A study of Aryl radical cyclization in enaminone esters

Article abstract of DOI:10.1021/jo0107857

Aryl radical cyclization in N-phenyl, N-benzyl, and N-phenethyl enaminone esters 1a-f was studied. N-Benzyl and N-phenethyl enaminones afforded 5-exo and 6-exo cyclization products, respectively, but radical cyclization did not occur in N-phenyl enaminones. The rate constants for the 5-exo and 6-exo cyclization processes in secondary enaminones were estimated as being on the order of 10⁷ s^-1 at 353 K; since DNMR experiments showed the rate constant for rotation around the enaminone C3-N bond to be on the order of 10⁴ s^-1 at this temperature, the initial enaminone configuration is maintained throughout the cyclization process. PM3 calculations suggested that the nonoccurrence of endo and 4-exo cyclizations is due to the corresponding transition structures involving significant distortion of the conjugated enaminone system.

Full text of DOI:10.1021/jo0107857

J . Org. Chem. 2002, 67, 3213-3220
3213
A Stu d y of Ar yl Ra d ica l Cycliza tion in En a m in on e Ester s†
Armando Navarro-Va´zquez, Alberto Garc´ıa, and Domingo Dom´ınguez*
Departamento de Quı´mica Orga´nica y Unidad Asociada al CSIC, Facultad de Qu´ımica, Universidad de
Santiago de Compostela, 15782 Santiago de Compostela, Spain
qomingos@usc.es
Received August 2, 2001
Aryl radical cyclization in N-phenyl, N-benzyl, and N-phenethyl enaminone esters 1a -f was studied.
N-Benzyl and N-phenethyl enaminones afforded 5-exo and 6-exo cyclization products, respectively,
but radical cyclization did not occur in N-phenyl enaminones. The rate constants for the 5-exo and
6-exo cyclization processes in secondary enaminones were estimated as being on the order of 107
s-1 at 353 K; since DNMR experiments showed the rate constant for rotation around the enaminone
C3-N bond to be on the order of 104 s-1 at this temperature, the initial enaminone configuration
is maintained throughout the cyclization process. PM3 calculations suggested that the nonoccurrence
of endo and 4-exo cyclizations is due to the corresponding transition structures involving significant
distortion of the conjugated enaminone system.
In tr od u ction
Radical cyclizations of highly reactive aryl radicals onto
double and triple bonds have proven to be very useful
for construction of both carbocycles and heterocycles,1 aza
heterocycles in particular.1c Aza heterocycles of various
F igu r e 1.
sizes have been obtained by radical addition to N-vinyl
amides (enamides).2,3 The use of other compounds con-
Sch em e 1
taining the N-vinyl unit such as enamines,4 N-sulfonyl-
enamines,5 and enaminones6,7 has been less frequent.
Electronically, enaminone esters can be described as
push-pull systems with extensive charge donation from
the nitrogen to the carbonyl group. Their structure is
accordingly best represented as a resonance hybrid of the
neutral and zwitterionic forms depicted in Figure 1. Due
to this extended conjugation, their reactivities are very
† Dedicated to Prof. Michael P. Cava on the occasion of his 75th
birthday.
(1) For reviews, see: (a) Giese, B. Radicals in Organic Synthesis:
Formation of Carbon-Carbon Bonds; Pergamon Press: New York,
1986. (b) Curran, D. P. Synthesis 1988, 417-439. (c) Curran, D. P.
Synthesis 1988, 489-513. (d) J asperse, C. P.; Curran, D. P.; Fevig, T.
L. Chem. Rev. 1991, 91, 1237-1286. (e) Curran, D. P. In Comprehensive
different from those of simple enamides or enamines.8
To investigate whether these differences might make
them of interest as radical acceptors, we explored the
synthetic potential and mechanistic features of intra-
molecular aryl radical cyclization onto enaminone esters.
Organic Synthesis; Trost, B. M., Felming, I. Eds; Pergamon Press: New
York, 1991; Vol. 4, pp 779-827.
(2) For some recent examples of the use of enamides as radicalofiles,
see the following papers and references therein: (a) D’Annibale, A.;
Nanni, D.; Trogolo, C.; Umani, F. Org. Lett. 2000, 2, 401-402. (b)
Davies, D. T.; Kapur, N.; Parsons, A. F. Tetrahedron Lett. 1999, 40,
8615-8618. (c) Clark, A. J .; Dell, C. P.; Ellard, J . M.; Hunt, N. A.;
McDonagh, J . P. Tetrahedron Lett. 1999, 40, 8619-8623. (d) Baker,
S. R.; Burton, K. I.; Parsons, A. F.; Pons, J . F.; Wilson, M. J . Chem.
Soc., Perkin Trans. 1 1999, 427-436. (e) Ishibashi, H.; Inomata, M.;
Ohba, M.; Ikeda, M. Tetrahedron Lett. 1999, 40, 1149-1152. (f)
Ishibashi, H.; Oata, K.; Niihara, M.; Sato, T.; Ikeda, M. J . Chem. Soc.,
Perkin Trans. 1 2000, 547-553. (g) Ishibashi, H.; Kato, I.; Takeda, Y.;
Kogure, M.; Tamura, O. Chem. Commun. 2000, 1527-1528.
(3) For related work by our group on 7-endo aryl radical cyclization
onto enamides see: (a) Fidalgo, J .; Castedo, L.; Domı´nguez, D.
Tetrahedron Lett. 1993, 34, 7317-7318. (b) Rodr´ıguez, G.; Cid, M. M.;
Saa´, C.; Castedo, L.; Dom´ınguez, D. J . Org. Chem. 1996, 61, 2780-
2782. (c) Cid, M. M.; Dom´ınguez, D.; Castedo, L.; Va´zquez-Lo´pez, E.
Tetrahedron 1999, 55, 5599-5610.
Resu lts a n d Discu ssion
As part of our study, we chose the enaminone esters
1a -f (Scheme 1, Table 1), which were prepared by
condensation of the appropriate amine with methyl
propiolate. The N-benzyl and N-phenethyl compounds
1c-f were easily obtained in very good yields at room
temperature,9 but high temperatures and acetic acid
(4) Glover, S. A.; Warkentin, J . J . Org. Chem. 1993, 58, 2115-2121.
(5) A° hman, J .; Somfai, P. J . Chem. Soc., Perkin Trans. 1 1994,
1079-1082.
(8) Pitacco, G.; Valentin, E. In The Chemistry of Functional Groups,
Supplement F: The Chemistry of Amino, Nitroso and Nitro compounds
and their Derivatives; Patai, S., Ed.; J ohn Wiley and Sons: New York,
1982; Part 1, pp 623-703.
(9) Cossu, S.; De Lucchi, O.; Durr, R. Synth. Commun. 1996, 26,
4597-4601.
(6) Middleton, D. S.; Simpkins, N. S.; Terret, N. K. Tetrahedron Lett.
1989, 30, 3865-3868.
(7) Berteina, S.; De Mesmaeker, A. Synlett 1998, 1227-1230.
10.1021/jo0107857 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/19/2002

3214 J . Org. Chem., Vol. 67, No. 10, 2002
Navarro-Va´zquez et al.
