The cycloaddition reaction between α-bromo vinylketenes and imines: A combined experimental and theoretical study

Article abstract of DOI:10.1002/adsc.200800348

The unusual behaviour of α-bromo vinylketenes in the cycloaddition reactions with imines is described. This class of vinylketenes behaves as dienophiles in [2+2] reactions, but also displays an unusual diene reactivity in [4+2] reactions. Interestingly, the reactivity of α-bromo vinylketenes can be modulated via a fine tuning of the substituents. For instance, a methyl group in the b-position completely inhibits the [2+2] reaction and the [4+2] pathway is almost exclusively followed. A more hindered ketimine (instead of a simple imine) is enough to activate again the [2+2] mechanism. We have carried out a DFT theoretical investigation to rationalise these experimental observations. We have considered two pathways for the [2+2] reaction involving imine, that is, the endo and exo pathways. The former is favoured in the case of α-bromo vinylketenes, while the latter is preferred for non-substituted vinylketenes. Since the [4+2] cycloaddition becomes possible only when the s-Z-conformation of vinylketene is significantly populated, the presence of bromine substituents in this substrate is crucial in determining the [2+2] or [4+2] mechanisms. For unsubstituted vinylketenes, the barrier connecting the s-E- to the s-Z-conformation is too high to be easily overcome. Thus, the s-Z-structure has a low population and the [2+2] mechanism is favoured. In the case of α-bromo vinylketenes (especially the β-methyl-substituted ones), this barrier can be surmounted and the [4+2] mechanism becomes available.

Full text of DOI:10.1002/adsc.200800348

FULL PAPERS
DOI: 10.1002/adsc.200800348
The Cycloaddition Reaction Between a-Bromo Vinylketenes and
Imines: A Combined Experimental and Theoretical Study
Fides Benfatti,a Andrea Bottoni,a,* Giuliana Cardillo,a Serena Fabbroni,a
Luca Gentilucci,a Marco Stenta,a,* and Alessandra Tolomellia
a
Dipartimento di Chimica “G. Ciamician”, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
Fax : (+39)-51-209-9456; e-mail: andrea.bottoni@unibo.it
Received: June 5, 2008; Published online: September 9, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800348.
Abstract: The unusual behaviour of a-bromo vinyl- latter is preferred for non-substituted vinylketenes.
ketenes in the cycloaddition reactions with imines is Since the [4+2] cycloaddition becomes possible only
described. This class of vinylketenes behaves as dien- when the s-Z-conformation of vinylketene is signifi-
ophiles in [2+2] reactions, but also displays an un- cantly populated, the presence of bromine substitu-
usual diene reactivity in [4+2] reactions. Interesting- ents in this substrate is crucial in determining the
ly, the reactivity of a-bromo vinylketenes can be [2+2] or [4+2] mechanisms. For unsubstituted vi-
modulated via a fine tuning of the substituents. For nylketenes, the barrier connecting the s-E- to the s-
instance, a methyl group in the b-position completely Z-conformation is too high to be easily overcome.
inhibits the [2+2] reaction and the [4+2] pathway is Thus, the s-Z-structure has a low population and the
almost exclusively followed. A more hindered ket- [2+2] mechanism is favoured. In the case of a-
imine (instead of a simple imine) is enough to acti- bromo vinylketenes (especially the b-methyl-substi-
vate again the [2+2] mechanism. We have carried tuted ones), this barrier can be surmounted and the
out a DFT theoretical investigation to rationalise [4+2] mechanism becomes available.
these experimental observations. We have considered
two pathways for the [2+2] reaction involving imine, Keywords: azetidinones; a-bromo vinylketenes; cy-
that is, the endo and exo pathways. The former is fav- cloaddition; DFT computations; pyridinones; reac-
oured in the case of a-bromo vinylketenes, while the tion mechanism
Introduction
ners and as a diene component in [4+2] cycloaddi-
tions with electron-poor species.[28,46] Vinylketenes
Ketenes exhibit a very peculiar cycloaddition chemis- usually react with imines via the Staudinger reaction
try because of their structural and electronic proper- and, to the best of our knowledge, only silyl-vinylke-
ties.[1,2] One of the most valuable and exploited cyclo- tenes have been shown to undergo [4+2] cycloaddi-
addition of ketenes is unquestionably the reaction tion with imines.[47,48] However, we have recently car-
with imines to afford b-lactams, which was discovered ried out an experimental investigation on the reactivi-
by Staudinger at the beginning of the 20th century.[3] ty of a new class of vinylketenes, the a-bromo-vinyl-
In view of the importance of b-lactams in medicinal ketenes, with imines[49] and we have described suc-
chemistry as antibacterial agents[4–8] and enzymatic in- cessful synthetic routes toward a-bromo-substituted
hibitors,[9–12] the Staudinger reaction has been exten- 4-alkyl-5,6-diyhdropyridin-2-ones. Halogen substitu-
sively studied and a large number of experimen- ents[22,50–56] dramatically affect the a-bromo-vinylke-
tal[13–25] and theoretical[26–40] papers are now available tene reactivity in the cycloaddition to imines, promot-
in the literature.
ing an unusual diene behaviour. A fine tuning of the
An interesting class of ketenes are vinylketenes, substituents on both vinylketene and imine moieties
that have been demonstrated to be versatile building allows us to selectively obtain [2+2] or [4+2] prod-
blocks in cycloaddition reactions with various double ucts (Scheme 1). Moreover, these heterocycles are
bonds.[41–45] They behave as electron-deficient dieno- suitable for further manipulations that involve the
philes in [2+2] cycloadditions with electron-rich part- substitution of the halogen atom and the transforma-
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chloride and a-bromocrotonyl chloride, respectively,
in the presence of triethylamine.
