Efficient Synthesis of Diastereomerically Pure Vicinal Diamines: meso-2,3-Bis(methylamino)butane and cis-1,2-Bis(methylamino)cycloalkanes

Full text of DOI:10.1021/jo961972l

J . Org. Chem. 1997, 62, 431-434
431
Compound 1 was hydrogenated over PtO2 at 1500 psi
in glacial acetic acid over the course of 7 days to yield
60% of cis-1,3,4,5-tetramethylimidazolidin-2-one (2). Due
to their heteroaromatic character, catalytic hydrogena-
tion of imidazolin-2-ones is reported to be very slow and
requires active catalysts as well as high pressure. Dush-
insky and Dolan reported the successful use of PtO2 as
catalyst and later demonstrated that the N,N′-diacylimi-
dazolin-2-ones underwent hydrogenation over palladium
on carbon under milder conditions. Simon13 used excess
Raney nickel catalyst, but gave no details concerning
yields or stereochemistry.
Through the course of our investigation, we found that
1 was inert to hydrogenation over palladium on carbon
or Raney nickel (W-2). Furthermore, heating the reaction
solution to 80 °C did not significantly increase the yield
of 2 or substantially decrease the reaction time. Thus,
this procedure should be applied to compounds which do
not have functionalities which are sensitive to active
hydrogenation conditions.
Compound 2 was then hydrolyzed by refluxing in 6 M
aqueous HCl for 7 days to yield 83% of meso-2,3-bis-
(methylamino)butane dihydrochloride salt (3). Imidazo-
lidin-2-ones are remarkably resistant to hydrolysis under
a variety of acidic and basic conditions and display
reactivity very similar to tetraalkylated ureas.14 Finally,
reaction of 40% NaOH regenerated the free vicinal
diamine, 4, in 94% isolated yield. This is the first
synthesis of diastereomericaly pure meso-2,3-bis(methy-
lamino)butane.
Efficien t Syn th esis of Dia ster eom er ica lly
P u r e Vicin a l Dia m in es:
m eso-2,3-Bis(m eth yla m in o)bu ta n e a n d
cis-1,2-Bis(m eth yla m in o)cycloa lk a n es
J eff Akester, J ingji Cui, and Gideon Fraenkel*
Department of Chemistry, The Ohio State University,
Columbus, Ohio 43210
Received October 21, 1996
Vicinal diamines are excellent ligands for metal ions
(Li+, Mg2+, Zn2+) as well as for a multitude of pharma-
cological applications.1,2 For example, their Pt(II) com-
plexes are effective in cancer therapy. Vicinal diamines,
particularly N,N,N′,N′-tetramethylethylenediamine (TME-
DA), are well-known catalysts for the reactions of orga-
nolithium compounds, an effect that has not been ad-
equately explained.3 From low-temperature NMR data,
it is known that organolithium compounds form bridged
dimers in the presence of TMEDA with each Li biden-
tately complexed to the diamine.4 In principle, such
complexes should be favored if the amino groups were
constrained cis, such as in cyclic, cis vicinal tertiary
diamines.
Cis vicinal analogs of TMEDA have not been investi-
gated as potential catalysts of organolithium reactions,
largely because such compounds were not commercially
available. Among the many published syntheses,5-8 few
are inexpensive and efficient to carry out.9
Our approach is based on the reported condensation
of R-hydroxy ketones or 1,2-disiloxyalkenes with ureas
to give imidazolin-2-ones.10 Then, hydrogenation of the
latter followed by hydrolysis of the resulting imidazolidin-
2-ones should yield a variety of vicinal (including cis
vicinal) diamines. This report describes such a proce-
dure, see Scheme 1. Thus the acid-catalyzed (0.1 equiv
of tosyl acid) condensation of N,N′-dimethylurea with
3-hydroxybutanone to form 38% of 1,3,4,5-tetrameth-
ylimidazolin-2-one (1) is complete within 12 h in refluxing
cumene.12 At lower temperatures, using refluxing ben-
zene or toluene only starting material was recovered from
the reaction mixture. Use of reactant concentrations
above 0.1 M significantly reduced the yield of 1, most
likely due to competing polymerization of the reactants.
