Cyclopropyl building blocks in organic synthesis, 51. An easy access to 1-azaspiropentane-2-carboxamides - The first derivatives of a new type of amino acids

Article abstract of DOI:10.1002/(sici)1099-0690(199909)1999:9<2017::aid-ejoc2017>3.0.co;2-0

Azaspiropentanecarboxamides 10 and 12 are formed with remarkable ease in two steps in a one-pot operation from methyl 2-chloro-2- cyclopropylideneacetate (4) by addition of a primary amine in tetrahydrofuran and subsequent treatment with sodium hydride/triethylamine in the presence of another equivalent of a primary amine or ammonia. Achievable yields of the amides 10, 12 were moderate to good (27-59%, 12-48%), while the corresponding esters 9 could only be obtained in poor yields (4-14%). The new α-amino acid amides are surprisingly stable, and they can be incorporated into small peptides as demonstrated with the preparation of the glycine 13e and the spirocyclopropaneoxazoline derivative 14e.

Full text of DOI:10.1002/(sici)1099-0690(199909)1999:9<2017::aid-ejoc2017>3.0.co;2-0

FULL PAPER
Cyclopropyl Building Blocks in Organic Synthesis, 51[°]
An Easy Access to 1-Azaspiropentane-2-carboxamides – The First Derivatives
of a New Type of Amino Acids
Markus Tamm,[a] Michael Thutewohl,[a] Carsten B. Ricker,[a] M. Teresa Bes,[b][°°]
and Armin de Meijere*[a]
Dedicated to Professor Murray Goodman on the occasion of his 70th birthday
Keywords: Amino acids / Azaspiropentanes / Heterocycles / Peptides / Strained molecules
Azaspiropentanecarboxamides 10 and 12 are formed with
remarkable ease in two steps in a one-pot operation from
methyl 2-chloro-2-cyclopropylideneacetate (4) by addition of
good (27–59% , 12–48% ), while the corresponding esters 9
could only be obtained in poor yields (4–14% ). The new α-
amino acid amides are surprisingly stable, and they can be
incorporated into small peptides as demonstrated with the
preparation of the glycine 13e and the spirocyclopro-
paneoxazoline derivative 14e.
a
primary amine in tetrahydrofuran and subsequent
treatment with sodium hydride/triethylamine in the presence
of another equivalent of a primary amine or ammonia.
Achievable yields of the amides 10, 12 were moderate to
more reactive than simple aziridines due to the spiro-linked
cyclopropane ring. In fact, azaspiropentanes show interest-
Introduction
Quite a variety of unusual amino acids including at least ing alkylating activity even in weakly acidic media.[8b,8d]
26 with a cyclopropyl group have been found in nature, and The amino acid 2 must also be viewed as a spirocyclopro-
many of them exhibit special biological activities.[1][2] In ad- pane derivative of aziridinecarboxylic acid (3),[10] which has
dition, cyclopropyl group containing homologs of other been applied in interesting peptidomimetics.[10c] We have
natural amino acids are attracting an ever increasing inter- now uncovered a rather facile formation of 1-azaspiropen-
est as potential enzyme inhibitors[3] and conformationally tane-2-carboxylic acid derivatives from methyl 2-chloro-2-
restricted building blocks for peptidomimetics.[4] A wide cyclopropylideneacetate (4),[11] which has previously been
range of biological activities has been uncovered for such described as a versatile and highly reactive small-ring build-
unnatural amino acid analogs and small peptides contain- ing block for various types of compounds.[12]
ing them.[5][6] The most highly strained amino acid occur-
ring naturally, (S)-2-azabicyclo[2.1.0]pentane-3-carboxylic
acid (1), has a remarkable antimicrobial activity.[7] Neither
the isomeric 1-azaspiropentane-2-carboxylic acid (2), nor
any of its derivatives have yet been described; in fact, only
relatively few azaspiropentane derivatives have been re-
ported so far.[8] In addition to its structural particularity, 2
Figure 1. Three unusually strained small-ring α-amino acids
and its derivatives should be of interest in view of their po-
tential biological activity due to the aziridine subunit,[9]
which in 2 is especially strained and should therefore be
The Michael adduct 6a-Bn of dibenzylamine (5a-Bn) to
Results and Discussion
[°] Part 50: V. N. Belov, C. Funke, T. Labahn, M. Es-Sayed, A. de
Meijere, Eur. J. Org. Chem. 1999, 1345Ϫ1356. Ϫ Part 49: M.
Brandl, S. I. Kozhushkov, D. S. Yufit, J. A. K. Howard, A. de
Meijere, Eur. J. Org. Chem. 1998, 2785Ϫ2795.
the reactive acrylate 4 can be prepared in tetrahydrofuran
(THF) solution as a stable compound, but it cleanly re-
arranges when heated in dimethylformamide (DMF) at
[°°] New address: Departamento de Bioquimica y Biologia Mole- 80 °C for 48 h to yield the 2-dibenzylaminocyclobutene-1-
carboxylate 8a-Bn.[13] This rearrangement probably in-
cular y Celular, Facultad de Ciencias, Universidad de Zara-
goza,
volves a cationic azaspiropentane intermediate 7a-Bn
(Scheme 1), it is facilitated by polar solvents and elevated
temperatures. The Michael adduct 6a-H of benzylamine
(5a-H) to 4 can also be prepared in THF solution, but the
isolated product 6a-H turned out to be rather unstable even
at Ϫ20 °C and to rapidly rearrange to 2-benzylaminocyclo-
butenecarboxylate 8a-H. The latter was also obtained di-
Pza. San Francisco s/n, E-50009 Zaragoza, Spain
Institut für Organische Chemie, Georg-August-Universität Göt-
tingen,
[a]
[b]
Tammannstraße 2, D-37077 Göttingen, Germany
Fax: (internat.) ϩ 49(0)551/399475
E-mail: ameijer1@uni-goettingen.de
Institut für Anorganische Chemie, Georg-August-Universität
Göttingen,
Tammannstraße 4, D-37077 Göttingen, Germany
Eur. J. Org. Chem. 1999, 2017Ϫ2024
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0909Ϫ2017 $ 17.50ϩ.50/0
2017

M. Tamm, M. Thutewohl, C. B. Ricker, M. T. Bes, A. de Meijere
FULL PAPER
rectly upon treatment of 4 with benzylamine in DMF at Virtually no diastereoselectivity was observed with enanti-
room temperature. When the adduct 6b-H was treated in omerically pure (S)-α-phenylethylamine 5d-H (see Table 2).
methanol (MeOH) solution with triethylamine, the ex-
pected ring-enlargement product, the cyclobutene 8b-H,
was accompanied by a small amount of the methyl aza-
spiropentanecarboxylate 9b. Under these conditions, 6a-H
and 6c-H gave the azaspiropentane derivatives 9a and 9c as
the only isolable products (14 and 13%, respectively) (Table
Scheme 2. Synthesis of 1-azaspiropentane-2-carboxylic acid alkyl-
amides 10; for details see Table 2
The ring closure to the azaspiropentane most likely occurs
at the stage of the β-amino-α-chloro esters 6-H to first yield
the methyl azaspiropentanecarboxylates 9, which sub-
sequently react with the second equivalent of the amine to
the more stable amides 10. However, an attempt to trans-
form 9a into 10aa by treatment with benzylamine under the
optimized conditions for the conversion of 6a-H to 10aa
only led to decomposition of 9a. Alternatively, the β-amino
esters 6-H might first be transformed to the amides 11 with
subsequent γ-dehydrochlorination into the final products 10.
Apparently, the stability of these azaspiropentane deriva-
tives is greatly enhanced by the arylalkyl substituents on the
Scheme 1. Synthesis of methyl cyclobutenecarboxylates 8 and
methyl azaspiropentanecarboxylates 9; for details see Table 1
Table 1. Methyl cyclobutenecarboxylates 8 and methyl azaspiropentanecarboxylates 9 from methyl 2-chloro-2-cyclopropylideneacetate
(4); see Scheme 1
R1R2NH
R1
R2
Conditions
A
Conditions
B
Product
Yield
Product
9
Yield
9 (%)
5-R2
8-R2
8-R2 (%)
5a-Bn
5a-H
5b-H
5a-H
Bn
Bn
H
THF, r.t., 24 h
DMF, r.t., 1 h
THF, r.t., 3 h
DMF, 80°C, 48 h
8a-Bn
8a-H
95
Ϫ
Ϫ
0
Bn
DMF, r.t., 48 h
51[a]
42[a]
0
9a
CH2CO2tBu
Bn
H
MeOH, NEt3, r.t., 9 d 8b-H
MeOH, NEt3, r.t., 24 h 8a-H
9b[b]
9a[b]
4[a]
14
H
THF, r.t., 30 min
[a] Overall yield in two steps. Ϫ [b] Slow decomposition at room temp.
