systems Optimelt automated melting point
system using a gradient of 1 °C per min. Unless stated otherwise, re-
agents were obtained from commercial sources and used without pu-
rification. The removal of solvent under reduced pressure was carried
out with a standard rotary evaporator.
In conclusion, we have described an efficient flow route
for the generation and the reaction of hazardous and reac-
tive intermediates in a fully contained environment. The
high heating efficiency of a new flow microwave reactor
was applied to the preparation of primary ketenes from a
range of 2-diazoketones, which were reacted in situ with
amines and imines, affording amides and β-lactams, re-
spectively. The safety and the reliability of the system
during the reaction scale-up were tested, as demonstrated
by the continuous multigram preparation of N-benzylpro-
prionamide. The β-lactams were obtained in moderate to
good yields and with a preferential trans-configuration. The
operational mechanism of this transformation, involving a
rapid isomerisation step for both aliphatic and aromatic
imines at high temperature, was rationalised by DFT level
calculations. The resulting computed structures were rep-
resented by means of a new web-based Augmented Reality
application, which should provide wider access and dis-
semination of molecular computational data.
Geometries of all structures (minima and saddle points) were opti-
mised at the ωB97xd/cc-PVDZ level ωB97xD/cc-PVTZ//ωB97xD/cc-
PVDZ35 level calculations36 using the implicit Solvation Model based
on Density (SMD)37 implemented in Gaussian 09 software38 in aceto-
nitrile as a solvent (using the SMD solvation model, ε = 35.688). Sub-
sequent vibrational frequency calculations were performed at the
same level for all calculated structures. When needed, multiple initial
guesses (no more than four) were used to explore the conformational
space fully. All transition states thus found possess exactly one nega-
tive Hessian eigenvalue, while all other stationary points were con-
firmed to be genuine minima on the potential energy surface (PES).
Intrinsic reaction coordinate (IRC) analysis was performed to unam-
biguously assign located transition states when needed. Electronic
energies were obtained by performing single-point calculations at the
ωB97xd/cc-pVTZ level in solvent. Gibbs energies were calculated as
ΔG = ΔH – TΔS at 438 K where enthalpies and entropies were ob-
tained by using standard statistical mechanical formulae for the ideal
gas, rigid rotor, and harmonic oscillator approximations following the
normal-mode analysis in vacuum. A correction of (3.0∙Δn) kcal mol–1
(corresponding to the difference between the concentration of the
ideal gas at 438 K and 1 atm and its 1 mol l–1 concentration; Δn is the
change in number of moles in the reaction) has been applied so that
the computed values refer to 1 mol l–1 standard state at a given tem-
perature.
The multidisciplinary approach adopted in this work
could find application in other similar synthesis programs.
Instrumentation and General Methods
Flash column chromatography (FCC) was performed using Breckland
Scientific silica gel 60, particle size 40–63 nm under air pressure. An-
alytical thin-layer chromatography (TLC) was performed using silica
gel 60 F254 pre-coated glass backed plates and visualised by ultravio-
let radiation (254 nm) and/or potassium permanganate or ammoni-
um molybdate as appropriate. Isolated yields are reported to zero dec-
1
imal places and “quant.” signifies a yield of 99.5% or higher. H NMR
spectra were recorded with a Bruker DRX-400 (400 MHz) or DRX-600
(600 MHz) spectrometer. Chemical shifts are reported in ppm with
the resonance resulting from incomplete deuteration of the solvent as
the internal standard (CDCl3: δ = 7.26 ppm). 13C NMR spectra were re-
corded with a Bruker DRX-400 (100 MHz) or DRX-600 (150 MHz)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

