One-Pot Reactions of N-(Mesyloxy)phthalimides with Secondary Amines to 2-Ureidobenzamides, 2-Ureidobenzoic Acids, Ethyl 2-Ureidobenzoates, or Isatoic Anhydrides

Article abstract of DOI:10.1021/jo9900634

The reaction of N-(mesyloxy)phthalimides with secondary amines was examined. Transformations are accomplished by one-pot reactions to optionally afford corresponding 2-ureidobenzamides, 2-ureidobenzoic acids, ethyl 2-ureidobenzoates, or isatoic anhydrides, respectively. The mechanism of the acid-catalyzed hydrolysis (or alcoholysis) of intermediate 2-ureidobenzamides to 2-ureidobenzoic acids (or esters) is discussed. A proton transfer mechanism involving the ureido moiety as an internal acid catalyst is proposed. Intermediate 2-ureidobenzoic acids undergo a further transformation to isatoic anhydrides. The utilization of the obtained 2-ureidobenzamides, 2-ureidobenzoic acids, and ethyl 2-ureidobenzoates to prepare 3,1-benzoxazin-4-ones is demonstrated.

Full text of DOI:10.1021/jo9900634

J . Org. Chem. 1999, 64, 5109-5115
5109
On e-P ot Rea ction s of N-(Mesyloxy)p h th a lim id es w ith Secon d a r y
Am in es to 2-Ur eid oben za m id es, 2-Ur eid oben zoic Acid s, Eth yl
2-Ur eid oben zoa tes, or Isa toic An h yd r id es
Michael Gu¨tschow*
Institute of Pharmacy, University of Leipzig, D-04103 Leipzig, Germany
Received J anuary 13, 1999
The reaction of N-(mesyloxy)phthalimides with secondary amines was examined. Transformations
are accomplished by one-pot reactions to optionally afford corresponding 2-ureidobenzamides,
2-ureidobenzoic acids, ethyl 2-ureidobenzoates, or isatoic anhydrides, respectively. The mechanism
of the acid-catalyzed hydrolysis (or alcoholysis) of intermediate 2-ureidobenzamides to 2-ureido-
benzoic acids (or esters) is discussed. A proton transfer mechanism involving the ureido moiety as
an internal acid catalyst is proposed. Intermediate 2-ureidobenzoic acids undergo a further trans-
formation to isatoic anhydrides. The utilization of the obtained 2-ureidobenzamides, 2-ureidobenzoic
acids, and ethyl 2-ureidobenzoates to prepare 3,1-benzoxazin-4-ones is demonstrated.
In tr od u ction
ing an intramolecular quinazoline cyclization to III. This
can be achieved either by introduction of branched
substituents R (R′ ) H) or with 2-sec-amino substituted
benzoxazinones I (R, R′ * H).1-6 Therefore, 2-sec-ami-
nobenzoxazinone represents an attractive structure for
the ongoing efforts in the design of serine protease
inhibitors.
4H-3,1-Benzoxazin-4-ones have attracted considerable
attention as inhibitors of serine proteases. The interac-
tion of 3,1-benzoxazin-4-ones with serine proteases in-
volves enzyme acylation due to the nucleophilic attack
of the active site serine on the lactone carbon, ring
cleavage, and the subsequent deacylation of the acyl-
enzyme formed. For such acyl-enzyme inhibitors (alter-
nate substrate inhibitors), strong inhibition can be
achieved by increasing the rate of acylation as well as
decreasing the rate of deacylation. Efforts have focused
on improving both the kinetic parameters of enzyme
inhibition and intrinsic stability (in aqueous hydrolysis).
Introduction of 2-amino substituents has been used as a
successful strategy to improve the chemical stability of
benzoxazin-4-ones1 and isosteric thieno[2,3-d][1,3]oxazin-
4-ones.2 The inhibition of amino-substituted benzoxazi-
nones I toward human leukocyte elastase,1,3,4 human
cathepsin G,5 chymotrypsin,5-7 C1r serine protease of the
complement system,8 thrombin,9 and human cytomega-
lovirus protease10 has been reported. The deacylation of
acyl-enzymes II (Ser-OH ) active site serine) formed in
the reaction of amino-substituted benzoxazinones I with
serine proteases can favorably be decelerated by prevent-
Compounds I (R, R′ * H) were usually obtained by
cyclocondensation of ureidobenzoic acids IV on treatment
with concd H2SO4 or carbodiimides.1,7,8,11 The precursors
IV (R, R′ * H) can be prepared either by the reaction of
isatoic anhydrides with secondary amines12 or by alkaline
hydrolysis of the corresponding alkyl 2-ureidoben-
(1) Krantz, A.; Spencer, R. W.; Tam, T. F.; Liak, T. J .; Copp, L. J .;
Thomas, E. M.; Rafferty, S. P. J . Med. Chem. 1990, 33, 464.
(2) Gu¨tschow, M.; Neumann, U. J . Med. Chem. 1998, 41, 1729.
(3) Krantz, A.; Spencer, R. W.; Tam, T. F.; Thomas, E.; Copp, L. J .
J . Med. Chem. 1987, 30, 589.
(4) (a) Uejima, Y.; Kokubo, M.; Oshida, J .; Kawabata, H.; Kato, Y.;
Fujii, K. J . Pharmacol. Exp. Ther. 1993, 265, 516. (b) Uejima, Y.;
Oshida, J .; Kawabata, H.; Kokubo, M.; Kato, Y.; Fujii, K. Biochem.
Pharmacol. 1994, 48, 426.
(5) Gu¨tschow, M.; Neumann, U. Bioorg. Med. Chem. 1997, 5, 1935.
(6) Neumann, U.; Gu¨tschow, M. Bioorg. Chem. 1995, 23, 72.
(7) Hedstrom, L.; Moorman, A. R.; Dobbs, J .; Abeles, R. H. Biochem-
istry 1984, 23, 1753.
(8) Hays, S. J .; Caprathe, B. W.; Gilmore, J . L.; Amin, N.; Emmer-
ling, M. R.; Michael, W.; Nadimpalli, R.; Nath, R.; Raser, K. J .; Staf-
ford, D.; Watson, D.; Wang, K.; J aen, J . C. J . Med. Chem. 1998, 41,
1060.
(11) Other synthetic routes to I (R, R′ * H): (a) From anthranilic
acid via 2-benzotriazolyl-4H-3,1- benzoxazin-4-one: Butula, I.; Vela,
V.; Zorc, B. Croat. Chem. Acta 1981, 54, 105. (b) From isatoic anhydride
via 2-isothiocyanatobenzoyl chloride: Ulrich, H.; Tucker, B.; Sayigh,
A. A. R. J . Org. Chem. 1967, 32, 4052. (c) From methyl 2-aminoben-
zoate via 2-methoxycarbonylphenylcarbamoyl chloride: ref 1. (d) From
methyl 2-aminobenzoate and phosgene-iminium salts: Bitter, I.;
Szo¨cs. L.; To¨ke, L. Acta Chim. Acad. Hung. 1981, 107, 57.
