A New Method for Synthesis of Unsymmetrical Ureas Using Electrochemically Prepared Trifluoroethyl Carbamates

Full text of DOI:10.1021/jo991076k

J . Org. Chem. 2000, 65, 1549-1551
1549
Ta ble 1. P r ep a r a tion of Un sym m etr ica l Ur ea s 1
A New Meth od for Syn th esis of
2
3
Un sym m etr ica l Ur ea s Usin g
Electr och em ica lly P r ep a r ed Tr iflu or oeth yl
Ca r ba m a tes
R R NH
NaH
entry
4
(2.0 equiv)
(equiv)
yield of 1 (%)a
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
n-BuNH2
n-BuNH2
0
1a a
1a a
1a b
1a c
1a d
1a e
1a f
1a g
1bb
1cb
1d b
0b
86
81
2.0
1.1
1.1
2.0
2.0
2.0
2.0
1.1
1.1
1.1
Yoshihiro Matsumura,*,† Yuki Satoh,‡
Osamu Onomura, and Toshihide Maki
piperidine
piperazinec
morpholine
allylamine
66
80
42
27
0
d
‡
‡
Institute for Fundamental Research of Organic Chemistry,
Kyushu University, 6-10-1 Hakozaki, Higashi-ku,
Fukuoka 812-8581, and Faculty of Pharmaceutical Sciences,
Nagasaki University, 1-14 Bunkyo-machi,
(S)-phenethylamine
diisopropylamine
piperidine
piperidine
piperidine
93
91
97
Nagasaki 852-8521, J apan
10
1
1
Received J uly 6, 1999
a
Isolated yield. b Starting material was recovered. c 1.1 equiv
to 4a . d The yield is determined after the acetylation of 1a c.
Substituted ureas have attracted much attention be-
cause of their important biological activities, and thus
1
there have been a variety of the synthetic methods.2
However, most of the methods are limited to the prepa-
ration of symmetrical ureas and have the drawback that
highly toxic reagents such as phosgene must be used. On
the other hand, some methods applicable to the prepara-
tion of unsymmetrical ureas 1 without the use of any
tert-butoxy group, would make the method more useful
for the synthesis of substituted ureas in respect to the
applicability and selectivity. This paper describes a
successful result using trifluoroethyl carbamates 4, which
were easily obtained by our recently reported method (the
electrochemically induced Hofmann rearrangement of
3
8
toxic reagent have been devised. One promising methods
amides 6). The transformation of amides 6a -f to 4a -f
as examples are shown in eq 2.
4
is to use an aminolysis of alkoxycarbonylated amines
5
in which the OR group is a phenoxy (2) or tert-butoxy
6
group (3) (eq 1).
Because the OR group works as a leaving group to gen-
erate an isocyanate 5 as an intermediate from alkoxy-
carbonylated amines, the rate of aminolysis may depend
on the ability of OR as a leaving group. Thus, we
supposed that a new alkoxy group, possessing an ability
as a leaving group different from that of a phenoxy or
Aminolysis of 4a -d thus obtained was carried out
under several reaction conditions, and the results are
shown in Table 1 , which indicates the following features.
The absence of NaH did not give ureas 1a a (entry 1). On
the other hand, a variety of unsymmetrical ureas 1a a -
a e, bb, cb, and d b were obtained in good to moderate
yields by the reaction of 4a -d with primary and second-
ary amines such as n-butylamine, piperidine, piperazine,
morpholine, and allylamine in the presence of NaH
(entries 2-6, 9-11), whereas bulky amines such as
7
*
Tel (Fax): +81-95-843-2442. E-mail: matumura@ms.ifoc.kyushu-
u.ac.jp.
†
Kyushu University.
Nagasaki University.
‡
(1) (a) Vishnyakowa, T. P.; Golubeva, I. A.; Glebova, E. V. Russ.
Chem. Rev. (Engl. Transl.) 1985, 54, 249. (b) Getman, D. P.; De-
Crescenzo, G. A.; Heintz, R. M.; Reed, K. L.; Tally, J . J .; Bryant, M.
