Pericyclic cascade with chirality transfer: Reaction pathway and origin of enantioselectivity of the hetero-claisen approach to oxindoles

Article abstract of DOI:10.1002/anie.201105412

A new pericyclic cascade is proposed for the chiral auxiliary-controlled synthesis of 3,3-disubstituted oxindoles from nitrones and ketenes. The remarkable acyclic 1,6-stereochemical induction, hitherto unexplained, is rationalized by a stereoselective 3+

Full text of DOI:10.1002/anie.201105412

Communications
DOI: 10.1002/anie.201105412
Pericyclic Cascades
Pericyclic Cascade with Chirality Transfer: Reaction Pathway and
Origin of Enantioselectivity of the Hetero-Claisen Approach to
Oxindoles**
Nihan C¸ elebi-ꢀlÅꢁm, Yu-hong Lam, Edward Richmond, Kenneth B. Ling, Andrew D. Smith,*
and Kendall N. Houk*
Cascade reactions[1] are of increasing value in organic syn-
thesis due to their potential for expedient generation of
molecular complexity. Pericyclic cascades[1,2] are especially
appealing by virtue of their often predictable and exquisite
stereochemical control. The diverse pericyclic cascades
devised for target-oriented syntheses often act on substrates
bearing well-recognized structural motifs with amply docu-
mented reactivity requirements and stereochemical proper-
ties. Nevertheless, the interplay between theory and experi-
ment continues to uncover novel cascade mechanisms with
new or underexplored reactivity patterns. Indeed, for the
2+2 cycloadditions of ketenes with 1,3-dienes[3] and imines,[4]
the pericyclic mechanisms once formulated have recently
been revised to cascades of more than one elementary
mechanistic step. Other more elaborate pericyclic cascades
of synthetic interest have also been elucidated by computa-
tions.[5] We recently developed an efficient enantioselective
route to 3,3-disubstituted oxindoles from chiral nitrones and
disubstituted ketenes, but the origin of the asymmetric
induction remained unclear from existing mechanistic pro-
posals.[6] We now propose a novel pericyclic cascade com-
posed of a 3+2 cycloaddition and a hetero-[3,3]-sigmatropic
rearrangement, featuring chirality transfer in each of the two
constituent steps, which proves crucial in engendering
impressive enantioselectivity.
reported[6] that treatment of nitrone 1a, derived from
Garnerꢀs aldehyde,[11] with an alkylarylketene (2) afforded,
after aqueous workup, oxindoles (S)-3a–c in 80–88% yield
and 81–90% ee (Table 1, entries 1–3). Further experimental
Table 1: Enantioselective oxindole synthesis from homochiral nitrones 1
and alkylarylketenes 2.
Entry PG[d]
R/Ar
Product Yield
ee
[%][a] [%][b]
1[c]
2[c]
3[c]
4
5
6
Boc[d] (1a)
Me/Ph (2a)
Et/Ph (2b)
Et/p-(MeO)C6H4 (2c) 3c
3a
3b
85
80
88
75
84
81
79
60
87
81
90
91
96
98
98
98
Boc[d] (1a)
Boc[d] (1a)
Ts[d] (1b)
Et/Ph (2b)
3b
3b
TIPBS[d] (1c) Et/Ph (2b)
TIPBS[d] (1c) Et/p-(MeO)C6H4 (2c) 3c
7
8
TIPBS[d] (1c) Et/p-FC6H4 (2d)
TIPBS[d] (1c) Me/Ph (2a)
3d
3a
[a] Yield of isolated 3. [b] Determined by HPLC on a purified sample of 3.
[c] Ref. [6]. [d] PG=protecting group. Boc=tert-butoxycarbonyl.
Ts =para-toluenesulfonyl. TIPBS=2,4,6-triisopropylbenzenesulfonyl.
The reactions of N-phenylnitrones with diphenylketene to
form oxindoles were first investigated by Staudinger[7] and
subsequently by Lippmann[8] and Taylor.[9] Building upon this
precedent, and the utility of 3-alkyl-3-aryloxindoles (3) as
valuable synthetic intermediates that can be derivatized to
numerous natural products and medicinal targets,[10] we
optimization of this process showed that nitrones derived
from Garnerꢀs aldehyde are critical to achieve high asym-
metric induction, with increasing size of the oxazolidine N-
substituent (1b–c) consistently leading to improved enantio-
selectivities. For example, nitrone 1c incorporating the bulky
2,4,6-triisopropylbenzenesulfonyl group led to excellent ste-
reoinduction in its reaction with alkylarylketenes 2a–d
(entries 4–8), giving ee values of up to 98%.
