Functionalized azamacrocycles and large-ring α-amino esters by one-pot syntheses from methyl 2-siloxy-2-vinylcyclopropanecarboxylates

Article abstract of DOI:10.1002/1099-0690(200111)2001:22<4195::AID-EJOC4195>3.0.CO;2-3

Siloxycyclopropane 1 served as starting material for intermediate alkylation products 2, 7, 11, 14, and 17, which were elongated to provide a variety of precursor compounds bearing terminal N-benzyl groups. These substrates were subjected to a cesium fluoride -promoted ring- opening/ring-closure sequence to afford azamacrocycles 19, 21, 22, 23, 25, 26, 27, and 28 in moderate to good yields. The cyclic products have different ring sizes and numbers of nitrogen atoms, and may incorporate meta-substituted benzene or pyridine units. A second approach employed glycine derivative 29 as the key building block for construction of precursors 31 and 34, which on fluoride treatment furnished macrocyclic α-amino esters 32 and 35, respectively, in moderate yields. A few reactions, such as transformations into macrocyclic pyridazinone derivatives 37 and 38, illustrate the potential of the synthesized azamacrocycles for preparation of complex compounds. Our concept for construction of macrocyclic compounds using siloxycyclopropane 1 as zwitterionic synthon A has thus successfully been extended to the synthesis of a variety of highly functionalized azamacrocycles.

Full text of DOI:10.1002/1099-0690(200111)2001:22<4195::AID-EJOC4195>3.0.CO;2-3

FULL PAPER
Functionalized Azamacrocycles and Large-Ring α-Amino Esters
by One-Pot Syntheses from Methyl 2-Siloxy-2-vinylcyclopropanecarboxylates
Pranab K. Patra,[a] Hans-Ulrich Reißig*[a]
Keywords: Alkylations / Cyclophanes / Macrocyclic ligands / Michael additions / Siloxycyclopropanes
Siloxycyclopropane 1 served as starting material for interme- key building block for construction of precursors 31 and 34,
diate alkylation products 2, 7, 11, 14, and 17, which were
elongated to provide a variety of precursor compounds bear- esters 32 and 35, respectively, in moderate yields. A few reac-
ing terminal N-benzyl groups. These substrates were sub-
tions, such as transformations into macrocyclic pyridazinone
which on fluoride treatment furnished macrocyclic α-amino
jected to a cesium fluoride-promoted ring-opening/ring-clos- derivatives 37 and 38, illustrate the potential of the synthe-
ure sequence to afford azamacrocycles 19, 21, 22, 23, 25, 26, sized azamacrocycles for preparation of complex compounds.
27, and 28 in moderate to good yields. The cyclic products
have different ring sizes and numbers of nitrogen atoms, and
may incorporate meta-substituted benzene or pyridine units.
A second approach employed glycine derivative 29 as the
Our concept for construction of macrocyclic compounds us-
ing siloxycyclopropane 1 as zwitterionic synthon A has thus
successfully been extended to the synthesis of a variety of
highly functionalized azamacrocycles.
Introduction
Compound 1 may be deprotonated and substituted by
treatment with electrophiles at C(1), while the vinyl group
may be transformed by fluoride-induced ring-cleavage into
an enone unit capable of accepting nucleophiles at the ter-
minal carbon. These useful properties of 1 have hence paved
the way to a number of interesting products.[21Ϫ26]
The preparation of medium- and large-sized ring systems
is a permanent challenge[1Ϫ7] for synthetic chemists, as such
systems are widespread, ranging from naturally occurring
compounds to macrocyclic synthetic receptors or
ligands.[8Ϫ13] Ring systems containing two or more nitrogen
atoms are potentially useful because of their ability to act
as ligands and in some cases to mimic enzymatic
functions.[14Ϫ15] Their synthesis using direct cyclization has
hardly been reported.[16Ϫ19] Over the years, our laboratory
has had a special interest in the reactivity of donor-acceptor
substituted cyclopropane derivatives such as methyl 2-si-
loxy-2-vinylcyclopropanecarboxylate (1), the potential of
which for a variety of chemical transformations is well
documented.[20] The key feature of its synthetic use is its
equivalence to the 1,5-zwitterionic synthon A (Scheme 1).
We have recently published one-pot syntheses of medium-
to large-ring carbocycles C, in which the key step is an in-
tramolecular Michael addition (IMA).[27Ϫ30] The precursor
siloxycyclopropanes B contain remote pronucleophilic units
CYZ at suitable distances from the cyclopropane core; these
add to the enone generated in situ on fluoride treatment by
desilylation and ring-opening of B (Scheme 1). More re-
cently, we have described an extension of this methodology
to nitrogen-containing large-ring systems involving the
benzylamino group as the nucleophilic terminus.[31] This
new route provides direct access to a variety of func-
tionalized azamacrocycles with varying ring sizes, together
with control over the number of nitrogen atoms in the ring.
In this paper we wish to provide full details of these cycliza-
tion reactions. The extension of this concept to α-amino
esters is presented, followed by a few typical reactions of
the azamacrocycles, demonstrating the potential of this ap-
proach for syntheses of highly functionalized large-ring
compounds.
Results
Syntheses of Precursor Compounds
Alkylation of siloxycyclopropane 1 in the presence of
LDA with an excess of dihalides such as 1,4-dibromobutene
furnished the known bromide 2.[32] We found that benzyla-
mine was the best amine substrate for the proposed syn-
theses of azamacrocycles. Thus, treatment of 2 in a concen-
trated solution of benzylamine in dichloromethane afforded
Scheme 1
[a]
Freie Universität Berlin, Institut für Chemie Ϫ Organische
Chemie
Takustr. 3, 14195 Berlin, Germany
Fax: (internat.) ϩ 49-(0)30/8385-5367
E-mail: hans.reissig@chemie.fu-berlin.de
Eur. J. Org. Chem. 2001, 4195Ϫ4206
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/1122Ϫ4195 $ 17.50ϩ.50/0
4195

P. K. Patra, H.-U. Reißig
FULL PAPER
the corresponding amine 3 in 68% yield, together with the
dialkylated product 4,[33] formed in small amounts
(Scheme 2). The two compounds could easily be separated
by column chromatography. An excess of benzylamine was
required to minimize the amount of undesired double al-
kylation. The precursor diamine 6 was prepared in moder-
ate yield by alkylation of 1,4-(dibenzylamino)butene dihy-
drochloride salt 5[34] with bromide 2 in the presence of pot-
assium carbonate. Small amounts of a dialkylation product
were detected, but not isolated in pure form. Similarly,
Scheme 3. a) PhCH2NH2, CH2Cl2, room temp., 3 h; b) K2CO3,
CH3CN, room temp. to reflux, 24 h
bromide 7[29] was benzylaminated to afford the extended
derivative 8 in 78% yield, again together with the inevitably
formed dialkylated product 9. Bromide 7 was also treated
with the diammonium salt 5 in the presence of potassium
carbonate to furnish the long-chain diamine 10 in 50%
yield.