(12) The reaction of isatoic anhydrides with amines (or alcohols)
produce two different types of products, 2-aminobenzamides (or alkyl
esters) and 2-ureidobenzoic acids (or 2-alkoxycarbonylaminobenzoic
acids) depending on the nucleophile and the reaction conditions. For
examples see: (a) Staiger, R. P.; Wagner, E. C. J . Org. Chem. 1953,
18, 1427. (b) Bunnett, J . F.; Naff, M. B. J . Am. Chem. Soc. 1966, 88,
4001. (c) Hegarty, A. F.; Ahern, E. P.; Frost, L. N.; Hegarthy, C. N. J .
Chem. Soc., Perkin Trans. 2 1990, 1935. (d) Coppola, G. M. Synthesis
1980, 505. (e) Kappe, T.; Stadlbauer, W. Adv. Heterocycl. Chem. 1981,
28, 127. (f) Heyman, D. J . Heterocycl. Chem. 1978, 15, 1131. (g)
Hinman, C.; Vaughan, K. Synthesis 1980, 719.
(9) Brown, A. D.; Powers, J . C. Bioorg. Med. Chem. 1995, 3, 1091.
(10) Abood, N. A.; Schretzman, L. A.; Flynn, D. L.; Houseman, K.
A.; Wittwer, A. J .; Dilworth, V. M.; Hippenmeyer, P. J .; Holwerda, B.
C. Bioorg. Med. Chem. Lett. 1997, 7, 2105.
10.1021/jo9900634 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/15/1999

5110 J . Org. Chem., Vol. 64, No. 14, 1999
Gu¨tschow
Sch em e 1a
Sch em e 2
HCl for a short time. The precipitate formed was shown
to be pure isatoic anhydride 19. Clearly, the unex-
pected formation of 19 is a result of a consecutive trans-
formation, and the intermediates were elucidated as
follows. First, the reaction was carried out under similar
conditions, and the residue was treated with 0.25 M
HCl, but cooled for several days instead of being heated
to produce the pure ureidobenzoic acid 11. Compound
11 was found to be converted in boiling HCl to isatoic
anhydride 19, indicating 11 as an intermediate of the
transformation of 1 to 19. When 1 was reacted with
morpholine and the mixture was not treated with HCl,
the ureidobenzamide 4 was formed. Addition of HCl
to 4 led to the formation of the ureidobenzoic acid 11
when the cooled mixture was stored for several days.
Thus, 4 is the first intermediate of the transformation
of 1 to 19.
The reaction of 1 with morpholine followed by treat-
ment with ethanolic HCl yielded the ethyl 2-ureidoben-
zoate 15 in high purity. Again, the transformation occurs
via the ureidobenzamide 4, which was found to be
converted to 15 upon treatment with ethanolic HCl. To
elucidate structure 15 unambiguously, the isomeric car-
bamate 29 was prepared from 28 (Scheme 2) and proved
to be distinct from 15.
The three urea derivatives obtained could easily be
converted to 2-morpholino-3,1-benzoxazin-4-one 21: For
that, compound 11 was treated with acetic anhydride,
and compound 4 and 15, respectively, with concd H2SO4
(Scheme 1). In each case, the final benzoxazinone 21 was
obtained in high purity. Under both basic or acidic
conditions, 21 underwent a ring cleavage as a result of
the attack of the corresponding nucleophile at the lactone
structure. Thus, alkaline hydrolysis of 21 furnished 11,
reaction with morpholine gave 4, and treatment with
ethanolic HCl yielded 15.
a
Reagents and conditions: (a) morpholine, acetone, reflux, 25
min; (b) 0.25 M HCl, reflux, 2 min; then 5 °C; (c) 0.25 M HCl, 5
°C, 14 d; (d) 0.25 M ethanolic HCl, reflux, 2 min; then -15 °C; (e)
acetic anhydride reflux, 15 min; (f) concd H2SO4, rt; (g) Na2CO3,
H2O, acetone, rt, 16 h; (h) morpholine, acetone, rt, 24 h; (i)
morpholine, H2O, rt, 15 min.
On the basis of the results shown in Scheme 1, one-
pot reactions were applied to prepare isatoic anhydride
19 also from pyrrolidine, diethylamine, respectively, and
N-(mesyloxy)phthalimide 1 (Table 1). Accordingly, the
dimethyl-substituted isatoic anhydride 20 was obtained
from 2 and morpholine. The 2-ureidobenzamides 5-9,
2-ureidobenzoic acids 12-14, and ethyl 2-ureidoben-
zoates 16-18 could be prepared conveniently by one-pot
reactions from N-(mesyloxy)phthalimides 1-3 and ap-
propriate secondary amines (Table 1). The resulting urea
derivatives were used as substrates to synthesize 2-sec-
amino-4H-3,1-benzoxazin-4-ones. These results are sum-
marized in Table 2. The conditions for the cyclization of
the corresponding morpholino derivatives 4, 11, and 15
to prepare morpholinobenzoxazinon 21 (Scheme 1) were
applied to the synthesis of benzoxazinones 22-27 from
various precursors.
zoates.1,8 To extend these synthetic methods to precursors
of 2-sec-aminobenzoxazinones the reaction of N-(mesyl-
oxy)phthalimides with secondary amines was investi-
gated and is described in this report. The reaction of
N-(mesyloxy)phthalimide with morpholine was chosen as
a model reaction. The mechanisms of the observed
transformations are discussed and some applications
with substituted N-(mesyloxy)phthalimides and other
secondary amines are described. The utilization of the
precursors to synthesize 2-sec-aminobenzoxazinones is
also reported herein.
Resu lts a n d Discu ssion
Scheme 1 summarizes the transformations which occur
as a result of the reaction of N-(mesyloxy)phthalimide 1
with morpholine under different conditions. A mixture
of 1, morpholine, and acetone was refluxed, the solvent
was evaporated, and the residue was boiled in 0.25 M
The reaction of N-(mesyloxy)phthalimide 1 with mor-
pholine (Scheme 1) to isatoic anhydride 19 via 4 and 11
was unexpected in the light of the mild conditions used.

