Novel syntheses of alpha-morpholinoamides from alpha,alpha-dichloroacetamides.

Article abstract of DOI:10.1021/jo020335u

Dichloroacetamides, on heating with benzotriazole, morpholine, and triethylamine, produce, in a one-pot reaction, alpha-benzotriazolyl-alpha-morpholinoacetamides 4a,b. Intermediates 4a and 4b react with nucleophiles such as allylsilanes, silyl ethers, and organozinc reagents to afford diverse alpha-morpholinoamides.

Full text of DOI:10.1021/jo020335u

We now report the development of a novel method for
the preparation of N-(R-aminocarbamoylmethyl)benzo-
triazoles 4a ,b and an easy access from 4a ,b to a variety
of R-morpholinoamides, utilizing the leaving group ability
of benzotriazole in nucleophilic substitutions.
Novel Syn th eses of r-Mor p h olin oa m id es
fr om r,r-Dich lor oa ceta m id es
Alan R. Katritzky,* Yuming Zhang, and
Sandeep K. Singh
P r epar ation of Ben zotr iazolyl In ter m ediates 4a,b.
Acid-catalyzed replacement of the methoxy group by the
benzotriazolyl group has been used to prepare benzo-
triazolyl intermediates from easily available ketals.7a,8
Accordingly, we prepared the dimethoxyacetamido de-
rivative 3a in 93% yield by the reaction of dichloro-
acetamide 2a with sodium methoxide. Dichloroacetamide
2a was readily obtained in 87% yield from dichloroacetyl
chloride and benzylamine following the Schotten-Bau-
mann procedure.9 However, attempts to replace, succes-
sively or simultaneously, both methoxy groups in 3a by
one benzotriazolyl and one morpholine moiety failed.
Finally, treatment of dichloroamide 2a simultaneously
with 1 equiv of benzotriazole and 1 equiv of morpholine
in the presence of triethylamine provided the desired
2-(1H-1,2,3-benzotriazol-1-yl)-N-benzyl-2-morpholino-
acetamide (4a ) in 60% yield. No competing displacement
of the newly attached benzotriazolyl group in 4a by
another morpholine moiety occurred. Similarly, starting
from dl-R-methylbenzylamine (1b), the N-(R-aminocar-
bamoylmethyl)benzotriazole intermediate 4b was ob-
tained in 35% yield as a mixture of diastereomers in a
1:1 ratio, as determined by the 1H NMR spectrum
(Scheme 1).
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received May 15, 2002
katritzky@chem.ufl.edu
Abstr a ct: Dichloroacetamides, on heating with benzotria-
zole, morpholine, and triethylamine, produce, in a one-pot
reaction, R-benzotriazolyl-R-morpholinoacetamides 4a ,b. In-
termediates 4a and 4b react with nucleophiles such as
allylsilanes, silyl ethers, and organozinc reagents to afford
diverse R-morpholinoamides.
R-Aminoamides are biologically active and have been
claimed as antiinflammatory,1 antibacterial,2 anticon-
vulsant,3 and cerebro-protective4 agents.
R,R-(Disubstituted-morpholino)amides have previously
been prepared by two main routes. In the first, a
secondary amine such as morpholine reacts with an
R-chloroamide to form the R-morpholinoamide.1-5 This
method is restricted by the availability of the R-chloro-
amide and is used mainly to prepare simple R-morpholi-
noamides. A second preparation of R-morpholinoamides
is by reaction of γ-carboxy-R,â-unsaturated amides with
morpholine6 and is naturally restricted to the preparation
of R-amino-γ-carboxyamides.
N-(R-Aminoalkyl)benzotriazoles have been recognized
as versatile intermediates for the preparation of a wide
variety of amines by nucleophilic displacement of the
benzotriazolyl group.7 Condensations of benzotriazole
with an aldehyde or ketone and a primary or secondary
amine readily give N-(R-aminoalkyl)benzotriazoles, usu-
ally in high yields and purity.7a A similar approach to
R-aminoamides would require the preparation of N-(R-
aminocarbamoylmethyl)benzotriazoles that are not easily
available by the aforementioned simple condensations.
