Versatile access to 2-aminocyclobutene-1-carboxylic acid derivatives and their incorporation into small peptides

Article abstract of DOI:10.1002/ejoc.201000283

Under a newly developed set of mild conditions [EtN(iPr)₂, LiI, DMF, 20 °C, 3 d], methyl 2-chloro-2-cyclopropylideneacetate (1) smoothly undergoes Michael addition of various benzylamines (4 examples) with ensuing ring enlargement and elimination to give in very good yields (81-99%) the correspondingly substituted methyl 2-(benz-ylammojcyclobutenecarboxylates 3a-d, which were subsequently converted into the N-Boc-protected derivatives 4a-d. After hydrolysis of the esters, the free β-amino acids 5a, b were cleanly condensed with the methyl esters of glycine, (S)-proline, (S)-phenylglycine and (S)-tryptophan to give the dipeptides 6a-8a, 9b in 58-89% yield. The cyclic dipeptides 15e,f, consisting of a 2-aminocyclobutenecarboxylic acid and a glycine fragment, were obtained in 38 and 45 % yield, respectively, upon treatment of the spirocyclopropanated chlorohexahydrodiazepinediones 10e,f with sodium cyanide in DMSO at elevated temperatures. Palladium-catalyzed hydrogenation of 4a afforded, methyl N-Boc-2-aminocyclobutanecarboxylate 19 as a mixture of cis and trons isomers.

Full text of DOI:10.1002/ejoc.201000283

FULL PAPER
DOI: 10.1002/ejoc.201000283
Versatile Access to 2-Aminocyclobutene-1-carboxylic Acid Derivatives and
Their Incorporation into Small Peptides[‡]
Armin de Meijere,*[a] Michael Limbach,[a] André Janssen,[a] Alexander Lygin,[a] and
Vadim S. Korotkov[a]
Keywords: Cyclopropanes / Amino acids / Cyclobutenes / Peptidomimetics / Molecular diversity
Under a newly developed set of mild conditions [EtN(iPr)2,
LiI, DMF, 20 °C, 3 d], methyl 2-chloro-2-cyclopropylid-
eneacetate (1) smoothly undergoes Michael addition of
various benzylamines (4 examples) with ensuing ring en-
largement and elimination to give in very good yields (81–
99%) the correspondingly substituted methyl 2-(benz-
ylamino)cyclobutenecarboxylates 3a–d, which were sub-
sequently converted into the N-Boc-protected derivatives
4a–d. After hydrolysis of the esters, the free β-amino acids
5a,b were cleanly condensed with the methyl esters of gly-
cine, (S)-proline, (S)-phenylglycine and (S)-tryptophan to
give the dipeptides 6a–8a, 9b in 58–89% yield. The cyclic
dipeptides 15e,f, consisting of a 2-aminocyclobutenecarbox-
ylic acid and a glycine fragment, were obtained in 38 and
45% yield, respectively, upon treatment of the spirocyclopro-
panated chlorohexahydrodiazepinediones 10e,f with sodium
cyanide in DMSO at elevated temperatures. Palladium-cata-
lyzed hydrogenation of 4a afforded methyl N-Boc-2-amino-
cyclobutanecarboxylate 19 as a mixture of cis and trans iso-
mers.
tives.[10] Notably, only a few examples of 2-aminocyclobut-
enecarboxylic acid derivatives, all of them with a dialkyl-
amino group on the double bond, have previously been
synthesized.[11,12] Here we report on a convenient synthesis
of some new 2-aminocyclobut-1-ene-1-carboxylates, and
their incorporation into conformationally restricted dipep-
tide mimics as well as their possible catalytic hydrogenation
to provide 2-aminocyclobutanecarboxylates.
Introduction
Methylenecyclopropane and its derivatives[1] are en-
dowed with enhanced reactivities across their double
bonds[2] as well as their three-membered rings,[3] and this
has been utilized in a multitude of synthetically useful
transformations. With an electron-withdrawing group at-
tached to the double bond such as in an alkyl 2-cyclopro-
pylideneacetate,[4] a dialkyl cyclopropylidenemalonate,[5]
methyl
2-(benzyloxycarbonylamino)-2-cyclopropylidene-
acetate,[6] an alkyl 2-bromo-2-cyclopropylideneacetate[7] or
an alkyl 2-chloro-2-cyclopropylideneacetate such as 1,[8]
methylenecyclopropanes are particularly good dienophiles
as well as Michael acceptors.
Results and Discussion
Michael adducts of benzophenoneimine and secondary
amines with 1 have been found to undergo facile transfor-
mations to protected 2-aminocyclobutene-1-carboxylates
under appropriate conditions.[9,10] So far, the only two ex-
amples of sensitive adducts of primary amines to 1 have
been prepared in moderate yields and employed in the syn-
thesis of the first 2-azaspiropentanecarboxylic acid deriva-
Upon treatment of the meanwhile conveniently accessible
methyl 2-chloro-2-cyclopropylideneacetate (1)[13] with ben-
zylamine (2a) in N,N-dimethylformamide in the presence of
1 equiv. of lithium iodide and ethyldiisopropylamine
(Hünig’s base) at 0–20 °C for 3 d, methyl 2-(benzylamino)-
cyclobut-1-ene-1-carboxylate (3a) was isolated in 85% yield.
Apparently, the initially formed Michael adduct of 2a onto
1, just like those of benzophenoneimine and secondary
[‡] Cyclopropyl Building Blocks for Organic Synthesis, 155. Part amines under certain conditions,[9,10] immediately under-
154: A. de Meijere, A. F. Khlebnikov, H. W. Sünnemann, K.
went rearrangement with ring enlargement and ensuing eli-
Rauch, D. S. Yufit, Eur. J. Org. Chem., submitted. Part 153: M.
mination of hydrogen chloride. As the multifunctional
structural unit of 3a appeared to be interesting for incorpo-
ration into small peptides to be subjected to biological
screening, p-chloro- (2b), m-methoxy- (2c) and o-methoxy-
benzylamine (2d) were employed under the same conditions
to furnish the correspondingly substituted products 3b–d in
very good yields (Scheme 1 and Table 1).