We also prepared precursors 12, 13, 15, 16, and 18, in-
corporating benzene and pyridine spacer units, which
should allow preparation of cyclophane derivatives. Hence,
starting with the previously described siloxycyclopropane
11,[30] we obtained 12 in 83% yield and diamine 13 in 55%
yield under the established conditions (Scheme 3). Similarly,
upon alkylation with benzylamine or diammonium salt 5,
the related (bromomethyl)pyridylmethyl-substituted cyclo-
propane 14[30] furnished the required cyclization precursors
15 and 16 in good yields. The amine 18, with a longer pyrid-
ine-containing spacer, was also prepared in 78% yield from
elongated siloxycyclopropane derivative 17.[30]
Cyclization Reactions
With the intermediate amines in hand, we studied the
cyclization reactions. These involve cesium fluoride-induced
Scheme 2. a) PhCH2NH2, CH2Cl2, room temp., 3 h; b) K2CO3,
CH3CN, room temp. to reflux, 24 h
4196
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Functionalized Azamacrocycles and Large-Ring α-Amino Esters
FULL PAPER
desilylation of the siloxy group, subsequent ring-cleavage of the experiments described here are probably oligomers,
the cyclopropane and attack of the terminal nitrogen nucle- formation of which through intermolecular reactions could
ophile on the enone generated in situ. Thus, amine 3 was not be avoided even under the high-dilution conditions em-
slowly added over 25 h to
a
highly diluted ployed. Further loss of material may be due to saponifica-
(500 mL·mmolϪ1), warmed (90 °C) suspension of cesium tion and/or condensation reactions of the carbonyl groups
fluoride and TEBA (triethylbenzylammonium chloride) in induced by fluoride.
dimethylformamide. Workup and purification of the re-
Encouraged by the positive result with 3 as starting mat-
sulting residue by chromatography afforded the expected erial, we employed other benzylamine-substituted precursor
azecine derivative 19 (24%) and its dimer 20 (4%, one dia- compounds for the anticipated azamacrocycle syntheses.
stereomer) (Scheme 4). Although the yield of 19 seems low When amine 6 was subjected to the conditions described
it is nevertheless remarkable, since formation of ten-mem- above, the corresponding 15-membered macrocycle 21 was
bered rings is usually rather unfavourable.[35] Our attempts isolated in 31% yield. Similarly, amine 8 afforded the corres-
to cyclize the corresponding tosylamine, the primary amine ponding functionalized macrocycle 22, although in rela-
or an alcohol related to 3 failed to provide the expected tively low yield. We could not detect or isolate even traces
heterocyclic compounds.[36] We also have to mention that of dimers or higher oligomers in any of these reactions.
an experiment with 3 as precursor under less dilute condi- However, when the long-chain amine 10 was cyclized in the
tions did not provide higher yields of the interesting diaza- presence of CsF under similar conditions, the 20-membered
macrocycle 20; oligomers were formed in large quantities azamacrocycle 23 was obtained in surprisingly high yield
instead. The missing quantities in the mass balance in all (62%).[37]
In order to synthesize azacyclophanes, we first attempted
to cyclize dibenzylamine derivative 12 (Scheme 5). However,
we could not detect the desired azacyclophane 24, nor its
dimer, nor higher oligomers, as has been observed in the
Scheme 4. a) CsF, TEBA, DMF, 90 °C, 22Ϫ25 h
Eur. J. Org. Chem. 2001, 4195Ϫ4206
Scheme 5. a) CsF, TEBA, DMF, 90 °C, 22Ϫ25 h
4197

P. K. Patra, H.-U. Reißig
FULL PAPER
case of a similar compound with a malonic ester as ter-
minus. We attribute the failure to obtain 24 to the strain
developed in its formation. Interestingly, this effect is con-
siderably diminished when the benzene ring of precursor
12 is substituted by a pyridine unit. Thus, cesium fluoride-
promoted reaction of compound 15 furnished the corres-
ponding pyridinophane 25 as the sole product, in 33%
yield. A possible explanation for the difference between the
formation of a benzocyclophane and that of the corres-
ponding pyridinophane has been discussed in our previous
publication.[30] Cyclization of the long-chain diamine 13 af-
forded the desired azacyclophane 26 with moderate effici-
ency (33% yield). Further examples such as 16 and 18, in-
corporating meta-substituted pyridine units as spacers,
demonstrated smooth formation of the azapyridinophanes
27 and 28 in good yields (54% and 49%).
Scheme 7. a) i. 29, LDA, Ϫ78 °C, ii. silica gel; b) i. PhCHO,
MgSO4, ii. NaBH4, MeOH, room temp.; c) CsF, TEBA, DMF,
90 °C, 28 h
and 35 may be regarded as highly functionalized expanded
proline derivatives.
Synthesis of Macrocyclic α-Amino Esters
A second approach was used to open a pathway to mac-
rocyclic α-amino esters. The enolate generated from N-di-
silylated glycine derivative 29[38] by treatment with LDA
was alkylated, with siloxycyclopropane 2 used as the elec-
trophile (Scheme 6). After purification by column chroma-
tography on silica gel (which apparently causes N-desilyl-
ation), substitution product 30 was isolated in high yield as
the expected 1:1 mixture of two diastereomers. The primary
amino group of 30 was smoothly benzylated by formation
of the corresponding Schiff base with benzaldehyde, fol-
lowed by reduction with sodium borohydride.[39] Thus, cyc-
lization precursor 31 was obtained in good yield. Its treat-
ment with cesium fluoride under the above conditions
caused transformation to the 11-membered ring compound
32 in 42% yield. As expected, this compound was isolated
as a 1:1 mixture of two diastereomers.
Reactions of Azamacrocycles
The simplest derivative in our series of azamacrocycles,
compound 19, could be converted into saturated azecane
derivative 36 by hydrogenation in the presence of Pd-C. The
N-benzyl group is not affected under these conditions, but
the moderate yield of 47% does not preclude the formation
of other products, lost during workup and purification
(Scheme 8). A second transformation made use of the γ-
oxo ester moiety of azamacrocycles 22 and 27. Upon treat-
ment with hydrazine hydrate in a solution of methanol,
these compounds were converted into the macrocyclic pyri-
dazinone[40] derivatives 37 and 38. Again, the yields were
Scheme 6. a) i. LDA, Ϫ78 °C, ii. Silica gel; b) i. PhCHO, MgSO4,
ii. NaBH4, MeOH, room temp.; c) CsF, TEBA, DMF, 90 °C, 25 h
The analogous sequence applied to the extended siloxycy-
clopropane derivative 7 furnished α-amino ester 33 and its
N-benzylated derivative 34 in good yields (Scheme 7). Cyc-
lization of 34 provided 16-membered azamacrocycle 35 in
low yield. The reactions resulting in 32 and 35 have not so
far been optimized. We believe that this new approach to
macrocyclic α-amino esters deserves some interest, since 32 Scheme 8
4198
Eur. J. Org. Chem. 2001, 4195Ϫ4206

Functionalized Azamacrocycles and Large-Ring α-Amino Esters
FULL PAPER
Conclusion
only moderate, which may be due to formation of other
condensation products of higher molecular weight in these
examples. Nevertheless, the synthesis of unusual pyridazi-
none derivatives is notable, since this class of compounds is
known to be of considerable pharmaceutical interest.[41]
We have demonstrated here that our concept of sequen-
tial fluoride-promoted ring-opening/ring-closure in the
presence of terminal pronucleophilic units was smoothly ex-
tendable to the preparation of a fair number of highly func-
tionalized azamacrocycles. Though yields are variable, the
transformations may certainly be optimized further. The
highly flexible building block system developed permits the
syntheses of compounds with variable ring sizes, differing
number of incorporated nitrogen atoms, and various func-
tional groups. Many spacer units may be incorporated be-
tween the protected enone unit provided by the siloxycyclo-
propane part derived from 1 and the nucleophilic terminus.