Rea ction s of Syn th on s 4a ,b w ith Allylsila n es a n d
Silyl Eth er s. Lewis acid promoted reaction of allylsi-
lanes with benzotriazolyl intermediates has been well
studied.7c Using a similar approach, we examined the
direct preparation of R-(allylamino)amides from synthons
4a ,b. Nucleophilic replacement of the benzotriazolyl
group in 4a with 1 equiv of allyltrimethylsilane (5a ) and
(2-methylpropenyl)trimethylsilane (5b) in the presence
of BF3‚Et2O gave the allylic R-aminoamides 6a and 6b
in 67 and 72% yields, respectively. The structures of the
R-(allylamino)amides 6a and 6b are supported by their
1
1H and 13C NMR spectra. The H NMR spectrum of 6a
showed no signals for any benzotriazolyl moiety in the
aromatic region at 8.08 and 7.35-7.45 ppm but did
demonstrate the appearance of vinylic protons signals at
5.20-5.31 ppm. The H(2) signal in 6a was shifted upfield
from that in 4a and now appeared as a well-defined
triplet at 3.19 ppm. The 1H NMR spectrum of 6b also
showed similar changes in addition to the appearance of
a new signal at 1.81 ppm due to the three protons of C(4)-
methyl group. Similar treatment of 4b with allyltri-
methylsilane (5a ) gave 6c in 73% yield. 1H and 13C NMR
spectra revealed 6c as a mixture of two diastereomers
in a 3:1 ratio. R-(Allylamino)amides are potentially useful
as building blocks, as γ,δ-double bonds can easily be
transformed into other functionalities.10 Although reac-
(1) Marcincal-Lefebvre, A.; Gesquiere, J . C.; Lemer, C.; Dupuis, B.
J . Med. Chem. 1981, 24, 889.
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A.; Houziaux, P.; Danree, B. Eur. J . Med. Chem. 1990, 25, 71.
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1962, 17, 601; Chem. Abstr. 1963, 58, 1377h. (b) Abbady, M. A.; Abde-
Hafez, Sh. H. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 160, 121;
Chem. Abstr. 2000, 133, 150649x. (c) Shafeeque, S.; Mohan, S.;
Manjunatha, K. S. Ind. J . Heterocycl. Chem. 1999, 8, 297; Chem. Abstr.
1999, 131, 170237y. (d) Padia, J . K.; Patel, P. B. J . Inst. Chem. (India)
1989, 61, 109; Chem. Abstr. 1991, 114, 23513f.
(6) (a) Bergman, J .; Brimert, T. Acta Chem. Scand. 1999, 53, 48;
Chem. Abstr. 1999, 130, 237422e. (b) Ismail, M. F.; Enayat, E. I.; El
Bassiouny, F. A. A.; Younis, H. A. Acta Chim. Hung. 1991, 128, 365;
Chem. Abstr. 1991, 115, 158859q.
(8) Katritzky, A. R.; Bayyuk, S. I.; Rachwal, S. Synthesis 1991, 279.
(9) Isshiki, T.; Kuwada, Y. J . Pharm. Soc. J pn. 1952, 72, 72; Chem.
Abstr. 1952, 46, 11147.
(10) (a) Bolton, G. L.; Hodges, J . C.; Rubin, J . R. Tetrahedron 1997,
53, 6611. (10b) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am.
Chem. Soc. 1996, 118, 9606.
(7) (a) Katritzky, A. R.; Lan, X.; Yang, J .; Denisko, O. Chem. Rev.
1998, 98, 409. (b) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J . J .
Org. Chem. 1999, 64, 1979. (c) Katritzky, A. R.; Qui, G.; He, H.-Y.;
Yang, B. J . Org. Chem. 2000, 65, 3683.
10.1021/jo020335u CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002
J . Org. Chem. 2002, 67, 8239-8242
8239

SCHEME 1a
SCHEME 2
a
Key: (i) Cl2CHCOCl, Et3N, CH2Cl2; (ii) NaOMe, THF; (iii)
BtH, morpholine, p-TSA, PhMe; (iv) BtH, morpholine, Et3N, 100
°C.
tions of R-imino esters with allylic organometallic com-
pounds have been reported extensively to prepare allylic
R-amino esters,11 there is no report on similar preparation
of R-aminoamides from R-iminoamides probably owing
to the low reactivity of R-iminoamides. Thus, benzotri-
azolyl intermediates 4 offer an easy and efficient route
for the direct preparation of R-(allylamino)amides.