Limbach, A. V. Lygin, V. S. Korotkov, M. Es-Sayed, A. de Mei-
jere, Org. Biomol. Chem. 2009, 7, 3338–3342.
[a] Institut für Organische und Biomolekulare Chemie,
Georg-August-Universität Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: +49-551-399475,
E-mail: ameijer1@gwdg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000283.
Eur. J. Org. Chem. 2010, 3665–3671
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3665

A. de Meijere, M. Limbach, A. Janssen, A. Lygin, V. S. Korotkov
FULL PAPER
Scheme 2. Preparation of some dipeptides from the N-protected 2-
(benzylamino)cyclobut-1-ene-1-carboxylic acids 5a,b (for details
see Table 2).
Table 2. Preparation of some dipeptides from the N-protected 2-
(benzylamino)cyclobut-1-ene-1-carboxylic
Scheme 2).
acids
5a,b
(see
Starting
material
R1
R2
R3
R4
Product
Yield [%]
Scheme 1. Optimized conditions for the conversion of methyl 2-
chloro-2-cyclopropylideneacetate (1) with benzylamines 2 to 2-
[(benzyl)(tert-butoxycarbonyl)amino]cyclobut-1-ene-1-carboxylic
acids 5 (for details see Table 1).
5a
5a
5a
5b
H
H
H
H
H
H
H
H
H
H
H
Cl
H
6a
7a[a]
8a
89
87
58
84
CH2(indol-3-yl)
C6H5
9b
[a] For the structure of 7a, see Scheme 2.
Table 1. 2-[(Benzyl)(tert-butoxycarbonyl)amino]cyclobut-1-ene-1-
carboxylic acids 5 from of methyl 2-chloro-2-cyclopropylideneacet-
ate (1) and benzylamines 2 (see Scheme 1).
Due to the coplanar arrangement of the amino and the
carboxy group in the 2-aminocyclobutenecarboxylic acid,
dipeptides like 6a–8a and 9b incorporating this conforma-
tionally rigid moiety, have an extended conformation. This
apparently leads to an enhanced driving force for self-or-
ganization as evidenced by the fact that 7a, 8a and 9b read-
ily crystallize. If such dipeptides were endowed with appro-
priate pharmacophoric groups, this special arrangement
might be favorable for their biological activity. However, the
Entry R1
R2
R3
Yield of 3
Yield of 4
Yield of 5
[%]
[%]
[%]
a
b
c
H
H
H
H
H
OMe
H
H
Cl
H
H
85
99
87
81
85
82
75
79
89
95
91
82
d
OMe
The enamine moieties in 3a–d are sensitive towards hy- current compounds 6a–8a and 9b turned out to be inactive
drolysis; thus, upon an attempted acylation of 3a with bro- in general cell tests.
moacetyl chloride under Schotten–Baumann conditions,
A 2-aminocyclobutenecarboxylic acid fragment would
only benzylamine (2a) and N-benzyl-2-bromoacetamide also be incorporated in a cyclobutene-annelated tetrahydro-
were isolated. However, the amino function in the vinylog- diazepinedione of type 15, which would constitute a simple
ous carbamates 3a–d could be deprotonated by treatment cyclic dipeptide of the former with glycine. In principle,
with n-butyllithium at –78 °C, and the thus formed anions such compounds should be accessible by Lewis acid in-
were readily trapped with di-tert-butyl pyrocarbonate duced ring-enlarging rearrangement of the cycloprop-
(Boc2O) to yield 4a–d in 75–85% yield as colorless and ylmethyl chloride subunit in the spirocyclopropanated
stable solids, which could be purified by column chromatog- hexahydrodiazepinediones of type 10, which are also easily
raphy. Mild hydrolysis of the ester functions in 4a–d with obtained from methyl 2-chloro-2-cyclopropylideneacetate
aqueous lithium hydroxide and 2-propanol as cosolvent fur- (1) by Michael addition of a primary amine, condensation
nished the N-protected α,β-unsaturated β-amino acids 5a– of the adduct with N-Boc-glycine and cyclization of the re-
d as colorless solids (Scheme 1, Table 1).
sulting open-chain dipeptide ester by treatment with so-
Condensation of 5a with glycine (Gly) and with (S)-pro- dium carbonate in dichloromethane[14a] or better with am-
line (Pro) by employing dicyclohexylcarbodiimide (DCC) in monia in methanol.[13b] Yet, treatment of the N-n-pentyl de-
the presence of 2,4,6-collidine yielded the dipeptides 6a and rivative 10f[15] with LiI and Hünig’s base in DMF neither
7a, respectively, in very good yields of 89 and 87% at room temperature nor at 80 °C yielded the cyclobutene-
(Scheme 2, Table 2). The coupling of 5a with (S)-phenylgly- annelated tetrahydrodiazepinedione. Even the attempt to
cine (Phg) and of 5b with (S)-tryptophan (Trp) furnished enforce the cationic rearrangement in 10f by treatment with
the dipeptides 8a (84%) and 9b (58% yield). An attempted the much stronger Lewis acid aluminum trichloride in
removal of the N-(tert-butoxycarbonyl) (Boc) group from dichloromethane (20 °C, 18 h) led to the recovery of 95%
9b by treatment with 50% trifluoroacetic acid in dichloro- of the starting material. Since cyclopropylcarbenes are
methane led to a complex mixture of unidentified products. known to spontaneously rearrange to cyclobutenes,[16] α-
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Versatile Access to 2-Aminocyclobutene-1-carboxylic Acid Derivatives
elimination of hydrogen chloride from 10b to generate the effect of one of the phenyl groups, which may come close
carbene 14 was attempted. Yet, treatment of 10b with the to the proton on C-6ЈЈ.