L.; Clare, M.; Houseman, K. A.; Marr, J . J .; Mueller, R. A.; Vazquez,
M. L.; Shieh, H.-S.; Stallings, W. C.; Stegeman, R. A. J . Med. Chem.
1
-phenethylamine or diisopropylamine gave the desired
product 1a f in low yield (entry 7) or did not afford the
desired urea 1a g (entry 8).
1
993, 36, 288. (c) Matsuda, K. Med. Res. Rev. 1994, 14, 271.
2) Peterson, U. In Methoden der Organischen Chemie, Houben-
(
To use our new method conveniently in organic syn-
thesis, it is necessary to clarify the advantage of 4 or the
differences with the methods using 2 and 3. In this
respect, the reactivity of 4a was compared with those of
2a and 3a and also with those of methyl (7a ) and benzyl
carbamates (8a ) in the reaction with piperidine (eq 3).
Table 2 summarizes the results of those competitive
reactions, which show that 4a was more reactive than
Weyl, E4; G. Thieme Verlag: New York, 1983; p 334. (b) Majer, P.;
Randad, R. S. J . J . Org. Chem. 1994, 59, 1937. (c) Katritzky, A. R.;
Pleynet, D. P. M.; Yahg, B. J . Org. Chem. 1997, 62, 4155. (d) Sonoda,
N.; Yasuhara, T.; Kondo, K.; Tsutsumi, S. J . Am. Chem. Soc. 1971,
9
3
3, 691. (e) Yamazaki, N.; Iguchi, T.; Higashi, F. Tetrahedron 1975,
1, 3031.
(3) (a) Ozaki, S. Chem. Rev. 1972, 72, 457-496. (b) Reichen, W. Helv.
Chim. Acta 1977, 60, 498-506. (c) Kn o¨ lker, H.-J .; Braxmeier, T.;
Schlechtingen, G. Synlett 1996, 503. (d) Batey, R. A.; Santhakumar,
V.; Y.-Ishii, C.; Taylor, S. D. Tetrahedron Lett. 1998, 39, 6267.
(
(
4) Basha, A. Tetrahedron Lett. 1988, 29, 2525.
5) (a) Adamiak, R. W.; Stawi n˜ ski, J . Tetrahedron Lett. 1977, 22,
3
a (entry 2), 7a (entry 3), and 8a (entry 4) but was less
1
5
935. (b) Thavonekham, B. Synthesis 1997, 1189.
6) Lamothe, M.; Perez, M.; C-Gotteland, V.; Halazy, S. Synlett 1996,
07.
7) The kinetic study on the leaving ability of trifluoroethoxy group
reactive than 2a (entry 1). The difference in the reac-
(
(
(8) (a) Matsumura, Y.; Maki, T.; Satoh, Y. Tetrahedron Lett. 1997,
38, 8879. (b) Matsumura, Y.; Maki, T.; Satoh, Y.; Onomura, O.
Electrochim. Acta 2000, in press.
has already been reported; Aquirre, I. De; Collot, J . Bull. Soc. Chim.
Belg. 1989, 98, 19.
1
0.1021/jo991076k CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/09/2000

1
550 J . Org. Chem., Vol. 65, No. 5, 2000
Notes
Ta ble 2. Com p a r ison of th e Rea ctivity of 4a w ith th a t of
2
a , 3a , 7a , or 8a
entry recoveries of 4a , 2a , 3a , 7a , or 8a (%) yielda of 1a b (%)
1
2
3
4
75 (4a )
0 (4a )
3 (4a )
4 (4a )
0 (2a )
87 (3a )
89 (7a )
90 (8a )
81
69
83
74
a
The yields of urea were based on the amount of piperidine.
Sch em e 1
tivities of those carbamates is explainable in terms of the
acidity of phenol, 2,2,2-trifluoroethanol, and normal
alcohols.9
Furthermore, the competitive reaction between 3a and
a showed that 3a was more reactive than 7a (eq 4). Also,
reactivities different from that of phenyl and tert-butyl
carbamates.
