A novel fragmentation of 7-azabicyclo[2.2.1]hepta-2,5-dienes: Synthesis of cis-5-amidino-pyrrolidine-2-acetic acid derivatives

Article abstract of DOI:10.1055/s-2005-870011

A new fragmentation reaction of 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene carboxylic esters with 2-amino or 2-aminomethyl anilines is described. It leads to cis-5-(benzimidazol-2-yl)- or cis-5-(3,4-dihydroquinazolin-2-yl)-pyrroline-2- acetic acid esters.

Full text of DOI:10.1055/s-2005-870011

PAPER
2357
A Novel Fragmentation of 7-Azabicyclo[2.2.1]hepta-2,5-dienes: Synthesis of
cis-5-Amidino-pyrrolidine-2-acetic Acid Derivatives
AcidDerivativesWeber,a,1 Eberhard Heller,a,2 Christoph Hoenke, Stefan Hörer, Peter Bäuerle, Volkhard Austel*
b
b
a
a
c
D
is-5-Amidino-pyr
i
rolidine
r
-2-aceti
k
c
a
Abteilung Organische Chemie II, Universität Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany
E-mail: volkhard.austel@chemie.uni-ulm.de
b
Boehringer Ingelheim Pharma GmbH & Co. KG, Abteilung Chemische Forschung, Abteilung Leitstrukturfindung, Birkendorferstr. 65,
8397 Biberach, Germany
8
Received 22 February 2005; revised 6 April 2005
retro Dieckmann reaction from a 2-oxo-7-azabicy-
Abstract: A new fragmentation reaction of 3-bromo-7-azabicy-
clo[2.2.1]hepta-2,5-diene carboxylic esters with 2-amino or 2-ami-
nomethyl anilines is described. It leads to cis-5-(benzimidazol-2-
yl)- or cis-5-(3,4-dihydroquinazolin-2-yl)-pyrroline-2-acetic acid
2
1
clo[2.2.1]heptane-1-carboxylate, and by retro Diels–Al-
der reaction.22 A side-chain benzylidene derivative of
ethyl (5-carboxy-2,5-dihydropyrrol-2-yl acetate was ob-
esters. Substituents on the nitrogen atoms or in the aromatic ring are tained by a fragmentation that resembles the one reported
tolerated as long as they do not strongly reduce the nucleophilicity here (Scheme 1).23 Many of these syntheses are aimed at
of the nitrogen atoms. The primary reaction products are not very
5
-carboxy-pyrrolidin-2-yl acetic acids as precursors of
stable but hydrogenation of the pyrroline and/or cleavage of the es-
ter give products that are suitable for subsequent structural modifi-
cations, particularly ones that are interesting for combinatorial
syntheses.
12,13c,14a,17b,20,24
carbapenam antibiotics.
Key words: amines, ring closure, ring opening, heterocycles, nu-
cleophilic additions
This report describes a new fragmentation reaction, which
leads to the synthesis of novel pyrroline and pyrrolidine 2-
acetic acid derivatives that carry a cyclic amidine function
in 5-position cis to the acetic acid moiety.
Scheme 1
Pyrrolidines represent a very important class of heterocy-
cles. They are not only found in a large number of
alkaloids and biologically active molecules such as the
The present work originates from our interest in non-pla-
nar molecular scaffolds as a basis for combinatorial li-
brary synthesis in drug research. Such scaffolds open
additional possibilities for adapting the shape of drug mol-
ecules to the requirements of binding sites on biological
targets.
3
neuraminidase inhibitors A-192558, A-315675, and oth-
4
ers. They have also gained attention as precursors in the
5
6
synthesis of dipeptide mimics or as chiral ligands and
chiral auxiliaries.
7
In this connection we became interested in 7-azabicy-
The significance of pyrrolidines is also witnessed by the
many reported stereoselective syntheses of 2,5-disubsti-
tuted pyrrolines and pyrrolidines (reviews: syntheses in
clo[2.2.1]hepta-2,5-dienes of type 1 (Figure 1) whose
2
5
synthesis had been reported in the literature. These com-
pounds contain four functional groups that can be further
modified with well established chemistry: the bromoalk-
ene, the (protected) carboxyl and secondary amino
groups, as well as the unsubstituted C=C double bond.
8
9
general, via intramolecular N-addition to a double bond,
1
0
11
via ring closing metathesis, via [3+2] cycloadditions ).
Specifically, pyrrol-2-yl-acetic acid derivatives have been
synthesized in various ways, e.g., hydrogenation of pyr-
1
2
rol-2-acetic acid esters, reduction of the C=C double
bond of pyrrolidin-2-ylidene acetic and malonic esters,
intramolecular Michael addition, iodocylization,
1
3
1
4
14d,15
in-
tramolecular reductive amination of a (4-aminobutyr-
1
6
yl)acetic acid ester,
intramolecular nucleophilic
1
7
substitution, from crotyl silanes, methylcarbamate and
aromatic aldehyde acetals with a Lewis acid, carbonyla-
1
8
tion and reductive cyclization starting from 3-(N-phe-
1
9
20
nylselenoethylamino)acrylates, ring contraction, by
Figure 1
SYNTHESIS 2005, No. 14, pp 2357–2366
x
x.
x
x
.
2
0
0
5
Advanced online publication: 13.07.2005
DOI: 10.1055/s-2005-870011; Art ID: Z04105SS
Georg Thieme Verlag Stuttgart · New York
©

2
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D. Weber et al.
PAPER
According to literature reports the bromine of 1 is readily an aromatic system develops during fragmentation, which
2
3
– 25c
replaced by nucleophiles such as Et NH or MeO . In should therefore be especially favored.
2
the former case the substitution product was not isolated
These experiments showed that 1 (R = Et) reacted with a
but converted to the corresponding ketone whereas in the
latter case the final product was the acetal 2 (Figure 1).
However, our attempts to exchange this bromine for sub-
stituted amino groups gave only mixtures of products.26
Therefore, we looked for modifications of the reaction
that would make it more uniform.
variety of differently substituted ortho-phenylene di-
amines (8) in the expected way and afforded the corre-
sponding ethyl cis-5-(benzimidazol-2-yl)pyrrolidin-2-yl
acetates 9 (Scheme 4).
The failure of the reaction between 1 and amines to give
defined products may be due to a relative instability of the
primarily formed enamines 3 under the reaction condi-
tions, e.g. addition of a second molecule of the amine 4,
followed perhaps by further structural changes
(
Scheme 2).
Scheme 4
1
The H NMR signals were in accordance with structure 9.
However, the signals were not well resolved and some of
Scheme 2
1
3
them appeared as two sets (as did some of the C signals)
probably due to syn,anti isomerism of the tert-butoxycar-
bonyl (Boc) amino moiety. This view was supported by
the reduction to a single set of NMR signals on cleavage
of the Boc group of 9a and 9f to the corresponding free
pyrrolidines 10a and 10f, respectively (Scheme 5).
Provided this assumption is correct, a greater uniformity
may be achieved with diamines in which the two amino
groups are positioned so that the second addition forms a
five- or six-membered ring (6). If at least one of the two
amino groups is primary, a further stabilization is con-
ceivable, in which simultaneous ring opening to a cis-2,5-
disubstituted pyrroline and conversion of the aminal to an
amidine takes place (7). The driving force for this reaction
would come from relief of steric strain and from the for-
The cis position of the 2- and 5-substituents was con-
firmed by an NOE between the two H-atoms in this posi-
tion. An NOE between the CH group of the acetic acid
2
side chain and the 5-H-atom was not observed.
mation of a functional group that is stabilized by reso- The compounds of type 9 turned out to be relatively unsta-
nance (Scheme 3).
ble and could therefore be characterized only via NMR
data. In order to obtain additional support for the struc-
tures, 9a was converted to the free carboxylic acid 11,
which was a solid and could be more easily characterized
To test the principal validity of this concept, ortho-phe-
nylene diamines were chosen as reaction partners because
they are set up for ring formation. Moreover, in this case,
(
Scheme 6).