strong and sterically demanding base potassium tert-butox-
Unexpectedly, an attempted transformation of the chlo-
ide in dimethyl sulfoxide did not yield the expected re- rohexahydrodiazepinedione 10e with sodium cyanide in di-
arrangement product 15b, but the bis(lactam) 13, which was methyl sulfoxide at 100–140 °C to the corresponding cyano-
obviously formed by nucleophilic substitution of chlorine substituted heterocycle furnished the cyclobutene-annelated
in 10b by the amide anion 11 arising by deprotonation of a tetrahydrodiazepinedione 15e in 38% yield (Scheme 3). Un-
1
second molecule of 10b. According to the H NMR spec- der the same conditions, 10f gave the analogous 15f in 45%
trum of the crude product, 13 was formed as a single dia- yield. This interesting transformation can be rationalized as
stereomer (Scheme 3). The 1Ј-6ЈЈ rather than 6Ј-6ЈЈ connec- occurring via the initially formed substitution product 12,
tion of the two seven-membered rings in 13 was assigned which, due to its enhanced C–H acidity at the cyano-substi-
on the basis of two resonances in the 13C NMR spectrum tuted position, may undergo α-elimination of hydrogen cya-
at δ = 64.6 and 66.7 ppm with positive DEPT signals and nide. The resulting carbene 14 would then rearrange to the
of the HMQC spectrum. Whereas the C-6Ј signal is corre- cyclobutene derivative 15.
lated to the resonance at δ = 3.92 ppm (s), the cross peak
In view of the growing interest in peptides derived from
for the C-6ЈЈ signal is in the range of the aromatic proton cis- and trans-2-aminocyclobutanecarboxylic acids,[17] it ap-
resonances at δ = 7.20 ppm, probably due to an anisotropy peared worthwhile to test the hydride-induced reduction
and/or catalytic hydrogenation of the double bond in
methyl 2-aminocyclobutenecarboxylates of type 3 and/or 4.
The shortest and possibly even enantioselective route to
these β-amino acids would be by reduction of the chirally
modified 2-aminocyclobutenecarboxylate 17, prepared
from 1 and (R)-1-phenylethylamine, with sodium boro-
hydride in acetic acid in complete analogy to a previously
published protocol for the conversion of the homologue 16
to 2-aminocyclopentanecarboxylate, which proceeded with
high diastereo- and enantioselectivity (Scheme 4).[18]
Under the same conditions as employed for 16, however,
the reaction of the cyclobutene analogue 17 provided the
open-chain (S)-aminovalerate derivative 18 in 74% yield as
the sole product. This again is a consequence of the vicinal
donor/acceptor substitution pattern – previously termed
captodative substituent effect by Viehe et al.[19] – in the ini-
tially formed saturated analogue of 17.
An attempted hydrogenation of 4a in the presence of a
palladium on carbon catalyst under different conditions al-
ways led to mixtures of products. Apparently, hydrogena-
tion of the double bond was accompanied by removal of
the benzyl group and partial ring opening of the initially
formed cyclobutene derivative. Under the best conditions
found (10% Pd/C, 3 atm H2, 80 °C, 12 h), a 3:1 mixture of
methyl cis- and trans-2-(tert-butoxycarbonylamino)cyclo-
butanecarboxylate (19) was isolated in a total yield of 91%
Scheme 3. Two unexpected reactions of spirocyclopropanated chlo-
(Scheme 4). The isomers could be separated by column
rohexahydrodiazepinediones 10.
Scheme 4. Hydride-induced reduction and catalytic hydrogenation of the double bond in two methyl 2-aminocyclobutenecarboxylates.
Eur. J. Org. Chem. 2010, 3665–3671
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A. de Meijere, M. Limbach, A. Janssen, A. Lygin, V. S. Korotkov
FULL PAPER
chromatography on silica gel. In a control experiment it was gidifyed cyclobutene subunits. The successful catalytic
shown that under the employed conditions for hydrogena- hydrogenation of methyl 2-[(benzyl)(tert-butoxycarbonyl)-
tion, cis-19 is not converted to trans-19 to any extent.
amino]cyclobutenecarboxylate (4a) opens up a new access
Hydrogenation of 4a under homogeneous-catalysis con- to cis- and trans-2-aminocyclobutanecarboxylic acids 19.
ditions, if successful, would be more attractive, as it could Whether this carries any advantage over previously devel-
also be carried out in an enantioselective fashion by oped routes[16] is debatable. One advantage might be, that
employing appropriate chirally modified catalysts.[20,21] the new route is extendable to 3- and 4-substituted ana-
As a test, 4a in methanol under hydrogen was treated with logues of 4a, which would be accessible from the corre-
Wilkinson’s catalyst [RhCl(PPh3)3]. Surprisingly, no cyclo- spondingly substituted 2-chloro-2-cyclopropylideneacetates
butane amino acid derivative was detected in the reaction according to previously published procedures.[9]
mixture, but only dimethyl glutarate (22-Me) and N-(tert-
butoxycarbonyl)benzylamine (23). In 2-propanol, the mixed
isopropyl methyl ester of glutaric acid 22-iPr along with
the carbamate 23 was observed. Interestingly, without the
(phosphane)rhodium complex present, with the complex
Experimental Section
General Remarks: All reagents were used as purchased from com-
mercial suppliers without further purification. All reactions in non-
present and under nitrogen instead of hydrogen, or in the
aqueous solvents were carried out by using standard Schlenk tech-
presence of triphenylphosphane and otherwise the same
niques under dry nitrogen. Solvents were purified and dried accord-
conditions, the cyclobutenecarboxylate 4a remained intact.
ing to conventional methods prior to use. 1H and 13C NMR spectra
The mechanism of this transformation is unclear; most
probably it involves a somehow catalyzed Michael addition
of an alcohol to 4a. The adduct 20 then undergoes a retro-
Claisen ring opening, once again a consequence of the cap-
were recorded with a Bruker AM 250 (250 MHz for 1H and
62.9 MHz for 13C) or Varian UNITY-300 (300 MHz for 1H and
75.5 MHz for 13C) instrument. Chemical shifts δ are given in ppm
relative to residual resonances of solvents (1H: δ = 7.26 ppm for
todative substituent effect,[18] to provide the iminium salt CHCl3, δ = 2.50 ppm for [D5]DMSO; 13C: δ = 77.0 ppm for CDCl3,
δ = 39.52 ppm for [D6]DMSO) or tetramethylsilane (1H: δ =
21, which is easily hydrolyzed by traces of water in the sol-
0.00 ppm; 13C: δ = 0.0 ppm); coupling constants J are given as
vent or upon workup. However, carrying out the reaction
absolute values in Hz. The multiplicities of 13C signals were deter-
in anhydrous alcohols did not change the final result
mined by the DEPT or the APT technique. IR: Bruker IFS 66 (FT-
(Scheme 5).