The cycloaddition reaction of a-bromo vinylketenes
1a, b with imines 2a–d occurred preferentially via a
[2+2] mechanism, affording, as major products, the
cis-b-lactams 3a–d and 6a. The formation of the six-
membered 5,6-dihydropyridin-2-ones 5a–d and 8a
could not be avoided, even using a variety of experi-
mental conditions (see Scheme 2).
The reaction of vinylketenes with imines, reported
several years ago by Bose and Manhas,[68–71] afforded
3-alkenyl-azetidin-2-ones exclusively, no traces of the
six-membered lactams being observed. Thus, our re-
sults prompted us to investigate the effect of the halo-
gen on the reactivity of the intermediate ketene.
The reaction of a-bromo vinylketene 1a with imine
Scheme 1. Synthesis of 3-bromo-3-alkenylazetidin-2-ones
and 3-bromo-4-alkyl-5,6-dihydropyridin-2-ones.
tion of the double bond.[57–63] Furthermore, it is inter- 2a was carried out under a number of different condi-
esting to note that derivatives of 3-bromo-3-alkenyl- tions in order to increase the yield and selectivity in
A
din-2-ones have been shown to behave as inhibitors best result in terms of diastereoselectivity could be
of the ACAT enzyme and antagonists of aVb3 and obtained in CH2Cl2 at reflux by adding a-bromohexe-
a5b1 integrins, respectively.[64–67]
noyl chloride to a hot solution of imine 2a and TEA.
Herein we report an advanced investigation on the Following this procedure, b-lactams 3a–d, 4a–d and
synthesis of four- and six-membered lactams via cy- 6a, 7a were obtained in good yield and high selectivity
cloaddition reactions between a-bromo vinylketenes favouring the cis-isomer. However, these products
and imines. Furthermore, we describe the results of a were associated with a significant amount of 5a–d and
theoretical study aimed to elucidate the mechanism of 8a (see data reported in Table 1). Product distribution
1
these reactions and the origin of their stereoselectiv- was determined by H NMR integration of distinctive
ity. Our work provides a rationalisation for the unusu- key signals and by the yields of the individual isomers
al behaviour of this class of vinylketenes.
obtained after chromatographic separation.
Table 1. Reaction of vinylketenes 1a–b with imines 2b–d.
Entry Ketene Imine 3+4 [%][a] 3:4 [%] 5 [%][a]
Experimental Results
Reaction of Linear a-Bromo Vinylketenes with
Imines
1
2
3
4
5
1a
1a
1a
1a
1b
2a
2b
2c
2d
2a
57
60
50
55
30
95:5
22
27
23
14
15
80:20
80:20
93:7
Recently, we have investigated the straightforward
synthesis of 3-bromo-3-alkenylazetidin-2-ones via he
Staudinger reaction between a-bromo vinylketenes
and an imine. The a-bromo vinylketenes 1a and 1b
were prepared in situ starting from a-bromohexenoyl
90:10
[a]
Reported yields refer to isolated products. A small
amount of amide was observed in all the reactions.
Scheme 2. Reaction of 1a and 1b with imines 2a–d.
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The Cycloaddition Reaction Between a-Bromo Vinylketenes and Imines
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The obtained compounds 3b–d and 4b–d were ex-
clusively characterised by an E configuration at the
double bond of the side chain, as shown by the cou-
pling constant (J=15.6 Hz). The cis-configuration of 3
was established by nOe experiments using DPFGSE
pulse sequence (see Supporting Information for de-
tails).
Isomer 3 exihibited a strong nOe between H-4 and
the double bond protons on C-3, which indicated a cis
relationship between these two moieties. The same
experiment performed on the minor isomer 4 did not
show any nOe effect, thus suggesting a trans geometry
between H-4 and the alkenyl group.
Staudinger reactions carried out with a-bromo vi-
nylketenes 1a, b and imine 2e [obtained from benzal-
dehyde and (S)-1-phenylethylamine], afforded enan-
tiomerically pure b-lactams (Scheme 3). Although
four stereoisomers could possibly arise from this reac-
tion, complete cis-diastereoselectivity was observed
and mixtures of cis-b-lactams, together with a consid-
erable amount of d-lactams, were isolated both in the
Figure 1. ORTEP diagram of 4e.
case of 1a and 1b.
The major isomer 3e was isolated by flash chroma-
tography as a sticky oil, while the minor isomer 4e
was a solid that was crystallised from methanol. The previous paper.[57] Indeed, a-bromo vinylketene 1d
(1S’,3S,4R) absolute configuration of 4e was estab- was prepared with excellent regioselectivity treating
lished by X-ray diffraction (Figure 1). On the basis of 2-bromo-3-methyl-2-hexenoyl chloride with 2equiv. of
these considerations, the assignment of the TEA, despite the possibility of deprotonation of the
(1S’,3R,4S) absolute configuration to 3e could be methylene group to give an isomeric vinylketene.[72]
1
made. The comparison of the H NMR data for 3e
No trace of the b-lactam was detected in the HPLC
1
and 4e and the data for 6e and 7e showed a complete analysis and in the H NMR spectra of the crude reac-
regularity that allowed the (1S’,3R,4S) configuration tion mixture (Scheme 4).
of 6e and the (1S’,3S,4R) configuration of 7e to be at-
tributed.
Reaction of b-Substituted a-Bromo Vinylketenes with
Imines
We observed that the diene behaviour of a-bromo vi-
nylketenes could be enhanced by the introduction of
a branch in the b position. Actually, the [4+2] path-
way was exclusively followed in the reactions of 1c, d
with imines 2a–d, and the dihydropyridinones 9a–e
could be obtained in high yields, as we reported in a
Scheme 4. Reaction of b-substituted-a-bromo vinylketenes
1c–d with imines 2a–d.
Scheme 3. Reaction of 1a and 1b with imine 2e.
