One-pot neat reactions of carboxylic esters and alkylenediamines for efficient preparation of N-acylalkylenediamines

Full text of DOI:10.1021/jo980830j

J . Org. Chem. 1998, 63, 10015-10017
10015
Sch em e 1
On e-P ot Nea t Rea ction s of Ca r boxylic
Ester s a n d Alk ylen ed ia m in es for Efficien t
P r ep a r a tion of N-Acyla lk ylen ed ia m in es
Wen-Chih Chou,* Chang-Wei Tan,
Shyh-Fong Chen, and Hao Ku
Natural Product & Medicinal Chemistry, Pharmaceutical
R&D Laboratories, Development Center for Biotechnology,
Taipei 106, Taiwan, Republic of China
Received May 1, 1998
The amide unit is one of the most widely occurring
functional groups. It is present as a key feature in many
important natural products and man-made compounds.1
For example (Scheme 1), N-acylalkylenediamines2 are
used to react with 4-amino-2-chloro-6,7-dimethoxyquinazo-
lines to give a variety of antihypertensive agents.3
Though the direct conversion of esters to amides has been
reported, the previous application of this method is
somewhat limited because it requires solvent and special
reagents such as sodium methoxide,4 sodium hydride,5
sodium metal,6 potassium amide,7 butyllithium,5 Grig-
nard reagents,8 lithium aluminum hydride,9 and silicon
tetrachloride,10 which may interfere with other functional
groups in the molecule. Milder catalysts such as 2-pyri-
done11 and boron tribromide12 have also been used;
however, the generality of these reactions has not been
examined. Another method using activated amines such
as tin,13 titanium14 and aluminum15 amides has been
addressed; however, no practical technique is available
for the synthesis of tertiary amides. Furthermore, there
is no precedent synthesis of N-acylalkylenediamines by
direct monoamidation of esters. Monoamidation of alky-
lenediamines with an acid chloride has been reported for
the preparation of N-acylalkylenediamines; however, the
reaction requires appropriately mask diamines such as
monoacetates or hydrogen halides.2,3 Otherwise, undes-
ired diamidation can also occur. An alternative approach
by conversion of esters to N-acylalkylenediamines is
worthwhile. We report herein a convenient and efficient
monoamidation, even for the preparation of tertiary
amides, by one-pot neat reaction of carboxylic esters with
a variety of alkylenediamines. The yields of N-acylalky-
lenediamines were thus greatly improved.
As shown in Table 1, we prepared N-acylalkylenedi-
amine 3, a useful precursor of the popular antihyperten-
sive drug Doxazosin, in 94% yield by heating ethyl 2,3-
dihydrobenzo[1,4]dioxin-2-carboxylate (1a) with piperazine
(2a ) under reflux for 3 h. Only 1 equiv of ethanol was
released in this clean transformation. The amide 3 was
readily obtained by simple acid-base extraction. No
diamide was formed. A previous preparation of 3 (61%
yield) requires a tedious procedure: (i) saponification of
the ester 1a , (ii) treatment of the resulting acid with
SOCl2 to give the acid chloride, and (iii) amidation with
piperazine hydrobromide in MeOH. Our present method
is obviously superior in terms of high yield and simple
operation.
We also examined the effects of solvents and additives.
However, no desired amidation occurred on treatment of
the ester 1a with piperazine in refluxing THF, CH3CN,
DMF, or benzene for several hours in the presence of
sodium methoxide. Heating at higher temperature in a
sealed tube for prolonged duration only caused saponi-
fication of 1a to give the corresponding carboxylic acid.
Thus, the amidation is best performed with neat sub-
strates, without addition of any base, catalyst, or solvent.