Taking into account the difficulties involved in the genera-
tion of large-membered heterocycles, due to unfavourable
enthalpic and entropic effects,[42] our method could be
very useful.
Since the new macroheterocycles incorporate γ-oxo ester
moieties, they may be exploited for further transformations,
but also Ϫ with participation of double bonds or the aro-
matic units Ϫ for transannular reactions. Thanks to these
various opportunities, these azamacrocycles may also serve
as templates for diversity-orientated syntheses. We are cur-
rently introducing dipeptides and small oligopeptides as
spacer units into the precursor compounds to obtain prod-
ucts of higher complexity. After cyclization, conforma-
tionally restricted peptidomimetics[43] should be made avail-
able.
Discussion
As mentioned above, we had previously studied macrocy-
clizations of compounds with dimethyl malonate units as
C-nucleophilic termini, and now several closely related de-
rivatives with benzylamino groups as N-nucleophilic ter-
mini have been investigated. It is therefore tempting to com-
pare the efficiencies in both series, but there seems to be no
general rule. Starting material 3 provided the azamacrocycle
19 in 24% yield and its dimer in 4% yield, whereas the re-
lated dimethyl malonate precursor gave the ten-membered
carbocyclic compound in only 11% yield, but its dimer and
trimer in 24% and 8% yields.[28] The cyclization of benzyl-
amine derivative 10 to diazamacrocycle 23 is considerably
more efficient (62% yield) than that of the corresponding
all-carbon precursor with two dimethyl malonate units,
which provides the 20-membered ring in 40% yield. On the
other hand, the quite respectable yield for cyclization of 18
into 28 (49% yield) is even surpassed by the related trans-
formation of the malonate precursor into the corresponding
pyridinocyclophane, which proceeded in an excellent 78%
yield.[30] However, these comparisons should be regarded
with some reservations, since the mass balances of the cyc-
lizations studied are often rather low. Thus, product loss Experimental Section
during workup or purification can never be ruled out.
1H NMR and 13C NMR spectra were recorded with Bruker instru-
It should also briefly be mentioned that precursor com-
pounds 39 and 40, prepared by analogous routes, did not
provide any cyclized compounds under the standard reac-
tion conditions (Scheme 9). Apparently, steric hindrance
caused by branching near the nucleophilic terminus com-
pletely prevents ring-formation with these compounds.
ments (AC 250, AC 300, or DRX 500) in CDCl3 solution. The
chemical shifts are given relative to TMS from the solvent (CDCl3)
signal (δH ϭ 7.25, δC ϭ 77.0). The 2D NMR COSY, HSQC (het-
eronuclear single quantum coherence), and HMBC (heteronuclear
multiple quantum correlation) spectra were recorded on the DRX
500 spectrometer with an inverse TBI probe-head using pulsed two-
field gradients. The final resolution of the 2D spectra was 2.5 Hz
1
per point for H and 20.5 Hz per point for 13C.
To facilitate comparison of NMR spectroscopic data, the num-
bering of C and H atoms used for the siloxycyclopropanes 3, 4, 6,
8, 9, 10, 12, 13, 15, 16, and 18 is as depicted below (Scheme 10),
independent of the systematic nomenclature of the compounds.
Scheme 10
IR spectra were measured with a Nicolet 205 FT-IR spectrometer
and 5 SXC Nicolet FT-IR spectrometer using a DTGS detector.
Mass spectra were recorded on a Varian MAT 711 or MAT 311
A spectrometer.
Scheme 9
Eur. J. Org. Chem. 2001, 4195Ϫ4206
4199

P. K. Patra, H.-U. Reißig
FULL PAPER
All reactions were performed under argon atmosphere in flame-
dried flasks, and the reagents were introduced by syringe. All solv-
ents were dried by standard methods. Silica gel (0.040Ϫ0.063 mm,
MerckϪSchuchardt) was used for column chromatography. Com-
mercially available (E)-1,4-dibromo-2-butene and α,αЈ-dibromo-m-
xylene were used as received. Benzylamine (Merck) was distilled
before use. Other starting materials were synthesized as described
in the literature [siloxycyclopropanes 2,[32] 7,[29] 11, 14, 17,[30] diam-
monium salt 5,[34] 2,6-bis(bromomethyl)pyridine[44]].
Ϫ C24H36NO3Si (414.6): calcd. C 69.52, H 8.75, N 3.37; found C
69.40, H 9.15, N 3.81.
Ϫ1
˜
Compound 4: IR (film): ν ϭ 3090Ϫ2890 cm (ϭCϪH, CϪH),
1
1730 (CO2Me), 1670 (CϭC). Ϫ H NMR (300 MHz, CDCl3): δ ϭ
7.17Ϫ7.07 (m, 5 H, Ph), 5.57 (dd, J ϭ 17.0, 10.5 Hz, 2 H, 2-H),
5.46 (mc, 4 H, 7-H, 8-H), 5.14 (dd, J ϭ 17.0, 1.5 Hz, 2 H, 1-H),
4.97 (dd, J ϭ 10.5, 1.5 Hz, 2 H, 1-H), 3.46 (s, 6 H, CO2Me), 3.38
(mc, 2 H, CH2Ph), 2.88 (mc, 4 H, 9-H), 2.78 (dd, J ϭ 15.5, 6.5 Hz,
2 H, 6-H), 2.11 (dd, J ϭ 15.5, 6.5 Hz, 2 H, 6-H), 1.71 (d, J ϭ
6.3 Hz, 2 H, 4-H), 0.90 (d, J ϭ 6.3 Hz, 2 H, 4-H), 0.79 (s, 18 H,
tBu), 0.02, 0.00 (2 s, 12 H, SiMe2). Ϫ 13C NMR (75.5 MHz,
CDCl3): δ ϭ 171.8, 51.7 (s, q, CO2Me), 139.4, 128.9, 128.7, 126.6
(s, 3 d, Ph), 136.7, 130.7 (2 d, C-2, C-8), 128.0 (d, C-7), 115.1 (t,
C-1), 64.9 (s, C-3), 57.0, 55.3 (2 t, CH2Ph, C-9), 37.4 (s, C-5), 31.7,
23.6 (2 t, C-6, C-4), 25.8, 18.1 (q, s, tBu), Ϫ3.5, Ϫ3.7 (2 q, SiMe2).