IR) spectrometer, measured as KBr pellets or oils between KBr
plates. EI-MS: Finnigan MAT 95, 70 eV. ESI-MS: Finnigan LCQ.
High resolution mass spectrometry (HRMS): APEX IV 7T
FTICR, Bruker Daltonic. Chromatography: Separations were car-
ried out on Merck Silica 60 (0.063–0.200 mm, 70–230 mesh
ASTM). TLC: Macherey–Nagel, TLC plates Alugram® Sil G/
UV254. Detection under UV light at 254 nm, development with
MOPS reagent (10% molybdophosphoric acid solution in ethanol).
Melting points: Büchi 540 capillary melting point apparatus; values
are uncorrected. Elemental analyses: Mikroanalytisches Laborato-
rium des Instituts für Organische und Biomolekulare Chemie der
Universität Göttingen.
Scheme 5. Attempted RhI-catalyzed hydrogenation of 4a in meth-
Methyl 2-(Benzylamino)cyclobut-1-enecarboxylate (3a): To a solu-
tion of benzylamine (2a) (1.63 g, 15.2 mmol) in DMF (10 mL) was
added a solution of methyl 2-chloro-2-cyclopropylideneacetate (1)
(2.23 g, 15.2 mmol) in DMF (10 mL), EtN(iPr)2 (2.18 g,
16.9 mmol) and LiI (2.26 g, 16.9 mmol). The solution was stirred
at 20 °C for 3 d, then aq. satd. NaHCO3 solution (400 mL) was
added, and the aqueous phase was extracted with Et2O (3ϫ
100 mL). The combined organic phases were washed with aq. satd.
NaHCO3 solution (2ϫ 200 mL) and dried (Na2SO4). Chromato-
graphic purification of the residue on 50 g of silica [3ϫ20 cm, pen-
tane/Et2O = 1:1, Rf = 0.64 (Et2O), ninhydrine] yielded the crude
product, which was crystallized from Et2O/pentane to yield 2.81 g
anol and 2-propanol.
It remains a challenge to find a homogeneous catalyst
and conditions, under which the enantioselective hydrogen-
ation of the dehydro-β-amino acids of type 4 would proceed
without ring opening.
Conclusions
The β-amino acid derivatives 4a–d with a cyclobutene
backbone, which are efficiently obtained by Michael ad-
dition of primary amines to 1 with ensuing cyclopropyl-
carbinyl-to-cyclobutyl cation ring enlargement and elimi-
nation as well as subsequent N-Boc protection, constitute
new conformationally rigid building blocks for oligopep-
tides. Condensation of 5a,b with the methyl esters of gly-
cine, tryptophan, phenylglycine and proline leads to the di-
peptides 6a–8a, 9b, three of which are crystalline materials,
(85%) of 3a as colorless needles, m.p. 66 °C. IR (KBr): ν = 3327
˜
(N–H) , 2928 (C–H), 2863 (C–H), 1620 (C=C), 1456 (CH2), 1354
(OCH3), 1293, 1242, 1220, 1187, 1133, 1100, 1077, 1032, 967, 936,
1
763, 738, 697, 601, 522, 457 cm–1. H NMR (250 MHz, CDCl3): δ
= 2.42–2.46 (m, 2 H, cbt-H), 2.48–2.59 (m, 2 H, cbt-H), 3.66 (s, 3
3
H, OCH3), 4.32 (d, J = 6.6 Hz, 2 H, CH2Ph), 5.77–5.87 (br. s, 1
H, NH), 7.26–7.39 (m, 5 H, aryl-H) ppm. 13C NMR (62.9 MHz,
CDCl3, DEPT): δ = 21.6 (–, CH2), 26.7 (–, CH2), 47.5 (–, CH2),
50.1 (+, OCH3), 92.3 (Cquat, cbt-C), 127.0 (+, 2 C, aryl-C), 127.5
apparently as a consequence of their conformationally ri- (+, aryl-C), 128.7 (+, 2 C, aryl-C), 138.6 (Cquat, Cipso), 158.7 (Cquat
,
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Versatile Access to 2-Aminocyclobutene-1-carboxylic Acid Derivatives
cbt-C), 164.6 (Cquat, C=O) ppm. MS (EI, 70 eV): m/z (%) = 217
(36) [M+], 186 (16) [M+ – OMe], 158 (17) [M+ – CO2Me], 91 (100)
[PhCH2+], 65 (10). C13H14NO2 (217.3): calcd. C 71.87, H 6.96, N
6.45; found C 71.74, H 6.89, N 6.41.
Rf = 0.32 (pentane/Et2O = 1:2)] provided 1.58 g (89%) of 6a as a
colorless oil. IR (film): ν = 3386, 2991, 2935, 1717, 1653, 1635,
˜
1
1540, 1457, 1368, 1265, 1239, 1208, 1153, 741, 703 cm–1. H NMR
(250 MHz, CDCl3): δ = 1.42 (s, 9 H, tBu-H), 2.27–2.52 (m, 2 H,
cbt-H), 2.81–3.07 (m, 2 H, cbt-H), 3.71 (s, 3 H, OCH3), 5.24 (d, 2J
Methyl 2-{(Benzyl)(tert-butoxycarbonyl)amino]cyclobut-1-ene-
carboxylate (4a): A solution of 3a (2.98 g, 13.7 mmol) in THF
(100 mL) was cooled to –78 °C, nBuLi (7.46 mL, 16.4 mmol, 2.2 
in hexane) was added over 10 min, and the deeply colored solution
was stirred at the same temperature for 30 min. A solution of
Boc2O (3.59 g, 16.5 mmol) in THF (20 mL) was added, and the
mixture was stirred under rewarming to 20 °C for 16 h. The reac-
tion was quenched with satd. aq. NH4Cl solution (10 mL), and the
mixture extracted with CH2Cl2 (100 mL). Drying (Na2SO4) and
chromatographic purification of the residue by column chromatog-
raphy on 50 g of silica (3ϫ20 cm, pentane/Et2O = 10:1, Rf = 0.40,
ninhydrine) yielded 3.68 g (85%) of 4a as a colorless solid, m.p.