To demonstrate the general utility of this procedure,
we also prepared N-acylalkylenediamines 4-12 (Table
1) in satisfactory yields. Compounds 4-9 are especially
useful in the synthesis of generic antihypertensive drugs,
Prazosin, Terazosin, Neldazosin, Metazosin, Bunazosin,
(1) (a) Beckwith, A. L. J . In The Chemistry of Amides: Synthesis of
Amides; Zabicky, J ., Ed.; Interscience: New York, 1970; p 96. (b) North,
M. Contemp. Org. Synth. 1994, 1, 475.
(2) (a) Koo, J .; Avakian, S.; Martin, G. J . J . Am. Chem. Soc. 1955,
77, 5373. (b) Desai, M.; Watthey, J . W. H.; Zuckerman, M. Org. Prep.
Proced. Int. 1976, 8, 85. (c) Butora, G.; Blaha, L.; Rajsner, M.; Helfert,
I. Collect. Czech. Chem. Commun. 1992, 57, 1967. (d) Boschi, D.; Stilo,
A. D.; Fruttero, R.; Medana, C.; Sorba, G.; Gasco, A. Arch. Pharm.
(Weinheim Ger.) 1994, 327, 661. (e) Novelli, F.; Sparatore, F. Farmaco.
1996, 51, 551.
(3) (a) Althuis, T. H.; Hess, H.-J . J . Med. Chem. 1977, 20, 146. (b)
Manoury, P. M.; Binet, J . L.; Dumas, A. P.; Lefevre-Borg, F.; Cavero,
I. J . Med. Chem. 1986, 29, 19. (c) Campbell, S. F.; Davey, M. J .;
Hardstone, J . D.; Lewis, B. N.; Plamer, M. J . J . Med. Chem. 1987, 30,
49. (d) Hokanen, E.; Pippuri, A.; Kairisalo, P.; Thaler, H.; Kolvisto,
M.; Taomi, S. J . Heterocycl. Chem. 1980, 17, 797. (e) Hess, H.-J . U.S.
Pat. 3,511,836, 1970. (f) Winn, M.; Kyncl, J . U.S. Pat. 4,093,726, 1978.
(g) Partyka, R. A.; Crenshaw, R. R. U.S. Pat. 4,001,237 and 4,001,-
238, 1977. (h) Campell, S. F. U.S. Pat. 4,188,390, 1980. (i) Manoury,
P. M. U.S. Pat. 4,315,007, 1982. (j) Roteman, R. U.S. Pat. 4,251,532,
1981. (k) Igarashi, T. Eur. Pat. 0,209,089, 1986. (l) Schlager, L. H. Eur.
Pat. 0,225,886, 1986. (m) Konig, J . Ger. Pat. 3,419, 223, 1984.
(4) (a) Russel, P. B. J . Am. Chem. Soc. 1950, 72, 1853. (b) De Feo,
R. J .; Strickler, P. D. J . Org, Chem. 1963, 28, 2915.
(5) (a) Yang, K. W.; Cannon, J . G.; Rose, J . G. Tetrahedron Lett.
1970, 1791. (b) Singh, B. Tetraherdron Lett. 1971, 321.
(6) Stern, E. S. Chem. Ind. (London) 1956, 277.
(7) Levi, E. M.; Mao, C. L.; Hauser, C. R. Can. J . Chem. 1969, 47,
3761.
(8) (a) Bodroux, F. Bull. Chim. Fr. 1905, 33, 831. (b) Holley, R. W.;
Holly, A. W. J . Am. Chem. Soc. 1949, 71, 2124, 2129. (c) Basstee, H.
L.; Thomas, C. R. J . Chem. Soc. 1954, 1188. (d) Houghton, R. P.;
Willams, C, S. Tetrahedron Lett. 1967, 3929.
(9) Evans, D. A. Tetradehron Lett. 1969, 1573.
(10) Chan, T. H.; Wong L. T. L. J . Org. Chem. 1969, 34, 2766.
(11) Openshaw, H. I.; Whittaker, N. J . Chem. Soc. C 1969, 89.
(12) Yazawa, H.; Tanaka, K.; Kariyone, K. Tetrahedron Lett. 1974,
3995.