[*] Dr. N. C¸elebi-ꢀlÅꢁm, Dr. Y.-h. Lam, Prof. Dr. Dr. K. N. Houk
Department of Chemistry and Biochemistry
University of California, Los Angeles
607 Charles E. Young Drive East, Los Angeles, CA 90095 (USA)
E-mail: houk@chem.ucla.edu
The initially proposed reaction pathways for this process
(pathway I, Scheme 1),[6–9] involved the ketene (shown here as
2a) reacting as an electrophile towards the nitrone (shown
here as 4), giving, after rearomatization, the experimentally
isolable imino acids 5 bearing a quaternary carbon. Subse-
quent hydrolysis and cyclization afford the oxindole products
3.
We computationally explored possible reaction pathways
in this system, using 4 and 2a as model reactants (Scheme 1).
Intriguingly, although the pericyclic step in pathway I is
analogous[12] to the proposed mechanisms of the Brunner
oxindole[13] and Fischer indole syntheses,[14] all our attempts in
E. Richmond, Dr. K. B. Ling, Dr. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews
North Haugh, St Andrews, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
[**] We thank the UCLA IDRE, the ShaRCS Pilot Project for the UC
systems, and the NCSA TeraGrid for computer time. The NIGMS-
NIH (grant GM-36700 to K.N.H.), Royal Society (URF to A.D.S.),
EPSRC (K.B.L.) and Cancer Research UK (E.R.) are thanked for
funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105412.
11478
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11478 –11482

formation of 5. The key imino acid 5 arises from 4 and 2a
through a pericyclic cascade composed of a 1,3-dipolar
cycloaddition and a hetero-[3,3]-sigmatropic rearrangement
(Scheme 1, pathway II). A novel mode of chirality transfer
through the pericyclic steps explains the origin of the
asymmetric induction.
Ketenes are versatile compounds known to undergo
nucleophilic attack, but can also react as 2p components in
cycloadditions.[16] We studied the TSs for the 3+2 cycloaddi-
tion of 4 and 2a (pathway II) and the subsequent fate of the
intermediates (Figure 1). Remarkably, the most favorable
=
mode of the cycloaddition was predicted to be across the C O
bond of 2a forming the substituted 1,4,2-dioxazolidine 6, with
an activation free energy of only 11.8 kcalmolÀ1 (TS-32,
=
Figure 1). The cycloaddition across the C C bond has a
considerably higher activation free energy (22.4 kcalmolÀ1).
=
The ketene C O group has been shown to participate in
4+2,[3,17] 2+2,[18] and 3+2 cycloadditions.[19] TS-32 has a very
À
short partial C O bond (dCO = 1.57 ꢁ), which causes further
=
polarization of the C N bond of the nitrone. At the transition
state, the carbon of the 1,3-dipole possesses electrophilic
character (0.1e), and there is substantial negative charge
building up on the ketene oxygen (À0.6 e). The total charge
transfer in TS-32 is 0.2 e. The cycloaddition is concerted; the
intrinsic reaction coordinate (IRC) path connected reactants
4 and 2a to 6.[20,21]
Scheme 1. Nucleophilic addition/hetero-Claisen rearrangement path-
way proposed previously (pathway I) and novel pericyclic cascade
mechanism (pathway II).
The cycloadduct 6 features an exocyclic alkylidene group
suitably positioned with respect to the nitrogen-bound phenyl
ring for an aromatic hetero-[3,3]-rearrangement to proceed.
locating the transition structure (TS) for this step failed.[15]
Instead, we have identified a new mechanism for the
Figure 1. Energy profile for the pericyclic cascade mechanism of 4 and 2a. TS-32, TS-33, and TS-RO refer to the transition structures for the
3+2 cycloaddition, the hetero-Claisen rearrangement, and the rearomatization with concomitant ring opening, respectively. (M06-2X/6-311+G-
(d,p)(THF)//B3LYP/6-31G(d), gas-phase B3LYP/6-31G(d) energies are given in brackets).