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The detailed investigation of the reaction condi- Reaction of a-Bromo Vinylketenes with Ketimines
tions showed that the best results could be obtained
when 1 and 2 were refluxed in CH2Cl2. Under these The results above reported indicate that linear a-
reaction conditions, 9a–e were obtained in excellent bromo vinylketenes 1a and 1b react with imines pref-
yields (see Table 2).
erentially giving b-lactams, while b-substituted-a-
bromo vinylketenes 1c and 1d afford exclusively six-
membered rings. In order to gain deeper insight into
the problem, we studied the influence of the imine
substitution on the reactivity, by treating a-bromo vi-
nylketenes 1a–c with the ketimines 2f and 2g, derived
from benzophenone (Scheme 6).
Table 2. Formation of 3-bromo-4-alkyl-5,6-dihydropyridin-2-
one 3 via ketene-imine cyclisation.
Entry[a]
Ketene
Imine
Product
Yield [%][b]
The experimental results demonstrate that the sub-
stitution of the imine hydrogen with a phenyl group
dramatically inhibits the strong preference of 1c for
the [4+2] mechanism, selectively leading to 3-bromo-
3-alkenylazetidin-2-ones (Table 3).
1
2
3
4
5
1c
1c
1c
1c
1d
2a
2b
2c
2d
2e
9a
9b
9c
9d
9e
92
92
96
64
94
[a]
Reactions were performed in CH2Cl2.
Yields correspond to the compounds purified by flash
chromatography on silica gel.
Table 3. Formation of 3-bromo-3-alkenylazetidin-2-ones via
ketene-ketimine cyclisation.
[b]
Entry[a]
Ketene
Ketimine
Product
Yield [%][b]
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
2f
2g
2f
2g
2f
2g
14f
14g
15f
15g
16f
16g
97
84
93
90
80
87
Good yields and moderate diastereoselectivities
were observed in the reactions of 1c and 1d with the
chiral imine 2e (98% yield and 62/38 dr for the reac-
tion of 1c, 55% yield and 68/32 dr for 1d). The dihy-
dropyridinones 10/11 and 12/13 (see Scheme 5) were
easily separated and fully characterised by NMR
spectroscopy and LC-MS analysis.
[a]
Reactions were performed in CH2Cl2.
Yields correspond to the compounds purified by flash
chromatography on silica gel.
[b]
Scheme 5. Reaction of 1c and 1d with the chiral Schiff base 2e.
Scheme 6. Reaction of a-bromo vinylketenes with ketimines 2f and 2g.
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The Cycloaddition Reaction Between a-Bromo Vinylketenes and Imines
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These results clearly indicate that, in the cycloaddi- corresponding to Cis and Trans approaches, could be
tions between a-bromo vinylketenes and imines, sub- easily located. Thus, the inclusion of the solvent is of
stituents can be carefully changed to drive the reac- paramount importance in determining the shape of
tion toward the [2+2] or the [4+2] pathway and to the potential energy surface related to these reactions.
selectively obtain b-lactams or d-lactams.
Moreover, no influence of unpaired spin states has
been detected: single point calculations on the various
critical points, using either restricted (B3LYP) or un-
restricted (UB3LYP) methods, provide identical re-
sults and stable wave functions. For these reasons, a
restricted DFT formalism has been chosen and used
throughout the work. Geometry optimisation has
been carried out in redundant internal coordinates[81]
Computational Results
Choice of the Model Systemand Computational
Details
All computations have been performed at the DFT/ and the nature of the various critical points has been
B3LYP/DZVP[73–75] level, using the Gaussian03 pack- determined by frequency calculations.
age.[76] Geometry optimizations have been carried out
To lower the demand of computational time, all cal-
in the presence of solvent effects (dichloromethane), culations have been carried out on model systems
which have been simulated by the SCRF-CPCM[77–80] simpler than the real molecules used in the experi-
method. To validate this computational approach, we ment (Scheme 8). In particular, vinylketenes have
have investigated at the same theoretical level a
model system where the addition involves an unsub-
stituted imine and an unsubstituted ketene (see
Scheme 7). Then, we have compared our results to
Scheme 8. Model systems (1A, 1C, 1E and 2A, 2F) used in
the computational study.
Scheme 7. Possible paths for the reaction between ketene
been emulated by 1A (a-bromo-substituted), 1C (a-
and imine.
bromo-b-methyl-substituted) and 1E (unsubstituted).
Two different molecules have been used to describe
those obtained for the same reaction by Venturini imines and ketimines that is, 2A and 2F, respectively.
and Gonzalez at the CASSCF-CASPT2 level.[27] The The presence and the nature of the N-substituents
DFT computations in the gas phase (see Figure S1 have been considered unimportant since experimen-
and Table S1 in the Supporting Information) have tally they do not affect the outcome of the reaction.
provided energy and structural data similar to the Thus, they have been replaced by a hydrogen atom in
CASSCF ones. As outlined by Venturini[27] no transi- all calculations.
tion state connecting the two intermediates M_Cis
and M_Trans (i.e., TS_Cis-Trans) could be found in
the gas phase. Besides, according to what was suggest- Discussion
ed by this author, the inclusion of the solvent (di-
chloromethane) effects via the SCRF method, afford- The [2 +2] reaction between ketene and imine lead-
ed a different reaction profile. Since the solvent helps ing to b-lactams is commonly considered a step-wise
the stabilisation of the structures with charge separa- process. The first step is the nucleophilic attack of the
tion (see Scheme 7), the transition state TS_Cis-Trans, imine nitrogen on the ketene sp carbon leading to a
which represents a “gate”between the two pathways
zwitterionic intermediate (as indicated in Scheme 7).
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Table 4. Energy values E for the conformational equilibrium
of ketenes.
