An unexpected [1,5]-H shift in the synthesis of nitroanilines

Article abstract of DOI:10.1021/ol017149f

Equation Presented Addition of methyl acetoacetate to 2-nitrovinamidinium hexafluorophosphate salts leads to the formation of anilines or phenols in good to excellent yields depending on the alkylamine substituents. Small substituents, e.g., pyrrolidine,

Full text of DOI:10.1021/ol017149f

ORGANIC
LETTERS
2002
Vol. 4, No. 3
439-441
An Unexpected [1,5]-H Shift in the
Synthesis of Nitroanilines
Ian W. Davies,* Jean-Franc¸ois Marcoux, Jeremy D. O. Taylor, Peter G. Dormer,
Robert J. Deeth, Fe´lix-Antoine Marcotte, David L. Hughes, and Paul J. Reider
Department of Process Research, Merck & Co., Inc., R800-B263, P.O. Box 2000,
Rahway, New Jersey 07065-0900
ian_daVies1@merck.com
Received November 29, 2001
ABSTRACT
Addition of methyl acetoacetate to 2-nitrovinamidinium hexafluorophosphate salts leads to the formation of anilines or phenols in good to
excellent yields depending on the alkylamine substituents. Small substituents, e.g., pyrrolidine, lead to the formation of anilines while large
substituents, e.g., N,N-diisopropyl, exclusively give phenols. Labeling studies implicate a [1,5]-H shift proceeding with excellent isotopic fidelity.
The [1,5]-hydrogen shift is an example of a Woodward-
Hoffmann pericyclic process which has been extensively
studied by experimental and computational methods.1 In
degenerate systems, e.g., 1,3-pentadiene, the activation
energy is 36.3 kcal/mol.2 Substituent and steric effects are
well understood.3 As a general trend, decreasing the electron
density of the π-system destabilizes the aromatic transition
structure and increases the activation energy whereas electron-
donating groups stabilize the transition structure.4 In con-
formationally constrained systems, the activation energy is
further reduced, e.g., cyclopentadiene 23.6 kcal/mol.5 The
[1,5]-H shift is also accelerated by appropriate oxy-anionic
substitution, reducing the activation energy to 13.8 kcal/mol.6
Vinamidinium salts are important synthetic intermediates.
They form the basis of the synthesis of the clinically
significant Cox-2 inhibitor etoricoxib7 as well as a variety
of other heterocycles, e.g., pyrroles, pyrimidines, and pyra-
zoles.8 As a result of the ease of access to these salts, we
have continued to explore their synthetic utility.9 In this Letter
we disclose a simple tunable transformation that is able to
deliver anilines or phenols in high yield together with
mechanistic studies that confirm the involvement of a
concerted [1,5]-H shift.
Addition of methyl acetoacetate (MAA) to the nitrovina-
midinim hexafluorophosphate salt 1a at room temperature
led to the formation of a 9:1 mixture of aniline and phenol
in high yield (Table 1). Similar results were obtained using
a range of solvents and bases although potassium tert-
butoxide gave the highest yield. There is no reaction in the
absence of base; however, catalytic quantities (10-20 mol
%) did give similar results with extended reaction times.
Repeating the reaction at preparative scale using THF and
KOtBu gave the aniline 2a in 75% isolated yield.10
The formation of anilines in the reaction was somewhat
surprising, but a mechanistic proposal was readily forthcom-
ing (Scheme 1). Addition of MAA to the nitrovinamidinium
(1) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969,
8, 781.
(2) Roth, W. R.; Konig, J. Liebigs Ann. 1966, 699, 24.
(3) Houk, K. N.; Li, Y.; Evanseck, J. D. Angew. Chem., Int. Ed. Engl.
1992, 31, 682.
(4) Saettel, N. J.; Wiest, O. J. Org. Chem. 2000, 65, 2331.
(5) Bachrach, S. J. Org. Chem. 1993, 58, 5414. Roth, W. R. Tetrahedron
Lett. 1964, 1009.
(6) Paquette, L. A.; Crouse, G. D.; Sharman, A. K. J. Am. Chem. Soc.
1980, 102, 3972.
(7) Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, 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.
(8) Gupton, J. T.; Krolikowski, D. A.; Yu, R. H.; Riesinger, S. W.
Sikorski, J. A. J. Org. Chem. 1990, 55, 4735. Gupton, J. T.; Petrich, S. A.;
Hicks, F. A.; Wilkinson, D. R.; Vargas, M.; Hosein, K. N.; Sikorski, J. A.
Heterocycles 1998, 47, 689. Kase, K.; Katayama, M.; Ishirara, T.;
Yamanaka, H.; Gupton, J. T. J. Fluorine Chem. 1998, 90, 29.
(9) Marcoux, J.-F.; Marcotte, F.-A.; Wu, J.; Dormer, P.; Davies, I. W.;
Hughes, D.; Reider, P. J. J. Org. Chem. 2001, 66, 4194.
10.1021/ol017149f CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/05/2002