(13) Wang, W.-B.; Roskamp, E. J . J . Org. Chem. 1992, 57, 6101.
(14) (a) George, T. A.; Lappert, M. P. J . Chem. Soc. A 1969, 992. (b)
Chandra, G.; George, T. A.; Lappert, M. P. J . Chem. Soc. C 1969, 2565.
(15) (a) Basha, A,; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 4171. (b) Rao, V. B.; George, C. F.; Wolff, S.; Agosta, W. C. J .
Am. Chem. Soc. 1985, 107, 5732. (c) Hart, D. J .; Hong, W.-P.; Hsu,
L.-Y. J . Org. Chem. 1987, 52, 4665. (d) Dolle, R. E.; Nicolaou, K. C. J .
Am. Chem. Soc. 1985, 107, 1695.
10.1021/jo980830j CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/08/1998

10016 J . Org. Chem., Vol. 63, No. 26, 1998
Notes
Ta ble 1. P r ep a r a tion of N-Acyla lk ylen ed ia m in esa
1
spectra were recorded at an ionizing voltage 70 eV. H and 13C
NMR spectra were measured at 500 and 125 MHz, respectively.
Ester 1a was prepared from catechol and ethyl 2,3-dibro-
mopropionate according to reported procedure.2a Esters 1b and
1c were prepared by Fischer esterification of the corresponding
carboxylic acids, other esters 1d -g are commercially available.
N -(2,3-Dih yd r ob e n zo[1,4]d ioxin -2-ca r b on yl)p ip e r a -
zin e (3). Under a nitrogen atmosphere, ethyl 2,3-dihydrobenzo-
[1,4]dioxin-2-carboxylate (1a ) (31.20 g, 150 mmol) and piperazine
(2a ) (15.48 g, 180 mmol) were heated at 110 °C for 3 h. After
cooling the reaction to room temperature, the mixture was
partitioned between CHCl3 and saturated aqueous NaHCO3. The
organic layer was washed with water and then dried over Na2-
SO4. The extract was concentrated and chromatographed on a
silica gel column (EtOAc/MeOH/Et3N, 7:3:1) to give the amide
3 (34.96 g, 94%):16 solid; mp 84-85 °C; TLC (EtOAc/MeOH/Et3N,
7:3:1) Rf 0.32; IR (KBr) 3430, 1642 cm-1; MS m/z (rel intensity)
248 (30, M+), 111 (100); 1H NMR (CDCl3) δ 2.20 (s, 1 H, NH),
2.90-2.95 (m, 2 H), 2.95-3.00 (m, 2 H), 3.56-3.61 (m, 2 H),
3.75-3.82 (m, 2 H), 4.37 (dd, J ) 11.9, 8.2 Hz, 1 H), 4.53 (dd, J
) 11.9, 2.5 Hz, 1 H), 4.87 (dd, J ) 8.2, 2.5 Hz, 1 H), 6.88-6.96
(m, 4 H); 13C NMR (CDCl3) δ 43.2 (t), 45.8 (t), 46.4 (t), 47.0 (t),
65.2 (t), 70.5 (d), 117.3 (d), 117.4 (d), 121.5 (d), 122.2 (d), 142.6
(s), 143.3 (s), 164.8 (s); HRMS for C13H16N2O3 calcd 248.1161,
found 248.1152. Anal. Calcd for C13H16N2O3: C, 62.89; H, 6.50;
N, 11.28. Found: C, 62.73; H, 6.56; N,11.21.
