Regioselective formation of six- and seven-membered ring by intramolecular Pd-catalyzed amination of N-allyl-anthranilamides

Article abstract of DOI:10.1021/jo0495135

A divergent synthesis of quinazolin-4-ones and l,4-benzodiazepin-5-ones by Pd(II)-catalyzed intramolecular amination of tosylated N-allyl-anthranilamides is described. Both kinds of products were available in high yields depending on the different reactio

Full text of DOI:10.1021/jo0495135

Regioselective F or m a tion of Six- a n d Seven -Mem ber ed Rin g by
In tr a m olecu la r P d -Ca ta lyzed Am in a tion of
N-Allyl-a n th r a n ila m id es
Egle M. Beccalli,† Gianluigi Broggini,*,‡ Giuseppe Paladino,† Andrea Penoni,‡ and
Caterina Zoni†
Istituto di Chimica Organica “A. Marchesini”, Facolta` di Farmacia, Universita` di Milano,
via Venezian 21, 20133 Milano, Italy, and Dipartimento di Scienze Chimiche e Ambientali,
Universita` dell’Insubria, via Valleggio 11, 22100 Como, Italy
gianluigi.broggini@uninsubria.it
Received March 25, 2004
A divergent synthesis of quinazolin-4-ones and 1,4-benzodiazepin-5-ones by Pd(II)-catalyzed
intramolecular amination of tosylated N-allyl-anthranilamides is described. Both kinds of products
were available in high yields depending on the different reaction conditions.
SCHEME 1. P r ep a r a tion a n d Cycliza tion of
Tosyla ted N-Allyl-a n th r a n ila m id es 4a -e
In recent years, the synthesis of a large number of
nitrogen heterocycles has made use of Pd-catalyzed
intramolecular cyclization by exploiting, among other
reactions, the amination of unsaturated systems.1 These
reactions were first investigated by Hegedus and co-
workers,2 and subsequently, many other papers and
reviews have been published on this matter.3
As we continue our research in the field of Pd-catalyzed
intramolecular cyclizations aimed at the synthesis of
biologically interesting heterocyclic derivatives,4 we are
reporting in this paper a study on the reactivity of
N-allyl-anthranilamides under Pd-catalyzed amination
conditions.
As the starting building block, we devised o-nitroben-
zoyl chloride, which reacts with the commercially avail-
able allylamines 1a -e to afford o-nitrobenzamides 2a -
e. The subsequent reduction with Fe/EtOH in aqueous
AcOH gave aminoamides 3a -e (Scheme 1). Tosylation
of the latter to produce 4a -e was effected in order to
decrease the basicity of the amino group and conse-
quently make the Pd-catalyzed cyclization easier.5
† Universita` di Milano.
‡ Universita` dell’Insubria.
(1) (a) Li, J . J .; Gribble, G. W. Palladium in Heterocyclic Chemis-
try: A Guide for the Synthetic Chemist; Pergamon: New York, 2000.
(b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (c) Zeni,
G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
(2) (a) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J . Am. Chem.
Soc. 1976, 98, 2674. (b) Hegedus, L. S.; Allen, G. F.; Bozell, J . J .;
Waterman, E. L. J . Am. Chem. Soc. 1978, 100, 5800. (c) Hegedus, L.
S.; McKearin, J . M. J . Am. Chem. Soc. 1982, 104, 2444. (d) Hegedus,
L. S.; Akemark, B.; Zetterberg, K.; Olsson, L. F. J . Am. Chem. Soc.
1984, 106, 7122. (e) Wieder, P. R.; Hegedus, L. S.; Hideki, A.; D’Andreq,
S. V. J . Org. Chem. 1985, 50, 4276. (f) Hegedus, L. S. Angew. Chem.
1988, 1113.