I
B. Musio et al.
Paper
Synthesis
For each computed structure a JavaScript file was generated. This file
consisted of an array of atoms describing the element and Cartesian
coordinates for each atom and an array of bonds with their computed
multiplicity. The JavaScript file was passed to a client-side HTML
viewer where each atom object was constructed from a JavaScript
atom object prototype, defining atomic radius39 and CPK colouring40
for each element. Each atom object was then rendered as an icosahe-
dral geometric primitive at its location with the required radius and
colour, using the WebGL API through the open-source three.js li-
brary.41 For each interatomic bond, two half-bond objects were gen-
erated. The two half-bond objects were parented with the atom ob-
ject they respectively originate from before being rendered as two
collinear cylindrical geometric primitives. For each half-bond geome-
try, the direction was set parallel to the interatomic bond orientation,
while the length was constrained to the half value of the interatomic
distance. Both length and direction of the half-bond could be con-
strained for each frame, allowing the animation of the molecular
structure by only interpolation of the atoms position. The amount as
well as the radius of cylindrical geometries for a single interatomic
bond was defined by the computed multiplicity of the bond. For mul-
tiple bonds, cylindrical geometries were distributed on the plane de-
fined by the positions of three geminal atoms. Considering the rela-
tively low molecular weight of most of the computed structures, the
3D molecular representation of each molecule could be quickly
achieved with a minimal amount of geometric primitives and with-
out the need for the implementation of geometry shaders (i.e., ray-
casted geometry impostors) in WebGL1.0 in order to save on graphic
rendering resources.42 However, as the simultaneous representation
of several computed structures within the same WebGL renderer was
required, each molecular structure was exported as a JSON file43 to be
called on request. The molecular structures were rendered in a stan-
dard three.js scene.44 For the Augmented Reality, the camera calibra-
tion, adaptive thresholding, contours detection, corners sorting,
markers identification and coplanar pose estimation were handled by
the OpenCV.js and js-ArUco.js libraries.45 The resulting computed ex-
trinsic parameters of the camera were then employed to overlay the
molecular structures to their associated marker, with the help of a
modified version of the skarf.js library,46 developed by our group. A
simple performance test was carried out by tracking several ArUco
markers simultaneously on a 640 × 480 pixel canvas HTML element,
on a standard desktop PC (Dell™ Optiplex9010, 3.4 GHz Intel® Core™
i7–3770 CPU, 8 GB of RAM, Windows7™ – 64 bits) equipped with a
web camera (Microsoft® LifeCam Cinema™, wide angle F/2.0 HD
lens, 720p HD 30 fps, Autofocus) and running Mozilla Firefox™ 44.0
or Google Chrome™ 48 (for more details see Figure 4).
Preparation of 2-Diazoketones 1a–I; General Procedure
Compounds 1a–e and 1h–i were prepared according to a reported
procedure by reaction of bromoacetates with N,N′-ditosylhydrazine
and DBU.47 Compounds 1f and 1g were prepared according to a re-
ported two-step procedure by reaction of acetylketones with 4-acet-
amidobenzenesulfonylazide (p-ABSA),48 and subsequent basic treat-
ment (NaOH 1 M) of the resulting diazo-diketone derivatives.49 The
spectroscopic data of 1f48 and 1g50 are in accordance with reported
values.
2-Diazo-1-[4-(trifluoromethyl)phenyl]-ethan-1-one (1a)
Yield: 52%; yellow solid; mp 64–65 °C.
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 8.1 Hz, 2 H), 7.71 (d,
J = 8.2 Hz, 2 H), 5.94 (s, 1 H).
13C NMR (150.0 MHz, CDCl3): δ = 184.9, 139.4, 134.1 (q, J = 32.7 Hz),
127.1, 125.7 (q, J = 3.7 Hz), 123.5 (q, J = 272.3 Hz), 55.0.
19F NMR (100.0 MHz, CDCl3): δ = 64.0.
IR (neat): 3084, 2106, 1600, 1415, 1319, 1111, 860 cm–1
.
Anal. Calcd. for C9H5F3N2O: C, 50.48; H, 2.35; N, 13.08. Found: C,
50.88; H, 2.30; N, 12.60.
Preparation of Amides 4a–f; General Procedure
A solution of 2-diazoketone 1e–f (0.06 M in MeCN) and benzylamine
2 (0.12 M in MeCN) were pumped into the tubular glass reactor cov-
ered with a polytetrafluoroethylene film for safety and insulation rea-
sons (i.d. 3.6 mm, internal volume: 5.5–6.0 mL) at the same flow rate
(total flow rate of 1.0 mL min–1). An internal pressure of 2.0 MPa by a
back pressure regulator (BPR) and a MW irradiation of 80 W were as-
sured. After 10 min, the exit temperature reached a steady state at
165 °C (Figure 1d; green line), and collection of the crude reaction
mixture was started at this time. The crude product was concentrated
in vacuo and the residue was purified by flash column chromatogra-
phy on silica gel (hexane–EtOAc) to give amides 4a–f. CAUTION: spe-
cial precautions must be taken because of the hazards associated with
diazo compounds and the ketene derivatives. All work was carried in
a well ventilated fumehood, with an automatic shut down of the sys-
tem in case of an increase of the temperature and pressure over the
maximum value set. The spectroscopic data of 4b,51 4c,52 4d,53 4e,54
and 4f50 are in accordance with reported values.