An attractive extension of the above procedure was to
apply it to the preparation of cis, cyclic, vicinal diamines
(see Scheme 2). We were unable to confirm Ruhlmann’s
claim that urea condenses with cyclic acyloin products
in refluxing cyclohexanol/aqueous HCl to yield imidazo-
lin-2-ones.15 However, several cyclic acylion products
condensed reproducibly with N,N′-dimethylurea in re-
fluxing cumene containing a catalytic amount of tolu-
enesulfonic acid. Subsequent steps used to prepare 5
through 9 with n ) 1-4 were identical to the procedure
mentioned above. The isolated yields of these compounds
are listed in Table 1. As might be expected, the bicyclic
imidazolidin-2-ones 7, n ) 1-4, are very unreactive to
hydrolysis. They failed to react with hydrazine, refluxing
sulfuric acid, and Ba(OH)2 at 120 °C but did undergo
hydrolysis in refluxing 6 M aqueous HCl.
(1) Walker, J .; Bowen, W.; Walker, F.; Matsumoto, R.; DeCosta, B.;
Rice, K. Pharm. Rev. 1990, 42, 355.
(2) DeCosta, B. R.; Bowen, W.; Hellewell, S. B.; George, C.; Rothman,
R.; Reid, A.; Walker, M.; J acobson, A.; Rice, K. J . J . Med. Chem. 1989,
32, 1996.
(3) (a) Eberhardt, G. G.; Butte, W. A. J . Org. Chem. 1964, 29, 2928.
(b) Langer, A. W. N.Y. Acad. Sci. 1965, 27, 741.
(4) Fraenkel, G.; Hsu, H.; Su, B. M. “The Structure and Dyanamic
Behaviour of Organolithium Compounds in Solution; 13C, 6Li and 7Li
NMR” in Lithium: Current Applications in Science, Medicine and
Technology; Bach, R., Ed.; J ohn Wiley; New York, 1985; p 273.
(5) Toftlund, H.; Pederson, E. Acta. Chem. Scand. 1972, 26, 4019-
4030.
In sum we have developed an efficient synthesis of
diastereomerically pure, vicinal diamines employing
inexpensive and readily available starting materials.16
The procedure cannot be applied to molecules which have
unprotected functionalities sensitive to acid or catalytic
hydrogenation conditions. However, this synthesis is
very useful for the preparation of the title compounds
and provides a route to a class of cis vicinal diamines
which have previously been difficult to prepare. We are
currently investigating reactions which might further
enhance the above procedure, as well as the influence of
cis-tertiary-vicinal diamines prepared via the above
procedure on organolithium structure and reactivity.
(6) Potter, G. W. H.; Coleman, M. W.; Monro, A. M. J . Heterocyc.
Chem. 1975, 12, 611-614.
(7) Sharpless, K. B.; Chang, A. O.; Oshima, K. J . Am. Chem. Soc.
1977, 99, 3420-3426.
(8) Ba¨ckvall, J . Tetrahedron Lett. 1978, 163-166.
(9) Fraenkel, G.; Gallucci, J .; Rosenzweig, H. S. J . Org. Chem. 1989,
54, 677-681.
(13) Simon, J . U.S. Pat. 2,850,532, 1958.
(10) Corson, B. B.; Freeborn, E. Organic Syntheses; Wiley: New
York, 1943; Collect. Vol. II, p 231.
(14) Fraenkel, G.; Pramanik, P. J . Org. Chem. 1984, 49, 1314.
(15) (a) Ruhlmann, K.; Kokkali, A.; Becker, H.; Seefluth, H.;
Friedberger, U. J . Prakt. Chem. 1969, 311, 844. (b) Ruhlmann, K.
Synthesis 1971, 236.
(11) Kondo, T.; Kotachi, S.; Watanabe, Y. J . Chem. Soc., Chem.