On the N,N-diallyl-substituted substrate (4a ), the
reaction was first performed with a catalytic amount of
Pd(OAc)2 (10 mol %) and Na2CO3 in DMF at 100 °C (see
Table 1, entry 1) and afforded two products, which were
isolated in 65% and 5% yields, respectively, along with
1
22% of unreacted material. The H and 13C NMR spectra
(3) (a) Tsuji, J . Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; Wiley and Sons: Chichester, U.K., 1995. (b) Pugin,
B.; Venanzi, L. M. J . Am. Chem. Soc. 1983, 105, 6877. (c) Gowan, M.;
Caille´, A. S.; Lau, C. K. Synlett 1997, 1312. (d) Mu¨ller, T. E.; Beller,
M. Chem. Rev. 1998, 98, 675.
(4) (a) Beccalli, E. M.; Broggini, G.; Marchesini, A.; Rossi, E.
Tetrahedron 2002, 58, 6673. (b) Beccalli, E. M.; Broggini, G. Tetrahe-
dron Lett. 2003, 44, 1919. (c) Abbiati, G.; Beccalli, E. M.; Broggini, G.;
Zoni, C. J . Org. Chem. 2003, 68, 7625.
identified the major product as the 2-vinyl-quinazolin-
4-one structure (5a ), while for the minor one, NMR two-
dimensional studies were necessary to assign the 2-me-
thylene-1,4-benzodiazepin-5-onic structure (6a). The COSY
(5) (a) See ref 2c. (b) Fix, S. R.; Brice J . L.; Stahl, S. S. Angew.
Chem., Int. Ed. 2002, 41, 164.
10.1021/jo0495135 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/20/2004
J . Org. Chem. 2004, 69, 5627-5630
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Beccalli et al.
TABLE 1. Rea ction Con d ition s a n d Yield s for
In tr a m olecu la r Cycliza tion s of Tosyla ted
N,N-Dia llyla n th r a n ila m id e 4a a
TABLE 2. P r od u cts a n d Yield s for In tr a m olecu la r
Cycliza tion s of Tosyla ted N-Su bstitu ted
N-Allyla n th r a n ila m id es 4b-e
yield (%)
R
conditionsa
5
6b
temp time
entry
solvent
DMF
baseb
(°C)
(h)
4a
5a
6a
Me
Me
phenyl
A
B
A
B
A
B
A
B
94
59
63
66
56
1
2
3
4
5
6
7
Na2CO3
100
80
100
110
100
90
18
24
24
24
48
18
24
22
20
99
10
20
65
54
5
23
78
84
81
DMF/THFc Na2CO3
DMF
phenyl
cyclohexyl
cyclohexyl
cyclopentyl
cyclopentyl
toluene
xylene
Na2CO3
pyridine
Na2CO3
AcONa
10
45
58
DMF/H2Od
DMSO
94
96
100
a
b
A, see entry 7 of Table 1; B, see entry 5 of Table 1. All of the
a
b
Pd(OAc)2, 10 mol % in the presence of air. Na2CO3, 3 equiv;
reactions gave 15-20% unreacted starting material.
AcONa, 1 equiv; pyridine, 0.2 equiv. c 1:2 ratio. 10:1 ratio.
d
SCHEME 2. P r op osed Am in a tion Mech a n ism s of
Com p ou n d s 4a -e
experiment revealed a cross-peak between the two hy-
drogen atoms at 4.75 and 5.61 ppm, while the HETCOR
experiment showed these two hydrogens to be linked to
the same sp2 carbon.
This attractive result prompted us to optimize the
reaction, aiming for selective processes for both of the
heterocyclic skeletons, in view of the well-documented
pharmacological applications of these systems.6,7 For this
purpose, a variety of conditions, summarized in Table 1,
were screened with 3a as the trial material. The use of
a polar, aprotic solvent resulted essentially in formation
of the six-membered ring in good yield. In fact, compound
5a was not formed in xylene (Table 1, entry 5), while it
was quantitatively obtained when operating with DMF-
H2O/Na2CO3 at 90 °C or DMSO/AcONa at 100 °C (Table
1, entries 6 and 7). Conversely, the best conditions to form
the benzodiazepinic structure were given by the combi-
nation of xylene/pyridine at 100 °C (Table 1, entry 5).
