Demonstrating the Synergy of Synthetic, Mechanistic, and Computational Studies in A Regioselective Aniline Synthesis

Article abstract of DOI:10.1021/jo035677u

Tri- and tetrasubstituted anilines are formed in good to excellent yields by the addition of ketones to vinamidinium salts (up to 98%). The reaction proceeds via the formation of dienone intermediates, which react to form an enamine with the liberated amine. In the case of a nitro, or dimethylaminomethylene substituent, the enamines undergo a facile electrocyclic ring closure to form a cyclohexadiene, which goes on to form anilines with a high degree of selectivity (up to 50:1) with a minor competing pathway proceeding via the enol providing phenols. Competition experiments using isotopic substitution reveal that the rate determining step en route to dienone is enol/enolate addition to the vinamidinium salt, which is characterized by an inverse secondary isotope effect (k_H/D 0.7-0.9). Computational studies have been used to provide a framework for understanding the reaction pathway. The original proposal for a [1,5]-H shift was ruled out on the basis of the calculations, which did not locate a thermally accessible transition state. The minimum energy conformation of the enamine is such that a facile electrocyclic ring closure is ensured, which is corroborated by the experimental studies. A framework for understanding the reaction pathway is presented.

Full text of DOI:10.1021/jo035677u

Dem on str a tin g th e Syn er gy of Syn th etic, Mech a n istic, a n d
Com p u ta tion a l Stu d ies in a Regioselective An ilin e Syn th esis
Ian W. Davies,* J ean-Franc¸ois Marcoux, J effery T. Kuethe, Michael D. Lankshear,
J eremy D. O. Taylor, Nancy Tsou, Peter G. Dormer, and David L. Hughes
Department of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, New J ersey 07065-0900
K. N. Houk† and Vildan Guner
Department of Chemistry and Biochemistry, University of California, Los Angeles, 405 Hilgard Avenue,
Los Angeles, California 90095-1569
ian_davies1@merck.com
Received November 14, 2003
Tri- and tetrasubstituted anilines are formed in good to excellent yields by the addition of ketones
to vinamidinium salts (up to 98%). The reaction proceeds via the formation of dienone intermediates,
which react to form an enamine with the liberated amine. In the case of a nitro, or dimethyl-
aminomethylene substituent, the enamines undergo a facile electrocyclic ring closure to form a
cyclohexadiene, which goes on to form anilines with a high degree of selectivity (up to 50:1) with
a minor competing pathway proceeding via the enol providing phenols. Competition experiments
using isotopic substitution reveal that the rate determining step en route to dienone is enol/enolate
addition to the vinamidinium salt, which is characterized by an inverse secondary isotope effect
(kH/D 0.7-0.9). Computational studies have been used to provide a framework for understanding
the reaction pathway. The original proposal for a [1,5]-H shift was ruled out on the basis of the
calculations, which did not locate a thermally accessible transition state. The minimum energy
conformation of the enamine is such that a facile electrocyclic ring closure is ensured, which is
corroborated by the experimental studies. A framework for understanding the reaction pathway is
presented.
In tr od u ction
ceutical program these methods enable the synthesis of
a large range of compounds in a serial, parallel, or even
combinatorial fashion from common precursors. They
allow for the display of a wide range of functionality
possessing interesting steric and electronic architectures
to probe and ultimately optimize for the desired phar-
macological properties.
The selective Cox-2 inhibitor etoricoxib (Arcoxia) 1 was
discovered in an extremely successful medicinal chem-
istry program that relied heavily on state of the art cross-
coupling reactions.4 Inevitably the synthesis of the
trisubstitued pyridine such as etoricoxib using a conven-
tional cross-coupling reaction requires a trisubstituted
precursor as a reaction partner. Hence the level of
complexity of the starting material is similar to that of
the product, which is clearly unattractive with respect
to atom economy and synthetic efficiency.5 Reactions that
lead to an increase in molecular complexity are important
synthetic tools. Attractive alternatives to substitutive
The practice of synthetic organic chemistry is con-
stantly evolving as new methodologies are crafted to
tackle contemporary problems that present unique chal-
lenges for chemical synthesis. Catalytic transition-metal
cross-coupling technologies are now well-established and
allow for the rapid construction of complex molecules.
Recently, the advent of powerful new ligand/catalyst
systems for carbon-carbon and carbon-heteroatom bond
formation has significantly increased the utility of these
coupling methodologies1 and has significantly broadened
the scope of compounds that can be prepared that have
established value in medicinal chemistry. The extension
of cross-coupling partners by Denmark and MacMillan
to include silicon2 and nitrogen3 derivatives, respectively,
has further enhanced the synthetic utility of cross-
coupling strategies. In the discovery phase of a pharma-
† Email for K.N.H.: houk@ucla.chem.edu.
(1) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(2) (a) Denmark, S. E.; Choi, J . Y. J . Am. Chem. Soc. 1999, 121,
5821. (b) Denmark, S. E.; Wu, Z. Org. Lett. 1999, 1, 1495. (c) Denmark,
S. E.; Wang, Z. Synthesis 2000, 999. (d) Denmark, S. E.; Wehrli, D.
Org. Lett. 2000, 2, 565. (e) Denmark, S. E.; Neuville, L. Org. Lett. 2000,
2, 3221. (f) Denmark, S. E.; Pan, W. Org. Lett. 2001, 3, 61. (g) Denmark,
S. E.; Sweis, R. F. J . Am. Chem. Soc. 2001, 123, 6439. (h) Denmark,
S. E.; Ober, M. H. Org. Lett. 2003, 5, 1357.
(4) (a) Friesen, R. W.; Brideau, C.; Chan, C.-C.; Charleson, S.;
Deschenes, D.; Dube, D.; Ethier, D.; Fortin, R.; Gauthier, J . Y.; Girard,
Y.; Gordon, R.; Greig, G. M.; Riendeau, D.; Savoie, C.; Wang, Z.; Wong,
E.; Visco, D.; Xu, L. J .; Young, R. N. Bioorg. Med. Chem. Lett. 1998, 8,
2777. (b) Dube, D.; Brideau, Deschenes, D.; Fortin, R.; Friesen, R. W.;
Gordon, R.; Girard, Y.; Riendeau, D.; Savoie, C.; Chan, C.-C. Bioorg.
Med. Chem. Lett. 1999, 9, 1715.
(3) Blakey, S. B.; Macmillan, D. W. C. J . Am. Chem. Soc. 2003, 125,
6406.
(5) Trost, B. M. Science 1991, 254, 1471. Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 259.
10.1021/jo035677u CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/20/2004
1298
J . Org. Chem. 2004, 69, 1298-1308

Synthetic, Mechanistic, and Computational Synergy
SCHEME 1
of ammonia.13 Gupton has also used vinamidinium salts
very effectively for the synthesis of pyrroles,14 pyrim-
idines,15 and pyrazoles.16
CHART 1
With access to a wide range of vinamidinium salts in
our laboratories, we have continued to explore their
synthetic utility.17,18 While examining the addition of
methylacetoacetate 2 (MAA) to a â-nitrovinamidinium
salt 3, we discovered a novel reaction manifold where
formation of aniline 4 and phenol 5 was observed rather
than the expected pyridine in the presence or absence of
ammonia (Scheme 1).
cross-coupling reactions that increase molecular complex-
ity include C-H activation using transition metals, e.g.,
Ru,6 Rh,7 Ir,8 and are currently attracting substantial
efforts. These methods will undoubtedly mature to
provide useful mainstream methodologies and may allow
for the identification of new strategies for diversity
synthesis.9 However there is still a significant opportu-
nity to establish new “classical” approaches involving
multicomponent coupling reactions that construct aro-
matic and heteroaromatic compounds.