Use of silyl enol ethers as nucleophiles produced the
expected γ-oxo-R-aminoamides. Thus, reaction of synthon
4a with 1-methoxy-2-methyl-1-propenyl trimethylsilyl
ether (7a ) and 1-phenylvinyl trimethylsilyl ether (7b)
gave 8a and 8b in 72 and 63% yields, respectively. The
1H NMR spectrum of 8a showed a singlet for the methoxy
protons at 3.69 ppm; the two methyls at C(2) resonated
as separate singlets at 1.32 and 1.29 ppm. The 13C NMR
spectrum showed the appearance of a new carbonyl
signal at 177.9 ppm due to the 4-oxo moiety in 8a .
Similarly, 1H NMR spectrum of 8b showed signals in the
aromatic region due to the benzoyl group and two protons
at C(3) resonated separately (as a doublet of doublets)
at 4.50 and 4.42 ppm, respectively.
7b resulted in the formation of R,â-unsaturated amide
10 in 52% yield, apparently via loss of morpholine moiety
from the initially formed product in the reaction mixture.
Although 8a could be purified by recrystallization from
dichloromethane, attempted column chromatography on
Al2O3 resulted in its conversion into the cyclized dike-
toamide 9. Compounds 8a and 9 were characterized by
their 1H and 13C NMR spectra and by microanalysis.
After cyclization, the singlet for methoxy protons at 3.69
ppm in 8a disappeared and the two methyls at C(2) (as
separate singlets at 1.32 and 1.29 ppm) shifted upfield
to 1.25 and 1.23 ppm, respectively. The disappearance
of the C(4) oxo-carbonyl signal at 177.9 ppm in the 13C
NMR spectrum and the presence of a downfield signal
at 182.0 ppm due to the new imido-carbonyl further
confirmed the cyclization of 8a to 9. However, similar
reaction of 4b with silyl ether 7a , followed by chromato-
graphic purification on Al2O3, furnished 8c in 62% yield,
without any further reaction. Compound 8c was obtained
as a mixture of diastereomers in a 1:1 ratio as determined
1
The H NMR spectrum of 10 showed the olefinic protons
each as a doublet at 8.03 and 7.18 ppm with a coupling
constant of 15.0 Hz, which further supports the formation
of 10 as a single E- isomer (Scheme 2).12
Interestingly, Lewis acid mediated reaction of 4a with
1-(trimethylsiloxy)cyclohex-1-ene (11) gave products 13
and 14. Formation of 13 and 14 appears to be a result of
intramolecular cyclization of the secondary amide func-
tionality onto the keto group of the initially formed
product 12 in the reaction mixture.13 Compounds 13 and
1
14 were characterized by their H and 13C NMR spectra
and by elemental analyses or high-resolution MS data.
J (3-H,3a-H) values of 9.9 and 9.3 Hz in 13 and 14,
respectively, correspond to those of cis isomers in similar
structures.14a Also, similar ring formations have been
1
by its H NMR spectrum. Reaction of 4b with silyl ether
(12) (a) Singh, R. P.; Cao, G.; Kirchmeier, R. L.; Shreeve, J . M. J .
Org. Chem. 1999, 64, 2873. (b) Shen, Y.; Zhang, Y.; Zhou, Y. J . Chem.
Soc., Perkin Trans. 1 1999, 1759.
(13) Kitamura, T.; Harano, K.; Hisano, T. Chem. Pharm. Bull. 1992,
40, 2255.