Scheme 3
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PAPER
cis-5-Amidino-pyrrolidine-2-acetic Acid Derivatives
2359
in which a principally basic function is created which al-
lows separation from N-Boc-pyrrol by a convenient acid-
base workup. However, the basicity of the new function
must be high enough to allow complete protonation at pH
values that leave the N-Boc group unaffected. Benzimida-
zoles do not generally meet this requirement satisfactori-
ly. On the other hand, very basic amidines like those
derived from aliphatic diamines are less favorable as they
would in general be too highly soluble in water. There-
fore, diamines that lead to amidines with intermediate ba-
sicity should be ideal for the procedure discussed here. In
this respect, diamines containing one aromatic and one al-
iphatic amino group ought to be most suitable. As a model
for such diamines we chose 2-amino-benzylamine (12),
which would give dihydroquinazolines of type 13
Scheme 5
(
Scheme 7). However, these compounds turned out to
share the instability of their benzimidazole analogues 9.
Scheme 6
Contrary to the methoxycarbonyl derivative, three other
ortho-phenylene diamines which carried electronegative
groups in the 5-position (NO , COPh, CF ) gave, in addi-
2
3
Scheme 7
tion to others, mainly products that had the mass of the ex-
1
pected pyrrolines but differed in the H NMR spectra. In
all three cases (some of the) aromatic H-atoms appeared The reason for this instability is not clear. Conceivably, an
between d = 6.5 and 6.8 ppm (in CDCl ) indicating the oxidation process takes place in which a free radical in po-
3
presence of an aniline-type phenyl ring. In addition, there sition 5 is involved. Its formation would be facilitated by
2
7
were signals at d = 4.8–5.3 ppm (2 H) as well as at 3.75 captodative effects from the amidino group and the ring
ppm and 3.18–3.21 ppm (together 1 H). The former sig- nitrogen in conjunction with the mesomeric effect of the
nals correspond to the bridgehead H-atoms and the latter double bond. Hydrogenation of the latter might therefore
one to the H-atom next to the ester group (double set due lead to more stable products. Consequently, compounds
to syn,anti isomerism of the Boc-amino moiety). Even of type 13 were only isolated in crude form and subjected
though it was not possible to purify these products suffi- to hydrogenation prior to further purification.
ciently, the NMR data suggest that the reaction has
stopped at the intermediates 6 (Scheme 3). Possibly, the
electron-withdrawing character of the substituents pre-
vented the fragmentation of the bicyclic system.
The resulting pyrrolidine derivatives 14 need to be at least
partially deprotected before they can serve as starting ma-
terials for combinatorial syntheses. As a means of increas-
ing synthesis economy, deprotection of the carboxylate
Nevertheless, considering the successful examples listed can be combined with the hydrogenation step by working
in Scheme 4, this chemistry appears to have a relatively with benzyl instead of ethyl esters (13a, Scheme 8).
broad scope and its products would be suitable as starting
Following the strategy outlined above, 1 (R = Bn) was
materials for combinatorial syntheses. However, their use
prepared from bromopropynoic acid benzyl ester and a
for such purposes meets with two obstacles: First, the syn-
ten-fold excess of N-Boc-pyrrole. Treating the reaction
thesis of 1 requires a large excess of N-Boc-pyrrol which
mixture directly with 2-(aminomethyl)aniline (12) in eth-
afterwards needs to be separated from the product by
anol afforded 13 (R = Bn), which could be separated from
2
5c
chromatography. In our hands this procedure did not
work satisfactorily on a larger scale. Secondly, com-
pounds 8 were oily and decomposed too rapidly to be
stored.
the excess N-Boc-pyrrole by extraction with 0.01 M citric
acid. After hydrogenation of crude 13 (isolated from the
extracts) the resulting 14a was stable and could be puri-
fied by column chromatography in 13% yield over all
The first problem may be circumvented by removing the three steps.
excess N-Boc-pyrrol not until after the fragmentation step
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D. Weber et al.
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Scheme 8
Like in the case of the benzimidazoles 8 the presence of The cis relationships between the substituents in the 2-
the N-Boc group gave rise to a number of poorly resolved and 5-positions are demonstrated by ROESY experiments
NMR signals. In order to improve the quality of the spec- with 14a, 17a, and 18b, which all showed an NOE be-
trum the Boc group was removed with concentrated HCl tween the H-atoms in the 2- and 5-positions of the pyrro-
(
Scheme 8). The resulting dihydrochloride of 15 was lidine. Additional support came from an X-ray analysis of
well-crystallized and showed well-resolved signals in the the dihydrochloride of 7b (Figure 2).
1
H NMR spectrum.
A novel fragmentation reaction has been found by which
In an attempt to extend the fragmentation reaction to the cis-5-amidino-pyrrolidine-2-acetic acid esters can be pre-
synthesis of N-alkylated quinazoline derivatives, di- pared from readily accessible starting materials, i.e., N-
amines 16a,b were investigated. The two methyl deriva- Boc-pyrrol, propynoic acid esters, and N-unsubstituted or
tives behaved like the parent compound yielding products N-monosubstituted diamines. Aliphatic as well as aromat-
1
7a and 18a, respectively (Scheme 9), which on treatment ic amino groups can participate unless the latter ones are
with aqueous HCl afforded the well-crystallized products deactivated by strong electron-withdrawing substituents.
7b and 18b. The corresponding phenyl derivatives did The cis-relationship of the substituents in the 2- and 5-po-
1
not give satisfactory results probably due to the electron- sitions of the pyrrolin ring was proven by X-ray crystal-
withdrawing effect of the aromatic systems.
Scheme 9
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PAPER
cis-5-Amidino-pyrrolidine-2-acetic Acid Derivatives
2361
were recorded for: 9a on a Varian MAT 711, 9e and 10a on a Varian
MAT 8200, 14a–18 on a Micromass QTOF-2 instrument.
Single-Crystal Structure Determination
A suitable crystal of 7b was coated with Paratone N oil, suspended
in a small fiber loop and placed in a cooled N gas stream at 100 K
2
on a Rigaku AFC7R graphite monochromated Cu K (1.5418 Å)
a
diffractometer. The data were collected using the w-2q scan tech-
nique to a maximum 2q value of 119.8°. Data collection, indexing,
and initial cell refinements were all carried out using WinAFC soft-
ware. Frame integration and final cell refinements were done using
WinAFC software. The TEXSAN program was used to carry out
absorption corrections. The structure was solved using direct meth-
2
8
ods and difference Fourier techniques. Hydrogen atoms were
placed at their expected chemical positions and were included in the
final cycles of least squares with isotropic Uij’s related to the atoms
ridden upon. All non-hydrogen atoms were refined anisotropically.
Scattering factors and anomalous dispersion corrections are taken
Figure 2 X-ray molecular structure of 17b. The cis-relationship be-
tween the substituents in the 2- and 5-positions could be confirmed.
2
9
from the International Tables for X-ray Crystallography. Structure
solution, refinement, graphics, and generation of publication mate-
rials were performed by using TEXSAN software. CCDC 257637
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
lography and additionally supported by NOEs between
the H-atoms in these positions.