In a preliminary account of this work, we reported the
formation of the regioisomeric aniline 6, and the reaction
was rationalized as proceeding through a facile [1,5]-
hydrogen or hydride shift.19 A combination of experimen-
tal studies using isotopically labeled substrates and DFT
calculations were to further characterize the reaction
pathway. The isotope studies provided kinetic isotope
effects and product isotope effects that were difficult to
understand within the context of a [1,5]-hydrogen shift.
This would be a unique case and would require a
hydrogen migration to be insensitive to isotopic substitu-
tion. An extensive series of calculations did not locate a
thermally accessible transition state of <50 kcal/mol. On
the basis of the compelling mechanistic and theoretical
studies, the assignment of structure was revisited.20 The
regioisomeric aniline product 4 was demonstrated to be
the unambiguous product in the reaction by authentic
synthesis, NOE studies, and X-ray crystallographic analy-
sis of an analogue. In this paper we provide full details
of the synthetic, mechanistic and computational aspects
of our program. We develop a conceptual framework for
understanding the mechanistic features of the conversion
We previously described how vinamidinium salts may
be exploited as important synthetic intermediates in the
synthesis of bipyridines such as etoricoxib. A variety of
other di- and trisubstitued pyridines (Chart 1)10 with
substituents including trifluoromethyl, aryl, protio, and
nitro groups have also been prepared by extension of this
methodology to substituted and unsubstituted vinami-
dinium salts and aldehyde, ketone,11 ester, or acid
enolates.12 Pyridine N-oxides are also readily accessible
by using hydroxylamine as the third component in place
(6) (a) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org. Lett. 2002, 4, 1783.
(b) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529. (c) Murai, S.; Kakiuchi,
F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Pure
Appl. Chem. 1994, 66, 1527-1534. (d) Kakiuchi, F.; Sekine, S.; Tanaka,
Y.; Kamatini, A.; Sonoda, M.; Chatani, N.; Murai, S. Bull. Chem. Soc.
J pn. 1995, 68, 62. (e) Murai, S.; Chatani, N.; Kakiuchi, F. Bull. Chem.
Soc. J pn. 1997, 69, 55589. (f) Trost, B. M.; Imi, K.; Davies, I. W. J .
Am. Chem. Soc. 1995, 117, 5371.
(7) (a) Ahrendt, K. A.; Bergman, R. G.; Ellman, J . A. Org. Lett. 2003,
5, 1301. (b) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J .
A. J . Am. Chem. Soc. 2001, 123, 9692. (c) Tan, K. L.; Bergman, R. G.;
Ellman, J . A. J . Am. Chem. Soc. 2001, 123, 2685.
(13) Davies, I. W.; Marcoux, J .-F.; Reider, P. J . Org. Lett. 2001, 3,
209.
(14) Gupton, J . T.; Krolikowski, D. A.; Yu, R. H.; Riesinger, S. W.;
Sikorski, J . A. J . Org. Chem. 1990, 55, 4735.
(15) Gupton, J . T.; Petrich, S. A.; Hicks, F. A.; Wilkinson, D. R.;
Vargas, M.; Hosein, K. N.; Sikorski, J . A. Heterocycles 1998, 47, 689.
(16) Kase, K.; Katayama, M.; Ishirara, T.; Yamanaka, H.; Gupton,
J . T. J . Fluorine Chem. 1998, 90, 29.
(17) Marcoux, J .-F.; Marcotte, F.-A.; Wu, J .; Dormer, P.; Davies, I.
W.; Hughes, D.; Reider, P. J . J . Org. Chem. 2001, 66, 4194.
(18) For a review on the reactivity of vinamidinium salts see: Lloyd,
D.; McNab, H. Angew. Chem. 1976, 88, 496.
(19) Davies, I. W.; Marcoux, J .-F.; Taylor, J . D. O.; Dormer, P. G.;
Deeth, R. J .; Marcotte, F.-A.; Hughes, D. L.; Reider, P. J . Org. Lett.
2002, 4, 439.
(20) Davies, I. W.; Marcoux, J .-F.; Taylor, J . D. O.; Dormer, P. G.;
Deeth, R. J .; Marcotte, F.-A.; Hughes, D. L.; Reider, P. J . Org. Lett.
2002, 4, 2969.
(8) Cho, J .-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., J r.; Smith,
M. R., III. Science 2002, 295, 305.
(9) Sezen, B.; Sames, D. J . Am. Chem. Soc. 2003, 125, 10580.
(10) Davies, I. W.; Marcoux, J .-F.; Corley, E. G.; J ournet, M.; Cai,
D.-W.; Palucki, M.; Wu, J .; Larsen, R. D.; Rossen, K.; Pye, P. J .;
DiMichele, L.; Dormer, P.; Reider, P. J . J . Org. Chem. 2000, 65, 8415.
(11) Marcoux, J .-F.; Corley, E. G.; Rossen, K.; Pye, P.; Wu, J .;
Robbins, M. A.; Davies, I. W.; Larsen, R. D.; Reider, P. J . Org. Lett.
2000, 2, 2339.
(12) Marcoux, J .-F.; Marcotte, F.-A.; Wu, J .; Dormer, P.; Davies, I.
W.; Hughes, D.; Reider, P. J . J . Org. Chem. 2001, 66, 4194.
J . Org. Chem, Vol. 69, No. 4, 2004 1299

Davies et al.
TABLE 1. p Ka Va lu es
of ketones to substituted aromatic compounds in a highly
convergent fashion.
a
entry
R-CH3
pKa
1
2
3
4
5
6
7
8
9a , R ) H
56
43
41
41
31
29
Resu lts a n d Discu ssion
9b, R ) Ph
9c, R ) Cl
Reaction of enolates and vinamidinium salts leads to
the formation of dienones 7a -h .21 These dienones are
merocyanines based on resonance theory22 and are typi-
cally formed as a ∼3:1 mixture of 3-E:Z isomers.23 They
possess interesting solvato-, thermo-, and photochromic
properties due to the potential of valence isomerization
to 2H-pyrans 8a -h .24
9d , R ) F
9e, R ) CN
9f, R ) SO2Ph
9g, R ) NO2
9h , R ) CdNMe2
17.2 (11)b
(11)b
+
a
b
In DMSO In methanol/water
due to the generation of phenol 5 in the reaction mixture
is 6.1.30 Because the reaction may be performed using
catalytic amounts of potassium tert-butoxide, the reaction
should therefore proceed with a much weaker base as
long as the pKa of the conjugate acid is ∼6. In fact
potassium phenoxide works effectively in THF to give
aniline 4 in 80% assay yield (1 equiv, 6:1 selectivity, 20
°C, 12 h). The reaction is also promoted by sodium acetate
albeit at a much lower rate (6:1 selectivity, 48 h, 65%
assay). Phenol or acetic acid do not catalyze the reaction.
Reaction of nitrovinamidinium 3 in acetonitrile (ꢀ 35.9)
at -10 °C led to a 39:1 mixture of aniline 4 (81% assay)
and phenol 5 vs 9.5:1 selectivity in THF (ꢀ 7.58), indicat-
ing the reaction is sensitive to solvent polarity.