Notably, the presence of the base was essential to
obtain any result. Also, the presence of the tosyl sub-
stituent on the amino group was proven to be essential
to the cyclization; in fact, the attempt to cyclize the N,N-
diallylanthranilamide with Boc-protected nitrogen amine
failed, as only unreacted material was recovered.
All of the reactions with Pd(OAc)2 were carried out in
the presence of air. The air was a crucial factor for the
reaction efficiency: No conversion products were formed
when the reaction was carried out under a nitrogen
atmosphere. Most amination reactions were described as
using an oxidant as a cocatalyst (benzoquinone, CuCl2,
Cu(OAc)2, etc.) in order to achieve the reoxidation of Pd-
(0) to Pd(II), but some examples using molecular oxygen
were also reported.8 The latter protocol is attractive for
simplicity of the procedure, economical advantage, and
friendly environmental impact.
With the goal being to verify the generality of the two
different synthetic pathways, we reacted the tosylated
N-substituted N-allyl-anthranilamides 4b-e under the
conditions corresponding to entries 5 and 7 in Table 1.
The results, described in Table 2, well reflect the behavior
of the N,N-diallyl derivative, i.e., total regioselectivity as
a function of the different experimental conditions.
The literature data report two possible mechanisms for
Pd-catalyzed amination reactions involving olefins: (i)
Pd activation of the carbon-carbon double bond followed
by nucleophilic attack of the amine to the π-coordinated
olefin; (ii) Pd activation of the amine N-H bond by
metal-nitrogen formation of the amido-hydride complex
H-[Pd]-NR2, followed by attack of the olefin to the
Pd-N bond.9
In the present case, the formation of seven-membered
cyclic compounds 5a -e can be justified only by invoking
the intermediacy of η3-allyl-Pd complex 7, which would
undergo selective attack of the tosylated amine to the
internal allylic carbon, as depicted in part A of Scheme
2. The intramolecular amination by formation of an η3-
allyl-Pd complex has already been reported, and many
other Pd-catalyzed reactions involving this mechanism
are known.10 The possible intervention of preliminary
isomerization of the allyl pendant group was ruled out
(6) (a) Olesen, H.; Cowan, D.; Bruunshuus, I.; Klempel, K.; Hill, G.
Pure Appl. Chem. 1997, 69, 1081. (b) Bekhit, A. A.; Khalil, M. A.
Pharmazie 1998, 53, 539. (c) Welch, W. M.; Ewing, F. E.; Huang, J .;
Menniti, F. S.; Pagnozzi, M. J .; Kelly, K.; Seymour, P. A.; Guanowsky,
V.; Guhan, S.; Guinn, M. R.; Critchett, D.; Lazzaro, J .; Ganong, A. H.;
DeVries, K. M.; Staigers, T. L.; Chenard, B. L. Bioorg. Med. Chem.
Lett. 2001, 11, 177. (d) Ogasawara, M.; Matsunaga, T.; Takahashi, S.;
Saiki, I.; Suzuki, H. Biol. Pharm. Bull. 2002, 25, 1491.
(7) (a) Sharp, J . T. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds; Pergamon Press: Oxford, 1984; Vol.
7, Chapter 5, p 608. (b) Baldessarini, R. J . In The Pharmacologic Basis
of Therapeutics; Gilman, A. G., Goodman, L. S., Ralland, T. W., Murad,
F., Eds.; Macmillan: New York, 1985; pp 391-413. (c) Walser, A.;
Fryer, R. I. Bicyclic Diazepines; Wiley: New York, 1991; Chapter VII.
(d) Tucker, H.; Le Count, D. J . In Comprehensive Heterocyclic Chem-
istry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
1996; Vol. 9, p 151.
(8) (a) See ref 5b. (b) Ro¨nn, M.; Ba¨ckvall, J .-E.; Andersson, P. G.
Tetrahedron Lett. 1995, 36, 7749. (c) Larock, R. C.; Hightower, T. R.;
Hasvold, L. A.; Peterson, K. P. J . Org. Chem. 1996, 61, 3584. (d)
Hagelin, H.; Oslob, J . D.; Akemark, B. Chem.sEur. J . 1999, 5, 2413.