Commun. 1992, 1318.
(12) (a) Duschinsky, R.; Dolan, L. A. J . Am. Chem. Soc. 1945, 67,
2079. (b) Duschinsky, R.; Dolan, L. A. J . Am. Chem. Soc. 1948, 70,
657.
(16) All assigned structures for compounds are consistent with their
spectroscopic data and method of preparation. No evidence was
detected for the trans-substituted imidazolidin-2-ones.
S0022-3263(96)01972-X CCC: $14.00 © 1997 American Chemical Society

432 J . Org. Chem., Vol. 62, No. 2, 1997
Notes
Sch em e 1a
a
Key: (a) 1,3-dimethylurea, TosOH (cat), cumene, 152 °C; (b) 1500 psi H2, PtO2, acetic acid, 7 days, rt; (c) 12 M HCl, 7 days, 105 °C;
(d) 40% NaOH(aq).
Sch em e 2a
cis-1,3,4,5-Tetr a m eth ylim id a zolid in -2-on e (2). Compound
1 (10.09 g, 0.072 mol), platinum oxide (1.00 g, 0.004 mol, 0.055
equiv), and glacial acetic acid (170 mL, freshly distilled) were
charged into a Parr high-pressure hydrogenator. The chamber
was closed, evacuated and purged with hydrogen three times
and then pressurized to 1500 psi and stirred at room tempera-
ture for 7 days. The system was periodically checked and
returned to 1500 psi as the reactants absorbed hydrogen. After
7 days, the chamber was opened and charged with Celite to
destroy any unreacted catalyst. The reaction solution was
filtered through a 2 cm layer of Celite on a glass frit to yield a
light yellow solution which distilled to yield 2 (6.11 g, 0.043 mol,
60%) at 93 °C/3 Torr. Roughly 30% of starting material was
recovered, and analysis of the product showed only the cis
stereoisomer; 10% palladium on carbon was ineffective as a
hydrogenation catalyst. 2: 1H NMR (CDCl3, 200 MHz) δ 3.35
a
(m, 2H), 2.59 (s, 6H), 0.95 (d, 6H); 13C NMR (CDCl3, 50 MHz) δ
Key: (a) TMSCl, Na, toluene, 111 °C; (b) 1,3-dimethylurea,
TosOH (cat), cumene, 152 °C; (c) 1500 psi H2, PtO2, acetic acid, 7
days, rt; (d) 12 M HCl, 14 days, 105 °C; (e) 40% NaOH(aq).
161.3, 54.8, 28.5, 12.1; GC/MS/IR purity > 97%; m/ z 142, calcd
142.21.
m eso-2,3-Bis(m eth yla m in o)bu ta n e Dih yd r och lor id e (3).
Ta ble 1. Isola ted Yield s (%) of
Compound 2 (6.11 g, 0.043 mol) and 12 M hydrochloric acid (108
cis-1,2-Bis(m eth yla m in o)cycloa lk a n es
mL, 1.296 mol, 30 equiv) was charged into a round bottom flask.
n
5
6
7
8
9a
A stir bar and heating mantle were added; then a Liebig
condenser was attached to the flask. The solution was stirred
and refluxed (105 °C) for 7 days and then rotary evaporated to
dryness to yield 3 (6.75 g, 0.036 mol, 83%): mp 233 °C; 1H NMR
(D2O, 200 MHz) δ 3.51 (m, 2H), 2.63 (s, 6H), 1.30 (d, 6H); 13C
NMR (D2O, 50 MHz) δ 56.7, 31.3, 11.6.