Using MAA as a prototypical stabilized enolate we
have prepared a range of pyridines and pyridine N-
oxides, including 5-chloro, 5-aryl, and 5-trifluoromethyl
substitution, which arise via the intermediacy of the
dienone 7a -h . During our studies to further expand the
scope of this methodology we investigated the reaction
of MAA and the nitrovinamidinium salt 325 at 45 °C in
THF. To our surprise, none of the expected pyridine was
observed, and two aromatic compounds, aniline 426 and
phenol 5,27 were isolated in 65% and 10% yield, respec-
tively, prior to the addition of ammonia (∼4:1 in the crude
reaction mixture). The identity of the aniline 4 was
confirmed by comparison with an authentic sample
prepared from dimethylamine and 2-chloro-5-nitro-ben-
zoate28 and was further supported by X-ray crystal-
lographic analysis of analogue 21d . The observation of
phenol 5 was precedented since â-fluorovinamidinium
tetrafluoroborate salts reacts with 3-oxo-pentanedionate
to give the 5-fluoro-2-hydroxyisophthalate in 31% yield.29
After trivial optimization of the reaction temperature,
the selectivity could be increased to 7:1 at 20 °C and 9:1
at 0 °C. The reaction does not proceed in the absence of
base but does proceed with reduced rate using catalytic
quantities of tert-butoxide (10 mol %). The leveling pKa
We verified that the protio-,31 phenyl-,32 chloro-,33
fluoro-,34 and dienones 7a -d did not undergo cyclization
in refluxing THF. The cyano-substituted dienone 7e is
also reported to be stable,35 and we reasoned that the
unexpected reactivity of nitro-substituted dienone 7g was
due to the ability of the nitro group to stabilize a
developing negative charge in the transition state in the
formation of a cyclohexadiene intermediate. A simple
measure of this charge-stabilizing ability is available
from the pKa value of the corresponding methyl deriva-
tives 9a -h (Table 1). However, the reaction may be more
accurately viewed as a disrotatory electrocyclization36 (the
orbital interactions that favor Michael-type addition also
enhance electrocyclization), which would also be pro-
moted by electron-withdrawing groups in the 6π-transi-
tion state.37
If the cyclization event is driven by charge stabilization
in a transition state, the sulfonyl dienone 7f, derived
from the â-sulfonyl vinamidinium salt 10 (previously
described by Gupton38), should be more reactive than the
nitrile. In the event, reaction of 10 in THF at 20 °C (12
(21) Nair, V.; Cooper, C. S. J . Org. Chem. 1981, 46, 4759.
(22) (a) Booker, L. G. S.; Keyes, G. H.; Sprague, R. H.; VanDyke, R.
H.; VanLarne, E.; VanZandt, G.; White, F. L.; Cressman, H. W. J .;
Dent, S. G., J r. J . Am. Chem. Soc. 1951, 73, 5326. (b) Booker, L. G. S.;
Keyes, G. H.; Sprague, R. H.; VanDyke, R. H.; VanLarne, E.; VanZandt,
G.; White, F. L.; Cressman, H. W. J .; Dent, S. G., J r. J . Am. Chem.
Soc. 1951, 73, 5332.
(23) This level of selectivity is common for enolate additions to
vinamidinium salts: Malleron, J . L.; Roussel, G. F.; Gueremy, G.;
Ponsinet, G.; Robin, J . L. J . Med. Chem. 1990, 33, 2744.
(24) (a) Krasnaya, Z. A.; Prokof’ev, E. P.; Kakovlev, I. P.; Lubuzh,
E. D. Izv. Akad. Nauk SSSR, Ser. Khim. 1980, 2325. (b) Dvornikov,
A. S.; Krasnaya, Z. A.; Malkin, Y. A. Izv. Akad. Nauk SSSR, Ser. Khim.
1981, 390.
(25) Davies, I. W.; Marcoux, J .-F.; Wu, J .; Palucki, M.; Corley, E.
G.; Robbins, M.; Tsou, N.; Ball, R. G.; Dormer, P.; Larsen, R. D.; Reider,
P. J . Org. Chem. 2000, 65, 4571.
(26) Krasnaya, Zh. A.; Stytsenko, T. S.; Bogdanov, V. S.; Daeva, E.
D. Izv. Akad. Nauk SSSR, Ser. Khim. 1985, 7, 1604-12.
(27) Smith; Knerr J . Am. Chem. Soc. 1886, 8, 99.
(30) The pKa of the phenol ethyl ester has been experimentally
determined as 6.1 in chloroform (ꢀ 4.8); see: Bureiko, S. F.; Oktiabr’sky,
V. P. J . Mol. Struct. 1995, 349, 53.
(31) Kiesel, M.; Haug, E.; Kantlehner, W. J . Prakt. Chem. 1997, 339,
159. For the ethyl ester, see: Nair, V.; Cooper, C. S. Tetrahedron Lett.
1980, 21, 3155.
(32) Krasnaya, Z. A.; Prokof’ev, E. P.; Yakovlev, I. P.; Lubuzh,
E. D. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Ed.) 1980, 29,
2325.
(33) Krasnaya, Z. A.; Stytsenko, T. S.; Bogdanov, V. S.; Daeva, E.
D.; Dvornikov, A. S. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl.
Ed.) 1985, 34, 1075.
(34) Krasnaya, Z. A.; Stytsenko, T. S.; Bogdanov, V. S.; Monich, N.
V.; Kul’chitskii, M. M.; Pazenok, S. V.; Yagupol’skii, L. M. Bull. Acad.
Sci. USSR, Div. Chem. Sci. (Engl. Ed.) 1989, 38, 562.
(35) Krasnaya, Z. A.; Stytsenko, T. S.; Bogdanov, V. S.; Dvornikov,
A. S. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Ed.) 1989, 38, 1206.
(36) Woodward, R. B.; Hoffmann, R. J . Am. Chem. Soc. 1965, 87,
395.
(28) Kosary, J .; Szabo, I. K.; Kasztreiner, E. Pharmazie 1982, 37,
484. Nagarajan, K.; Venkateswarlu, A.; Kulkarni, C. L.; Goud, A.;
Nagana; Shah, R. K. Ind. J . Chem. 1974, 12, 236.
(37) For a simple model to predict rates of electrocylization see:
Carpenter, B. Tetrahedron 1978, 34, 1877.
(29) Reichardt, C.; Halbritter, K. Liebigs Ann. Chem. 1975, 470.
1300 J . Org. Chem., Vol. 69, No. 4, 2004

Synthetic, Mechanistic, and Computational Synergy
h) led to isolation of phenol 11 in 7% yield with the
remainder of the mass balance accounted for by starting
vinamidinium and dieneone. Performing the reaction in
THF at reflux led to the formation of the phenol 11 in
69% isolated yield together with aniline 12 in 3% yield.
The use of DMAP (0.4 equiv) in acetonitrile at 75 °C gave
a 5:1 mixture 11/12.39
Scop e
We have surveyed the scope of the ketone enolates that
undergo addition to the nitrovinamidinium 3 in aceto-
nitrile (Table 2). Reaction of homologue 17a at 70 °C led
to the formation of aniline 18a in 81% assay yield (75%
isolated) and phenol 19a 44 in 4%. Pentan-2,4-dione gave
the aniline 18b45 in 80% (15:1) and traces of phenol (4%)
19b46 in acetonitrile at -10 °C. Acetone was reacted using
a range of bases to give the aniline 18c.47 The best results
in terms of yield were obtained using sodium acetate
since competing aldol reactions were minimized. These
results contrast nicely with the reaction of activated and
unactivated ketones and the sodium salt of nitromalonal-
dehyde, which led to the formation of the nitrophenols
in good yields.48 This reactivity of substituted malonates
to give phenolic products is general,49 and pyrimidines
behave as masked 1,3-dicarbonyls in a similar manner.50
The current work reinforces the complimentary reactivity
of the masked 1,3-dicarbonyl embedded in the vinami-
dinium salts.
To demonstrate the formation of biaryls, a series of
1-aryl-nitrovinamidiniums 20a -d was prepared using
procedures analogous to those described by Gupton51
followed by the straightforward nitration using nitric
acid/acetic anhydride.52 These 1-aryl-vinamidiums also
proved to be good partners in the coupling reaction giving
rise to anilines in 80-98% yield using DMAP as base.
