An NMR study of the kinetics of 1,4-N,N'-migration of the acyl group vinylogs on aromatic 1,2-diamines

Full text of DOI:10.1021/jo981405t

1426
J . Org. Chem. 1999, 64, 1426-1428
An NMR Stu d y of th e Kin etics of
1,4-N,N′-Migr a tion of th e Acyl Gr ou p
Vin ylogs on Ar om a tic 1,2-Dia m in es
Andris Strakovs,† Marina V. Petrova,†
Natalia N. Tonkih,† Elwood E. Brooks,‡
Susan J . Biehle,‡ and George P. Kreishman*,‡
Department of Chemical Technology, Azenes Iela 14, Riga
Technical University, Riga Latvia LV-1048, and Department
of Chemistry, University of Cincinnati, P.O. Box 210172,
Cincinnati, Ohio 45221-0172
Received J uly 20, 1998
As part of our continuing studies of the reactions of
aromatic 1,2-diamines with 2-acyl-1,3-cyclandiones,1-3
the reactions of 2,3-diaminopyridine were attempted with
2-acyl-1,3-cyclohexanediones to produce pyrido[2,3-b][1,4]-
benzodiazapine derivatives. This class of compounds have
been shown to exhibit a wide range of biological activity.4-6
Specifically, 2,3-diaminopyridine (1) and 2-formyldime-
done (2) were used to synthesize 2-(2-amino-3-pyridy-
laminomethylene)- (3) and 2-(3-amino-2-pyridylaminom-
ethylene)-5,5-dimethyl-1,3-cyclohexanedione (4).1-3 Both
F igu r e 1. The 400 MHz 1H NMR spectrum of 3 as a function
of time at 293.1 K.
F igu r e 2. Van’t Hoff plot of ln K vs 1/T.
4 is reached. The process, an intramolecular transami-
nation, is much more rapid in DMSO-d6 than in CDCl3
1
and can be followed by H NMR spectroscopy. In Figure
1, the spectrum of 3 immediately after dissolving in
DMSO-d6 indicates only one isomer. After a given amount
of time, a second resonance signal for each proton from
the other isomer, 4, appears and continues to grow until
a ratio of 1 to 1.3 (3 to 4) is observed at 303.1 K.
The equilibrium constant, K ) [4]/[3], increases slightly
with increasing temperature (Figure 2). From the Van’t
Hoft plot, the ∆H° for the reaction is 4 kJ /mol ( 1 kJ /
mol. The ∆S° for the reaction is 12 J /(mol K) ( 2 J /(mol
K). At 303.1 K, the ∆G° for the reaction is -0.7 kJ /mol
( 0.2 kJ /mol.
compounds were separated from the reaction mixture by
chromatography and structurally characterized by IR and
NMR spectroscopy. They were shown to be rigid amino
vinyl ketones having a 3J (H,H)CH-NH ≈ 12-13 Hz,
stabilized with an intramolecular hydrogen bond of the
type N-H‚‚‚O ) δ (NH ≈ 12-13 ppm).
Although the two isomers are stable in the solid state,
upon dissolving either individual isomer in CDCl3 or
DMSO-d6, it begins to convert to the other one and the
process continues until an equilibrium mixture of 3 and
In Figure 3, the initial region of the plot of the natural
logarithm of the spectral intensity versus time is shown.
Since only 5-10% of 3 has been converted and the back
reaction is still negligible, the decrease is exponential and
a plot of ln I vs t for the first-order rate process yields a
straight line. The rate constants as a function of tem-
perature were calculated from the initial linear portions
of the curves and are summarized in Table 1. An
Arrhenius plot of these data yielded a straight line
(Figure 4) and an activation energy of 70 kJ /mol ( 4 kJ /
mol as well as an ln A of 17 ( 1 in DMSO-d6. Substitution
of the vinyl proton by a methyl group blocks the migra-
tion. The transamination is catalyzed by OH- where the
increase in the reaction rate constant is linear with
[OH-].
† Riga Technical University.
‡ University of Cincinnati.
(1) Strakov, A. Y.; Petrova, M. V.; Dishs A.; Strakova, I. A.; Lahvich,
O. F. Chem. Heterocycl. Comput. 1995, 31, 289-295.
(2) Strakov, A. Y.; Petrova, M. V.; Tonkih, N. N.; Gurkovsky, A. I.;
Popelis, J .; Kreishman, G. P.; Belyakov, S. V. Chem. Heterocycl.
Comput. 1997, 33, 379-391.
(3) Strakov, A. Y.; Tonkih, N. N.; Petrova, M. V.; Gurkovsky, A. 16th
International Congress of Heterocyclic Chemistry; Bozeman, Montana,
1997; Abstract POII-253.