N-Benzyl-2-[4-(trifluoromethyl)phenyl]acetamide (4a)
Yield: 65%; white solid; mp 134–136 °C.
1H NMR (600 MHz, CDCl3): δ = 7.61 (d, J = 8.05 Hz, 2 H), 7.41 (d,
J = 8.00 Hz, 2 H), 7.32 (d, J = 7.53 Hz, 2 H), 7.28–7.34 (m overlapping d
at 7.32 ppm, 1 H), 7.22 (d, J = 7.13 Hz, 2 H), 5.89 (br. s, 1 H), 4.43 (d,
J = 5.8 Hz, 2 H), 3.64 (s, 2 H).
13C NMR (150.0 MHz, CDCl3): δ = 169.7, 138.8 (br s), 137.8, 129.6,
129.59 (q, JC–F = 32.5 Hz), 128.7, 127.62, 127.59, 125.8 (q, JC–F
3.8 Hz), 124.0 (q, JC–F = 272.0 Hz), 43.8, 43.3.
=
IR (neat): 3238, 3063, 1625, 1556, 1328, 1122, 1070, 753, 698 cm–1
.
HRMS: m/z [M
+
H]+ calcd for C15H15F3NO: 294.1100; found:
Figure 4 Link to the web-based interactive 3D molecular viewer with AR.
294.1090.
https://github.com/es605/HTMoLar
Preparation of Imines (E)-5a–m; General Procedure
Imines (E)-5a and (E)-5b were obtained from commercial sources and
used without purification. All the other imines were prepared accord-
ing a reported procedure by reaction of appropriate aldehyde and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

J
B. Musio et al.
Paper
Synthesis
imine in dichloromethane in the presence of MgSO4.55 The spectro-
scopic data of (E)-5c–e,56 (E)-5h–j,57 (E)-5f,58 (E)-5g,59 (E)-5k,60 (E)-
5l,61 and (E)-5m47 are in accordance with reported values.
(2) (a) Mitic, A.; Gernaey, K. V. Chem. Eng. Technol. 2015, 38, 1699.
(b) Hessel, V.; Kralisch, D.; Kockmann, N.; Noël, T.; Wang, Q.
ChemSusChem 2013, 6, 746. (c) Ley, S. V. Chem. Rec. 2012, 12,
378. (d) McQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78,
6384.
Preparation of β-Lactams 6a–r; General Procedure
(3) (a) Porta, R.; Benaglia, M.; Puglisi, A. Org. Process Res. Dev. 2016,
20, 2. (b) Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem.
2015, 11, 1194. (c) Ghislieri, D.; Gilmore, K.; Seeberger, P. H.
Angew. Chem. Int. Ed. 2014, 678. (d) Gutmann, B.; Cantillo, D.;
Kappe, C. O. Angew. Chem. Int. Ed. 2015, 54, 6688.
(4) (a) Ley, S. V.; Fitzpatrick, D. E.; Ingham, R. J.; Myers, R. M. Angew.
Chem. Int. Ed. 2015, 54, 3449. (b) Ley, S. V.; Fitzpatrick, D. E.;
Myers, R. M.; Battilocchio, C.; Ingham, R. J. Angew. Chem. Int. Ed.
2015, 54, 10122.
(5) (a) Kirschning, A.; Solodenko, W.; Mennecke, K. Chem. Eur. J.
2006, 12, 5972. (b) Tsubogo, T.; Oyamada, H.; Kobayashi, S.
Nature 2015, 520, 329. (c) Munirathinam, R.; Huskens, J.;
Verboom, W. Adv. Synth. Catal. 2015, 357, 1093. (d) Hornung, C.;
Hallmark, B.; Mackley, M. R.; Baxendale, I. R.; Ley, S. V. Adv.
Synth. Catal. 2010, 352, 1736. (e) Suzuki, Y.; Laurino, P.;
McQuade, D. T.; Seeberger, P. H. Helv. Chim. Acta 2012, 95, 2578.
(f) Brahma, A.; Musio, B.; Ismayilova, U.; Nikbin, N.;
Kamptmann, S. B.; Siegert, P.; Jeromin, G.; Ley, S. V.; Pohl, M.