Reactions of N-(Mesyloxy)phthalimides with Secondary Amines
J . Org. Chem., Vol. 64, No. 14, 1999 5111
Ta ble 1. Tr a n sfor m a tion s of N-(Mesyloxy)p h th a lim id es 1-3 to 2-Ur eid oben za m id es 4-9, 2-Ur eid oben zoic Acid s 11-14,
Eth yl 2-Ur eid oben zoa tes 15-18, a n d Isa toic An h yd r id es 19 a n d 20
Ta ble 2. Cycliza tion s to 4H-3,1-Ben zoxa zin -4-on es 21-27
However, the first step, formation of the ureidobenzamide
4,13 can easily be explained as a result of nucleophilic
attack of morpholine at the lactam carbon of 1, followed
by ring cleavage, elimination of methanesulfonic acid,
Lossen rearrangement to 4-(2-isocyanatobenzoyl)mor-
pholine, and subsequent addition of morpholine.15
The second step, transformation of the ureidobenz-
amide 4 to the ureidobenzoic acid 11 (Scheme 1), is
An elimination-addition mechanism17 was taken into
formally an acid-catalyzed amide hydrolysis. However,
consideration to explain the ready hydrolysis (or alco-
neither benzoylmorpholine 30 nor the carbamate 29 were
holysis) of 4: Elimination of morpholine from the ureido
found to react on treatment with HCl under conditions
residue, followed by intramolecular addition to the
used for the transformation of 4 to 11.
intermediate, masked isocyanate 31,18 which could be
attacked by water (or ethanol) at C-4 might produce 11
(or 15). Consequently, an acyl transfer would occur and
(13) N-(Mesyloxy)phthalimide was reported to react with piperidine
to the analogue 2-ureidobenzamide derivative; see ref 14.
(14) Ku¨hle, E.; Wegler, R. Liebigs Ann. Chem. 1958, 616, 183.
the morpholine portion of the amide residue in 4 would

5112 J . Org. Chem., Vol. 64, No. 14, 1999
Gu¨tschow
Sch em e 3
lecular hydrogen bonding in 2-ureidobenzamides is pre-
vented by steric hindrance, the ready conversion did not
occur. Thus, when compound 6 was treated with 0.25 M
ethanolic HCl under conditions used for the conversion
of 4 to 15, unchanged starting material was isolated
quantitatively.
The third step in the conversion of N-(mesyloxy)-
phthalimide 1 to isatoic anhydride 19 (Scheme 1), the
transformation of the 2-ureidobenzoic acid 11 to 19, is
proposed to occur by direct nucleophilc attack of the
carboxyl oxygen at the protonated urea structure rather
then by an elimination-addition mechanism. This is
supported by the following experiments. The urea deriva-
tives 32 and 15, respectively, failed to react when treated
with 0.25 M HCl under conditions used for the prepara-
tion of isatoic anhydride 19 from 11 (Scheme 1). Thus,
the neighboring carboxyl group is prerequisite to the
transformation of the ureido residue. Furthermore, the
urea moiety in 11 was replaced by the urethane moiety
in 33. No reaction occurred when compound 33 was
treated similarly with 0.25 M HCl, indicating the ureido
residue to be prerequisite to isatoic anhydride formation
under the acidic conditions used.22
Sch em e 4
become part of the urea residue in 11 (or 15). To check
this hypothesis, compound 10 was prepared from benz-
oxazinone 25 and morpholine and then treated with HCl
(Scheme 3). The diethylurea derivative 14 was obtained
exclusively, clearly indicating that the acyl transfer did
not occur.
Therefore, the mechanism outlined in Scheme 4 was
proposed for the acid-catalyzed hydrolysis (or alcoholysis)
of 4. Protonation of the urea residue,19 followed by proton
transfer to the amide oxygen provides enhanced suscep-
tibility of the amide group to nucleophilic attack. Likely,
the intramolecular acid catalysis of the appropriately
placed, protonated urea group is assisted by internal
hydrogen bonding.20 An intramolecular hydrogen bond
in the 2-ureidobenzamides 4-10 as it was concluded from
1H NMR data in CDCl3 (see below) and NOE experi-
ments21 might also be operative in aqueous or ethanolic
solution.20b Furthermore, if the formation of an intramo-
The 1H NMR spectra (CDCl3) of the 2-ureidobenz-
amides 4-10, 2-ureidobenzoic acids 11-14, and ethyl
2-ureidobenzoates 15-18 show significant downfield
shifts of the H-3 protons.23 This is interpreted as a result
of the anisotropic deshielding effect of the urea carbonyl
on the H-3 proton, indicating that the urea CdO bond is
(20) For the interdependence of intramolecular hydrogen bonding
and intramolecular general catalysis, see: (a) Benkovic, S. J ., Duni-
koski, L. K., J r. Biochemistry 1970, 9, 1390. For intramolecular acid
catalysis of the hydrolysis of 3,1-benzoxazin-4-ones by a neighboring
carboxyl group, see: (b) Hegarty, A. F.; Pratt, R. F.; Giudici, T.; Bruice,
T. C. J . Am. Chem. Soc. 1971, 93, 1428. (c) Cremin, D. J .; Hegarty, A.
F. J . Chem. Soc., Perkin Trans. 2 1978, 208.
(15) The reaction of N-(sulfonyloxy)phthalimides with primary
amines as well as O-, S-, and C-nucleophiles has widely been uti-
lized in organic syntheses. For examples, see: (a) Bauer, L.; Exner,
O. Angew. Chem., Int. Ed. Engl. 1974, 13, 376. (b) Fahmy, A., F.
M.; Aly, N. F.; Nada, A.; Aly, N. Y. Bull. Chem. Soc. J pn. 1977, 50,
2678. (c) Fahmy, A. F. M.; Aly, N. F.; Orabi, M. O. Bull. Chem. Soc.
J pn. 1978, 150, 2148. (d) Gu¨tschow, M.; Tonew, E.; Leistner, S.
Pharmazie 1995, 50, 672. (e) Chapman, T. M.; Freedman, E. A. J . Org.
Chem. 1973, 38, 3908. (f) Sheradsky, T.; Itzhak, N. J . Chem. Soc.,
Perkin Trans. 1 1986, 13. See also ref 14. For an application of the
Lossen rearrangement of N-(sulfonyloxy)phthalimides in the design
of mechanism-based inhibitors of serine proteases, see ref 16.
(16) Neumann, U.; Gu¨tschow, M. J . Biol. Chem. 1994, 269, 21561.
(17) For a review on E1cB processes in acyl transfer reactions, see:
Williams, A.; Douglas, K. T. Chem. Rev. 1975, 75, 627. See also:
Gu¨tschow, M.; Hecker, T.; Eger, K. Synthesis 1999, 410.
(21) Relevant NOE enhancements in 4 and 11:
(22) Isatoic anhydride was obtained from benzoic acids with an
adjacent carbamate residue under basic conditions or on thermal
treatment: (a) Frost, L. N.; Hegarty, A. F. J . Chem. Soc., Chem.
Commun. 1973, 82. (b) Hegarty, A. F.; Frost, L. N.; Cremin, D. J . Chem.
Soc., Perkin Trans. 2 1974, 1249. See also ref 12f.