The intermediate can undergo a conrotatory electro-
cyclic ring closure to give the final product. Theoreti-
cal studies have provided an insight into the origins of
the stereoselectivity,[34,36,38] which certainly is the most
intriguing problem. Recently, a detailed study report-
ed by Xu and co-workers[26] has elucidated the role of
the substituents in controlling the stereoselectivity.
The conformations of vinylketenes have been com-
putationally investigated.[28,46] The equilibrium be-
tween the s-E-conformation and the s-Z-conformation
is of particular interest since it may be crucial for dis-
criminating between the [2+2] and the [4+2] path-
ways. The s-E-conformation is more stable than the s-
Z-conformation for all vinylketenes (Table 4). How-
ever, the energy values of the conformational transi-
tion state are markedly lower for 1A and 1C with re-
spect to 1E. This suggests that the bromine substitu-
Molecule
E (kcalmolÀ1)[a]
ø (8)[b]
1A s-Z
1A_TS
1A s-E
1C s-Z
1C_TS
1C s-E
1E s-Z
1E_TS
1E s-E
3.09
5.81
0.00
2.09
5.07
0.00
2.18
7.01
0.00
0
108
180
À43.39
À112.39
180
0
98.24
180
[a]
Energy values are relative to the s-E conformer.
ø is the dihedral angle that describes the rotation around
the central single bond.
[b]
ent plays a key role in stabilising the less favoured imine 2A exists in the E configuration. Our data (see
conformation. On the basis of these results it is clear Table S3 in the Supporting Information) suggest a
that all examined ketenes adopt a s-E-conformation barrier of about 30 kcalmolÀ1 for the E/Z-isomerisa-
at the equilibrium. However, at ambient conditions tion of 2A.
the rotation around the single bond is possible and
As previously reported in the literature,[27,30] differ-
this process must be faster for 1C.
ent approaches can lead to b-lactams: two endo ap-
The possibility of E/Z-imine isomerisation has been proaches (cis_endo and trans_endo) and two exo ap-
taken into account,[26] and both experimental and proaches (cis_exo and trans_exo) as illustrated in
computational evidences indicate that the model Scheme 9. In the following discussion, endo indicates
Scheme 9. General scheme for all possible [2+2] pathways.
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The Cycloaddition Reaction Between a-Bromo Vinylketenes and Imines
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the approach of imine on the vinyl group side of between a-bromo vinylketene 1A and aldimine 2A,
ketene, while exo denotes the approach on the R5 since the [2+2] endo pathway, leading to the (Br-Ph)-
group side. As previously pointed out for both exo cis-b-lactam, is favoured with respect to the exo path-
and endo pathways, the cis and trans approaches are way by 4.46 kcalmolÀ1 (see Table 5 and experimental
connected by a rotational transition state (TS_rot_exo products ratio in Table 1). The analysis of the [2+2]
and TS_rot_endo) between the two minima M_trans pathway preference has been extended to other react-
and M_cis.
ing pairs that is, 1C+2A, 1E+2F, 1A+2F, 1C+2F.
The energy values of the various critical points lo- In these cases the calculations have been carried out
cated for the [2+2] reaction between ketenes 1A, 1C only on the most important critical points (i.e., reac-
and 1E and imine 2A and ketimine 2F are reported in tants and TS1), since we have confidently assumed
Table 5. The energy profiles for the two reactions that all reaction surfaces considered here are qualita-
1E+2A and 1A+2A are shown in Figure 2 and tively similar.
Figure 3, respectively. In all cases (i.e., the four path-
We have examined the isomerisation of the zwitter-
ways 1E+2A endo/exo and 1A+2A endo/exo) the ionic intermediates (see Scheme 9) from the more
rate-determining step coincides with the electrocyclic stable (E) to the less stable (Z) imine geometry. This
ring closure of the minimum M_cis to give the b- pathway, if active, would connect the endo and exo
lactam. The comparison of the barriers associated to pathways resulting in an opposite diasteroselectivity.
the corresponding transition state TS1 in the endo Even if some authors have described the occurrence
and exo approaches (TS1_endo and TS1_exo) ac- of this mechanism in the case of benzaldehyde
counts for the preference of the system to give differ- imines[82], no connection between endo and exo path-
ent b-lactam diastereoisomers. A qualitative relation ways has been found in the present case. In spite of
was observed between the DETS1
values report- an extensive search no transition states connecting
(exo-endo)
ed in Table 5 (i.e., the difference between the energy M_cis_endo and M_cis_exo (i.e., TS_isom_cis) or
of the two transition states) and the corresponding ex- M_trans_endo and M_trans_exo (i.e., TS_isom_trans)
perimental ratio of products. In the case of vinylke- were located.
tene 1E (R3 =H) the greatest barrier (see Table 5 and
To get a deeper understanding of the peculiar diene
Figure 2) is associated with the endo approach behaviour of a-bromo vinylketenes, [4+2] pathways
(TS1_endo=15.75 kcalmolÀ1), while the rate-deter- have also been studied. First, on the basis of the com-
mining step of the exo approach has a much lower putational evidences, we excluded that the zwitterion-
barrier (TS1_exo=10.16 kcalmolÀ1, the barrier differ- ic intermediates located for the [2+2] pathway (i.e.,
ence being 5.60 kcalmolÀ1). This result is in good M_cis_endo and M_cis_exo) could lead to the six-
agreement with the observed experimental data,[70] membered product by rotation of the vinyl group and
since the exo approach leads to cis-b-lactams. The op- subsequent ring closure. No minima and/or transition
posite behaviour has been observed in the reaction states related to this mechanism were found on the
Table 5. Energy values (kcalmolÀ1)[a] of the various critical points located for the [2+2] reaction.