1).[14] Apart from the very low yields, the isolated methyl ring nitrogen atom. All attempts to remove the N-benzyl
esters 9-R were unstable at room temperature and under- group from the skeleton of 10aa led to complete destruction
went decomposition when stored for a couple of hours. of the system. However, the N-arylalkyl group on the car-
However, in an attempt to improve the yield of the azirid- boxamide group is not essential. Treatment of 6a-H in THF
ine-ring-closed product from 6a-H by using a second equiv- solution with gaseous ammonia in the presence of triethyl-
alent of benzylamine (5a-H) to possibly transform the ester amine and sodium hydride gave the primary N-benzyl-1-
function into a potentially more stable amide,[15] and also azaspiropentane-2-carboxamide 12a. Analogously, the N-
adding triethylamine as well as two equivalents of sodium (2Ј-phenylethyl)-1-azaspiropentane-2-carboxamide 12e was
hydride, the N-benzyl-1-azaspiropentane-2-carboxylic acid obtained along this route, but in lower yield. Probably, the
N-benzylamide 10aa was obtained in 59% yield as the only stability of the compounds 12 depends on the bulk of the
isolable product (Scheme 2). This compound, a colorless substituent on the ring nitrogen atom.
solid (m.p. 36 °C), turned out to be remarkably stable with
The N-benzylazaspiropentanecarboxamide 12a could be
no detectable decomposition even after long-term storage crystallized from ethanol and characterized by X-ray crys-
at room temperature. A variety of analogous N-arylalkyl- tallography.[16] This represents the first crystal structure
1-azaspiropentane-2-carboxylic acid N-(arylalkyl)amides 10 analysis of any azaspiropentane derivative.
was prepared by the same protocol with various combi-
nations of (arylalkyl)amines 5aϪd-H applied in sequence. dal, the average of the CϪN distances is 1.465 A and the
The nitrogen atom in the aziridine ring of 12a is pyrami-
˚
2018
Eur. J. Org. Chem. 1999, 2017Ϫ2024

Cyclopropyl Building Blocks in Organic Synthesis, 51
FULL PAPER
Table 2. 1-Azaspiropentane-2-carboxylic acid alkylamides 10 from 4 and amines 5-H
R1NH2
5-H
R1
R3NH2
5-H
R3
Time
[h]
Product
10
Yield
(%)
d. r.
5a-H
5c-H
5a-H
5a-H
5d-H
Bn
5a-H
5c-H
5c-H
5d-H
5a-H
Bn
48
36
18
48
36
10aa
10cc
10ac
10ad
10da
59
27
47
47
36
Ϫ
Ϫ
Ϫ
1.1:1
1.6:1
4-MeOC6H4CH2
4-MeOC6H4CH2
4-MeOC6H4CH2
(S)-C6H5C(CH3)H
Bn
Bn
Bn
(S)-C6H5C(CH3)H
into simple peptides were made. Indeed, after depro-
tonation of the amide function in 12e by treatment with
sodium hydride, a nucleophilic substitution on ethyl bromo-
acetate could be achieved to give the azaspiropentylcarbon-
ylglycine ester 13e. Reaction of the deprotonated 12e with
4 did not give the expected Michael adduct, which would
also be a simple dipeptide, but rather the azaspiropentylox-
azoline 14e as the only isolated product. The latter consists
of N-(2-phenylethyl)-1-azaspiropentane-2-carboxylic acid
and the unnatural cyclopropane analog of the amino acid
isoserine. Further investigations on this new oxazoline-
forming reaction will be published separately.[19]
Scheme 3. Synthesis of 1-azaspiropentane-2-carboxamides 12; for
details see Table 3
Table 3. 1-Azaspiropentane-2-carboxamides 12 from 4, amines
5-H and ammonia
RNH2
5-H
R
Time
[h]
Product
12
Yield
(%)
5a-H
5e-H
Bn
C6H5C2H4
24
50
12a
12e
48
33
Scheme 4. Transformation of the amide 12e to the dipeptide 13e
and the oxazoline 14e
Conclusion
An easy access to 1-azaspiropentane-2-carboxamides and
the corresponding esters, derivatives of a new class of amino
acids, starting from the Michael acceptor 4, has been devel-
oped. The structure of amide 12a was verified by X-ray
crystallography, the first X-ray structure of any azaspiro-
pentane. The amides 10 and 12 are stable at room tempera-
ture, and those with a primary amide group can easily be
incorporated into small peptides. Biological testing of the
glycine derivative 13e and the spirocyclopropaneoxazoline
14e is currently in progress.
Figure 2. Structure of 12a in the crystal, showing 50% probability
displacement ellipsoids; of the two independent molecules in the
asymmetric unit only one is shown for clarity[16]
˚
CϪC distances are 1.471(3) and 1.467(3) A for the two in-
dependent molecules in the asymmetric unit. The CϪC dis-
tances in the spirofused cyclopropane ring show the typical
alternation as in spiropentane[17] and [3]rotane[18] with a
˚
shorter proximal [1.463(3)] and a longer distal [1.532(3) A]
bond. The angle between the plane of the aziridine ring and
the plane of the cyclopropane ring is 88.4(1)° and 87.6(1)°
for the two independent molecules in the asymmetric unit.
In recent years, the simple aziridinecarboxylic acid (3) Experimental Section
has been incorporated into small peptides, and this, in some
cases, has led to remarkable biological activities.[10c] In or-
der to prove the feasibility, the first basic attempts for the
General: The used chemicals are commercially available except for
methyl 2-chloro-2-cyclopropylideneacetate (4),[20] which was pre-
pared by a literature method.[11] All reactions were performed un-
incorporation of the novel azaspiropentanecarboxamides der anhydrous conditions and N2. Solvents were distilled under N2
Eur. J. Org. Chem. 1999, 2017Ϫ2024 2019

M. Tamm, M. Thutewohl, C. B. Ricker, M. T. Bes, A. de Meijere
FULL PAPER
from sodium benzophenone (THF) or CaH2 (DMF, NEt3,
CH2Cl2). All other reagents and solvents were purified when neces-
sary by standard procedures. Ϫ Reactions were monitored by thin-
layer chromatography on silica gel plates (MachereyϪNagel SIL
G/UV254). The chromatograms were visualized by UV light and
by staining with Merck ninhydrin spray reagent. Silica gel 60 (I,
0.063Ϫ0.200 mm, 230Ϫ400 mesh) obtained from Merck, silica gel
60 (II, 0.004Ϫ0.063 mm, 230Ϫ400 mesh, “flash”) obtained from
MachereyϪNagel, and aluminum oxide [III, neutral, activation
grade 2 (4%)] obtained from ICN were used for column chromatog-
raphy. Eluting solvents were distilled before use. When silica gel
was utilized, the column material was deactivated with 3% NEt3,
and the eluents contained 3% NEt3. Ϫ NMR spectra were recorded
with a Bruker AM 250 instrument at 250 MHz (1H) and at
62.9 MHz (13C) in CDCl3. Chemical shifts δ are reported in ppm
Methyl 2-Chloro-2-[1-(tert-butoxycarbonylmethylamino)cyclopro-
pyl]acetate (6b-H): To a solution of 4 (395 mg, 2.69 mmol) in THF
(10 mL) was added 5b-H (362 mg, 2.76 mmol). After having stirred
the mixture for 3 h at room temp., the solvent was removed in
vacuo, and the residue was purified by column chromatography (I,
20 g, LP/Et2O, 4:1Ϫ1:1) to give 6b-H (679 mg, 91%) as a colorless
liquid. Ϫ Rf ϭ 0.44 (LP/Et2O, 1:1). Ϫ IR (neat): ν˜ ϭ 3275 cmϪ1
(NϪH), 2980 (CϪH), 2955 (CϪH), 1740 (CϭO), 1677 (CϭO),
1527, 1437, 1395, 1370, 1254, 1157, 1018, 934, 886, 844, 802, 750.
1
Ϫ H NMR (250 MHz, CDCl3): δ ϭ 0.70Ϫ0.80 (m, 1 H, cPrϪH),
0.84Ϫ1.04 (m, 3 H, cPrϪH), 1.44 [s, 9 H, C(CH3)3], 2.24 (br. s, 1
H, NH), 3.39 (d, 2J ϭ 17.4 Hz, A-part of an AB system, 1 H,
NCH2), 3.50 (d, 2J ϭ 17.4 Hz, B-part of an AB system, 1 H,
NCH2), 3.79 (s, 3 H, CO2CH3), 4.18 (s, 1 H, 2-H). Ϫ 13C NMR
(62.9 MHz, CDCl3, DEPT): δ ϭ 14.80 (Ϫ, cPrϪC), 15.52 (Ϫ,
relative to CHCl3 (1H, δ ϭ 7.26) and CDCl3 (13C, δ ϭ 77.0) as cPrϪC), 28.01 [ϩ, C(CH3)3], 41.71 (Cquat, cPrϪC), 48.98 (Ϫ,
internal standard; cPr ϭ cyclopropyl; cBu ϭ cyclobutyl. Ϫ Melting
points are uncorrected.
NCH2), 52.96 (ϩ, OCH3), 63.93 (ϩ, C-2), 81.20 [Cquat, C(CH3)3],
168.69 (Cquat, CO2R), 171.63 (Cquat, CO2R). Ϫ MS (70 eV, EI);
m/z (%): 279/277 (2/5) [Mϩ], 242 (1) [Mϩ Ϫ Cl], 223/221 (4/11)
[Mϩ Ϫ C4H8], 192/190 (2/5) [Mϩ Ϫ C4H8 Ϫ CH3O], 186 (100)
[Mϩ Ϫ Cl Ϫ C4H8], 178/176 (10/32) [Mϩ Ϫ CO2C(CH3)3], 154 (38)
[Mϩ Ϫ Cl Ϫ C4H8 Ϫ CH4O], 57 (12) [C4H9ϩ]. Ϫ HRMS [Mϩ]; m/z
calculated for C12H20ClNO4: 277.1081; found 277.1080.