N-(F u r a n -2-ca r bon yl)p ip er a zin e (4) a n d N,N′-Bis(fu r a n -
2-ca r bon yl)p ip er a zin e (4′). Under a nitrogen atmosphere,
ethyl furan-2-carboxylate (1b) (0.71 g, 5 mmol) and piperazine
(2a ) (1.29 g, 15 mmol) were heated at 110 °C for 3 h. After cooling
the reaction to room temperature, the residue was extracted with
CH2Cl2 and 0.5 N HCl. The aqueous layer was adjusted to pH
10 with saturated aqueous K2CO3, followed by extraction with
CHCl3. The organic layer was washed with water and then dried
over Na2SO4. The extract was concentrated and chromato-
graphed on a silica gel column (EtOAc/MeOH/Et3N, 7:3:1) to give
the amide 4 (0.80 g, 89%). The CH2Cl2 layer was washed with
saturated aqueous NaHCO3 and water and dried over Na2SO4.
Concentration gave diamide 4′ (0.08 g, 6%). Amide 4: solid; mp
68-69 °C (lit.3a mp 67-68 °C); TLC (EtOAc/MeOH/Et3N, 7:3:1)
Rf 0.26; IR (KBr) 3442, 1620 cm-1; MS m/z (rel intensity) 180
(54, M+), 95 (100); 1H NMR (CDCl3) δ 2.27 (br s, 1 H, NH), 2.92-
2.96 (m, 4 H), 3.79 (br s, 4 H), 6.49 (dd, J ) 3.5, 1.8 Hz, 1 H),
7.00 (dd, J ) 3.5, 0.8 Hz, 1 H), 7.50 (dd, J ) 1.8, 0.8 Hz, 1 H);
13C NMR (CDCl3, -50 °C) δ 43.3 (t), 45.7 (t), 46.3 (t), 47.7 (t),
111.4 (d), 116.4 (d), 144.2 (d), 146.8 (s), 159.2 (s); HRMS for
C9H12N2O2 calcd 180.0899, found 180.0900. Anal. Calcd for
C9H12N2O2: C, 59.99; H, 6.71; N, 15.55. Found: C, 59.81; H,
6.69; N, 15.48. Diamide 4′: solid; mp 127-128 °C; TLC (EtOAc/
hexane, 7:3) Rf 0.19; IR (KBr) 1628 cm-1; MS m/z (rel intensity)
a
The reaction was conducted by heating a mixture of ester and
diamine at 110 °C for the indicated duration. No solvent is used.
A small amount of diamide (3-6%) was also produced.
b
and Alfuzosin. In each reaction, appropriate ester and
diamine (1.2-2.0 equiv) were refluxed for several hours
to give the desired N-acylalkylenediamines 4-12 in
nearly pure form. The reactions proceeded smoothly with
aliphatic or aromatic esters including the substrates
bearing oxy substituents at the R- or â-positions. All of
the examined acyclic and cyclic diamines were suitable
to the monoamidation reactions, even the hydroxyl group
on the side chain of piperazine did not interfere with this
reaction (entry 8). The primary amine appeared to have
higher reactivity than the secondary amine in the ami-
dation (entries 7 and 9). A small amount of diamide (3-
6%) could be formed in case a more reactive aromatic
ester was used as the starting material (entries 2 and
10). Fortunately, the side product could be removed by
simple extraction. Because ethyl thiophene-2-carboxylate
did not mix well with piperazine even at a higher
temperature (150 °C) in a sealed tube, the yield of amide
12 was not optimized (entry 10). It was noted that the
four carbons on the piperazine ring of 4 or 12 underwent
fast equilibrium in CDCl3 solution at room temperature,
presumably due to the restricted rotation of the amide
bond. However, these carbons could be resolved when the
13C NMR spectra were recorded at -50 °C.
1
274 (5, M+), 69 (100); H NMR (CDCl3) δ 3.90 (br s, 8 H), 6.51
(dd, J ) 3.4, 1.8 Hz, 2 H), 7.08 (d, J ) 3.5 Hz, 2 H), 7.51 (d, J )
1.8 Hz, 2 H); 13C NMR (CDCl3, -50 °C) δ 42.5 (t), 42.9 (t), 46.4
(t), 46.9 (t), 111.8 (d, 2 C), 117.6 (d, 2 C), 144.5 (d), 144.6 (d),
146.8 (s), 146.9 (s), 159.2 (s), 159.3 (s); HRMS for C14H14N2O4
calcd 274.0954, found 274.0943. Anal. Calcd for C14H14N2O4: C,
61.31; H, 5.14; N, 10.21. Found: C, 61.35; H, 5.17; N, 10.15.