2
= 7.76 Hz, 1 H, A-part of an AB system), 5.33 (d, J = 7.76 Hz, 1
H, B-part of an AB system), 5.57 (dd, 2J = 3.57 Hz, 1 H, CH),
6.48 (dd, 2J = 3.57 Hz, 1 H, CH), 7.28–7.49 (m, 5 H, aryl-H) ppm.
13C NMR (62.9 MHz, CDCl3, DEPT): δ = 23.3 (–, CH2), 28.0 (+,
tBu-C), 32.8 (–, CH2), 49.8 (–, CH2), 52.8 (–, CH2), 56.1 (+,
OCH3), 82.5 (Cquat, tBu-C), 109.5 (Cquat, cbt-C), 127.2 (+, 2 C,
aryl-C), 128.3 (+, 2 C, aryl-C), 128.4 (+, aryl-C), 132.4 (Cquat
Cipso), 146.3 (Cquat, cbt-C), 152.8 (Cquat, NC=O), 161.6 (Cquat
,
,
NC=O), 171.4 (Cquat, C=O) ppm. MS (ESI, 70 eV): m/z (%) = 771
(96) [2 M + Na]+, 397 (100) [M + Na]+, 375 (70) [M + H]+.
C20H26N2O5 (374.4): calcd. C 64.15, H 7.00, N 7.48; found C 64.19,
H 6.98, N 7.43.
63 °C. IR (KBr): ν = 2980 , 2942, 1726, 1700, 1603, 1453, 1385,
˜
1368, 1234, 1219, 1139, 1111, 1008, 755, 699 cm–1 1H NMR
.
6Ј-Chloro-4Ј-(4-chlorobenzyl)-2Ј,3Ј,4Ј,5Ј,6Ј,7Ј-hexahydrospiro[cyclo-
propane-1,5Ј-[1H][1,4]diazepine]-3Ј,7Ј-dione (10b): To a solution of
4-chlorobenzylamine (4.83 g, 34.1 mmol) in THF (50 mL) at 0 °C
was added dropwise a solution of methyl 2-chloro-2-cyclopropyl-
ideneacetate (1) (5.00 g, 34.1 mmol) in THF (50 mL), and stirring
was continued at the same temperature for 5 h. The mixture was
treated at 0 °C with a solution of Boc-Gly-OH (11.9 g, 67.9 mmol)
and pyridine (5.39 g, 68.1 mmol) in THF (50 mL) and DCC
(14.1 g, 68.3 mmol) in THF (50 mL). After stirring under rewarm-
ing to room temp. overnight, the precipitated DCU was removed
by filtration, and the solution was concentrated in vacuo. The resi-
due was dissolved in CH2Cl2 (100 mL), and the solution was
washed with cold 15% KHSO4 solution (20 mL), water (20 mL),
satd. aq. NaHCO3 solution (3ϫ 20 mL) and dried (Na2SO4). After
concentration in vacuo, the adduct of 4-chlorobenzylamine to 1
was obtained as a yellow solid (14.0 g, 92%) by column chromatog-
raphy on 500 g of silica gel (petroleum ether/EtOAc = 6:3, Rf =
0.4). This adduct was dissolved in CH2Cl2 (50 mL), and trifluoro-
acetic acid (20.0 g, 175 mmol) was added dropwise at 0 °C to the
resulting stirred solution. The reaction mixture was warmed to
room temp. with stirring overnight and was poured into a well-
stirred mixture of satd. aq. Na2CO3 solution (50 mL) and CH2Cl2
(50 mL). The organic phase was separated, and the aqueous phase
was extracted with CH2Cl2 (2ϫ 100 mL). The combined organic
phases were washed with brine (100 mL), dried (Na2SO4) and con-
centrated in vacuo. The residue was treated with diethyl ether, the
precipitate was filtered off and recrystallized from EtOAc to give
10b (6.51 g, 66% over two steps) as a colorless solid, m.p. 203–
3
(250 MHz, CDCl3): δ = 1.41 (s, 9 H, tBu-H), 2.41 (t, J = 4.4 Hz,
2 H, cbt-H), 2.97 (t, 3J = 4.4 Hz, 2 H, cbt-H), 3.61 (s, 3 H, OCH3),
5.35 (s, 2 H, CH2), 7.18–7.37 (m, 5 H, aryl-H) ppm. 13C NMR
(62.9 MHz, CDCl3, DEPT): δ = 24.0 (–, cbt-C), 28.0 (+, tBu-C),
32.3 (–, cbt-C), 50.5 (–, CH2), 50.9 (+, OCH3), 82.5 (Cquat, tBu-C),
106.7 (Cquat, cbt-C), 126.7 (+, 2 C, aryl-C), 128.2 (+, 2 C, aryl-C),
131.6 (+, aryl-C), 138.6 (Cquat, Cipso), 150.1 (Cquat, cbt-C), 152.7
(Cquat, NC=O), 162.5 (Cquat, C=O) ppm. MS (ESI, 70 eV): m/z (%)
= 656 (14) [2 M + Na]+, 340 (100) [M + Na]+. C18H23NO4 (317.4):
calcd. C 68.12, H 7.30, N 4.41; found C 68.33, H 7.04, N 4.36.
2-[(Benzyl)(tert-butoxycarbonyl)amino]cyclobut-1-enecarboxylic
Acid (5a): To a solution of 4a (2.56 g, 8.07 mmol) in water/THF/
iPrOH (1:1:1, 90 mL) was added LiOH·2H2O (1.45 g, 24.2 mmol)
at 20 °C, and the mixture was stirred for 24 h. The solvents were
evaporated under reduced pressure, the residue was taken up with
EtOAc (100 mL), the mixture was acidified with aq. 1  HCl solu-
tion (30 mL), the phases were separated, the aqueous layer was
extracted with EtOAc (2ϫ 50 mL), and the organic phases were
dried (Na2SO4) to yield 2.18 g (89%) of 5a as a colorless solid, m.p.