An excess (>2 equiv) of MAA was required to drive the
reactions to completion. The aniline/phenol ratio was
excellent in all cases, and none of the regioisomeric
anilines resulting from initial reaction at the 1-aryl
Substitution by a dimethylaminomethylene group at
the γ-position should further increase the reactivity of
the dienone since the pKa of the corresponding methano-
derivative is 11.40 We have prepared the mixed tetrafluo-
roborate/hexafluorophosphate salt 13,41 which had ex-
cellent solubility in organic solvents (>15 wt % in
acetonitrile).42
Reaction of 13 with MAA at 20 °C in acetonitrile led
to an extremely facile reaction and gave an 8:1 mixture
of the aniline 14 and phenol 1543 after 4 h. The formyl
aniline 14 was isolated as a yellow oil in 56% yield
following chromatography on silica gel. The reaction was
complicated by overaddition of MAA to give crotonate 16
as a 1.5:1 mixture of (Z:E) olefin isomers in up to 6%
yield. Performing the reaction at -10 °C using the
vinamidinium salt in slight excess (1.25 equiv) increased
the aniline/phenol 14/15 selectivity to 11:1 and reduced
the crotonate 16 to <4%. Under these reaction conditions,
the assay yield of aniline 14 was 68% (65% isolated), and
when a large excess of the vinamidinium salt was used,
the yield increased to 71% with the crotonate observed
at 1%. DMAP (0.4 equiv) was also quite effective in place
of potassium tert-butoxide and gave a 73% assay yield of
aniline 14 (11:1 selectivity, 20 h, -10 °C) with the
crotonate at <0.5%.
(38) Gupton, J . T.; Riesinger, S. W.; Shah, A. S.; Gall, J . E.; Bevirt,
K. M. J . Org. Chem. 1991, 56, 976.
(39) Performing the reaction in a sealed tube at 80 °C led to 1:1
aniline/phenol selectivity.
(44) Pierre Fabre S. A., U.S. Patent 3,958,002; Chem. Abs. 1976,
88, 55070.
(45) Varma, R. S.; Sarin, S.; Chatterjee, R. K. Ind. J . Chem. 1992,
31, 711.
(40) pKa’s (in methanol/water) and proton affinities are available
by experimental and theoretical methods for
a
range of tertiary
(46) J oshi, S. J . Am. Chem. Soc. 1954, 76, 4993.
(47) Bamberger, T. Chem. Ber. 1899, 32, 1897. For preparation via
SNAr see: Gupton, J . T.; Idoux, J . P.; Baker, G.; Colon, C.; Crews, D.
A. J . Org. Chem. 1983, 48, 2933.
(48) J ones, E. C. S.; Kenner, J . J . Chem. Soc. 1931, 1842.
(49) (a) Prelog, V.; Wursch, J .; Konigsbacher, K. Helv. Chim. Acta
1951, 34, 358. (b) Hirota, K.; Kitade, Y.; Senda, S. J . Org. Chem. 1981,
46, 3949. (c) Nantz, M. H.; Fuchs, P. L. Synth. Commun. 1987, 17,
761.
(50) Remennikov, G. Y.; Kurilenko, L. K.; Boldyrev, I. V.; Cherkasov,
V. Chem. Heterocyl. Compd. 1987, 23, 422 (English). Remennikov, G.
Y.; Kurilenko, L. K.; Boldyrev, I. V.; Cherkasov, V. Khim. Geterotsikl.
Soedin. 1987, 4, 508 (Russian).
vinylamines. (a) Adams, R.; Mahan, J . E. J . Am. Chem. Soc. 1942, 64,
2588. (b) Cook, M. J .; Katritsky, A. R.; Linda, P.; Tack, R. D. J . Chem.
Soc., Perkin Trans. 2 1972, 1295. (c) Ellenberger, M. R.; Dixon, D. A.;
Farneth, W. E. J . Am. Chem. Soc. 1981, 103, 5377.
(41) Davies, I. W.; Tellers, D. M.; Schultz, C. S.; Fleitz, F. J .; Cai,
D.; Sun, Y.-K. Org. Lett. 2002, 4, 2969.
(42) The trimethinium bisperchlorate salt was first reported by
Arnold and has been used successfully in the synthesis of pyrimidines.
(a) Arnold, Z. Collect. Czech. Chem. Commun. 1961, 26, 3051. (b)
Arnold, Z. Collect. Czech. Chem. Commun. 1965, 30, 2125. (c) Gupton,
J . T.; Gall, J . E.; Riesinger, S. W.; Dahl, M. L.; Arnold, A. J . Heterocycl.
Chem. 1991, 28, 1281. For the preparation of the bistetrafluoroborate
see: Keshavarz, K. M.; Cox, S. D.; Angus, R. O., J r.; Wudl, F. Synthesis
1988, 641.
(51) Gupton, J . T.; Moebus, M. A. M.; Buck, T. Synth. Commun.
1986, 16, 1561-74.
(52) Kucera, J .; Arnold, Z. Collect. Czech. Chem. Commun. 1967,
32, 1704.
(43) Wayne; Cohen J . Chem. Soc. 1922, 121, 1022. For NMR data,
see: Filler, R.; Lin, S.; Zhang, Z. J . Fluorine Chem. 1995, 74, 69.
J . Org. Chem, Vol. 69, No. 4, 2004 1301

Davies et al.
TABLE 2. Rea ction of Su bstitu ted Keton es w ith
N,N-Dim eth yl-2-n itr o-tr im eth in iu m
Hexa flu or op h osp h a tea
TABLE 4. Rea ction of MAA a n d N,N-Su bstitu ted
2-Nitr o-tr im eth in iu m Hexa flu or op h osp h a tea
entry
1
X )
aniline (%)b
phenol 5 (%)b
entry
R1
R2
assay yield (%)b
24a (93)
(5)
1
2
3
4
CO2Me
C(O)Me
H
CH3
H
H
18a (81)
19a (4)
19b (5)
19d (-)d
19d (35)
18b (79)
18c (30)c
18d (10)
23a
2
24b (89)
24c (-)
(11)
(63)
4-F-C6H4
H
a
Unless otherwise noted, all reactions were conducted in
acetonitrile using 1.05 equiv of t-BuOK and 1.1 equiv of 3g. b Assay
yield determined by HPLC analysis using analytically pure
standard. c Sodium acetate (3 equiv) was used in place of t-BuOK
at 45 °C. Not detected in the crude reaction mixture by NMR or
LCMS of the crude reaction mixture.
23b
23c
3
d
a
Unless otherwise noted, all reactions were conducted in THF
at 20 °C using 1.05 equiv of t-BuOK and 1.1 equiv of vinamidinium
salt. b Assay yield determined by HPLC analysis using analytically
pure standard. c Not detected by 1H NMR or LCMS of the crude
reaction mixture.
TABLE 3. Rea ction of MAA a n d
1-Ar yl-2-n itr o-tr im eth in iu m Hexa flu or op h osp h a tesa
formation of a phenol in 31% yield.29 The observation of
an aniline in the reaction was somewhat surprising.55
A
road map was generated to account for the products of
the reaction based on the known reactivity profile of
vinamidinium salts (Scheme 2). Addition of MAA to the
nitrovinamidinium salt leads to the adduct 25, which
undergoes elimination of dimethylamine to give dienone
7g. A simple keto-enol tautomerism to 26 sets the stage
for an electrocyclic ring closure to generate enol 27.
Aromaticity can be achieved by the elimination of dim-
ethylamine to give phenol 5. To explain the formation of
aniline 6, a [1,5]-H shift of enol 27 to enamine 30 was
invoked followed by a facile elimination of water.56 This
[1,5]-H shift would have a low activation barrier since
the reactions were routinely conducted at or below room
temperature. Such a small activation energy would be
unprecedented, so we aggressively set out to understand
the reaction using experimental and computational stud-
ies. The experimental studies and the computational
aspects of the program are presented below.
entry
R
assay yield (%)b
1
2
3
4
Cl
21a (98)
22a (1)
22b (5)
22c (7)
22d (8)
H
21b (95)
21c (88)
21d (75)
CH3
OMe
a
Unless otherwise noted, all reactions were conducted in
acetonitrile at 20 °C using 2 equiv of DMAP, 1 equiv of vinami-
dinium salt, and 2-4 equiv of MAA. Assay yield determined by
HPLC analysis using an analytically pure standard.
b
position were detected.53 The identity of the aniline 21d
was unambiguously assigned by X-ray crystallography
(see Supporting Information), and the other isomers
21a -c were assigned by analogy and supporting NOE
data between OMe and NMe2.