N-(Tetr a h yd r ofu r a n -2-ca r bon yl)p ip er a zin e (5). By a pro-
cedure similar to that for 3, a mixture of methyl tetrahydrofuran-
2-carboxylate (1c) (6.50 g, 50 mmol) and piperazine (2a ) (5.16
g, 60 mmol) were heated at 110 °C for 5 h to give the amide 3
(8.37 g, 91%): oil; TLC (EtOAc/MeOH/Et3N, 7:3:1) Rf 0.30; IR
(neat) 3464, 1639 cm-1; MS m/z (rel intensity) 184 (10, M+), 71
1
(100); H NMR (CDCl3) δ 1.87-1.91 (m, 1 H), 1.93-2.07 (m, 2
H), 2.22-2.27 (m, 1 H), 2.45 (s, 1 H, NH), 2.85-2.91 (m, 4 H),
3.48-3.57 (m, 2 H), 3.60-3.69 (m, 2 H), 3.86-3.90 (m, 1 H),
3.93-3.99 (m, 1 H), 4.61 (dd, J ) 7.3, 5.4 Hz, 1 H); 13C NMR
(CDCl3) δ 25.6 (t), 28.4 (t), 43.0 (t), 45.8 (t), 46.2 (t), 46.6 (t),
68.9 (t), 75. 6 (d), 169.8 (s); HRMS for C9H16N2O2 calcd 184.1212,
found 184.1220. Anal. Calcd for C9H16N2O2: C, 58.67; H, 8.75;
N, 15.20. Found: C, 58.46; H, 8.77; N, 15.29.
In summary, we have demonstrated a general and
efficient method of one-pot neat amidation. The operation
is simple. The desired secondary and tertiary amides are
prepared in high yields for further elaboration to anti-
hypertensive agents.
N-(3-Hyd r oxybu tyr yl)p ip er a zin e (6). By a procedure simi-
lar to that for 3, a mixture of ethyl 3-hydroxybutyrate (1d ) (3.56
Exp er im en ta l Section
All reactions were carried out under a nitrogen atmosphere.
Merck silica gel 60 F-254 sheets were used for analytical TLC.
Column chromatography was conducted on silica gel 60 (Merck,
70-230 mesh ASTM). Melting points were uncorrected. Mass
(16) For an actual application, the extract was concentrated and
used in the subsequent coupling reaction for preparation to give
Doxazosin. The U.S and R.O.C. patent applications are under review.

Notes
J . Org. Chem., Vol. 63, No. 26, 1998 10017
g, 27 mmol) and piperazine (2a ) (3.44 g, 40 mmol) were heated
at 110 °C for 10 h to give the amide 6 (4.18 g, 90%): yellow oil;
TLC (EtOAc/MeOH/Et3N, 7:3:1) Rf 0.18; IR (neat) 3412, 1624;
MS m/z (rel intensity) 172 (8, M+), 69 (100); 1H NMR (CDCl3) δ
1.23 (d, J ) 6.4 Hz, 3 H), 2.31 (dd, J ) 16.4, 9.6 Hz, 1 H), 2.49
(dd, J ) 16.4, 2.4 Hz, 1 H), 2.83-2.88 (m, 4 H), 3.08 (br s, 2 H,
NH and OH), 3.40-3.44 (m, 2 H), 3.55-3.62 (m, 1 H), 3.61-
3.67 (m, 1 H), 4.21 (ddq, J ) 9.6, 6.4, 2.4 Hz, 1 H); 13C NMR
(CDCl3) δ 22.3 (q), 40.8 (t), 42.3 (t), 45.6 (t), 46.0 (t), 46.3 (t),
64.0 (d), 170.8 (s); HRMS for C8H16N2O2 calcd 172.1212, found
172.1217. Anal. Calcd for C8H16N2O2: C, 55.79; H, 9.36; N, 16.27.
Found: C, 55.51; H, 9.42; N, 16.19.
