Synthesis, reactions, and rearrangements of 2,4-diazabicyclo[3.1.0]hexan-3- ones

Article abstract of DOI:10.3987/COM-12-12543

Copper-mediated cyclopropanation of 1,3-dialkyl-1,3- dihydroimidazol-2-ones with diazomethane and methyl diazoacetate yields 2,4-diazabicyclo[3.1.0]hexan- 3-ones and the first diaza[4.3.1]propellane. The bicyclic system survives elevated temperatures and in strongly basic and acidic solutions, but drastic conditions cleave the (C-1)-(C-6) bond affording 1,3-dihydroimidazol-2-ones. Catalytic hydrogenation removes N-benzyl groups and opens the (C-1)-(C-6) bond. Lithium aluminium hydride reduces 2,4-dibenzyl-2,4-diazabicyclo[3.1.0]hexan-3- one to a bicyclic aminal. Acid-induced cleavage of its imidazolidine ring is followed by unexpected transformations that probably procede via an acyclic intermediate, which comprises an azomethine ylide and an iminium moiety. 1,3-Cyclization involving both functional groups leads to N,N'-dibenzyl-trans-1, 2-cyclopropanediamine, while 1,5-cyclization gives rise to the formation of N-benzylpyrrole along with N-benzylamine.

Full text of DOI:10.3987/COM-12-12543

HETEROCYCLES, Vol. 85, No. 10, 2012
2449
HETEROCYCLES, Vol. 85, No. 10, 2012, pp. 2449 - 2463. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 9th July, 2012, Accepted, 31st July, 2012, Published online, 14th August, 2012
DOI: 10.3987/COM-12-12543
SYNTHESIS,
REACTIONS,
AND
REARRANGEMENTS
OF
2,4-DIAZABICYCLO[3.1.0]HEXAN-3-ONES
Helmut Quast,* Josef Walter Stawitz, and Bodo Mueller
Institute of Organic Chemistry, University of Wuerzburg, Am Hubland, 97074
Wuerzburg, Germany; hquast@uni-osnabrueck.de
Abstract
–
Copper-mediated
cyclopropanation
of
1,3-dialkyl-1,3-
dihydroimidazol-2-ones with diazomethane and methyl diazoacetate yields
2,4-diazabicyclo[3.1.0]hexan-3-ones and the first diaza[4.3.1]propellane. The
bicyclic system survives elevated temperatures and in strongly basic and acidic
solutions, but drastic conditions cleave the (C-1)–(C-6) bond affording
1,3-dihydroimidazol-2-ones. Catalytic hydrogenation removes N-benzyl groups
and opens the (C-1)–(C-6) bond. Lithium aluminium hydride reduces
2,4-dibenzyl-2,4-diazabicyclo[3.1.0]hexan-3-one
to
a
bicyclic
aminal.
Acid-induced cleavage of its imidazolidine ring is followed by unexpected
transformations that probably procede via an acyclic intermediate, which
comprises an azomethine ylide and an iminium moiety. 1,3-Cyclization involving
both functional groups leads to N,N’-dibenzyl-trans-1,2-cyclopropanediamine,
while 1,5-cyclization gives rise to the formation of N-benzylpyrrole along with
N-benzylamine.
INTRODUCTION
Since the Sixties, an increasing number of heterobicyclo[3.1.0]hexanes have been synthesized by [2+1]
cycloaddition reactions of carbenes and carbenoids at CC double bonds that are part of five-membered
heterocycles.1–6 In search of a novel route to cis-1,2-cyclopropanediamines, we employed the [2+1]
cycloaddition strategy and synthesized the first 2,4-diazabicyclo[3.1.0]hexan-3-ones by copper-mediated
cyclopropanation of 1,3-dihydroimidazol-2-ones with diazo compounds.7 Thereafter, several examples
appeared in the literature: 2,4-Diazabicyclo[3.1.0]hexan-3-ones 1 were obtained as byproducts of the
Curtius degradation of cis-1,2-cyclopropanedicarboxylic acids.8,9 Cyclopropanation of 1,3-diacetyl-1,3-
dihydroimidazol-2-ones, either copper-catalyzed with diazomethane10 or by Simmons-Smith reaction,11
Dedicated to Professor Waldemar Adam on the occasion of his 75th birthday