Ϫ C41H65NO6Si2 (724.1): calcd. C 68.00, H 9.04, N 1.93; found C
68.28, H 8.83, N 2.32.
General Procedure A for N-Alkylation of Benzylamine: The alkyl
bromide (1.0 equiv.) was added at room temperature to a stirred
solution of benzylamine (10.0 equiv.) in dichloromethane
(5 mL·mmolϪ1). After 3 h, the reaction mixture was diluted with
dichloromethane (10 mL·mmolϪ1) and washed with saturated
NaHCO3 solution. The organic layer was dried with MgSO4 and
the solvent was evaporated. The residue was purified by column
chromatography as described in the individual experiments.
Synthesis of Diamine 6: According to general procedure B, cyclo-
propyl bromide 2 (0.83 g, 2.12 mmol) in dry acetonitrile (50 mL)
was treated with diammonium salt 5 (1.43 g, 4.24 mmol) in the
presence of K2CO3 (1.46 g, 10.6 mmol), followed by workup and
purification using silica gel column chromatography (hexane/
General Procedure B for N-Alkylation of Ammonium Salt 5: The
alkyl bromide (1.0 equiv.) and the diammonium salt 5 (2.0 equiv.)
were added to a stirred suspension of anhyd. K2CO3 (5 equiv.) in
dry acetonitrile (20 mL·mmolϪ1). The reaction mixture was stirred
at room temperature for 12 h, refluxed for a further period of 12 h,
cooled, and poured into ice water, followed by extraction with ethyl
acetate (3 ϫ 20 mL). The combined organic layers were washed
with water and brine and then dried with Na2SO4. After evapora-
tion of the solvent, the residue was purified by column chromato-
graphy as described in the individual experiments.
EtOAc, 1:9) to afford 6 (633 mg, 52%) as a light yellow liquid. Ϫ
Ϫ1
˜
IR (film): ν ϭ 3340 cm (NϪH), 3085Ϫ2800 (ϭCϪH, CϪH),
1
1730 (CO2Me), 1640 (CϭC). Ϫ H NMR (300 MHz, CDCl3): δ ϭ
7.20Ϫ7.08 (m, 10 H, 2 Ph), 5.70 (dd, J ϭ 17.1, 10.5 Hz, 1 H, 2-H),
5.56 (mc, 2 H, 8-H, 12-H), 5.47 (mc, 2 H, 7-H, 13-H), 5.14 (dd, J ϭ
17.1, 1.0 Hz, 1 H, 1-H), 4.98 (dd, J ϭ 10.5, 1.0 Hz, 1 H, 1-H), 3.66
(s, 2 H, CH2Ph), 3.46 (s, 3 H, CO2Me), 3.46Ϫ3.42 (m, 2 H,
CH2Ph), 3.14Ϫ2.91 (m, 6 H, 14-H, 11-H, 9-H), 2.78 (dd, J ϭ 15.3,
5.0 Hz, 1 H, 6-H), 2.09 (dd, J ϭ 15.3, 5.0 Hz, 1 H, 6-H), 1.71 (d,
J ϭ 6.3 Hz, 1 H, 4-H), 1.61 (br. s, 1 H, NH), 0.90 (d, J ϭ 6.3 Hz,
1 H, 4-H), 0.79 (s, 9 H, tBu), 0.00, Ϫ0.03 (2 s, 6 H, SiMe2). Ϫ 13C
NMR (75.5 MHz, CDCl3): δ ϭ 172.0, 51.8 (s, q, CO2Me), 140.2,
139.5, 128.9, 128.4, 128.2, 128.1, 126.9, 126.7 (2 s, 6 d, Ph), 136.7
(d, C-2), 131.5, 130.9, 129.6, 128.6 (4 d, C-13, C-12, C-8, C-7),
115.2 (t, C-1), 65.1 (s, C-3), 57.3, 55.5, 55.2, 53.2, 50.8 (5 t, 2
CH2Ph, C-14, C-9, C-11), 37.5 (s, C-5), 31.8, 23.7 (2 t, C-6, C-4),
25.8, 18.2 (q, s, tBu), Ϫ3.4, Ϫ3.6 (2 q, SiMe2). Ϫ MS (EI, 80 eV):
m/z (%) ϭ 574 (7) [Mϩ], 483 [Mϩ Ϫ 91] (7), 91 (100). Ϫ HRMS:
calcd. for C35H50N2O3Si: 574.35972; found 574.35896.
General Procedure C for Fluoride-Induced Cyclization: A solution
of siloxycyclopropyl-substituted amine (1.0 equiv.) in dry DMF
(50 mL) was slowly added to a warm suspension (90 °C) of cesium
fluoride (3.0 equiv.) and benzyltriethylammonium chloride (1.5
equiv.) in dry DMF (ഠ 500 mL·mmolϪ1 siloxycyclopropyl com-
pound). The addition was performed by syringe pump, over a
period of time listed in each experiment. After evaporation of all
volatile components (16 mbar, 70 °C), the residue was diluted with
saturated aqueous NH4Cl solution and extracted with ethyl acetate
(5 ϫ 20 mL). The combined organic layers were washed with brine
and dried with MgSO4. Removal of the solvent was followed by
evaporation of the remaining DMF (0.01 mbar, 50 °C). The residue
was purified by chromatography as indicated in the individual ex-
periments.