Methyl 2-Dibenzylaminocyclobutene-1-carboxylate (8a-Bn): A solu-
tion of 6a-Bn[21] (800 mg, 2.33 mmol) in DMF (20 mL) was heated
for 48 h at 80 °C. After cooling to room temp., H2O (30 mL) and
NEt3 (10 mL) were added. The mixture was extracted with Et2O
(3 ϫ 50 mL), the organic layers were dried with Na2SO4 and con-
centrated in vacuo. The residue was purified by column chromato-
graphy on silica gel [I, 30 g, light petroleum ether (LP)/Et2O, 10:1]
to give 8a-Bn (680 mg, 95%) as a colorless solid which crystallized
from Et2O at Ϫ20 °C. Ϫ M.p. 65 °C; Rf ϭ 0.16 (LP/Et2O, 10:1). Ϫ
IR (KBr): ν˜ ϭ 2929 cmϪ1 (CϪΗ), 2858 (CϪΗ), 1734 (CϭO), 1667
(CϭC), 1593, 1449, 1424, 1365, 1351, 1275, 1218, 1114, 1077, 1059,
1028, 955, 754, 701, 627, 473. Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ
2.45Ϫ2.51 (m, 2 H, C2H4), 2.57Ϫ2.63 (m, 2 H, C2H4), 3.66 (s, 3 H,
Methyl
2-(tert-Butoxycarbonylmethylaminocyclobutene-1-carb-
oxylate (8b-H): To a solution of 4 (500 mg, 3.41 mmol) in THF
(15 mL) was added 5b-H (447 mg, 3.41 mmol). After the mixture
had been stirred for 3 h, the solvent was evaporated in vacuo. The
crude yellow liquid of 6b-H was dissolved in MeOH (8 mL), and
NEt3 (5.0 mL, 35.9 mmol) was added. The solution was stirred for
9 d, then concentrated in vacuo. To the residue were added H2O
(2 mL) and Et2O (10 mL). After separation of the two phases, the
water layer was extracted with Et2O (3 ϫ 10 mL). The combined
organic layers were dried with Na2SO4, then the solution was con-
centrated to 5 mL. After storing at Ϫ20 °C 8b-H (248 mg,
2
2
OCH3), 4.60 (d, J ϭ 14.3 Hz, 2 H, PhCH2), 4.70 (d, J ϭ 14.5 Hz,
2 H, PhCH2), 7.13Ϫ7.41 (m, 10 H, Ph). Ϫ 13C NMR (62.9 MHz,
CDCl3, DEPT): δ ϭ 20.97 (Ϫ, C2H4), 27.73 (Ϫ, C2H4), 50.28 (ϩ,
OCH3), 51.57 (Ϫ, CH2), 90.43 (Cquat, C-2), 127.22 (ϩ, Ph), 127.43
(ϩ, Ph), 128.36 (ϩ, Ph), 137.27 (Cquat, Ph), 157.58 (Cquat, C1),
163.62 (Cquat, CO2Me). Ϫ MS (70 eV, EI); m/z (%): 307 (56) [Mϩ],
276 (18) [Mϩ Ϫ OMe], 248 (7) [Mϩ Ϫ CO2Me], 216 (42)
1.03 mmol) crystallized as a colorless solid. Ϫ M.p. 96 °C; Rf
ϭ
0.27 (LP/Et2O, 1:1). Ϫ IR (KBr): ν˜ ϭ 3392 cmϪ1 (NϪH), 2974
(CϪH), 2948 (CϪH), 2927 (CϪH), 1744 (CϭO), 1675 (CϭO),
1631 (CϭC), 1470, 1393, 1305, 1230, 1187, 1159, 1122, 1039, 849,
1
[Mϩ Ϫ PhCH2], 184 (58), 156 (11), 91 (100) [PhCH2ϩ].
Ϫ
764. Ϫ H NMR (250 MHz, CDCl3): δ ϭ 1.46 [s, 9 H, C(CH3)3],
2.42Ϫ2.45 (m, 4 H, C2H4), 3.64 (s, 3 H, CO2CH3), 3.78Ϫ3.93 (m, 2
H, NCH2), 5.63 (br. s, 1 H, NH). Ϫ 13C NMR (62.9 MHz, CDCl3,
DEPT): δ ϭ 21.48 (Ϫ, cBuϪC), 26.43 (Ϫ, cBuϪC), 27.95 [ϩ,
C20H21NO2 (307.4): calcd. C 78.15, H 6.89, N 4.55; found C 78.22,
H 6.92, N 4.68.
Methyl 2-Benzylaminocyclobutene-1-carboxylate (8a-H): To a solu-
tion of 4 (500 mg, 3.41 mmol) in DMF (10 mL) was added 5a-H
(370 mg, 3.45 mmol), and the solution was stirred for 48 h at room
temp. After addition of H2O (50 mL) and NEt3 (10 mL), the mix-
ture was worked up as in the preceding procedure. Column chroma-
tography on silica gel (I, 15 g, LP/Et2O, 2:1Ϫ1:1) gave 8a-H as a
colorless solid which crystallized from Et2O at Ϫ20 °C. Ϫ M.p.
63 °C; Rf ϭ 0.17 (LP/Et2O, 1:1). Ϫ IR (KBr): ν˜ ϭ 3327 cmϪ1
(NϪH), 2928 (CϪΗ), 2863 (CϪΗ), 1741 (CϭO), 1620 (CϭC),
C(CH3)3], 45.77 (Ϫ, NCH2), 50.20 (ϩ, CO2CH3), 82.29 [Cquat
C(CH3)3], 93.64 (Cquat, C1), 157.13 (Cquat, C-2), 164.35 (Cquat
,
,
CO2R), 169.12 (Cquat, CO2R). Ϫ MS (DCI); m/z (%): 483 (100) [2
M ϩ Hϩ], 259 (6) [M ϩ NH4ϩ], 242 (81) [M ϩ Hϩ].
ϫ
Ϫ
C12H19NO4 (241.3): calcd. C 59.73, H 7.94, N 5.81; found C 59.67,
H 7.97, N 5.82. Ϫ From the mother liquor, the solvent was evapo-
rated, and the remaining substance was chromatographed on silica
gel (I, 45 g, LP/Et2O, 2:1Ϫ1:2) to give additional 101 mg of 8b-H
(total yield: 42%). Ϫ In a second fraction as a colorless liquid
1456, 1354, 1293, 1242, 1220, 1187, 1133, 1100, 1077, 1032, 967,
936, 763, 738, 697, 601, 522, 457. Ϫ H NMR (250 MHz, CDCl3): boxylate (9b) (30 mg, 4%) was isolated. Ϫ Rf ϭ 0.13 (LP/Et2O, 1:1).
methyl
N-(tert-butoxycarbonylmethyl)-1-azaspiropentane-2-car-
1
δ ϭ 2.45Ϫ2.48 (m, 2 H, C2H4), 2.53Ϫ2.56 (m, 2 H, C2H4), 3.66 (s,
3 H, OCH3), 4.33 (d, 3J ϭ 6.4 Hz, 2 H, PhCH2), 5.88 (br. s, 1 H,
NH), 7.29Ϫ7.39 (m, 5 H, Ph). Ϫ 13C NMR (62.9 MHz, CDCl3,
DEPT): δ ϭ 21.52 (Ϫ, C2H4), 26.68 (Ϫ, C2H4), 47.51 (Ϫ, CH2),
50.02 (ϩ, OCH3), 92.29 (Cquat, C-2), 126.94 (ϩ, Ph), 127.45 (ϩ,
Ϫ IR (neat): ν˜ ϭ 2973 cmϪ1 (CϪH), 2915 (CϪH), 1731 (CϭO),
1683 (CϭO), 1438, 1393, 1340, 1290, 1156, 1041, 963, 849, 759,
618. Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ 0.83Ϫ0.91 (m, 1 H,
cPrϪH), 0.93Ϫ1.22 (m, 3 H, cPrϪH), 1.43 [s, 9 H, C(CH3)3], 2.56
2
(s, 1 H, 2-H), 3.03 (d, J ϭ 16.1 Hz, A-part of an AB system, 1 H,
Ph) 128.65 (ϩ, Ph), 138.60 (Cquat, Ph), 158.34 (Cquat, C1), 164.59 NCH2), 3.32 (d, 2J ϭ 16.1 Hz, B-part of an AB system, 1 H,
(Cquat, CO2Me). Ϫ MS (70 eV); m/z (%): 217 (36) [Mϩ], 186 (16) NCH2), 3.75 (s, 3 H, CO2CH3). Ϫ 13C NMR (62.9 MHz, CDCl3,
[Mϩ Ϫ OMe], 158 (17) [Mϩ Ϫ CO2Me], 91 (100) [PhCH2ϩ], 65 DEPT): δ ϭ 1.99 (Ϫ, cPrϪC), 3.54 (Ϫ, cPrϪC), 27.95 [ϩ,
(10); C13H15NO2 (217.3): calcd. C 71.87, H 6.96, N 6.45; found C
71.74, H 6.89, N 6.41.