7
Exp er im en ta l Section
Gen er a l. All solvents were dried by standard techniques.
Sodium hydride, n-butylamine, piperidine, piperazine, morpho-
line, allylamine, 1-phenethylamine, diisopropylamine, carboxa-
mides 6a -d , and â-alaninamide hydrochloride were commer-
cially available. Compounds 6e,f were prepared according to
conventional known methods as shown below. 2,2,2-Trifluoro-
ethyl carbamates 4a -f were prepared according to the reported
8
method by us. Ureas 1bb (39531-35-6) and 1d b (2645-36-5) are
known compounds.11
3
-Ben zyloxyca r bon yla m in op r op a n oxa m id e (6e). Into a
solution of methylene chloride (20 mL) containing â-alaninamide
hydrochloride (8 mmol), DMAP (1 mmol), and triethylamine (26
mmol) was added benzyl chloroformate (18 mmol) at 0 °C under
a nitrogen atmosphere, and the resulting solution was stirred
at room temperature for 6 h. The solution was worked up with
8
a was found to be slightly reactive than 7a by the
1
0
competitive reaction between 7a and 8a . Those results
indicate the order of the reactivities of alkyl carbamates
2
-4, 7, and 8 as shown in Scheme 1.
4
aqueous NH Cl, and the organic portion was extracted with
On the basis of this finding, subjecting unsymmetri-
methylene chloride. Evaporation of the solvent in vacuo gave a
residue, which was subjected on a column chromatography (silica
gel, methanol/AcOEt )1/1) to give 6e in 20% yield: mp 160-
cally protected diamines 4e and 4f to a condition contain-
ing NaH and piperidine gave unsymmetrical ureas 1eb
and 1fb, in which only the amino group protected with
CF CH OCO group was converted to the corresponding
3 2
ureido group (eqs 5 and 6).
1
1
3
1
62 °C; H NMR (300 MHz, CDCl
3
) δ 2.48 (t, J ) 6.2 Hz, 2H),
.49 (t, J ) 6.0 Hz, 2H), 5.09 (s, 2H), 5.40 (br s, 2H), 5.60 (br s,
H), 7.23-7.40 (m, 5H); IR (neat) 3378, 3333, 3193, 1684, 1646
cm . Anal. Calcd for C11
Found: C, 59.21; H, 6.28; N, 12.46.
-N-Boc-a m in op r op a n oxa m id e (6f). Di-tert-butyl dicar-
bonate (18 mmol) was added to solution of methylene chloride
20 mL) containing â-alaninamide hydrochloride (8 mmol),
-1
14 2 3
H N O : C, 59.45; H, 6.35; N, 12.60.
3
(
triethylamine (26 mmol), and DMAP (1 mmol). After being
stirred for 6 h at room temperature, the solution was worked
up with an aqueous NH Cl solution, and the organic portion was
4
extracted with methylene chloride. Evaporation of the solvent
in vacuo gave a residue, which was subjected on a column
chromatography (silica gel, methanol/AcOEt )1/1) to give 6f in
1
a 30% yield: mp 160-161 °C; H NMR (300 MHz, CDCl
3
) δ 1.44
(
s, 9H), 2.46 (t, J ) 5.9 Hz, 2H), 3.42 (q, J ) 6.0 Hz, 2H), 5.13
br s, 1H), 5.35 (br s, 1H), 5.71 (br s, 1H); IR (Nujol) 3343, 3200,
692, 1634 cm . Anal. Calcd for C H N O : C, 51.05; H, 8.57;
8 16 2 3
(
-
1
1
N, 14.88. Found: C, 50.71; H, 8.17; N, 15.05.
Electr och em ica lly In d u ced Hofm a n n Rea r r a n gem en t.