1E+2A
1A+2A
1C+2A
1E+2F
1A+2F
1C+2F
Reactants
0.0
0.0
0.0
0.0
0.0
0.0
TS_trans_endo
M_trans_endo
TS_rot_endo
TS_cis_endo
M_cis_endo
TS1_endo
Products_endo
TS_trans_exo
M_trans_exo
TS_rot_exo
TS_cis_exo
M_cis_exo
##[b]
##[b]
À6.05
À4.05
3.95
À4.19
15.75
À28.05
3.26
À9.64
À4.94
##[b]
À5.40
10.16
À26.89
À5.60
À12.62
À11.13
2.01
À11.26
6.72
10.83
11.01
2.95
9.56
À29.72
3.95
À13.21
À10.94
##[b]
À10.61
11.18
À29.86
+4.46
TS1_exo
13.80
5.45
6.10
8.11
Products_exo
DETS1
+2.97
À5.57
3.14
À1.45
(exo-endo)
[a]
Energy values are relative to reactants.
[b]
The geometry obtained after the optimisation was found to be a saddle of order higher than 1 and so was considered ir-
relevant for a chemical point of view.
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Figure 2. Energy profile for the 1E+2A [2+2] reaction.
Figure 3. Energy profile for the 1A+2A [2+2] reaction.
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The Cycloaddition Reaction Between a-Bromo Vinylketenes and Imines
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Scheme 10. General scheme for the [4+2] pathway.
Table 6. Energy values (E, kcalmolÀ1)[a] of the various criti-
cal points located for the [4+2] reaction.
potential surfaces (see Supporting Information for the
structures conjectured for this pathway). On the con-
trary, an independent two-step mechanism originating
from the s-Z-vinylketene has been discovered for the
[4+2] cycloaddition. The capability of bromo sub-
stituents to stabilise the s-Z-conformation of a-bromo
vinylketenes indeed enables a new reaction pathway.
This path is schematically depicted in Scheme 10,
where the conformational equilibrium between the s-
1E+2A 1A+2A 1C+2A 1C+2F
Reactants
TS_rot_ketene 7.01
0.0
0.0
5.81
0.0
5.07
0.0
5.07
M0
TS1
M1
TS2
M2
TS3
M3
2.18
10.63
3.09
8.26
2.09
7.27
2.09
8.68
À1.30
À8.08
À8.11
À2.95
7.66
2.20
2.78
3.43
E
and s-Z conformations is also represented
À49.68
À48.05
À51.51
À53.93
À52.02
À55.78
À54.80
À52.93
À56.72
À46.76
À43.43
À47.76
(TS_Rot_Ketene is the transition state connecting the
s-E- and s-Z-structures).
The nucleophilic attack of the imine nitrogen on
the sp carbon of the a-bromo vinylketene in the s-Z-
conformation is the first step of the [4+2] reaction.
The energy values for the various critical points locat-
ed for this reaction are collected in Table 6. This
[a]
Energy values are relative to reactants.
attack, leading to the M1 intermediate, corresponds sentation of the [4+2] pathway for the 1A+2A reac-
to the rate-determining step (transition state TS1) of tion is depicted in Figure 4. The energy diagrams for
the process.[28] The subsequent ring closure (originat- the [4+2] reaction of 2A with 1E, 1A and 1C are
ing from M1), affords, through transition state TS2, shown in Figure 5, Figure 6, Figure 7 and Figure 8
the final six-membered product M2 with the phenyl and are compared to the highest energy barriers that
group in an axial position. A low barrier (transition feature the competitive [2+2] pathways (i.e.,
state TS3) is required for the isomerisation process TS1_endo and TS1_exo). It is worthwhile to note that
leading to the more stable conformer M3 where the the diasteroselectivity predicted by the proposed
A
phenyl group is equatorial. A “ball and stick”repre- 2] mechanism is consistent with the observed stereo-
Figure 4. Structures of the various critical points located for the for 1E+2A [4+2] reaction.
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FULL PAPERS
Figure 5. Energy profile for the 1E+2A [4+2] reaction.
Figure 6. Energy profile for the 1A+2A [4+2] reaction.
Figure 7. Energy profile for the 1C+2A [4+2] reaction.
Figure 8. Energy profile for the 1C+2F [4+2] reaction.
nylketene (TS_rot_ketene: 7.01 kcalmolÀ1). In the re-
action between 1A and 2A, the relative magnitude of
the computed barriers of the rate-determining step
for the [2+2] (TS1 exo: 11.18 kcalmolÀ1and
TS1 endo: 6.72 kcalmolÀ1) and [4+2] reaction (TS1:
8.26 kcalmolÀ1) are in good qualitative agreement
with the experimental products ratio (Table 1). Con-
cerning the cycloaddition 1C+2A, the preference for
the [4+2] product is fully explained by the difference
between the barrier found for TS1 (7.27 kcalmolÀ1)
and those for TS1_exo (13.80 kcalmolÀ1) and
TS1_endo (10.83 kcalmolÀ1).
In general, we can state that the [4+2] pathway is
available only for vinylketenes characterised by a sig-
nificant population of the s-Z-structure. This explains
the unusual behaviour of the a-bromo vinylketenes
with respect to unsubstituted vinylketenes.
However, with ketimine 2F (R4 =Ph, Scheme 8) the
energy of TS1 increases (8.68 kcalmolÀ1) and the [4+
2] pathway is disfavoured with respect to the [2+2]
one (TS1_exo: 8.11 kcalmolÀ1; TS1_endo: 9.56 kcal
molÀ1 as reported in Table 5). This is also evident
from the diagram of Figure 7.