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HETEROCYCLES, Vol. 85, No. 10, 2012
furnished low yields of 2a and 2b, respectively. The latter was converted into 2c and 2d.11 Recently,
Schaumann and coworkers reported formation and X-ray diffraction analysis of the annelated
2,4-diazabicyclo[3.1.0]hexan-3-one 3.12 Apart from being attractive in their own right,
2,4-diazabicyclo[3.1.0]hexan-3-ones promise to show interesting pharmacological properties as they are
homologues of 1,3-dihydroimidazol-2-ones, which exhibit broad biological activities.13 Therefore, it
comes as no surprise that the 2,4-diazabicyclo[3.1.0]hexane system emerged as integral part of bioactive
molecules in the medicinal chemistry literature.14
Here we give a full account of our earlier7 and subsequent experiments with the view of (i) exploring
scope and limitations of the copper-mediated cyclopropanation of 1,3-dihydroimidazol-2-ones with diazo
compounds and (ii) probing stability and some aspects of the reactivity of
2,4-diazabicyclo[3.1.0]hexanones.
R2
R2
Me
Me
Ph
R1
R1
R1
R1
N
N
N
t-Bu
O
O
N
N
R2
O
S
N
Me
Me
H
1
2
O
1a: R1 = R2 = H8
2a: R1 = H, R2 = CO-Me10
2b: R1 = Me, R2 = CO-Me11
2c: R1 = Me, R2 = H11
3
1b: R1 = H, R2 = CO2t-Bu8
1c: R1 = H, R2 = CO2CH2Ph8,9
1d: R1 = Me, R2 = CO2CH2Ph9
2d: R1 = Me, R2 = NO2
11
Chart 1. 2,4-Diazabicyclo[3.1.0]hexan-3-ones
RESULTS AND DISCUSSION
Cyclopropanation of cis-1,2-ethenediamines whose configuration is fixed by a ring may be imagined as
key step of a novel access to cis-1,2-cyclopropanediamines.7 In principle, this strategy for the synthesis of
cis-1,2-substituted cyclopropanes is not new: For example, Maier and Sayrac employed it as early as 1966
to synthesize cis-1,2-cyclopropanedicarboxaldehyde.2 In pursuit of our synthetic objective, we conceived
1,3-dihydroimidazol-2-ones (4, 6) as equivalents of cis-1,2-ethenediamines in the projected [2+1]
cycloaddition reaction, which thus would lead to 2,4-diazabicylo[3.1.0]hexan-3-ones.7 N-Benzyl
compounds 4 were preferred over the corresponding N-methyl analogs, because these tend to be
hygroscopic.15 More important, N-benzyl substituents provide a convenient criterion for the distinction
between planar starting materials and 2,4-diazabicylo[3.1.0]hexanes: N-Benzyl protons of the former are
1
enantiotopic (i. e., they appear equivalent in normal H NMR spectra), whereas those of the latter are
diastereotopic.

HETEROCYCLES, Vol. 85, No. 10, 2012
2451
While 1,3-dihydroimidazol-2-ones undergo sensitized [2+2] and [4+2] photocycloaddition reactions,16
they are reluctant toward thermal cycloaddition. Therefore, we tried in exploratory experiments one of the
most efficient cyclopropanation procedures, viz. the Gaspar-Roth method,17 which involves passing
gaseous diazomethane carried in a stream of dry nitrogen18 into a suspension of cuprous chloride in the
liquid, olefinic substrate or concentrated solutions thereof. Even benzene is attacked by the intermediate
in the copper-mediated decomposition of diazomethane.17 Likewise, the Gaspar-Roth method
cyclopropanated N-carbomethoxypyrrol to afford the first example of the 2-azabicyclo[3.1.0]hexane ring
system.3
It was gratifying to observe a single product (5a) when the Gaspar-Roth protocol was applied to 4a.
Unfortunately, numerous attempts to achieve more than ca. 15 – 20 % conversion in this way met with
failure. The conversion increased to 50 %, however, when a very large excess of diazomethane in diethyl
ether19 was allowed to distill into concentrated solutions of 4a in the presence of cuprous chloride (under
nitrogen and strict exclusion of moisture). The mixture turned dark due to formation of colloidal
copper(0)20 and was worked-up with the view to avoid the deleterious effect of further dilution and to
renew the catalyst. The resulting oil was again subjected to the cyclopropanation procedure to improve
the ratio 4a:5a to 18:82. Chromatography on silicagel readily separated 4a and 5a, which could be
purified further by short-path distillation under high vacuum. A yield of almost 80% was realized in this
way.
Already a single treatment of 4,5-dimethylimidazolone 4b with diazomethane/CuCl furnished a
reasonable conversion to 5b, whereas this procedure had to be repeated several times to achieve an
acceptable conversion of the annelated imidazolone 6 to diaza[4.3.1]propellane 7 (Scheme 1).21
CH2Ph
O
CH2Ph
N
R
R
N
R
CH2N2
.
.
O
R
N
CuCl, Et2O
N
CH2Ph
CH2Ph
4
5
4a, 5a (79 %): R = H
4b, 5b (36 %): R = Me
Me
Me
N
N
CH2N2
O
O
N
CuCl, Et2O
47 %
N
Me
Me
6
7
Scheme 1. Copper-mediated cyclopropanation of 1,3-dihydro-2H-imidazol-2-ones 4 and 6 with
diazomethane

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HETEROCYCLES, Vol. 85, No. 10, 2012
A number of unsaturated five-membered rings have been cyclopropanated by methyl and ethyl
diazoacetate in the presence of copper bronze, copper salts, and copper complexes. The 6-alkoxycarbonyl
groups of the resulting (hetero)bicyclo[3.1.0]hexane derivatives adopted preferentially the exo position,
corresponding to a trans-selective [2+1] cycloaddition.1,3–5,22
Mixtures of 4a and methyl diazoacetate were heated in boiling diethyl ether in the presence of copper
bronze, the oldest copper catalyst23 (Scheme 2). Two isomeric products arose in almost quantitative
combined yield, along with some dimethyl fumarate and maleate. An excess of copper bronze (1.4
mol/mol 4a) was required for a smooth reaction since smaller amounts (0.9 mol/mol 4a) resulted in
recovery of substantial fractions of starting material, even after extended periods of time. The crystalline
major product 8 was isolated conveniently in good yield, while the minor, oily product had to be
separated from small amounts of the former by chromatography. Analytical and spectroscopic evidence
suggested structure
9
for the minor product, which corresponds to an insertion of
methoxycarbonylcarbene into a ring C–H bond of the starting material 4a. Copper-mediated insertion of
methoxycarbonylcarbene into sp2 C–H bonds has been observed.6 However, 9 is also formed by
rearrangement of the major product 8 at elevated temperatures (see below). Consequently, speculation as
to the way of formation of 9 is not warranted in the absence of experimental evidence.
Ring-methylated imidazolone 4b reacted slower than 4a. Therefore, a higher excess of both methyl
diazoacetate and copper bronze and THF instead of diethyl ether were employed. The product consisted
of at least five components. Chromatography allowed to isolate a mixture of the isomers 10 and 11.
High-vacuum distillation of this fraction gave a mixture of 10 and 11 (2:3) and left 11 as pure oil.
Apparently, 10 is thermally labile and rearranges in a homo-[1.5]H shift to 11. This rearrangement is
well-kown for alkyl cis-2-methylcyclopropanecarboxylates.24 Structure 11 of the major product is
suggested by NMR spectroscopic comparison with the similar compound 12, which arises besides 4b by
1
benzylation of 4,5-dimethyl-1,3-dihydroimidazol-2-one (see Supporting Information). The H NMR
spectra of both compounds exhibit the expected doublet pattern for the diastereotopic protons of
methylene groups at C-4 and C-5. Other 1,3,5,5-tetraalkyl-4-methyleneimidazolidin-2-ones of type 12 are
known for long.25
A number of attempts to employ dimethyl diazomalonate in the copper-catalyzed cyclopropanation of 4a
met with failure. Heating of solutions of 4a and dimethyl diazomalonate in the presence of copper bronze
gave complex mixtures. None of the fractions separated by chromatography showed the typical AB
pattern of diastereotopic N-benzyl protons in the NMR spectrum.