1
2
3
4
58
79
45
46
58
56
67
77
76
74
62
78
40
45
83
80
95
92
96
92
a
Determined by GC.
m eso-2,3-Bis(m eth yla m in o)bu ta n e (4). Upon dissolving 3
(6.75 g, 0.036 mol) in 10 mL of 40% aqueous NaOH, a light
yellow layer oiled out of solution. The basic aqueous layer was
transferred to a 60 mL separatory funnel and extracted with 3
× 10 mL of diethyl ether; the organic extracts were combined,
washed with 3 mL of saturated NaCl, and then dried over Na2-
SO4. The organic solution was distilled to yield 4 (4.00 g, 0.034
mol, 94%): bp ) 135 °C/1 atm; 1H NMR (CDCl3, 200 MHz) δ
2.45 (m, 2H), 2.29 (m, 6H), 1.78 (m, 2H), 0.90 (s, 6H); 13C NMR
(CDCl3, 50 MHz) δ 57.9, 34.4, 15.1; GC/MS/IR purity > 97%;
M+ 116 amu, calcd 116.21 amu.
Exp er im en ta l Section
All solvents, reagents, and starting materials are com-
mercially available. FT-NMR spectra of synthetic compounds
were obtained using a Bruker AC-200 spectrometer. All hydro-
genations were carried out using a 450 mL Parr stainless steel
bomb (model 4562) with a maxium pressure rating of 2000 psi.
Platinum oxide (Adam’s catalyst) was always activated by
hydrogenation before use.
1,3,4,5-Tetr a m eth ylim id a zolin -2-on e (1). A Dean-Stark
trap was attached to a round bottom flask, and a Friedrich
condenser was attached to the trap. A septum was placed over
the mouth of the condenser, and the system was flame dried
under vacuum and purged with argon twice. Cumene (1000 mL,
freshly distilled, degassed with argon) was charged into the flask
together with a stir bar, followed by 1,3-dimethylurea (8.81 g,
0.100 mol), 3-hydroxybutanone (8.81 g, 0.100 mol), and p-
toluenesulfonic acid monohydrate (1.97 g, 0.010 mol, 0.1 equiv).
Since these reagents are hygroscopic they were dried in a
desiccator before use to avoid misleading water measurements.
The trap was filled with cumene, and a heating mantle and
stirrer were attached to the flask. The reaction solution was
stirred and refluxed (152 °C) for 12 h under argon. By the time
ca. 4 mL (theoretical, 3.6 mL) of water had collected in the trap,
the reaction was assumed to be complete. The solvent was
removed by distillation into the open trap. The ca. 20 mL of a
dark red oil which remained in the reaction flask was vacuum-
distilled at 125 °C/3 Torr, giving a light yellow oil which solidified
on standing at room temperature. To prevent product solidifica-
tion in the head, the latter was warmed gently with a flame.
The solid was vacuum filtered and washed with 3 mL of cold
distilled water and then with 3 mL of cold acetone to yield 1
(5.32 g, 0.038 mol, 38%) as a white solid, mp 95 °C. This reaction
produced lower yields when run at concentrations higher than
0.1 M. 1: 1H NMR (CDCl3, 200 MHz) δ 2.75 (s, 6H), 1.58 (s,
6H); 13C NMR (CDCl3, 50 MHz) δ 153.3, 112.9, 27.1, 8.4; GC/
MS/IR purity > 97%; m/ z 140, calcd 140.19.
1,2-Bis(tr im eth ylsiloxy)cycloh exen e (5, n ) 1). A three-
neck, round bottom flask was fitted with a Friedrich condenser,
a Herschberg stirrer, and a pressurized addition funnel. Septa
were placed over the mouths of the condenser and funnel. The
system was flame dried under vacuum and purged with argon
twice. Toluene (700 mL, distilled from CaH2, degassed with Ar)
was charged into the flask through the addition funnel followed
by sodium (27.1 g, 1.18 mol, 4.7 equiv) in pieces, cut under
pentane. The solution was refluxed (110 °C) and stirred for 2 h
to produce a sodium dispersion. The pressurized addition funnel
was charged with toluene (250 mL), dimethyl adipate (43.55 g,
0.250 mol, distilled), and trimethylsilyl chloride (108.64 g, 1.00
mol, 4 equiv, distilled from CaH2). The solution in the addition
funnel was mixed via Ar ebulition and then added dropwise over
6 h to the refluxing reaction mixture, with stirring. The reaction
mixture turned purple upon addition and then became brown
one-third of the way through the addition. After addition,
stirring and reflux were continued for 12 h. After being cooled
to room temperature, the mixture was vacuum filtered through
glass wool and then vacuum filtered through 1 cm of Celite on
a glass frit to remove residual sodium particles. The resulting
light yellow filtrate was distilled to yield 5 (n ) 1) (37.19 g, 0.144
mol, 58%): bp 76-81 °C/0.4 Torr; 1H NMR (CDCl3, 200 MHz) δ
2.04 (m, 4H), 1.57 (m, 4H), 0.15 (s, 18H); 13C NMR (CDCl3, 50
MHz) δ 132.1, 29.6, 23.3, 0.8.