2.50-2.55 (m, 1 H), 2.56-2.64 (m, 5 H), 3.60-3.65 (m, 2 H),
3.66-3.70 (m, 2 H), 3.79-3.85 (m, 2 H), 4.33 (dd, J ) 11.9, 8.1
Hz, 1 H), 4.48 (dd, J ) 11.9, 2.2 Hz, 1 H), 4.83 (dd, J ) 8.1, 2.2
Hz, 1 H), 6.85-6.93 (m, 4 H); 13C NMR (CDCl3) δ 42.0 (t), 45.7
(t), 52.5 (t), 53.2 (t), 57.9 (t), 59.4 (t), 65.2 (t), 70.6 (d), 117.3 (d),
117.4 (d), 121.5 (d), 122.2 (d), 142,5 (s), 143.3 (s), 164.8 (s); HRMS
for C15H16N2O4 calcd 292.1423, found 292.1420. Anal. Calcd for
C15H16N2O4: C, 62.49; H, 5.59; N, 9.72. Found: C, 62.28; H, 5.62;
N, 9.70.
N-[2-(Meth yla m in o)eth yl]-2,3-d ih yd r oben zo[1,4]d ioxin -
2-ca r boxa m id e (11). By a procedure similar to that for 3, a
mixture of ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxylate (1a )
(2.08 g, 10 mmol) and 3-(methylamino)ethylamine (2e) (0.89 g,
12 mmol) were heated at 110 °C for 3 h to give the amide 11
(2.34 g, 99%): solid; mp 60-61 °C; TLC (EtOAc/MeOH/Et3N,
7:3:1) Rf 0.26; IR (KBr) 3382, 1677 cm-1; MS m/z (rel intensity)
N-(2-Meth oxyp r op ion yl)p ip er a zin e (7). By a procedure
similar to that for 3, a mixture of methyl 2-methoxypropionate
(1e) (1.18 g, 10 mmol) and piperazine (2a ) (1.29 g, 15 mmol)
were heated at 110 °C for 6 h to give the amide 7 (1.55 g, 90%):
yellow oily solid; TLC (EtOAc/ MeOH/ Et3N, 7:3:1) Rf 0.26; IR
(neat) 3495, 1635 cm-1; MS m/z (rel intensity) 172 (11, M+), 59
(100); 1H NMR (CDCl3) δ 1.43 (d, J ) 6.8 Hz, 3 H), 2.00 (s, 1 H,
NH), 2.89-2.98 (m, 4 H), 3.39 (s, 3 H), 3.64-3.70 (m, 4 H), 4.19
(q, J ) 6.8 Hz, 1 H); 13C NMR (CDCl3) δ 17.5 (q), 42.8 (t), 45.8
(t, 2 C), 46.1 (t), 56.6 (q), 76.8 (d), 170.4 (s); HRMS for C8H16N2O2
calcd 172.1212, found 172.1208. Anal. Calcd for C8H16N2O2: C,
55.79; H, 9.36; N, 16.27. Found: C, 55.57; H, 9.20; N, 16.33.