(e) Ferriera, E. M.; Stoltz, B. M. J . Am. Chem. Soc. 2003, 125, 9578.
(f) Nishimura, T.; Uemura, S. Synlett 2004, 201.
(9) (a) See ref 3d. (b) Beller, M.; Breindl, C.; Eichberger, M.; Hartung,
C. G.; Seayad, J .; Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett 2002,
1579.
5628 J . Org. Chem., Vol. 69, No. 17, 2004

Regioselective Formation of Ring Structure
SCHEME 3. Cycliza tion of Tosyla ted
N-Meth a llyl-a n th r a n ila m id e 9
SCHEME 4. η3-Allyl-P d Com p lexes Ar isin g fr om
Tosyla ted N-Meth a llyl-a n th r a n ila m id e 9
because of the negative results of isomerization tests on
compound 4a in the absence of Pd catalyst (DMF solution
with Na2CO3 or potassium tert-butoxide at 80 °C, and
THF solution with LDA at room temperature). Because
the η3-allyl-Pd complexes have frequently originated
from deprotonation of the more common π-olefin-Pd
complexes, the initial Pd-activation of the olefin (Scheme
2, part B) is reasonable, and the formation of compound
6 could arise from intramolecular nucleophilic attack of
the amine to the π-olefin complex. On this assumption,
the yield of compound 5 should increase according to the
basic medium. Actually, the cyclization reaction of 4a was
performed in DMSO using three bases with different
pKa’s. While the reaction using pyridine gave a 1:1
mixture of compounds 5a and 6a , along with 30% of the
starting compound, the use of 2-bromopyridine gave only
traces of compound 6a (5%) along with 80% of the
starting material. Conversely, the reaction with more
basic p-(dimethylamino)pyridine gave compound 5a in
65% yield, along with 6a (5%) and 4a (20%).
8 should be reversible, as it lacks the subsequent
â-hydrogen elimination step.
In summary, we set up divergent syntheses of 2-vinyl-
quinazolin-4-ones and 2-methylene-1,4-benzodiazepin-5-
ones starting from tosylated N-allyl-anthranilamides.
Both kinds of heterocyclic products were available in high
yields depending on the reaction conditions and on the
nature of the intermediate Pd(II) complex; specifically,
an intramolecular amination via an η3-allyl-Pd complex
is essential for the formation of the six-membered ring.
Studies are in progress to clarify the mechanistic role of
the amide nitrogen bearing the unsaturated system.
To deal with the problem from a different point of view,
we felt that it was advisable to examine an anthranil-
amide bearing a substituent on the central carbon atom
of the allylic group. According to the synthetic sequence
employed for compounds 4a -e, tosylamide 9 was pre-
pared from commercially available ethyl(2-methylallyl)-
amine (Scheme 3). The observed reactivity of this sub-
strate can be summarized as follows: (a) The experiment
that was performed according to entry 5 (Table 1) led only
to unchanged starting compound; (b) under the conditions
of entry 7 (Table 1), the reaction afforded, besides some
unreacted material (20%), the expected 2-(2-propenyl)-
quinazolin-4-one 10 (62%) along with a new product
(16%). The latter was assigned an eight-membered ring
structure, namely 3-methylene-1,5-benzodiazocin-6-one
11.
The latter evidence fortified our mechanistic consid-
erations. In fact, the reaction outcome under entry 7
(Table 1) conditions was diagnostic for a process via η3-
allyl-Pd complex. The presence of a methyl group on the
allyl pendant group allowed the generation of two
isomeric complexes of this type, as illustrated in Scheme
4. Complex 12 was able to behave similarly to 7, forming
quinazolin-4-one skeleton 10; however, complex 13 could
only undergo intramolecular nucleophilic attack to gener-
ate an eight-membered ring. The subsequent selective
elimination of the exocylic â-hydrogen resulted in com-
pound 11. The inert nature of tosylamide 9 toward giving
any 1,4-benzodiazepine product may well be justified,
because ring closure to a potential intermediate of type
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Nitr o-
ben za m id es. A solution of N-substituted N-allylamine (20.2
mmol) and TEA (1.36 mL, 13.5 mmol) in CH2Cl2 (5 mL) was
added dropwise to a solution of 2-nitro-benzoyl chloride (2.5
g, 13.5 mmol) in CH2Cl2 (20 mL) at 0 °C. After stirring for 2 h
at room temperature, the solution was washed with 5%
aqueous HCl (3 × 25 mL), water (1 × 25 mL), and 5% aqueous
NaOH (3 × 25 mL). The organic layer was dried over Na2SO4
and evaporated under reduced pressure to give 2a -e as oils.