1,2-Bis(tr im eth ylsiloxy)cycloh ep ten e (5, n ) 2). The
procedure described above was followed using diethyl pimelate

Notes
J . Org. Chem., Vol. 62, No. 2, 1997 433
(58.2 g, 0.27 mol), sodium (29.3 g, 1.28 mol), and trimethylchlo-
rosilane (135.5 g, 1.25 mol) to yield 5, n ) 2 (57.8 g, 0.212 mol,
79%) 86-92 °C/0.65 Torr: 1H NMR (CDCl3, 200 MHz) δ 2.14 (t,
4H), 1.57 (m, 6H), 0.13 (s, 18H); 13C NMR (CDCl3, 50 MHz) δ
136.5, 33.0, 30.5, 25.5, 0.6.
mol, 76%): bp 96-100 °C/0.25 Torr; 1H NMR (CDCl3, 200 MHz)
δ 3.00 (m, 2H), 2.39 (s, 6H), 1.6-0.9 (m, 8H); 13C NMR (CDCl3,
50 MHz) δ 162.1, 55.0, 28.2, 25.0, 20.3; GC/MS/IR purity > 95%;
m/ z 168, calcd 168.24.
1,3-Dim eth yl-4,5-p en ta m eth ylen eim id a zolid in -2-on e (7,
n ) 2). Following the hydrogenation procedure described above,
6, (n ) 2) (18.74 g, 0.104 mol), platinum oxide (1.39 g, 6.1 mmol),
and glacial acetic acid (180 mL) were used to give 7 (n ) 2) (14.05
g, 0.077 mol, 74%): bp 104 °C/0.3 Torr; 1H NMR (CDCl3, 200
MHz) δ 3.35 (t, 2H), 2.48 (s, 6H), 1.6-1.0 (m, 10H); 13C NMR
(CDCl3, 50 MHz) δ 160.4, 59.6, 30.4, 28.4, 27.8, 24.1.
1,2-Bis(tr im eth ylsiloxy)cycloocten e (5, n ) 3). Following
the procedure described above, diethyl suberate (51.5 g, 0.224
mol), sodium (24.4 g, 1.07 mol), and trimethylchlorosilane (134.3
g, 1.24 mol) were used to yield 5, n ) 3 (28.4 g, 0.099 mol, 45%)
82-87 °C/0.3 Torr: 1H NMR (CDCl3, 200 MHz) δ 2.09, 1.49, 0.13;
13C NMR (CDCl3, 50 MHz) δ 133.1, 31.1, 28.7, 26.4, 1.0.
1,3-Dim eth yl-4,5-h exa m eth ylen eim id a zolid in -2-on e (7, n
) 3). Following the above procedure, 6 (n ) 3) (9.91 g, 0.051
mol), platinum oxide (0.9 g, 3.95 mmol), and glacial acetic acid
(150 mL) were used to yield 7 (n ) 3) (6.22 g, 0.032 mol, 62%):
bp 117-122 °C/0.09 Torr; 1H NMR (CDCl3, 200 MHz) δ 3.26 (t,
2H), 2.60 (s, 6H), 1.6-1.2 (m, 18H); 13C NMR (CDCl3, 50 MHz)
δ 160.5, 61.3, 29.0, 27.3, 25.3, 23.8.
