Trapping intermediates in an [8 + 2] cycloaddition reaction with the help of DFT calculations

Article abstract of DOI:10.1021/ol200910z

DFT calculations predict that the [8 + 2] cycloaddition reaction between ketenes and 8-azaheptafulvenes occurs stepwise through antiaromatic zwitterionic intermediates. With adequate modifications of both the electronic properties of the ketene and the re

Full text of DOI:10.1021/ol200910z

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2892–2895
Trapping Intermediates in an [8 þ 2]
Cycloaddition Reaction with the Help of
DFT Calculations
ꢀ
Marta L. Lage, Israel Fernandez,* Miguel A. Sierra,* and M. Rosario Torres
´
Departamento de Quımica Organica I and Laboratorio de Difraccion de Rayos-X,
Facultad de Ciencias Quımicas, Universidad Complutense de Madrid, 28040 Madrid, Spain
ꢀ
ꢀ
´
israel@quim.ucm.es; sierraor@quim.ucm.es
Received April 7, 2011
ABSTRACT
DFT calculations predict that the [8 þ 2] cycloaddition reaction between ketenes and 8-azaheptafulvenes occurs stepwise through antiaromatic
zwitterionic intermediates. With adequate modifications of both the electronic properties of the ketene and the reaction conditions, these elusive
intermediates have been successfully trapped and fully characterized (X-ray), thus confirming the predicted stepwise nature of the transformation.
Cycloaddition reactions play a pivotal role in modern
organic synthesis because of their ability to increase the
molecular complexity in a single synthetic step.1 It is
generally accepted that while thermal cycloadditions
usually involve (4n þ 2) π electrons participating in the
starting materials, 4n π electrons are required in cycloaddi-
tions occurring with photochemical activation.2 Both type
of transformations have been traditionally understood
according to the WoodwardꢀHoffmann rules,3 which
are related to the principles of orbital symmetry.
to be concerted.4 Despite many cycloaddition processes
having been suggested to proceed through stepwise me-
chanisms, the experimental isolation of the corresponding
intermediates is still challenging. The main reason under-
lying this difficult task is the high reactivity of these
intermediate species.
(4) (a) Huisgen, R. J. Org. Chem. 1968, 33, 2291. (b) Firestone, R. A.
J. Org. Chem. 1968, 33, 2285. (c) Houk, K. N.; Firestone, R. A.;
Munchausen, L. L.; Mueller, P. H.; Arison, B. H.; Garcia, L. A. J.
ꢀ
Am. Chem. Soc. 1985, 107, 7227. (d) Houk, K. N.; Gonzalez, J.; Li, Y.
Nowadays, the initial idea of a concerted reaction
mechanism for cycloaddition reactions has evolved to a
range of different possibilities, i.e., from fully synchronous
and concerted transformations to highly asynchronous or
even stepwise mechanisms involving biradicals or zwitter-
ionicintermediates. For instance, the concertedor stepwise
mechanism of 1,3-dipolar reactions was hotly debated in
the past, but most of these reactions have been determined
Acc. Chem. Res. 1995, 28, 81. (e) McDouall, J. J. W.; Robb, M. A.; Niazi,
U.; Bernardi, F.; Schlegel, H. B. J. Am. Chem. Soc. 1987, 109, 4642.
(f) Hiberty, P. C.; Ohanessian, G.; Schlegel, H. B. J. Am. Chem. Soc.
1983, 105, 719. (g) Huisgen, R. J. Org. Chem. 1968, 33, 2291. (h)
Firestone, R. A. J. Org. Chem. 1968, 33, 2285. (i) Firestone, R. A. J.
Org. Chem. 1972, 37, 2181.
(5) Some examples of trapped or detected zwitterions in different
cycloaddition reactions: (a) Pacansky, J.; Chang, J. S.; Brown, D. W.;
Schwarz, W. J. Org. Chem. 1982, 47, 2233. (b) Quiao, G. G.; Andraos, J.;
Wentrup, C. J. Am. Chem. Soc. 1996, 118, 5634. (c) Lecea, B.; Arrastia, I.;
ꢀ
Arrieta, A.; Roa, G.; Lopez, X.; Arriortua, M. I.; Ugalde, J. M.; Cossıo,
F. P. J. Org. Chem. 1996, 61, 3070. (d) Sustmann, R.; Tappanchai, S.;
Bandmann, H. J. Am. Chem. Soc. 1996, 118, 12555. (e) Martelli, G.;
Spunta, G.; Panunzio, M. Tetrahedron Lett. 1998, 39, 6257. (f) Panunzio,
M.; Bacchi, S.; Campana, E.; Fiume, L.; Vicennati, P. Tetrahedron Lett.