N,N-Dia llyl-2-n itr o-ben za m id e (2a ). Yield: 93%. Oil. IR
1
(Nujol): 1627 cm-1. H NMR (400 MHz, CDCl3, δ): 3.70 (2H,
dd, J ) 1.2, 5.6 Hz), 4.12 (2H, br s), 5.09 (1H, dd, J ) 1.2, 17.0
Hz), 5.17 (1H, dd, J ) 1.0, 10.2 Hz), 5.28 (1H, dd, J ) 1.0,
10.2 Hz), 5.31 (1H, J ) 1.2, 17.1 Hz), 5.65 (1H, tdd, J ) 5.3,
6.1, 17.1 Hz), 5.95 (1H, tdd, J ) 5.6, 10.2, 17.0 Hz), 7.40 (1H,
dd, J ) 1.0, 7.6 Hz), 7.57 (1H, ddd, J ) 1.0, 7.5, 8.2 Hz), 7.69
(1H, ddd, J ) 1.1, 7.5, 7.6 Hz), 8.19 (1H, dd, J ) 1.1, 8.2 Hz).
13C NMR (100 MHz, CDCl3, δ): 47.1 (t), 50.8 (t), 118.6 (t), 118.9
(t), 125.1 (d), 128.4 (d), 130.2 (d), 132.6 (d), 132.7 (d), 134.7
(d), 133.4 (s), 145.5 (s), 168.1 (s). MS m/z: 246 (M+). Anal. Calcd
for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.25;
H, 5.75; N, 11.49.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Am in o-
ben za m id es. A solution of 20% aqueous AcOH (20 mL) and
powdered Fe (3.36 g, 60.3 mmol) was added to a solution of
2a -e (8.1 mmol) in EtOH (15 mL) at 50 °C under vigorous
stirring. The mixture was refluxed for 6 h and then filtered
through a Celite path. The solvent was removed under reduced
pressure, and the crude slurry was dissolved in AcOEt (25 mL).
The solution was adjusted to pH 7 with 5% aqueous NaHCO3,
washed with water (30 mL), dried over Na2SO4, and taken to
dryness under reduced pressure. The crude product was
purified by silica gel column chromatography with AcOEt/light
petroleum 1:4 as the eluent to give 3a -e.
(10) (a) Trost, B. M. Acc. Chem. Res. 1980, 13, 385. (b) Heathcock,
C. H.; Stafford, J . A.; Clark, D. L. J . Org. Chem. 1992, 57, 2575. (c)
Van der Schaaf, P. A.; Sutter, J .-P.; Grellier, M.; Van Mier, G. P. M.;
Spek, A. L.; Van Koten, G.; Pfeffer, M. J . Am. Chem. Soc. 1994, 116,
5134.
N,N-Dia llyl-2-a m in o-ben za m id e (3a ). Yield: 75%, mp
69-70 °C (diisopropyl ether). IR (Nujol): 1626, 2856, 2931
1
cm-1. H NMR (400 MHz, CDCl3, δ): 3.85-4.16 (4H, overlap-
J . Org. Chem, Vol. 69, No. 17, 2004 5629

Beccalli et al.