Angew. Chem. Int. Ed. 2011, 50, 11478 –11482
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11479

Communications
This process (TS-33) is predicted to be facile, with an
activation free energy of 11.2 kcalmolÀ1 from 4 and 2a,
giving the intermediate 7 with the quaternary stereocenter
installed, with an exergonicity of 33.5 kcalmolÀ1. The tran-
sition state is highly asynchronous; an excessively long
À
forming C C bond (dCC = 3.47 ꢁ) predicts almost no bonding
between the interacting orbitals at the TS. However, both the
IRC calculations and the potential energy surface (PES) scan
in the gas phase and in solvent reveal no intermediates
between TS-33 and 7.[21] The PES also shows that the
transition state is mainly associated with the breaking of the
À
À
N O bond. The formation of the C C bond is found to be a
spontaneous downhill process, presumably driven by the high
exergonicity of the transformation. Intermediate 7 then
undergoes cleavage of the hemiaminal linkage and aromati-
zation via TS-RO to give the aromatic imino acid 5. The free-
energy barrier is calculated to be 17.2 kcalmolÀ1 for this step.
However, TS-RO involves an intramolecular proton transfer,
which is more likely to be a catalyzed process under
experimental conditions.[21]
These calculations establish that pathway II, composed of
tandem 3+2 cycloaddition/hetero-[3,3]-sigmatropic rear-
rangement is energetically viable under the experimental
conditions, while the hetero-Claisen rearrangement of the
ketene–nitrone adduct in pathway I is prohibitively high in
energy.
The stereochemical aspects of pathway II were then
considered. The reaction of 1a and 2a gave oxindole (S)-3a
in 87% ee (Table 1, entry 1).[6] As illustrated in Scheme 2, the
cycloaddition installs a stereogenic center at C3 and an
Scheme 2. Chirality transfer between the pericyclic steps. R*=Boc-
protected chiral auxiliary.
=
unsymmetrically substituted C C double bond in the diaste-
reomeric intermediates 6a–c, the stereochemical information
of which is transferred to the intermediate 7a–c through the
stereospecific [3,3]-rearrangement. Ring opening and rear-
omatization will destroy the stereocenter at C3 but the
quaternary stereocenter will remain intact. The configuration
of the quaternary stereocenter in the imino acid and the
oxindole is, therefore, determined at the 3+2 cycloaddition
step simultaneously by two factors: the face of the nitrone
exposed for cycloaddition, and the direction of attack of the
ketene, where the phenyl group can be oriented trans or cis to
the incipient O6–C5 bond. The transition state TS32-S1
corresponds to the cycloaddition involving the Si face of the
nitrone and the ketene with a trans-oriented phenyl group.
This will give rise to cycloadduct 6b featuring an E-configured
group (TS-32-S1). This predicts the further improvement in
enantioselectivity with increasing size of the N-protecting
group, which was indeed observed experimentally (Table 1).
The trans preference of the aryl group of ketenes observed
here is in accord to our previous findings about reactions with
chiral alcohol nucleophiles.[23]
The other stereodetermining factor, the p-facial selectiv-
ity induced by the chiral auxiliary on the nitrone,[24] can be
understood by examining the conformation of the nitrone
about the C2–C3 bond in TS-32-S1 and TS-32-R2 (Figure 2).
When the nitrone reacts through its Si face (TS-32-S1), the
=
À
C C double bond. Subsequent [3,3]-sigmatropic rearrange-
ketene approaches the nitrone, anti to the oxazolidine C N
ment through the Re face of the alkene will install the S
stereocenter. On the other hand, the R enantiomer will be
obtained by reversing either the orientation of the ketene
(TS32-R1) or the face of the nitrone attacked (TS32-R2)
during the cycloaddition.
The optimized TSs are illustrated in Figure 2. TS-32-S1
leading to (S)-3a is lowest in energy, while TS-32-R1 and TS-
32-R2 are less stable by 1.5 and 3.6 kcalmolÀ1, respectively.[22]
The free-energy difference between TS-32-S1 and TS-32-R1
corresponds to an ee value of 84%, in good agreement with
experiment. The steric contact of the ketene cis substituent
with the tert-butoxycarbonyl (Boc) group is more unfavorable
for the bulkier phenyl group (TS-32-R1) than for a methyl
bond (t(1234) = À177.18), and, thus, away from the steric bulk
of the Boc group. The hydrogen atom and the ring methylene
group adopt the inside and the outside positions, respectively.