C(CH3)3], 43.82 (ϩ, C-2), 45.14 (Cquat, C-3), 52.32 (ϩ, CO2CH3),
58.97 (Ϫ, NCH2), 81.58 [Cquat, C(CH3)3], 168.52 (Cquat, CO2R),
2020
Eur. J. Org. Chem. 1999, 2017Ϫ2024

Cyclopropyl Building Blocks in Organic Synthesis, 51
FULL PAPER
170.45 (Cquat, CO2R). Ϫ MS (70 eV, EI): m/z (%): 241 (23) [Mϩ],
was stirred for 48 h. Workup was carried out according to method
226 (42) [Mϩ Ϫ CH3], 210 (5) [Mϩ Ϫ OCH3], 185 (26) A. Column chromatography on silica gel (I, 30 g, LP/Et2O,
[Mϩ Ϫ C4H8], 170 (35) [Mϩ Ϫ C4H8 Ϫ CH3], 154 (5)
[Mϩ Ϫ C4H8 Ϫ OCH3], 140 (48) [Mϩ Ϫ CO2C(CH3)3], 126 (45) tallized as a colorless solid. Ϫ M.p. 36 °C; Rf ϭ 0.55 (Et2O). Ϫ IR
1:1Ϫ1:2, CH2Cl2/MeOH 10:1) gave 10aa (590 mg, 59%) which crys-
[Mϩ Ϫ C4H8 Ϫ CO2CH3], 98 (20) [Mϩ Ϫ C4H8 Ϫ CO2CH3 Ϫ CO],
(KBr): ν˜ ϭ 3307 cmϪ1, (NϪH), 3062 (CϪH), 3031 (CϪH), 2928
74 (33) [C3H6O2ϩ], 57 (100) [C4H9ϩ]. Ϫ MS (DCI); m/z (%): 500 (CϪH), 1663 (CϭO), 1526, 1496, 1454, 1266, 1155, 1077, 1029,
(7) [2 ϫ M ϩ NH4ϩ], 483 (100) [2 ϫ M ϩ Hϩ], 276 (10) 737, 700, 668, 458. Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ 0.84Ϫ1.03
[M ϩ NH3 ϩ NH4ϩ], 259 (100) [M ϩ NH4ϩ], 242 (63) [M ϩ Hϩ]. (m, 2 H, cPrϪH), 1.05Ϫ1.19 (m, 2 H, cPrϪH), 2.66 (s, 1 H, CHN),
Ϫ HRMS [Mϩ]; m/z calculated for C12H19NO4: 241.1314; found
241.1314. Ϫ In a third fraction 73 mg (8%) of 6b-H could be reco-
vered.
3.56 (d, J ϭ 13.8 Hz, A-part of an AB system, 1 H, PhCH2), 3.67
2
2
(d, J ϭ 13.8 Hz, B-part of an AB system, 1 H, PhCH2), 4.40 (dd,
3J ϭ 4.8, 2J ϭ 14.5 Hz, A-part of an ABX system, 1 H, PhCH2),
4.48 (dd, B-part of an ABX system, 3J ϭ 4.8, 2J ϭ 14.5 Hz, 1 H,
Methyl N-Aryl-1-azaspiropentane-2-carboxylates (9). ؊ General
Procedure (GP1): To a solution of 4 (0.71 mmol) in THF (10 mL)
was added an amine 5-H (0.71 mmol). After stirring for 30 min at
room temp., the solution was concentrated in vacuo. The residue
was purified by column filtration through silica gel (I, n-pentane/
Et2O, 3:1). The isolated amine adduct 6-H was immediately dis-
solved in MeOH, and NEt3 (1.0 mL, 7.2 mmol) was added. After
the solution had been stirred at room temp., the solvent was re-
moved in vacuo, and the residue was purified by column chroma-
tography to give product 9.
PhCH2), 7.13Ϫ7.35 (m, 11 H, Ph, CONH).
Ϫ
13C NMR
(62.9 MHz, CDCl3, DEPT): δ ϭ 2.04 (Ϫ, cPrϪC), 2.95 (Ϫ,
cPrϪC), 42.59 (Ϫ, PhCH2), 45.07 (Cquat, C-3), 45.83 (ϩ, C-2),
60.20 (Ϫ, PhCH2), 127.16 (ϩ, Ph), 127.23 (ϩ, Ph), 127.54 (ϩ, Ph),
127.58 (ϩ, Ph), 128.46 (ϩ, Ph), 128.54 (ϩ, Ph), 138.38 (Cquat, Ph),
138.47 (Cquat, Ph), 169.84 (Cquat, CϭO). Ϫ MS (70 eV, EI); m/z
(%): 292 (< 1) [Mϩ], 291 (< 1) [Mϩ Ϫ H], 235 (1), 201 (3) [Mϩ
Ϫ
PhCH2], 186 (11) [Mϩ
Ϫ
PhCH2NH], 159 (19) [Mϩ
Ϫ
PhCH2NCO], 106 (7) [PhCH2NHϩ], 105 (7) [PhCHNHϩ], 91 (100)
[PhCH2ϩ]. Ϫ C19H20N2O (292.4): calcd. C 78.06, H 6.89, N 9.58;
found C 77.97, H 6.91, N 9.61.
Methyl N-Benzyl-1-azaspiropentane-2-carboxylate (9a): Reaction of
4 (104 mg, 0.71 mmol) with 5a-H (76 mg, 0.71 mmol) according to
GP1 gave 6a-H (168 mg, 93%) as a colorless liquid. Stirring of 6a-
H (160 mg, 0.63 mmol) in MeOH (6 mL) in the presence of NEt3
(1.0 mL, 7.2 mmol) for 24 h, followed by workup as described
above, furnished after column chromatography on aluminum oxide
(III, 30 g, Et2O) as a colorless liquid 9a (20 mg, 14%). Ϫ Rf ϭ 0.36
(n-pentane/Et2O, 1:1). Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ
0.84Ϫ1.25 (m, 4 H, cPrϪH), 2.59 (s, 1 H, 2-H), 3.52 (d, 2J ϭ
13.9 Hz, A-part of an AB system, 1 H, PhCH2), 3.73 (s, 3 H,
OCH3), 3.78 (d, 2J ϭ 13.8 Hz, B-part of an AB system, 1 H,
PhCH2), 7.24Ϫ7.33 (m, 5 H, Ph). Ϫ 13C NMR (62.9 MHz, CDCl3,
DEPT): δ ϭ 1.94 (Ϫ, cPrϪC), 3.53 (Ϫ, cPrϪC), 43.56 (ϩ, C-2),
45.83 (Cquat, C-3), 52.26 (ϩ, OCH3), 61.23 (Ϫ, CH2Ph), 127.09 (ϩ,
Ph), 127.66 (ϩ, Ph), 128.39 (ϩ, Ph), 138.09 (Cquat, Ph). Ϫ MS
(70 eV, EI); m/z (%): 217 (1) [Mϩ], 202 (2) [Mϩ Ϫ CH3], 186 (6)
[Mϩ Ϫ OCH3], 158 (7) [Mϩ Ϫ CO2CH3], 129 (6), 126 (5)
[Mϩ Ϫ PhCH2], 91 (100) [PhCH2ϩ]. HRMS (Mϩ); m/z calculated
for C13H15NO2: 217.1102; found 217.1102. Ϫ In a second fraction
20 mg (26%) of 5a-H could be recovered.
N-(p-Methoxybenzyl)-1-azaspiropentane-2-carboxylic Acid p-Meth-
oxybenzylamide (10cc): A solution of 4 (500 mg, 3.41 mmol) in
THF (20 mL) was treated with 5c-H (940 mg, 6.85 mmol) accord-
ing to GP2, and the mixture was stirred for 36 h. Workup was
carried out according to method B. Column chromatography on
silica gel (I, 30 g, LP/Et2O, 1:1 Ϫ Et2O) gave 10cc (320 mg, 22%)
which crystallized as a colorless solid. Ϫ M.p. 87 °C; Rf ϭ 0.42
(Et2O). Ϫ IR (KBr): ν˜ ϭ 3261 cmϪ1 (NϪΗ), 3060 (CϪΗ), 3006
(CϪΗ), 2957 (CϪΗ), 2836 (CϪΗ), 1651 (CϭO), 1614, 1585, 1513,
1456, 1360, 1301, 1254, 1174, 1032, 831, 805, 734, 583, 513. Ϫ
1H NMR (250 MHz, CDCl3): δ ϭ 0.80Ϫ0.93 (m, 2 H, cPrϪH),
1.04Ϫ1.23 (m, 2 H, cPrϪH), 2.61 (s, 1 H, 2-H), 3.47 (d, 2J ϭ
13.4 Hz, A-part of an AB system, 1 H, PhCH2), 3.60 (d, 2J ϭ
13.4 Hz, B-part of an AB system, 1 H, PhCH2), 3.79 (s, 6 H,
PhOCH3), 4.31 (dd, 3J ϭ 6.1, 2J ϭ 14.9 Hz, A-part of an ABX sys-
tem, 1 H, PhCH2), 4.40 (dd, 3J ϭ 6.1, 2J ϭ 14.9 Hz, B-part of an
ABX system, 1 H, PhCH2), 6.83 (d, 3J ϭ 8.6 Hz, 4 H, Ph), 7.00 (br.
s, 1 H, NH), 7.09Ϫ7.19 (m, 4 H, Ph). Ϫ 13C NMR (62.9 MHz,
CDCl3, DEPT): δ ϭ 1.98 (Ϫ, cPrϪC), 2.86 (Ϫ, cPrϪC), 42.07 (Ϫ,
PhCH2), 44.92 (ϩ, OCH3), 45.82 (Cquat, cPrϪC), 5.20 (ϩ, OCH3),
55.21 (ϩ, C-2), 59.67 (Ϫ, PhCH2), 113.81 (ϩ, Ph), 113.88 (ϩ, Ph),
N-Alkyl-1-azaspiropentane-2-carboxylic Acid Alkylamides and N-
Arylmethyl-1-azaspiropentane-2-carboxylic Acid Arylmethylamides
(10). ؊ General Procedure (GP2): To a solution of 4 (500 mg,
3.41 mmol) in THF (20 mL) was added an amine 5-H (3.41 mmol).