Conclusions
In the present paper we have described the unusual
behaviour of a-bromo vinylketenes in the cycloaddi-
tion reactions with imines. The peculiar feature of this
class of vinylketenes is the fact that they behave as di-
enophiles in [2+2] reactions, but also display an un-
usual diene reactivity in [4+2] reactions. As a conse-
chemistry as reported in a previous paper (see Sup- quence a-bromo vinylketenes are versatile building
porting Information for more details).[57]
blocks in the synthesis of highly functionalised hetero-
In the 1E + 2A cycloaddition, the energies of TS1 cycles, since a-bromo substituted 3-alkenyl-azetidin-2-
([4+2] process) and TS1 exo ([2+2] process) are ones and 4-alkyl-5,6-diyhdropyridin-2-ones can be
similar. The exclusive formation of the b-lactam prod- easily obtained from the [2+2] and [4+2] reactions
uct may be ascribed to the more favoured attack of with imines, respectively. Interestingly, the reactivity
the imine (TS_trans_exo: 3.26 kcalmolÀ1) on the s-E- of a-bromo vinylketenes can be modulated via a fine
vinylketene upon its isomerisation to give the s-Z-vi- tuning of the substituents. The introduction of a
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The Cycloaddition Reaction Between a-Bromo Vinylketenes and Imines
FULL PAPERS
characterisation of compounds 5e, 9a–e, 10, 11, 12, 13 and
X-ray data for compound 12 have been reported in ref.[59]
methyl group in the b-position, for example, com-
pletely inhibits the dienophile reactivity and the
A
General Procedure for the Reaction of Ketene 1 with
Imine 2 at Reflux
obtained. The usage of a more hindered ketimine in
the place of a simple imine is enough to activate
again the [2+2] mechanism (both b-methyl substitut-
ed and unsubstituted a-bromo vinylketenes give azeti-
dinones when reacted with ketimines).
To a refluxing solution of the imine (1 mmol) and TEA
(2 mmol, 2 equiv., 0.280 mL) in CH2Cl2 (10 mL) under a ni-
trogen atmosphere, acyl chloride (1.25 mmol, 1.25 equiv.) in
We have carried out a DFT theoretical investiga- CH2Cl2 (2 mL) was added dropwise very slowly. The solu-
tion was refluxed for 4 h and then allowed to reach room
temperature. After quenching with 5 mL of 0.1M HCl, the
mixture was diluted with CH2Cl2 (10 mL) and washed twice
with water. The organic layer was dried over Na2SO4 and
solvent was removed under reduced pressure. The products
were obtained, after purification by flash chromatography
on silica gel (cyclohexane/Et2O, 95/5), with the yields report-
ed in Table 1.
tion to rationalise these experimental evidences. We
have considered two pathways for the [2+2] reaction
involving imine, that is, the endo and exo pathways.
The former has been found to be favoured in the case
of a-bromo vinylketenes, while the latter is preferred
for non-substituted vinylketenes. Since the [4+2] cy-
cloaddition becomes possible only when the s-Z-con-
formation of vinylketene is significantly populated,
the presence of Br substituents in this substrate is cru-
cial in determining the [2+2] or [4+2] mechanisms.
For unsubstituted vinylketenes, the barrier connecting
the s-E- to the s-Z-conformation is too high to be
easily overcome. Thus, the s-Z-structure has a low
population and the [2+2] mechanism is favoured. In
the case of a-bromo vinylketenes (especially the b-
methyl-substituted ones), this barrier can be sur-
mounted and the [4+2] mechanism becomes avail-
able. Interestingly, in the reactions involving keti-
mines, the presence of an additional phenyl group
makes more difficult the formation of the zwitterionic
intermediate along the [4+2] pathway. Consequently,
the [2+2] path becomes again favoured with all a-
bromo vinylketenes.
Supporting Information
Full analytical characterisations of the [2+2] and [4+2]
products, X-ray data for compound 4e and the geometries of
critical points are given in the Supporting Information.
References
[1] T. T. Tidwell, Ketenes, Wiley, New York, 1995.
[2] T. T. Tidwell, Angew. Chem. Int. Ed. 2005, 44, 5778.
[3] H. Staudinger, Justus Liebigs Ann. Chem. 1907, 356, 51.
[4] C. T. Walsh, G. D. Wright, Chem. Rev 2005, 105, 391.
[5] R. Southgate, C. Branch, S. Coulton, E. Hunt, in:
Recent Progress in the Chemical Synthesis of Antibiotics
and Related Microbital Products, Vol. 2, (Ed.: G. Luck-
acs), Springer-Verlag, Berlin, 1993, p 621.
[6] J. D. Buynak, Curr. Med. Chem. 2004, 11, 1951.
[7] R. Lysek, K. Borsuk, B. Furman, Z. Kałuza, A. Kazi-
mierski, M. Chmielewski, Curr. Med. Chem. 2004, 11,
1813.
Experimental Section
[8] J. F. Fisher, S. O. Meroueh, S. Mobashery, Chem. Rev
2005, 105, 395.
General Remarks
Unless stated otherwise, solvents and chemicals were ob-
tained from commercial sources and used without further
purification. Flash chromatography was performed on
Merck silica gel 60 (230–400 mesh). NMR spectra were re-
corded with Varian Gemini 200, Inova 300, Mercury 400 or
Inova 600 MHz spectrometers. Chemical shifts are reported
as d values relative to the solvent peak of CDCl3 set at d=
7.27 (1H NMR) or d=77.0 (13C NMR). DPFGSE-nOe
(double pulse field gradient-nuclear Overhauser effect) ex-
periments have been performed in CDCl3 at 258C on a
Varian INOVAꢁ 400 MHz (Oxford Magnet).
Melting points are uncorrected. MS analyses were per-
formed on an HP1100 liquid chromatograph coupled with
an electrospray ionisation-mass spectrometer (LC-ESI-MS),
using H2O/CH3CN as solvent at 258C (positive scan 100–
500 m/z, fragmentor 70 V). Imines 2a–e[57] and ketimines
2f, g[83] were prepared following a known procedure and
characterised by comparison with literature data.
[9] J. W. Clader, J. Med. Chem. 2004, 47, 1.
[10] D. A. Burnett, Curr. Med. Chem. 2004, 11, 1873.