Garnerꢀs aldehyde,[11] from which 1a is derived, often obeys
Felkin–Anh stereochemical control in nucleophilic addi-
tions.[25] A feature shared by this model and the cycloaddition
À
TSs here is the preference for the C N bond on the
stereocenter to be anti to the forming bond. In our cyclo-
addition TSs, however, the inside position, instead of the
outside position, is sterically the more demanding site because
of 1,3-allylic strain[26] of any substituent with the nitrone
oxygen. The outside position is also sterically favored in the
cycloaddition TSs than in the Felkin–Anh model because of
11480 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11478 –11482

Experimental Section
Representative procedure: To a solution of nitrone 1c (0.070 g,
0.144 mmol) in dry tetrahydrofuran (THF) (2 mL) under nitrogen at
À788C was added dropwise a solution of ketene 2c (0.043 g,
0.288 mmol) in dry THF (1 mL). The mixture was stirred at À788C
overnight. The reaction was then quenched with 2m HCl (aq)
(0.5 mL) and stirred for 30 min, allowing to warm to RT before
extraction with Et2O (3 ꢃ 10 mL). The combined organic phases were
washed with NaHCO3 (aq), dried over Na2SO4, filtered, and
concentrated in vacuo to give a crude oil which was purified by
column chromatography over silica (0–30% EtOAc in petroleum
ether) to yield 3c (0.031 g, 81%) as an off-white solid.
All calculations were carried out at the M06-2X/6-311 + G(d,p)-
(THF)//B3LYP/6-31G(d) level of theory with Gaussian 09.[28] Com-
putational details are given in the Supporting Information. In the text,
M06-2X free energies including solvation corrections are reported.
Received: August 1, 2011
Revised: September 5, 2011
Published online: October 4, 2011
Keywords: asymmetric synthesis ·
.
density functional calculations · pericyclic reactions ·
reaction mechanisms
Figure 2. Stereoisomeric transition structures and their relative free
energies. (M06-2X/6-311+G(d,p)(THF)//B3LYP/6-31G(d), gas-phase
B3LYP/6-31G(d) energies are given in brackets).
[1] a) E. A. Anderson, Org. Biomol. Chem. 2011, 9, 3997 – 4006;
b) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167 –
178; c) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38,
2993 – 3009; d) T. Newhouse, P. S. Baran, R. W. Hoffmann,
Chem. Soc. Rev. 2009, 38, 3010 – 3021; e) A. Padwa, Chem.
Soc. Rev. 2009, 38, 3072 – 3081; f) J. Poulin, C. M. Grisꢄ-Bard, L.
Barriault, Chem. Soc. Rev. 2009, 38, 3092 – 3101; g) E. A. Ilardi,
C. E. Stivala, A. Zakarian, Chem. Soc. Rev. 2009, 38, 3133 – 3148;
h) C. J. Morten, J. A. Byers, A. R. Van Dyke, I. Vilotijevic, T. F.
Jamison, Chem. Soc. Rev. 2009, 38, 3175 – 3192; i) B. B. Tourꢄ,
D. G. Hall, Chem. Rev. 2009, 109, 4439 – 4486; j) K. C. Nicolaou,
D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118, 7292 –
7344; Angew. Chem. Int. Ed. 2006, 45, 7134 – 7186.
the nearly perpendicular angle of attack from the ketene
oxygen (O4-C3-N7 = 84.58), rather than the obtuse, Bꢂrgi–
Dunitz angle in carbonyl additions.[27] Thus, although the anti
À
À
relationship between the forming C O bond and the C N
bond is maintained in both TS-32-R2 and TS-32-S1, TS-32-R2
is destabilized by steric crowding because of the ring
methylene group occupying the inside position.