The problem inherent in purifying the intermediate Diels–
Alder product 1 whose preparation requires a large excess
of N-Boc-pyrrol can be circumvented by removing the lat-
ter after the subsequent fragmentation step if the resulting
amidines exert a moderate basicity. These are separated
from the N-Boc-pyrrol by extraction into a weakly acidic
aqueous phase. The primary products of the fragmentation
Additional details of data collection and structure refinement are
given in Table 1.
Table 1 Data Collection and Structure Refinement Details of Crys-
tal Structure of Compound 7b
reaction are not stable, particularly if they do not crystal- Empirical formula
C H N O Cl
15 21 3 2 2
lize, which makes a final purification impossible or at
least impractical. However, as could be demonstrated for
Formula mass
346.26
the dihydroquinazolines, hydrogenating the pyrroline Crystal color, habit
double bond abolishes the instability. Additional conver-
sion of the esters into the free acids gives crystalline prod-
colorless, prismatic
0.20 × 0.20 × 0.05 mm
Monoclinic
Crystal dimensions
ucts, which can be purified and subsequently used as Crystal system
starting materials in combinatorial syntheses. Starting
Lattice type
Primitive
from propynoic acid benzyl ester these starting materials
may be obtained in a one-pot synthesis from the initial
fragmentation products.
No. of reflections used for unit 25 (51.2 – 66.6°)
cell determination (2q range)
Omega scan peak width at half- 0.26
height
Chemicals were purchased from VWR International (Darmstadt,
Germany), Sigma–Aldrich (Taufkirchen, Germany), or ABCR
Lattice parameters
a = 18.207(1) Å
(
Karlsruhe, Germany). Diels–Alder reactions were carried out in 7
mL clear vials (screw cap, solid cap with PTFE liner) from Supelco
Bellefonte, PA, USA) or in 50 mL sealed glass tubes (Schütt
Labortechnik, Germany). For chromatography, silica gel 60 (230–
00 mesh) from Merck (Darmstadt, Germany) was used. Melting
points were determined on a Büchi B-545 melting point apparatus
b = 6.3905(5) Å
c = 14.3122(9) Å
b = 102.153(6) o
V = 1627.9(2) Å3
(
4
1
13
and are uncorrected. H and C NMR spectra of compounds 9–11
were recorded in CDCl (internal reference: TMS d = 0.00 ppm for
3
1
13
13
H; CDCl d = 77.16 ppm for C) on a Bruker AC 200 or
AMX500 spectrometer unless otherwise stated. H, C, and 2D
3
1
13
Space group
Z value
Dcalc
P2 /n (#14)
1
NMR spectra of compounds 9a, 14a–18 were recorded at T = 303
4
K on a Bruker DPX 400 spectrometer at 303 K using DMSO-d and
6
one drop of trifluoroacetic acid as solvent (internal reference: TMS
1.413 g/cm3
1
13
13
d = 0.00 ppm for H and C-DMSO d = 39.50 ppm for C). Peak
assignment of compounds 14a–18 are based on 2D COSY, HSQC,
and HMBC experiments. IR spectra were recorded on a Perkin-
Elmer Spectrum 2000 instrument. CI mass spectra were obtained on
a Finnigan SSQ7000 mass spectrometer and ESI mass spectra on a
Micromass ZMD mass spectrometer. High-resolution mass spectra
F
728.00
000
m(CuKa)
36.79 cm–1
Rigaku AFC7R
Diffractometer
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D. Weber et al.
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Table 1 Data Collection and Structure Refinement Details of Crys-
tal Structure of Compound 7b (continued)
Benzimidazole Derivatives
cis-5-(1H-Benzimidazol-2-yl)-2-(ethoxycarbonylmethyl)-2,5-di-
hydropyrrole-1-carboxylic Acid tert-Butyl Ester (9a)
Radiation
CuKa (l = 1.54178 Å)
Graphite monochromated
Ni foil (factor = 9.77)
6.0°
Compound 1 (R = Et) (0.69 g, 2.0 mmol), 8a (0.24 g, 2.2 mmol), and
Et N (0.6 mL, 4.0 mmol) were dissolved in EtOH (80 mL) and
3
stirred at r.t. for 24 h. The solvent was removed in vacuo and the res-
idue was passed through basic Al O (EtOAc). After removal of the
solvent the product was purified by column chromatography (neu-
Attenuator
2
3
Take-off angle
Detector aperture
tral Al O ; petroleum ether–EtOAc, 1:1) to give 9a (0.69 g, 93%) as
2
3
a yellowish oil.
3.0 mm horizontal
1H NMR: d = 11.1, 10.7 (br, 1 H, NH), 7.58 (br, 2 H, H4¢, H7¢), 7.22
(
5
m, 2 H, H5¢, H6¢), 6.28, 5.85 (br, 1 H, H4), 6.14, 5.85 (br, 1 H, H3),
.85 (q, J = 2.4 Hz. 1 H, H5), 4.94 (br, 1 H, H2), 4.10 (br, 2 H,
OCH ), 3.26, 2.82 (br, 1 H, CH ), 2.73, 2.52 (br, 1 H, CH ), 1.52,
3
.0 mm vertical
Crystal to detector distance
Voltage, current
Temperature
235 mm
2
2
2
1
.27 (s, 9 H, t-Bu), 1.25 (t, J = 7.2 Hz, 3 H, CH3).
50 kV, 100 mA
100 K
13C NMR: d = 170.9 (COOEt), 153.4 (COOt-Bu), 130.8, 129.0
(C3), 128.5, 126.2 (C4), 122.2 (C5¢, C6¢), 119.0, 110.9 (C4¢, C7¢),
8
1.3 (Ct-Bu), 64.3 (C5), 61.8 (C2), 60.9, 60.4 (OCH ), 39.8, 38.0
2
Scan type
w – 2q
(CCH ), 28.2 (t-BuCH ), 13.9 (EtCH ); assignments were made via
2 3 3
cross peaks in a 500 MHz/125 MHz HMQC spectrum.
Scan rate
16.0–32.0°/min (in w) (up to 4
scans)
1H NMR (400 MHz, DMSO): d = 12.2 (v br, 1 H, NH), 7.52 (m, 2
H, H4¢, H7¢), 7.15 (m, 2 H, H5¢, H6¢), 6.05 (d, J = 5.8 Hz, 1 H, H3),
5.97 (br, 1 H, H4), 5.68 (br, 1 H, H5), 4.82 (m, 1 H, H2), 4.12 (q,
J = 7.0 Hz, 2 H, OCH ), 3.29, 3.08 (br d, J = 12.5 Hz, 1 H, CH ),
Scan width
(0.68 + 0.30 tanq)°
119.8°
2
2
2
qmax
2.73 (m, 1 H, CH ), 1.41, 1.19 (s, 9 H, t-Bu), 1.20 (m, 3 H, Me).
2
13C NMR (100 MHz, DMSO): d = 170.6 (COOEt), 153.7, 153.0
COOt-Bu), 130.0 (C3), 127.9 (C4), 121.5 (C5¢, C6¢), 115.9 (C4¢,
C7¢), 79.7, 79.3 (Ct-Bu), 62.9, 62.4 (C5), 61.1 (C2), 60.0 (OCH2),
0.1, 38.9 (CCH ), 27.8 (t-BuCH ), 14.0 (EtCH ); strong NOEs
No. of reflections measured
Total: 4036
(
Unique: 2555 (Rint = 0.031)
Lorentz-polarization
Absorption
4
2
3
3
Corrections
(ROESY spectrum) between H4 and H5, and between H2 and H3
respectively, NOEs between H2 and H5; assignments were made
via cross peaks in a 400 MHz HC–HSQC–TOCSY spectrum.