Sch em e 2
Ta ble 1. P r od u ct Yield s u p on Cycliza tion of En a m in on e
Ester s 1a
cyclized compounds showed the loss of a ‚CH2CO2Me
fragment, and all the HMBC spectra showed a three-bond
correlation between the methine proton and the meth-
ylene carbon R to the nitrogen (the lowest-field methylene
in the 13C spectrum); the HMBC spectra of the N-methyl
compounds also showed a three-bond correlation between
the N-methyl carbon and the methine proton.
enaminone 1
n
R
2 (%)
3 (%)
a
b
c
d
e
0
0
1
1
2
H
Me
H
Me
H
43
55
71
56
42b
82
51
12
49
The phenethyl compounds 1e and 1f furnished the
isoquinolines 3e and 3f in moderate to good yields (Table
1). Since not using slow addition techniques for addition
of the tin hydride/AIBN solution halved the yield of the
first reaction examined, 1e f 3e (Table 1), syringe pump
addition was used for all the other experiments. The
yields of the isoindoles 3c and 3d were comparable to
those of the isoquinolines 3e and 3f, and the phenyl
compounds 1a and 1b completely failed to furnish any
cyclized product. The N-methyl compounds 1d and 1f
furnished lower yields of the cyclization products than
the secondary enaminones 1c and 1e, accompanied by
higher amounts of reduced products (2d and 2f, respec-
tively) that are associated with [1-5] or [1-6] hydrogen
shifts.
f
2
Me
19
a
Reaction conditions: syringe pump addition, over 3 h, of a
solution of 2 equiv of Bu3SnH and AIBN (20% w/w) in benzene to
a refluxing 0.01 M solution of enaminone 1 in the same solvent.
b
Refluxing of a 0.01 M solution of enaminone 1 in benzene
containing 1.1 equiv of Bu3SnH and AIBN (20% w/w).
catalysis10 were required in order to obtain the N-phenyl
derivatives 1a and 1b in even moderate yields.
Formation of the aryl radicals of compounds 1a -f
(radicals 5) could in principle be followed by several
reaction pathways (Scheme 2). Direct reduction of 5 by
tributyltin hydride leads to the reduced products 2 (the
N-methyl compounds 2d and 2f could also be formed via
a stabilized R-amino radical produced by a [1-5] or [1-6]
11
NMR Exp er im en ts to Deter m in e Ra tes a n d Con -
for m a tion s. We surmised that the outcome of the
intramolecular reaction was probably influenced by the
rigidity imparted on enaminone esters by their large
conjugated systems. The enaminones are known to exist
in several conformations;13 in the case under study, the
most relevant conformations are those obtained by the
rotation around the C3-N bond and the cis and trans
isomerization of the double bond (Figure 2). Taking this
into account, if compounds 1 existed largely in a confor-
mation favoring the exo reaction, and if the entire
cyclization reaction was faster than any relevant process
of conformational change, then no endo reaction would
take place. Note that the s-(E) conformation of the C3-N
bond leads to a geometry that certainly favors the exo
reaction, while for the s-(Z) conformation, both endo and
exo processes might be possible. Furthermore, rotation
around the C3-N bond seemed likely to be slower than
hydrogen shift,
followed by Bu3SnH reduction). The
other reaction paths are exo and endo cyclizations onto
the enaminone double bond, furnishing radicals 6 and
7, respectively, followed by reduction to compounds 3 and
4.
Ra d ica l Cycliza tion : Exp er im en ta l Resu lts. When
the enaminone esters 1a -f were subjected to standard
conditions for aryl radical formation (Bu3SnH/AIBN), the
only reaction products isolated were those formed by
reduction of the aryl radical by tin hydride, 2, and for
1c-f, the corresponding exo cyclization products 3 (Scheme
1). The latter were distinguished from the alternative
endo products 4, by mass spectrometry and 2D NMR
spectroscopy (HMBC).12 The mass spectra of all the
(10) Miller, L. A. U.S. Patent 3 093 679, 1963; Chem. Abstr. 1963,
59, 11331b.
(11) Renaud, P.; Giraud, L. Synthesis 1996, 913-926 and references
therein.
(12) (a) Bax, A.; Summers, M. F. J . Am. Chem. Soc. 1986, 108, 2903-
2904. (b) Wilker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W. Magn.
Reson. Chem. 1993, 31, 287-292. (c) Ru´ız-Cabello, J .; Vuister, G. W.;
Moonen, C. T. W.; van Gelderen, P.; Cohen, J . S.; van Zijl, P. C. M. J .
Magn. Reson. 1992, 100, 282-303.
(13) (a) Nogueira Ebberlin, M.; Takahata, Y.; Kascheres, C. J . Mol.
Struct. (THEOCHEM) 1990, 207, 143-156. (b) Vdovenko, S. I.; Gerus,
I. I.; Gorbunova, M. G. J . Chem. Soc., Perkin Trans. 2 1993, 559-562.

Study of Aryl Radical Cyclization in Enaminone Esters
J . Org. Chem., Vol. 67, No. 10, 2002 3215
the ratio of 2c and 3c in the resulting mixture of reduced
and cyclized products was measured by integration of the
1H NMR spectra. From the slope of the line so obtained
(Figure 3), and assuming a value of 109 M-1 s-1 for kH,16
we calculated the 5-exo cyclization rate constant kc at 80
°C as (3.5 ( 0.1) × 107 s-1. A similar kinetic study for
the phenethyl enaminone 1e gave a 6-exo rate constant
kc of (7.1 ( 0.5) × 107 s-1, likewise at 80 °C. In both cases,
the intercept was close to zero to within the experimental
error, indicating that the cyclization is fundamentally
irreversible (k-c ≈ 0) as expected for a highly exothermic
aryl radical cyclization. The kc values found show that
enaminones are only moderate radical acceptors in
comparison to enamines; for example, the relative rate
constants for 5-exo and 6-endo aryl radical cyclization of
N-butyl-N-(2-bromobenzyl)-1-cyclohexenylamine obtained
F igu r e 2. Principal conformers on secondary and tertiary
enaminone esters.