Typ ica l P r oced u r e. A solution of 6a (2.5 mmol) and Et
4
NBr
(1.25 mmol) in acetonitrile (10 mL) containing 2,2,2-trifluoro-
ethanol (12.5 mmol) was charged in a one-compartment cell
equipped with platinum plate anode and cathode (1 cm × 2 cm),
and a constant current (100 mA) was passed through the cell at
ambient temperature (30-40 °C) until 2.2 F/mol of electricity
was passed. After the removal of acetonitrile, the residue was
In summary, trifluoroethyl carbamates 4 obtained by
the electrochemically induced Hofmann rearrangement
of amides 6 could be used as good precursors for the
preparation of unsymmetrical ureas 1, and 4 showed
extracted with methylene chloride
.
The extract was dried on
MgSO , and the solvent was evaporated in vacuo to give a
4
(
9) Riddick, J . A.; Bunger, W. B.; Sakano, T. K. In Organic Solvents,
th ed.; J ohn Wiley & Sons: New York, 1986; p 700.
10) Carbamate 8a was 2 times reactive than 7a in the reaction with
piperidine in THF in the presence of NaH (reflux, 3 h).
mixture of carbamate 4a and a small amount of recovered 6a .
4
(
(11) Nec, R. Chem. Prum. 1979, 29, 589.

Notes
J . Org. Chem., Vol. 65, No. 5, 2000 1551
The mixture was subjected to column chromatography (silica gel)
with n-hexane/ethyl acetate to give 4a .
N-2,2,2-Tr iflu or oeth oxyca r bon ylp en tyla m in e (4a ): 83%;
(m, 2H), 2.11 (s, 3H), 3.21 (q, J ) 5.6 Hz, 2H), 3.33 (t, J ) 5.5
Hz, 2H), 3.40 (s, 4H), 3.62 (t, J ) 5.5 Hz, 2H), 4.80-4.92 (br s,
-
1
1H); IR (neat) 3357, 1653 cm ; HRMS calcd for C12
23 3 2
H N O
1
oil; H NMR (200 MHz, CDCl
1
4
3
) δ 0.90 (t, J ) 6.7 Hz, 3H), 1.23-
241.1790, found 241.1774. Anal. Calcd for C12H N O : C, 59.72;
23 3 2
.65 (m, 6H), 3.21 (q, J ) 6.8 Hz, 2H), 4.45 (q, J ) 8.5 Hz, 2H),
H, 9.61; N, 17.41. Found: C, 59.35; H, 9.45; N, 17.25.
N ,N -1,5-(3-Oxa p e n t a m e t h yle n e d iyl)-N ′-n -p e n t ylu r e a
-
1
.79-4.98 (br s, 1H); IR (neat) 3361, 2963, 1750, 1550 cm
NO 213.0976, found 213.0977. Anal.
: C, 45.07; H, 6.62; N, 6.57. Found: C,
5.07; H, 6.70; N, 6.57.
N-2,2,2-Tr iflu or oeth oxyca r bon ylben zyla m in e (4b): 66%;
;
1
HRMS calcd for C
8
H
14
F
3
2
(1a d ): 80%; colorless oil; H NMR (200 MHz, CDCl
3
) δ 0.90 (t,
Calcd for C NO
8
H
14
F
3
2
J ) 6.8 Hz, 3H), 1.22-1.43 (m, 4H), 1.43-1.60 (m, 2H), 3.23 (q,
4
J ) 6.5 Hz, 2H), 3.33 (t, J ) 4.8 Hz, 4H), 3.69 (t, J ) 4.8 Hz,
-1
4H), 4.35-4.61 (br s, 1H); IR (neat) 3335, 1664 cm . Anal. Calcd
1
mp 59 °C; H NMR (200 MHz, CDCl
3
) δ 4.45 (q, J ) 8.5 Hz,
H), 3.35 (d, J ) 5.9 Hz, 2H) 7.19-7.41 (m, 5H); IR (neat) 3326,
701, 1673, 1279, 1254, 1183 cm-1. Anal. Calcd for C10
: C, 51.51; H, 4.32; N, 6.01. Found: C, 51.64; H, 4.40; N,
.06.
N-2,2,2-Tr iflu or oeth oxyca r bon ylcycloh exyla m in e (4c):
for C10
H, 9.92; N, 13.86.