N-(Bu tyr yl)h om op ip er a zin e (8). By a procedure similar to
that for 3, a mixture of methyl butyrate (1f) (3.06 g, 30 mmol)
and homopiperazine (2b) (4.51 g, 45 mmol) were heated at 110
°C for 6 h to give the amide 8 (4.69 g, 92%): yellow oil; TLC
1
236 (2, M+), 57 (100); H NMR (CDCl3) δ 1.90 (br s, 1 H, NH),
2.43 (s, 3 H), 2.72-2.81 (m, 2 H), 3.41-3.49 (m, 2 H), 4.23 (dd,
J ) 11.4, 7.2 Hz, 1 H), 4.55 (dd, J ) 11.4, 2.7 Hz, 1 H), 4.71 (dd,
J ) 7.2, 2.7 Hz, 1 H), 6.89-6.94 (m, 3 H), 6.98-7.02 (m, 1 H),
7.16 (br s, 1 H); 13C NMR (CDCl3) δ 35.9 (q), 38.4 (t), 50.3 (t),
65.3 (t), 73.2 (d), 117.2 (d), 117.5 (d), 121.8 (d), 122.2 (d), 141.7
(s), 143.2 (s), 167.3 (s); HRMS for C12H16N2O3 calcd 236.1161,
found 236.1167. Anal. Calcd for C12H16N2O3: C, 61.00; H, 6.83;
N, 11.86. Found: C, 60.86; H, 6.81; N, 11.81.
N-(Th iop h en e-2-ca r bon yl)p ip er a zin e (12) a n d N,N′-Bis-
(t h iop h en e-2-ca r b on yl)p ip er a zin e (12′). By a procedure
similar to that for 4 and 4′, a mixture of ethyl thiophene-2-
carboxylate (1g) (1.56 g, 10 mmol) and piperazine (2a ) (1.72 g,
20 mmol) were heated at 110 °C for 16 h to give the amide 12
(1.18 g, 60%) and the diamide 12′ (0.10 g, 3%). Amide 12: yellow
oily solid; TLC (EtOAc/MeOH/Et3N, 7:3:1) Rf 0.27; IR (neat)
3449, 1613 cm-1; MS m/z (rel intensity) 196 (8, M+), 111 (100);
1H NMR (CDCl3) δ 2.08 (s, 1 H, NH), 2.89-2.93 (m, 4 H), 3.70-
3.74 (m, 4 H), 7.04 (dd, J ) 5.1, 3.7 Hz, 1 H), 7.28 (dd, J ) 3.7,
1.1 Hz, 1 H), 7.44 (dd, J ) 5.1, 1.1 Hz, 1 H); 13C NMR (CDCl3,
-50 °C) δ 43.5 (t), 45.6 (t), 46.3 (t), 48.9 (t), 126.9 (d), 128.9 (d),
129.1 (d), 136.6 (s), 163.7 (s); HRMS for C9H12N2OS calcd
196.0670, found 196.0668. Anal. Calcd for C9H12N2OS: C, 55.08;
H, 6.16; N, 14.27. Found: C, 54.89; H, 6.36; N, 14.41. Diamide
12′: solid; mp 177-178 °C; TLC (EtOAc/hexane, 7:3) Rf 0.32;
IR (KBr) 1602 cm-1; MS m/z (rel intensity) 306 (8, M+), 111 (100);