[11] R. C. Wilmouth, N. J. Westwood, K. Anderson, W.
Brownlee, T. D. W. Claridge, I. J. Clifton, G. J. Pritch-
ard, R. T. Aplin, C. J. Schofield, Biochemistry 1998, 37,
17506.
[12] P. R. Bonneau, F. Hasani, C. Plouffe, E. Malenfant,
S. R. LaPlante, I. Guse, W. W. Ogilvie, R. Plante, W. C.
Davidson, J. L. Hopkins, M. M. Morelock, M. G. Cor-
dingley, R. Deziel, J. Am. Chem. Soc. 1999, 121, 2965.
[13] P. V. Bharatam, R. S. Kumar, M. P. Mahajan, Org. Lett.
2000, 2, 2725.
[14] M. Komatsu, H. Ogawa, M. Mohri, Y. Ohshiro, Tetra-
hedron Lett. 1990, 31, 3627.
[15] W. Kirmse, N. G. Rondan, K. N. Houk, J. Am. Chem.
Soc. 1984, 106, 7989.
[16] G. I. Georg, P. He, J. Kant, Z. J. Wu, J. Org. Chem.
1993, 58, 5771.
Complete characterization of compounds 3a, 3c–e, 4a,
[17] G. I. Georg, The Organic Chemistry of b-Lactams,
Verlag Chemie, New York, 1993.
4c–e, 6a, 6e, 7a, 7e have been reported in ref.[60] Complete
Adv. Synth. Catal. 2008, 350, 2261 – 2273
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2271

Fides Benfatti et al.
FULL PAPERS
[18] C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide,
Eur. J. Org. Chem. 1999, 1999, 3223.
[19] G. S. Singh, Tetrahedron 2003, 59, 7631.
[20] M. Benaglia, M. Cinquini, F. Cozzi, Eur. J. Org. Chem.
2000, 2000, 563.
[21] D. J. Hart, D. C. Ha, Chem. Rev 1989, 89, 1447.
[22] H. W. Moore, L. Hernandez, A. Sing, J. Am. Chem.
Soc. 1976, 98, 3728.
[23] B. Alcaide, P. Almendros, Curr. Med. Chem. 2004, 11,
1921.
[48] D. M. Bennett, I. Okamoto, R. L. Danheiser, Org. Lett.
1999, 1, 641.
[49] G. Cardillo, S. Fabbroni, L. Gentilucci, R. Perciaccante,
A. Tolomelli, Tetrahedron: Asymmetry 2004, 15, 593.
[50] B. B. Snider, M. Walner, Tetrahedron 1989, 45, 3171.
[51] W. T. Brady, R. A. Owens, Tetrahedron Lett. 1976,
1553.
[52] H. W. Moore, G. Hughes, Tetrahedron Lett. 1982, 23,
4003.
[53] K. Araki, J. A. Wichtowski, J. T. Welch, Tetrahedron
Lett. 1991, 32, 5461.
[24] A. R. A. S. Deshmukh, B. M. Bhawal, D. Krishnaswa-
my, V. V. Govande, B. A. Shinkre, A. Jayanthi, Curr.
Med. Chem. 2004, 11, 1889.
[54] P. D. Dey, A. K. Sharma, P. V. Bharatam, M. P. Maha-
jan, Tetrahedron 1997, 53, 13829.
[55] A. K. Sharma, M. P. Mahajan, Tetrahedron 1997, 53,
13841.
[25] C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide,
Curr. Med. Chem. 2004, 11, 1837.
[26] L. Jiao, Y. Liang, J. Xu, J. Am. Chem. Soc. 2006, 128,
6060.
[56] J. D. Buynak, J. Mathew, M. Narayana Rao, E. Haley,
C. George, U. Siriwardane, J. Chem. Soc. Chem.
Commun. 1987, 735.
[57] G. Cardillo, S. Fabbroni, L. Gentilucci, R. Perciaccante,
F. Piccinelli, A. Tolomelli, Tetrahedron 2004, 60, 5031.
[58] F. Benfatti, G. Cardillo, S. Fabbroni, L. Gentilucci, R.
Perciaccante, F. Piccinelli, A. Tolomelli, Synthesis 2005,
61.
[59] F. Benfatti, G. Cardillo, S. Fabbroni, L. Gentilucci, R.
Perciaccante, A. Tolomelli, Arkivoc 2005, vi, 136.
[60] G. Cardillo, S. Fabbroni, L. Gentilucci, R. Perciaccante,
F. Piccinelli, A. Tolomelli, Org. Lett. 2005, 7, 533.
[61] G. Cardillo, S. Fabbroni, L. Gentilucci, R. Perciaccante,
A. Tolomelli, Adv. Synth. Catal. 2005, 347, 833.
[62] F. Benfatti, G. Cardillo, L. Gentilucci, A. Tolomelli,
Eur. J. Org. Chem. 2007, 2007, 3199.
[63] F. Benfatti, G. Cardillo, L. Gentilucci, A. Tolomelli, M.
Monari, F. Piccinelli, Adv. Synth. Catal. 2007, 349, 1256.
[64] F. Benfatti, G. Cardillo, S. Fabbroni, L. Gentilucci, R.
Perciaccante, A. Tolomelli, M. Baiula, S. Spampinato,
Tetrahedron: Asymmetry 2006, 17, 167.
[27] A. Venturini, J. Gonzalez, J. Org. Chem. 2002, 67, 9089.
[28] C. Zhou, D. M. Birney, J. Am. Chem. Soc. 2002, 124,
5231.
[29] B. K. Banik, B. Lecea, A. Arrieta, A. de Cózar, F. P.
Cossío, Angew. Chem. Int. Ed. 2007, 46, 3028.
[30] F. P. Cossio, J. M. Ugalde, X. Lopez, B. Lecea, C.