(18) For the formation of mesoionic quinazolines from 2-isocyana-
tobenzamides, see ref 14.
(19) For comparison, pKa values of PhNHCONH2 (-0.3) and Ph-
CONH2 (≈-2): Collumeau, A. Bull. Soc. Chim. Fr. 1968, 5087.

Reactions of N-(Mesyloxy)phthalimides with Secondary Amines
J . Org. Chem., Vol. 64, No. 14, 1999 5113
layer chromatography was performed on Merck aluminum
situated in the plane of the phenyl ring. A internal
hydrogen bond between the urea hydrogen and the
carbonyl oxygen of the adjacent carboxamide, carboxyl,
or ester group, respectively, would cause an orientation
of the urea carbonyl into the plane of the phenyl ring.
The hydrogen bonding is further indicated by the chemi-
cal shifts of the urea NH protons in 2-ureidobenzamides
4-10 (8.35-9.14 ppm, except 6), 2-ureidobenzoic acids
11-14 (10.42-10.63 ppm), and ethyl 2-ureidobenzoates
15-18 (10.52-10.81 ppm). For a comparison, in 4-(phe-
nylcarbamoyl)morpholine 32 bearing no adjacent hydro-
gen bond acceptor, the NH signal appeared at 6.63 ppm.
In the case of the dimethyl-substituted 2-ureidobenz-
amide 6 (see above), a planar orientation of the substit-
uents and therefore the formation of an internal hydro-
gen bond is sterically hindered. The NH signal of 6
appeared at 6.63 ppm. The prevented rotation about the
C1-CO single bond leads to atropisomerism. The mol-
ecule is chiral, and the eight methylene hydrogen atoms
of the amide structure are diasterotopic and gave eight
sheets, silica gel 60 F254
.
2-[(Morpholinocarbonyl)amino]benzoic acid (11) was pre-
pared from 2-morpholino-4H-3,1-benzoxazin-4-one (21) or isa-
toic anhydride (19), respectively, as previously reported.6,12a
4-Benzoylmorpholine (30)24 and 2-(ethoxycarbonyl)ami-
nobenzoic acid (33)7 were synthesized as reported.
4,5-Dimethylphthalic anhydride25 and 3,6-dimethylphthalic
anhydride26 were reacted with hydroxylamine hydrochloride
to afford the corresponding N-hydroxyphthalimide derivatives.
N-(Mesyloxy)phthalimides (1-3) were obtained from N-
hydroxyphthalimides and methanesulfonyl chloride using a
standard procedure.16
N-(Mesyloxy)-4,5-dimethylphthalimide (2): mp 179-180 °C
(EtOH); 1H NMR δ 2.44 (s, 6H), 3.45 (s, 3H), 7.67 (s, 2H). Anal.
Calcd for C11H11NO5S: C, 49.07; H, 4.12; N, 5.20, S, 11.91.
Found: C, 49.03; H, 4.17; N, 5.43; S, 12.29.
N-(Mesyloxy)-3,6-dimethylphthalimide (3): mp 113-114 °C
(acetone/petroleum ether); 1H NMR δ 2.67 (s, 6H), 3.46 (s, 3H),
7.44 (s, 2H). Anal. Calcd for C11H11NO5S: C, 49.07; H, 4.12;
N, 5.20, S, 11.91. Found: C, 49.22; H, 4.05; N, 5.37; S, 11.80.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Ur eid o-
ben za m id es 4, 5, 6, 9 fr om N-(Mesyloxy)p h th a lim id es. A
solution of 1, 2, or 3 (7.5 mmol) in anhydrous acetone (25 mL)
was stirred under argon and heated. As soon as the solution
started refluxing, a solution of morpholine (1.96 g, 22.5 mmol)
or N-methylcyclohexylamine (2.55 g, 22.5 mmol) in anhydrous
acetone (7 mL) was added dropwise over 10 min. The mixture
was refluxed for additional 15 min, and the precipitate was
separated by filtration. The filtrate was evaporated to dryness
to obtain the product. See Table 1 for yields.
1
distinct signals in the H NMR spectrum of 6. As it has
been mentioned, compound 6 failed to react in the acid-
catalyzed alcoholysis. These results provide supporting
evidence for the postulated proton-transfer mechanism
of the hydrolysis (or alcoholysis) of 2-ureidobenzamides
assisted by internal hydrogen bonding (Scheme 4).
In summary, an efficient synthetic entry to 2-sec-
amino-3,1-benzoxazin-4-ones based on the reaction of
N-(mesyloxy)phthalimides 1-3 with secondary amines
has been found. This approach is particularly attractive
to utilize symmetrically disubstituted phthalimide de-
rivatives. Thus, dimethyl-substituted benzoxazinones
(e.g., 22, 23, 27) can be obtained in two-step routes. The
enzymatic assays of the new benzoxazinones as inhibitors
of serine proteases will be presented in due course.
The transformation of N-(mesyloxy)phthalimides in-
volves the formation of 2-ureidobenzamides which un-
dergo a ready hydrolysis, or alcoholysis, to corresponding
2-ureidobenzoic acids, or ethyl esters, respectively. The
synthesis of these compounds can be achieved by conve-
nient one-pot procedures using N-(mesyloxy)phthalimides
as substrates. The reactivity of the intermediate 2-ure-
idobenzamides is proposed to arise from intramolecular
acid catalysis. Minor changes in the acidic reaction
conditions lead to a further transformation of intermedi-
ate 2-ureidobenzoic acids and allow for the controlled
preparation of isatoic anhydrides. For example, a one-
4-[2-[(Morpholinocarbonyl)amino]benzoyl]morpholine (4):5
1
mp 78-80 °C (MeOH); IR (KBr) 1650, 1605 cm-1; H NMR δ
3.47-3.51 (m, 4H) 3.65-3.77 (m, 12H), 6.98-7.04 (m, 1H), 7.19
(dd, 1H, J ) 7.7, 1.3 Hz), 7.37-7.44 (m, 1H), 8.17 (dd, 1H, J
) 8.5, 1.1 Hz), 8.83 (s, 1H); EIMS (m/z, %)27 319 (M+, 80), 233
(24), 146 (100).
4-[4,5-Dimethyl-2-[(morpholinocarbonyl)amino]benzoyl]-
morpholine (5): mp 158-159 °C (MeOH/H2O); IR (KBr) 1654,
1606; 1H NMR δ 2.20 (s, 3H), 2.26 (s, 3H), 3.42-3.50 (m, 4H),
3.62-3.78 (m, 12H), 6.92 (s, 1H), 7.92 (s, 1H), 8.71 (s, 1H);
EIMS (m/z, %)27 347 (M+, 36), 261 (92), 174 (100). Anal. Calcd
for C18H25N3O4: C, 62.23; H, 7.25; N, 12.10. Found: C, 61.61;
H, 7.09; N, 11.85.