HETEROCYCLES, Vol. 85, No. 10, 2012
2453
CH2Ph
O
MeO2C
CH2Ph
N
N
MeO2CCHN2
Cu, Et2O
MeO2C
4a
O
N
N
CH2Ph
CH2Ph
8 (77 %)
9 (20 %)
MeO
MeO2C
Me
CH2Ph
CH2Ph
Homo-
[1.5]H-shift
O
H
N
MeO2CCHN2
Cu, THF, 76 %
N
Me
4b
O
O
N
N
CH2Ph
CH2Ph
10 (12 %)
11 (64 %)
Ph
Me
CH2Ph
N
O
N
12
CH2Ph
Scheme 2. Copper bronze-mediated cyclopropanation of 1,3-dihydro-2H-imidazol-2-ones 4 with methyl
diazoacetate
The 2,4-diazabicyclo[3.1.0]hexan-3-one structures 5, 7, 8, and 10 of the cyclopropanation products were
immediately evident from NMR spectra: These indicate the presence of a symmetry plane passing
through C-3 and C-6 and bisecting the bond between the bridgehead carbon atoms; protons of N-benzyl
groups are diastereotopic due to the presence of centres of chirality (C-1 and C-5); and signals of
cyclopropane protons appear at high field. They were assigned for 5a to 6-Hexo and 6-Hendo on the basis of
3
3
the well-established rule for vicinal coupling between cyclopropane protons, viz., Jtrans< Jcis.26,27 The
6-methoxycarbonyl group of 8 was attributed the exo configuration as suggested by the small size of the
vicinal coupling constant 3J1-H,6-H = 1.8 Hz = 3Jtrans
.
General chemical properties and stability of 2,4-diazabicyclo[3.1.0]hexan-3-ones have not been reported
so far. An exploratory study of these aspects employed those of the present work. Reaction conditions and
results are summarized in Scheme 3.
The 2,4-diazabicyclo[3.1.0]hexan-3-ones 5a and 5b can be recovered unchanged after dry heating at
150 °C or heating for several hours in boiling acetic acid. Under these conditions, 8 opens the
(C-1)–(C-6) bond to afford 1,3-dihydroimidazol-2-one 9. In strongly basic media, 5a and 8 differ in the
same way: While 5a survives unchanged in an ethanolic solution of 10% potassium hydroxide at elevated
temperatures, 8 undergoes (C-1)–(C-6) ring opening with concomitant hydrolysis of the ester group under
similar conditions (→16). However, the bicyclic system remains intact and only hydrolysis is observed
when 8 is heated in aqueous sodium carbonate (→13). Decarboxylation and (C-1)–(C-6) ring cleavage

2454
HETEROCYCLES, Vol. 85, No. 10, 2012
occur on heating of the acid 13 at 150 °C to yield 15. The same compound is obtained on brief heating of
both 5a and 8 in dilute aqueous sulfuric acid. Catalysis by both strong acid and strong base of these
rearrangements indicate operation of polar mechanisms.
As expected, catalytic hydrogenation removes the N-benzyl groups of 8 and selectively cleaves one of the
cyclopropane bonds adjacent to the methoxycarbonyl group to furnish 14.
9
(a) (b)
CH2Ph
O
HO2C
H
N
N
MeO2C
8
O
(c)
(d)
(g)
N
N
H
CH2Ph
14
_
_
(e)
CO2
CO2 (f)
13
CH2Ph
N
CH2Ph
N
Me
HO2C
5a
O
O
(f)
N
N
CH2Ph
CH2Ph
16
15
(a): HOAc, 3 h, 115 °C; quant.
(b): 140-150 °C; quant.
(d): H2, Pd/C, EtOH, 54 °C, 24 h; 75 %
(e): 150 °C; 88 %
(c): aq. Na2CO3 (1M), 100 °C; 90 %
(f): aq. H2SO4 (1
M), 80-90 °C; 81-85 %
(g): aq. KOH (20 %), 80 °C; 85 %
Scheme 3. Reactions and rearrangements of 2,4-diazabicyclo[3.1.0]hexan-3-ones 5a and 8
The results of the preceding section suggest that selective cleavage of the five-membered ring of
2,4-diazabicyclo[3.1.0]hexan-3-ones is not feasible. In pursuit of our original objective of developing a
novel route to cis-1,2-cyclopropanediamines, we reduced of 5a using lithium aluminium hydride.28 An
almost quantitative yield of the corresponding bicyclic aminal 17 was realized in this way. Aminal 17 can
be distilled under high vacuum and is stable in methanol in the presence of sodium hydroxide but
decomposes slowly, even under nitrogen, yielding red-brown polymeric products.
While N,N’-dibenzyltetrahydroimidazol was rapidly hydrolyzed by dilute hydrochloric acid to afford a
quantitative yield of N,N’-dibenzyl-1,2-ethanediamine dihydrochloride,7 17 reacted in acidic media in
puzzling ways. It dissolved in acetic acid with dark red color. An intense red color was also observed on
addition of strong acids to solutions of 17 in ethanol. Work-up yielded resin-like products that lacked
cyclopropane rings. Introduction of dry hydrogen chloride into a solution of 17 in dry diethyl ether gave a
1
colorless precipitate, which decomposed above 68 °C and deliquesced on exposure to air. The H NMR
spectrum recorded for a solution in trifluoracetic acid showed an ABX2 spectrum attributable to protons
of a cis-1,2-disubstituted cyclopropane, which disappeared overnight, however.