Scheme 2
Table 1. Reaction of MAA and 2-Nitrovinamidinium
Hexafluorophosphate 1aa
The isotope labeling experiment implicates a [1,5] trans-
position of deuterium. However this result needs to be
interpreted with caution since it does not rigorously exclude
the intermediacy of a carbanion or ion-pair association.
Further studies to unambiguously determine the nature of
the [1,5]-H shift were guided by the classic Cram experi-
ments on an inter- and intramolecularity in base-catalyzed
proton transfers.15 Conducting the reaction of 8 using
potassium tert-butoxide in tert-butyl alcohol and sodium
methoxide in methanol provides a very large isotopic
reservoir of protons. In both cases only the deuterio aniline
9 and phenol 10 were observed. Reaction of protionitrovi-
namidinium 1a using potassium tert-butoxide in tert-butyl
alcohol-OD and sodium methoxide in CH3OD only led to
the protio aniline 2a and phenol 3.16
a Reactions were conducted at room temperature with 1.05 equiv of base
and 1.1 equiv of 1a for 4 h. Assay yield was determined by HPLC analysis
using analytically pure standards.
leads to the dienone 4.11 A simple keto-enol tautomerism
to 5 sets the stage for an electrocyclic ring closure of the
hexatriene to generate enol 6.12 At this point aromaticity can
be achieved by the elimination of dimethylamine. However
a [1,5]-H shift leads to enamine 7 with aromaticity being
achieved by the elimination of water.
A range of nitrovinamidinium salts, 1b-d, were also
examined in the reaction with MAA and potassium tert-
butoxide (Table 2).17
A clear trend emerges from this panel of experiments. The
smaller the groups on nitrogen, the higher the preference
To confirm the involvement of a [1,5]-H shift, the per-
deuterio nitrovinamidinium hexafluorophosphate 8 was
prepared starting with d7-dimethylformamide and chloro-
acetic acid.13 Reaction of 8 and MAA in the presence of
potassium tert-butoxide cleanly gave the aniline 9 and phenol
10 with no trace of the protio analogues (Scheme 2).14
(10) Typical procedure: To a stirred solution of methyl acetoacetate
(580 mg, 5 mmol) in THF (10 mL) at room temperature was added
potassium tert-butoxide (5.25 mL, 1.0 M in THF) over 5 min. The solution
was aged for 5 min, and nitrovinamidinium hexafluorophosphate 1a (1.74
g, 5.5 mmol) was added in one portion. The mixture was stirred at room
temperature for 8 h. The reaction mixture was diluted with ethyl acetate
and washed with water. Concentration of the organic extracts and chro-
matography on silica gel eluting with ethyl acetate/heptane gave the aniline
2a (842 mg, 75%) as a light yellow solid. DSC peak 88.4 °C (lit. mp 71.5
°C, Reverdin, F. Chem. Ber. 1907, 40, 2442). Found: C, 53.66; H, 5.39;
N, 12.30. C10H12N2O4 requires C, 53.57; H, 5.39; N, 12.49. 1H NMR (400
MHz, CDCl3) δ 8.55 (1H, d, J ) 3 Hz), 8.15 (1H, dd, J ) 9, 3 Hz), 6.85
(1H, d, J ) 9 Hz), 3.93 (3H, s), 3.03 (6H, s). 13C NMR (100 MHz, CDCl3)
δ 167.1, 155.0, 137.1, 128.9, 127.4, 116.6, 114.6, 52.5, 42.9. HRMS, [M
+ H]+ 225.0864.
Scheme 1
(11) Nair, V.; Cooper, C. S. J. Org. Chem. 1981, 46, 6, 4759.
(12) For a simple model to predict the effect of substituents on the rates
of thermal pericyclic reactions, see: Carpenter, B. Tetrahedron 1978, 34,
1877.
(13) The per-deuterio nitrovinamidinim salt was prepared analogously
to the protio compound in two steps via pTSA/PPh3 reduction of the
chlorovinamidinium salt followed by nitration, see: Davies, I. W.; Marcoux,
J.-F.; Wu, J.; Corley, E. G.; Robbins, M. A.; Palucki, M.; Tsou, N.; Ball,
R. G.; Dormer, P.; Larsen, R. D.; Reider, P. J. J. Org. Chem. 2000, 65,
4571. Davies, I. W.; Taylor, M.; Hughes, D.; Reider, P. J. Org. Lett. 2000,
2, 3385.
(14) The products were characterized by proton and deuterium NMR
spectroscopy, elemental analysis, and high-resolution mass spectrometry.
The limit of detection for the proton signal is < 0.3 mol %.
(15) Almy, J.; Uyeda, R. T.; Cram, D. J. J. Am. Chem. Soc. 1967, 89,
6768.
(16) In these cases, deuterium was incorporated in up to 47% at the site
derived from the enolizable methyl ketone without incorporation at any
other site.
(17) The vinamidinium salts were prepared via amine exchange, see:
Davies, I. W.; Taylor, M.; Marcoux, J.-F.; Wu, J.; Dormer, P. G.; Hughes,
D.; Reider, P. J. J. Org. Chem. 2001, 66, 251.
440
Org. Lett., Vol. 4, No. 3, 2002