(11) (a) Yamamoto, Y.; Ito, W. Tetrahedron 1988, 44, 5415. (b) Fang,
X.; J ohannsen, M.; Yao, S.; Gathergood, N.; Hazell, R. G.; J orgensen,
K. A. J . Org. Chem. 1999, 64, 4844.
8240 J . Org. Chem., Vol. 67, No. 23, 2002

2-(1H -1,2,3-Ben zot r ia zol-1-yl)-2-m or p h olin o-N-(1-p h en yl-
eth yl)a ceta m id e (4b). A mixture of benzotriazole (2.38 g, 20
mmol), dichloroacetamide 2a or 2b (20 mmol), morpholine (1.74
mL, 20 mmol), and Et3N (5.56 mL, 40 mmol) was heated with
stirring at 100 °C for 5 h. After being cooled to 20 °C, the reaction
mixture was dissolved in ethyl acetate and then washed with
5% NaHCO3 and water. The organic layer was dried over
anhydrous Na2SO4. Removal of the solvent gave 4a or 4b as a
semisolid residue, which was dried under vacuum and used
directly for the subsequent reactions.
SCHEME 3
2-(1H -1,2,3-Ben zot r ia zol-1-yl)-N-b en zyl-2-m or p h olin o-
a ceta m id e (4a ): yield 60%; 1H NMR δ 8.08 (d, J ) 8.1 Hz, 1H),
7.66 (brs, 1H), 7.35-7.45 (m, 8H), 6.17 (s, 1H), 4.59-4.61 (m,
2H), 3.66-3.71, (m, 4H), 2.66-2.74 (m, 2H), 2.55 (brs, 2H).
2-(1H -1,2,3-Ben zot r ia zol-1-yl)-2-m or p h olin o-N-(1-p h e-
n yleth yl)a ceta m id e (4b): yield 35%; 1H NMR δ 8.10-7.10 (m,
10H), 6.18 (s, 0.5H, one isomer), 6.11 (s, 0.5H, another isomer),
5.40-5.10 (m, 1H), 3.90-3.50 (m, 4H), 3.00-2.40 (m, 4H), 1.60-
1.40 (m, 3H).
Gen er a l P r oced u r e for th e Rea ction of 4a or 4b w ith
Allylsila n es a n d Silyl Eth er s. To a solution of 4a or 4b (1
mmol) and allylsilanes 5a ,b or silyl ethers 7a ,b or 11 (2 mmol)
in dry CH2Cl2 (10 mL) was added BF3‚Et2O (0.24 mL, 2 mmol)
at 0 °C, and the mixture was stirred for 3 h. Then the reaction
mixture was allowed to warm to 20 °C and stirred for another
10 h. The mixture was washed with 5% NaHCO3 and H2O, and
the combined aqueous phase was extracted with CH2Cl2. The
organic layer was dried over Na2SO4 and evaporated in vacuo
to give a residue, which was purified by column chromatography
on Al2O3 using hexanes/EtOAc (2:1) as eluent to give the
products 6a -c, 8b-c, 9, 10, 13, or 14. Compound 8a was
purified by recrystallization of the residue obtained after workup.
N-Ben zyl-2-m or ph olin o-4-pen ten am ide (6a): white prisms
(from ethyl acetate/hexanes); mp 73-74 °C; yield 67%; 1H NMR
δ 7.60-7.40 (m, 6H), 6.15-5.90 (m, 1H), 5.31-5.20 (m, 2H),
4.70-4.54 (m, 2H), 3.90-3.70 (m, 4H), 3.19 (t, J ) 6.0 Hz, 1H),
2.86-2.58 (m, 6H); 13C NMR δ 172.0, 138.5, 135.1, 128.8, 127.8,
127.5, 117.5, 69.4, 67.2, 50.9, 43.3, 32.6. Anal. Calcd for
reported to be more favorable with substituents at the
ring junction in cis orientation as compared to that in
trans,14b-d so we believe that Bt2 and 3a-H in 13 are in
cis-orientation (Scheme 2).
Nu cleop h ilic Su bstitu tion of 4a w ith Or ga n ozin c
Rea gen ts. Nucleophilic substitution of the benzotriazolyl
group in 4a by alkyl and aryl groups was achieved by
treatment of 4a with alkyl- or arylzinc reagents prepared
in situ by reaction of zinc chloride with the corresponding
Grignard reagents. Excess zinc chloride functions as a
Lewis acid to facilitate the loss of benzotriazolyl anion
and forms an iminium cation, which can be easily
attacked by organozinc reagents.15 R-Aminoamides 15a-c
were obtained in 32-52% yields and the structures were
confirmed by their 1H and 13C NMR spectra and by
1
elemental analyses or high-resolution MS data. H and
13C NMR spectra of 15a -c showed the disappearance of
signals for benzotriazolyl moiety and appearance of the
expected signals corresponding to the alkyl or aryl
functionality. These results illustrate the general ap-
plicability of this method for the preparation of a variety
of R-morpholinoamides (Scheme 3).