1,3-Dim eth yl-4,5-h ep ta m eth ylen eim id a zolid in -2-on e (7,
n ) 4). The above hydrogenation procedure was followed using
6 (n ) 4) (9.37 g, 0.045 mol) and platinum oxide (1.1 g, 4.8 mmol)
in glacial acetic acid (150 mL) to yield 7 (n ) 4) (7.36 g, 0.035
mol, 78%): bp 127-129 °C/0.07 Torr; 1H NMR (CDCl3, 200 MHz)
δ 3.25 (t, 2H), 2.59 (s, 6H), 1.6-1.2 (m, 18H); 13C NMR (CDCl3,
50 MHz) δ 161.0, 62.6, 29.0, 27.7, 25.6, 25.0, 24.3.
1,2-Bis(tr im eth ylsiloxy)cyclon on en e (5, n ) 4). Following
the above procedure, diethyl azelate (61.0 g, 0.23 mol), sodium
(27.6 g, 1.2 mol), and trimethylchlorosilane (125.5 g, 1.15 mol)
were used to yield 5, n ) 4 (32.1 g, 0.107 mol, 46%): bp 92-93
1
°C/0.1 Torr; H NMR (CDCl3, 200 MHz) δ 2.17, 1.51, 0.17; 13C
NMR (CDCl3, 50 MHz) δ 134.0, 30.5, 25.8, 24.9, 24.7, 1.1.
1,3-Dim eth yl-4,5-tetr a m eth ylen eim id a zolin -2-on e (6, n
) 1). A Dean-Stark trap was attached to a round bottom flask
with a side arm. A Friedrich condenser was attached to the
mouth of the trap, a septum was placed over the mouth of the
condenser, and the system was flame dried under vacuum and
then purged twice with argon. Cumene (700 mL, freshly
distilled, degassed with Ar) was charged into the flask together
with a stir bar followed by 1,3-dimethylurea (8.81 g, 0.100 mol),
5 (n ) 1) (25.85 g, 0.100 mol) and p-toluenesulfonic acid
monohydrate (1.97 g, 0.010 mol, 0.1 equiv). The urea and acid
are hygroscopic and should be dried in a desiccator before use
to avoid misleading water measurements. The trap was filled
with cumene, and a heating mantle and stirrer were attached
to the flask. The reaction solution was stirred and refluxed (153
°C) for 12 h under Ar. When 1.9 mL (theoretical 3.6 mL) of
water had collected in the trap, the reaction was assumed to be
complete. The solvent was removed by opening the valve at the
bottom of the trap and allowing the condensing solvent to drain
through the trap into a flask. The remaining 60 mL of a dark
red oil was vacuum distilled to yield 6 (n ) 1) (9.77 g, 0.058
mol, 58%) as a light yellow oil: bp 116-121 °C/0.07 Torr; 1H
NMR (CDCl3, 200 MHz) δ 2.90 (s, 6H), 2.09 (m, 4H), 1.57 (m,
4H); 13C NMR (CDCl3, 50 MHz) δ 153.3, 116.2, 26.7, 22.2, 19.4;
GC/MS/IR purity > 95%; m/ z 166, calcd 166.22.
cis-1,2-Bis(m eth yla m in o)cycloh exa n e Dih yd r och lor id e
(8, n ) 1). Compound 7 (n ) 1) (8.75 g, 0.052 mol) and 12 M
hydrochloric acid (130 mL, 1.56 mol, 30 equiv) were charged into
a round bottom flask with a stir bar. A reflux condenser and a
heating mantle were attached to the flask. The reaction mixture
was refluxed (108 °C) and stirred for 2 weeks and then rotary
evaporated to dryness to yield 8 (n ) 1) (4.83 g, 0.021 mol,
1
40%): mp ) 208 °C; H NMR (D2O, 200 MHz) δ 3.71 (m, 2H),
2.81 (s, 6H), 1.79 (m, 4H), 1.46 (m, 4H); 13C NMR (D2O, 50 MHz)
δ 57.5, 31.4, 23.0, 20.0.