Palomo, J. Am. Chem. Soc. 1993, 115, 995.
[31] J. A. Sordo, J. Gonzalez, T. L. Sordo, J. Am. Chem. Soc.
1992, 114, 6249.
[32] A. Macias, E. Alonso, C. delPozo, A. Venturini, J. Gon-
zalez, J. Org. Chem. 2004, 69, 7004.
[33] A. Bongini, M. Panunzio, G. Piersanti, E. Bandini, G.
Martelli, G. Spunta, A. Venturini, Eur. J. Org. Chem.
2000, 2000, 2379.
[34] M. Alajarín, A. Vidal, F. Tovar, A. Arrieta, B. Lecea,
F. P. Cossío, Chem. – Eur. J. 1999, 5, 1106.
[35] I. Arrastia, A. Arrieta, J. M. Ugalde, F. P. Cossio, B.
Lecea, Tetrahedron Lett. 1994, 35, 7825.
[36] A. Arrieta, F. P. Cossio, B. Lecea, J. Org. Chem. 2000,
65, 8458.
[37] B. Lecea, I. Arrastia, A. Arrieta, G. Roa, X. Lopez,
M. I. Arriortua, J. M. Ugalde, F. P. Cossio, J. Org.
Chem. 1996, 61, 3070.
[38] E. Martín-Zamora, A. Ferrete, J. M. Llera, J. M.
MuÇoz , R. R. Pappalardo, R. Fernꢂndez, J. M. Lassa-
letta, Chem. – Eur. J. 2004, 10, 6111.
[39] B. Li, Y. Wang, D. M. Du, J. Xu, J. Org. Chem. 2007,
72, 990.
[40] A. PeÇa-Gallego, J. Rodríguez-Otero, E. M. Cabaleiro-
Lago, Tetrahedron 2007, 63, 4937.
[41] S. Y. Lee, Y. S. Kulkarni, B. W. Burbaum, M. I. John-
ston, B. B. Snider, J. Org. Chem. 1988, 53, 1848.
[42] T. Nguyen Minh, T. K. Ha, R. A. More OꢃFerrall, J.
Org. Chem. 1990, 55, 3251.
[65] F. Benfatti, G. Cardillo, L. Gentilucci, R. Perciaccante,
A. Tolomelli, A. Catapano, J. Org. Chem. 2006, 71,
9229.
[66] F. Benfatti, G. Cardillo, S. Fabbroni, P. Galzerano, L.
Gentilucci, R. Juris, A. Tolomelli, M. Baiula, A. Sparta,
S. Spampinato, Bioorg. Med. Chem. 2007, 15, 7380.
[67] F. Benfatti, G. Cardillo, L. Gentilucci, A. Tolomelli,
Bioorg. Med. Chem. Lett. 2007, 17, 1946.
[68] A. K. Bose, L. Krishnan, D. R. Wagle, M. S. Manhas,
Tetrahedron Lett. 1986, 27, 5955.
[69] A. K. Bose, M. S. Manhas, M. Ghosh, M. Shah, V. S.
Raju, S. S. Bari, S. N. Newaz, B. K. Banik, A. G.
Chaudhary, K. J. Barakat, J. Org. Chem. 1991, 56, 6968.
[70] M. S. Manhas, M. Ghosh, A. K. Bose, J. Org. Chem.
1990, 55, 575.
[71] R. A. Firestone, P. L. Barker, J. M. Pisano, B. M. Ashe,
M. E. Dahlgren, Tetrahedron 1990, 46, 2255.
[72] B. B. Snider, E. Ron, B. W. Burbaum, J. Org. Chem.
1987, 52, 5413.
[43] A. D. Allen, L. Gong, T. T. Tidwell, J. Am. Chem. Soc.
1990, 112, 6396.
[44] R. L. Danheiser, R. G. Brisbois, J. J. Kowalczyk, R. F.
Miller, J. Am. Chem. Soc. 1990, 112, 3093.
[45] A. G. Birchler, F. Liu, L. S. Liebeskind, J. Org. Chem.
1994, 59, 7737.
[73] P. Geerlings, F. De Proft, W. Langenaeker, Chem. Rev
2003, 103, 1793.
[74] A. D. Becke, J. Chem. Phys. 1993, 98, 1372.
[75] N. Godbout, D. R. Salahub, J. Andzelm, E. Wimmer,
Can. J. Chem. 1992, 70, 560.
[46] G. Barbaro, A. Battaglia, P. Giorgianni, J. Org. Chem.
1987, 52, 3289.
[47] J. L. Loebach, D. M. Bennett, R. L. Danheiser, J. Org.
Chem. 1998, 63, 8380.
[76] M. J. Frisch, Gaussian 03, Revision, Wallingford, CT,
Gaussian Inc., 2004.
2272
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2261 – 2273

The Cycloaddition Reaction Between a-Bromo Vinylketenes and Imines
FULL PAPERS
[77] V. Barone, M. Cossi, J. Phys. Chem. A 1998, 102, 1995.
[78] V. Barone, M. Cossi, J. Tomasi, J. Comput. Chem. 1998,
19, 404.
[79] M. Cossi, V. Barone, J. Chem. Phys. 1998, 109, 6246.
[80] M. Cossi, N. Rega, G. Scalmani, V. Barone, J. Comput.
Chem. 2003, 24, 669.
[81] C. Peng, P. Y. Ayala, H. B. Schlegel, M. J. Frisch, J.
Comput. Chem. 1996, 17, 49.
[82] L. S. Hegedus, J. Montgomery, Y. Narukawa, D. C.
Snustad, J. Am. Chem. Soc. 1991, 113, 5784.
[83] M. J. OꢃDonnell, R. L. Polt, J. Org. Chem. 1982, 47,
2663.
Adv. Synth. Catal. 2008, 350, 2261 – 2273
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2273