1999, 40, 8495. (g) Bandini, E.; Favi, G.; Martelli, G.; Panunzio, M.;
Piersanti, G. A. Org. Lett. 2000, 2, 1077. (h) Vivanco, S.; Lecea, B.;
Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossıo, F. P. J. Am. Chem.
Soc. 2000, 122, 6078. (i) Machiguchi, T.; Okamoto, J.; Takachi, J.;
Hasegawa, T.; Yamabe, S.; Minato, T. J. Am. Chem. Soc. 2003, 125,
14446. (j) Machiguchi, T.; Okamoto, J.; Morita, Y.; Hasegawa, T.;
Yamabe, S.; Minato, T. J. Am. Chem. Soc. 2006, 128, 44.
(1) (a) Cycloaddition Reactions in Organics Synthesis; Kobayashi, S.,
Jorgensen, K. A., Eds.; Wiley-VCH: Weinheim, 2001. (b) Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Hetero-
cycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley: New
York, 2002.
(2) Sankararaman, S. Pericyclic Reactions;A Textbook: Reactions,
Applications and Theory; Wiley: Weinheim, 2005.
(3) (a) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl.
1969, 8, 781. (b) Woodward, R. B.; Hoffmann, R. The Conservation of
Orbital Symmetry; VCH: Weinheim, 1970.
r
10.1021/ol200910z
Published on Web 05/11/2011
2011 American Chemical Society

Nevertheless, the wise selection of substituents and reac-
tion conditions has allowed the isolation and characteriza-
tion of intermediates in very specific transformations.5
However, interest in capturing intermediates in stepwise
cycloadditions remains unabated.
This process yields zwitterion intermediate 3, which readily
evolves to the final cycloadduct 4 through a ring closure (in
a conrotatory process) via TS2, a saddle point associated
with the final CꢀC bond formation.10 Therefore, this
process resembles the stepwise mechanism of the [2 þ 2]
cycloaddition reaction between ketenes and imines to form
2-azetidinones.11
Scheme 1. [8 þ 2] Cycloaddition Reaction between Ketenes and
8-Azaheptafulvenes
Scheme 2. Computed Reaction Profile for the Cycloaddition
Reaction between Ketene 1 and Azaheptafulvene 2aa
Within the context of our ongoing work in the reaction
mechanims and synthetic applications of cycloaddition
reactions involving organic and organometallic reagents,6
the [8 þ 2] cycloaddition reaction of 8-azaheptafulvenes
and ketenes attracted our attention.7 This process, origin-
ally described by Kanemasa and co-workers,8a exclusively
leads to the corresponding trans-[8 þ 2] cycloadducts at
room temperature in excellent yields (Scheme 1).8 Infor-
mation about the concerted or stepwise nature of these
reactions was not provided. The possibility of using very
different ketenes and reaction conditions renders this
transformation a good target for a combined computa-
tional-experimental study of its reaction mechanism. Re-
ported herein is the computational (DFT) evidence of the
stepwise nature of the process, which led us to the experi-
mental isolation and complete characterization of the
involved intermediates.
DFT calculations (B3LYP and M06-2X/6-311þG(d)
levels)9 were carried out to study the [8 þ 2] cycloaddition
reaction between phenylketene 1 and 8-azaheptafulvene 2a
(Scheme 2). Our calculations suggest that the reaction
occurs stepwise through the initial nucleophilic attack of
the nitrogen atom of the cyclic imine to the electrophilic
carbonyl group of the ketene (via transition state TS1).
a Values close to the arrows indicate the computed PCM corrected
free energies (ΔG298, at 298 K in kcal/mol) using CH2Cl2 as solvent.
Bond lengths are given in angstroms. All data have been computed at the
M06-2X/6-311þG(d) level and B3LYP/6-311þG(d) level (in paren-
theses).