MS (CI): m/z = 372 [M + H+].
(
trans. factors: 0.8216–0.9953)
HRMS: m/z calcd for C H N O : 371.1845; found: 371.1843.
Decay (3.27% decline)
Direct Methods (SHELXS86)
Full-matrix least-squares on F2
S w (|Fo| – |Fc|)2
20 25
3
4
Structure solution
Refinement
cis-2-(Ethoxycarbonylmethyl)-5-(1-methyl-1H-benzimidazol-2-
yl)-2,5-dihydropyrrole-1-carboxylic Acid tert-Butyl Ester (9b)
Prepared analogously to 9a. Reaction time: 1.5 d; yield: 67%; yel-
lowish oil.
Function minimized
Anomalous dispersion
–
1
IR (film): 1733, 1700 cm .
All non-hydrogen atoms
1H NMR: d = 7.74 (m, 1 H, H7¢), 7.33 (m, 1 H, H4¢), 7.25 (m, 2 H,
H5¢, H6¢), 6.30, 6.27 (br, 1 H, H3), 5.86 (br, 1 H, H5), 5.70–5.90 (1
No. observations (I > 3.00 s(I)) 1792
H, H4), 4.94 (br, 1 H, H2), 4.18 (q, J = 7.4, 2 H, OCH ), 4.02, 3.82
2
No. variables
199
(s, 3 H, NMe), 3.55, 3.10 (br, 1 H, CH ), 2.93 (dd, A of AB, J =
2
1
1
6.7 Hz, J = 10.3 Hz, 1 H, CH ), 1.43, 1.24 (br, 9 H, t-Bu), 1.27 (t,
2
2
Reflection/parameter ratio
Residuals: R1 (I > 3.00 s(I))
Residuals: wR2 (I > 3.00 s(I))
Goodness-of-fit indicator
Max shift/error in final cycle
9.01
J = 7.4 Hz, 3 H, CCH3).
13C NMR: d = 171.5, 153.0, 142.6, 135.7, 131.7, 126.8, 122.4,
21,9, 119.9, 109.6, 80.4, 61.6, 60.3, 59.2, 40.1, 30.2, 28.4, 14.2.
0.032
0.033
1.108
0.022
1
cis-2-(Ethoxycarbonylmethyl)-5-(1-phenyl-1H-benzimidazol-2-
yl)-2,5-dihydropyrrole-1-carboxylic Acid tert-Butyl Ester (9c)
Prepared analogously to 9a. Reaction time: 1.5 d; yield: 78%; yel-
lowish oil.
–
3
Maximum peak in final diff.
map
0.18 e /Å
IR (film): 1733, 1700 cm–1.
1H NMR: d = 7.77 (d, J = 6.9, 1 H, H7¢), 7.55 (m, 4 H, H2¢¢, H3¢¢,
H5¢¢, H6¢¢), 7.38 (m, 1 H, H4¢¢), 7.22 (m, 2 H, H5¢, H6¢), 7.06 (m, 1
H, H4¢), 6.08 (d, J = 5.4 Hz, 1 H, H3), 5.71 (br, 1 H, H5), 5.70 (d,
–
3
Minimum peak in final diff.
map
–0.21 e /Å
J = 5.4 Hz, 1 H, H4), 4.87 (br, 1 H, H2), 4.16 (m, 2 H, OCH ), 3.46,
2
3
.23 (br d, B of AB, J = 15.5 Hz, 1 H, CH ), 2.87, 2.54 (dd, A of
2
AB, J = 15.5 Hz, J = 10.0 Hz, 1 H, CH ), 1.44, 1.24 (s, 9 H, t-Bu),
1
2
2
1
.25 (t, J = 7 Hz, 3 H, CH3).
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cis-5-Amidino-pyrrolidine-2-acetic Acid Derivatives
2363
13C NMR: d = 171.7, 153.2, 136.9, 135.7, 131.2, 129.8, 129.0,
1H NMR: d = 11.52, 11.00 (br, 1 H, NH), 8.44, 8.25 (br, 1 H, H4¢),
7.96 (dd, J = 8.4 Hz, J = 0.9 Hz, 1 H, H6¢), 7.71, 755 (br, 1 H, H7¢),
1
6
27.5, 126.6, 122.7, 122.3, 119.8, 110.0, 80.2, 62.0, 61.4, 61.2,
0.8, 60.1, 39.7, 38.4, 28.3, 28.0, 14.1.
1
2
6.24, 5.92 (br, 1 H, H4), 6.14, 5.86 (br, 1 H, H3), 5.86 (q, J = 2.2
Hz, 1 H, H5), 4.96 (m, 1 H, H2), 4.12 (m, 2 H, OCH ), 3.94 (s, 3 H,
CH ), 3.36, 2.81 (br d, J = 12.6 Hz, 1 H, CH ), 2.50–2.80 (m, 1 H,
MS (CI): m/z = 448 [M + H+].
2
3
2
CH ), 1.52, 1.25 (s, 9 H, Ot-Bu), 1.25 (m, 3 H, CH ).
2
3
cis-2-(Ethoxycarbonylmethyl)-5-(5-methyl-1H-benzimidazol-2-
yl)- 2,5-dihydropyrrole-1-carboxylic Acid tert-Butyl Ester (9d)
Prepared analogously to 9a. Reaction time: 24 h. Yield: 75%; Yel-
lowish oil.
13C NMR: d = 170.9, 167.5, 155.1, 130.8, 129.3, 129.3, 128.2,
124.1,123.4, 113.4,110.7, 81.6, 64.4, 62.2, 61.8, 61.2, 60.5, 60.2,
51.9, 39.6, 37.6, 14.0.
–
1
IR (film): 1733, 1705 cm .
1H NMR: d = 10.93, 10.57 (br, 1 H, NH), 7.48 (br, 1 H, H4¢), 7.36
cis-5-(1H-Benzimidazol-2-yl)-2-ethoxycarbonylmethyl-2,5-di-
hydropyrrole dihydrochloride (10a)
(
br, 1 H, H7¢), 7.03 (dd, J = 8.4 Hz, J = 1.3 Hz, 1 H, H6¢), 6.28,
1 2
Compound 9a (0.90 g, 2.4 mmol) was dissolved in anhyd Et O (100
2
5
.93 (br, 1 H, H4), 6.14, 5.88 (br, 1 H, H3), 5.82 (q, J = 2.2 Hz. 1 H,
mL). EtOH–HCl (2 M, 10 mL) solution was added and the mixture
was left for 12 h at r.t. On cooling to 4 °C a solid material precipi-
H5), 4.93 (br, 1 H, H2), 4.10 (br, 2 H, OCH ), 3.26, 2.80 (br d, J =
2
1
3.2 Hz, 1 H, CH ), 2.69, 2.49 (br, 1 H, CH ), 2.45 (s, 3 H, arom.
2
2
tated which was crystallized from Et O–EtOH. Yield: 0.58 g (70%)
2
CH ), 1.51, 1.26 (s, 9 H, t-Bu), 1.24 (m, 3 H, aliph. CH ).
3
3
of crude beige-colored 10a, which decomposed at 180 °C.
IR (KBr): 1718 cm–1.
13C NMR: d = 170.9, 155.1, 153.2, 130.8, 128.6, 128.5, 126.3,
1
2
23.6, 118.6, 110.9, 81.3, 64.3, 61.8, 61.8, 60.9, 60.5, 39.9, 38.1,
8.3, 21.5, 14.0.