HETEROCYCLES, Vol. 85, No. 10, 2012
2455
CH2Ph
NH2
2Cl
CH2Ph
CH2Ph
NH
N
LiAlH4, Et2O
94 %
H
H
5a
N
N
NH2
CH2Ph
CH2Ph
18
CH2Ph
17
cis-19
cis-
CH2Ph
CH2Ph
NH
NH CH2Ph
N
N
N
N
CH2Ph
CH2Ph
CH2Ph
21
trans-18
20
25 %
89 %
CH2Ph
NH2
PhCH2-NH3 Cl
N
H2N
CH2Ph
CH2Ph
2Cl
23
trans-19
22
Scheme 4. Synthesis and acid-induced cleavage of 2,4-dibenzyl-2,4-diazabicyclo[3.1.0]hexane (17)
Treatment of 17 with 0.1–1 M hydrochloric acid and separation of neutral, unknown products furnished,
surprisingly, trans-19 rather than expected cis-19. The trans configuration of this product was evident
1
from an AA’XX’ spin system, present according to the H NMR spectrum, and established by
comparison with the authentic dihydrobromide.9 Experiments using higher concentrations of hydrochloric
acid (10–35 %) afforded substantial amounts of colored decomposition products and, after basic work-up
and distillation at 10-3 Torr, oily mixtures that exhibited ABX2 systems at high field, corresponding to
cis-1,2-substituted cyclopropanes. Weakly acidic media such as 2 M aqueous acetic acid or a two-phase
system consisting of chloroform and a saturated aqueous solution of copper(II) sulfate converted 17 into
N-benzylpyrrole (22)29 and N-benzylammonium chloride (23). Signals of cyclopropane protons were not
observed in these experiments. The appearance of acid-sensitive 22 would explain the deep red-brown
colors developed by 17 in acidic media.
The results may be rationalized in terms of Scheme 4, which is based on extensive studies of the reactions
of 1,2-cyclopropanediamines with aldehydes and ketones.30 Opening of the five-membered ring of
protonated 17 leads to the iminium ion cis-18. In strongly acidic solution, this can be hydrolyzed in part
to yield cis-19, because ring cleavage to azomethine ylide 20 is disfavored due to protonation of the
amino group of cis-18. Lower concentrations of hydrochloric acid give rise to cis/trans isomerization
cis-18→20→trans-18 followed by hydrolysis of the latter (→trans-19). Weakly acidic media favor

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HETEROCYCLES, Vol. 85, No. 10, 2012
ring-expansion cis-18→20→21, which finally leads to 22. Azomethine ylide 20 is invoked as common
intermediate that may explain the cis/trans rearrangement to trans-1,2-cyclopropanediamine trans-19 as
well as the cyclization to N-benzylpyrrol (22). Clearly, these unexpected transformations prevented
realization of our original objective. However, they provided the impetus for productive studies of
1,2-cyclopropanediamines.30
The present work delineates
a
straightforward route to and some reactions of
2,4-diazabicyclo[3.1.0]hexan-3-ones, as yet a somewhat neglected heterobicyclic system. It is quite
robust under a variety of conditions due to the inherent urea partial structure. Owing to the stability,
2,4-diazabicyclo[3.1.0]hexan-3-ones may replace cyclic urea moieties in many instances and thus lead to
novel systems and properties. Reduction yields an aminal (2,4-diazabicyclo[3.1.0]hexane). This
undergoes surprising reactions, probably involving an acyclic intermediate, which comprises an
azomethine ylide and an iminium moiety. The results of this study may be expected to foster
investigations of heterobicyclo[3.1.0]hexanes with the view of advanced applications. Extensions could
include cyclopropanation of differently substituted 1,3-dihydroimidazol-2-ones and heteroanalogs thereof
using modern transition metal catalysts.
EXPERIMENTAL
General Experimental and preparation of the 1,3-dialkyl-1,3-dihydroimidazol-2-ones 4a, 4b, and 6 used
1
as starting materials are detailed in the Supporting Information. H1H coupling constants given are
absolute values.
Copper-mediated cyclopropanation of 1,3-dihydroimidazol-2-ones with diazomethane, General
Procedure. Diazomethane was generated from N-nitroso-N-methylurea according to the method of
Arndt.19 Caution! N-nitroso-N-methylurea is suspected of being a carcinogen and diazomethane is highly
toxic and explosive. It must be handled in an efficient fume hood behind a protection shield. In a
brand-new 1L-Erlenmeyer flask (not etched or scratched), a solution of diazomethane was prepared from
N-nitroso-N-methylurea (51.5 g, 0.50 mol), aq. KOH (40%, 175 mL) and Et2O (0.3–0.5 L), cooled at 5 °C.
The ethereal solution was decanted, carefully dried with KOH pellets, and distilled under N2. To avoid
ground-glass joints, we used a distillation apparatus made in a single piece from a 1L-flask, attached to a
N2 supply, and a Liebig condensor, which was cooled at –30 °C. The adapter at the lower end of the
condensor carried a fire-polished glass tube. The tube passed through a two-holed rubber stopper and
reached almost the surface of a stirred, cooled (–15 to –10 °C) suspension in a 0.5-L-Erlenmeyer flask
protected by a drying tube. The suspension consisted of CuCl (dried over P2O5), the
1,3-dihydroimidazol-2-one and dry Et2O (4a, 7) or dry CH2Cl2 (4b). Distillation was interrupted as soon