N-Allyl-N′-n -p en tylu r ea (1a e): 42%; mp 31-32 °C; H NMR
(200 MHz, CDCl ) δ 0.89 (t, J ) 6.6 Hz, 3H), 1.19-1.39 (m, 4H),
20 2 2
H N O : C, 59.97; H, 10.06; N, 13.99. Found: C, 59.66;
2
1
NO
1
10 3
H F -
2
3
6
1.39-1.58 (m, 2H), 3.15 (q, J ) 6.8 Hz, 2H), 3.74-3.86 (m, 2H),
4.66-4.98 (br s, 2H), 5.05-5.28 (m, 2H), 5.75-5.98 (m, 1H); IR
1
-1
9
1
5%; mp 73 °C; H NMR (200 MHz, CDCl
.56-1.82 (m, 4H), 1.85-2.03 (m, 2H), 3.37-3.60 (m, 1H), 4.44
3
) δ 1.03-1.48 (m, 4H),
(neat) 3339, 1593 cm ; HRMS calcd for C
9
H
18
N
2
O 170.1419,
found 170.1400. Anal. Calcd for C H N O: C, 63.49; H, 10.66;
9 18 2
(
1
q, J ) 8.5 Hz, 2H), 4.63-4.85 (br s, 1H); IR (neat) 3440, 1794,
748, 1383, 1095 cm-1. Anal. Calcd for C
NO : C, 48.00;
H, 6.27; N, 6.22. Found: C, 48.12; H, 6.19; N, 6.22.
N-2,2,2-Tr iflu or oeth oxyca r bon yla n ilin e (4d ): 58%; mp 57
N, 16.45. Found: C, 63.16; H, 10.38; N, 16.06.
9
H
14
F
3
2
N-n -P en tyl-N′-(S)-r-p h en etylu r ea (1a f): 27%; mp 45-47
°C; [R]19 -14.7 (c 0.97, MeOH), (uncorrected); 1H NMR (200
D
MHz, CDCl ) δ 0.85 (t, J ) 5.8 Hz, 3H), 1.05-1.53 (m, 6H), 1.42
3
1
°
C; H NMR (200 MHz, CDCl
3
) δ 4.56 (q, J ) 8.4 Hz, 2H), 6.78-
.93 (br s, 1H), 7.20-7.48 (m, 5H); IR (KBr) 3058, 2982, 1748,
277, 1171, 1100 cm-1. Anal. Calcd for C
NO : C, 49.32;
(d, J ) 6.6 Hz, 3H), 2.94-3.22 (m, 2H), 4.43-4.72 (br s, 1H),
6
1
4.69-4.84 (m, 1H), 4.85-5.10 (br s, 1H); IR (neat) 3335, 1633
-1
9
H
8
F
3
2
22 2
cm ; HRMS calcd for C14H N O 234.1732, found 234.1714.
H, 3.68; N, 6.39. Found: C, 49.08; H, 3.75; N, 6.31.
Anal. Calcd for C14
C, 71.52; H, 9.49; N, 11.66.
N-Ben zyl-N′,N′-1,5-p en ta m eth ylen ed iylu r ea (1bb): 93%;
22 2
H N O: C, 71.76; H, 9.46; N, 11.95. Found:
N-Ben zyloxyca r bon yl-N′-2,2,2-tr iflu or oeth oxyca r bon yl-
1
11
1
,2-eth a n ed ia m in e (4e): 77%; mp 115-117 °C; H NMR (300
1
MHz, CDCl
5
3
3
) δ 3.25-3.40 (m, 4H), 4.44 (q, J ) 8.4 Hz, 2H),
mp 98-99 °C; H NMR (300 MHz, CDCl ) δ 1.49-1.65 (m, 6H),
3
.00-5.20 (m, 3H), 5.40 (br s, 1H), 7.23-7.42 (m, 5H); IR (neat)
3.24-3.40 (m, 4H), 4.43 (d, J ) 5.4 Hz, 3H), 4.65-4.83 (br s,
328, 1706, 1694 cm-1. Anal. Calcd for C13
H
F
N
O
: C, 48.75;
1H), 7.24-7.39 (m, 5H); IR (neat) 3334, 1624 cm ; HRMS calcd
-1
15
3
2
4
H, 4.72; N, 8.75. Found: C, 49.05; H, 4.91; N, 8.70.