Sch em e 3
by Warkentin are 4.0 × 108 s-1 and 1.3 × 109 s-1
,
respectively.17
Rotation Around the C3-N Bond. We determined the
barrier to rotation around the C3-N bond by means of
1
dynamic H NMR experiments carried out between 248
and 303 K on a 0.08 M solution of the N,N-dimethyl
tertiary enaminone 8 in CDCl3 (Figure 4). The broad
N-methyl signal observed at room temperature split into
two singlets upon cooling. Full line shape analysis18
optimized both the chemical shifts of the methyl groups
and the rate constants for C3-N rotation (Table 2), the
latter of which were used to construct a plot of ln(k/T)
against 1/T (Figure 4). Fitting these data with the Eyring
equation19 (eq 2; we assume transmission coefficients of
unity) then afforded the values ∆Hq ) 15.6 ( 0.6 kcal/
mol and ∆Sq ) 7.6 ( 0.3 e.u., which imply a rate constant
k ) 7.1 × 104 s-1 at 353 K. Therefore, since we saw in
the previous section that for exo cyclizations of 1c and
1e kc ≈ 107 s-1, rotation around the enaminone C3-N
bond is ca. 1000-fold slower than the cyclization process,
which must occur without alteration of the configuration
with respect to this bond.
cyclization because rotation around the amide bond is
known to be slower than aryl radical cyclization of
amides.14
To support this interpretation of our synthetic results,
we carried out NMR experiments to determine the
predominant conformations of 1a -f in benzene and
estimate the orders of the rate constants for cyclization
and for rotation around the C3-N bond.
kB
k
∆Hq
ln ) ln e∆Sq/R
-
(2)
T
h
RT
Rates of Cyclization. The rates of the 5-exo and 6-exo
cyclization processes, relative to that of direct abstraction
of hydrogen from tributyltin hydride by the aryl radicals,
were determined by performing experiments with 1c and
1e at different Bu3SnH concentrations. On the basis of
the mechanism shown in Scheme 3, the steady-state
approximation leads to eq 1,15 which gives the ratio [2]/[3]
as a linear function of the initial tributyltin hydride
concentration, [Bu3SnH]0. The slope of the line is kH/ kc,
and the intercept is an estimate of the constant k-c/ kc
governing the equilibrium between the open-chain radical
5 and the cyclized radical 6.
Conformations of 1a -f in Benzene. To determine the
predominant conformations of 1a -f in benzene, in which
rotation around the C3-N bond is fast on the NMR time
scale at the temperature of interest, we performed NOE
experiments in deuterated benzene (for instrumental
safety, these experiments were carried out at 343 rather
than 353 K). Note that the conformational distribution
in radicals 5a -f will be dictated by that of the parent
bromide compounds 1a -f since, as we have seen in the
previous section, thermal equilibration between conform-
ers is a much slower process than radical reactions. All
the tertiary enaminones 1b, 1d , and 1f exist exclusively
in the trans form with respect to the enaminone double
bond, as shown by the large coupling constants between
the olefinic protons (J ) 13.1, 13.0, and 12.9 Hz,
respectively). Irradiation of the vinylic C3 and C2 protons
of 1b, respectively, induced NOE of 1.8% with the
k
kHk-c
kH'kc
[2]
[3]
)
H[Bu3SnH]0 +
(1)
kc
A 6.0 × 10-3 M solution of enaminone 1c in benzene
containing 25% (w/w) of AIBN was treated with four
different initial concentrations of tributyltin hydride, and
(16) Garden, S. J .; Avila, D. V.; Beckwith, A. L. J .; Bowry, V. W.;
Ingold, K. U.; Lusztyk, J . J . Org. Chem. 1996, 61, 805-809.
(17) In the original paper (ref 4) a different kH value was used (3.52
× 108 M-1 s-1); therefore, for the purpose of comparison, we recalcu-
lated the reported values using the new kH from ref 16.
(18) Line shape analysis was performed using Gnmr3.6: Budzeelar,
P. H. M.; Cherwell Scientific Publishing: Oxford, 1995.
(14) (a) Snieckus, V.; Cuevas, J . C.; Sloan, C. P.; Liu, H.; Curran,
D. P. J . Am. Chem. Soc. 1990, 112, 896-898. (b) Curran, D. P.;
DeMello, N. C. J . Chem. Soc., Chem. Comm. 1993, 1314-1317.
(15) Kim, S.; Yoon, K. S.; Kim, Y. S. Tetrahedron 1997, 53, 73-80.
(b) Curran, D. P.; DeMello, N. C. J . Chem. Soc., Chem. Comm. 1993,
1314-1317.
(19) Eyring, H. J . Chem. Phys. 1935, 3, 107-115.

3216 J . Org. Chem., Vol. 67, No. 10, 2002
Navarro-Va´zquez et al.
F igu r e 3. Kinetic measurements of the aryl radical cyclization of enaminone esters 1c and 1e (standard errors in parentheses).
F igu r e 5. Definition of the enaminone distortion parameter
D.
and for 1e J cis ) 7.9 and J trans ) 12.9, all in Hz). For 1a ,
the cis:trans ratio is 7.5:1 at 300 K and 24:1 at 343 K;
for 1c, 2.8:1 at 300 K and 4.1:1 at 343 K; and for 1e, 2.2:1
at 300 K and 4.80:1 at 343 K. The cis form necessarily
adopts an s-(E) conformation around the C3-N bond due
to the hydrogen bond, while the trans form may in
principle adopt both s-(E) and s-(Z) conformations. Ir-
radiation of the methylene protons of the trans form of
1c at 343 K induced NOE of 3.6% on the C2 proton and
2.9% on the C3 proton, showing a mixture of s-(Z) and
s-(E) conformations, whereas, as expected, irradiation of
the methylene protons of the cis form, induced NOE only
with the C3-H proton (2.7%). Similarly, with enaminone
1e, irradiation of the CH2N protons of the trans form gave
NOE of 2.6% with C2-H and 1.0% with C3-H, and
irradiation of those of the cis form gave NOE of 1.9% with
C3-H. Taken together, these results show that, like the
tertiary enaminones, the secondary enaminones exist
mainly in the s-(E) conformation, since this is the one
adopted by the more abundant cis form of secondary
enaminones.
P M3 Ca lcu la tion s on th e Cycliza tion Rea ction s.
To get a theoretical support of the synthetic results, we
carried out PM320 calculations, using an unrestricted
formalism, on the cyclization of the N-methyl radicals 5b,
5d , and 5f (the methoxy groups on the aryl ring, which
should not affect the reaction course significantly, were
supressed for simplicity). Minima and transition state
structures were identified, by means of numerical Hes-
sian calculations, (although only the latter will be
presented in this work, structures and energies of the
former are available as Supporting Information) for both
s-(E) and s-(Z) conformations with respect to the C3-N
bond. The connection between the transition structures
and products was verified by IRC21 calculations. Since
F igu r e 4. Plots of ln(k/T) vs 1/T data for rotation about the
C3-N bond of enaminone ester 8 obtained by DNMR rate
constant measurements.
Ta ble 2. Ch em ica l Sh ifts of N-Meth yl P r oton s in
En a m in on e Ester 8 a n d Cor r esp on d in g Ra te Con sta n ts
for Rota tion a r ou n d th e C3-N Bon d , a s Ca lcu la ted by
Lin esh a p e An a lysis of DNMR Da ta Obta in ed betw een 248
a n d 303 K
T (K)
k (s-1
0a
14
52
141
193
344
513
1230
1630
)
δ1
δ2
248
258
268
278
283
288
293
298
303
2.75
2.75
2.74
2.74
2.74
2.74
2.74
2.71
2.71
3.04
3.03
3.03
3.02
3.02
3.02
3.02
3.05
3.04
a
Assumed to be zero.
aromatic protons and 5.0% with the N-methyl protons
(Scheme 4), showing that 1b had mainly adopted the
s-(E) conformation around the C3-N bond. Irradiation
of the C3 proton of 1d induced NOE with the methylene
group (5.7%) and the methyl group (ca 1%), and irradia-
tion of the C3 and C2 protons in the phenethyl compound
1f, respectively, induced NOE of 5.0% with one of the
methylene groups and 5.1% with the N-methyl protons.