The mixture was stirred at room temp. overnight, then cooled to
Ϫ10 °C, before NEt3 (2 mL), a second equivalent of an amine 5-
H (3.41 mmol) and NaH (270 mg, 6.75 mmol, 60% suspension in
mineral oil) were added. The resulting suspension was allowed to
warm to room temp. and stirred (for the exact time, see the particu-
lar example). Workup: Method A: To the resulting orange mixture
were added MeOH (5 mL) and silica gel (5 g). The solvent was
evaporated, and the remaining solid was chromatographed on silica
gel. Method B: To the resulting suspension was added H2O
(50 mL), and the mixture was extracted with Et2O (3 ϫ 30 mL).
The organic layers were dried with Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography on sil-
ica gel. The product resulting from both methods was recrys-
tallized, if possible, from Et2O at Ϫ20 °C.
128.57 (ϩ, Ph), 128.79 (ϩ, Ph), 130.41 (Cquat, Ph), 130.43 (Cquat
,
Ph), 158.71 (Cquat, Ph), 158.79 (Cquat, Ph), 169.82 (Cquat, CONH).
Ϫ MS (70 eV, EI): m/z (%): 352 (< 1) [Mϩ], 247 (2), 136 (19)
[MeOPhCH2NHϩ], 121 (100) [MeOPhCH2ϩ]; C21H24N2O3 (352.4):
calcd. C 71.57, H 6.86; found C 71.42, H 6.92.
N-Benzyl-1-azaspiropentane-2-carboxylic Acid p-Methoxybenzyl-
amide (10ac): A solution of 4 (3.00 g, 20.5 mmol) in THF (20 mL)
was treated first with 5a-H (2.20 g, 20.5 mmol) and then with 5c-
H (2.80 g, 20.4 mmol) according to GP2, and the mixture was
stirred for 18 h. Workup was carried out according to method A.
Column chromatography on silica gel (I, 30 g, LP/Et2O, 1:1 Ϫ
Et2O) gave 10ac (3.10 g, 47%) which crystallized as a colorless
solid. Ϫ M.p. 79 °C; Rf ϭ 0.43 (Et2O). Ϫ IR (KBr): ν˜ ϭ 3297 cmϪ1
(NϪΗ), 3028 (CϪΗ), 3003 (CϪΗ), 2957 (CϪΗ), 2936 (CϪΗ),
2874 (CϪΗ), 2835 (CϪΗ), 1664 (CϭO), 1587, 1516, 1451, 1356,
1305, 1254, 1161, 1117, 1037, 1008, 811, 737, 699, 625, 574, 518,
N-Benzyl-1-azaspiropentane-2-carboxylic Acid Benzylamide (10aa): 455. Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ 0.81Ϫ0.97 (m, 2 H,
A solution of 4 (500 mg, 3.41 mmol) in THF (20 mL) was treated cPrϪH), 1.05Ϫ1.19 (m, 2 H, cPrϪH), 2.64 (s, 1 H, 2-H), 3.57 (d,
with 5a-H (730 mg, 6.81 mmol) according to GP2, and the mixture 2J ϭ 13.8 Hz, A-part of an AB system, 1 H, PhCH2), 3.66 (d, J ϭ
2
Eur. J. Org. Chem. 1999, 2017Ϫ2024
2021

M. Tamm, M. Thutewohl, C. B. Ricker, M. T. Bes, A. de Meijere
FULL PAPER
13.8 Hz, B-part of an AB system, 1 H, PhCH2), 3.79 (s, 3 H,
PhCH2), 7.04Ϫ7.45 (m, 11 H, Ph, NH). Ϫ Minor isomer: 1H NMR
(250 MHz, CDCl3): δ ϭ 0.70Ϫ1.44 (m, 4 H, cPrϪH), 1.27 (d, J ϭ
7.4 Hz, 3 H, CH3), 2.49 (s, 1 H, 2-H), 3.02Ϫ3.20 (m, 1 H, PhCH),
3
3
PhOCH3), 4.29Ϫ4.45 (m, 2 H, PhCH2), 6.84 (d, J ϭ 8.6 Hz, 2 H,
Ph), 7.03 (br. s, 1 H, NH), 7.13 (d, 3J ϭ 8.6 Hz, 2 H, Ph), 7.24Ϫ7.35
(m, 5 H, Ph). Ϫ 13C NMR (62.9 MHz, CDCl3, DEPT): δ ϭ 1.96 5.10Ϫ5.23 (m, 2 H, PhCH2), 7.04Ϫ7.43 (m, 11 H, Ph, NH). Ϫ MS
(Ϫ, cPrϪC), 2.84 (Ϫ, cPrϪC), 42.07 (Ϫ, PhCH2), 45.03 (ϩ,
OCH3), 45.82 (Cquat, cPrϪC), 55.23 (ϩ, C-2), 60.20 (Ϫ, PhCH2),
113.92 (ϩ, Ph), 127.12 (ϩ, Ph), 127.49 (ϩ, Ph), 128.42 (ϩ, Ph),
(70 eV, EI); m/z (%): 306 (7) [Mϩ], 202 (17), 162 (18), 105 (100)
[PhCHCH3ϩ], 91 (43) [PhCH2ϩ], 86 (39).
N-Alkyl-1-azaspiropentane-2-carboxylic Acid Amides and N-
Arylmethyl-1-azaspiropentane-2-carboxylic Acid Amides (12). ؊
General Procedure (GP3): A solution of 4 (500 mg, 3.41 mmol) and
an amine 5-H (3.45 mmol) in THF (20 mL) was stirred at room
temp. for 5 h. The mixture was saturated with gaseous ammonia at
Ϫ10 °C, after which NEt3 (2 mL) and NaH (280 mg, 7.00 mmol,
60% suspension in mineral oil) were added. The resulting suspen-
sion was allowed to warm to room temp. and stirred (for the exact
time, see the particular example). MeOH (5 mL) and silica gel (5 g)
were added. The solvents were evaporated and the remaining solid
was chromatographed on silica gel. The product was recrystallized
from Et2O at Ϫ20 °C.
128.59 (ϩ, Ph), 130.45 (Cquat, Ph), 138.33 (Cquat, Ph), 158.77 (Cquat
Ph), 169.69 (Cquat, CONH). Ϫ MS (70 eV, EI): m/z (%): 322 (2)
[Mϩ], 231 (1) [Mϩ Ϫ PhCH2], 203 (4) [Mϩ Ϫ PhCH2 Ϫ C2H4], 186
,
(11)
[Mϩ Ϫ MeOPhCH2NH],
159
(20),
136
(44)
[MeOPhCH2NHϩ], 121 (51) [MeOPhCH2ϩ], 91 (100) [PhCH2ϩ].
Ϫ C20H22N2O2 (322.4): calcd. C 74.51, H 6.88; found C 74.40,
H 6.88.
N-Benzyl-1-azaspiropentane-2-carboxylic Acid (S)-Phenylethyl-
amide (10ad): A solution of 4 (1.00 g, 6.82 mmol) in THF (20 mL)
was treated first with 5a-H (740 mg, 6.90 mmol) and then with 5d-
H (840 mg, 6.93 mmol) according to GP2, and the mixture was
stirred for 48 h. Workup was carried out according to method B.
Column chromatography on silica gel (I, 30 g, LP/Et2O, 2:1Ϫ1:1)
gave 10ad (986 mg, 47%) as a colorless liquid which consisted of
two diastereomers in a ratio of 1.1:1. Ϫ Rf ϭ 0.17 (LP/Et2O, 1:1).
Ϫ IR (neat): ν˜ ϭ 3379 cmϪ1 (NϪΗ), 3062 (CϪH), 3030 (CϪH),
2973 (CϪH), 2927 (CϪH), 2868 (CϪH), 1669 (CϭO), 1526, 1496,
1454, 1361, 1266, 1210, 1155, 1132, 1100, 1076, 1029, 972, 737, 701.