N-Boc-N′-2,2,2-t r iflu or oet h oxyca r b on yl-1,2-et h a n ed i-
18 2
for C13H N O 218.1419, found 218.1418.
N-Cycloh exyl-N′,N′-1,5-p en ta m eth ylen ed iylu r ea (1cb):
1
1
a m in e (4f): 46%; mp 133-135 °C; H NMR (300 MHz, CDCl
3
)
91%; mp 140-141 °C; H NMR (200 MHz, CDCl ) δ 0.97-1.44
3
δ 1.45 (s, 9H), 3.20-3.40 (m, 4H), 4.46 (q, J ) 8.7 Hz, 2H), 4.81
(m, 6H), 1.44-1.85 (m, 8H), 1.85-2.02 (m, 2H), 3.22-3.37 (m,
4H), 3.54-3.75 (m, 1H), 4.27 (br d, J ) 7.2 Hz, 1H); IR (neat)
3332, 1615 cm ; HRMS calcd for C12
210.1741. Anal. Calcd for C12
13.32. Found: C, 68.42; H, 10.32; N, 13.19.
N,N-1,5-P en ta m eth ylen ed iyl-N′-p h en ylu r ea (1d b): 97%;
-1
(
br s, 1H), 5.44 (br s, 1H); IR (neat) 3324, 1680 cm . Anal. Calcd
for C10 : C, 41.96; H, 5.99; N, 9.79. Found: C, 41.98;
H, 5.70; N, 9.75.
-
1
H
17
F
3
N
2
O
4
H
22
N
2
O 210.1732, found
22 2
H N O: C, 68.53; H, 10.54; N,
Ur ea F or m a tion . Typ ica l P r oced u r e. Into a dry, 50 mL
flask equipped with a nitrogen inlet adapter, a rubber septum,
and a magnetic stirring bar was placed 4a (0.5 mmol) and
n-butylamine (1 mmol) in THF. Sodium hydride (1 mmol) was
added to the mixture at 0 °C. The resulting solution was stirred
1
1
1
mp 160-161 °C; H NMR (300 MHz, CDCl
3
) δ 1.52-1.75 (m,
6H), 3.36-3.53 (m, 4H), 6.33-6.48 (br s, 1H), 6.97-7.04 (m, 1H),
-1
7.22-7.32 (m, 2H), 7.32-7.43 (m, 2H); IR (neat) 3324, 1650 cm
HRMS calcd for C12 O 204.1262, found 204.1272.
;
at room temperature, and after 5 h aqueous NH
4
Cl was added
16 2
H N
to the mixture. After the removal of the solvent in vacuo, the
residue was extracted with ethyl acetate. The extract was dried
N-2-Ben zyloxyca r b on yla m in oet h yl-N′,N′-1,5-p en t a m e-
1
th ylen ed iylu r ea (1eb): 64%; mp 106-108 °C; H NMR (200
on MgSO
4
, and the solvent was evaporated in vacuo to give a
3
MHz, CDCl ) δ 1.42-1.62 (m, 6H), 3.23-3.40 (m, 8H), 5.08 (s,
residue, which was subjected to column chromatography (silica
gel) with n-hexane/ethyl acetate to give N-n-butyl-N′-pentylurea
2H), 5.19 (br s, 1H), 5.60 (br s, 1H), 7.30-7.42 (m, 5H); IR (neat)
-
1
23 3 3
3320, 1718, 1638 cm . Anal. Calcd for C16H N O : C, 62.93;
(
1a a ) in 86% yield.