1H NMR (CDCl3) δ_3.84 (br s, 8 H), 7.09 (dd, J ) 4.8, 3.8 Hz, 2
H), 7.34 (d, J ) 3.8 Hz, 2 H), 7.50 (d, J ) 4.8 Hz, 2 H); 13C NMR
(CDCl3, -50 °C) δ 42.5 (t), 43.1 (t), 47.6 (t), 48.2 (t), 127.2 (d),
127.3 (d), 129.4 (d), 129.5 (d), 129.8 (d), 130.0 (d), 136.2 (s, 2 C),
164.0 (s, 2 C); HRMS for C14H14N2O2 S2 calcd 306.0497, found
306.0511. Anal. Calcd for C14H14N2O2S2: C, 54.88; H, 4.61; N,
9.14. Found: C, 54.89; H, 4.65; N, 9.05.
(EtOAc/MeOH/Et3N, 7:3:1) Rf 0.35; IR (neat) 3427, 1628 cm-1
;
MS m/z (rel intensity) 170 (100, M+); 1H NMR (CDCl3) δ 0.97 (t,
J ) 5.1 Hz, 3 H), 1.64-1.71 (m, 2 H), 1.75-1.84 (m, 2 H), 1.90
(s, 1 H, NH), 2.27-2.33 (m, 2 H), 2.85-2.89 (m, 2 H), 2.92-2.97
(m, 2 H), 3.46-3.50 (m, 1 H), 3.53-3.57 (m, 1 H), 3.58-3.64 (m,
2 H); 13C NMR (CDCl3) {the sample existed as a mixture of two
rotatomers (1:1)} δ 13.9 (q, 2 C), 18.5 (t), 18.6 (t), 29.5 (t), 30.8
(t), 34.9 (t), 35.1 (t), 44.5 (t), 46.8 (t), 47.6 (t), 48.4 (t), 48.6 (t),
48.9 (t), 50.1 (t), 50.8 (t), 172.4 (s), 172.5 (s); HRMS for C9H18N2O
calcd 170.1419, found 170.1422. Anal. Calcd for C9H18N2O: C,
63.49; H, 10.66; N, 16.45. Found: C, 63.44; H, 10.70; N, 16.52.
N-[3-(Meth yla m in o)p r op yl]tetr a h yd r ofu r a n -2-ca r boxa -
m id e (9). By a procedure similar to that for 3, a mixture of
methyl tetrahydrofuran-2-carboxylate (1c) (1.30 g, 10 mmol) and
3-(methylamino)propylamine (2c) (1.76 g, 20 mmol) were heated
at 110 °C for 4 h to give the amide 9 (1.54 g, 83%): yellow oil;
TLC (EtOAc/MeOH/Et3N, 7:3:1) Rf 0.18; IR (neat) 3419, 1658
cm-1; MS m/z (rel intensity) 186 (10, M+), 71 (100); 1H NMR
(CDCl3) δ 1.63-1.68 (m, 2 H), 1.73 (br s, 1 H, NH), 1.81-1.89
(m, 2 H), 1.98-2.05 (m, 1 H), 2.17-2.26 (m, 1 H), 2.39 (s, 3 H),
2.57-2.64 (m, 2 H), 3.26-3.34 (m, 2 H), 3.80-3.85 (m, 1 H),
3.86-3.91 (m, 1 H), 4.30 (dd, J ) 8.4, 5.7 Hz, 1 H), 7.22 (br s, 1
H, NH); 13C NMR (CDCl3) δ 25.4 (t), 28.9 (t), 30.2 (t), 36.1 (q),
37.3 (t), 49.6 (t), 69.2 (t), 78.4 (d), 173.2 (s); HRMS for C9H18N2O2
calcd 186.1368, found 186.1360. Anal. Calcd for C9H18N2O2: C,
58.04; H, 9.74; N, 15.04. Found: C, 57.86; H, 9.68; N, 15.09.
N-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ca r b on yl)-N′-(2-h y-
d r oxyeth yl)p ip er a zin e (10). By a procedure similar to that
for 3, a mixture of ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxy-
late (1a ) (2.08 g, 10 mmol) and 2-hydroxyethylpiperazine (2d )
(1.56 g, 12 mmol) were heated at 110 °C for 3 h to give the amide
10 (2.86 g, 98%): solid; mp 61-62 °C; TLC (EtOAc/MeOH/Et3N,
7:3:1) Rf 0.33; IR (KBr) 3449, 1646 cm-1; MS m/z (rel intensity)
292 (6, M+), 261 (100); 1H NMR (CDCl3) δ 1.62 (br s, 1 H, OH),
Ack n ow led gm en t. Financial support from the Min-
istry of Economic (grant *87-EC-2-A-17-0182) is grate-
fully acknowledged. We also thank Prof. J im-Min Fang
(National Taiwan University) for his helpful discussion.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for compounds 3-12 (24 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O980830J