Synthesis of Amine 8: Following general procedure A, cyclopropyl
bromide 7 (2.63 g, 4.53 mmol) was treated with benzylamine
Synthesis of Amine 3: According to general procedure A, cyclopro-
pyl bromide 2 (2.00 g, 5.00 mmol) was treated with benzylamine (4.86 g, 45.3 mmol) in dichloromethane (50 mL). Subsequent
(5.50 g, 25.0 mmol) in dichloromethane (20 mL), followed by puri- workup and purification by column chromatography (silica gel,
fication using silica gel column chromatography (hexane/EtOAc, hexane/EtOAc, 1:4) afforded 8 (2.10 g, 78%) as a light yellow li-
1:1) to give the corresponding amine 3 (1.40 g, 68%) as a light
yellow liquid and dialkylamine 4 (0.12 g, 7%) as the second fraction
(elution with hexane/EtOAc, 1:9). Ϫ IR (film): ν˜ ϭ 3470Ϫ3005
quid, along with dialkylamine 9 (0.40 g, 16%) as the second frac-
Ϫ1
˜
tion (elution with hexane/EtOAc, 1:1). Ϫ IR (film): ν ϭ 3445 cm
(NϪH), 3090Ϫ3030 (ϭCϪH), 3000Ϫ2860 (CϪH), 1735 (CO2Me),
1
cmϪ1 (NϪH, ϭCϪH), 2990Ϫ2740 (CϪH), 1725 (CO2Me), 1640 1620 (CϭC). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 7.19Ϫ7.10 (m,
1
(CϭC). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 7.24Ϫ7.12 (m, 5 H, 5 H, Ph), 5.69 (dd, J ϭ 17.0, 10.5 Hz, 1 H, 2-H), 5.52Ϫ5.18 (m, 4
Ph), 5.72 (dd, J ϭ 17.0, 10.5 Hz, 1 H, 2-H), 5.52 (mc, 2 H, 7-H, 8-
H), 5.18 (dd, J ϭ 17.0, 1.0 Hz, 1 H, 1-H), 5.02 (dd, J ϭ 10.5,
H, 7-H, 8-H, 12-H, 13-H), 5.14 (dd, J ϭ 17.0, 1.0 Hz, 1 H, 1-H),
4.97 (dd, J ϭ 10.5, 1.0 Hz, 1 H, 1-H), 3.62 (s, 2 H, CH2Ph), 3.56,
1.0 Hz, 1 H, 1-H), 3.67 (s, 2 H, CH2Ph), 3.53 (s, 3 H, CO2Me), 3.51, 3.49 (3 s, 9 H, 3 CO2Me), 3.07 (mc, 2 H, 14-H), 2.72 (dd, J ϭ
3.12 (mc, 2 H, 9-H), 2.81 (br. dd, J ϭ 15.5, 6.0 Hz, 1 H, 6-H), 2.13 15.5, 6.5 Hz, 1 H, 6-H), 2.47 (mc, 4 H, 9-H, 11-H), 2.06 (dd, J ϭ
(br. dd, J ϭ 15.5, 6.0 Hz, 1 H, 6-H), 1.75 (d, J ϭ 6.0 Hz, 1 H, 4- 15.5, 6.5 Hz, 1 H, 6-H), 1.69 (d, J ϭ 6.0 Hz, 1 H, 4-H), 1.31 (br. s,
H), 1.43 (br. s, 1 H, NH), 0.94 (d, J ϭ 6.0 Hz, 1 H, 4-H), 0.82 (s, 1 H, NH), 0.88 (d, J ϭ 6.0 Hz, 1 H, 4-H), 0.79 (s, 9 H, tBu), 0.00,
9 H, tBu), 0.02, 0.00 (2 s, 6 H, SiMe2). Ϫ 13C NMR (75.5 MHz,
Ϫ0.03 (2 s, 6 H, SiMe2). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ
CDCl3): δ ϭ 172.1, 51.9 (s, q, CO2Me), 140.3, 129.6, 128.4, 128.2 171.5, 170.8, 52.0, 51.6 (2 s, 2 q, CO2Me), 140.1, 132.0, 128.1, 127.9
(s, 3 d, Ph), 136.7 (d, C-2), 129.8, 126.9 (2 d, C-7, C-8), 115.2 (t,
C-1), 65.1 (s, C-3), 53.2, 51.1 (2 t, CH2Ph, C-9), 37.5 (s, C-5), 31.7,
(s, 3 d, Ph), 136.5, 133.1 (2 d, C-2, C-7), 126.6, 125.6, 124.8 (3 d,
C-8, C-12, C-13), 114.9 (t, C-1), 64.8 (s, C-3), 57.7 (s, C-10), 52.8,
23.6 (2 t, C-6, C-4), 25.8, 18.2 (q, s, tBu), Ϫ3.4, Ϫ3.6 (2 q, SiMe2). 50.5 (2 t, CH2Ph, C-14), 37.1 (s, C-5), 35.6, 35.1, 31.5 (3 t, C-9, C-
4200 Eur. J. Org. Chem. 2001, 4195Ϫ4206

Functionalized Azamacrocycles and Large-Ring α-Amino Esters
FULL PAPER
11, C-6), 25.6, 17.9 (q, s, tBu), 23.4 (t, C-4), Ϫ3.7, Ϫ3.8 (2 q, 53.0, 52.9 (2 t, NϪCH2), 38.5 (s, C-5), 34.1 (t, C-6), 25.7, 18.1 (q,
SiMe2). Ϫ MS (EI, 80 eV): m/z (%) ϭ 599 (7) [Mϩ], 508 [Mϩ
s, tBu), 23.8 (t, C-4), Ϫ3.4, Ϫ3.6 (2 q, SiMe2). Ϫ MS (EI, 80 eV):
91] (5), 73 (100). Ϫ HRMS: calcd. for C33H49NO7Si: 599.32783; m/z (%) ϭ 465 (4) [Mϩ], 480 [Mϩ Ϫ 57] (3), 360 [Mϩ Ϫ 105] (17),
Ϫ
found 599.32759.
73 (100). Ϫ HRMS: calcd. for C28H39NO3Si: 465.26992; found
465.26632.
Ϫ1
˜
Compound 9: IR (film): ν ϭ 3090Ϫ2860 cm (CϪH, ϭCϪH),
1
1735 (CO2Me), 1640 (CϭC). Ϫ H NMR (300 MHz, CDCl3): δ ϭ Synthesis of Diamine 13: According to general procedure B, cyclo-
7.19Ϫ7.10 (m, 5 H, Ph), 5.69 (dd, J ϭ 17.0, 10.5 Hz, 2 H, 2-H), propyl bromide 11 (2.00 g, 4.60 mmol) in dry acetonitrile (25 mL)
5.48Ϫ5.13 (m, 8 H, 7-H, 8-H, 12-H, 13-H), 5.17 (dd, J ϭ 17.0, was treated with diammonium salt 5 (3.10 g, 9.28 mmol) in the
1.5 Hz, 2 H, 1-H), 5.00 (dd, J ϭ 10.5, 1.5 Hz, 2 H, 1-H), 3.55 (s, presence of K2CO3 (3.20 g, 23.0 mmol), followed by purification
12 H, 4 CO2Me), 3.50 (s, 6 H, 2 CO2Me), 3.37 (br. s, 2 H, CH2Ph),
using silica gel column chromatography (hexane/EtOAc, 1:4) to af-
˜
2.84 (mc, 4 H, 14-H), 2.73 (dd, J ϭ 15.5, 6.5 Hz, 2 H, 6-H), 2.45 ford 13 (1.58 g, 55%) as a light yellow liquid. Ϫ IR (film): ν ϭ 3340
(mc, 8 H, 9-H, 11-H), 2.02 (dd, J ϭ 15.5, 6.5 Hz, 2 H, 6-H), 1.69 cmϪ1 (NϪH), 3085Ϫ2710 (ϭCϪH, CϪH), 1730 (CO2Me), 1680,
1
(d, J ϭ 6.3 Hz, 2 H, 4-H), 0.87 (d, J ϭ 6.3 Hz, 2 H, 4-H), 0.78 (s,
1640 (CϭC). Ϫ H NMR (250 MHz, CDCl3): δ ϭ 7.39Ϫ7.06 (m,
18 H, tBu), 0.00, Ϫ0.03 (2 s, 12 H, SiMe2). Ϫ 13C NMR (75.5 MHz, 14 H, Ar), 5.85 (dd, J ϭ 17.0, 11.2 Hz, 1 H, 2-H), 5.70 (mc, 2 H,
CDCl3): δ ϭ 171.8, 171.1, 52.3, 51.9 (2 s, 2 q, CO2Me), 139.3, ϭCH), 5.29 (dd, J ϭ 17.0, 1.5 Hz, 1 H, 1-H), 5.12 (dd, J ϭ 11.2,
132.1, 127.1, 126.8 (s, 3 d, Ph), 136.7, 132.2, 128.8, 128.8, 125.1 (5 1.5 Hz, 1 H, 1-H), 3.77 (s, 2 H, CH2Ph), 3.52 (s, 3 H, CO2Me),
d, C-2, C-7, C-8, C-12, C-13), 115.2 (t, C-1), 65.1 (s, C-3), 58.1 (s, 3.57Ϫ3.03 (m, 9 H, NϪCH2, 6-H), 2.83 (d, J ϭ 15.4 Hz, 1 H, 6-
C-10), 57.2, 55.2 (2 t, CH2Ph, C-14), 35.7, 35.5, 31.8 (3 t, C-9, C-11, H), 1.91 (d, J ϭ 5.8 Hz, 1 H, 4-H), 1.25 (br. s, 1 H, NH), 1.18 (d,
C-6), 25.8, 18.2 (q, s, tBu), 23.6 (t, C-4), Ϫ3.5, Ϫ3.6 (2 q, SiMe2). Ϫ J ϭ 5.8 Hz, 1 H, 4-H), 0.92 (s, 9 H, tBu), 0.14, 0.12 (2 s, 6 H,
C59H89NO14Si2 (1092.6): calcd. C 64.86, H 8.21, N 1.28; found C
62.77, H 7.85, N 1.61; no correct elemental analysis was obtained CO2Me), 140.2, 140.0, 139.9, 139.8, 129.2, 128.9, 128.7, 128.6,
SiMe2). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 171.7, 50.8 (s, q,
for this minor component.