Ϫ Major isomer: 1H NMR (250 MHz, CDCl3): δ ϭ 0.73Ϫ1.19 (m,
4 H, cPrϪH), 1.46 (d, 3J ϭ 7.0 Hz, 3 H, CH3), 2.60 (s, 1 H, 2-H),
N-Benzyl-1-azaspiropentane-2-carboxamide (12a): A solution of 4
(500 mg, 3.41 mmol) in THF (20 mL) was first treated with 5a-H
(370 mg, 3.45 mmol) and subsequently with ammonia according to
GP3. The mixture was stirred for 24 h and then worked up. Column
chromatography on silica gel (I, 30 g, LP/Et2O, 1:1 Ϫ Et2O) gave
12a (330 mg, 48%), which crystallized as a colorless solid. Ϫ M.p.
135 °C, Rf ϭ 0.15 (Et2O). Ϫ IR (KBr): ν˜ ϭ 3370 cmϪ1 (NϪH),
3144 (NϪH), 2861 (CϪH), 1683 (CϭO), 1610, 1429, 1407, 1357,
1153, 1092, 1016, 915, 755, 725, 698, 667, 638, 513. Ϫ 1H NMR
(250 MHz, CDCl3): δ ϭ 0.83Ϫ0.98 (m, 2 H, cPrϪH), 1.03Ϫ1.14
2
3.43 (d, J ϭ 13.9 Hz, A-part of an AB system, 1 H, PhCH2), 3.51
(d, 3J ϭ 13.9 Hz, B-part of an AB system, 1 H, PhCH2), 5.02Ϫ5.19
(m, 1 H, PhCH), 7.08 (br. s, 1 H, NH), 7.12Ϫ7.47 (m, 10 H, Ph).
2
(m, 2 H, cPrϪH), 2.54 (s, 1 H, 2-H), 3.59 (d, J ϭ 11.4 Hz, A-part
2
Ϫ
13C NMR (62.9 MHz, CDCl3, DEPT): δ ϭ 1.67 (Ϫ, cPrϪC),
of an AB system, 1 H, PhCH2), 3.68 (d, J ϭ 11.4 Hz, B-part of an
AB system, 1 H, PhCH2), 6.48 (br. s, 1 H, NH), 6.59 (br. s, 1 H,
NH), 7.20Ϫ7.38 (m, 5 H, Ph). Ϫ 13C NMR (62.9 MHz, CDCl3,
DEPT): δ ϭ 2.05 (Ϫ, cPrϪC), 2.88 (Ϫ, cPrϪC), 44.71 (ϩ, C-2),
45.76 (Cquat, cPrϪC), 60.10 (Ϫ, PhCH2), 126.96 (ϩ, Ph), 127.30
(ϩ, Ph), 128.28 (ϩ, Ph), 138.21 (Cquat, Ph), 173.22 (Cquat, CONH2).
Ϫ MS (70 eV, EI); m/z (%): 201 (1) [Mϩ Ϫ H], 185 (9) [Mϩ Ϫ NH3],
157 (10) [Mϩ Ϫ NH3 Ϫ C2H4], 91 (100) [PhCH2ϩ], 77 (2) [Phϩ], 65
2.50 (Ϫ, cPrϪC), 21.85 (ϩ, CH3), 44.69 (ϩ, C-2), 45.53 (Cquat
cPrϪC), 47.54 (ϩ, CHCH3), 58.81 (Ϫ, PhCH2), 125.60 (ϩ, Ph),
126.85 (ϩ, Ph), 126.98 (ϩ, Ph), 127.30 (ϩ, Ph), 128.20 (ϩ, Ph),
,
128.29 (ϩ, Ph), 138.08 (Cquat, Ph), 142.92 (Cquat, Ph), 168.68 (Cquat
,
CONH). Ϫ Minor isomer: 1H NMR (250 MHz, CDCl3): δ
ϭ
3
0.73Ϫ1.19 (m, 4 H, cPrϪH), 1.48 (d, J ϭ 7.0 Hz, 3 H, CH3), 2.62
2
(s, 1 H, 2-H), 3.70 (d, J ϭ 13.9 Hz, A-part of an AB system, 1 H,
PhCH2), 3.76 (d, 2J ϭ 13.9 Hz, B-part of an AB system, 1 H,
PhCH2), 5.02Ϫ5.19 (m, 1 H, PhCH), 7.08 (br. s, 1 H, NH),
7.12Ϫ7.47 (m, 10 H, Ph). Ϫ 13C NMR (62.9 MHz, CDCl3, DEPT):
δ ϭ 1.85 (Ϫ, cPrϪC), 2.62 (Ϫ, cPrϪC), 21.99 (ϩ, CH3), 44.73 (ϩ,
C-2), 45.53 (Cquat, cPrϪC), 47.57 (ϩ, CHCH3), 58.88 (Ϫ, PhCH2),
126.82 (ϩ, Ph), 126.91 (ϩ, Ph), 127.17 (ϩ, Ph), 127.30 (ϩ, Ph),
(11).
Ϫ C12H14N2O (202.3): calcd. C 71.27, H 6.98; found
C 71.22, H 7.07.
N-(2Ј-Phenylethyl)-1-azaspiropentane-2-carboxamide (12e): A solu-
tion of 4 (2.00 g, 13.6 mmol) in THF (70 mL) was treated with 5g-
H (1.65 g, 13.6 mmol) and then with ammonia according to GP3.
The mixture was stirred for 50 h and then worked up. Column chro-
matography on silica gel (I, 40 g, Et2O/EtOAc, 1:1Ϫ1:2) gave 12e
(985 mg, 33%), which crystallized as a colorless solid. Ϫ M.p.
71 °C; Rf ϭ 0.25 (Et2O/EtOAc, 1:1). Ϫ IR (KBr): ν˜ ϭ 3425 cmϪ1
(NϪH), 3177 (NϪH), 3080 (CϪH), 3030 (CϪH), 3002 (CϪH),
2943 (CϪH), 2932 (CϪH), 2846 (CϪH), 1657 (CϭO), 1602, 1496,
1454, 1402, 1151, 1111, 1092, 749, 700, 646. Ϫ 1H NMR (250 MHz,
CDCl3): δ ϭ 0.77Ϫ0.86 (m, 3 H, cPrϪH), 0.88Ϫ1.05 (m, 1 H,
cPrϪH), 2.32 (s, 1 H, 2-H), 2.58Ϫ2.86 (m, 4 H, CH2), 5.87 (br. s,
128.20 (ϩ, Ph), 128.29 (ϩ, Ph), 138.17 (Cquat, Ph), 143.22 (Cquat
,
Ph), 168.78 (Cquat, CONH). Ϫ MS (70 eV, EI); m/z (%): 306 (< 1)
[Mϩ], 235 (7), 186 (18) [Mϩ Ϫ PhCHCH3NH], 159 (23), 120 (18)
[PhCHCH3NHϩ], 105 (39) [PhCHCH3ϩ], 91 (100) [PhCH2ϩ]. Ϫ
C20H22N2O (306.4): calcd. C 78.40, H 7.24, N 9.14; found C 78.78,
H 7.08, N 8.99.
N-(S)-Phenylethyl-1-azaspiropentane-2-carboxylic Acid Benzyl-
amide (10da): A solution of 4 (500 mg, 3.41 mmol) in THF (20 mL)
was treated first with 5d-H (420 mg, 3.47 mmol) and then with 5a- 1 H, NH2), 6.48 (br. s, 1 H, NH2), 7.17Ϫ7.32 (m, 5 H, Ph). Ϫ
H (370 mg, 3.45 mmol) according to GP2, and the mixture was 13C NMR (62.9 MHz, CDCl3, DEPT): δ ϭ 1.92 (Ϫ, cPrϪC), 2.98
stirred for 36 h. Workup was carried out according to method B.
Column chromatography on silica gel (I, 15 g, LP/Et2O, 1:1 Ϫ
Et2O) gave 10da (371 mg, 36%) as a colorless liquid consisting of
two diastereomers in a ratio of 1.6:1. Ϫ Rf ϭ 0.24 (LP/Et2O, 1:1).
Ϫ IR (neat): ν˜ ϭ 3384 cmϪ1 (NϪΗ), 3054 (CϪΗ), 2985 (CϪΗ),
1670 (CϭO), 1526, 1496, 1454, 1420, 1265, 1155, 1076, 1029, 896,
(Ϫ, cPrϪC), 36.17 (Ϫ, PhCH2), 44.78 (ϩ, C-2), 45.62 (Cquat, C-3),
58.30 (Ϫ, NCH2), 126.26 (ϩ, Ph), 128.36 (ϩ, Ph), 128.69 (ϩ, Ph),
139.56 (Cquat, Ph), 173.34 (Cquat, CONH2). Ϫ MS (70 eV, EI): m/z
(%): 217 (1) [Mϩ ϩ H], 216 (1) [Mϩ], 215 (1) [Mϩ Ϫ H], 199 (2)
[Mϩ Ϫ NH3],
[Mϩ ϩ H Ϫ CONH2 Ϫ C2H4],
172
(3)
[Mϩ Ϫ CONH2],
125 (31),
145
112
(3)
(30)
745, 704. Ϫ Major isomer: 1H NMR (250 MHz, CDCl3): δ ϭ [Mϩ ϩ H Ϫ PhC2H4], 105 (100) [PhC2H4ϩ], 91 (15) [PhCH2ϩ], 77
0.70Ϫ1.44 (m, 4 H, cPrϪH), 1.46 (d, J ϭ 7.4 Hz, 3 H, CH3), 2.70 (18) [Phϩ], 65 (4) [C5H5ϩ]. Ϫ C13H16N2O (216.3): calcd. C 72.19,
3
(s, 1 H, 2-H), 3.02Ϫ3.20 (m, 1 H, PhCH), 4.24Ϫ4.68 (m, 2 H,
H 7.46, N 12.95; found C 72.37, H 7.46, N 12.96.