HETEROCYCLES, Vol. 85, No. 10, 2012
2457
as the distillate became colorless. The dark suspension was filtered (Celite) and the solvent distilled i. vac.
to afford
a
pale yellow oily residue. The ratio 2,4-diazabicyclo[3.1.0]hexan-3-one vs.
1
1,3-dihydroimidazol-2-one was determined by H NMR. Treatment with diazomethane/CuCl was
repeated with the residue until a satisfactory ratio was obtained. Starting material and product were
separated by preparative layer or flash chromatography on silicagel with Et2O/hexane. The
cyclopropanation products were collected in the first fractions. Further purification by recrystallization
(5b) or short-path distillation in a sublimation apparatus (cold finger kept at –30 °C) under high vacuum
(5a, 7) afforded the pure cyclopropanation products (TLC, 1H NMR).
2,4-Dibenzyl-2,4-diazabicyclo[3.1.0]hexan-3-one (5a): The first treatment of 4a (7.92 g, 30 mmol,
solution in Et2O, 50 mL) with diazomethane in the presence of CuCl (5.0 g, 50 mmol) resulted in a pale
yellow oil (8.67 g) with a ratio 4a:5a = 52:48, the second gave a pale yellow oil (9.41 g) with a ratio
4a:5a = 18:82. Chromatography followed by distillation at 70–90 °C bath temp./10-5 Torr afforded a pale
1
yellow oil (6.80 g, 79%). IR (neat oil) ν [cm-1] = 1690 (s). MS (EI, 70 eV) m/z = 278 (M+). H NMR
(600.1 MHz, CDCl3): δ [ppm] = –0.130 (dt, 2J = 6.3 Hz, 3Jtrans = 2.7 Hz, 1 H, 6-Hendo), 0.296 (dt, 2J = 6.3
3
3
3
2
Hz, Jcis = 5.6 Hz, 1 H, 6-Hexo), 2.837 (dd, Jcis = 5.6 H, Jtrans = 2.7 Hz, 2 H, 1-H, 5-H), 4.265 (d, J =
2
14.8 Hz, 1 H, ½ CH2), 4.517 (d, J = 14.8 Hz, 1 H, ½ CH2), 7.17–7.27 (m, 10 H, 2 Ph). IR (neat oil) ν
[cm-1] = 1705 (s). MS (EI, 70 eV) m/z = 180 (M+). 13C NMR (150.9 MHz, CDCl3): δ [ppm] = 9.74 (CH2),
29.29 (CH), 47.82 (CH2), 127.21 (p-CH), 128.04, 128.33 (o, m-CH), 137.15 (ipso-C), 158.92 (C=O).
Anal. Calcd for C18H18N2O: C, 77.67; H, 6.52. Found: C, 77.49; H, 6.86.
2,4-Dibenzyl-1,5-dimethyl-2,4-diazabicyclo[3.1.0]hexan-3-one (5b): According to the General
Procedure, diazomethane was distilled into a mixture of 4b (8.77 g, 30 mmol), CuCl (5.0 g, 50 mmol) and
dry CH2Cl2 (35 mL). Filtration, distillation of the solvent i. vac., and treatment of the residue with cold
1
pentane yielded colorless crystals (9.17 g), which consisted of 4b and 5b with a ratio 38:62 (TLC, H
NMR). Chromatography and recrystallization from pentane yielded colorless crystals (3.35 g, 36 %), mp
1
88–90 °C. IR (KBr) ν [cm-1] = 1695 (s), 1680 (m). MS (EI, 70 eV) m/z = 306 (M+). H NMR (60 MHz,
2
CDCl3): δ [ppm] = –0.13, 0.01 (AB spectrum, J = 6.4 Hz, 2 H, 6-Hendo, 6-Hexo), 1.24 (s, 6 H, 2 CH3),
4.35, 4.69 (AB spectrum, 2J = 15.4 Hz, 4 H, 2 CH2), 7.34 (mc, 10 H, 2 Ph). Anal. Calcd for C20H22N2O: C,
78.40; H, 7.24; N, 9.14. Found: C, 78.34; H, 7.21; N, 9.16.
7,9-Dimethyl-7,9-diazatricyclo[4.3.1.01,6]decan-8-one (7): According to the General Procedure,
diazomethane was distilled into a mixture of 6 (15.0 g, 90 mmol), CuCl (5.0 g, 50 mmol) and Et2O (30
mL). The resulting pale yellow oil was treated once again with diazomethane/CuCl. Short-path
distillation of the oil at 50–75 °C bath temp./3×10-5 Torr yielded a colorless oil (14.0 g) consisting of
1
polymethylene (δH = 1.26 ppm), 6 and 7 (45:55, H NMR). Two further treatments of the oil with
diazomethane/CuCl and short-path distillation of the product at 50–75 °C bath temp./3×10-5 Torr gave a