4-[3,6-Dimethyl-2-[(morpholinocarbonyl)amino]benzoyl]-
morpholine (6). The mixture was refluxed and then cooled at
5 °C for 2 d. The precipitate was collected by filtration,
suspended in ice-water (200 mL), and filtered: mp 247-250
°C (MeOH); IR (KBr) 1654, 1610 cm-1; 1H NMR δ 2.20 (s, 3H),
2.21 (s, 3H), 3.12-3.31 (m, 2H), 3.41-3.62 (m, 8H), 3.68-3.72
(m, 4H), 3.81-3.88 (m, 1H), 4.04-4.12 (m, 1H), 6.63 (s, 1H,
NH), 6.99 (d, 1H, J ) 7.9 Hz), 7.12 (d, 1H, J ) 7.9 Hz); EIMS
(m/z, %)27 347 (M+, 24), 261 (87), 174 (100). Anal. Calcd for
C
18H25N3O4: C, 62.23; H, 7.25; N, 12.10. Found: C, 62.31; H,
pot procedure was accomplished to prepare 4,5-dimeth-
ylisatoic anhydride 20 from 2. This route to isatoic
anhydrides involves the stepwise elimination of both
secondary amine portions. A ring-opening attack of the
released amine at the final isatoic anhydride is prevented
due to the acidic conditions used.
7.47; N, 11.70.
2-(3-Cyclohexyl-3-methylureido)-N-cyclohexyl-N-methyl-
benzamide (9): mp 112.5-113.5 °C (MeOH/H2O); IR (KBr)
1662, 1618 cm-1; 1H NMR δ 1.00-1.83 (m, 20H), 2.84 (s, 3H),
2.90 (br s, 3H), 3.97-4.52 (m, 2H), 6.94-7.00 (m, 1H), 7.16
(dd, 1H, J ) 7.6, 1.5 Hz), 7.32-7.38 (m, 1H), 8.21 (d, 1H, J )
8.3 Hz), 8.52 (br s, 1H); EIMS (m/z, %)28 371 (M+, 3), 258 (13),
146 (100). Anal. Calcd for C22H33N3O2: C, 71.12; H, 8.95; N,
11.31. Found: C, 71.44; H, 8.63; N, 11.06.
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-Ur eid o-
ben za m id es 7, 8 fr om N-(Mesyloxy)p h th a lim id e. A mix-
ture of 1 (2.41 g, 10 mmol) and anhydrous toluene (20 mL)
Melting points are not corrected. 13C NMR spectra (75 MHz)
and 1H NMR spectra (300 MHz) were recorded in CDCl3,
unless otherwise stated. NOE difference spectra were obtained
for the following compounds: 4, 11, 20, 23. Mass spectra were
performed using electron impact ionization (EI, 70 eV). Thin-
(24) Iwata, C.; Watanabe, M.; Okamoto, S.; Fujimoto, M.; Sakae,
M.; Katsurada, M., Imanishi, T. Heterocycles 1988, 27, 323.
(25) Hennige, H.; Kreher, R. P.; Konrad, M.; J elitto, F. Chem. Ber.
1988, 121, 243.
(23) Values were calculated based on the 1H NMR data of the urea
derivative 32 (δH-2 ) 7.3 ppm) and substituent parameters for CO2H,
CO2Et, CONRR′, and Me, respectively, and compared to the observed
values. The shift differences were 0.77-0.85 ppm for 2-ureidobenz-
amides (4, 5, 7-10), 1.09-1.19 ppm for 2-ureidobenzoic acids (11-
14), and 1.16-1.32 ppm for ethyl 2-ureidobenzoates (15-18).
(26) Newman, M. S.; Lord, B. T. J . Am. Chem. Soc. 1944, 66, 733.
(27) First mass spectral fragment: (M+ - NRR′); second fragment:
(M+ - NRR′ - HNRR′).
(28) First mass spectral fragment: (M+ - HNRR′); second frag-
ment: (M+ - HNRR′ - NRR′).

5114 J . Org. Chem., Vol. 64, No. 14, 1999
Gu¨tschow
was stirred at 0 °C. Pyrrolidine (2.4 g, 34 mmol) or diethy-
lamine (2.5 g, 34 mmol) was added slowly. The mixture was
stirred at room temperature for 7 h, diluted with brine (100
mL), and extracted with ethyl acetate. The combined organic
layers were washed with H2O, dried (Na2SO4), and evaporated
in vacuo. See Table 1 for yields.
1-[2-[(Pyrrolidinocarbonyl)amino]benzoyl]pyrrolidine (7): mp
132-133 °C (MeOH/H2O); IR (KBr) 1670, 1620 cm-1; 1H NMR
δ 1.82-2.00 (m, 8H), 3.42-3.68 (m, 8H), 6.91-6.98 (m, 1H),
7.30-7.39 (m, 2H), 8.25 (d, 1H, J ) 8.3 Hz), 9.14 (s, 1H); EIMS
(m/z, %)27 287 (M+, 5), 217 (72), 146 (52), 55 (100). Anal. Calcd
for C16H21N3O2‚0.5H2O: C, 64.84; H, 7.48; N, 14.19. Found:
C, 64.85; H, 7.22; N, 13.99.
2-(3,3-Diethylureido)-N,N-diethylbenzamide (8): colorless
oil; IR (KBr) 1670, 1622 cm-1; 1H NMR δ 1.18-1.26 (m, 12H),
3.35 (q, 4H, J ) 7.1 Hz), 3.30-3.50 (m, 4H), 6.93-7.00 (m,
1H), 7.18 (dd, 1H, J ) 7.7, 1.6 Hz), 7.30-7.38 (m, 1H), 8.19
(d, 1H, J ) 8.5 Hz), 8.35 (s, 1H); EIMS (m/z, %)27 291 (M+, 5),
219 (63), 146 (100).
P r ep a r a tion of 4-[2-[(Mor p h olin oca r bon yl)a m in o]ben -
zoyl]m or p h olin e (4) fr om 2-Mor p h olin o-4H-3,1-ben zox-
a zin -4-on e (21). A mixture of 21 (929 mg, 4 mmol), morpho-
line (1.4 g, 16 mmol), and anhydrous acetone (12 mL) was
stirred at room temperature for 24 h and concentrated in
vacuo. The residue was recrystallized from MeOH to yield 4
(1.13 g, 84%).
ben zoyl]m or p h olin e (4). Compound 4 (2.53 g, 7.5 mmol) was
stirred with 0.25 M HCl (100 mL) to obtain a solution which
was kept at 5 °C for 14 d. The precipitate was collected by
filtration to obtain 11 (1.7 g, 91%).
P r ep a r a tion of 2-(3,3-Dieth ylu r eid o)ben zoic Acid (14)
fr om 4-[2-(3,3-Dieth ylu r eid o)ben zoyl]m or p h olin e (10).