C
16H22N2O2: C, 70.04; H, 8.08; N, 10.21. Found: C, 69.72; H,
8.40; N, 10.48.
N-Ben zyl-4-m eth yl-2-m or p h olin o-4-p en ten a m id e (6b):
white prisms (from ethyl acetate/hexanes); mp 96.5-98.5 °C;
1
yield 72%; H NMR δ 7.20-7.10 (m, 6H), 4.83 (s, 1H), 4.81 (s,
In summary, we have introduced a convenient method
for the preparation of a variety of R-morpholino amides
via readily available benzotriazole intermediates 4a and
4b.
1H), 4.52-4.36 (m, 2H), 3.72-3.54 (m, 4H), 3.22 (t, J ) 7.2 Hz,
1H), 2.70-2.40 (m, 6H), 1.81 (s, 3H); 13C NMR δ 172.4, 143.3,
138.9, 129.1, 128.1, 127.9, 113.7, 67.8, 67.7, 50.8, 43.7, 36.5, 22.8.
Anal. Calcd for C17H24N2O2: C, 70.80; H, 8.39; N, 9.71. Found:
C, 70.78; H, 8.66; N, 9.70.
2-Mor ph olin o-N-(1-ph en yleth yl)-4-pen ten am ide (6c). Ob-
tained as a mixture of two diastereomers in 3:1 ratio: white
prisms (from ethyl acetate/hexanes); yield 73%; 1H NMR δ 7.36-
7.20 (m, 6H), 5.87-5.81 (m, 1H), 5.20-4.94 (m, 3H), 3.69-3.61
(m, 4H), 2.99 (t, J ) 6.1 Hz, 0.25H, minor isomer), 2.93 (t, J )
6.1 Hz, 0.74H, major isomer), 2.66-2.40 (m, 6H), 1.48 (d, J )
7.0 Hz, 3H); 13C NMR 171.1, 143.3, 135.2 (minor isomer), 134.9,
128.8, 127.5, 126.2, 117.6, 117.4 (minor isomer), 69.3, 67.3, 51.1,
50.9 (minor isomer), 48.4, 32.9, 32.4 (minor isomer), 22.1. Anal.
Calcd for C17H24N2N2: C, 70.80; H, 8.39; N, 9.71. Found: C,
70.98; H, 8.68; N, 9.72.
Exp er im en ta l Section
N-Benzyl-2,2-dichloroacetamide (2a ) and N-(1-phenylethyl)-
2,2-dichloroacetamide (2b) were prepared by literature methods.9
N-Ben zyl-2,2-d im eth oxya ceta m id e (3a ).16 N-Benzyl-2,2-
dichloroacetamide (2a ) (1.0 g, 4.54 mmol) was dissolved in THF
(25 mL), and NaOMe (0.54 g, 10 mmol) was added. The mixture
was stirred at 20 °C overnight. Water was added, and the
mixture was extracted with ethyl acetate. The organic layer was
dried on MgSO4 and evaporated in vacuo to give product 3a as
a colorless oil: yield 93%; 1H NMR δ 7.33-7.26 (m, 5H), 6.96
(brs, 1H), 4.73 (s, 1H), 4.46 (d, J ) 5.9 Hz, 2H), 3.38 (s, 6H); 13
NMR δ 167.0, 137.6, 128.5, 127.6, 127.4, 99.7, 53.6, 42.9.