1
H NMR (CD OD): d = 7.95 (m, 2 H, H4¢, 7¢), 7.73 (m, 2 H, H5¢,
3
6
6
¢), 6.57 (m, 1 H, H3), 6.32 (dt, J = 5.9 Hz, J = 2.0 Hz, 1 H, H4),
.29 (m, 1 H, H5), 5.15 (m, 1 H, H2), 4.22 (q, J = 7.1 Hz, 2 H,
1 2
cis-5-(5-tert-Butyl-1H-benzimidazol-2-yl)-2-(ethoxycarbonyl-
methyl)-2,5-dihydropyrrole-1-carboxylic Acid tert-Butyl Ester
OCH ), 3.26 (B of ABM, J = 18.2 Hz, J = 3.9 Hz, 1 H, CH ), 3.05
2
1
2
2
(
A of ABM, J = 18.2 Hz, J = 9.3 Hz, 1 H, CH ), 1.30 (t, J = 7.1
1 2 2
(9e)
Hz, 3 H, Me).
Prepared analogously to 9a. Reaction time: 1.5 d; yield: 77%; yel-
lowish oil.
13C NMR: d = 171.5, 147.0, 136.3, 133.2, 128.9, 124.2, 115.9, 65.9,
–
1
62.9, 61.1, 37.8, 14.7.
MS (CI): m/z = 272 [M + H+].
IR (film): 1733, 1705 cm .
1H NMR: d = 11.10, 10.75 (br, 1 H, NH), 7.59 (br s, 1 H, H4¢), 7.53
(
d, J = 8.4 Hz, 1 H, H7¢), 7.30 (dd, J = 8.4 Hz, J = 2.0 Hz, 1 H,
HRMS: m/z calcd for C H N O : 271.13072; found: 271.13208.
1
2
15 17
3
2
H6¢), 6.25, 5.93 (br, 1 H, H4), 6.14, 5.85 (br, 1 H, H3), 5.84 (s, 1 H,
H5), 4.93 (br, 1 H, H2), 4.10 (br, 2 H, OCH ), 3.19, 2.82 (br d, J =
cis-2-(Ethoxycarbonylmethyl)-5-(5-methoxy-1H-benzimidazol-
2
1
1
5 Hz, 1 H, CH ), 2.70, 2.49 (br dd, J = 15 Hz, J = 9 Hz, 1 H, CH ),
.50, 1.37 (s, 9 H, Ot-Bu), 1.37, 1.28 (s, 9 H, Ct-Bu), 1.28 (m, 3 H,
2-yl)-2,5-dihydropyrrole dihydrochloride (10f)
Prepared analogously to 10a from 9f (0.12 g, 0.3 mmol), Et O (20
2
1
2
2
2
CH3).
mL), EtOH–HCl (2 mL), 3 h, r.t. The precipitate was a glassy ma-
terial that did not crystallize. Yield: 70 mg (54%).
13C NMR: d = 170.8, 155.0, 153.2, 145.5, 130.6, 129.0, 128.3,
–
1
1
3
26.3, 120.2, 115.0, 81.1, 64.1, 61.6, 61.6, 60.8, 60.3, 39.8, 38.3,
4.6, 28.1, 13.9.
IR (KBr): 1718 cm .
1
H NMR (CD OD): d = 7.80 (d, J = 8.9 Hz, 1 H, H7¢), 7.37 (d, J =
3
MS (CI): m/z = 428 [M + H+].
2.4 Hz, 1 H, H4¢), 7.31 (dd, J = 8.9 Hz, J = 2.4 Hz, 1 H, H6¢), 6.56
1
2
(
m, 1 H, H3), 6.32 (m, 1 H, H4), 6.30 (m, 1 H, H5), 5.13 (br, 1 H,
HRMS: m/z calcd for C H N O : 427.24714; found: 427.24711.
2
4
33
3
4
H2), 4.22 (q, J = 7.0 Hz, 2 H, OCH ), 3.96 (s, 3 H, OCH ), 3.25 (B
2
3
of ABM, J = 18.2 Hz, J = 4.4 Hz, 1 H, CH ), 3.06 (A of ABM,
1
2
2
cis-2-(Ethoxycarbonylmethyl)-5-(5-methoxy-1H-benzimidazol-
-yl)-2,5-dihydropyrrole-1-carboxylic Acid tert-Butyl Ester (9f)
Prepared analogously to 9a. Reaction time: 2 d; yield: 75%; yellow-
J = 18.2 Hz, J = 9.4 Hz, 1 H, CH ), 1.29 (t, J = 6.9 Hz, 3 H, Me).
1
2
2
2
13C NMR: d = 171.5, 161.5, 145.5, 136.2, 134.3, 127.4, 124.2,
ish oil.
119.7, 116.7, 97.3, 65.8, 62.8, 61.1, 57.0, 37.9, 14.7.
–
1
IR (film): 1733, 1708 cm .
1H NMR: d = 8.6–9.7 (1 H, NH), 7.46 (d, J = 8.9 Hz, 1 H, H7¢), 7.03
cis-5-(1H-Benzimidazol-2-yl)-2-(carboxymethyl)-2,5-dihydro-
pyrrole-1-carboxylic Acid tert-Butyl Ester (11)
(
d, J = 2.4 Hz, 1 H, H4¢), 6.84 (dd, J = 8.9 Hz, J = 2.4 Hz, 1 H,
1 2
Compound 9a (0.44 g, 1.2 mmol) was dissolved in a mixture of ac-
etone (20 mL) and water (10 mL) and treated with 1 M LiOH (6 mL)
at r.t. for 1 h. The solvents were removed in vacuo. To the remainder
were added a 20% NaH PO –H PO aq buffer (30 mL) to adjust pH
H6¢), 6.26, 5.91 (br, 1 H, H4), 6.10, 5.87 (br, 1 H, H3), 5.79 (q, J =
1
3
.9 Hz. 1 H, H5), 4.90 (br, 1 H, H2), 4.08 (m, 2 H, OCH ), 3.81 (s,
2
H, OCH ), 3.25, 2.78 (br d, J = 14.7 Hz, 1 H, CH ), 2.70, 2.44 (br
3
2
2
4
3
4
dd, J = 14.7 Hz, J = 9.3 Hz, 1 H, CH ), 1.49, 1.23 (s, 9 H, t-Bu),
1
2
2
to 5.5 and sat. aq NaCl (30 mL). The mixture was extracted CH Cl
2 2
1
.23 (m, 3 H, CH3).
(3 × 50 mL). The organic phase was evaporated to dryness and the
residue crystallized from MeCN–cyclohexane; yield: 0.29 g (70%);
colorless crystals; mp 216–218 °C (decomp.).
IR (KBr): 1698 (vs, br) cm–1.
13C NMR: d = 170.9, 156.3, 155.3, 153.1, 130.8, 129.0, 128.5,
1
4
26.3, 116.5, 111.7, 97.4, 81.4, 64.1, 61.9, 61.9, 61.1, 60.5, 55.2,
0.0, 38.0, 28.3, 27.9, 14.0.
MS (CI): m/z = 402 [M + H+].
1
H NMR (DMF-d ): d = 12.39 (v br, 1 H, OH), 7.62 (m, 2 H, H4¢,
7
H7¢), 7.22 (m, 2 H, H5¢, H6¢), 6.20 (m, 1 H, H4), 6.10 (br, 1 H, H3),
cis-2-(Ethoxycarbonylmethyl)-5-(5-methoxycarbonyl-1H-benz-
imidazol-2-yl)-2,5-dihydropyrrole-1-carboxylic Acid tert-Butyl
Ester (9g)
Prepared analogously to 9a. Reaction time: 7 d; yield: 56%; yel-
lowish oil.