Thus the s-(E) conformation also seems to be preferred
by 1d and 1f.
1
The H NMR spectra of the secondary enaminones 1a ,
1c, and 1e in benzene show all three to be mixtures of
(20) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209-220 and 221-
cis and trans forms with respect to the enaminone double
231.
1
bond, as determined by H NMR analysis (for 1a J cis
)
(21) Gonza´lez, C.; Schlegel, H. B. J . Phys. Chem. 1990, 94, 5523-
5527.
8.3 and J trans ) 12.9, for 1c J cis ) 8.2 and J trans ) 13.5,

Study of Aryl Radical Cyclization in Enaminone Esters
Sch em e 4
J . Org. Chem., Vol. 67, No. 10, 2002 3217
in all structures discussed here the nitrogen is to some
degree pyramidal, distortion of the C3-N bond can be
measured in terms of the quantity D defined by the
absolute value of the algebraic sum of the dihedral angles
R-N-CdC (d1) and Me-N-CdC (d2). D is close to 180°
in an undistorted enaminone and close to 0° when C3-N
conjugation is completely disrupted.
Cyclization of 5b. For both s-(E) and s-(Z) rotamers of
radical 5b (5b i and 5b ii, respectively; see Supporting
Information), 4-exo cyclization requires passing through
transition structure TS-5biii (Figure 6), which involves
almost complete disruption of conjugation in the enami-
none moiety (D ) 24°, see Table 3). The activation
barriers are accordingly high, 17.91 kcal/mol from the
s-(E) rotamer and 19.52 kcal/mol from 5bii. 5-Endo
cyclization, which takes place through TS-5biv, can
proceed only from the s-(Z) rotamer, 5bii. This involves
much less distortion of the enaminone moiety (D ) 202°),
and the activation barrier is accordingly much lower, 9.62
kcal/mol (Figure 7); this barrier is mainly due to the poor
alignment of the aryl radical center with the CdC double
bond, as the dihedral angle ‚C- CdC-N is only 25°
instead of the optimal 90°. Our failure to obtain either
4-exo or 5-endo cyclization products from 1b is attributed
to the activation barrier for the 4-exo process still being
large compared to those of the other cyclizations studied
(see below) and the lack of the s-(Z) conformation in
solution as seen by NOE experiments.
Cyclization of 5d . The s-(E) rotamer 5d i (see Support-
ing Information) can cyclize in a 5-exo fashion via
transition state TS-5d iii, in which the alkyl chain is
equatorial (Figure 6), the activation barrier for this
process being 4.46 kcal/mol. 5-Exo cyclization is also
possible from the s-(Z) rotamer 5d ii; this process has just
a slightly higher activation barrier, 4.72 kcal/mol, and
passes through TS-5d iv, with an axial alkyl chain. Endo
cyclization is impossible from the s-(E) conformer 5d i
because the reaction centers are too far apart, and in fact
no TS could be located, but can proceed from the s-(Z)
rotamer 5d ii via TS-5d v. This process has an activation
barrier of 5.87 kcal/mol (Figure 7), 1.1 kcal/mol higher
than that for exo cyclization of 5d ii. The barrier prevent-
ing 6-endo cyclization of 5d , like that preventing 5-endo
F igu r e 6. Geometries for transition structures calculated at
the UPM3 level.
cyclization of 5b, is a consequence of the nonoptimal
alignment of the radical center with the double bond
(‚C-CdC-N ) 47°). To sum up, both rotamers can in
principle undergo exo cyclization, whereas only the s-(Z)
rotamer can undergo endo cyclization, which also has a
higher activation barrier.

3218 J . Org. Chem., Vol. 67, No. 10, 2002
Navarro-Va´zquez et al.
F igu r e 7. Calculated UPM3 activation energies for radical cyclization of 5b,d ,f species. Grey: exo cyclizations. Black: endo
cyclizations.
Ta ble 3. Releva n t Geom etr ica l P a r a m eter s of th e
Cycliza tion Tr a n sition Str u ctu r es of Ra d ica ls 5
Ca lcu la ted a t th e P M3 Level of Th eor y
kinetic reasons, whereas the s-(Z) rotamer 5fii can cyclize
via either a 6-exo or a half-boat 7-endo transition
structure; however, since the preferred conformation in
solution for 5f is s-(E), as previously shown by NOE
studies in precursor 1f, no significant amounts of product
7f, derived from an endo cyclization of s-(Z) rotamer 5fii,
were expected.
parameters
Con clu sion s
TS
r (Å)
θ (deg)
D (deg)
6-Exo cyclization onto N-phenethyl enaminones is a
useful method for synthesis of functionalized isoquino-
lines, although high-dilution techniques are required.
5-Exo radical cyclization of N-benzyl enaminones affords
isoindoles in good yield. In both cases, yields are moder-
ate for tertiary enaminones. No cyclized product was
obtained from N-phenyl enaminones. Measurement of
relative rate constants for the cyclization of N-phenethyl
and N-benzyl enaminones showed them to be only
moderate radical acceptors allowing estimation of the
rate constant for this process to be on the order of 107
s-1. Since the rate constant for rotation around the C3-N
enaminone bond was 7.1 × 104 s-1, as estimated by
means of DNMR experiments, configuration with respect
to this bond is maintained throughout the cyclization
process, as in the case of amides.
PM3 studies confirmed that the course of the reaction
is strongly dependent on the initial configuration of the
starting enaminones with respect to the C3-N bond,
endo-type cyclizations requiring the s-(Z) conformation.
Since our secondary and tertiary enaminones were shown
by NMR experiments to exist mainly in the s-(E) confor-
mation, only exo cyclization products were obtained.
TS-5biii
TS-5biv
TS-5d iii
TS-5d iv
TS-5d v
TS-5fiii
TS-5fiv
TS-5fv
2.016
2.085
2.244
2.342
2.144
2.256
2.431
2.270
2.287
2.431
105.5
92.7
102.3
91.5
99.8
102.2
88.9
91.6
95.4
97.8
24
202
145
107
139
175
136
66
TS-5fvi
TS-5fvii
188
106
Cyclization of 5f. Now, both the s-(E) and s-(Z) rota-
mers, 5fi and 5fii, respectively, readily cyclize in an exo
fashion, the former via the chairlike transition structure
TS-5fiii (Figure 6) with a barrier of only 2.75 kcal/mol
and the latter via the likewise chairlike TS-5fiv with a
barrier of 3.58 kcal/mol (Figure 7). In the case of 5f, endo
cyclization is in principle possible for both rotamers. For
the s-(E) rotamer, endo cyclization requires passage
through the chair form TS-5fv, which involves consider-
able distortion of the enaminone (D ) 66°) and, therefore,
has a significant activation barrier, 7.58 kcal/mol. For
the s-(Z) rotamer 5fii, there are two endo cyclizations.