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1
colorless oil (12.9 g, 6:7 = 27:73, H NMR). Flash chromatography on silicagel with CHCl3 and
short-path distillation at 3×10-5 Torr yielded a colorless, hygroscopic oil (7.61 g, 47%). IR (neat oil) ν
[cm-1] = 1705 (s). MS (EI, 70 eV) m/z = 180 (M+). 1H NMR (600.1 MHz, CDCl3): δ [ppm] = –0.020 (d, 2J
2
= 5.9 Hz, 1 H), 0.195 (dd, J = 5.9 Hz, J = 0.8 Hz, 1 H), 0.97–1.05 (m, 2 H), 1.22–1.30 (m, 2 H),
13
1.65–1.77 (m, 4 H), 2.587 (dd, J = 1.7 Hz, J = 0.6 Hz, 6 H, 2 CH3). C NMR (150.9 MHz, CDCl3): δ
[ppm] = 16.11 (CH2), 20.38 (2 CH2), 25.09 (2 CH2), 27.56 (2 CH3), 160.21 (C=O).
exo-2,4-Dibenzyl-6-carbomethoxy-2,4-diazabicyclo[3.1.0]hexan-3-one (8): A solution of methyl
diazoacetate (2.20 g, 22 mmol) in dry Et2O (25 mL) was added dropwise during 30 min to a stirred,
boiling mixture of 4a (2.64 g, 10 mmol), copper bronze (0.89 g, 14 mmol) and dry Et2O (25 mL). Heating
under reflux was continued for 5 h followed by filtration and distillation of the solvent i. vac. Short-path
distillation at rt/10-3 Torr removed decomposition products of methyl diazoacetate (dimethyl fumarate and
maleate, 1H NMR). The solid, pale yellow residue was treated with cold Et2O (0 °C, 2 × 10 mL) and the
insoluble material recrystallized from cyclohexane to afford colorless crystals (2.06 g, 62%) mp
105–106 °C. The solvent from the combined washings and mother liquor was distilled i. vac. and the
residue separated by chromatography to yield a second crop of 8 (1st fraction, 0.52 g, 15%) mp
103–105 °C, and 9 as pale yellow oil (2nd fraction, 0.71 g, 20%), which was identical with the
1
isomerization product of 8 (IR, H NMR, see below). 8: IR (KBr) ν [cm-1] = 1723 (s), 1688 (s). MS (EI,
70 eV) m/z = 336 (M+). 1H NMR (600.1 MHz, CDCl3): δ [ppm] = 1.010 (t, 3Jtrans = 1.8 Hz, 1 H, 6-Hendo),
3
2
3.477 (d, Jtrans = 1.8 Hz, 2 H, 1-H, 5-H), 3.574 (s, 3 H, OCH3), 4.324 (d, J = 14.8 Hz, 1 H, ½ CH2),
2
13
4.666 (d, J = 14.9 Hz, 1 H, ½ CH2), 7.28–7.32 (m, 6 H, Ph), 7.33–7.38 (m, 4 H, Ph). C NMR (150.9
MHz, CDCl3): δ [ppm] = 23.88 (CH-6), 39.08 (CH-1, CH-5), 47.77 (CH2), 51.81 (OCH3), 127.81 (p-CH),
128.16, 128.77 (o-, m-CH), 136.30 (ipso-C), 158.57 (C=O), 170.68 (CO2Me). Anal. Calcd for
C20H20N2O3: C, 71.41; H, 5.99; N, 8.32. Found: C, 71.80; H, 6.02; N, 8.36.
1,3-Dibenzyl-4-carbomethoxymethyl-1,3-dihydroimidazol-2-one (9): (a) 8 (1.35 g, 4.0 mmol) was
heated at 140–150 °C for 1 h to afford a pale yellow, very viscous oil (1.35 g, quant.). Attempts at
crystallization met with failure. IR (neat oil) ν [cm-1] = 1735 (CO2Me), 1678 (C=O). MS (EI, 70 eV) m/z
= 336 (M+). 1H NMR (60 MHz, CDCl3): δ [ppm] = 3.08 (s, 2 H, CH2), 3.47 (s, 3 H, OCH3), 4.69 (s, 2 H,
CH2), 4.80 (s, 2 H, CH2), 6.00 (s, 1 H, 5-H), 7.13, 7.19 (mc, 10 H, 2 Ph). Anal. Calcd for C20H20N2O3: N,
8.32. Found: N, 8.42.
(b) A solution of 8 (1.35 g, 4.0 mmol) in acetic acid (15 mL) was heated at 80 °C for 3 h followed by
evaporation of the solvent at rt/10-2 Torr to afford 9 (1.36 g, quant.) as a pale yellow viscous oil (TLC, IR,
1H NMR).
exo-2,4-Dibenzyl-6-carbomethoxy-2,4-diazabicyclo[3.1.0.]hexan-3-one (10) and 1,3-Dibenzyl-5-
carbomethoxymethyl-5-methyl-4-methylene-1,3-dihydroimidazol-2-one (11): A solution of methyl