5
1
.89 (br, 1 H, H5), 4.97 (m, 1 H, H2), 3.43, 3.18 (br d, J = 13.8 Hz,
H, CH ), 2.83 (br, 1 H, CH ), 1.51, 1.28 (s, 9 H, t-Bu).
2
2
13C NMR: d = 172.6, 154.3, 139.1, 130.6, 127.8, 121.6, 114.9, 79.6,
3.6, 61.7, 40.7, 27.5.
6
MS (CI): m/z = 344 [M + H+].
–
1
IR (film): 1713 (br) cm .
Synthesis 2005, No. 14, 2357–2366 © Thieme Stuttgart · New York

2
364
D. Weber et al.
PAPER
Anal. Calcd for C H N O : C, 62.96; H, 6.16; N, 12.24. Found: C,
cis-2-(Carboxymethyl)-5-(3-methyl-3,4-dihydroquinazolin-2-
yl)pyrrolidine-1-carboxylic Acid tert-Butyl Ester (17a)
1
8
21
3
4
6
2.79; H, 6.25; N, 12.07.
3
4
Prepared analogously to 14a from 16a (10.0 g, 73.6 mmol); hy-
drogenation for 10 h. Purification by column chromatography
[SiO ; aq NH (25%)–MeOH–CH Cl , 1:10:140 then aq NH
3
Dihydroquinazoline Derivatives
Propynoic Acid Benzyl Ester
2
3
2
2
The compound has been prepared previously from propynoic acid
and benzyl alcohol3 but the present method gives higher yields.
Propynoic acid (7.98 g, 113.9 mmol) was added to a solution of
KOH (6.39 g, 113.9 mmol) in MeOH (70 mL). After 15 min at r.t.
the solution was evaporated to dryness. The residue was twice sus-
pended in toluene, which was subsequently removed in vacuo. The
remaining solid was dissolved in DMSO (70 mL), (bromometh-
yl)benzene (15.12 g, 88.7 mmol) was added and the mixture kept at
(25%)–MeOH–CH Cl , 1:10:120) yielded 17a (4.34 g, 17%) as a
beige amorphous material.
2 2
0,31
1
+
H NMR (400 MHz, DMSO-d + TFA): d = 11.25 (s, 1 H, NH ),
6
7
.38 (t, J = 7.0 Hz, 1 H, H7¢), 7.28 (dt, J = 7.7 Hz, J = 1.0 Hz, 1 H,
1 2
H6¢), 7.24 (d, J = 7.2 Hz, 1 H, H5¢), 7.21 (m, 1 H, H8¢), 5.09 (t, J =
7
1
2
.7 Hz, 1 H, H5), 4.93 (AB, JAB = 15.7 Hz, 2 H, H4¢), 4.18–4.35 (m,
H, H2), 3.33 (s, 3 H, CH ), 2.73 (m, 1 H, H2¢¢), 2.56 (m, 1 H, H2¢¢),
3
.50 (m, 1 H, H4), 2.08–2.24 (m, 2 H, H3, H4), 1.75–1.88 (m, 1 H,
4
0 °C for 2 h. EtOAc (150 mL) and water (100 mL) were added. The
H3), 1.20–1.49 (br, 9 H, H3¢¢¢).
organic layer was separated, washed with aq NaHCO and water,
3
1
3
C NMR (100 MHz, DMSO-d + TFA): d = 175.5 (C1¢¢), 161.9–
and the solvent removed under vacuum. Yield: 12.4 g [87% based
on (bromomethyl)benzene].
6
1
1
62.7 (br, C2¢), 152.9–154.0 (br, C1¢¢¢), 130.4 (C9¢), 129.1 (C7¢),
27.0 (C6¢), 126.3 (C5¢), 117.6 (C10¢), 116.2 (C8¢), 80.6–81.6 (br,
Bromopropynoic Acid Benzyl Ester25a,32
Prepared according to a literature method.
C2¢¢¢), 57.6 (C5), 55.3 (C2), 51.4 (C4¢), 38.5 (CH ), 37.8 (C2¢¢),
29.2–30.6 (br, C3), 27.6 (C3¢¢¢), 26.9 (C4).
MS (ESI): m/z = 374 [M + H+].
3
3
3
cis-2-(Carboxymethyl)-5-(3,4-dihydroquinazolin-2-yl)pyrroli-
dine-1-carboxylic Acid tert-Butyl Ester (14a)
A mixture of bromopropynoic acid benzyl ester (16.0 g, 66.9 mmol)
and N-Boc pyrrole (111.8 g, 669 mmol) was shaken at 80 °C for 48
h in a sealed vial under argon. After cooling to r.t., EtOH (300 mL),
+
HRMS: m/z [M + H ] calcd for C H N O : 374.2080; found:
2
0
28
3
4
3
74.2094.
cis-2-(Carboxymethyl)-5-(1-methyl-3,4-dihydroquinazolin-2-
yl)pyrrolidine-1-carboxylic Acid tert-Butyl Ester (18a)
1
2 (9.0 g, 73.6 mmol), and Et N (13.5 g, 133.6 mmol) were added.
3
34
Prepared analogously to 14a from 16b (10.0 g, 73.6 mmol); hy-
After stirring at r.t. for 3 h the mixture was concentrated in vacuo,
EtOAc (300 mL) and EtOH (75 mL) were added and the solution
was extracted with 0.01 M aq citric acid (6 × 250 mL). The com-
drogenation for 11 h. Purification by column chromatography
[
SiO ; aq NH (25%)–MeOH–CH Cl , 1:10:120] yielded 18a [3.28
2 3 2 2
g, 13%] as a beige amorphous material.
1H NMR (400 MHz, DMSO-d + TFA): d = 9.84 (br, 1 H, NH+),
7.46 (dt, J = 8.4 Hz, J = 1.8 Hz, 1 H, H7¢), 7.44 (m, 1 H, H8¢), 7.37
(dt, J = 7.4 Hz, J = 1.8 Hz, 1 H, H6¢), 7.33 (d, J = 7.4 Hz, 1 H, H5¢),
5.06 (t, J = 7.6 Hz, 1 H, H5), 4.73 (AB, JAB = 20.2 Hz, 2 H, H4¢),
4.15–4.24 (m, 1 H, H2), 3.58 (s, 3 H, CH ), 2.80–2.97 (m, 1 H,
H2¢¢), 2.61 (dd, J = 15.3 Hz, J = 8.2 Hz, 1 H, H2¢¢), 2.45–2.55 (m,
bined aqueous layers were brought to pH = 8 with NaHCO and ex-
3
tracted with EtOAc (2 × 400 mL). The organic phase was
concentrated to 300 mL in vacuo and extracted with 0.01 M aq citric
acid (4 × 400 mL) and then 0.1 M aq citric acid (250 mL). The com-
bined aqueous layers were saturated with NaCl and the product was
extracted (as a hydrochloride) twice with a mixture of EtOAc (250
mL) and EtOH (150 mL). The organic layers were concentrated in
vacuo, the residue dissolved in EtOAc (300 mL) and treated with aq
citric acid/NaCl as before. The combined final organic phases were
6
1
2
1
2
3
1
2
1 H, H4), 2.06–2.23 (m, 2 H, H3, H4), 1.73–1.81 (m, 1 H, H3),
1.18–1.52 (br, 9 H, H3¢¢¢).
washed with sat. aq NaHCO (2 × 500 mL) and evaporated in vacuo
13
3
C NMR (100 MHz, DMSO-d + TFA): d = 173.8 (br, C1¢¢), 164.8
6
leaving a brown foam (6.73 g). It was dissolved in DMF (130 mL)
and hydrogenated (10% Pd/C, 14 h, atmospheric pressure). After
filtration the solvent was removed in vacuo and the residue purified
by column chromatography [SiO ; aq NH (25%)–MeOH–CH Cl ,
(
br, C2¢), 153.7 (br, C1¢¢¢), 134.8 (C9¢), 129.1 (C7¢), 127.4 (C6¢),
1
5
2
26.8 (C5¢), 119.7 (C10¢), 115.7 (C8¢), 80.9 (br, C2¢¢¢), 58.8 (C5),
5.8 (C2), 41.6 (C4¢), 38.4 (C2¢¢), 33.9 (CH ), 29.8 (C3), 28.1 (C4),
7.7 (C3¢¢¢).