Nitrovinamidinium salts derived from a range of
secondary amines were examined as partners in the
reaction using 1.05 equiv of t-BuOK and 1.1 equiv of
vinamidinium salt in THF (Table 4). The piperidinyl
vinamidinium salt 23a gave aniline 2454 with good
selectivity at room temperature (9:1). The N,N-diisopro-
pylvinamidinium salt 23b gave the phenol 5 in 60%
isolated yield with none of the aniline 24c detected by
1H NMR analysis of the crude reaction mixture.
As a probe of the mechanistic features of the reaction
we decided to investigate the effect of isotopic substitu-
tion on the reaction.57 Without a good basis for specula-
tion on the rate-determining step, a competition method
was employed.58 Initially for the sake of expediency,
perdeuterio nitrovinamidinium hexafluorophosphate 31
(55) For preparation of anilines via Diels-Alder reaction of dim-
ethylacetylene dicaraboxylate and 1,3-(dialkylamino)butadiene, which
was prepared insitu from a 1-methylvinamidinium perchlorate salt,
see: Gompper, R.; Heinemann, U. Angew. Chem., Int. Ed. Engl. 1980,
19, 216.
Mech a n istic Stu d ies
(56) J ia, Z. S.; Brandt, P.; Thibblin, A. J . Am. Chem. Soc. 2001, 123,
10147. The elimination of water from benzene hydrate in glycerol/water
at pH 5.57 is exothermic by -39 kcal/mol with a rate constant of 58
M-1 s-1. A value of 190 M-1 s-1 has been reported for the acetic acid
catalyzed dehydration of benzene hydrate in water: Rao, S. N.; More
O’Ferrall, R. A.; Kelly, S. C.; Boyd, D. R.; Agarwal, R. J . Am. Chem.
Soc. 1993, 115, 5458.
(57) For discussions see: Melander, L.; Saunders, W. H., J r. Reaction
Rates of Isotopic Molecules; J ohn Wiley and Sons: New York, 1980.
Westheimer, F. H. Chem. Rev. 1961, 61, 265.
The formation of phenols as the minor product in the
reaction was not altogether unexpected on the basis of a
report that the fluorovinamidinium and salt led to the
(53) Gupton, J . T.; Krumpe, K. E.; Burnham, B. S.; Dwornik, K. A.;
Petrich, S. A.; Du, K. X.; Bruce, M. A.; Vu, P.; Vargas, M.; Keertikar,
K. M.; Hosein, K. N.; J ones, C. R.; Sikorski, J . A. Tetrahedron 1998,
54, 5075.
(54) Arnone, C.; Consiglio, G.; Frenna, V.; Spinelli, D. J . Org. Chem.
1997, 62, 3093.
(58) Cohen, T.; McMullen, C. H.; Smith, K. J . Am. Chem. Soc. 1968,
90, 6866.
1302 J . Org. Chem., Vol. 69, No. 4, 2004

Synthetic, Mechanistic, and Computational Synergy
SCHEME 2
aniline 33, which indicates attack of the liberated dim-
ethylamine on an intermediate (Figure 1). The stack plot
confirms the initial interpretation after the purified
isotopic analogues were available for unambiguous as-
signment.
For a more rigorous study of the effect of isotopic sub-
stitution, the nitrovinamidinium d2-35 was prepared
from d1-DMF.
F IGURE 1. Stack plot analysis of 1H NMR (500 MHz) in
CDCl3.
was prepared starting with d7-dimethylformamide and
chloroacetic acid.59 Initial competition experiments using
10 equiv of a 1:1 mole ratio of 3/31 vs MAA were
performed at 20 °C in THF using tert-butoxide as base.
Competition experiments using 0.1-0.15 equiv of MAA
and a 1:1 mole ratio of 3/35 were performed at 25 °C in
THF using tert-butoxide as base. At the end of reaction
the yield was determined by HPLC analysis to ensure
consistency with the experiments performed with a
synthesis objective. Following concentration, the ratio of
all four possible compounds was determined by 1H NMR
at 500 MHz. The total amount of deuterium observed in
the product distribution is fixed downstream after the
first irreversible step en route to the products. Since the
elimination of dimethylamine from 25/36 is essentially
irreversible,60 the total amount of deuterium observed in
the products is controlled by the addition of the enol/
enolate to the vinamidinium salt. Once the irreversible
step has been traversed the relative partitioning path-
ways are no longer in isotopic competition. It follows that
(sum of hydrogen products)/(sum of deuterium products),
i.e., (4 + 5)/(32 + 34) represents a secondary kinetic
isotope effect.61 From the competition experiments of
1
Analysis of the crude reaction mixture by H NMR at
500 MHz revealed the presence of up to 40 mol % of the
(60) Attack of a nucleophile by microscopic reversibility can be
envisioned at C-4, attack of nucleophiles occurs in these systems is at
the distal carbon (C-6) by analogy with organometallic reagents and
heteroatoms (e.g., ammonia, see ref 16).
(59) Whilst a deuterium label is only required at the sp2 methine
bond, the availability of d7-DMF initially dictated our choice of labeling
strategy.
J . Org. Chem, Vol. 69, No. 4, 2004 1303

Davies et al.
SCHEME 3
3/35, the experimentally determined inverse isotope effect
kH/D was 0.7 at 25 °C in THF for the nitrovinamidinium
using tert-butoxide. It also follows that (4/5)/(32/34)
represents a product isotope effect, and a value of 1.15
was observed.
Competition experiments using 0.1-0.15 equiv of MAA
and a 1:1 mole ratio of 13/37 were performed at -10 °C
in acetonitrile using tert-butoxide or DMAP as base.
Trimethinium salt d3-37 was prepared from d1-DMF. As
in the nitro series, the (sum of hydrogen products)/(sum
of deuterium products), i.e., (14 + 15)/(38 + 39) repre-
sents a secondary kinetic isotope effect. The experimen-
tally determined value kH/D was 0.93. A small product
isotope effect of 1.25 was also observed (14/15)/(38/39).
The small observed isotope effects are inconsistent with
the intermediacy of a [1,5]-H shift since the migration
would have to be almost insensitive to isotopic substitu-
tion.62 Taken together, these experimental data and the
calculations provide overwhelming data that precludes
the involvement of a [1,5]-H shift or oxyanionic variants
en route to 6. This prediction turned out to be extremely
gratifying since the calculations served as a predictive
tool that led us to question and eventually reassign the
identity of the major product to aniline 4.
nus (Scheme 3). These reactions involving a reversible
disrotatory electrocylization are very close analogues for
the electrocylization of 26 and 28, and elimination occurs
at slightly higher temperatures to the reactions of
vinamidium salts described in this article.
The downstream elimination of dimethylamine from
27 or 29 is expected to be extremely facile on the basis
of the literature precedent for 46. The generation of the
aromatic systems is expected to be extremely favorable
and provide a thermodynamic driving force, and as such
the aminocyclohexadienes may not be long-lived discrete
intermediates.67
The inverse secondary kinetic isotope effect found
experimentally is fully consistent with rate-limiting
addition of the enol/enolate to the vinamidinium salt.68
The smaller inverse isotope effect (0.93 vs 0.75) in the
case of the dimethylaminomethylene vinamidinium 13
is consistent with an earlier transition state during the
addition reaction.69
The observation of aniline products and the intermo-
lecular scrambling of isotopically distinct dimethylamine
species provided strong evidence for the intermediacy of
an enamine that is ultimately derived by the dimethy-
lamine liberated in the initial addition/elimination. To
provide further support for the intermediacy of an
enamine, we have investigated the direct reaction of
crystalline 48 derived from methyl acetoacetate and
pyrrolidine (Scheme 3).70 Reaction of the enamine 48 with
nitrovinamidinium 3 (3 equiv) led to the aniline 24a in
75% yield in acetonitrile at 60 °C in the absence of base
(Scheme 4). Under these conditions aniline 4 was ob-
served in 3% and phenol 5 was present at 1% by HPLC
analysis.71
With the correct structural assignment in hand, a more
conventional mechanistic proposal was developed focus-
ing on a key electrocylization of the intermediate triene
(as the enol or enamine).