cis-1,2-Bis(m eth yla m in o)cycloh ep ta n e Dih yd r och lor id e
(8, n ) 2). Acid hydrolysis followed that above using 7 (n ) 2)
(12.7 g, 0.070 mol) and 12 M hydrochloric acid (180 mL, 2.16
mol, 30 equiv) to give 8 (n ) 2) (7.82 g, 0.032 mol, 45%): 1H
NMR (D2O, 200 MHz) δ 3.75 (m, 2H), 2.81 (s, 6H), 2.2-1.5 (m,
12H); 13C NMR (D2O, 50 MHz) δ 60.0, 31.9, 25.4, 25.3, 22.4.
cis-1,2-Bis(m eth yla m in o)cycloocta n e Dih yd r och lor id e
(8, n ) 3). Following the hydrolysis procedure, described above,
7 (n ) 3) (4.12 g, 0.021 mol) and 12 M hydrochloric acid (87 mL,
1.04 mol, 50 equiv) were used to yield 8 (n ) 3) (4.39 g, 0.017
mol, 83%): 1H NMR (D2O, 200 MHz) δ 3.82 (t, 2H), 2.88 (s, 6H),
2.2-1.5 (m, 14H); 13C NMR (D2O, 50 MHz) δ 58.7, 32.0, 25.7,
25.0, 22.2.
cis-1,2-Bis(m eth yla m in o)cyclon on a n e Dih yd r och lor id e
(8, n ) 4). Acid hydrolysis as above of 7 (n ) 4) (5.05 g, 0.024
mol) with 12 M hydrochloric acid (80 mL, 0.96 mol, 40 equiv)
gave 8 (n ) 4) (5.17 g, 0.019 mol, 80%): 1H NMR (D2O, 200 MHz)
δ 3.74 (t, 2H), 2.84 (s, 6H), 2.2-1.4 (m, 16H); 13C NMR (D2O, 50
MHz) δ 58.8, 32.0, 25.0, 23.3, 22.0.
1,3-Dim eth yl-4,5-p en ta m eth ylen eim id a zolin -2-on e (6, n
) 2). The procedure described above was used except 5 (n ) 2)
(54.5 g, 0.200 mol), 1,3-dimethylurea (17.6 g, 0.200 mol), and
p-toluenesulfonic acid monohydrate (3.95 g, 0.020 mol) were used
in this preparation to yield 6 (n ) 2) (20.2 g, 0.112 mol, 56%):
bp 130-137 °C/0.07 Torr; 1H NMR (CDCl3, 200 MHz) δ 3.05 (s,
6H), 2.37 (t, 4H), 1.62 (m, 6H); 13C NMR (CDCl3, 50 MHz) δ
152.9, 118.7, 29.1, 27.1, 24.3.
1,3-Dim eth yl-4,5-h exa m eth ylen eim id a zolin -2-on e (6, n
) 3). Following the procedure described above 5 (n ) 3) (22.9
g, 0.080 mol), 1,3-dimethylurea (7.04 g, 0.080 mol), and p-
toluenesulfonic acid monohydrate (1.6 g, 0.008 mol) were used
to yield 6 (n ) 3) (10.39 g, 0.053 mol, 67%): bp 130-136 °C/
0.09 Torr; 1H NMR (CDCl3, 200 MHz) δ 2.68 (s, 6H), 2.05 (m,
4H), 1.15 (m, 4H), 0.96 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ
153.0, 116.9, 27.8, 26.4, 25.1, 21.4.
cis-1,2-Bis(m eth yla m in o)cycloh exa n e (9, n ) 1). Com-
pound 8 (n ) 1) (4.83 g, 0.021 mol) was dissolved in a minimum
volume of 40% aqueous NaOH. The free diamine separated as
1
a light yellow oil, 9 (n ) 7): 95% by GC; H NMR (CDCl3, 200
MHz) δ 2.50 (m, 2H), 2.30 (s, 6H), 1.7-1.1 (m, 8H); 13C NMR
(CDCl3, 50 MHz) δ 58.7, 34.1, 27.4, 22.3.