HETEROCYCLES, Vol. 85, No. 10, 2012
2459
diazoacetate (4.30 g, 43 mmol) in dry THF (30 mL) was added dropwise during 30 min to a stirred,
boiling mixture of 4b (1.82 g, 6.2 mmol), copper bronze (2.0 g, 31 mmol) and dry THF (20 mL). Heating
under reflux was continued for 6 h followed by filtration of the brown suspension and distillation of the
solvent at 15 Torr and finally at 70 °C bath temp./10-2 Torr to afford a brown resin (2.96 g), which
consisted of at least 5 components (TLC). Chromatography and drying of the main fraction for 1 h at
40–50 °C/10-5 Torr yielded a yellow oil (1.79 g). Short-path distillation at 100–120 °C bath temp./10-5
1
Torr furnished a colorless oil (0.69 g, 30%) consisting of 10 and 11 (2:3, TLC, H NMR). The residue
was pure 11 as yellow oil (1.04 g, 46%), (TLC, 1H NMR).
1
10: H NMR (60 MHz, CDCl3): δ [ppm] = 0.80 (s, 1 H, 6-Hendo), 1.44 (s, 6 H, 2 CH3), 3.46 (s, 3 H,
OCH3), 4.37, 4.61 (AB spectrum, 2J = 15.4 Hz, 4 H, 2 CH2), 7.29 (m, Ph).
10, 11 (2:3): Anal. Calc. for C22H24N2O: C, 72.51; H, 6.64; N, 7.69. Found: C, 72.38; H, 6.59; N, 7.65
11: 1H NMR (60 MHz, CDCl3): δ [ppm] = 1.25 (s, 3 H, CH3), 2.47, 2.66 (AB spectrum, 2J = 16 Hz, 2 H,
CH2), 3.39 (s, 3 H, OCH3), 3.85, 3.95 (AB spectrum, 2J = 2.8 Hz, 2 H, = CH2), 4.45, 4.62 (AB spectrum,
2J = 16 Hz, 2 H, CH2), 4.69 (s, 2 H, CH2), 7.29 (mc, 10 H, 2 Ph).
exo-2,4-Dibenzyl-6-carboxy-2,4-diazabicyclo[3.1.0]hexan-3-one (13): A suspension of 8 (1.35 g, 4.00
mmol) in aq. Na2CO3 (1 M, 25 mL) was heated under reflux for 4 h. Filtration and acidification of the
filtrate with aq. HCl (2 M) yielded a preciptate, which was isolated by filtration and washed with water to
yield colorless crystals (1.16 g, 90 %) mp 119–120 °C (dec.). IR (KBr) ν [cm-1] = 1710 (s, br.), 1670 (s,
1
3
br.). H NMR (60 MHz, CDCl3): δ [ppm] = 0.88 (br., 1 H, 6-Hendo), 3.45 (d, Jtrans = 1.6 Hz, 1-H, 5-H),
2
4.37, 4.62 (AB spectrum, J = 15 Hz, 4 H, 2 CH2), 7.30 (mc, 10 H, 2 Ph), 9.74 (br., 1 H, CO2H). Anal.
Calcd for C19H18N2O3: N, 8.69. Found: N, 8.62.
4-Carbomethoxymethyl-1,3-dihydroimidazol-2-one (14): A quantitative micro hydrogenation
apparatus by NORMAG, O. Fritz, Hofheim am Taunus, Germany, was used. A vigorously stirred
suspension of Pd/C (10%, 200 mg) in a solution of 8 (342 mg, 1.02 mmol) in EtOH (15 mL) was kept at
735 Torr H2 pressure and 54 °C. Consumption of H2 ceased after 24 h, when 85.3 mL of H2 (3.08 mmol)
had been consumed. Filtration, washing of the catalyst with EtOH (50 mL), distillation of the solvent i.
vac., and recrystallization of the residue from benzene yielded colorless crystals (121 mg, 75%), mp
108–109 °C. IR (KBr) ν [cm-1] = 1730 (s), 1695 (s). MS (EI, 70 eV) m/z = 158 (M+). 1H NMR (90 MHz,
D2O, LAOCOON III simulation of the ABMX2 spectrum): δ [ppm] = 2.71 (d, X part of an ABMX2
spectrum, 3JMX = 6.4 Hz, 2 HX, 4-CH2), 3.25 (m, 2JAB = –9.3 Hz, 3JAM = 6.2 Hz, HA, 5-H), 3.72 (m, 2JAB
=
–9.3 Hz, 3JBM = 9.1 Hz, HB, 5-H), 4.21 (m, 3JAM = 6.2 Hz, 3JBM = 9.1 Hz, 3JMX = 6.4 Hz, HM, 4.H), 3.76 (s,
1
3 H, OCH3); H NMR in CDCl3: Ref.31 Anal. Calcd for C6H10N2O3: C, 45.56; H, 6.37. Found: C, 45.02;
H, 6.36.