In summary, for the chiral auxiliary-controlled synthesis
of oxindoles from nitrones and ketenes, the enantioselectivity
of this process has been optimized (up to 98% ee) through the
use of an oxazolidine N-2,4,6-triisopropylbenzenesulfonyl
substituent. We delineated a new pericyclic cascade com-
posed of a 3+2 cycloaddition involving the ketene carbonyl
group and a hetero-[3,3]-sigmatropic rearrangement. The
high enantioselectivity is attained by both effective p-facial
control from the chiral auxiliary of the nitrone and the high
propensity of the ketene to adopt the aryl-trans orientation
during the cycloaddition. The stereochemical information
embedded in the cycloadduct formed is then transferred,
through the sigmatropic rearrangement, to the imino acid (S)-
5b, which is converted in situ to oxindole (S)-3a, thus
achieving an overall acyclic 1,6-stereochemical induction
from the chiral auxiliary to the final product. Computational
data on reactants with different N-protecting groups and
[2] a) K. N. Houk, J. Gonzalez, Y. Li, Acc. Chem. Res. 1995, 28, 81 –
90; b) P. H.-Y. Cheong, C. Legault, J. M. Um, N. C¸ elebi-ꢅlÅꢂm,
K. N. Houk, Chem. Rev. 2011, 111, 5042 – 5137.
[3] T. Machiguchi, T. Hasegawa, A. Ishiwata, S. Terashima, S.
Yamabe, T. Minato, J. Am. Chem. Soc. 1999, 121, 4771 – 4786.
[4] F. P. Cossꢆo, A. Arrieta, M. A. Sierra, Acc. Chem. Res. 2008, 41,
925 – 936.
[5] a) R. S. Paton, S. E. Steinhardt, C. D. Vanderwal, K. N. Houk, J.
Am. Chem. Soc. 2011, 133, 3895 – 3905; b) A. B. Gonzꢇlez Pꢄrez,
J. A. Souto, C. Silva Lꢈpez, ꢉ. R. de Lera, Eur. J. Org. Chem.
2011, 2933 – 2939; c) R. Pal, R. J. Clark, M. Manoharan, I. V.
Alabugin, J. Org. Chem. 2010, 75, 8689 – 8692; d) M. W. Lode-
wyk, M. J. Kurth, D. J. Tantillo, J. Org. Chem. 2009, 74, 4804 –
4811; e) A. E. Hayden, H. Xu, K. C. Nicolaou, K. N. Houk, Org.
Lett. 2006, 8, 2989 – 2992; f) Z. R. Akerling, J. E. Norton, K. N.
Houk, Org. Lett. 2004, 6, 4273 – 4275.
[6] N. Duguet, A. M. Z. Slawin, A. D. Smith, Org. Lett. 2009, 11,
3858 – 3861.
[7] H. Staudinger, K. Miescher, Helv. Chim. Acta 1919, 2, 554 – 582.
[8] C. H. Hassall, A. E. Lippmann, J. Chem. Soc. 1953, 1059 – 1063.
[9] a) C. P. Falshaw, N. A. Hashi, G. A. Taylor, J. Chem. Soc. Perkin
Trans. 1 1985, 1837 – 1843; b) M. Hafiz, G. A. Taylor, J. Chem.
Soc. Perkin Trans. 1 1980, 1700 – 1705; c) D. P. Stokes, G. A.
Taylor, J. Chem. Soc. C 1971, 2334 – 2336; d) R. N. Pratt, D. P.
Stokes, G. A. Taylor, J. Chem. Soc. C 1968, 1653 – 1657; e) A. F.
Gettins, D. P. Stokes, G. A. Taylor, J. Chem. Soc. Perkin Trans. 1
1977, 1849 – 1855.
=
substituents on the nitrone C N bond and the nitrone
aromatic ring are consistent with our model and will be
disclosed in a full article. The findings described here
demonstrate the power of modern, accurate quantum
mechanical computations in the discovery of novel asymmet-
ric pericyclic cascades of synthetic interest.
Angew. Chem. Int. Ed. 2011, 50, 11478 –11482
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11481

Communications
[10] a) B. Tan, N. R. Candeias, C. F. Barbas III, Nat. Chem. 2011, 3,
[17] a) S. Yamabe, T. Dai, T. Minato, T. Machiguchi, T. Hasegawa, J.
Am. Chem. Soc. 1996, 118, 6518 – 6519; b) R. Maurya, C. A.
Pittol, R. J. Pryce, S. M. Roberts, R. J. Thomas, J. O. Williams, J.
Chem. Soc. Perkin Trans. 1 1992, 1617 – 1621.
473 – 477; b) A. Ashimori, B. Bachand, M. A. Calter, S. P.
Govek, L. E. Overman, D. J. Poon, J. Am. Chem. Soc. 1998,
120, 6488 – 6499; c) L. E. Overman, D. J. Poon, Angew. Chem.
1997, 109, 536 – 538; Angew. Chem. Int. Ed. Engl. 1997, 36, 518 –
521; d) A. Ashimori, T. Matsuura, L. E. Overman, D. J. Poon, J.