1,3-Dim eth yl-4,5-h ep ta m eth ylen eim id a zolin -2-on e (6, n
) 4). Following the above procedure 5 (n ) 4) (22.2 g, 0.074
mol), 1,3-dimethylurea (6.52 g, 0.074 mol), and p-toluenesulfonic
acid monohydrate (2.0 g, 0.010 mol) were used to yield 6 (n ) 4)
(11.99 g, 0.057 mol, 77%): bp 139-146 °C/0.08 Torr; 1H NMR
(CDCl3, 200 MHz) δ, 3.06 (s, 6H), 2.40 (t, 4H), 1.6-1.2 (m, 10H);
13C NMR (CDCl3, 50 MHz) δ 153.6, 117.7, 26.9, 25.3, 24.5, 23.2,
20.8.
cis-1,2-Bis(m eth yla m in o)cycloh ep ta n e (9, n ) 2). Com-
pound 8 (n ) 2) (7.81 g, 0.032 mol) was dissolved in a minimum
volume of 40% aqueous NaOH. Free diamine, 9, n ) 2,
separated as a light yellow oil: 92% by GC; 1H NMR (CDCl3,
200 MHz) δ 2.54 (t, 2H), 2.33 (s, 6H), 1.7-1.1 (m, 12H); 13C NMR
(CDCl3, 50 MHz) δ 62.1, 34.7, 29.6, 27.8, 23.2.
cis-1,2-Bis(m eth yla m in o)cycloocta n e (9, n ) 3). Com-
pound 8 (n ) 3) (4.39 g, 0.017 mol) was dissolved in a minimum
volume of 40% aqueous NaOH to give free amine 9 (n ) 3) as a
light yellow oil (96% by GC): 1H NMR (CDCl3, 200 MHz) δ 2.55
(t, 2H), 2.29 (s, 6H), 1.8-1.1 (m, 14H); 13C NMR (CDCl3, 50 MHz)
δ 60.3, 34.6, 28.6, 26.9, 24.4.
cis-1,2-Bis(m eth yla m in o)cyclon on a n e (9, n ) 4). The free
diamine 9 (n ) 4) was released as a light yellow oil from its
dihydrochloride 8 (n ) 4) as above: 92.2% by GC; 1H NMR
(CDCl3, 200 MHz) δ 2.45 (t, 2H), 2.20 (s, 6H), 1.5-1.1 (m, 16H);
13C NMR (CDCl3, 50 MHz) δ 59.7, 34.6, 26.5, 25.7, 23.3, 22.0.
1,3-Dim eth yl-4,5-tetr a m eth ylen eim id a zolid in -2-on e (7,
n ) 1). Compound 6 (n ) 1) (11.47 g, 0.069 mol), platinum oxide
(1.2 g, 5.27 mmol, 0.07 equiv), and glacial acetic acid (150 mL,
freshly distilled) were charged into a Parr hydrogenator. The
chamber was sealed, evacuated, and purged with hydrogen three
times and then pressurized to 1500 psi and stirred at room
temperature for 7 days. After 7 days, the chamber was opened
and a scoop of Celite was added; then the reaction mixture was
vacuum filtered through 1 cm of Celite on a glass frit to produce
a yellow filtrate which distilled to yield 7 (n ) 1) (8.72 g, 0.052

434 J . Org. Chem., Vol. 62, No. 2, 1997
Notes
Su p p or tin g In for m a tion Ava ila ble: Spectral data for all
compounds (48 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.
Ack n ow led gm en t. This work and procurement of
the NMR equipment was generously funded by the
National Science Foundation, Grant CHE9317298, The
Ohio State University Office of Research, and by a gift
from the American Cyanamid Company. We thank Dr.
J ose Cabral and Dr. Uta Vitinuis for their help and Mr.
Bruce Dressman who initiated this research.
J O961972L