The 1,6-diphenyl-3-nitro-1,3,5-hexatriene 40, which
has the 1E,3E,5E configuration as determined by X-ray
crystallography,63 undergoes electrocyclization at 60 °C
to the corresponding cyclohexadiene 41. Alkyl and vinyl
substituents at the 3-position of hexatriene decrease the
electrocyclization activation energy by 3-5 kcal/mol.64
Aromatic compounds 44 and 47 are obtained from
hexatrienes when a latent leaving group, e.g., chloro65
42 or dimethylamino66 45 is located at the triene termi-
To provide confirmation that entering the reaction with
a preformed enamine 48 was not a significant perturba-
(67) For the rate of elimination of water from benzene hydrate, see
ref 55. A kinetic study of the rate of elimination of dimethylamine has
not been reported. Related cyclohexadienes have been prepared via
photochemically initiated addition of amines to chlorobenzene, al-
though not in pure form. Gilbert, A.; Krestonosich, S.; Westover, D. L.
J . Chem. Soc., Perkin Trans. 1 1981, 295.
(68) This value is in agreement with enol ether addition to benzal-
dehyde and may suggest a later transition state for the addition to 3g
than for 11d : Myers, A. G.; Widdowson, K. L.; Kukkola, P. J . J . Am.
Chem. Soc. 1992, 114, 2765.
(69) For a discussion of secondary isotope effects in carbonyl addition
see: (a) Gajewski, J . J .; Bocian, W.; Harris, N. J .; Olson, L. P. J . Am.
Chem. Soc. 1999, 121, 326. (b) Gajewski, J . J .; Bocian, W.; Brichford,
N. L.; Henderson J . L. J . Org. Chem. 2002, 67, 4236.
(70) Biera¨ugel, H.; Akkerman, J . M.; Armande, J . C. L.; Pandit, U.
K. Recl. J . R. Neth. Chem. Soc. 1976, 95, 268.
(61) See Supporting Information for a road map of isotopic distribu-
tion and formulae for the calucluation of kinetic and product isotope
effects (Scheme S-1).
(62) Wiberg, K. Chem. Rev. 1955, 55, 713. Wiberg, K.; Motell, E. L.
Tetrahedron 1963, 19, 2009.
(63) Dell’ Erba, C.; Gabellini, A.; Mugnoli, A.; Novi, N.; Petrillo, G.;
Tavani, C. Tetrahedron 2001, 57, 9025.
(64) Substituent effects on electrocyclization reactions. (a) Spangler,
C. W.; Ibrahim, S.; Bookbinder, D. C.; Ahmad, S. J . Chem. Soc., Perkin
Trans. 2 1979, 6, 717. (b) Spangler, C. W. Tetrahedron 1976, 32, 2681.
(c) Schiess, P.; Dinkel, R. Tetrahedron Lett. 1973, 29, 2503. (d) Marvell,
E. N.; Caple, G.; Delphey, C.; Platt, J .; Polston, N.; Tashiro, J .
Tetrahedron 1973, 29, 3797.
(65) Ogura, K.; Takeda, M.; Xie, J . R.; Akazome, M.; Matsumoto, S.
Tetrahedron Lett. 2001, 42, 1923.
(66) J utz, C.; Wagner, R. M. Angew. Chem. 1972, 11, 315.
(71) For the preparation of phenols from enamines, see: Kang, G.
J .; Chan, T. H. J . Org. Chem. 1985, 50, 452.
1304 J . Org. Chem., Vol. 69, No. 4, 2004

Synthetic, Mechanistic, and Computational Synergy
SCHEME 4
tion of reaction upstream of the electrocylization, we
again investigated the effect of isotopic substitution.
From the competition experiments of enamine 48 and
3/35, the experimentally determined secondary kinetic
isotope effect kH/D was 0.75 at 60 °C. The yield of aniline
24a under these competition conditions with a large
excess of vinamidinium (total 10 equiv vs enamine) was
85% and phenol 5 was again present at <1%.
Com p u ta tion a l Stu d ies
F IGURE 2. Transition structure for the degenerate [1,5]-
hydrogen shift in 1,3-cyclohexadiene.
Gen er a l Con sid er a tion s. All calculations were per-
formed with GAUSSIAN 98.72 All structures, reactants,
transition structures, and products were optimized with
the B3LYP functional73 and the 6-31G*74 and 6-31++G**
basis sets.75 The effect of solvent was explored with the
Cosmo Polarized Continuum Model (CPCM)76 for THF
solvent. All minima and transition states were character-
ized by their vibrational frequencies. All energy changes
reported in this paper include zero-point energies that
are scaled by 0.9804. The initial conformational searches
were performed with Monte Carlo calculations employing
the Macromodel program (MM2 force field).77
1,5-Hyd r ogen Sh ift. The preliminary assignment of
aniline 6 as the product from reaction of MAA and the
nitrovinamidnium 3 invoked the intermediacy of a [1,5]-
H shift in our road map. However, the [1,5]-H shift would
have to occur at or below room temperature, which would
be unprecedented based on previous experimental stud-
ies.
energy.79 The kinetic study of 1,3-cyclohexadiene was
performed at temperatures from 303 to 330 °C, and the
activation energy was 40 kcal/mol.80
In a related observation 5-methyl-1,3-cyclohexadiene
isomerizes to 4-methyl- and 2-methyl-1,3-cyclohexadienes
at temperatures between 350 and 420 °C.81 As a starting
point for the computational studies and to serve as a
calibration, the degenerate [1,5]-H shift in 1,3-cyclohexa-
diene 49 was used. The calculated transition structure
is shown Figure 2.
Transition structure 50 for the degenerate 1,5-H shift
in 1,3-cyclohexadiene has C1 symmetry with C1-H6 and
C5-H6 distances of 1.49 Å. The C1-H6-C5 bond angle
is 97.9°. The calculated activation enthalpy is 41.9 kcal/
mol, in close agreement with the experimental value and
in accord with the recent calculations of 41.7 kcal/mol
reported by Alabugin.82 Calculations were then carried
out for the reactions studied experimentally. Geometries
for 27 and 30 and the transition structure 51 intercon-
verting these species are shown in Figure 3.
Enol 27 is 4.9 kcal/mol more stable than the enamine
30, which would not provide a thermodynamic driving
force for isomerization. Significantly, the calculated
activation enthalpy for conversion of 27 to 30 is 51.2 kcal/
mol, even higher than the activation energy of the parent
[1,5]-H shift in cyclohexadiene. The reactions are per-
formed in fairly polar solvents (THF or acetonitrile); the
The [1,5]-H migration in 1,3-cyclohexadiene 49, unlike
that in 1,3-cyclopentadiene78 requires a high activation
(72) Gaussian 98, Revision A.9; Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.;
Zakrzewski, V. G.; Montgomery, J . A., J r.; Stratmann, R. E.; Burant,
J . C.; Dapprich, S.; Millam, J . M.; Daniels, A. D.; Kudin, K. N.; Strain,
M. C.; Farkas, O.; Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J .;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski, J .; Ortiz,
J . V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; J ohnson, B.; Chen, W.; Wong, M. W.; Andres, J . L.; Gonzalez,
C.; Head-Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian, Inc.:
Pittsburgh, PA, 1998.
(73) (a) Becke, A. D. J . Chem. Phys. 1993, 98, 5648-5652. (b) Lee,
C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785-789. (c) Becke,
A. D. J . Chem. Phys. 1993, 98, 1372-1377.
(74) (a) Harihar, P. C.; Pople, J . A. Theor. Chem. Acta 1973, 28, 213-
222. (b) Ditchfield, R.; Hehre, W. J .; Pople, J . A. J . Chem. Phys. 1971,
54, 724-728. (c) Hehre, W. J .; Ditchfield, R.; Pople, J . A. J . Chem.