(4) Watanabe, T.; Kinoyama, I.; Kakefuda, A.; Okazaki, T.; Tak-
izawa, K.; Hirano, S.; Shibata, H.; Yanagisawa, I. Chem. Pharm. Bull.
1997, 45, 996-1007.
(5) Watanabe, T.; Kakefuda, A.; Kinoyama, I.; Takizawa, K.; Hirano,
S.; Shibata, H.; Yanagisawa, I. Chem. Pharm. Bull. 1997, 45, 1458-
1469.
(6) Woolard, F. X.; Paetsch, J .; Ellman, J . A. J . Org. Chem. 1997,
62, 6102-6103.
10.1021/jo981405t CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/26/1999

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1427
F igu r e 3. A plot of ln I vs t for the 3 isomer at 303.1 K.
F igu r e 5. NOESY spectrum of a mixture of 3 and 4 in DMSO-
d6. A: Cross-peak between the vinyl proton and the 4-H of
the pyridine ring of 3. B: Region where the expected cross-
peak between the vinyl proton and the 4-H proton of the
pyridine was not observed.
In str u m en ta tion . The 1H NMR spectrum were run on either
a Bruker AM-360 or AMX 400 WB spectrometer. The natural
abundance 13C and 15N NMR spectra were obtained on Bruker
AM-360 spectrometer at frequencies 90.5 and 36.51 MHz,
respectively. The 15N-1H coupling constants were measured
from 1H NMR spectra using HMQC pulse sequence. For calcu-
lating the delays in HMQC sequences, a 1J (15N, 1H) ) 90 Hz
coupling constant was used. The NOESY spectra were obtained
using a mixing time of 500 ms. The two isomers can be
differentiated by the presence of a cross-peak in the NOESY
spectrum of 3 between the vinyl proton and the 4-H of the
pyridine ring which is not observed in the NOESY spectrum of
4 (Figure 5). The kinetic data were obtained at a spectrometer
frequency of 400.13 MHz using a multiple ZG program with a
fixed delay time (20-60 min) between acquisitions. The spectral
intensity was taken as the peak height in the absolute intensity
mode since the line width did not vary with time. The sample
was prepared immediately before use by dissolving in DMSO-
d6 (Sigma, 100% D). This procedure usually took a minute, and
the mixing time was not included in the time used for kinetic
analysis. The temperature was maintained to (0.1 K using a
B-VT 1000 variable-temperature unit. For the catalytic experi-
ments, increments of 2.5 µL of 0.10 M NaOH in H2O were added
to the sample prior to spectral acquisition. The IR spectra were
obtained on a Specord-75 IR spectrometer.
F igu r e 4. Arrhenius plot of ln k vs 1/T.
Ta ble 1. Ra te Con sta n ts for Migr a tion in DMSO-d 6 a t
Va r iou s Tem p er a tu r es
T (K)
k (1/s)
ln k (1/s)
293
303
310
318
325
3.85E-06
1.031E-05
2.028E-05
4.222E-05
6.514E-05
-12.467
-11.483
-10.806
-10.073
-9.639
One proposed intermediate for this rearrangement is
structure 5, but the exact mechanism has yet to be
confirmed. Deprotonation of the proposed intermediate
by base is consistent with the observed catalysis by OH-.
Com p ou n d s. 2-(2-Am in o-3-p yr id yla m in om eth ylen e)-5,5-
d im eth yl-1,3-cycloh exa n ed ion e: pale yellow solid, mp 136-
137 °C; IR (KBr) 3320, 3164, 1668, 1620, 1568; 1H NMR (360
MHz, CDCl3) δ 1.08 (6H, s, 2CH3), 2.40 (2H, s, CH2), 2.44 (2H,
3
The N substituent of 1,2-diaminopyridine in compounds
3 and 4 can be considered as a vinylog of the acyl group,
thus the process, an intramolecular transamination, may
qualify as the first example of 1,4-N,N′-migration of acyl
group vinylogs.