It has been suggested that the [8 þ 2]-cycloaddition
reaction between 8-azaheptafulvenes and ethynyl-Fischer
carbene complexes occurs through similar zwitterionic
intermediates12 because of the significant contribution of
the corresponding resonance form where the positive
charge is delocalized within the ring. This species, which
resembles the tropyl cation, should possess an important
aromatic character and, therefore, an important degree of
stability favoring the stepwise mechanism. However, the
computed positive values of the nuclear independent che-
mical shift (NICS)13 at the [3,þ1] ring critical point of the
electron density,14 as defined by Bader15 (NICS = þ5.3
ppm), and the corresponding out-of-plane component
ꢀ
(6) (a) Fernandez, I.; Sierra, M. A.; Cossıo, F. P. J. Org. Chem. 2006,
ꢀ
71, 6178. (b) Fernandez, I.; Cossıo, F. P.; Sierra, M. A. Organometallics
ꢀ
2007, 26, 3010. (c) Fernandez, I.; Sierra, M. A.; Cossıo, F. P. J. Org.
ꢀ
Chem. 2008, 73, 2083. (d) Fernandez, I.; Cossıo, F. P.; Sierra, M. A.
ꢀ
Chem. Rev. 2009, 109, 6687. (e) Fernandez, I.; Bickelhaupt, F. M.;
ꢀ
Cossıo, F. P. Chem.;Eur. J. 2009, 15, 13022. (f) Fernandez, I.; Cossıo,
ꢀ
F. P. Curr. Org. Chem. 2010, 14, 1578. (g) Fernandez, I.; Cossıo, F. P.; de
ꢀ
ꢀ
~
Cozar, A.; Lledos, A.; Mascarenas, J. L. Chem.;Eur. J. 2010, 16, 12147.
(11) For a recent review, see: (a) Cossıo, F. P.; Arrieta, A.; Sierra,
M. A. Acc. Chem. Res. 2008, 41, 925. Selected computational studies on
ꢀ
ꢀ
(h) Andrada, D. M.; Granados, A. M.; Sola, M.; Fernandez, I. Orga-
ꢀ
ꢀ
nometallics 2011, 30, 466. (i) Fernandez, I.; Cossıo, F. P.; Bickelhaupt,
the mechanism of the Staudinger reaction: (b) Sordo, J. A.; Gonzalez, J.;
F. M. J. Org. Chem. 2011, 76, 2310.
Sordo, T. L. J. Am. Chem. Soc. 1992, 114, 6249. (c) Cossıo, F. P.; Ugalde,
ꢀ
J. M.; Lopez, X.; Lecea, B.; Palomo, C. J. Am. Chem. Soc. 1993, 115, 995.
(7) For a review, see: (a) Nair, V.; Abhilash, K. G. Top. Heterocycl.
Chem. 2008, 13, 173. (b) Nair, V.; Abhilash, K. G. Tetrahedron Lett.
2006, 49, 8707.
(8) (a) Yamamoto, K.; Kajigaeshi, S.; Kanemasa, S. Chem. Lett.
1977, 6, 91. (b) Takaoka, K.; Aoyama, T.; Shioiri, T. Heterocycles 2001,
54, 209.
ꢀ
ꢀ
ꢀ
(d) Assfeld, X.; Ruiz-Lopez, M. F.; Gonzalez, J.; Lopez, R.; Sordo, J. A.;
Sordo, T. L. J. Comput. Chem. 1994, 15, 479. See also ref 5c.
ꢀ
(12) Barluenga, J.; Garcıa-Rodrıguez, J.; Suarez-Sobrino, A. L.;
ꢀ
Tomas, M. Chem.;Eur. J. 2009, 15, 8800.
(13) Chen, Z.; Wannere, C. S.; Corminboeuf, C.; Puchta, R.;
Schleyer, P. v. R. Chem. Rev. 2005, 105, 3842.
(9) See the computational details in the Supporting Information.
(10) The corresponding reaction path leading to the cis isomer was
also computed. Our calculations indicate that selection occurs in the
initial attack of the cyclic imine to the ketene. This is similar to the
process involving ketenes derived from Fischer carbene complexes. See:
(14) NICS values have been computed at the (3,þ1) ring critical point
of the electron density due to its high sensitivity to diamagnetic effects
and its unambiguous character to define the “center” of a ring in terms of
electron density.
ꢀ
~
ꢀ
Fernandez, I.; Sierra, M. A.; Mancheno, M. J.; Gomez-Gallego, M.;
(15) Bader, R. F. W. Atoms in Molecules: A Quantum Theory;
Clarendon: Oxford, 1990.
Cossıo, F. P. J. Am. Chem. Soc. 2008, 130, 13892.
Org. Lett., Vol. 13, No. 11, 2011
2893

(NICS(1)zz = þ7.4 ppm) clearly reflect the antiaromatic
nature of intermediate 3.16
ketene by nucleophilic attack of the enolate carbon atom.