128.4, 127.3, 127.2, 127.0, 126.8 (4 s, 9 d, Ar), 136.9 (d, C-2), 130.9,
130.6 (2 d, ϭCH), 115.7 (t, C-1), 65.4 (s, C-3), 58.2, 58.1, 55.5,
53.2, 52.0 (5 t, NCH2), 38.9 (s, C-5), 34.4 (t, C-6), 26.1, 18.5 (q, s,
tBu), 24.2 (t, C-4), Ϫ3.1, Ϫ3.2 (2 q, SiMe2). Ϫ MS (EI, 80 eV): m/
z (%) ϭ 624 (6) [Mϩ], 533 [Mϩ Ϫ 91] (4), 91 (100). Ϫ HRMS:
calcd. for C39H52N2O3Si: 624.37472; found 624.37121.
Synthesis of Diamine 10: According to general procedure B, cyclo-
propyl bromide 7 (1.00 g, 1.74 mmol) in dry acetonitrile (20 mL)
was treated with diammonium salt 5 (1.18 g, 3.48 mmol) in the
presence of K2CO3 (1.20 g, 8.70 mmol), followed by purification
using silica gel column chromatography (hexane/EtOAc, 1:4) to af-
ford 10 (642 mg, 50%) as a light yellow liquid. Ϫ IR (film): ν˜ ϭ Synthesis of Amine 15: Following general procedure A, cyclopropyl
3360 cmϪ1 (NϪH), 3090Ϫ3030 (ϭCϪH, CϪH), 1735 (CO2Me), bromide 14 (471 mg, 1.07 mmol) was treated with benzylamine
1
1640 (CϭC). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 7.30Ϫ7.19 (m,
(1.15 g, 10.7 mmol) in dichloromethane (25 mL). Workup and puri-
10 H, Ph), 5.79 (dd, J ϭ 17.3, 10.6 Hz, 1 H, 2-H), 5.69Ϫ5.26 (m, fication by column chromatography (silica gel, hexane/EtOAc, 3:7)
6 H, ϭCH), 5.22 (dd, J ϭ 17.3, 1.4 Hz, 1 H, 1-H), 5.07 (dd, J ϭ afforded 15 (390 mg, 78%) as a light yellow liquid. Ϫ IR (film):
Ϫ1
˜
10.6, 1.4 Hz, 1 H, 1-H), 3.76 (s, 2 H, CH2Ph), 3.67, 3.59 (2 s, 9 H, ν ϭ 3325 cm
3 CO2Me), 3.51 (s, 2 H, CH2Ph), 3.24 (mc, 2 H, 19-H), 3.00 (mc, 4
(NϪH), 3085Ϫ2860 (ϭCϪH, CϪH), 1725
(CO2Me), 1640 (CϭC), 1590, 1575 (pyridine). Ϫ 1H NMR
H, 14-H, 16-H), 2.82 (dd, J ϭ 15.4, 6.6 Hz, 1 H, 6-H), 2.55 (mc, 4 (250 MHz, CDCl3): δ ϭ 7.48 (t, J ϭ 7.5 Hz, 1 H, pyr-H),
H, 9-H, 11-H), 2.15 (dd, J ϭ 15.4, 6.6 Hz, 1 H, 6-H), 1.79 (d, J ϭ 7.37Ϫ7.18 (m, 5 H, Ph), 7.01, 6.93 (2 d, J ϭ 7.5 Hz each, 2 H, pyr-
5.8 Hz, 1 H, 4-H), 1.49 (br. s, 1 H, NH), 0.96 (d, J ϭ 5.8 Hz, 1 H, H), 5.88 (dd, J ϭ 16.9, 10.3 Hz, 1 H, 2-H), 5.30 (dd, J ϭ 16.9,
4-H), 0.88 (s, 9 H, tBu), 0.09, 0.06 (2 s, 6 H, SiMe2). Ϫ 13C NMR 1.5 Hz, 1 H, 1-H), 5.11 (dd, J ϭ 10.3, 1.5 Hz, 1 H, 1-H), 3.83, 3.81
(75.5 MHz, CDCl3): δ ϭ 171.7, 171.0, 52.1, 51.7 (2 s, 2 q, CO2Me), (2 s, 2 H each, NCH2), 3.69, 3.04 (2 d, J ϭ 16.1 Hz, 1 H each, 6-
140.2, 139.4, 128.7, 128.1, 126.9, 126.8, 126.7 (2 s, 5 d, Ph), 136.6 H), 3.52 (s, 3 H, CO2Me), 2.37 (br. s, 1 H, NH), 1.92 (d, J ϭ
(d, C-2), 132.1, 132.0, 131.6, 129.3, 128.3, 124.9 (6 d, ϭCH), 115.1
6.6 Hz, 1 H, 4-H), 1.20 (d, J ϭ 6.6 Hz, 1 H, 4-H), 0.89 (s, 9 H,
(t, C-1), 65.0 (s, C-3), 57.9 (s, C-10), 57.4 (t, C-19), 55.3, 55.1 (2 t, tBu), 0.12, 0.09 (2 s, 6 H, SiMe2). Ϫ 13C NMR (62.9 MHz, CDCl3):
C-14, C-16), 53.2, 50.7 (2 t, CH2Ph), 37.3 (s, C-5), 35.6, 35.4 (2 t, δ ϭ 172.2, 51.7 (s, q, CO2Me), 159.7, 158.7 (2 s, C-pyr), 140.3,
C-9, C-11), 31.7, 18.1 (2 t, C-6, C-4), 25.8, 14.1 (q, s, tBu), Ϫ3.5, 128.3, 128.2, 126.8 (s, 3 d, Ph), 136.7, 136.3, 120.6, 119.5 (4 d, C-
Ϫ3.7 (2 q, SiMe2). Ϫ C44H62N2O7Si (759.1): calcd. C 69.62, H 8.23, 2, C-pyr), 115.3 (t, C-1), 65.4 (s, C-3), 54.2, 53.4 (2 t, NCH2), 37.3
N 3.69; found C 68.99, H 8.02, N 3.42.