One proceeds via the 7-endo chair TS-5fvii, in which
distortion of the enaminone (D ) 106°) again creates a
significant barrier, 7.26 kcal/mol; however, the other
proceeds via a half-boat structure, TS-5fvi, for which D
) 188°, allowing the conjugation of the enaminone system
to be mantained throughout the cyclization process. The
barrier to the latter process is only 3.36 kcal/mol, lower
than that for the 6-exo cyclization of 5fii. To sum up, the
s-(E) rotamer 5fi must cyclize in a 6-exo fashion for
Exp er im en ta l Section 22
All spectra were recorded in CDCl3 unless otherwise stated.
The 13C NMR spectra for tertiary enaminones 1b, 2b, 1d , 2d ,
1f, and 2f were recorded in C6D6 at 75 °C in order to achieve
(22) For general procedures and protocols, see ref 3b.

Study of Aryl Radical Cyclization in Enaminone Esters
J . Org. Chem., Vol. 67, No. 10, 2002 3219
1
fast exchange between the s-(E) and s-(Z) rotamers. H NMR
coupling constants are given in hertz.
MS: m/z (%) 328(3), 326(3), 278(57), 264(42), 231 (97), 229-
(100), 218(33). HRMS: calcd for C14H18BrNO4, 343.0419; found,
343.0410.
Meth yl 3-[(2-Br om o-4,5-dim eth oxyp h en yl)a m in o]pr op -
2-en oa te (1a ). 2-Bromo-4,5-dimethoxyaniline (0.27 g, 1.13
mmol), methyl propiolate (0.11 mL, 1.21 mmol), and AcOH
(0.050 mL) were dissolved in 4 mL of dry benzene, and the
solution was heated at 110 °C for 4 days with an extra 0.11
mL of methyl propiolate being added every 24 h. After the
mixture was cooled, the solvent was evaporated and the
residue chromatographed (SiO2, 70:30 hexane/EtOAc), afford-
ing 0.25 g (74%) of 1a as a yellowish oil. 1H NMR analysis
showed only the cis (2Z) conformer. IR (film CsI): 3366, 3219,
Meth yl 3-{[2-(2-Br om o-4,5-d im eth oxyp h en yl)eth yl]-
a m in o}p r op -2-en oa te (1e). 2-Bromo-4,5-dimethoxypheneth-
ylamine (0.88 g, 3.07 mmol) and methyl propiolate (0.30 mL,
3.37 mmol) were dissolved in 20 mL of dry THF, and the
solution was stirred at room temperature for 30 min. Evapora-
tion of the solvent gave 1e as a solid in almost quantitative
yield. Recrystallization from CH2Cl2/hexane afforded a white
solid of mp 58-61 °C, which 1H NMR analysis showed to be
an approximately 4:1 mixture of cis (2Z) and trans (2E)
conformers at room temperature. IR (film CsI): 3378, 3341,
3010-2840, 1677, 1640, 1521, 1477, 1209 cm-1 1H NMR: δ
.
10.17 (d, J ) 12.4, 1H), 7.15 (dd, J ) 12.4, J ) 8.3, 1H), 7.02
(s, 1H), 6.61 (s, 1H), 4.92 (d, J ) 8.3, 1H), 3.89 (s, 3H), 3.84 (s,
3H), 3.75 (s, 3H). 13C NMR: δ 170.7 (CO), 149.9 (C), 145.3
(C), 142.7 (CH), 132.8 (C), 116.3 (CH), 102.1 (C), 99.2 (CH),
88.3 (CH), 56.8 (OCH3), 56.5 (OCH3), 51.2 (OCH3). MS: m/z
(%) 317 (38), 315 (38), 285 (19), 283 (19), 270 (24), 268 (24),
204 (53), 176 (100). HRMS: calcd for C12H14BrNO4, 315.0106;
found, 315.0113.
2999-2841, 1668, 1616, 1509, 1383 cm-1 1H NMR: δ 7.88
.
(broad, 4/5H), 7.47 (dd, J ) 13.4, 8.4, 1/5H), 7.00 (s, 1H), 6.67
(s, 1H), 6.49 (dd, J ) 14.1, 8.0, 4/5H), 4.83 (d, J ) 13.4, 1/5H),
4.51 (broad, 1/5H), 4.43 (d, J ) 8.0, 4/5H), 3.85 (s, 3H), 3.83
(s, 3H), 3.62 (s, 3H), 3.42-3.28 (m, 2H), 2.96-2.85 (m, 2H).
13C NMR (major cis conformer): 171.4 (CO), 152.6 (CH), 152.5
(C), 148.7 (C), 129.7 (C), 116.0 (CH), 114.4 (C), 114.3 (CH),
82.1 (CH), 56.5 (OCH3), 56.3 (OCH3), 50.5 (OCH3), 48.7 (CH2),
38.3 (CH2). MS: m/z (%) 328(3), 326 (3), 278 (57), 264 (42),
231 (97), 229 (100), 218 (33). Anal. Calcd for C14H18BrNO4: C,
48.85; H, 5.27; N, 4.07. Found: C, 48.85; H, 5.37; N, 4.11.
Meth yl 3-{[2-(2-Br om o-4,5-d im eth oxyp h en yl)eth yl]-
(m eth yl)a m in o}p r op -2-en oa te (1f). N-Methyl-2-bromo-4,5-
dimethoxyphenethylamine (1.20 g, 4.35 mmol) and methyl
propiolate (0.32 mL, 3.68 mmol) were dissolved in 20 mL of
dry THF, and the solution was stirred at room temperature
for 30 min. Evaporation of the solvent gave an almost
quantitative yield of 1f as a solid that was recrystallized from
Met h yl 3-[(2-Br om o-4,5-d im et h oxyp h en yl)(m et h yl)-
am in o]pr op-2-en oate (1b). N-Methyl-2-bromo-4,5-dimethoxy-
aniline (1.1 g, 4.47 mmol), methyl propiolate (0.50 mL, 5.58
mmol), and AcOH (0.10 mL) were dissolved in 15 mL of dry
toluene, and the solution was heated at 150 °C for 4 days with
an extra 0.50 mL of methyl propiolate being added every 24
h. After the mixture was cooled, the solvent was evaporated
and the residue chromatographed (SiO2, 70:30 hexane/EtOAc),
affording 0.73 g (50%) of 1b as a yellowish solid. 1H NMR
analysis showed only the trans (2E) conformer. Mp: 93-95
°C. IR (film CsI): 3000-2840, 1692, 1593, 1505, 1232, 1157
1
Et2O (0 °C); mp 71-73 °C. H NMR analysis showed only the
cm-1. H NMR: δ 7.54 (d, J ) 13.1, 1H), 7.04 (s, 1H), 6.70 (s,
trans (2E) conformer. IR (film CsI): 2996-2913, 1678, 1612,
1
1
1H), 4.80 (broad, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.67 (s, 3H),
3.15 (broad s, 3H). 13C NMR (C6D6, 75 °C): 169.0 (CO), 151.7
(CH), 150.7 (C), 150.4 (C), 138.9 (C), 117.6 (CH), 113.0 (CH),
112.0 (C), 89.7 (CH), 56.4 (OCH3), 56.4 (OCH3), 50.4 (OCH3),
39.7 (NCH3). MS: m/z (%) 331 (19), 329 (19), 300 (5), 298 (5),
1509, 1219 cm-1. H NMR: δ 7.46 (d, J ) 12.9, 1H), 7.00 (s,
1H), 6.65 (s, 1H), 4.57 (d, J ) 12.9, 1H), 3.85 (s, 6H), 3.66 (s,
3H), 3.37 (t, J ) 7.5, 2H), 2.90 (t, J ) 7.5, 2H), 2.80 (broad s,
3H). 13C NMR (C6D6, 75 °C): 169.4 (CO), 152.0 (CH), 150.4
(2C), 130.5 (C), 118.0 (CH), 116.1 (CH), 115.0 (C), 86.4 (CH),
56.7 (OCH3), 56.4 (OCH3), 55.2 (CH2), 50.2 (OCH3), 37.6 (CH2),
34.9 (NCH3). MS: m/z (%) 328 (52), 326 (53), 279 (67), 278
(95), 244 (53), 242 (53), 129 (48), 128 (100). Anal. Calcd for
250 (83), 218 (100), 191 (57), 176 (68). HRMS: calcd for C13H16
BrNO4, 329.0262; found, 329.0271.