Phys. 1972, 56, 2257-2261.
(78) ,5-Hydrogen shift in cyclopentadiene: (a) McLean, S.; Haynes,
P. Tetrahedron 1965, 21, 2329. (b) De Haan, J . W.; Kloosterziel, H.
Recl. Trav. Chim. 1968, 87, 298. Roth, W. R. Tetrahedron Lett. 1964,
1009.
(79) For a thorough discussion and analysis of 1,5-H shifts in 1,3-
cyclohexadiene, see: Hess, B. A., J r..; Baldwin, J . E. J . Org. Chem.
2002, 67, 6025.
(80) 1,5-Hydrogen shift in cyclohexadiene: Dobbelaere, J . R.;
Zeeventer, E. L.; Haan, J . W.; Buck, H. M. Theor. Chim. Acta 1975,
38, 241-244.
(81) Miranov, V. A.; Feodorovich, A. D.; Akrem, A. A. Izv. Akad.
Nauk, USSR Ser. Khim. 1971, 11, 2613.
(75) Hehre, W. J .; Radom, L.; Schleyer, P. V.; Pople, J . A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986.
(76) (a) Barone, V.; Cossi, M. J . J . Phys. Chem. A 1998, 102, 1995-
2001. (b) Barone, B.; Cossi, M.; Tomasi, J . J . Comput. Chem. 1998,
19, 404-417.
(77) Mohamadi, F.; Richard, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C.
“MacroModel-an Integrated Software System for Modeling Organic
and Bioorganic Molecules Using Molecular Mechanics” J . Comput.
Chem. 1990, 11, 440.
(82) Alabugin, I. V.; Monoharan, M.; Breiner, B.; Lewis, F. D. J .
Am. Chem. Soc. 2003, 125, 9329.
J . Org. Chem, Vol. 69, No. 4, 2004 1305

Davies et al.
F IGURE 3. Optimized structures for 27 and 30 and [1,5]-shift transition structure 51.
estimation of solvent effects using CPCM for THF
predicts that the [1,5]-H shift activation energy will be
increased by 4.1 kcal/mol.
nonplanar conformers tZc and cZc. B3LYP/6-31G** pre-
dicts that the tZt isomer is the most stable and cZc the
least.89
Cope rearrangements of 3-hydroxy-1,5-hexadienes are
accelerated by deprotonation of the hydroxyl-substitu-
ent: anionic oxy-Cope rearrangements are very rapid.83
The computed activation energy for the parent anionic
oxy-Cope rearrangement is 8.3 kcal/mol, which is 26.4
kcal/mol lower than the oxy-Cope rearrangement.84 The
effect of oxyanionic substitution in the [1,5]-H shift has
been observed experimentally. In the case of 5-hydroxy-
1,3-cycloheptadiene, activation energies measured for the
alcohol and its potassium alkoxide are 24.6 and 13.8 kcal/
mol, respectively.85 The analogous anionic oxy-[1,5]-H
shift involving 27 was studied using the larger B3LYP/
6-31++G** basis set. The calculated activation energy
was found to be 15.5 kcal/mol higher than that of the
neutral system, since in this case the ground state is
stabilized more than the transition state by deprotona-
tion.
Taken together, these calculations provide overwhelm-
ing data that precludes the involvement of a [1,5]-H shift
or oxyanionic variants en route to 6. This prediction
turned out to be extremely gratifying since the calcula-
tions served as a predictive tool that led us to question
and eventually reassign the identity of the major product
to aniline 4. With the correct structural assignment in
hand, a more conventional mechanistic proposal was
developed involving a key electrocylization of the inter-
mediate triene.
The conformations accessible to enol 26 and enamine
28 were also calculated. The rotational barriers about Cd
C double bonds are quite low in push-pull ethylenes
containing electron-donor groups (typically amino groups)
at one terminus and an acceptor group (NO2, CN, etc.)
at the other end of the double bond.90 The CdC rotational
barrier ranges from 10 to 25 kcal/mol for a variety of
substituted compounds. The low barriers are explained
in terms of the capacity of the donor and acceptor groups
to stabilize the developing dipolar transition states.91 The
experimentally determined rotational barrier for 1,1-
diamino-2,2-dicyanoethylene is 11.2 kcal/mol.92 The ini-
tial addition/elimination step of ketone to the vinami-
dinium leads to a ∼3:1 mixture of 3(E,Z)-isomers of the
dienone.93 Energy differences between the most and the
least stable conformations are 9.7 and 7.7 kcal/mol for
enol 26 and enamine 28, respectively.94 Significantly, the
minimum energy conformations for 26 and 28 are es-
sentially aligned for electrocyclization (Figure 4).
The structural features of transition structures and
energies for electrocyclic ring closing process are given
in Table 5. Since anionic substitution has important con-
sequences in some pericyclic processes such as the anionic
oxy-Cope rearrangement, we studied the neutral and
anionic closures of hexatriene 53 to cyclohexadiene 54.
The activation energies for these processes were calcu-
lated to be 29.9 and 29.6 kcal/mol, respectively. That is,
there is essentially no effect of the deprotonation of the
We first studied computationally the ring closure of
1,3,5-hexatriene 52 to form 1,3-cyclohexadiene, which is
probably the simplest disrotatory electrocyclization ini-
tially described by Woodward and Hoffmann.86 Kinetic
studies in the gas phase at 117-190 °C were performed
by Lewis and Steiner.87 The activation energy for this
reaction is 29.9 ( 0.5 kcal/mol. The reaction has also
been studied extensively computationally.88 The hexatriene
52 has three conformers, a planar tZt conformer and
(89) Rodriguez-Otero, J . J . Org. Chem. 1999, 64, 6842.
(90) (a) Sandstrom, J . Top. Stereochem. 1983, 14, 83-176. (b)
Taddei, F. THEOCHEM 1996, 363, 139. (c) Benassi, R.; Bertarini, C.;
Taddei, F.; Kleinpeter, E. THEOCHEM 2001, 541, 101. (d) Benassi,
R.; Taddei, F. THEOCHEM 2001, 572, 169.
(91) Dwyer, T. J .; J asien, P. G. THEOCHEM 1996, 363, 139.
(92) Didkovskii, V. E.; Iksanova, S. V.; Egarov, Y. P. Teor. Eksp.
Khim. 1986, 22, 316.
(83) (a) Evans, D. A.; Golob, A. M. J . Am. Chem. Soc. 1975, 97, 4765.
(b) See Paquette, L. A.; Reddy, Y. R.; Vayner, G.; Houk, K. N. J . Am.
Chem. Soc. 2000, 122, 10788 for recent experimental and theoretical
studies and references to earlier work.
(84) Wiest, O.; Black, K. A.; Houk. K. N. J . Am. Chem. Soc. 1994,
116, 10336.
(85) Paquette, L. A.; Crouse, G. D.; Sharma, A. K. J . Am. Chem.
Soc. 1980, 102, 3972-73.
(93) This level of selectivity is common for a range of enolate
additions to vinamidinium salts: Malleron, J . L.; Roussel, G. F.;
Gueremy, G.; Ponsinet, G.; Robin, J . L. J . Med. Chem. 1990, 33, 2744.
(94) Conformations correspond to 29A: s-trans carbonyl, E-dim-
ethylamine, 29F : s-cis carbonyl, Z-dimethlyamine, 10F : s-trans
carbonyl, E-dimethylamine, 10B: cis-carbonyl, Z-dimethylamine, 7F :
s-cis carbonyl, Z-dimethylamine, 7B: s-cis carbonyl, Z-dimethylamine.
The most and the least stable conformations are A and F for 29, F
and B for 10 and 7.
(86) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital
Symmetry; Academic Press: New York, 1970.
(87) Lewis, K. E.; Steiner, H. J . Chem. Soc. 1964, 3080.