109 °C. R = 0.53 (pentane/Et O = 1:1, ninhydrine). IR (KBr): ν =
˜
f
2
2936, 1731, 1663, 1570, 1457, 1369, 1345, 1233, 1217, 1143 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.41 (s, 9 H, tBu-H), 2.40 (t, J
= 3.6 Hz, 2 H, cbt-H), 2.84 (t, J = 3.6 Hz, 2 H, cbt-H), 5.17 (s, 2
3
3
H, CH2Ph), 7.15–7.36 (m, 5 H, aryl-H), 11.95 (br. s, 1 H, CO2H)
ppm. 13C NMR (75.5 MHz, CDCl3, APT): δ = 23.6 (–, cbt-C), 27.9
(+, tBu-C), 31.3 (-, cbt-C), 50.6 (–, CH2), 83.4 (–, tBu-C), 107.4
(–, cbt-C), 126.7 (+, 2 C, aryl-C), 127.0 (+, aryl-C), 128.3 (+, 2 C,
aryl-C), 138.4 (Cquat, Cipso), 150.2 (–, cbt-C), 153.1 (–, NC=O),
165.9 (–, C=O) ppm. MS (ESI, 70 eV): m/z (%) = 629 (26) [2 M +
Na]+, 627 (76) [2 M – 2 H + Na]–, 326 (100) [M + Na]+, 304 (8)
[M + H]+, 302 (30) [M – H]–. C17H21NO4 (303.4): calcd. C 67.31,
H 6.98, N 4.62; found C 67.16, H 6.75, N 4.73.
204 °C (dec., EtOAc). IR (KBr): ν = 3319 (NH), 3213 (NH), 3090,
˜
3068, 2961, 2928, 1682 (C=O), 1495, 1462, 1443, 1325, 1229, 1092,
1
1016, 819, 813, 804, 735, 604, 553, 433 cm–1. H NMR (250 MHz,
[D6]DMSO): δ = 0.96–1.09 (m, 2 H, cPr-H), 1.47–1.52 (m, 2 H,
2
cPr-H), 3.45 (dd, J = 14.5, 7.8 Hz, 1 H), 4.31 (s, 1 H), 4.33 (d, J
2
= 16.2 Hz, 1 H), 4.57 (d, J = 14.5 Hz, 1 H), 5.01 (d, 2J = 16.2 Hz,
3
3
1 H), 7.13 (d, J = 8.4 Hz, 2 H, aryl-H), 7.32 (d, J = 8.4 Hz, 2 H,
aryl-H), 8.43 (d, 3J = 7.8 Hz, 1 H, NH) ppm. 13C NMR (62.9 MHz,
[D6]DMSO, DEPT): δ = 14.1 (–, cPr-C), 19.6 (–, cPr-C), 42.1
(Cquat, cPr-C), 46.7 (–, CH2), 51.5 (–, CH2), 65.9 (+, CH), 127.9
Methyl ({2-[(Benzyl)(tert-butoxycarbonyl)amino]cyclobut-1-yl-
carbonyl}amino)acetate (6a): To a solution of 5a (1.44 g,
4.75 mmol) in THF (50 mL) at 0 °C were added glycine methyl
ester hydrochloride (656 mg, 5.23 mmol), 2,4,6-collidine (1.38 g,
11.4 mmol) and DCC (1.18 g, 5.70 mmol), and the suspension was
stirred under rewarming to 20 °C for 12 h. The precipitate was fil-
tered off, all volatile components were removed under reduced
pressure, the residue was dissolved in EtOAc (150 mL), the solution
washed with aq. 1  HCl solution (50 mL), satd. aq. NaHCO3 solu-
tion (2ϫ 50 mL) and brine (50 mL). Drying (Na2SO4) and chroma-
tographic purification of the residue by column chromatography
on 50 g of silica [3ϫ20 cm, pentane/Et2O = 1:1 Ǟ 1:2, ninhydrine,
(+, 2 aryl-C), 128.5 (+, 2 aryl-C), 131.5 (Cquat, aryl-C), 137.8 (Cquat
,
aryl-C), 167.1 (Cquat, C=O), 171.1 (Cquat, C=O) ppm. MS (EI,
70 eV): m/z (%) = 312 (1) [M+], 279/277 (23/69) [M+ – Cl], 251/249
(2/5) [M+ – Cl – C2H4], 222/220 (23/71), 127/125 (33/100)
[C7H6Cl+]. C14H14Cl2N2O2 (313.2): calcd. C 53.69, H 4.51, Cl
22.64, N 8.94; found C 53.85, H 4.70, Cl 22.36, N 8.80.
6Ј-Chloro-4Ј-(4-chlorobenzyl)-1Ј-{4ЈЈ-(4-chlorobenzyl)-2ЈЈ,3ЈЈ,4ЈЈ,
5ЈЈ,6ЈЈ,7ЈЈ-hexahydro-3ЈЈ,7ЈЈ-dioxospiro[cyclopropane-1ЈЈЈ,5ЈЈ-[1H]-
Eur. J. Org. Chem. 2010, 3665–3671
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3669

A. de Meijere, M. Limbach, A. Janssen, A. Lygin, V. S. Korotkov
FULL PAPER
[1,4]diazepin]-6ЈЈ-yl}-2Ј,3Ј,4Ј,5Ј,6Ј,7Ј-hexahydrospiro[cyclopropane-
1,5Ј-[1H][1,4]-diazepine]-3Ј,7Ј-dione (13): To a solution of 10b
(1.10 g, 3.51 mmol) in DMSO (10 mL) was added freshly sublimed
KOtBu (394 mg, 3.51 mmol), and the solution was stirred at 20 °C
for 24 h. The reaction mixture was poured into an ice-cold aq. 2 
oily residue (2.91 g, 92%) was used in the next step without further
purification. 1H NMR (300 MHz, CDCl3): δ = 1.48 (d, J = 6.9 Hz,
3 H, CH3), 2.19–2.25 (m, 1 H, cbt-H), 2.30–2.50 (m, 3 H, cbt-H),
3.65 (s, 3 H, OCH3), 4.49 (m, 1 H, CH), 5.83 (br. s, 1 H, NH),
7.20–7.34 (m, 5 H, Ph) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
HCl solution (150 mL), and the mixture was extracted with CH2Cl2 21.9 (CH2), 23.7 (CH2), 21.1 (CH3), 50.0 (OCH3), 53.2 (CH), 77.2
(3ϫ 50 mL). The combined organic phases were washed with brine
(100 mL) and dried (MgSO4). Purification of the residue by column
chromatography on 50 g of silica (2.5ϫ14 cm, CH2Cl2/MeOH =
100:5, Rf = 0.33, ninhydrine) yielded 421 mg (41%) of 13 as a color-
(Cquat, cbt-C), 92.4 (Cquat, cbt-C), 125.7 (2 CH, aryl-C), 127.2 (CH,
aryl-C), 128.6 (2 CH, aryl-C), 144.0 (Cquat, Cipso), 158.5 (Cquat, cbt-
C), 164.6 (Cquat, C=O) ppm. MS (ESI = 70 eV): m/z (%) = 231.4
(30) [M+], 105.2 (100). HRMS: calcd. for C14H17NO2 231.12593;
found 231.12597.