(s, C-5), 36.7 (t, C-6), 25.8, 18.2 (q, s, tBu), 24.2 (t, C-4), Ϫ3.4,
Ϫ3.5 (2 q, SiMe2). Ϫ MS (EI, 80 eV): m/z (%) ϭ 466 (60) [Mϩ],
407 [Mϩ Ϫ 59] (13), 375 [Mϩ Ϫ 91] (36), 212 (100). Ϫ HRMS:
calcd. for C27H38N2O3Si: 466.26517; found 466.26531.
Synthesis of Amine 12: According to general procedure A, cyclo-
propyl bromide 11 (1.10 g, 2.50 mmol) was treated with benzylam-
ine (2.68 g, 25.0 mmol) in dichloromethane (30 mL), followed by
purification using silica gel column chromatography (hexane/
Synthesis of Diamine 16: According to general procedure B, cyclo-
EtOAc, 1:4) to give the corresponding amine 12 (967 mg, 83%) as propyl bromide 14 (1.50 g, 3.40 mmol) in dry acetonitrile (25 mL)
a light yellow liquid. Ϫ IR (film): ν˜ ϭ 3345 cmϪ1 (NϪH),
was treated with diammonium salt 5 (2.30 g, 6.80 mmol) in the
3065Ϫ2890 (ϭCϪH, CϪH), 1730 (CO2Me), 1640 (CϭC). Ϫ 1H presence of K2CO3 (2.34 g, 17.0 mmol), followed by purification
NMR (250 MHz, CDCl3): δ ϭ 7.49Ϫ7.18 (m, 9 H, Ar), 5.93 (dd, using silica gel column chromatography (hexane/EtOAc, 1:4) to af-
J ϭ 17.3, 10.0 Hz, 1 H, 2-H), 5.48 (dd, J ϭ 17.3, 1.0 Hz, 1 H, 1-
H), 5.20 (dd, J ϭ 10.0, 1.0 Hz, 1 H, 1-H), 3.82, 3.81 (2 s, 2 H each,
NCH2), 3.60, 2.92 (2 d, J ϭ 14.9 Hz, 1 H each, 6-H), 3.58 (s, 3 H, (CϭC). Ϫ H NMR (250 MHz, CDCl3): δ ϭ 7.52 (t, J ϭ 7.7 Hz,
ford 16 (1.02 g, 49%) as a light yellow liquid. Ϫ IR (film): ν˜ ϭ 3340
cmϪ1 (NϪH), 3085Ϫ2800 (ϭCϪH, CϪH), 1725 (CO2Me), 1640
1
CO2Me), 2.00 (d, J ϭ 5.8 Hz, 1 H, 4-H), 1.71 (br. s, 1 H, NH),
1 H, pyr-H), 7.39Ϫ7.17 (m, 11 H, Ph, pyr-H), 7.01 (d, J ϭ 7.7 Hz,
1.28 (d, J ϭ 5.8 Hz, 1 H, 4-H), 1.00 (s, 9 H, tBu), 0.17, 0.16 (2 s, 1 H, pyr-H), 5.90 (dd, J ϭ 17.3, 10.6 Hz, 1 H, 2-H), 5.72 (mc, 2
6 H, SiMe2). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 171.7, 51.6 (s, H, ϭCH), 5.33 (dd, J ϭ 17.3, 1.4 Hz, 1 H, 1-H), 5.15 (dd, J ϭ
q, CO2Me), 140.3, 140.2, 140.1, 128.8, 128.2, 128.0, 127.0, 126.7, 10.6, 1.4 Hz, 1 H, 1-H), 3.76 (s, 3 H, CO2Me), 3.76, 3.69, 3.61 (3
125.8 (3 s, 6 d, Ar), 136.6 (d, C-2), 115.3 (t, C-1), 65.0 (s, C-3), br s, 6 H, NϪCH2), 3.76Ϫ3.52 (m, 2 H, NCH2), 3.20Ϫ3.00 (m, 4
Eur. J. Org. Chem. 2001, 4195Ϫ4206
4201

P. K. Patra, H.-U. Reißig
FULL PAPER
H, NCH2, 6-H), 1.93 (d, J ϭ 5.8 Hz, 1 H, 4-H), 1.64 (br. s, 1 H, 2.39Ϫ2.30 (4 m, 2 H, 6 H, 12 H, 2 H, CH2, CH). Ϫ 13C NMR
NH), 1.27 (d, J ϭ 5.8 Hz, 1 H, 4-H), 0.89 (s, 9 H, tBu), 0.13, 0.11 (75.5 MHz, CDCl3): δ ϭ 210.6 (s, CϭO), 175.0, 51.9 (s, q, CO2Me),
(2 s, 6 H, SiMe2). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 172.1,
138.5 (s, Ph), 130.2, 130.0, 129.4, 129.0, 127.1 (5 d, Ph, C-3, C-4,
51.8 (s, q, CO2Me), 159.4, 159.2 (2 s, C-pyr), 140.2, 139.5 (2 s, Ph), C-13, C-14), 58.5 (t, CH2Ph), 50.0, 48.4, 42.7 (3 t, C-2, C-5, C-10,
136.8, 136.3 (2 d, C-2, C-pyr), 131.5, 129.5, 128.7, 128.3, 128.1,
126.8, 126.7 (7 d, ϭCH, Ph), 120.3, 119.9 (2 d, C-pyr), 115.1 (t, C-
1), 65.3 (s, C-3), 59.6, 57.9, 55.5, 53.2, 50.7 (5 t, NCH2), 37.1 (s, C-
5), 36.8 (t, C-6), 25.8, 18.1 (q, s, tBu), 24.4 (t, C-4), Ϫ3.5 (q, SiMe2).
Ϫ MS (EI, 80 eV): m/z (%) ϭ 625 (22) [Mϩ], 361 (100). Ϫ HRMS:
C-12, C-15, C-20), 38.8 (d, C-16, C-6), 37.9 (t, C-7, C-17), 26.9 (t,
C-9, C-19). Ϫ MS (FAB): m/z (%) ϭ 603 [Mϩ ϩ 1] (4), 91 (100).
Methyl (3E,8E)-1,6-Dibenzyl-13-oxo-1,6-diazacyclopentadeca-3,8-
diene-11-carboxylate (21): According to general procedure C, di-
amine 6 (456 mg, 0.79 mmol) was cyclized in the presence of CsF
(362 mg, 2.38 mmol) and TEBA (270 mg, 1.19 mmol) in dry DMF
(450 mL) for 24 h, followed by workup and column chromato-
graphy using silica gel (EtOAc/hexane, 4:6) to yield 21 (110 mg,
calcd. for C38H51N3O3Si: 625.36997; found 625.36933.