Eur. J. Org. Chem. 1999, 2017Ϫ2024
2022

Cyclopropyl Building Blocks in Organic Synthesis, 51
N -(2 Ј -P h eny let hy l)-1-a z a s pi r o pe nt a n e- 2- ca r b ox y l ic 44.21 (Cquat, C-3Ј), 52.18 (ϩ, CO2CH3), 52.76 (Cquat, C-3), 59.77
FULL PAPER
Acid Ethoxycarbonylmethylamide (13e): To
(232 mg, 1.07 mmol) in THF (10 mL) was added NaH (44 mg,
1.10 mmol, 60% suspension in mineral oil) at Ϫ15 °C. The mixture (Cquat, CO2Me). Ϫ MS (70 eV, EI): m/z (%): 327 (3) [Mϩ ϩ H], 326
was stirred for 8 h at room temp., then cooled to Ϫ15 °C and ethyl (3) [Mϩ], 325 (2) [Mϩ Ϫ H], 298 (13) [Mϩ Ϫ C2H4], 283 (3) [Mϩ
bromoacetate (198 mg, 1.19 mmol) was added dropwise. After the Ϫ C3H7], 235 (23) [Mϩ Ϫ PhCH2], 221 (8) [Mϩ Ϫ PhC2H4], 205
a
solution of 12e
(Ϫ, NCH2), 79.61 (ϩ, CHCO2Me), 126.14 (ϩ, Ph), 128.48 (ϩ, Ph),
128.72 (ϩ, Ph), 139.58 (Cquat, Ph), 164.82 (Cquat, CϭN), 169.06
mixture had been stirred for 43 h at room temp., EtOH (1 mL) was
added and the solvent was evaporated in vacuo. Purification of the H2ϩ]. Ϫ HRMS [Mϩ]; m/z calculated for C19H22N2O3: 326.1630;
(10) [Mϩ Ϫ NH2C2H4Ph], 105 (100) [PhC2H4ϩ], 91 (100) [PhC-
residue by flash chromatography (I, 40 g, LP/EtOAc, 4:3 Ϫ EtOAc)
gave 13e (83 mg, 25%) as a colorless oil. Ϫ Rf ϭ 0.19 (LP/EtOAc,
4:3). Ϫ IR (neat): ν˜ ϭ 3383 cmϪ1 (NϪH), 3063 (CϪH), 3025
(CϪH), 2980 (CϪH), 2932 (CϪH), 2847 (CϪH), 1750 (CϭO),
1675 (CϭO), 1522, 1496, 1453, 1409, 1375, 1354, 1195, 1156, 1028,
found 326.1630. Ϫ In a second fraction 83 mg (28%) of 12e could
be recovered.
Acknowledgments
1
752, 701, 518. Ϫ H NMR (250 MHz, CDCl3): δ ϭ 0.76Ϫ1.04 (m,
4 H, cPrϪH), 1.26 (t, 3J ϭ 7.1 Hz, 3 H, CO2CH2CH3), 2.37 (s, 1 H,
2-H), 2.58Ϫ2.84 (m, 4 H, NC2H4Ph), 3.85Ϫ4.07 (m, 2 H,
NCH2CO2Et), 4.19 (q, 3J ϭ 7.1 Hz, 2 H, CO2CH2CH3), 7.09Ϫ7.29
(m, 6 H, Ph, NH). Ϫ 13C NMR (62.9 MHz, CDCl3, DEPT): δ ϭ
1.76 (Ϫ, cPrϪC), 2.95 (Ϫ, cPrϪC), 14.11 (ϩ, CH3), 36.23 (Ϫ,
PhCH2), 40.65 (Ϫ, NCH2CO2Et), 44.76 (ϩ, C-2), 45.64 (Cquat, C-
3), 58.33 (Ϫ, NCH2), 61.30 (Ϫ, OCH2), 126.25 (ϩ, Ph), 128.35 (ϩ,
Ph), 128.76 (ϩ, Ph), 139.59 (Cquat, Ph), 169.58 (Cquat, CONH),
170.49 (Cquat, CO2Et). Ϫ MS (70 eV, EI); m/z (%): 303 (1)
[Mϩ ϩ H], 302 (1) [Mϩ], 257 (4) [Mϩ Ϫ OC2H5], 212 (5)
[Mϩ ϩ H Ϫ PhCH2], 211 (43) [Mϩ Ϫ PhCH2], 198 (18)
[Mϩ ϩ H Ϫ PhC2H4], 172 (7), 137 (4), 105 (100) [PhC2H4ϩ]. Ϫ
HRMS [Mϩ]; m/z calculated for C17H22N2O3: 302.1630; found
302.1630. Ϫ In a second fraction 52 mg (22%) 12e could be reco-
vered.
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 416, Project A3) and the Fonds der Chemischen Industrie.
We are grateful to the companies BASF, Bayer, Degussa, Hoechst
and Hüls AG for generous gifts of chemicals. M. T. B. thanks the
European Community for
ERBCHBGCT 940731).
a
postdoctoral fellowship (N.
[1]
Reviews: [1a] A. Alami, M. Calmes, J. Daunis, R. Jacquier, Bull.
[1b]
Soc. Chim. Fr. 1993, 130, 5Ϫ24. Ϫ
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hedron 1990, 46, 2231Ϫ2254. Ϫ
A. M. Serebryanyi, G. A.
Krasheninnikova, L. V. Vakhina, Biochemistry ( Moscow) 1995,
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N. Andres, H. Wolf, H. Zähner, E. Rössner, A. Zeeck, W.
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E. Rössner, A. Zeeck, W. A. König, Angew. Chem. 1990,
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[3] [3a]
Methyl
5-[N-(2ЈЈ-Phenylethyl)-1-azaspiropent-2Ј-yl]4-aza-6-oxa-
solution of 12e
M. C. Pirrung, J. Cao, J. Chen, J. Org. Chem. 1995, 60,
[3b]
spiro[2.4]hept-4-ene-7-carboxylate (14e): To
a
5790Ϫ5794. Ϫ
M. C. Pirrung, H. Han, J. Chen, J. Org.
Chem. 1996, 61, 4527Ϫ4531. Ϫ [3c] M. C. Pirrung, L. M. Kaiser,
J. Chen, Biochemistry 1993, 32, 7445Ϫ7450.
(297 mg, 1.37 mmol) in THF (5 mL) was added NaH (55 mg,
1.37 mmol, 60% suspension in mineral oil) at Ϫ15 °C. The mixture
was stirred for 6 h at room temp. and then cooled to Ϫ15 °C after
diluting with CH2Cl2 (5 mL). Now a solution of 4 (221 mg,
1.51 mmol) and dibenzo-18-crown-6 (72 mg, 0.20 mmol) in CH2Cl2
(10 mL) was added dropwise. After stirring for 2 d at room temp.,
ice-cold water (20 mL) was added and the phases were separated.
The water layer was extracted with CH2Cl2 (3 ϫ 30 mL), and the
organic layers were washed with saturated NaCl solution. The sol-
vent was evaporated and flash chromatography of the residue (II,
40 g, LP/EtOAc, 3:4Ϫ1:4) gave 14e (129 mg, 29%) as a slightly yel-
low liquid which consisted of two diastereomers in a ratio of 2:1.
Ϫ Rf ϭ 0.20 (LP/EtOAc, 4:3). Ϫ IR (neat): ν˜ ϭ 3062 cmϪ1 (CϪH),
3025 (CϪH), 3003 (CϪH), 2951 (CϪH), 2845 (CϪH), 1762 (Cϭ
O), 1738 (CϭO), 1662 (CϭN), 1583, 1496, 1453, 1437, 1415, 1355,
1286, 1202, 1178, 1161, 1055, 1023, 750, 700. Ϫ Major isomer:
1H NMR (250 MHz, CDCl3): δ ϭ 0.76Ϫ0.95 (m, 3 H, cPrϪH),
0.96Ϫ1.17 (m, 3 H, cPrϪH), 1.18Ϫ1.25 (m, 2 H, cPrϪH), 2.55 (s,
1 H, 2Ј-H), 2.58Ϫ2.95 (m, 4 H, 2 CH2), 3.72 (s, 3 H, OCH3), 4.77
(s, 1 H, CHCO2Me), 7.10Ϫ7.29 (m, 5 H, Ph). Ϫ 13C NMR
(62.9 MHz, CDCl3, DEPT): δ ϭ 1.40 (Ϫ, cPrϪC), 3.79 (Ϫ,
cPrϪC), 9.82 (Ϫ, cPrϪC), 14.48 (Ϫ, cPrϪC), 36.30 (Ϫ, PhCH2),
40.06 (ϩ, C-2Ј), 44.51 (Cquat, C-3Ј), 51.98 (ϩ, CO2CH3), 52.76
(Cquat, C-3), 59.88 (Ϫ, NCH2), 79.51 (ϩ, CHCO2Me), 126.07 (ϩ,
Ph), 128.31 (ϩ, Ph), 128.64 (ϩ, Ph), 139.49 (Cquat, Ph), 164.72
[4]
[5]
K. Burgess, K.-K. Ho, D. Moye-Sherman, Synlett 1994,
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Z. Huang, Y.-B. He, K. Raynor, M. Tallent, T. Reisine, M.