-
Meth yl 3-[(2-Br om o-4,5-d im eth oxyben zyl)a m in o]p r op -
2-en oa te (1c). 2-Bromo-4,5-dimethoxybenzylamine (3.48 g,
14.08 mmol) and methyl propiolate (1.37 mL, 15.48 mmol)
were dissolved in 30 mL of dry THF, and the solution was
stirred at room temperature for 30 min. After evaporation of
the solvent, the crude was beaten with Et2O and filtered,
giving 1c as a white solid of mp 70-73 °C in almost quantita-
tive yield. 1H NMR analysis showed an approximately 2:1
mixture of cis (2Z) and trans (2E) conformers. IR (film CsI):
C
15H20BrNO4: C, 50.29; H, 5.63; N, 3.91. Found: C, 50.29; H,
5.78; N, 3.93.
Meth yl 3-[(3,4-Dim eth oxyben zyl)a m in o]p r op -2-en oa te
(2c). 3,4-Dimethoxybenzylamine (0.66 g, 3.98 mmol) and
methyl propiolate (0.39 mL, 4.37 mmol) were dissolved in 20
mL of dry THF, and the solution was stirred at room temper-
ature for 30 min. Evaporation of the solvent gave an almost
quantitative yield of 2c as a solid that was pure according to
3381, 3346, 2999-2841, 1673, 1615, 1504 cm-1
.
1H NMR: δ
TLC and H NMR and, after recrystallization from Et2O, was
1
8.15 (broad, 2/3H), 7.60 (dd, J ) 13.3, 8.1, 1/3H), 7.02 (s, 1H),
6.79 (s, 1H), 6.70 (dd, J ) 13.0, 8.0, 2/3H), 4.81 (d, J ) 13.3,
1/3H), 4.75 (broad s, 1/3H), 4.56 (d, J ) 8.0, 2/3H), 4.34 (d, J
) 6.2, 2 × 2/3H), 4.23 (d, J ) 5.6, 2 × 1/3H), 3.86 (s, 3H), 3.85
(s, 3H), 3.65 (s, 3H). 13C NMR (major cis conformer): 171.4
(C), 152.4 (CH), 149.6 (C), 149.4 (C), 130.0 (C), 116.1 (CH),
113.6 (C), 112.6 (CH), 84.3 (CH), 56.6 (OCH3), 56.4 (OCH3),
52.5 (CH2), 50.6 (OCH3). MS: m/z (%) 331 (23), 329 (24), 316
(8), 314 (9), 300 (14), 298 (26), 296 (13), 251 (49), 250 (93), 232
(34), 231 (100), 230 (39), 229 (98), 218 (23), 190 (56), 151 (41).
Anal. Calcd for C13H16BrNO4: C, 47.29; H, 4.88; N, 4.24.
Found: C, 47.53; H, 5.15; N, 4.28.
shown by 1H NMR analysis to consist of an approximately 1.5:1
ratio mixture of cis (2Z) and trans (2E) conformers. Mp: 81-
83 °C. IR (film CsI): 3311, 3000-2837, 1656, 1610, 1513 cm-1
.
1H NMR: δ 8.07 (broad s, 3/5H), 7.58 (dd, J ) 13.3, 8.1, 2/5H),
6.83-6.75 (m, 18/5H), 4.81 (d, J ) 13.3, 2/5H), 4.68 (broad s,
2/5H), 4.55 (d, J ) 8.0, 3/5H), 4.29 (d, J ) 5.8, 6/5H), 4.15 (d,
J ) 5.2, 4/5H), 3.87 (s, 6H), 3.67 (s, 6/5H), 3.65 (s, 9/5H). 13C
NMR (major cis conformer): 170.3 (C), 152.3 (CH), 149.6 (C),
149.0 (C), 129.8 (C), 120.3 (CH), 111.6 (CH), 111.1 (CH), 86.6
(CH), 56.3 (2OCH3), 52.3 (CH2), 50.9 (CH3). MS: m/z (%) 251
(74), 236 (20), 218 (21), 152 (53), 151 (100), 107 (25), 106 (19).
Anal. Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found:
C, 62.13; H, 7.10; N, 5.67.
Met h yl 3-[(2-Br om o-4,5-d im et h oxyb en zyl)(m et h yl)-
a m in o]p r op -2-en oa te (1d ). N-Methyl-2-bromo-4,5-dimethox-
ybenzylamine (1.1 g, 4.19 mmol) and methyl propiolate (0.41
mL, 4.61 mmol) were dissolved in 20 mL of dry THF, and the
solution was stirred at room temperature for 30 min. After
evaporation of the solvent, the crude was chromatographed
(SiO2, 1:1 hexane/EtOAc), affording an 88% yield of 1d as a
solid. 1H NMR analysis showed only the trans (2E) conformer.
Mp: 97-100 °C. IR (film CsI): 3000-2840, 1689, 1613, 1507,
Meth yl 3-{[2-(3,4-Dim eth oxyp h en yl)eth yl]a m in o}p r op -
2-en oa te (2e). 3,4-Dimethoxyphenethylamine (0.76 g, 4.19
mmol) and methyl propiolate (0.41 mL, 4.61 mmol) were
dissolved in 20 mL of dry THF, and the solution was stirred
at room temperature for 30 min. Evaporation of the solvent
gave an almost quantitative yield of 2e as an oil, which 1H
NMR analysis showed to consist of a mixture of an ap-
proximately 1:1 ratio of cis (2Z) and trans (2E) conformers.
1260, 1147 cm-1. H NMR: δ 7.65 (d, J ) 13.0, 1H), 7.02 (s,
IR (film CsI): 3367, 2997-2836, 1668, 1615, 1516 cm-1 1H
.