Compound 10 (1.15, 3.75 mmol) was treated with 0.25 M HCl
(50 mL) as described above to obtain 14 (560 mg, 63%).
Gen er al P r ocedu r e for th e P r epar ation of Eth yl 2-Ur ei-
d oben zoa tes 15-18 fr om N-(Mesyloxy)p h th a lim id es. A
solution of 1 or 2 (7.5 mmol) in anhydrous acetone (25 mL)
was stirred under argon and heated to reflux. A solution of
the appropriate secondary amine (22.5 mmol) in anhydrous
acetone (7 mL) was added dropwise over 10 min. The mixture
was refluxed for additional 15 min and evaporated to dryness.
The residue was dissolved in 0.25 M anhydrous ethanolic HCl
(48 mL), refluxed for 2 min, and kept at -15 °C overnight.
The precipitate was collected by filtration, washed with H2O,
and dried. See Table 1 for yields.
Ethyl 2-[(morpholinocarbonyl)amino]benzoate (15): mp 117-
1
118 °C (EtOH), IR (KBr) 1676 (br) cm-1; H NMR δ 1.42 (t,
3H, J ) 7.1 Hz), 3.55-3.62 (m, 4H), 3.74-3.80 (m, 4H), 4.37
(q, 2H, J ) 7.1 Hz), 6.95-7.02 (m, 1H), 7.48-7.55 (m, 1H),
8.03 (dd, 1H, J ) 8.0, 1.6 Hz), 8.56 (d, 1H, J ) 8.6 Hz), 10.81
(s, 1H). Anal. Calcd for C14H18N2O4: C, 60.58; H, 6.52; N, 10.07.
Found: C, 60.21; H, 6.90; N, 9.83.
4-[2-(3,3-Dieth ylu r eido)ben zoyl]m or ph olin e (10). A mix-
ture of 25 (873 mg, 4 mmol), morpholine (1.4 g, 16 mmol), and
anhydrous acetone (12 mL) was stirred at room temperature
for 3 d and concentrated in vacuo. The residue was dissolved
in ethyl acetate. Silica gel was added, and the mixture was
stirred for 2 min and filtered. The filtrate was evaporated in
vacuo to yield 10 (1.04 g, 85%) as a colorless oil; IR (KBr) 1654,
Ethyl 4,5-dimethyl-2-[(morpholinocarbonyl)amino]benzoate
(16): mp 128-130 °C; IR (KBr) 1670 (br) cm-1 1H NMR δ
;
1.40 (t, 3H, J ) 7.1 Hz), 2.21 (s, 3H), 2.29 (s, 3H), 3.53-3.59
(m, 4H), 3.72-3.78 (m, 4H), 4.33 (q, 2H, J ) 7.1 Hz), 7.74 (s,
1H), 8.35 (s, 1H), 10.67 (s, 1H). Anal. Calcd for C16H22N2O4:
C, 62.73; H, 7.24; N, 9.14. Found: C, 62.39; H, 7.18; N, 9.12.
1
1625 cm-1; H NMR δ 1.22 (t, 6H, J ) 7.1 Hz), 3.37 (q, 4H, J
Ethyl 2-(3-cyclohexyl-3-methylureido)benzoate (17). The
residue was dissolved in ethanolic HCl and refluxed. The
solution was concentrated in vacuo to obtain 30 mL and then
) 7.1 Hz), 3.60-3.78 (m, 8H), 6.94-7.01 (m, 1H), 7.16 (dd,
1H, J ) 7.7, 1.6 Hz), 7.34-7.41 (m, 1H), 8.20 (d, 1H, J ) 8.3
Hz,), 8.55 (s, 1H); EIMS (m/z, %) 305 (M+, 45), 219 (44), 146
(100).
1
cooled: mp 80-81 °C; IR (KBr) 1688, 1664 cm-1; H NMR δ
1.03-1.88 (m, 10H), 1.40 (t, 3H, J ) 7.1 Hz), 2.94 (s, 3H), 4.10-
4.21 (m, 1H), 4.36 (q, 2H, J ) 7.1 Hz), 6.91-7.00 (m, 1H), 7.45-
7.52 (m, 1H), 8.01 (dd, 1H, J ) 8.0, 1.7 Hz), 8.61 (d, 1H, J )
8.6 Hz) 10.65 (s, 1H). Anal. Calcd for C17H24N2O3: C, 67.08;
H, 7.95; N, 9.20. Found C, 66.97; H, 7.62; N, 9.02.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Ur eid o-
ben zoic Acid s 11-14 fr om N-(Mesyloxy)p h th a lim id es. A
solution of 1 or 2 (7.5 mmol) in anhydrous acetone (25 mL)
was stirred under argon and heated to reflux. A solution of
the appropriate secondary amine (22.5 mmol) in anhydrous
acetone (7 mL) was added dropwise over 10 min. The mixture
was refluxed for additional 15 min and evaporated to dryness.
The residue was stirred with 0.25 M HCl (100 mL) to obtain
a solution which was kept at 5 °C for 14 d. The precipitate
was collected by filtration. See Table 1 for yields.
Ethyl 2-(3-cyclohexyl-3-methylureido)-4,5-dimethylbenzoate
(18). The crude product was obtained as described above and
recrystallized from EtOH/H2O: mp 89-90 °C; IR (KBr) 1682,
1
1664 cm-1; H NMR δ 1.04-1.87 (m, 10H), 1.41 (t, 3H, J )
7.1 Hz), 2.22 (s, 3H), 2.29 (s, 3H), 2.94 (s, 3H), 4.12-4.23 (m,
1H), 4.35 (q, 2H, J ) 7.1 Hz), 7.74 (s, 1H), 8.44 (s, 1H), 10.52
(s, 1H). Anal. Calcd for C19H28N2O3: C, 68.65; H, 8.49; N, 8.43.
Found: C, 68.35; H, 8.57; N, 8.37.
2-[(Morpholinocarbonyl)amino]benzoic acid (11): mp 156-
1
160 °C, lit.12a mp 164 °C; IR (KBr) 1690, 1630 cm-1; H NMR
δ 3.56-3.62 (m, 4H), 3.75-3.81 (m, 4H), 7.00-7.06 (m, 1H),
7.54-7.60 (m, 1H), 8.07 (dd, 1H, J ) 8.0, 1.4 Hz), 8.57 (d, 1H,
J ) 8.5 Hz), 10.63 (s, 1H).
P r ep a r a tion of Eth yl 2-[(Mor p h olin oca r bon yl)a m in o]-
ben zoa te (15) fr om 4-[2-[(Mor p h olin oca r bon yl)a m in o]-
ben zoyl]m or p h olin e (4). Compound 4 (1.27 g, 3.75 mmol)
was refluxed with 0.25 M anhydrous ethanolic HCl (24 mL)
for 2 min and kept at -15 °C overnight. The precipitate was
collected by filtration, washed with H2O, and dried to obtain
15 (880 mg, 84%).