3
2
3
2
2
1
:10:100, then aq NH3 (25%)–MeOH–CH Cl , 1:10:50], which
2 2
MS (ESI): m/z = 374.5 [M + H+].
gave 14a (3.22 g, 13% overall) as an amorphous material.
+
1
+
HRMS: m/z [M + H ] calcd for C H N O : 374.2080; found:
H NMR (400 MHz, DMSO-d , TFA): d = 11.74 (br, 1 H, NH ),
20 28
3
4
6
3
74.2075.
1
0.08 (br, 1 H, NH), 7.35 (dt, J = 7.4 Hz, J = 2.0 Hz, 1 H, H7¢),
1 2
7
.26 (dt, J = 7.6 Hz, J = 1.0 Hz, 1 H, H6¢), 7.23 (d, J = 6 Hz, 1 H,
1 2
[
cis-5-(3,4-Dihydroquinazolin-2-yl)pyrrolidin-2-yl]acetic Acid
H5¢), 7.14 (d, J = 7.7 Hz, 1 H, H8¢), 4.82 (AB, JAB = 17.5 Hz, 2 H,
H4¢), 4.57 (t, J = 7.7 Hz, 1 H, H5), 4.14–4.23 (m, 1 H, H2), 2.61–
2
Dihydrochloride (15)
Ester 14a (50 mg, 0.139 mmol) was stirred with concd aq HCl (10
mL) at r.t. for 2 h. Evaporation of the solvent in a N stream yielded
1
.93 (m, 2 H, H2¢¢), 2.32–2.45 (m, 1 H, H4), 2.10–2.25 (m, 2 H, 3-
H3, H4), 1.77-1.85 (m, 1 H, H3), 1.23–1.54 (br, 9 H, H3¢¢¢).
2
5 (40 mg, 87%) as colorless crystals; mp 238 °C.
1
3
C NMR (100 MHz, DMSO-d + TFA): d = 174.2 (br, C1¢¢), 163.7
6
1
H NMR (400 MHz, DMSO-d + TFA): d = 7.36 (dt, J = 7.7 Hz,
(br, C2¢), 153.0–154.5 (br, C1¢¢¢), 131.3 (C9¢), 129.1 (C7¢), 127.1
(C5¢, C6¢), 117.7 (C10¢), 116.8 (C8¢), 80.5–81.3 (br, C2¢¢¢), 59.0
(C5), 55.7 (C2), 42.0 (C4¢), 38.4 (C2¢¢), 29.5 (C3, C4), 27.9 (C3¢¢¢);
6
1
J = 1.8 Hz, 1 H, H7¢), 7.28 (dt, J = 7.4 Hz, J = 1.4 Hz, 1 H, H6¢),
2
1
2
7
4
1
1
1
.21–7.25 (m, 2 H, H5¢, H8¢), 4.82 (AB, JAB = 16.7 Hz, 2 H, H4¢),
.63 (t, J = 8.7 Hz, 1 H, H5), 3.92–4.01 (m, 1 H, H2), 3.01 (dd, J =
peak assignments are based on 2D COSY, HSQC and HMBC ex-
periments.
MS (ESI): m/z = 360.4 [M + H+].
1
7.8 Hz, J = 8.4 Hz, 1 H, H2¢¢), 2.88 (dd, J = 17.4 Hz, J = 5.4 Hz,
2
1
2
H, H2¢¢), 2.39–2.48 (m, 1 H, H4), 2.22–2.39 (m, 2 H, H3, H4),
.82–1.95 (m, 1 H, H3).
+
HRMS: m/z [M + H ] calcd for C H N O : 360.1923; found:
3
13
1
9
26
3
4
C NMR (100 MHz, DMSO-d + TFA): d = 171.8 (C1¢¢), 131.0
6
60.1930.
(C9¢), 129.0 (C7¢), 127.5 (C6¢), 126.9 (C5¢), 117.5 (C10¢), 116.9
(C8¢), 57.6 (C5), 56.9 (C2), 42.0 (C4¢), 36.2 (C2¢¢), 28.4 (C3), 26.9
(C4).
MS (ESI): m/z = 260 [M + H+].
Synthesis 2005, No. 14, 2357–2366 © Thieme Stuttgart · New York

PAPER
HRMS: m/z [M + H ] calcd for C H N O : 260.1399; found:
cis-5-Amidino-pyrrolidine-2-acetic Acid Derivatives
2365
+
(3) (a) Massiot, G.; Delande, C. In The Alkaloids, Vol. 27;
Brossi, A., Ed.; Academic Press: London, 1986, Chap 3.
1
4
18
3
2
2
60.1400.
(
b) Takahata, H.; Momose, T. In The Alkaloids, Vol. 44;
[
cis-5-(3-Methyl-3,4-dihydroquinazolin-2-yl)pyrrolidin-2-
Cordell, G. A., Ed.; Academic Press: London, 1993, Chap 3.
(c) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and
Biological Perspectives, Vol. 4; Pelletier, S. W., Ed.; Wiley:
New York, 1986, Chap 1. (d) O’Hagan, D. Nat. Prod. Rep.
2000, 17, 435.
yl]acetic Acid Dihydrochloride (17b)
Prepared analogously to 15 from 17a (100 mg, 0.268 mmol); yield:
7
0 mg (75%); colorless crystals; mp 222 °C.
1
H NMR (400 MHz, DMSO-d + TFA): d = 7.41 (dd, J = 7.9 Hz,
6
1
(
4) (a) Wang, G. T.; Chen, Y.; Wang, S.; Gentles, R.; Sowin, T.;
Kati, W.; Muchmore, S.; Giranda, V.; Stewart, K.; Sham, H.;
Kempf, D.; Laver, W. G. J. Med. Chem. 2001, 44, 1192.
J = 1.6 Hz, 1 H, H8¢), 7.37 (dt, J = 7.7 Hz, J = 1.3 Hz, 1 H, H7¢),
7
J2 = 0.8 Hz, 1 H, H5¢), 5.04 (t, J = 9.4 Hz, 1 H, H5), 4.92 (s, 2 H,
H4¢), 3.91–4.00 (m, 1 H, H2), 3.35 (s, 3 H, CH ), 3.07 (dd, J = 17.2
Hz, J = 8.7 Hz, 1 H, H2¢¢), 2.91 (dd, J = 17.2 Hz, J = 5.4 Hz, 1 H,
2
1
2
.29 (dt, J = 7.6 Hz, J = 1.6 Hz, 1 H, H6¢), 7.21 (dd, J = 7.0 Hz,
1
2
1
(
b) DeGoey, D. A.; Chen, H.-J.; Flosi, W. J.; Grampovnik,
D. J.; Yeung, C. M.; Klein, L. L.; Kempf, D. J. J. Org. Chem.
002, 67, 5445. (c) Watanabe, H.; Okue, M.; Kobayashi, H.;
3
1
2
1
2
2
H2¢¢), 2.45–2.55 (m, 1 H, H4), 2.24–2.41 (m, 2 H, H3, H4), 1.86–
.97 (m, 1 H, H3).