P r oced u r e for t h e P r ep a r a t ion of 2-(1H -1,2,3-Ben zo-
t r ia zol-1-yl)-N-b en zyl-2-m or p h olin oa cet a m id e (4a ) a n d
C
Meth yl 4-(ben zyla m in o)-2,2-d im eth yl-3-m or p h olin o-4-
oxobu ta n oa te (8a ): colorless needles (from CH2Cl2); mp 79-
1
80 °C; yield 72%; H NMR δ 7.40-7.20 (m, 5H), 6.70 (brs, 1H),
4.46 (d, J ) 5.8 Hz, 2H), 3.69 (s, 3H), 3.60 (t, J ) 4.4 Hz, 4H),
3.50 (s, 1H), 2.68-2.45 (m, 4H), 1.32 (s, 3H), 1.29 (s, 3H); 13C
NMR δ 177.9, 170.1, 138.4, 129.0, 128.1, 127.8, 74.7, 67.7, 52.5,
52.3, 45.7, 43.6, 24.2, 21.7. Anal. Calcd for C18H26N2O4: C, 64.56;
H, 7.84; N, 8.38. Found: C, 64.28; H, 8.16; N, 8.41.
(14) (a) Wojciechowski, K. Tetrahedron 1993, 49, 7277. (b) Dufour,
M.; Gramain, J .-C.; Husson, H.-P.; Sinibaldi, M.-E.; Troin, Y. J . Org.
Chem. 1990, 55, 5485. (c) Gardette, D.; Gramain, J .-C.; Sinibaldi, M.-
E. Heterocycles 1990, 31, 1439. (d) Gramain, J .; Husson, H.-P.; Troin,
Y. J . Org. Chem. 1985, 50, 5517.
(15) (a) Katritzky, A. R.; Urogdi, L.; Mayence, A. Synthesis 1989,
323. (b) Katritzky, A. R.; Odens, H. H.; Voronkov, M. V. J . Org. Chem.
2000, 65, 1886. (c) Katritzky, A. R.; Mehta, S.; He, H.-Y.; Cui, X. J .
Org. Chem. 2000, 65, 4364.
N-Ben zyl-2-m or p h olin o-4-oxo-4-p h en ylbu ta n a m id e (8b):
white prisms (from ethyl acetate/hexanes); mp 121-122 °C; yield
63%; 1H NMR δ 8.01 (d, J ) 7.3 Hz, 2H), 7.57 (t, J ) 7.0 Hz,
1H), 7.47 (t, J ) 7.7 Hz, 3H), 7.39-7.22 (m, 5H), 4.50 (dd, J )
15.3, 6.3 Hz, 1H), 4.42 (dd, J ) 15.3, 6.3 Hz, 1H), 4.18 (dd, J )
7.3, 4.7 Hz, 1H), 3.80-3.56 (m, 5H), 2.97 (dd, J ) 16.7, 4.7 Hz,
1H), 2.58 (t, J ) 4.4 Hz, 4H); 13C NMR δ 198.6, 171.4, 138.5,
(16) Ghosez, L.; Rossey, G.; Didderen, F.; Ger. Offen. 2 623 226;
Chem. Abstr. 1977, 86, 120998d.
J . Org. Chem, Vol. 67, No. 23, 2002 8241

137.2, 133.3, 128.9, 128.8, 128.4, 127.7, 127.6, 67.4, 65.0, 50.3,
43.6, 32.6. Anal. Calcd for C21H24N2O3‚0.5H2O: C, 69.78; H, 6.97;
N, 7.75. Found: C, 69.93; H, 6.86; N, 7.84.
15.1 Hz, 1H), 3.77 (t, J ) 4.7 Hz, 4H), 3.32 (d, J ) 9.3 Hz, 1H),
2.96-2.85 (m, 2H), 2.84-2.68 (m, 3H), 2.24-1.94 (m, 3H), 1.93-
1.81 (m, 1H), 1.62-1.34 (m, 2H); 13C NMR δ 172.6, 138.1, 136.4,
128.7, 127.4, 99.3, 70.5, 67.3, 50.1, 43.6, 36.1, 28.5, 23.1, 22.2;
HRMS calcd for C19H25N2O2 313.1916 (M + 1), found 313.1908.