to the formation of anilines or phenols depending on the
choice of vinamidinium salt and should lend itself to
synthetic application.19 This transformation may be rational-
ized as proceeding via two sequential pericyclic processes:
an electrocyclic ring closure and a facile [1,5]-H shift, a
transfer which proceeds with excellent isotopic fidelity. We
are continuing to explore the scope of this novel transforma-
tion and to study the mechanistic features of the [1,5]-H shift
including kinetic and computational studies.20
Table 2. Reaction of MAA and 2-Nitrovinamidinium
Hexafluorophosphates 1b-da
Supporting Information Available: Characterization and
spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL017149F
a Reactions were conducted at room temperature with 1.05 equiv of base
and 1.1 equiv of 1b-d for 12 h. Assay yield was determined by HPLC
analysis using analytically pure standards.
(18) Replacement of dimethylamine with diisopropylamine presumably
affects the k1/k-1 equilibrium more than the k2 and k3 elimination rates.
The elimination of dimethylamine from 6 or water from 7 is not expected
to be rate-limiting, see: Jia, Z. S.; Brandt, P.; Thibblin, A. J. Am. Chem.
Soc. 2001, 123, 10147. The rate of dehydration of benzene hydrate in
glycerol/water at pH 5.57 is 58 M-1 s-1 at 25 °C and is exothermic by
-39 kcal/mol.
(19) The 3-nitro-4-aminobenzoate motif is a feature of combinatorial
libraries directed at G protein-coupled receptors. Pan, P.-C.; Sun, C.-M.
Tetrahedron Lett. 1998, 39, 9505. For intermediates in the synthesis of
influenza neuraminidase inhibitors, see: Brouillette, J. W.; Atigadda, V.
R.; Luo, M.; Air, G. M.; Babu, Y. S.; Bantia, S. Bioorg. Med. Chem. Lett.
1999, 9, 1901. For the use of 3-nitro-4-aminobenzoates in the solid-phase
synthesis of benzopiperazinones, see: Morales, G.; Corbett, J. W.; DeGrabo,
W. F. J. Org. Chem. 1998, 63, 1172.
for the aniline. In fact, N,N-diisopropylamine led exclusively
to the formation of phenol 3. This trend does not reflect
leaving group ability. However, the o-nitro group and the
aniline alkyl substituents will face significant steric interac-
tions in the transition state leading to the diisopropyl
intermediate.18 The reaction is tunable for either anilines or
phenols by the choice of nitrogen substituent.
(20) Preliminary results indicate that the reaction is not limited to MAA
and 2,4-pentanedione works effectively with 1a to give a 30:1 mixture of
aniline and phenol in 80% yield.
In summary, we have described a simple synthesis of
nitroanilines from nitrovinamidinium salts. The reaction leads
Org. Lett., Vol. 4, No. 3, 2002
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