Kitahara, T. Tetrahedron Lett. 2002, 43, 861. (d) Shinya,
K.; Kim, J.-S.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1997, 38, 7079. (e) He, H.; Shen, B.;
Carter, G. T. Tetrahedron Lett. 2000, 41, 2067.
1
1
3
C NMR (100 MHz, DMSO-d + TFA): d = 172.2 (C1¢¢), 130.6
6
(
(
(
C9¢), 129.1 (C7¢), 127.5 (C6¢), 126.2 (C5¢), 117.8 (C10¢), 116.9
C8¢), 56.9 (C2), 56.0 (C5), 51.9 (C4¢), 39.8 (CH ), 36.3 (C2¢¢), 28.6
C3), 27.0 (C4).
3
(5) (a) Millet, R.; Domarkas, J.; Rombaux, P.; Rigo, B.;
Houssin, R.; Hénichart, J.-P. Tetrahedron Lett. 2002, 43,
5087. (b) Angiolini, M.; Araneo, S.; Belvisi, L.; Cesarotti,
E.; Checchia, A.; Crippa, L.; Manzoni, L.; Scolastico, C.
Eur. J. Org. Chem. 2000, 2571. (c) Hanessian, S.;
McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789.
6) Liu, G.; Ellman, J. A. J. Org. Chem. 1995, 60, 7712.
7) (a) Breuil-Desvergnes, V.; Compain, P.; Vatèle, J.-M.; Goré,
J. Tetrahedron Lett. 1999, 40, 5009. (b) Fuji, K. Chem. Rev.
MS (ESI): m/z = 274 [M + H+].
+
HRMS: m/z [M + H ] calcd for C H N O : 274.1556; found:
2
1
5
20
3
2
74.1559.
[
cis-5-(1-Methyl-3,4-dihydroquinazolin-2-yl)pyrrolidin-2-
(
(
yl]acetic Acid Dihydrochloride (18b)
Prepared analogously to 15 from 18a (50 mg, 0.134 mmol); yield:
3
7 mg (80%), colorless crystals; mp 215 °C.
1993, 93, 2037. (c) Schultz, A. G. Acc. Chem. Res. 1990, 23,
1
H NMR (400 MHz, DMSO-d + TFA): d = 7.45 (dt, J = 8.2 Hz,
207. (d) Enders, D.; Schubert, H.; Nübling, C. Angew.
Chem. Int. Ed. 1986, 25, 1109; Angew. Chem. 1986, 98,
1118.
6
1
J = 1.8 Hz, 1 H, H7¢), 7.41 (dd, J = 8.3 Hz, J = 1.8 Hz, 1 H, H8¢),
7
2
1
2
.36 (dt, J = 7.6 Hz, J = 1.4 Hz, 1 H, H6¢), 7.32 (dd, J = 7.4 Hz,
1
2
1
J2 = 1.4 Hz, 1 H, H5¢), 4.87 (t, J = 7.64 Hz, 1 H, H5), 4.73 (AB,
JAB = 16.5 Hz, 2 H, H4¢), 3.76–3.85 (m, 1 H, H2), 3.57 (s, 3 H, CH3),
(8) Pichon, M.; Figadère, B. Tetrahedron: Asymmetry 1996, 7,
927.
2
.83 (dd, J = 17.0 Hz, J = 8.0 Hz, 1 H, H2¢¢), 2.73 (dd, J = 16.8
(9) Puentes, C. O.; Kouznetsov, V. J. Heterocycl. Chem. 2002,
39, 595.
1
2
1
Hz, J = 6.0 Hz, 1 H, H2¢¢), 2.07–2.24 (m, 2 H, H3, H4), 2.37–2.49
2
(
1
m, 1 H, H4), 1.60–1.73 (m, 1 H, H3).
(10) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693.
(11) Pearson, W. H.; Stoy, P. Synlett 2003, 903.
3
C NMR (100 MHz, DMSO-d + TFA): d = 172.6 (C1¢¢), 162.5 (br,
6
(
12) Gilchrist, T. L.; Lemos, A.; Ottaway, C. J. J. Chem. Soc.,
Perkin Trans. 1 1997, 3005.
C2¢), 135.2 (C9¢), 129.0 (C7¢), 127.4 (C6¢), 126.7 (C5¢), 119.8
C10¢), 115.9 (C8¢), 56.3 (C2), 56.1 (C5), 41.8 (C4¢), 37.8 (C2¢¢),
4.4 (CH ), 29.3 (C3), 28.0 (C4).
(
3
(
13) (a) Hussaini, S. R.; Moloney, M. G. Tetrahedron Lett. 2004,
3
45, 1125. (b) Hussaini, S. R.; Moloney, M. G. Org. Biomol.
MS (ESI): m/z = 274.5 [M + H+].
Chem. 2003, 1, 1838. (c) Nagasaka, T.; Tsukada, A.;
Hamaguchi, F. Heterocycles 1986, 24, 2015.
+
HRMS: m/z [M + H ] calcd for C H N O : 274.1556; found:
1
5
20
3
2
2
74.1564.
(14) (a) Bycroft, B. W.; Chhabra, S. R.; Kellam, B.; Smith, P.
Tetrahedron Lett. 2003, 44, 973. (b) Verma, K. S.; Atanes,
M. N.; Busto, J. H.; Thai, D. L.; Rapoport, H. J. Org. Chem.
2002, 67, 1314. (c) Mulzer, J.; Schülzchen, F.; Bats, J.-W.
Tetrahedron 2000, 56, 4289. (d) Hart, P. B.; Rapoport, H. J.
Org. Chem. 2002, 64, 2050. (e) Collado, I.; Ezquerra, J.;
Vaquero, J. J.; Pedregal, C. Tetrahedron Lett. 1994, 35,
Acknowledgment
We would like to thank G. Kurz and M. Waitzinger (University of
Ulm) for technical assistance, W. Bolek and M. Cavegn, Boehringer
Ingelheim Pharma GmbH & Co. KG site Biberach, for assistance
with the NMR spectra, Dr. G. Schmidtberg, Section Mass Spectro-
metry, University of Ulm, and E. Endris (Boehringer Ingelheim
Pharma GmbH & Co. KG site Biberach) for assistance with the MS
spectra. Sponsorship of a guest professorship (V.A.) and a postdoc-
toral position (D.W.) as well as additional financial support by Boe-
hringer Ingelheim Pharma GmbH & Co. KG is gratefully
acknowledged.
8037.
(
(
(
15) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.;
Smith, A. D. Synlett 2004, 901.
16) Brun, M.-P.; Martin, A.-S.; Garbay, C.; Bischoff, L.
Tetrahedron Lett. 2003, 44, 7011.
17) (a) Sugiura, M.; Hagio, H.; Kobayashi, S. Helv. Chim. Acta
2002, 85, 3678. (b) Miyashita, M.; Chida, N.; Yoshikoshi,
A. J. Chem. Soc., Chem. Commun. 1984, 195.
(
18) (a) Schaus, V. J.; Jain, N.; Panek, J. S. Tetrahedron 2000, 56,
1
0263. (b) Panek, J. S.; Jain, N. F. J. Org. Chem. 1994, 59,
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