Goodman, J. Am. Chem. Soc. 1992, 114, 9390Ϫ9401. Ϫ [6b] Y. -
F. Zhu, T. Yamazaki, J. W. Tsang, S. Lok, M. Goodman, J. Org.
Chem. 1992, 57, 1074Ϫ1081.
[7]
M. Shimura, M. Iwata, S. Omoto, Y. Sekizawa, Agric. Biol.
Chem. 1979, 43, 2279Ϫ2281.
[8] [8a]
D. H. Aue, R. B. Lorens, G. S. Helwig, Tetrahedron Lett.
[8b]
1973, 48, 4795Ϫ4798. Ϫ
D. H. Aue, R. B. Lorens, G. S.
Helwig, J. Org. Chem. 1979, 44, 1202Ϫ1207. Ϫ [8c] J. K. Crand-
all, W. W. Conover, J. Chem. Soc., Chem. Commun. 1973,
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33Ϫ34. Ϫ
J. K. Crandall, W. W. Conover, J. Org. Chem.
1974, 39, 63Ϫ66. Ϫ [8e] O. Tsuge, T. Ohnishi, H. Watanabe, Het-
[8f]
erocycles 1981, 16, 2085Ϫ2090. Ϫ
O. Tsuge, H. Watanabe,
Heterocycles 1976, 4, 1905Ϫ1908. Ϫ [8g] O. Tsuge, H. Watanabe,
[8h]
Heterocycles 1977, 7, 907Ϫ912. Ϫ
O. Tsuge, H. Watanabe,
[8i]
Y. Kiryu, Bull. Chem. Soc. Jpn. 1979, 52, 3387Ϫ3390. Ϫ
Tlili, J. Soc. Chim. Tunis. 1988, 2, 3Ϫ7.
T.
[9]
In general, aziridines possess alkylating properties. Because of
this character, many natural and unnatural aziridine-containing
compounds show biological activities. See: A. R. Katritzky, C.
W. Rees, E. F. Criven, Comprehensive Heterocyclic Chemistry
II, Pergamon Press, New York, 1996, vol. 1A, pp. 58Ϫ60 and
references cited therein.
[10] [10a]
P. Dauban, L. Dubois, M. E. T. H. Dau, R. H. Dodd, J.
[10b]
Org. Chem. 1995, 60, 2035Ϫ2043. Ϫ
D. Tanner, Angew.
Chem. 1994, 106, 625Ϫ646; Angew. Chem. Int. Ed. Engl. 1994,
33, 599Ϫ620, and references cited therein. Ϫ [10c] M. Goodman,
Chem. Biol. 1994, 231.
1
(Cquat, CϭN), 169.13 (Cquat, CO2Me). Ϫ Minor isomer: H NMR
[11]
(250 MHz, CDCl3): δ ϭ 0.73Ϫ0.95 (m, 3 H, cPrϪH), 0.96Ϫ1.17
(m, 3 H, cPrϪH), 1.18Ϫ1.25 (m, 2 H, cPrϪH), 2.43 (s, 1 H, 2Ј-H),
2.58Ϫ2.95 (m, 4 H, 2 CH2), 3.77 (s, 3 H, OCH3), 4.73 (s, 1 H,
CHCO2Me), 7.10Ϫ7.29 (m, 5 H, Ph). Ϫ 13C NMR (62.9 MHz,
CDCl3, DEPT): δ ϭ 1.40 (Ϫ, cPrϪC), 3.37 (Ϫ, cPrϪC), 9.93 (Ϫ,
cPrϪC), 14.37 (Ϫ, cPrϪC), 36.18 (Ϫ, PhCH2), 40.06 (ϩ, C-2Ј),
T. Liese, F. Seyed-Mahdavi, A. de Meijere, Org. Synth. 1990,
69, 148Ϫ153.
[12] [12a]
M. Es-Sayed, C. Gratkowski, N. Krass, A. I. Meyers, A.
[12b]
de Meijere, Synlett 1992, 3, 962Ϫ964. Ϫ
M. Es-Sayed, C.
Gratkowski, N. Krass, A. I. Meyers, A. de Meijere, Tetrahedron
[12c]
Lett. 1993, 34, 289Ϫ292. Ϫ
L. Wessjohann, N. Krass, D.
Yu, A. de Meijere, Chem. Ber. 1992, 125, 867Ϫ882. Ϫ [12d] Re-
Eur. J. Org. Chem. 1999, 2017Ϫ2024
2023

M. Tamm, M. Thutewohl, C. B. Ricker, M. T. Bes, A. de Meijere
FULL PAPER
views see: A. de Meijere, L. Wessjohann, Synlett 1990, 1,
20Ϫ32; A. de Meijere in New Aspects of Organic Chemistry II,
Proceedings of the Fifth International Kyoto Conference on New
Aspects of Organic Chemistry Ϫ IKCOC 5, Kyoto Nov.11-Nov.15
1991 (Ed.: Y. Ohshiro) Kodansha, Tokyo, 1992, pp. 181Ϫ213;
A. de Meijere, L. Hadjiarapoglou, S. I. Kozhushkov, Top. Curr.
Chem., in press.
by the least-squares method with all data (SHELXL-96: Pro-
gram for Crystal Structure Refinement, University of Göttingen,
1996). Single crystal obtained from ethanol, colorless, space
˚
˚
group PϪ1; Z ϭ 4, a ϭ 7.7561(16) A, b ϭ 9.6162(19) A, c ϭ
˚
˚
16.034(3) A, α ϭ 80.08(3), β ϭ 82.21(3), γ ϭ 68.15(3)°; γ ϭ
3
1090.1(4) A ; ρcalcd. ϭ 1.232 Mg/m3. 11169 reflexions, 3112 un-
ique observed [I > 2σ(I)], were measured. The non-hydrogen
atoms were refined anisotropically. All hydrogen atoms were re-
fined on calculated positions by using a riding method. R1 ϭ
0.0391, wR2 ϭ 0.1047 (all data) for 272 parameters. Goodness-
of-fit on F2 ϭ 1.031. Crystallographic data (excluding structure
factors) for the structure reported in this paper have been de-
posited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-100381. Copies of the
data can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (Fax: int. code ϩ
44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk).
R. Boese, D. Bläser, K. Gomann, U. H. Brinker, J. Am. Chem.
Soc. 1989, 111, 1501Ϫ1503.
[13]
This rearrangement is analogous to the one previously observed
for the benzophenonimine adducts of methyl 2-chloro-2-cyclo-
propylideneacetate and its substituted analogs: L. Wessjohann,
K. Giller, B. Zuck, L. Skattebøl, A. de Meijere, J. Org. Chem.
1993, 58, 6442Ϫ6450.
[14]
The reaction of 2-bromo-2-(4Ј-tert-butylcyclohexylidene)acet-
ates with benzylamine under high pressure has recently been
reported to give spirocyclohexane-annelated aziridinecarboxyl-
´
ates in very good yields: A. Yu. Rulev, J. Maddalumo, G. Ple,
J.-C. Plaquevent, L. Duhamel, J. Chem. Soc., Perkin Trans. 1
1998, 1397Ϫ1401; see also: A. Yu. Rulev, Uspekhi Khim. 1998,
67, 317Ϫ332; Russ. Chem. Rev. 1998, 67, 279Ϫ293.
[17]
[18]
[15]
[16]
Unsubstituted aziridinecarboxamide has been found to be a
reasonably stable compound, cf.: K. Jähnisch, E. Schmitz, E.
Gründemann, J. Prakt. Chem. 1979, 321, 712Ϫ720.
R. Boese, T. Miebach, A. de Meijere, J. Am. Chem. Soc. 1991,
113, 1743Ϫ1748.
[19]
[20]
M. Tamm, M. Nötzel, A. de Meijere, J. Org. Chem., submitted.
The immediate precursor to methyl 2-chloro-2-cyclopropylid-
eneacetate (4), 1-chloro-1-(trichlorovinyl)cyclopropane[11] is
commercially available from Merck KGaA, Frankfurter Str.
250, D-64293 Darmstadt, Germany.
Crystallographic data for 9: Data were collected at Ϫ140°C
using a Siemens-Stoe Huber four-circle diffractometer equipped
with a SMART CCD area detector, with Mo-Kα radiation (λ ϭ
˚
0.71073 A). The sample-to-detector distance was set to be
[21]
5 cm. Reflexions were collected by means of a φ-scan rotation
(step width 0.5°), with an exposure time of 15 s/frame. Structure
was solved by direct methods (SHELXS-96: G.M. Sheldrick,
Acta Crystallogr., Sect. A 1990, 46, 467) and refined versus F2
L. Wessjohann, N. Krass, D. Yu, A. de Meijere, Chem. Ber.
1992, 125, 867Ϫ882.
Received January 22, 1999
[O99029]
2024
Eur. J. Org. Chem. 1999, 2017Ϫ2024