ping), 5.15-5.35 (4H, overlapping), 5.71-5.95 (2H, overlap-
ping), 6.67-6.78 (2H, overlapping), 6.98 (2H, br s, missing after
deuteriation), 7.14-7.22 (2H, overlapping). 13C NMR (100
MHz, CDCl3, δ): 51.2 (t), 117.2 (d), 117.8 (d), 118.1 (t), 120.6
(s), 127.4 (d), 131.0 (d), 133.3 (d), 145.6 (s), 171.8 (s). MS m/z:
216 (M+). Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N,
12.95. Found: C, 72.01; H, 7.41; N, 13.12.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zod i-
a zep in -5-on es. To a solution of 4a -e (0.77 mmol) in xylene
(5 mL) were added pyridine (12 mg, 0.15 mmol) and Pd(OAc)2
(18 mg, 0.08 mmol) in the presence of air. The mixture was
stirred for 48 h at 100 °C, and the solvent was removed under
reduced pressure. The residue was dissolved in CH2Cl2 (25 mL)
and then washed with water (2 × 20 mL). The organic layer
was dried over Na2SO4 and taken to dryness under reduced
pressure to give 6a -e.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 2-Tosyl-
a m in o-ben za m id es. To a solution of 3a -e (6.2 mmol) in
CH2Cl2, at 0 °C, was added a solution of TEA (0.62 g, 6.2 mmol)
and p-TsCl (2.35 g, 12.4 mmol) in CH2Cl2 (20 mL) dropwise.
After stirring for 2 h, the solution was washed with 5%
aqueous HCl (3 × 25 mL), water (1 × 25 mL), and 5% aqueous
NaOH (3 × 25 mL). The organic layer was dried over Na2SO4
and taken to dryness under reduced pressure to give 4a -e.
N,N-Dia llyl-2-tosyla m in o-ben za m id e (4a ). Yield: 78%,
4-Allyl-2-m eth ylen e-1-tosyl-1,2,3,4-tetr a h yd r o-ben zo[e]-
[1,4]d ia zep in -5-on e (6a ). Yield: 58%, mp 102-103 °C (di-
1
isopropyl ether). IR (Nujol): 1642 cm-1. H NMR (400 MHz,
CDCl3, δ): 2.44 (3H, s), 3.47-3.68 (4H, overlapping), 4.75 (1H,
s), 5.04 (1H, d, J ) 17.0 Hz), 5.10 (1H, d, J ) 10.1 Hz), 5.40
(1H, tdd, J ) 4.2, 10.1, 17.0 Hz), 5.61 (1H, s), 7.28-7.31 (3H,
overlapping), 7.50-7.59 (4H, overlapping), 7.74 (1H, d, J )
7.6 Hz). 13C NMR (100 MHz, CDCl3, δ): 22.0 (q), 48.2 (t), 51.2
(t), 104.2 (t), 118.5 (t), 128.6 (d), 129.6 (d), 129.7 (d), 129.9 (d),
130.5 (d), 130.9 (d), 132.1 (d), 132.5 (d), 132.8 (d), 133.6 (s),
135.3 (s), 135.5 (s), 142.2 (s), 144.7 (s), 167.2 (s). MS m/z: 368
(M+). Anal. Calcd for C20H20N2O3S: C, 65.20; H, 5.47; N, 7.60.
Found: C, 65.12; H, 5.60; N, 7.49.
mp 64-67 °C (diisopropyl ether). IR (Nujol): 1642, 2935 cm-1
.
1H NMR (400 MHz, CDCl3, δ): 2.38 (3H, s), 3.42-3.96 (4H,
m), 5.14-5.32 (4H, overlapping), 5.59-5.96 (2H, m), 7.10 (1H,
d, J ) 7.4 Hz), 7.20-7.41 (3H, overlapping), 7.64-7.71 (4H,
overlapping), 8.45 (1H, s, missing after deuteriation). 13C NMR
(100 MHz, CDCl3, δ): 21.8 (q), 47.0 (t), 51.7 (t), 118.0 (t), 119.0
(t), 123.8 (d), 124.3 (d), 126.4 (s), 127.3 (d), 127.5 (d), 129.4
(d), 130.0 (d), 131.5 (d), 132.8 (d), 136.5 (s), 137.3 (s), 144.0
(s), 170.3 (s). MS m/z: 370 (M+). Anal. Calcd for C20H22N2O3S:
C, 64.84; H, 5.99; N, 7.56. Found: C, 64.82; H, 6.14; N, 7.47.