1
1H), 6.62 (s, 1H), 4.64 (d, J ) 13.0, 1H), 4.34 (s, 2H), 3.87 (s,
3H), 3.83 (s, 3H), 3.67 (s, 3H), 2.78 (broad s, 3H). 13C NMR
(C6D6, 75 °C): 169.4 (CO), 152.7 (CH), 151.0 (C), 150.5 (C),
127.9 (C), 117.8 (CH), 113.9 (C), 113.0 (CH), 87.0 (CH), 58.7
(CH2), 56.4 (OCH3), 56.2 (OCH3), 50.3 (OCH3), 36.5 (NCH3).
NMR: δ 7.86 (broad s, 1/2H), 7.48 (dd, J ) 13.3, 8.2, 1/2H),
6.82 (d, J ) 8.0, 1H), 6.72 (d, J ) 8.0, 1H), 6.69 (s, 1H), 6.49
(dd, J ) 13.2, 8.0, 1/2H), 4.79 (d, J ) 13.3, 1/2H), 4.45 (broad
s, 1/2H), 4.43 (d, J ) 8.0, 1/2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.66
(s, 3/2H), 3.63 (s, 3/2H), 3.40-3.25 (m, 2H), 2.87-2.70 (m, 2H).

3220 J . Org. Chem., Vol. 67, No. 10, 2002
Navarro-Va´zquez et al.
13C NMR: δ 171.4 (C), 170.4 (C), 152.6 (2CH), 149.3 (C), 149.2
(C), 148.1 (C), 148.0 (C), 131.3 (C), 131.2 (C), 121.1 (CH), 120.9
(CH), 112.5 (CH), 112.1 (CH), 111.7 (2CH), 85.4 (CH), 81.7
(CH), 56.2 (2OCH3), 56.1 (2OCH3), 50.8 (2OCH3), 50.4 (2CH2),
37.8 (2CH2). MS: m/z (%) 265 (77), 234 (26), 165 (27), 164 (69),
prepared from N-methyl-3,4-dimethoxybenzylamine and meth-
yl propiolate. IR (CsI): 3020-2833, 1686, 1613, 1518 cm-1
.
1H NMR: δ 7.67 (d, J ) 12.9, 1H), 6.83 (d, J ) 8.1, 1H), 6.73
(dd, J ) 8.1, 1.9, 1H), 6.67 (d, J ) 1.9, 1H), 4.65 (d, J ) 12.9,
1H), 4.28 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.68 (s, 3H), 2.72
(broad s, 3H). 13C NMR: δ 169.5 (CO), 152.7 (CH), 151.2 (C),
150.6 (C), 130.1 (C), 120.6 (CH), 113.8 (CH), 113.0 (CH), 86.5
(CH), 59.1 (CH2), 56.3 (2OCH3), 50.2 (OCH3), 36.2 (NCH3).
MS: m/e (%) 265 (93), 250 (42), 234 (54), 206 (29), 191 (29),
152 (75), 151 (100), 107 (50). HRMS calcd for C14H19NO4,
265.1314; found 265.1315.
152 (55), 151 (84), 114 (100), 82 (98). HRMS: calcd for C14H19
NO4, 265.1314; found, 265.1311.
-
Meth yl (2E)-3-(3-Dim eth yla m in o)p r op -2-en oa te (8). To
a solution of methyl propiolate (0.18 mL, 0.82 mmol) in 2 mL
of dry THF was added a 2 M solution of N,N-dimethylamine
in the same solvent (0.42 mL, 0.84 mmol), and the mixture
was stirred at room temperature for 30 min. Evaporation of
the solvent gave a quantitative yield of 823 as a white solid
that was pure according to TLC and 1H NMR and further
purified by sonication in hexane and subsequent filtration. 1H
NMR: δ 7.44 (d, J ) 12.9, 1H), 4.52 (d, J ) 12.6, 1H), 3.66 (s,
3H), 2.88 (broad s, 6H).
F r om En a m in on e 1e. Eluent for chromatography: (90:10,
CH2Cl2/MeOH). Isoquinoline 3e was obtained as a colorless
oil in 82% yield. IR (film CsI): 3350, 3060-2836, 1721, 1612,
1520 cm-1. 1H NMR: δ 6.57 (s, 1H), 6.56 (s, 1H), 4.40 (m, 1H),
3.89 (s, 3H), 3.84 (s, 3H), 3.75 (s, 3H), 3,15 (m, 1H), 3.04 (m,
1H), 2.80-2.68 (m, 4H). 13C NMR (CD3OD): δ 174.3 (CO),
149.9 (C), 149.5 (C), 129.6 (C), 128.4 (C), 113.8 (CH), 111.2
(CH), 57.0 (OCH3), 56.8 (OCH3), 53.7 (CH), 52.8 (OCH3), 41.4
(CH2), 41.3 (CH2), 29.2 (CH2). MS: m/z (%) 265 (48), 250 (18),
232 (20), 192 (100), 177 (56), 176 (78), 148 (47). Anal. Calcd
for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.13;
H, 7.35; N, 5.30.
Bu 3Sn H-Med ia ted Ra d ica l Rea ction s: Gen er a l P r o-
ced u r e. At the 0.10 g scale, a 0.07 M benzene solution of Bu3-
SnH (200% mol) containing AIBN (20% w:w) was added over
3 h to a refluxing 0.01 M solution of the enaminone ester
bromide. After the mixture was cooled, the solvent was
evaporated and the residue dissolved in acetonitrile and
extracted with hexane (3 × 10 mL). The acetonitrile fraction
was concentrated and chromatographed on a SiO2 column.
F r om E n a m in on e 1a . Eluent for chromatography: (70:
30, hexane/AcOEt). 2a was obtained in 43% yield as a
yellowish oil, identical to an authentic sample prepared from
3,4-dimethoxyaniline and methyl propiolate. IR (CsI): 3316,
F r om En a m in on e 1f. Eluent for chromatography: (95:5,
CH2Cl2/MeOH). Isoquinoline 3f was obtained as an oil in 51%
yield. IR (film CsI): 2951-2852, 1733, 1668, 1609, 1515 cm-1
.
1H NMR: δ 6.54 (s, 2H), 4.05 (t, J ) 6.6, 1H), 3.82 (s, 3H),
3.80 (s, 3H), 3.69 (s, 3H), 3.10 (m, 1H), 2.90-2.70 (m, 3H),
2.60-2.45 (m, 2H), 2.44 (s, 3H). 13C NMR: δ 173.2 (CO), 148.1
(C), 147.8 (C), 129.1 (C), 126.3 (C), 111.8 (CH), 110.4 (CH),
59.9 (CH), 56.3 (OCH3), 56.2 (OCH3), 52.1 (OCH3), 46.2 (CH2),
42.4 (NCH3), 41.1 (CH2), 24.5 (CH2). MS: m/z (%) 206 (100),
190 (19), 162 (7). HRMS: calcd for C15H21NO4, 279.1470; found
279.1474.
3000-2835, 1668, 1639, 1595, 1520, 1208 cm-1 1H NMR: δ
.