Subsequent H-abstraction of the highly acidic hydrogen
atom at the central carbon atom of the dicarbonyl moiety
(either by the base present in the reaction or by the
formation of the corresponding enol) promotes the final
ring closure forming 7a.17
Scheme 3. [8 þ 2] Cycloaddition Reactions between Acyl
Chlorides 5 and 8-Azaheptafulvene 2b
The combination of an antiaromatic intermediate and a
favorable ring closure makes the isolation or trapping of
the zwitterionic intermediates 3 unpromising. However, as
stated above, the initial reagents are easily modifiable in
their reactivities, and reaction conditions can be also tuned
to achieve the desired endeavor. To this end, we first
performed the reaction between N-p-methoxyphenyl-8-
azaheptafulvene 2b and phenylketene at ꢀ78 °C. An
additional equivalent of ketene (generated in situ from
phenylacetyl chloride and Et3N at ꢀ78 °C) was used to
quench the corresponding intermediate by avoiding the
easy ring closure which leads to the [8 þ 2] cycloadduct.
Thus, the reaction of 2 equiv of acyl chloride 5aand 1 equiv
of azafulvene 2b produced a mixture of two compounds in
a 38:62 molar ratio (Scheme 3 and Table 1). The first
compound was characterized as the expected trans [8 þ 2]
cycloadduct 6a by comparison of its spectroscopic data
withthose reported inthe literature.7,8 Single crystalsofthe
new compound 7a suitable for X-ray diffraction analysis
were grown in hexanes/ethyl acetate solution (Figure 1).
Compound 7a contains two molecules of ketene and one
imine and can be viewed as the result of the trapping of
zwitterionic intermediate 3, which reacts with the excess of
Figure 1. ORTEP diagram of compound 7a.
To discard the possibility of the formation of 7a by the
base-promoted nucleophilic addition of the enolate of 6a
to the additional ketene equivalent, the isolated [8 þ 2]
cycloadduct 6a was reacted under reaction conditions
identical to those forming 7a (Et3N/CH2Cl2 and 1a
at ꢀ78 °C to rt). Compound 6a was recovered unaltered
(together with some minor decomposition products of
unknown structure), and no traces of compound 7a were
observed in the crude reaction mixtures. This control
experiment rules out the possibility of this alternative
process. Therefore, the isolation of this new compound
7a nicely confirms the computationally predicted stepwise
nature of the cycloaddition reaction between azaheptaful-
venes and ketenes.
To check the generality of this finding, different acyl
chlorides were tested as starting reactants against 2b
(Scheme 3).18 From the data in Table 1, it is clear that
Table 1. Cycloaddition Reactions of Acyl Chlorides 5 and
8-Azaheptafulvene 2b
(16) The antiaromaticity of 3 (nonplanar) is in part responsible for
the computed endergonicity of its formation (þ0.7 kcal/mol) and the
high exergonicity (ꢀ36.4 kcal/mol) computed for the final ring-closure
step.
(17) It is thought that compound 7a may be the result of the trapping
of the intermediate 3 by a molecule of acid chloride. However, the
reaction conditions used (ꢀ78 °C, acid chloride/Et3N, the so-called
“direct addition”) ensure the complete transformation of the acid
chlorides into the corresponding ketenes. See: Georg, G. I.; Ravikumar,
V. T. In The Organic Chemistry of β-Lactams; Georg, G. I., Ed.; VCH
Publishers, Inc.: New York, 1992; Chapter 6.
(18) Typical procedure: To a solution of the corresponding acid
chloride 5 (2.2 equiv) in CH2Cl2 (3 mL/ mmol) at ꢀ78 °C was added
Et3N (5 equiv) dropwise. The mixture was stirred at ꢀ78 °C for 20 min,
after which a solution of azaheptafulvene 2b (1 equiv) in CH2Cl2 (1.5
mL/mmol) was slowly transferred via cannula (dropwise) to the gener-
ated ketene. The resulting mixture was stirred at ꢀ78 °C for 30 min and
then warmed to room temperature overnight. The solvent was then
evaporated in vacuo and the crude mixture purified by flash column
chromatography using the mixture of eluents indicated for each case (see
the Supporting Information) rendering a mixture of compounds 6 and 7.
entry
acyl chloride
6/7 ratio
yielda (%)
others
1
2
5a
5b
5c
5d
5e
5f
40:60
68:32
95:5
42 (17:25)
44 (30:14)
26 (21:5)
42 (32:10)
80 (16:64)
6
3
4
76:24
20:80
100:0
100:0
100:0
100:0
100:0
5
6
cis-6f (3%)
cis-6g (6%)
7
5g
5h
5i
59
8
78
9
43
amide (25%)
10
5j
74
a The first value indicates the combined yields. In parentheses, the
first value corresponds to the isolated yield of 6 whereas the second one
indicates the isolated yield of 7.