N-Eth yl-N-(2-m eth yl-allyl)-2-tosylam in o-ben zam ide (9).
Yield: 96%, mp 75-76 °C (diisopropyl ether). IR (Nujol): 1623,
Rea ction of 9 w ith P d (OAc)2 in DMSO. The operative
conditions are the same as those for 5a -e.
3-Eth yl-2-isop r op en yl-1-tosyl-2,3-d ih yd r o-1H-qu in a zo-
lin -4-on e (10). Yield: 62%. Oil. IR (Nujol): 1636 cm-1 1H
.
NMR (400 MHz, CDCl3, δ): 1.05 (3H, t, J ) 7.2 Hz), 1.84 (3H,
s), 2.34 (3H, s), 3.04 (1H, dd, J ) 7.2, 13.9 Hz), 3.56 (1H, dd,
J ) 7.2, 13.9 Hz), 4.68 (1H, s), 4.93 (1H, s), 5.84 (1H, s), 7.13
(2H, AB system, J ) 8.1 Hz), 7.33 (2H, AB system, J ) 8.1
Hz), 7.35 (1H, dd, J ) 7.5, 7.6 Hz), 7.54 (1H, ddd, J ) 1.2, 7.6,
7.7 Hz), 7.75 (1H, d, J ) 7.7 Hz), 7.90 (1H, dd, J ) 1.0, 7.5
Hz). 13C NMR (100 MHz, CDCl3, δ): 13.4 (q), 19.4 (q), 21.9
(q), 41.9 (t), 74.0 (d), 115.9 (t), 125.7 (s), 126.3 (d), 127.5 (d),
127.6 (d), 128.2 (d), 129.4 (d), 130.0 (d), 131.2 (d), 133.0 (d),
135.1 (s), 135.8 (s), 139.6 (s), 145.0 (s), 161.6 (s). MS m/z: 356
(M+). Anal. Calcd for C20H22N2O3S: C, 64.84; H, 5.99; N, 7.56.
Found: C, 64.23; H, 6.09; N, 7.44.
1
2906 cm-1. H NMR (400 MHz, CDCl3, 50 °C, δ): 1.11 (3H, t,
J ) 6.3 Hz), 1.59 (3H, s), 2.39 (3H, s), 3.32 (2H, br s), 3.64
(2H, br s), 4.87 (1H, s), 4.98 (1H, s), 7.03 (1H, dd, J ) 7.5, 7.5
Hz), 7.22 (2H, AB system, J ) 8.1 Hz), 7.25 (1H, d, J ) 7.5
Hz), 7.32 (1H, dd, J ) 7.5, 8.2 Hz), 7.63 (1H, d, J ) 8.2 Hz),
7.72 (2H, AB system, J ) 8.1 Hz), 8.28 (1H, br s, missing after
deuteriation). 13C NMR (100 MHz, CDCl3, δ): 12.4 (q), 20.5
(q), 21.8 (q), 41.0 (t), 54.2 (t), 112.4 (t), 123.4 (d), 124.1 (d),
125.1 (s), 126.8 (d), 127.6 (d), 130.0 (d), 131.2 (d), 136.3 (s),
137.4 (s), 140.5 (s), 144.0 (s), 170.2 (s). MS m/z: 372 (M+). Anal.
Calcd for C20H24N2O3S: C, 64.49; H, 6.49; N, 7.52. Found: C,
64.42; H, 6.65; N, 7.40.
5-E t h yl-2-m e t h yle n e -1-t osyl-2,3,4,5-t e t r a h yd r o-1H -
ben zo[b][1,5]d ia zocin -6-on e (11). Yield: 16%, mp 180-183
Gen er a l P r oced u r e for th e P r ep a r a tion of Qu in a zolin -
4-on es. To a solution of 4a -e (1.2 mmol) in DMSO (5 mL)
were added AcONa (98 mg, 1.2 mmol) and Pd(OAc)2 (27 mg,
0.12 mmol) in the presence of air. The mixture was stirred for
24 h at 100 °C. The solution was washed with brine (25 mL)
and extracted with Et2O (2 × 25 mL). The organic layer was
dried over Na2SO4 and taken to dryness under reduced
pressure to give 5a -e.