less solid, m.p. 175–177 °C (CH Cl /Et O). IR (KBr): ν = 3539
˜
2
2
2
(NH), 3098, 3052, 3050, 2950, 1660 (C=O), 1492, 1398, 1345, 1299,
1189, 1092, 1015, 964, 794 cm–1. 1H NMR (250 MHz, CDCl3): δ =
0.80–0.87 (m, 1 H, cpr-H), 1.00–1.06 (m, 1 H, cpr-H), 1.13–1.28
(m, 5 H, cpr-H), 1.34–1.42 (m, 1 H, cpr-H), 1.46–1.55 (m, 1 H,
Methyl 5-[(R)-(1-Phenylethyl)amino]pentanoate (18): A solution of
NaBH(OAc)3 was prepared by adding NaBH4 (0.34 g, 9.0 mmol)
to glacial acetic acid (5 mL), while keeping the temperature be-
tween 10 and 20 °C. After 1 h, acetonitrile (5 mL) was added, and
the solution was cooled to 0 °C. The β-enamino ester 17 (693 mg,
3 mmol) was added and the mixture stirred at 0 °C for 4 h. The
acetic acid and acetonitrile were evaporated at room temp. in
vacuo, the residue dissolved in CH2Cl2 (100 mL) and the solution
washed with a satd. aq. Na2CO3 solution (2ϫ 50 mL). Drying of
the solution (Na2SO4) and evaporation of the solvent gave a crude
product, which was purified by column chromatography on 100 g
of silica gel (Et2O, Rf = 0.23) to give 522 mg (74%) of 18 as a
colorless oil. 1H NMR (300 MHz, CDCl3): δ = 1.34 (d, J = 6.6 Hz,
3 H, CH3), 1.43–1.52 (m, 2 H, CH2), 1.57–1.67 (m, 2 H, CH2), 2.28
(t, J = 7.4 Hz, 2 H, CH2), 2.37–2.55 (m, 2 H, CH2), 3.64 (s, 3 H,
3
3
CH), 1.82 (d, J = 18.4 Hz, 1 H), 2.74 (d, J = 18.4 Hz, 1 H), 3.92
2
2
(s, 1 H, 6Ј-H), 4.27 (d, J = 15.0 Hz, 1 H), 4.32 (d, J = 15.0 Hz, 1
2
2
H), 4.50 (d, J = 15.1 Hz, 1 H), 4.82 (d, J = 15.0 Hz, 1 H), 5.14
(d, J = 15.1 Hz, 1 H), 5.44 (d, 2J = 15.0 Hz, 1 H), 6.96 (s, 1 H,
2
3
NH), 7.10 (d, J = 8.4 Hz, 2 H, aryl-H), 7.15–7.29 (m, 6 H, aryl-
H, 6ЈЈ-H) ppm. 13C NMR (62.9 MHz, CDCl3, DEPT): δ = 13.3
(–, cpr-C), 14.9 (–, cpr-C), 17.8 (–, cpr-C), 20.7 (–, cpr-C), 34.6
(Cquat, cpr-C), 42.3 (Cquat, cpr-C), 44.1 (–, CH2), 48.1 (–, CH2),
48.9 (–, CH2), 51.9 (–, CH2), 64.6 (+, C-6Ј), 66.7 (+, C-6ЈЈ), 127.7
(+, 2 aryl-C), 128.97 (+, 2 aryl-C), 128.99 (+, 2 aryl-C), 129.1 (+,
2 aryl-C), 133.1 (Cquat, aryl-C), 133.6 (Cquat, aryl-C), 135.4 (Cquat
aryl-C), 136.5 (Cquat, aryl-C), 167.3 (Cquat, C=O), 168.7 (Cquat
,
,
OCH3), 3.74 (q, J = 3.3 Hz, 1 H, CH), 7.30 (m, 5 H, Ph) ppm. 13
C
C=O), 171.1 (Cquat, C=O), 171.2 (Cquat, C=O) ppm. MS (ESI,
70 eV): m/z (%) = 588 (Ͻ1) [M+], 554/552 (1/1) [M+ – Cl], 277
(22), 222/220 (6/12), 127/125 (32/100) [C7H6Cl+]. C28H27Cl3N4O4
(589.9): calcd. C 57.01, H 4.61, Cl 18.03, N 9.50; found C 57.07,
H 4.72, Cl 17.88, N 9.71.
NMR (75.5 MHz, CDCl3): δ = 22.7 (CH2), 24.3 (CH2), 29.7 (CH2),
33.9 (CH3), 47.3 (CH2), 51.4 (CH), 58.3 (OCH3), 126.5 (2 CH, aryl-
C), 128.8 (CH, aryl-C), 128.4 (2 CH, aryl-C), 145.8 (Cquat, aryl-C),
174.0 (Cquat, C=O) ppm. MS (ESI 70 eV): m/z (%) = 235.2 (4) [M+],
220.2 (32), 105.1 (100). HRMS: calcd. for C14H22NO2 [M + H]+
236.16451; found 236.16444.