P r ep a r a tion of Eth yl 2-[(Mor p h olin oca r bon yl)a m in o]-
ben zoa te (15) fr om 2-Mor p h olin o-4H-3,1-ben zoxa zin -4-
on e (21). Compound 21 (871 mg, 3.75 mmol) was treated with
ethanolic HCl using the procedure given above to obtain 15
(920 mg, 88%).
Gen er a l P r oced u r e for th e P r ep a r a tion of Isa toic
An h yd r id es 19-20 fr om N-(Mesyloxy)p h th a lim id es. A
solution of 1 or 2 (7.5 mmol) in anhydrous acetone (25 mL)
was stirred under argon and heated to reflux. A solution of
the appropriate secondary amine (22.5 mmol) in anhydrous
acetone (7 mL) was added dropwise over 10 min. The mixture
was refluxed for additional 15 min and evaporated to dryness.
After addition of 0.25 M HCl (100 mL), the mixture was
vigorously stirred and refluxed for 2 min (10 min in the case
of the reaction with diethylamine). The mixture was kept at 5
°C for 24 h. The precipitate was collected by filtration. For
yields and secondary amines used, see Table 1.
4,5-Dimethyl-2-[(morpholinocarbonyl)amino]benzoic acid (12).
The crude product was partionated between ethyl acetate and
NaHCO3 solution. The aqueous layer was acidified, and the
precipitate was collected by filtration: mp 159-161 °C; IR
1
(KBr) 1674 (br), 1640 (br) cm-1; H NMR δ 2.23 (s, 3H), 2.31
(s, 3H), 3.55-3.61 (m, 4H), 3.75-3.81 (m, 4H), 7.81 (s, 1H),
8.35 (s, 1H), 10.50 (s, 1H). Anal. Calcd for C14H18N2O4: C,
60.42; H, 6.52; N, 10.07. Found: C, 60.13; H, 6.85; N, 9.95.
2-[(Pyrrolidinocarbonyl)amino]benzoic acid (13). The crude
product was purified as described above: mp 169-170 °C; IR
1
(KBr) 1690, 1652 cm-1; H NMR δ 1.96-2.04 (m, 4H), 3.51-
3.59 (m, 4H), 6.96-7.03 (m, 1H), 7.52-7.58 (m, 1H), 8.08 (dd,
1H, J ) 8.0, 1.6 Hz), 8.67 (d, 1H, J ) 8.6 Hz), 10.42 (s, 1H).
Anal. Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96.
Found: C, 61.63; H, 6.11; N, 11.56.
2-(3,3-Diethylureido)benzoic acid (14): mp 133-139 °C,
1
lit.12a mp 151 °C; IR (KBr) 1690, 1644 cm-1; H NMR δ 1.27
(t, 6H, J ) 7.1 Hz), 3.46 (q, 4H, J ) 7.1 Hz), 6.95-7.01 (m,
1H), 7.51-7.57 (m, 1H), 8.08 (dd, 1H, J ) 8.0, 1.6 Hz), 8.64
(d, 1H, J ) 8.6 Hz), 10.59 (s, 1H).
P r ep a r a tion of 2-[(Mor p h olin oca r bon yl)a m in o]ben -
zoic Acid (11) fr om 4-[2-[(Mor p h olin oca r bon yl)a m in o]-

Reactions of N-(Mesyloxy)phthalimides with Secondary Amines
Isatoic anhydride (19): mp >230 °C, dec (ethyl acetate), lit.29
J . Org. Chem., Vol. 64, No. 14, 1999 5115
°C (diethyl ether/petroleum ether), lit.1 mp 46-47 °C; IR (KBr)
mp 243-247 °C; IR (KBr) 1766, 1728, 1618 cm-1
;
1H NMR
1760 cm-1; H NMR δ 1.26 (t, 6H, J ) 7.1 Hz, 3.57 (q, 4H, J
1
(DMSO-d6) δ 7.15 (d, 1H, J ) 8.0 Hz), 7.22-7.28 (m, 1H), 7.71-
7.77 (m, 1H), 7.91 (dd, 1H, J ) 7.9, 1.3 Hz), 11.71 (s, 1H); EIMS
(m/z, %) 163 (M+, 18), 119 (M+ - CO2, 94), 92 (100).
4,5-Dimethylisatoic anhydride (20). After evaporation, the
residue was refluxed with 0.25 M HCl (450 mL): mp 251-
254 °C; IR (KBr) 1778, 1732, 1632 cm-1; 1H NMR (DMSO-d6)
δ 2.24 (s, 3H), 2.30 (s, 3H), 6.92 (s, 1H), 7.67 (s, 1H), 11.57 (s,
1H); EIMS (m/z, %) 191 (M+, 46), 147 (M+ - CO2, 100). Anal.
Calcd for C10H9NO3: C, 62.82; H, 4.74; N, 7.33. Found: C,
62.90; H, 4.93; N, 7.66.
P r ep a r a tion of Isa toic An h yd r id e (19) fr om 2-[(Mor -
p h olin oca r bon yl)a m in o]ben zoic Acid (11). A mixture of
11 (1.88 g, 7.5 mmol) and 0.25 M HCl (100 mL) was vigorously
stirred and refluxed for 2 min. After being kept at 5 °C for 24
h, the preciptate was filtered to obtain 19 (830 mg, 68%).
Gen er a l P r oced u r e for th e P r ep a r a tion of 4H-3,1-
Ben zoxa zin -4-on es fr om 2-Ur eid oben za m id es 4-8. A
mixture of the appropiate 2-ureidobenzamide (3 mmol) and
concd H2SO4 (12 mL) was kept at room temperature for
overnight. It was poured onto a stirred mixture of ice-water,
NaHCO3, and ethyl acetate. After neutralization, the aqueous
layer was further extracted with ethyl acetate. The combined
organic layers were washed with H2O, dried (Na2SO4), and
evaporated to dryness. See Table 2 for yields.
) 7.1 Hz), 7.07-7.13 (m, 1H), 7.22 (d, 1H, J ) 7.2 Hz), 7.55-
7.62 (m, 1H), 8.00 (dd, 1H, J ) 7.9, 1.2 Hz).
Gen er a l P r oced u r e for th e P r ep a r a tion of 4H-3,1-
Ben zoxa zin -4-on es fr om 2-Ur eid oben zoic Acid s 11-14.
A mixture of the appropiate 2-ureidobenzoic acid (2 mmol) and
acetic anhydride (7 mL) was refluxed for 15 min. After cooling,
it was poured onto ice-water (100 mL). The precipitate was
filtered, washed with H2O, and dried. See Table 2 for yields.