°C (diisopropyl ether). IR (Nujol): 1635 cm-1 1H NMR (400
.
MHz, CDCl3, δ): 1.17 (3H, t, J ) 7.1 Hz), 2.43 (3H, s), 2.89-
2.96 (1H, m), 3.53 (1H, AB system, J ) 14.6 Hz), 3.54-3.62
(1H, m), 3.72 (1H, AB system, J ) 14.6 Hz), 3.78 (1H, AB
system, J ) 15.8 Hz), 4.87 (1H, AB system, J ) 15.8 Hz), 5.00
(1H, s), 5.20 (1H, s), 7.10 (1H, d, J ) 7.1 Hz), 7.28 (2H, AB
system, J ) 7.9 Hz), 7.41-7.47 (2H, overlapping), 7.60 (1H,
d, J ) 7.7 Hz), 7.63 (2H, AB system, J ) 7.9 Hz). 13C NMR
(100 MHz, CDCl3, δ): 12.4 (q), 21.9 (q), 40.0 (t), 51.3 (t), 55.8
(t), 117.8 (t), 127.9 (d), 129.8 (d), 130.0 (d), 130.2 (d), 130.4
(d), 131.7 (d), 137.6 (s), 137.9 (s), 138.9 (s), 139.4 (s), 143.7 (s),
168.0 (s). MS m/z: 356 (M+). Anal. Calcd for C20H22N2O3S: C,
64.84; H, 5.99; N, 7.56. Found: C, 64.98; H, 5.85; N, 7.72.
3-Allyl-1-t osyl-2-vin yl-2,3-d ih yd r o-1H -q u in a zolin -4-
on e (5a ). Yield: 96%, mp 96-98 °C (diisopropyl ether). IR
1
(Nujol): 1639 cm-1. H NMR (400 MHz, CDCl3, δ): 2.35 (3H,
s), 3.60 (1H, dd, J ) 7.8, 14.6 Hz), 4.20 (1H, dd, J ) 6.0, 14.6
Hz), 5.17 (1H, d, J ) 16.7 Hz), 5.21 (1H, d, J ) 10.0 Hz), 5.27
(1H, d, J ) 10.3 Hz), 5.30 (1H, d, J ) 16.3 Hz), 5.58 (1H, dddd,
J ) 6.0, 7.8, 10.0, 16.7 Hz), 5.70 (1H, ddd, J ) 4.6, 10.3, 16.3
Hz), 5.99 (1H, d, J ) 4.6 Hz), 7.14 (2H, AB system, J ) 8.2
Hz), 7.33 (2H, AB system, J ) 8.2 Hz), 7.35 (1H, ddd, J ) 1.0,
7.7, 7.8 Hz), 7.57 (1H, ddd, J ) 1.6, 7.8, 7.8 Hz), 7.79 (1H, dd,
J ) 1.0, 7.7 Hz), 7.93 (1H, dd, J ) 1.6, 7.8 Hz). 13C NMR (100
MHz, CDCl3, δ): 21.9 (q), 48.6 (t), 71.0 (d), 119.7 (t), 120.5 (t),
124.9 (s), 126.4 (d), 127.4 (d), 127.6 (d), 128.5 (d), 129.4 (d),
129.9 (d), 132.4 (d), 132.6 (d), 133.3 (d), 133.6 (d), 135.1 (s),
136.4 (s), 145.0 (s), 161.1 (s). MS m/z: 368 (M+). Anal. Calcd
for C20H20N2O3S: C, 65.20; H, 5.47; N, 7.60. Found: C, 65.37;
H, 5.56; N, 7.73.
Ack n ow led gm en t. The authors are grateful to Prof.
G. Zecchi for helpful suggestions. Thanks are due to the
Ministero dell’Istruzione, dell’Universita` e della Ricerca
for financial support.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for the compounds 2b-e, 3b-e, 4b-e, 5b-e, and 6b-
e. This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0495135
5630 J . Org. Chem., Vol. 69, No. 17, 2004