2894
Org. Lett., Vol. 13, No. 11, 2011

intermediates make the reaction with a second ketene
molecule more difficult.
Scheme 4. Computed Reaction Profile for the Cycloaddition
Reaction between Ketene 1 and Azaheptafulvene 2aa
In order to fully understand the formation of 7, we have
computationally explored the nucleophilic attack of zwit-
terion 3 to the additional ketene equivalent (Scheme 4). Our
calculations indicate that the transition state associated
with this process (TS3) lies 1.3 kcal/mol below TS2,
which is associated with the formation of the [8 þ 2]
cycloadduct (Scheme 2). Therefore, the formation of 7
should be kinetically favored. Although both processes
are essentially different, i.e., one is intermolecular
whereas the other is intramolecular, and obviously the
reaction rate depends on the concentrations of the
involved species, it can be suggested that there is a
competition between both processes rendering a mixture
of products (as experimentally observed) in view of the low
barrier energy difference of both transformations. Finally,
intermediate 9, formed from zwitterion 8, leads to the
observed cycloadduct 7 through a similar ring-closure step
via TS4 (activation barrier of 13.3 kcal/mol).
In summary, we have computationally predicted that
the [8 þ 2] cycloaddition reaction between ketenes and
azaheptafulvenes occurs in a stepwise manner through an
antiaromatic zwitterionic intermediate. With adequate
modifications of both the electronic properties of the ketene
reagents and the reaction conditions and stoichiometry, we
were successful in trapping this elusive intermediate. The
zwitterion was trapped as a 2:1 ketene/azafulvene adduct
formed by reaction of the enolate carbon atom of 3 with a
second molecule of ketene followed by base-promoted ring
closure. The stepwise nature of the [8 þ 2] cycloaddition
reaction between ketenes and 8-azaheptafulvenes is there-
fore confirmed. The computationalꢀexperimental quest for
additional examples of nonconcerted cycloaddition reac-
tions is underway in our laboratories.
a Values close to arrows indicate the computed PCM corrected free
energies (ΔG298, at 298 K in kcal/mol) using CH2Cl2 as solvent. Bond
lengths are given in angstroms. All data have been computed at the M06-
2X/6-311þG(d) level.
the zwitterionic intermediate can be trapped only when
R = aryl substituent (entries 1ꢀ5). Alkyl- or heteroatom-
substituted compounds (entries 6ꢀ10) produce the ex-
pected trans [8 þ 2] cycloadduct and, strikingly, also the
elusive cis [8 þ 2] cycloadduct for R = benzyloxy or
phtalimidyl (albeit in very low reaction yields). These
results clearly reflect the crucial role of the electronic
properties of the ketene (and azafulvene) in trapping the
zwitterionic intermediate 3, as we had initially envisaged.
Electron-donating groups (such as OMe) placed in the
para position of the phenyl group increase the overall
yield of the process and strongly favor the formation of
species 7. Although these experiments have been planned
to check the predicted stepwise nature of the [8 þ 2]
cycloaddition, the latter result indicates that the new
heterocycle can indeed be produced in good yields. In
contrast, the absence of π-donor groups or the presence
of electron-withdrawing groups (such as CF3) lead only to
moderate overall reaction yields (up to 44%, entry 2,
Table 1) and mainly to the formation of cycloadduct 6.
Moreover, hetereoatom-substituted ketenes as well as
sterically hindered terbutylketene failed to trap intermedi-
ate 3. The reasons for this behavior are not clear, but
probably the more reactive (derived from heteroatom
substituted ketenes) or sterically hindered (tert-butyl)
Acknowledgment. We are grateful for financial support
from the Spanish MICINN (CTQ2010-20714-C02-01/
BQU and Consolider-Ingenio 2010, CSD2007-00006) and
ꢀ
CAM (S2009/PPQ-1634). I.F. is a Ramon y Cajal fellow.
Supporting Information Available. Experimental de-
tails and NMR spectra of isolated compounds, computa-
˚
tional details, Cartesian coordinates (in A), and free
energies of all the stationary points discussed in the text.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 11, 2011
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