(88) (a) Evanseck, J . D.; Thomas, B. E., IV; Spellmeyer, D. C.; Houk,
K. N. J . Org. Chem. 1995, 60, 7134. (b) Sakai, S. H.; Takane, S. J .
Phys. Chem. A 1999, 103, 2878. (c) J iao, H.; Schleyer, R. J . Am. Chem.
Soc. 1995, 117, 11529.
1306 J . Org. Chem., Vol. 69, No. 4, 2004

Synthetic, Mechanistic, and Computational Synergy
TABLE 5. Ca lcu la ted Activa tion En er gies a n d Geom etr y P a r a m eter s for th e Tr a n sition Sta te of Electr ocyclic Closu r e
of Su bstitu ted Hexa tr ien es
dihedral angle (deg)
triene
∆Hq (kcal/mol)
distance C1-C6 (Å)
C1C2C3C4
C6C5C4C3
C2C3C4C5
C2C1C6C5
26
58
28
55
12.5
11.1
10.0
4.3
2.495
2.315
2.281
2.493
11.8
19.7
18.8
36.1
33.6
44.8
46.8
59.3
12.5
7.0
4.4
43.5
38.3
39.3
24.9
1.5
ropic hydrogen shift. These objectives were met, with the
calculations supporting facile electrocylization reactions
with systems possessing electron-withdrawing groups
(sulfonyl, nitro, iminium). These studies also ruled out
the intermediacy of the [1,5]-H shift and allowed for a
reassignment of the major product. With the data in hand
from these studies, we have attempted to provide a
detailed mechanistic road map. The schematic represen-
tation of the energetics that appear to control these
reactions are highlighted for the iminium series and are
shown in Figure 6. The interconversion of 55 and 58 is
expected to be very facile and to involve the dienone
intermediate.95 The products, aniline 14 and phenol 15,
are determined by the ease of electrocyclization, which
has a remarkably low activation barrier for the enamine
electrocylization (4.3 kcal/mol). A complicating feature in
this scheme is the interconvertibility of the downstream
intermediates 57 and 59. This process should be almost
as easy as the conversion of 55 and 58.96 However, the
downstream eliminations of dimethylamine from 57 or
59 are expected to be extremely facile, most likely much
faster than the interconversion of 57 and 59.97 This
interpretation is supported experimentally by the reac-
tions of preformed pyrrolidine enamine 48 with the
nitrovinamidinium salt and the observation of small but
consequential dialkylaniline product 4. Using a similar
rationale, for the nitro-substituted analogues, the lower
activation energy for enamine over enol electrocylization
(10.0 vs 12.5 kcal/mol) predicts a higher amount of aniline
4 over phenol 5. In the case of the sulfone analogue 7g
the calculations predict the phenol 11 as the major
product rather than aniline 12, (7.5 vs 10.0 kcal/mol),
which again is the case experimentally.
F IGURE 4. Minimum energy conformers for enol 26 and
enamine 28.
F IGURE 5. Minimum energy conformer for enamine 55 and
transition structure for elctrocylization 56.
alcohol in this case. Therefore the corresponding anionic
reactions of 27 were not considered as alternatives.
The activation energy for electrocylization is strongly
linked to substitution on the triene. Introduction of
oxygen or nitrogen substituents at C-1 and C-5 has a
marginal impact versus the parent 1,3,5-hexatriene 52.
Introduction of a conjugating, electron-withdrawing group
at C-4 reduces the activation energy by 4-5 kcal/mol,
whereas introduction of electron-withdrawing groups at
C-2 has a profound effect of 12-16 kcal/mol. In the nitro-
substituted cases the reactants 26 and 28 have the
conformation required for the ring closure. The lowest
activation energy calculated for any of the electrocyliza-
tions (4.3 kcal/mol) was observed for enamine 55 (Figure
5) with transition structure 56. These calculations pro-
vide a credible account of the facility with which the
observed products - anilines and phenols are produced
in the reaction from vinamidiniums that possess strongly
electron withdrawing groups at the â-carbon.
A satisfactory explanation for the product isotope effect
in these reactions remains elusive. Experimental studies
by Baldwin, Hess, and Schaad98 have established that
the diastereotopically distinct hydrogens in the electro-
(95) The activation energy is presumably <10 kcal/mol. Herrera,
F. G. An. Real Soc. Espan. Fis. Quim. 1961, 57B, 601.
(96) For a kinetic study on the role of the acidity of the ketone in
determining the mechanism of enolization via proton abstraction from
ketone, carbinolamine, or imine by primary, secondary, and tertiary
amines see: Yurkanis-Bruice, P. J . Am. Chem. Soc. 1990, 112, 7361.
(97) A kinetic study of the rate of elimination of dimethylamine has
not been reported. Related cyclohexadienes have been prepared via
photochemical initiated addition of amines to chlorobenzene although
not in pure form. Gilbert, A.; Krestonosich, S.; Westover, D. L. J . Chem.
Soc., Perkin Trans. 1 1981, 295.
Mech a n istic Im p lica tion s
The initial computational objectives were to character-
ize the electrocylization and the proposed [1,5]-sigmat-
(98) Baldwin, J . E.; Reddy, V. P.; Hess, B. A., J r.; Schaad, L. J . J .
Am. Chem. Soc. 1988, 110, 8555.
J . Org. Chem, Vol. 69, No. 4, 2004 1307

Davies et al.
F IGURE 6. Schematic representation of the energies responsible for controlling aniline/phenol product ratio.
cylization of 1,3,5-hexatriene 52 exhibit a SKIE of 0.88
for the IN and 1.05 for the OUT atom, which manifest
themselves in the rate of electrocylization. This system
has also been studied computationally by Houk.99 The
difference between IN and OUT isotope effects in the
degenerate 1,3,5-hexatriene system has proved to be a
very sensitive probe for reaction mechanism The mini-
mum energy conformations for the nitro and iminium
enol and enamines all have the hydrogen in the IN
position and isotopic substitution is expected to manifest
itself by a change in activation energy but would be
qualitatively quite similar in all systems.
mechanistic features of the reaction were probed by
isotopic substitution and computational studies and
precluded the proposed [1,5]-hydrogen shift. Taken to-
gether the two approaches provide a complete road map
for the mechanistic pathway from ketone (rate-determin-
ing addition to vinamidinium, kH/D 0.7-0.93) through a
remarkably facile electrocylization with an activation
energy (∆Hq 4.3-12 kcal/mol) that is strongly dependent
upon substitution of hexatriene. Facile elimination of
dimethylamine leads to aromatic products.
Ack n ow led gm en t. We are grateful to the National
Science Foundation for financial support for the com-
putational research. We also thank the San Diego
Supercomputing Center and the UCLA Office of Aca-
demic Computing for computational resources. V.G.
thanks the Scientific and Technical Research Council
(TUBITAK) for a NATO Science Fellowship.
Con clu sion
We have described a synthesis of nitro anilines and
formyl anilines from simple acyclic precursors in a
reaction that should lend itself to synthetic application.
Highly functionalized substituted benzenes including
biaryls are accessible using this methodology. The reac-
tion emphasizes that substituted aromatics are easily
accessible via de novo synthesis rather than the use of
conventional electrophilic substitution. The level of com-
plexity introduced in a single step is formidable. The
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
characterization data for all new compounds; refined data and
coordinates for X-ray analysis of 21b; B3LYP/6-31G* optimized
Cartesian coordinates for reactants and transition structures
of neutral 1,5-hydrogen migrations in cyclohexadienes, the
most stable conformers of hexatrienes and their transition
structures for electrocyclic ring closure. This material is
available free of charge via the Internet at http://pubs.acs.org.
(99) Wiest, O.; Houk, K. N.; Black, K. A.; Thomas, B., IV. J . Am.
Chem. Soc. 1995, 117, 8594.
J O035677U
1308 J . Org. Chem., Vol. 69, No. 4, 2004