Gen er a l P r oced u r e for th e P r ep a r a tion of 4H-3,1-
Ben zoxa zin -4-on es fr om Eth yl 2-Ur eid oben zoa tes 15-
18. A mixture of the appropriate ethyl 2-ureidobenzoate (5
mmol) and concd H2SO4 (5 mL) was kept at room temperature
for 3 h. It was poured onto a mixture of ice-water and
NaHCO3. After neutralization, the precipitate was collected
by fitration, washed with H2O, and dried. See Table 2 for
yields.
2-(N-Methylcyclohexylamino)-4H-3,1-benzoxazin-4-one
(26): mp 127.5-128 °C; IR (KBr) 1766 cm-1; 1H NMR δ 1.04-
1.90 (m, 10H), 3.03 (s, 3H), 4.25-4.40 (m, 1H), 7.06-7.13 (m,
1H), 7.24 (d, 1H, J ) 8.2 Hz), 7.55-7.62 (m, 1H), 7.99 (d, 1H,
J ) 7.9 Hz); EIMS (m/z, %) 258 (M+, 39), 176 (88), 146 (100).
Anal. Calcd for C15H18N2O2: C, 69.74; H, 7.02; N, 10.84.
Found: C, 69.98; H, 6.78; N, 11.15.
6,7-Dimethyl-2-(N-methylcyclohexylamino)-4H-3,1-benzox-
azin-4-one (27): mp 149-150 °C (diethyl ether/petroleum
2-Morpholino-4H-3,1-benzoxazin-4-one (21):5 mp 150.5-
151.5 °C (diethyl ether/petroleum ether), lit.1 mp 150-151 °C;
IR (KBr) 1760 (br) cm-1; 1H NMR δ 3.70-3.83 (m, 8H), 7.12-
7.27 (m, 2H), 7.59-7.66 (m, 1H), 8.02 (dd, 1H, J ) 7.9, 1.3
Hz).
6,7-Dimethyl-2-morpholino-4H-3,1-benzoxazin-4-one (22): mp
161-162 °C (ethyl acetate/petroleum ether); IR (KBr) 1768
cm-1; 1H NMR δ 2.29 (s, 3H), 2.33 (s, 3H), 3.70-3.79 (m, 8H),
7.06 (s, 1H), 7.27 (s, 1H); EIMS (m/z, %) 260 (M+, 82), 174
(100). Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76.
Found: C, 64.72; H, 6.21; N, 10.84.
5,8-Dimethyl-2-morpholino-4H-3,1-benzoxazin-4-one (23).
The mixture of 6 and concd H2SO4 was kept at room temper-
ature for 3 d and poured onto ice-water (150 mL). The
precipitate was collected by filtration, washed with NaHCO3
solution and H2O, and dried: mp: 180-183 °C (ethyl acetate);
IR (KBr) 1738 cm-1; 1H NMR δ 2.35 (s, 3H), 2.67 (s, 3H), 3.71-
3.82 (m, 8H), 6.86 (d, 1H, J ) 7.7 Hz), 7.35 (d, 1H, J ) 7.7
Hz); 13C NMR δ 17.3, 22.5, 44.4, 66.4, 111.0, 125.5, 130.3,
136.3, 140.0, 150.0, 152.5, 159.4; EIMS (m/z, %) 260 (M+, 61),
174 (100). Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N,
10.76. Found: C, 64.36; H, 5.84; N, 10.44.
ether); IR (KBr) 1762 cm-1; H NMR δ 1.03-1.90 (m, 10H),
1
2.27 (s, 3H), 2.31 (s, 3H), 3.00 (s, 3H), 4.24-4.39 (m, 1H), 7.05
(s, 1H), 7.74 (s, 1H); EIMS (m/z, %) 286 (M+, 50), 204 (100),
174 (78). Anal. Calcd for C17H22N2O2: C, 71.30; H, 7.74; N,
9.78. Found: C, 70.90; H, 7.55; N, 9.72.
4-[2-[(Eth oxycar bon yl)am in o]ben zoyl]m or ph olin e (29).
A mixture of 285 (1.15 g, 6 mmol), morpholine (2.1 g, 24 mmol),
and anhydrous acetone (18 mL) was stirred at room temper-
ature for 15 min. After being concentrated to dryness, the
residue was cooled and suspended in n-hexane. The precipitate
was collected by filtration to obtain 29 (1.5 g, 90%): mp 96-
97 °C (ethyl acetate/petroleum ether); IR (KBr) 1726, 1718
cm-1; H NMR δ 1.31 (t, 3H, J ) 7.1 Hz), 3.45-3.80 (m, 8H),
1
4.21 (q, 2H, J ) 7.1 Hz), 7.02-7.08 (m, 1H), 7.16 (dd, 1H, J )
7.7, 1.6 Hz), 7.37-7.43 (m, 1H), 8.12 (d, 1H, J ) 8.0 Hz), 8.12
(s, 1H). Anal. Calcd for C14H18N2O4: C, 60.42; H, 6.52; N, 10.07.
Found: C, 60.12; H, 6.23; N, 9.91.
4-(P h en ylca r b a m oyl)m or p h olin e (32). A solution of
phenyl isocyanate (3 g, 25 mmol) in diethyl ether (22 mL) was
added dropwise to a stirred solution of morpholine (2.18 g, 25
mmol) in diethyl ether (22 mL). The mixture was stirred at
room temperature for 45 min. The precipitate was collected
by filtration and washed with diethyl ether to obtain 32 (5 g,
97%): mp 161-162 °C (EtOH), lit.30 mp 161.5-162 °C; IR
2-Pyrrolidino-4H-3,1-benzoxazin-4-one (24). The mixture of
7 and concd H2SO4 was heated at 80 °C for 8 h: mp 108-109
°C (diethyl ether/petroleum ether), lit.1 mp 116-118 °C; IR
(KBr) 1760 cm-1; 1H NMR δ 1.93-2.01 (m, 4H), 3.55-3.62 (m,
4H), 7.03-7.11 (m, 1H), 7.21 (d, 1H, J ) 8.3 Hz), 7.52-7.60
(m, 1H), 7.97 (d, 1H, J ) 7.7 Hz).
(KBr) 1635 (br) cm-1 1H NMR δ 3.41-3.46 (m, 4H), 3.66-
;
3.70 (m, 4H), 6.63 (s, 1H), 7.00-7.08 (m, 1H), 7.24-7.37 (m,
4H).
2-(Diethylamino)-4H-3,1-benzoxazin-4-one (25). The mixture
of 8 and concd H2SO4 was heated at 80 °C for 3 h: mp 34-35
J O9900634
(29) Clark, R. H.; Wagner, E. C. J . Org. Chem. 1944, 9, 55.
(30) Henry, R. A.; Dehn, W. M. J . Am. Chem. Soc. 1949, 71, 2297.