s, CH2), 4.88 (2H, br s, NH2), 6.77 (1H, dd, J ) 4.9 and 7.9 Hz,
3
4
3
Py), 7.45 (1H, dd, J ) 7.9, J ) 1.5 Hz, Py), 8.01 (1H, dd, J )
4.9, 4J ) 1.5 Hz, Py), 8.44 (1H, d, 3J ) 12.8 Hz, dCH-), 12.74
(1H, d, 3J ) 12.8 Hz, NH); 1H NMR (360 MHz, DMSO-d6) δ 1.01
(6H, s, 2CH3), 2.33 (2H, s, CH2), 2.4 (2H, s, CH2), 5.97 (2H, br s,
3
3
NH2), 6.77 (1H, dd, J ) 4.9 and 7.8 Hz, Py), 7.64 (1H, dd, J )
7.8, 4J ) 1.4 Hz, Py), 7.91 (1H,dd, 3J ) 4.9, 4J ) 1.4 Hz, Py),
8.29 (1H, d, 3J ) 13.1 Hz, dCH-), 12.35 (1H, d, 3J ) 13.1, NH);
13C NMR (90.5 MHz, DMSO-d6) δ 28.04 (CH3), 30.7, 50.7 (CH2),
51.9 (CH2), 109.1, 113.7, 121.2, 127.6, 145.8, 152.2 (dCH-),
194.6 (CdO), 198.4 (CdO); 15N NMR (36.5 MHz, CDCl3) 1J (15N,
1H) ) 90.3 Hz, 1J (15N, 1H) ) 83.7 Hz.
Exp er im en ta l Section
Gen er a l P r oced u r e. To 5 mmol of 1 dissolved in 15 mL of
ethanol was added 5 mmol of 2 dissolved in 15 mL of ethanol,
and the mixture was allowed to stand at either 20 °C for 24 h
or 78 °C for 10 min. A mixture of 3 and 4 was obtained in a
yield of 4.78 g (96%). A 1.15-g aliquot of the mixture was applied
to 35-70 mp Aeros Silica gel with a pore diameter of 6 nm and
eluted with ethyl acetate-toluene (7:3). After removal of the
solvent, 0.39 g of 4, Rf ) 0.47, and 0.62 g of 3, Rf ) 0.08, were
obtained.
2-(3-Am in o-2-p yr id yla m in om eth ylen e)-5,5-d im eth yl-1,3,-
cycloh exa n ed ion e: pale yellow solid, mp 135-136 °C IR (KBr)
δ 3382, 3340, 1670, 1636, 1594, 1550; 1H NMR (360 MHz, CDCl3)
δ 1.08 (6H, s, 2CH3), 2.42 (2H, s, CH2), 2.46 (2H, s, CH2), 3.69
(2H, br s, NH2), 6.98 (1H, dd, 3J ) 4.6 and 7.9 Hz, Py), 7.11
3
4
3
4
(1H, dd, J ) 7.9, J ) 1.5 Hz, Py), 7.91 (1H, dd, J ) 4.6, J )

1428 J . Org. Chem., Vol. 64, No. 4, 1999
Additions and Corrections
3
3
1.5 Hz, Py), 9.26 (1H, d, J ) 12.5 Hz, dCH-), 13.16 (1H, d, J
) 12.5 Hz, NH); 1H NMR (360 MHz, DMSO-d6) δ 1.01 (6H, s,
2CH3), 2.37 (2H, s, CH2), 2.44 (2H, s, CH2), 5.22 (2H, br s, NH2),
7.04 (1H, dd, 3J ) 4.6 and 7.8 Hz, Py), 7.27 (1H, dd, 3J ) 7.8, 4J
) 1.4 Hz, Py), 7.79 (1H, dd, 3J ) 4.8, 4J ) 1.4 Hz, Py), 9.02 (1H,
d, 3J ) 12.6 Hz, dCH-), 12.62 (1H, d, 3J ) 12.6, NH); 13C NMR
(90.5 MHz, DMSO) δ 22.9 (CH3), 30.6, 50.72 (CH2), 51.0 (CH2),
109.1, 121.9, 125.4, 134.1, 137.4, 138.8, 147.1 (dCH-), 195.3
(CdO), 198.9 (CdO); 15N NMR (36.5 MHz, CDCl3) 1J (15N, 1H) )
89.9 Hz (NH), 1J (15N, 1H) ) 78.5 Hz.
Ack n ow led gm en t. The authors thank Professor
Allan R. Pinhas of the University of Cincinnati for his
help in the preparation of this paper.
J O981405T
Additions and Corrections
Vol. 62, 1997
Mich a el A. Ca lter , T. Keith Hollis, La r r y E. Over m a n ,*
J osep h Ziller , a n d G. Gr eg Zip p . First Enantioselective
Catalyst for the Rearrangement of Allylic Imidates to Allylic
Amides.
Page 1449, Scheme 1. The following correction to
Scheme 1 should be made: b: R1 ) CH2OTBDPS, R3 )
n-Bu, R4 ) CCl3, R5 ) H.
The rearrangement of 1b is described in Mehman-
doust, M.; Petit, Y.; Larcheveˆque, M. Tetrahedron Lett.
1992, 33, 4313.
J O984028T
10.1021/jo984028t
Published on Web 02/03/1999