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HETEROCYCLES, Vol. 85, No. 10, 2012
1,3-Dibenzyl-4-methyl-1,3-dihydroimidazol-2-one (15): (a) The acid 13 (645 mg, 2.00 mmol) was
heated at 120–140 °C for 2 h. The product was dissolved in a small amount of Et2O. Filtration followed
by cooling to –25 °C yielded pale yellow crystals (490 mg, 88 %), mp 68–70 °C.32 IR (KBr) ν [cm-1] =
1
4
1682 (s), 1673 (s). H NMR (60 MHz, CDCl3): δ [ppm] = 1.85 (d, J = 1.4 Hz, 3 H, CH3), 4.80 (s, 2 H,
4
CH2), 4.87 (s, 2 H, CH2), 5.83 (q, J = 1.4 Hz, 1 H, 5-H), 7.25, 7.28 (mc, 10 H, 2 Ph). Anal. Calcd for
C18H18N2O: N, 10.06. Found: N, 10.02
(b) A stirred mixture of 8 (673 mg, 2.00 mmol), and aq. H2SO4 (1 M, 10 mL) was heated at 80 °C for 30
min followed by extraction with Et2O. The org. layer was dried with K2CO3, the solvent distilled i. vac.,
and the residue recrystallized from Et2O at –25 °C to yield pale yellow crystals (451 mg, 81%), mp
69–70 °C.
(c) A solution of 5a (279 mg, 1.00 mmol) in aq. H2SO4 (1 M, 5 mL) was heated at 90 °C for 1 h. The
mixture was neutralized with aq. NaOH (2 M) and extracted with CH2Cl2. The org. layer was dried with
K2CO3. Distillation of the solvent i. vac. gave a yellow-brown oil (237 mg, 85 %), which was a single
compound (TLC) and identical with 15 (1H NMR).
1,3-Dibenzyl-4-carboxymethyl-1,3-dihydroimidazol-2-one (16): A stirred mixture of 8 (1.35 g, 4.00
mmol) and aq. KOH (20%, 20 mL) was heated at 70–80 °C for 30 min. The mixture was filtered and the
filtrate neutralized with aq. conc. HCl to afford colorless crystals (1.10 g, 85 %), mp 147–149 °C (dec).
1H NMR (60 MHz, CDCl3): δ [ppm] = 3.17 (s, 2 H, CH2), 4.83 (s, 2 H, CH2), 4.92 (s, 2 H, CH2), 7.23,
7.27 (mc, 10 H, 2 Ph), 9.2 (br., 1 H, CO2H).
2,4-Dibenzyl-2,4-diazabicyclo[3.1.0]hexane (17): A solution of 5a (2.79 g, 10 mmol) in Et2O (10 mL)
was added to a stirred solution of LiAlH4 (1.36 g, 35 mmol) in Et2O (100 mL). Stirring was continued for
2 d followed by decomposition of the excess of LiAlH4 with the calculated amount of ice-water, filtration,
and distillation of the solvent i. vac. to afford a pale yellow liquid (2.64 g). Short-path distillation in a
sublimation apparatus (cold finger at –30 °C) at 50–70 °C bath temp./10-5 Torr gave a colorless oil (2.49 g,
94 %). IR (neat oil) ν [cm-1] = 1600 (m), 1580 (w), 1490 (s). – MS (EI, 70 eV) m/z = 264 (M+). 1H NMR
(60 MHz, CDCl3, LAOCOON III simulation of the ABX2 spectrum): δ [ppm] = –0.02 (dt, 2JAB = –6.8 Hz,
3Jcis = 6.2 Hz, 1 H, 6-Hexo), 1.25 (dt, 2JAB = –6.8 Hz, 3Jtrans = 3.0 Hz, 1 H, 6-Hendo), 2.67 (d, 2J = 5.6 Hz, 1
H, 3-H), 2.85 (dd, 3Jcis = 6.2 Hz, 3Jtrans = 3.0 Hz, 2 H, 1-H, 5-H), 3.72 (s, 4 H, 2 CH2), 3.87 (d, 2J = 5.6 Hz,
1 H, 3-H), 7.2–7.6 (m, 10 H, 2 Ph). Anal. Calcd for C18H20N2: C, 81.77; H, 7.62; N, 10.59. Found: C,
81.32; H, 7.63; N, 10.60.
N,N’-Dibenzyl-trans-1,2-cyclopropanediamine Dihydrochloride (trans-19): Under N2, a solution of 17
(2.64 g, 10 mmol) in Et2O (6 mL) was added to stirred aq. HCl (1 M, 50 mL). Stirring was continued for 2
h followed by extraction with CHCl3. Water was distilled i. vac. at 30–40 °C bath temp. from the
colorless aq. layer. The solid residue was dried at 70 °C/0.001 Torr and triturated with a small amount of

HETEROCYCLES, Vol. 85, No. 10, 2012
2461
cold ethanol. The insoluble material was isolated by filtration and recrystallized from EtOH to afford pale
1
pink crystals (0.80 g, 25%), mp 225–230 °C (dec.). The H NMR spectrum (D2O) was superimposable
with the one recorded for the dihydrobromide.9 Anal. Calcd for C17H22Cl2N2: C, 62.77; H, 6.82; Cl,
21.80; N, 8.61. Found: C, 62.78; H, 7.01; Cl, 21.91; N, 8.77.
N-Benzylpyrrole (22): (a) A solution of 17 (132 mg, 0.50 mmol) in CHCl3 (10 mL) was vigorously
stirred for 1 h in the presence of sat. aq. CuSO4 (5 mL). The org. layer was dried with K2CO3 followed by
distillation of the solvent i. vac. to afford a pale brown oil (69 mg, 89%), which was pure and identical
with an authentic sample (IR, 1H NMR) prepared by phase transfer catalysed N-benzylation of pyrrole.29
(b) A solution of 17 (132 mg, 0.50 mmol) in Et2O (10 mL) was stirred for 0.5 h in the presence of aq.
acetic acid (2 M, 10 mL) followed by separation of the layers and extraction of the aq. layer with Et2O.
Drying of the combined org. layers with K2CO3 and distillation of the solvent i. vac. yielded almost pure
22 as yellow oil (1H NMR). Aq. HCl (2 M, 20 mL) was added to the aq. layer followed by distillation of
the solvent i. vac. and trituration of the residue with a small amount of EtOH to furnish N-
1
benzylammonium chloride (23) as colorless powder (IR, H NMR); picrate (from ethanol): mp
193–195 °C; authentic sample: mp 194 °C.
ACKNOWLEDGEMENTS
We express our gratitude to Mrs. Elfriede Ruckdeschel and Dr. Matthias Gruene, University of
Wuerzburg, for taking the high-field NMR spectra, and to Dr. Gerda Lange for recording the mass spectra.
Financial Support by the Deutsche Forschungsgemeinschaft (DFG) and the Fonds der Chemischen
Industrie, Frankfurt/Main, is gratefully acknowledged.
SUPPORTING INFORMATION AVAILABLE
General experimental, preparation of 1,3-dialkyl-1,3-dihydroimidazol-2-ones (4a, 4b, 6) (6 pages), and
NMR spectra recorded for 5a, 7, 8, 14, and 17 (8 pages). This material is available free of charge via the
Internet at http://www.heterocycles.com or from the author.
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