2,3,4,5,6,7-Hexahydro-1-pentyl-1H-cyclobuta[e][1,4]diazepine-2,5-di-
one (15f): To a solution of 10f[13a] (345 mg, 1.33 mmol) in DMSO
(15 mL) was added sodium cyanide (74 mg, 1.50 mmol), and the
reaction mixture was stirred at 100 °C for 3 h, then at 140 °C for
an additional 3 h. After cooling to 20 °C, the brown oil was treated
with water (100 mL) and the mixture extracted with CH2Cl2 (3ϫ
30 mL). The combined organic phases were washed with brine (2ϫ
50 mL) and dried (Na2SO4). Removal of the solvent under reduced
pressure and purification of the residue by column chromatography
on 25 g of silica (2ϫ10 cm, CH2Cl2/MeOH = 100:3 Ǟ 100:4, Rf =
tert-Butyl cis- and trans-2-(Methoxycarbonyl)cyclobutylcarbamate
(cis-/trans-19): A mixture of 4a (100 mg, 0.32 mmol), MeOH
(5 mL) and 10% Pd/C (34 mg, 10 mol-%) was shaken under hydro-
gen (3 atm H2) at 80 °C for 12 h. After cooling, the mixture was
filtered through a short pad of Celite, which was subsequently
washed with MeOH (50 mL). The solvent was removed under re-
duced pressure to provide the crude product (a 3:1 mixture of iso-
mers according to 1H NMR), which was purified by column
chromatography on 50 g of silica gel (pentane/Et2O = 4:1).
0.37) yielded 133 mg (45%) of 15f as a colorless oil. IR (film): ν =
˜
cis-19:[22] 50 mg (69%), Rf = 0.18 (pentane/Et2O, 4:1). 1H NMR
(300 MHz, CDCl3): δ = 1.36 (s, 9 H, tBu), 1.85–1.94 (m, 2 H, cbt-
H), 2.15 (quint, J = 10.3 Hz, 1 H, cbt-H), 2.26 (m, 1 H, cbt-H),
3.31 (m, 1 H, CH), 3.64 (s, 3 H, OCH3), 4.39 (m, 1 H, CH), 5.30
(br. s, 1 H, NH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 18.4
(CH2), 28.3 (CH3, tBu), 29.5 (CH2), 45.2 (CH), 45.7 (CH), 51.6
3390 (NH), 3243 (NH), 3175 (NH) cm–1
.
1H NMR (250 MHz,
3
CDCl3): δ = 0.78 (t, J = 6.7 Hz, 3 H, CH3), 1.14–1.38 (m, 4 H, 2
CH2), 1.70–1.81 (m, 2 H, CH2), 2.33 (t, J = 3.7 Hz, 2 H, cbt-H),
3
2.48 (t, 3J = 3.7 Hz, 2 H, cbt-H), 3.68–3.81 (m, 2 H, CH2), 3.86 (d,
3J = 5.2 Hz, 2 H, CH2), 6.65 (br. s, 1 H, NH) ppm. 13C NMR
(62.9 MHz, CDCl3, DEPT): δ = 13.7 (+, CH3), 21.4 (–, cbt-C), 22.0
(–, CH2), 27.2 (–, cbt-C), 27.7 (–, CH2), 28.5 (–, CH2), 45.8 (–,
CH2), 47.2 (–, CH2), 114.3 (Cquat, cbt-C), 148.5 (Cquat, cbt-C),
166.8 (Cquat, C=O), 167.4 (Cquat, C=O) ppm. MS (EI, 70 eV): m/z
(%) = 222 (100) [M+], 165 (18), 152 (43), 108 (52). C12H18N2O2
(222.28): calcd. C 64.84, H 8.16, N 12.60; found C 64.67, H 8.25,
N 12.55.
(OCH3), 79.4 (Cquat, tBu), 154.7 (Cquat, NC=O), 174.7 (Cquat
,
C=O) ppm. MS (ESI, 70 eV): m/z (%) = 481.3 (100) [2 M + Na+],
252.3 (64) [M + Na+]. HRMS: calcd. for C11H19NNaO4 [M +
Na]+ 252.1206; found 252.1211.
1
trans-19:[22] 16 mg (22%) Rf = 0.29 (pentane/Et2O, 4:1). H NMR
(300 MHz, CDCl3): δ = 1.45 (s, 9 H, tBu), 1.84 (m, 1 H, cbt-H),
2.08–2.19 (m, 2 H, cbt-H), 2.64 (quint, J = 10.5 Hz, 1 H, cbt-H),
3.22 (m, 1 H, CH), 3.37 (m, 1 H, CH), 3.65 (s, 3 H, OCH3), 4.44
(br. s, 1 H, NH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 17.6
(CH2), 26.0 (CH2), 28.3 (CH3, tBu), 45.8 (CH), 50.0 (CH), 51.6
(CH3), 79.4 (Cquat, tBu), 155.4 (Cquat,NC=O), 174.0 (Cquat, C=O)
ppm. MS (ESI = 70 eV): m/z (%) = 481.3 (100) [2 M + Na+], 252.3
(68) [M + Na+]. HRMS: calcd. for C11H19NNaO4 [M + Na]+
252.1206; found 252.1214.
Methyl 2-[(R)-(1-Phenylethyl)amino]cyclobut-1-enecarboxylate (17):
To a solution of 1 (2.0 g, 13.7 mmol) in DMF (10 mL) was added
(R)-(1-phenylethyl)amine (1.66 g, 13.7 mmol), LiI (2.05 g,
15.3 mmol) and EtN(iPr)2 (1.97 g, 15.3 mmol) at 0 °C, and the mix-
ture was stirred under rewarming to 20 °C for 3 d. Satd. aq.
NaHCO3 solution (150 mL) was added, and the mixture was ex-
tracted with Et2O (3ϫ 70 mL). The combined organic phases were
washed with satd. NaHCO3 (2ϫ 50 mL) and dried (Na2SO4). The
3670
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3665–3671

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1
9b, 15e, 22-Me, 22-iPr, 23, and copies of H and 13C NMR spectra
for all new compounds without elemental analysis data.
Acknowledgments
This work was supported by the Land Niedersachsen, the Fonds
der Chemischen Industrie, BayerCropScience AG as well as by Cel-
anese AG (chemicals). M. L. is indebted to the German Merit
Foundation (Studienstiftung des deutschen Volkes) for a student
(2000–2002) and
a doctoral student fellowship (2002–2004).
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Received: March 1, 2010
Published Online: May 14, 2010
Eur. J. Org. Chem. 2010, 3665–3671
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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