9.80 (d, J ) 12.6, 1H), 7.16 (dd, J ) 12.6, 8.2, 1H), 6.81 (d, J
) 9.2, 1H), 6.53 (m, 2H), 4.79 (d, J ) 8.2, 1H), 3.85 (s, 3H),
3.83 (s, 3H), 3.70 (s, 3H). MS: m/e (%) 237 (65), 205 (90), 190
(100), 162 (33), 120 (19). 13C NMR: δ 171.2 (CO), 150.3 (C),
145.4 (C), 144.5 (CH), 135.2 (C), 112.7 (CH), 107.1 (CH), 101.4
(CH), 86.2 (CH), 56.7 (OCH3), 56.3 (OCH3), 50.9 (OCH3).
HRMS: calcd for C12H15NO4, 237.1001; found 237.1001.
F r om En a m in on e 1b. Eluent for chromatography: (70:
30, hexane/AcOEt). 2b was obtained in 55% yield as a
yellowish solid, mp 53-56 °C, identical to an authentic sample
prepared from N-methyl-3,4-dimethoxyaniline and methyl
propiolate. IR (KBr): 3007-2839, 1694, 1593, 1516, 1246, 1150
cm-1. 1H NMR: δ 7.83 (d, J ) 13.1, 1H), 6.83 (d, J ) 9.4, 1H),
6.66 (m, 2H), 4.86 (d, J ) 13.1, 1H), 3.89 (s, 3H), 3.87 (s, 3H),
3.69 (s, 3H), 3.21 (s, 3H). 13C NMR (C6D6, 75 °C): δ 169.2 (CO),
151.5 (C), 149.5 (CH), 148.1 (C), 141.6 (C), 114.4 (CH), 113.6
(CH), 107.5 (CH), 90.6 (CH), 56.7 (OCH3), 56.3 (OCH3), 50.5
(OCH3), 37.3 (NCH3). MS: m/e (%) 251 (100), 236 (39), 220
(37), 204 (32), 192 (61), 176 (37), 134 (51), 79 (54). HRMS: calcd
for C13H17NO4, 251.1157; found 251.1153.
The reduction product, 2f, was obtained in 19% yield as a
white solid, mp 59-61 °C, identical to an authentic sample
prepared from N-methyl-3,4-dimethoxyphenethylamine and
methyl propiolate. IR (KBr): 3009-2839, 1684, 1609, 1512,
1358, 1247, 1234, 1143 cm-1 1H NMR: δ 7.45 (d, J ) 13.0,
.
1H), 6.81 (d, J ) 8.1, 1H), 6.69 (d, J ) 8.1, 1H), 6.66 (s, 1H),
4.55 (d, J ) 13.0, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.66 (s, 3H),
3.36 (t, J ) 7.4, 2H), 2.77 (s, 3H), 2.76 (t, J ) 7.4, 2H). 13C
NMR (C6D6, 75 °C): δ 169.4 (CO), 152.1 (CH), 151.1 (C), 149.9
(C), 132.0 (C), 121.6 (CH), 114.8 (CH), 114.2 (CH), 86.1 (CH),
57.0 (CH2), 56.6 (OCH3), 56.5 (OCH3), 50.2 (OCH3), 37.5
(NCH3), 34.5 (CH2). MS: m/e (%) 279 (2), 248 (5), 165 (7), 164
(29), 151 (8), 128 (100). HRMS: calcd for C15H21NO4, 279.1470;
found 279.1461.
Kin etic Mea su r em en ts. Deter m in a tion of kc for Ra d i-
ca ls 5c a n d 5e. For kinetic measurements, Bu3SnH was
distilled under a vacuum and 10, 20, 30, and 40 equiv were
reacted with compound 1c (for 3c) and 1e (for 3e) as follows.
Compound 1c or 1e (15 mg) was dissolved in 7.5 mL of dry
benzene along with 4 mg of AIBN. The solution was heated to
reflux, and Bu3SnH was added at once. After 3 h of refluxing,
the reaction mixture was allowed to cool; the solvent was
F r om En a m in on e 1c. Eluent for chromatography: (90:10,
CH2Cl2/MeOH). Isoindole 3c was obtained as a colorless oil in
71% yield. IR (film CsI): 3371, 2995-2871, 1733, 1608, 1506
1
cm-1. H NMR: δ 6.77 (s, 1H), 6.70 (s, 1H), 4.88 (m, 1H), 4.27
(s, 2H), 3.87 (s, 6H), 3.73 (s, 3H), 3.15 (broad s, NH), 2.85 (dd,
J ) 15.9, 3.2, 1H), 2.67 (dd, J ) 15.9, 8.9, 1H). 13C NMR: δ
172.7 (CO), 149.4 (C), 149.0 (C), 133.7 (C), 132.2 (C), 105.9
(CH), 105.5 (CH), 60.5 (CH), 56.5 (OCH3), 56.4 (OCH3), 52.2
(OCH3), 51.7 (CH2), 41.4 (CH2). MS: m/z (%) 251 (14), 250 (5),
236 (5), 190 (6), 179 (22), 178 (100), 163 (8), 162 (8), 147 (12).
HRMS: calcd for C13H17NO4, 251.1157; found, 251.1153.
F r om En a m in on e 1d . Eluent for chromatography: (96:4,
CH2Cl2/MeOH). Isoindole 3d was obtained as a brownish solid
in 56% yield; mp 62-66 °C. IR (film CsI): 3004-2789, 1726,
1
evaporated, and the crude was analyzed by H NMR (CDCl3)
to determine the 2c/3c and 2e/3e ratios (in the former case,
deconvolution of the signals of 2c and 3c was performed before
integration).
Ack n ow led gm en t. We thank the Centro de Super-
computacio´n de Galicia (CESGA) for allocation of com-
puter time. Support of this work by a grant from the
Spanish Ministry of Education (Project PB-98-0606) is
gratefully acknowledged.
1509, 1456 cm-1 1H NMR: δ 6.73 (s, 1H), 6.71 (s, 1H), 4.21
.
(d, J ) 12.4, 1H), 4.13 (m, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.74
(s, 3H), 3.65 (d, J ) 12.4, 1H), 2.74 (m, 1H) 2.67 (m, 1H), 2.55
(s, 3H). 13C NMR: δ 172.7 (CO), 148.8 (C), 148.5 (C), 134.3
(C), 131.1 (C), 105.7 (CH), 105.5 (CH), 67.3 (CH), 60.5 (CH2),
56.0 (2OCH3), 51.6 (OCH3), 41.0 (NCH3), 40.0 (CH2). MS: m/z
(%) 264 (3), 250 (5), 206 (23), 192 (100). HRMS: calcd for
Su p p or tin g In for m a tion Ava ila ble: Cartesian coordi-
nates and energies of all calculated structures, copies of the
1H and 13C NMR spectra of compounds 1a -f, 2a , 2b, 2d -f,
3c, 3d , and 3f, and NOE of compounds 1a -f. This material is
available free of charge via the Internet at http://pubs.acs.org.
C
14H19NO4, 265.1314; found 265.1310.
The reduction product, 2d , was obtained in 12% yield as a
white solid, mp 90-92 °C, identical to an authentic sample
(23) Rossler, U.; Blechert, S.; Steckhan, E. Tetrahedron Lett. 1999,
40, 7075-7078.
J O0107857