N-n -Bu tyl-N′-n -p en tylu r ea (1a a ): mp 51-52 °C; H NMR
200 MHz, CDCl ) δ 0.89 (t, J ) 7.0 Hz, 3H), 0.92 (t, J ) 6.8 Hz,
H), 1.13-1.60 (m, 10H), 3.05-3.25 (m, 4H), 4.53-4.83 (br s,
H); IR (neat) 3335, 1622 cm-1; HRMS calcd for C10
86.1732, found 186.1733. Anal. Calcd for C10 O: C, 64.47;
H, 7.59; N, 13.76. Found: C, 62.68; H, 7.57; N, 13.65.
1
N -2-B o c -a m in o e t h y l-N ′,N ′-1,5-p e n t a m e t h y le n e d iy l-
1
(
3
u r ea (1fb): 61%; mp 132-133 °C; H NMR (200 MHz, CDCl
3
) δ
3
1
1
1.44 (s, 9H), 1.46-1.66 (m, 6H), 3.20-3.40 (m, 8H), 5.03 (br s,
-1
H
22
N
2
O
1H), 5.25 (br s, 1H); IR (neat) 3359, 1694, 1622 cm . Anal. Calcd
H
22
N
2
25 3 3
for C13H N O : C, 57.54; H, 9.29; N, 15.49. Found: C, 57.38;
H, 11.90; N, 15.04. Found: C, 64.32; H, 11.83; N, 14.96.
Other ureas were prepared by similar procedures. In the case
of N,N-(3-azapentamethylenediyl)-N′-n-pentylurea 1a c, Et N (4
3
H, 9.02; N, 15.25.
Com p a r ison of Rea ctivity of Ca r ba m a tes (2a -3a , 4a , 7a ,
8a ). Typ ica l P r oced u r e. Into a dry, 50 mL flask equipped with
a nitrogen inlet adapter, a rubber septum, and a magnetic
stirring bar were placed 4a (0.5 mmol), 2a (0.5 mmol), and
piperidine (0.5 mmol) in THF. Sodium hydride in oil (0.5 mmol)
was added to the mixture at 0 °C. The resulting solution was
equiv to 1a c) and acetyl chloride (4 equiv to 1a c) were added to
the reaction mixture after it was stirred for 5 h, and then the
usual working up afforded N,N-1,5-(4-acetyl-4-azapentameth-
ylenediyl)-N′-n-pentylurea (a cetyl-1a c). Ureas 1eb and 1fb were
prepared by adding NaH (2 mmol) to a solution of piperidine (4
mmol) in THF and then adding 4e,f (1 mmol) to the solution.
Then, the resulting solution was stirred at room temperature
for 2 h.
stirred at room temperature for 5 h, and then aqueous NH
was added to the mixture. After the removal of the solvent, the
residue was extracted with ethyl acetate The extract was dried
on MgSO , and the solvent was evaporated in vacuo to give a
4
Cl
.
4
N,N-1,5-P en ta m eth ylen ed iyl-N′-n -p en tylu r ea (1a b): 81%;
mixture of 4a , 2a , and 1a b. The yields were determined by
integral intensity of H NMR spectra.
1
1
mp 52-53 °C; H NMR (300 MHz, CDCl
3
) δ 0.90 (t, J ) 6.7 Hz,
3
3
H), 1.12-1.43 (m, 4H), 1.43-1.67 (m, 8H), 3.16-3.26 (m, 4H),
.27-3.36 (m, 4H), 4.48-4.60 (br s, 1H); IR (neat) 3343, 1624
Ack n ow led gm en t. Y.M. expresses thanks for a
Grant-in-Aid for Scientific Research on Priority Area
(no. 236) from the Ministry of Education, Science and
Culture, J apan.
-
1
cm . Anal. Calcd for C11
22 2
H N O: C, 66.61; H, 11.19; N, 14.13.
Found: C, 66.61; H, 11.22; N, 13.96.
N,N-1,5-(4-Acetyl-4-a za p en ta m eth ylen ed iyl)-N′-n -p en ty-
1
lu r ea (a cetyl-1a c): 66%; colorless oil; H NMR (300 MHz,
CDCl
3
) δ 0.90 (t, J ) 7.0 Hz, 3H), 1.22-1.45 (m, 4H), 1.45-1.61
J O991076K