Synlett 2015, 262.
A solution of 2-diazoketone 1e–i (0.06 M in MeCN) and the appropri-
ate imine 5a–m (0.125 M in MeCN) were pumped into the tubular
glass reactor covered with a polytetrafluoroethylene film for safety
and insulation reasons (i.d. 3.6 mm, internal volume: 5.5–6.0 mL) at
the same flow rate (total flow rate of 1.0 mL min–1). An internal pres-
sure of 2.0 MPa by a back pressure regulator (BPR) and a MW irradia-
tion of 80 W were assured. After 10 min, the exit temperature reached
a steady state at 165 °C (Figure 1d; green line), and collection of the
crude reaction mixture was started at this time. The crude product
was concentrated in vacuo, and the residue was purified by flash col-
umn chromatography on silica gel (hexane–EtOAc) to give β-lactams
6a–r. CAUTION: special precautions must be taken because of the
hazards associated with the diazo compounds and the ketene deriva-
tives. All work was carried in a well ventilated fumehood, with an au-
tomatic shut down of the system in case of an increase of the tem-
perature and pressure over the maximum value set. The spectroscop-
ic data of trans-6a,62 trans-6d,20 trans-6g,63 trans-6i,55 cis-6j,64 trans-
6m,55 and trans-6n,65 are in accordance with reported values.
(6) (a) Gilmore, K.; Seeberger, P. H. Chem. Rec. 2014, 14, 410.
(b) Baumann, M.; Baxendale, I. R. React. Chem. Eng. 2016, 11.
(c) Plutschack, M. B.; Correia, C. A.; Seeberger, P. H.; Gilmore, K.
Organic Photoredox Chemistry in Flow, In Top. Organomet.
Chem.; vol. 27; Noël, T., Ed.; Springer: Switzerland, 2015, 43–76.
(d) Schuster, E. M.; Wipf, P. Isr. J. Chem. 2014, 54, 361. (e) Su, Y.;
Straathof, N. J. W.; Hessel, V.; Noël, T. Chem. Eur. J. 2014, 20,
10562. (f) Garlets, Z. J.; Nguyen, J. D.; Stephenson, C. R. J. Isr.
J. Chem. 2014, 54, 351.
(7) (a) Roth, G. P.; Stalder, R.; Long, T. R.; Sauer, D. R.; Djuric, S. W.
J. Flow Chem. 2013, 3, 34. (b) Kabeshov, M.; Musio, B.; Murray, P.
R. D.; Browne, D. L.; Ley, S. V. Org. Lett. 2014, 16, 4618.
(c) Stalder, R.; Roth, G. P. ACS Med. Chem. Lett. 2013, 4, 1119.
(d) Watts, K.; Gattrell, W.; Wirth, T. Beilstein J. Org. Chem. 2011,
7, 1108.
1-Benzyl-3-(benzofuran-2-yl)-4-phenylazetidin-2-one (trans-6b)
Yield: 61%; yellow oil; dr trans/cis 92:8.
1H NMR (600 MHz, CDCl3): δ = 7.52 (d, J = 7.6 Hz, 1 H), 7.24–7.46 (m,
12 H), 7.21 (td, J = 7.5, 1.0 Hz, 1 H), 6.64 (s, 1 H), 5.00 (d, J = 15.1 Hz,
1 H), 4.64 (d, J = 2.4 Hz, 1 H), 4.38 (d, J = 2.3 Hz, 1 H), 3.92 (d,
J = 15.2 Hz, 1 H).
13C NMR (150.0 MHz, CDCl3): δ = 165.5, 155.0, 150.7, 136.6, 135.1,
129.1, 128.9, 128.8, 128.4, 128.2, 127.8, 126.5, 124.3, 122.9, 120.9,
111.1, 105.2, 60.4, 59.1, 44.9.
IR (neat): 3674, 2988, 1755, 1453, 1252, 1076, 725 cm–1
.
HRMS: m/z [M + H]+ calcd for C24H20NO2: 354.1494; found: 354.1503.
Additional data related to this publication are available at the
http://dx.doi.org/10.17863/CAM.654 data repository.
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Acknowledgment
The authors would like to acknowledge Dr Aki Tomita and Professor
Jonathan M. Goodman for helpful discussions and suggestions. The
authors are also thankful to the EPSRC (Award Nos. EP/K009494/1,
EP/K039520/1 and EP/M004120/1) for financial support.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562579.
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