Meth yl 2,2-d im eth yl-3-m or p h olin o-4-oxo-4-[(1-p h en yl-
eth yl)a m in o]bu ta n oa te (8c): colorless oil, obtained as
a
mixture of two diastereoisomers in 1:1 ratio; yield 62%; 1H NMR
δ 7.50-7.20 (m, 5H), 6.75 (d, J ) 9.9 Hz, 0.5H, one isomer), 6.68
(d, J ) 8.1 Hz, 0.5H, other isomer), 5.22-5.06 (m, 1H), 3.69 (s,
0.5*3H, one isomer), 3.66-3.54 (m, 5.5H), 3.47 (s, 0.5H, one
isomer), 3.41 (s. 0.5H, other isomer), 2.71-2.61 (m, 1H), 2.60-
2.44 (m, 3H), 1.52 (d, J ) 6.9 Hz, 0.5 × 3H, one isomer), 1.44 (d,
J ) 6.9 Hz, 0.5 × 3H, other isomer), 1.36-1.19 (m, 6H); 13C NMR
δ 178.1, 169.3, 143.5, 143.3, 129.1, 127.9, 127.8, 126.6, 74.9, 74.8,
67.9, 67.8, 52.6, 48.9, 45.9, 45.5, 24.8, 24.5, 22.4, 22.1, 21.8, 21.6.
Anal. Calcd for C19H28N2O4: C, 65.49; H, 8.10; N, 8.04. Found:
C, 65.72; H, 8.52; N, 8.32.
1-Ben zyl-3,3-dim eth yl-4-m or ph olin odih ydr o-1H-pyr r ole-
2,5-d ion e (9): colorless oil; yield 54%; 1H NMR δ 7.37-7.25 (m,
5H), 4.62 (s, 2H), 3.61-3.57 (m, 4H), 3.13 (s, 1H), 2.74-2.62 (m,
2H), 2.53-2.40 (m, 2H), 1.25 (s, 3H), 1.23 (s, 3H); 13C NMR δ
182.0, 174.7, 136.0, 128.8, 128.7, 128.0, 72.7, 67.1, 51.3, 43.6,
42.0, 27.5, 18.1. Anal. Calcd for C17H22N2O3: C, 67.53; H, 7.33;
N, 9.26. Found: C, 67.12; H, 7.66; N, 9.55.
(E)-4-Oxo-4-ph en yl-N-(1-ph en yleth yl)-2-bu ten am ide (10):
colorless needles (from ethyl acetate/hexanes); mp 155-156 °C;
yield, 52%; 1H NMR δ 8.03 (d, J ) 15.0 Hz, 1H), 8.01 (d, J ) 6.9
Hz, 2H), 7.65 (t, J ) 7.5 Hz, 1H), 7.52 (t, J ) 7.2 Hz, 2H), 7.44-
7.26 (m, 5H), 7.18 (d, J ) 15.0 Hz, 1H), 6.94 (d, J ) 7.5 Hz, 1H),
5.33 (dq, J ) 7.3, 7.3 Hz, 1H), 1.62 (d, J ) 6.9 Hz, 3H); 13C NMR
δ 190.1, 163.2, 142.6, 136.8, 135.7, 133.8, 133.2, 128.9, 128.8,
127.6, 126.3, 49.4, 21.7. Anal. Calcd for C18H17NO2: C, 77.40;
H, 6.13; N, 5.01. Found: C, 77.01; H, 6.33; N, 5.14.
7a-(2H-1,2,3-Ben zotr iazol-2-yl)-1-ben zyl-3-m or ph olin ooc-
ta h yd r o-2H-in d ol-2-on e (13): colorless plates (from ethyl
acetate/hexanes); yield 30%; 1H NMR δ 7.77 (dd, J ) 6.6, 3.3
Hz, 2H), 7.34 (dd, J ) 6.6, 3.3 Hz, 2H), 7.04-6.92 (m, 5H), 4.53
(d, J ) 15.0 Hz, 1H), 4.13 (d, J ) 15.3 Hz, 1H), 3.86-3.76 (m,
1H), 3.66-3.54 (m, 4H), 3.37 (d, J ) 9.9 Hz, 1H), 3.34-3.24 (m,
1H), 3.16-3.02 (m, 2H), 2.84-2.72 (m, 2H), 1.98-1.20 (m, 7H);
13C NMR δ 171.9, 144.0, 136.9, 127.9, 127.8, 127.0, 126.8, 118.4,
83.8, 67.4, 67.1, 50.3, 43.5, 40.7, 32.8, 23.5, 20.9, 20.6. Anal. Calcd
for C25H29N5O2: C, 69.58; H, 6.77; N, 16.23. Found: C, 69.14;
H, 6.86; N, 16.32.