Org. Chem. 1993, 58, 6949 – 6951. For reviews, see e) C. V.
Galliford, K. A. Scheidt, Angew. Chem. 2007, 119, 8902 – 8912;
Angew. Chem. Int. Ed. 2007, 46, 8748 – 8758; f) C. Marti, E. M.
Carreira, Eur. J. Org. Chem. 2003, 2209 – 2219. For pharmaco-
logical activity of 3-alkyl-3-aryloxindoles, see: g) R. R. Goehr-
ing, Y. P. Sachdeva, J. S. Pisipati, M. C. Sleevi, J. F. Wolfe, J. Am.
Chem. Soc. 1985, 107, 435.
[18] a) T. Machiguchi, J. Okamoto, Y. Morita, T. Hasegawa, S.
Yamabe, T. Minato, J. Am. Chem. Soc. 2006, 128, 44 – 45; b) T.
Machiguchi, J. Okamoto, J. Takachi, T. Hasegawa, S. Yamabe, T.
Minato, J. Am. Chem. Soc. 2003, 125, 14446 – 14448.
[19] a) E. Fahr, E. Bꢂttner, K.-H. Keil, J. Markert, F. Scheckenbach,
R. Thiedemann, J. Fontaine, Liebigs Ann. Chem. 1981, 1433 –
1444; b) M. A. Abou-Gharbia, M. M. Joullie, J. Org. Chem.
1979, 44, 2961 – 2966; c) R. M. Kellogg, J. Org. Chem. 1973, 38,
844 – 846; d) F. Texier, R. Carriꢄ, J. Jaz, J. Chem. Soc. Chem.
Commun. 1972, 199 – 200.
[20] Computations in solvent models located a shallow intermediate
(dCO = 1.71 ꢁ) with a very similar optimized geometry to that of
TS-32 and only 0.2 kcalmolÀ1 below it, and with an enthalpy
barrier of 2.6 kcalmolÀ1 for cyclization.
[21] See the Supporting Information for the PES scan and IRC paths.
[22] TS-32-S2, in which both the face of nitrone attacked and the
orientation of the ketene are reversed, is over 5 kcalmolÀ1 higher
in energy than TS-32-S1.
[11] a) P. Garner, J. M. Park, Org. Synth. 1992, 70, 18; b) X. Liang, J.
Andersch, M. Bols, J. Chem. Soc. Perkin Trans. 1 2001, 2136 –
2157.
[12] S. Blechert, Synthesis 1989, 71 – 82.
[13] a) Z. Mao, S. W. Baldwin, Org. Lett. 2004, 6, 2425 – 2428; b) J.
Wolff, M. Taddei, Tetrahedron 1986, 42, 4267 – 4272.
[14] a) B. Robinson, Chem. Rev. 1963, 63, 373 – 401; b) N. C¸ elebi-
ꢅlÅꢂm, B. W. Boal, A. D. Huters, N. K. Garg, K. N. Houk, J. Am.
Chem. Soc. 2011, 133, 5752 – 5755.
[23] C. E. Cannizzaro, K. N. Houk, J. Am. Chem. Soc. 2004, 126,
10992 – 11008.
[15] Attempts to locate the TS for this step by constraining the
À
À
forming C C and the breaking N O bonds at various partial
bond distances in the gas phase and in solution yielded highly
unstable TSs with a free energy of at least 44.1 kcalmolÀ1 relative
to the separated reactants.
[24] K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998, 98, 863 – 910.
[25] A. Mengel, O. Reiser, Chem. Rev. 1999, 99, 1191 – 1224.
[26] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841 – 1860.
[27] a) H. B. Bꢂrgi, J. D. Dunitz, E. Shefter, J. Am. Chem. Soc. 1973,
95, 5065 – 5067; b) N. T. Anh, Top. Curr. Chem. 1980, 88, 145 –
162.
[16] For reviews on ketene chemistry, see: a) T. T. Tidwell, Ketenes,
2. ed., Wiley, 2006; b) J. A. Hyatt, P. W. Reynolds, Org. React.
1994, 45, 159; c) T. T. Tidwell, Acc. Chem. Res. 1990, 23, 273 –
279.
[28] M. J. Frisch et al. Gaussian09, revision A.2, Gaussian, Inc.,
Wallingford, CT, 2009.
11482 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11478 –11482