Gen er a l P r oced u r e for th e Nu cleop h ic Su bstitu tion of
4a w ith Or ga n ozin c Rea gen ts. A 1.0 M solution of zinc
chloride (1.2 mL, 1.2 mmol) in THF was added to a flask
containing a 1.0 M solution of the Grignard reagent (1.2 mL,
1.2 mmol) dissolved in 10 mL of THF at 0 °C. The reaction
mixture was stirred at 20 °C for 45 min and then cooled to 0 °C
again and 4a (0.30 g, 1.0 mmol) dissolved in THF (10 mL) was
added dropwise. The reaction mixture was stirred overnight at
25 °C, quenched with dilute NH4Cl, and extracted with diethyl
ether. The organic layer was washed with 5% NaHCO3, brine,
and dried (Na2SO4). The organic layer was filtered and evapo-
rated in vacuo to give a residue. The residue was purified by
column chromatography on Al2O3 (80-200 mesh) using hexanes/
ethyl acetate (2:1) as eluent to afford 15a -c.
N-Ben zyl-2-m or p h olin oh ep ta n a m id e (15a ): colorless oil;
yield 52%; 1H NMR δ 7.36-7.26 (m, 5H), 7.15 (s, 1H), 4.47-
4.44 (m, 2H), 3.65 (m, 4H), 2.85 (t, J ) 6.9 Hz, 1H), 2.59-2.44
(m, 4H), 1.71-1.62 (m, 2H), 1.43-1.28 (brs, 6H), 0.88 (t, J )
6.3 Hz, 3H); 13C NMR δ 172.7, 138.4, 128.6, 127.5, 127.3, 69.6,
67.0, 50.8, 43.0, 31.9, 28.2, 26.0, 22.3, 13.9. Anal. Calcd for
C18H28N2O2: C, 71.01; H, 9.27. Found: C, 70.78; H, 9.11.
N-Ben zyl-2-m or p h olin o-2-p h en yla ceta m id e (15b):17 col-
1
orless oil; yield 52%; H NMR δ 7.48-7.37 (m, 1H), 7.36-7.22
(m, 8H), 7.19-7.12 (m, 2H), 4.46 (dd, J ) 15.0, 6.3 Hz, 1H), 4.37
(dd, J ) 15.0, 6.0 Hz, 1H), 3.83 (s, 1H), 3.62 (t, J ) 4.5 Hz, 4H),
2.45-2.25 (m, 4H); 13C NMR δ 170.9, 138.3, 135.5, 128.8, 128.6,
128.3, 127.6, 127.4, 76.4, 66.8, 52.1, 43.1.
N-Ben zyl-2-(4-m et h ylp h en yl)-2-m or p h olin oa cet a m id e
(15c): white prisms (from ethyl acetate/hexanes); mp 109-110
°C; yield 32%; 1H NMR δ 7.34-7.26 (m, 4H), 7.22-7.20 (m, 4H),
7.15-7.12 (m, 2H), 4.51 (dd, J ) 14.7, 6.0 Hz, 1H), 4.42 (dd, J
) 15.0, 6.0 Hz, 1H), 3.83 (s, 1H), 3.72-3.58 (m, 4H), 2.45-2.36
(m, 4H), 2.34 (s, 3H); 13C NMR δ 171.4, 138.5, 138.4, 132.6, 129.6,
128.9, 128.8, 127.9, 127.3, 76.4, 67.1, 52.4, 43.4, 21.3; HRMS
calcd for C20H25N2O2 325.1916 (M + 1), found 325.1920.
J O020335U
1-Ben zyl-3-m or p h olin o-1,3,3a ,4,5,6-h exa h yd r o-2H-in d ol-
2-on e (14): colorless oil; yield 27%; 1H NMR δ 7.40-7.15 (m,
5H), 4.88-4.81 (m, 1H), 4.77 (d, J ) 15.2 Hz, 1H), 4.48 (d, J )
(17) Shah, K. J .; Trivedi, J . J . Indian J . Appl. Chem. 1967, 30, 11;
Chem. Abstr. 1968, 68, 59230 g.
8242 J . Org. Chem., Vol. 67, No. 23, 2002