Ϫ
C38H51N3O3Si (625.9): calcd. C 72.91, H 8.21, N 6.71; found C
72.66, H 7.97, N 6.76.
Synthesis of Amine 18: Following general procedure A, cyclopropyl
bromide 17 (740 mg, 1.18 mmol) was treated with benzylamine (ϭCϪH, CϪH), 1735 (CO2Me), 1715 (CϭO), 1640 (CϭC). Ϫ H
31%) as a colourless liquid. Ϫ IR (film): ν˜ ϭ 3085Ϫ2800 cmϪ1
1
(1.27 g, 11.8 mmol) in dichloromethane (25 mL). Workup and puri-
fication by column chromatography (silica gel, hexane/EtOAc, 1:4)
NMR (250 MHz, CDCl3): δ ϭ 7.40Ϫ7.22 (m, 10 H, Ph), 5.67 (mc,
2 H, 3-H, 4-H), 5.52 (mc, 2 H, 8-H, 9-H), 3.70 (s, 3 H, CO2Me),
afforded 18 (590 mg, 78%) as a light yellow liquid. Ϫ IR (film): 3.63Ϫ3.49 (m, 4 H, 2 CH2Ph), 3.20Ϫ2.41, 2.27Ϫ2.13 (2 m, 14 H,
Ϫ1
(NϪH), 3060Ϫ2860 (ϭCϪH, CϪH), 1735 1 H, CH2, CH). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 209.0 (s,
˜
ν ϭ 3325 cm
(CO2Me), 1640, 1590 (CϭC). Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ CϭO), 175.3, 51.9 (s, q, CO2Me), 139.4, 138.9, 128.9, 128.8, 128.7,
7.49 (t, J ϭ 7.7 Hz, 1 H, pyr-H), 7.39Ϫ7.21 (m, 5 H, Ph), 7.03 (d, 128.2 (2 s, 4 d, Ph), 131.6, 130.9 (2 d, C-3, C-4), 127.0, 126.9 (2 d,
J ϭ 7.7 Hz, 1 H, pyr-H), 6.93 (d, J ϭ 7.7 Hz, 1 H, pyr-H), 5.79 C-8, C-9), 60.2 (t, C-2), 58.7 (t, C-5), 55.5, 55.4, 55.4 (3 t, 2 CH2Ph,
(dd, J ϭ 16.7, 10.3 Hz, 1 H, 2-H), 5.30 (mc, 2 H, 7-H, 8-H), 5.24 C-7), 48.9 (t, C-15), 42.3, 41.1 (2 t, C-10, C-12), 39.2 (d, C-11), 34.0
(dd, J ϭ 16.7, 1.0 Hz, 1 H, 1-H), 5.08 (dd, J ϭ 10.3, 1.0 Hz, 1 H, (t, C-14). Ϫ MS (EI, 80 eV): m/z (%) ϭ 460 (14) [Mϩ], 429 [Mϩ Ϫ
1-H), 3.77 (s, 4 H, NCH2), 3.64, 3.63 (2 s, 9 H, 3 CO2Me), 3.36 (s,
2 H, 11-H), 2.81 (br. dd, J ϭ 17.2, 4.4 Hz, 1 H, 6-H), 2.48 (mc, 2 460.27259; found 460.27058. Ϫ C29H36N2O3 (460.6): calcd. C
31] (18), 369 [Mϩ Ϫ 91] (100). Ϫ HRMS: calcd. for C29H36N2O3:
H, 9-H), 2.16 (br. s, 1 H, NH), 2.15 (br. dd, J ϭ 17.2, 4.4 Hz, 1 H,
6-H), 1.80 (d, J ϭ 5.8 Hz, 1 H, 4-H), 0.97 (d, J ϭ 5.8 Hz, 1 H, 4-
H), 0.90 (s, 9 H, tBu), 0.10, 0.08 (2 s, 6 H, SiMe2). Ϫ 13C NMR
(62.9 MHz, CDCl3): δ ϭ 171.9, 171.4, 52.3, 51.9 (2 s, 2 q, CO2Me),
158.9, 156.4 (2 s, C-pyr), 140.0, 128.3, 128.3, 126.8 (s, 3 d, Ph),
136.7, 136.4 (2 d, C-pyr, C-2), 132.2 (d, C-7), 125.4 (d, C-8), 122.3,
120.0 (2 d, C-pyr), 115.2 (t, C-1), 65.1 (s, C-3), 57.5 (s, C-10), 54.3,
53.5 (2 t, NCH2), 39.3 (t, C-11), 37.5 (s, C-5), 35.3, 31.8 (2 t, C-6,
C-9), 25.8, 18.2 (q, s, tBu), 13.6 (t, C-4), Ϫ3.4, Ϫ3.6 (2 q, SiMe2).
Ϫ MS (EI, 80 eV): m/z (%) ϭ 650 (32) [Mϩ], 619 [Mϩ Ϫ 31] (26),
559 [Mϩ Ϫ 91] (21), 237 (100). Ϫ HRMS: calcd. for C36H50N2O7:
650.33873; found 650.33809.
75.62, H 7.87, N 6.08; found C 73.90, H 7.48, N 5.62.
Trimethyl (3E,8E)-1-Benzyl-13-oxo-1-azacyclopentadeca-3,8-diene-
6,6,11-tricarboxylate (22): Following general procedure C, amine 8
(1.25 g, 2.08 mmol) was cyclized in the presence of CsF (951 mg,
6.26 mmol) and TEBA (712 mg, 3.12 mmol) in dry DMF (750 mL)
for 25 h, followed by workup and column chromatography using
silica gel (EtOAc/hexane, 1:9) to yield 22 (191 mg, 19%) as a col-
Ϫ1
˜
ourless liquid. Ϫ IR (film): ν ϭ 3165Ϫ2610 cm (ϭCϪH, CϪH),
1
1705 (CO2Me), 1680 (CϭC). Ϫ H NMR (500 MHz, CDCl3): δ ϭ
7.28Ϫ7.24 (m, 2 H, Ph), 7.21Ϫ7.18 (m, 3 H, Ph), 5.59Ϫ5.54 (m, 1
H, 3-H), 5.42Ϫ5.36 (m, 1 H, 9-H), 5.29 (mc, 2 H, 8-H, 4-H), 3.66,
3.64 (2 s, 9 H, 3 CO2Me), 3.56, 3.45 (AB system, JAB ϭ 14.0 Hz,
2 H, CH2Ph), 2.95Ϫ2.78, 2.68Ϫ2.41, 2.19Ϫ2.13 (3 m, 6 H, 8 H, 1
H, CH2, CH). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 208.7 (s,
Methyl
(E)-1-Benzyl-4-oxo-1,2,3,4,5,6,7,10-octahydroazecine-6-
carboxylate (19): Following general procedure C, amine 3 (300 mg,
0.72 mmol) in DMF (50 mL) was treated with a warm suspension CϭO), 175.0, 171.4, 171.0, 52.5, 52.3, 51.8 (3 s, 3 q, CO2Me), 138.7,
of CsF (330 mg, 2.17 mmol) and TEBA (247 mg, 1.08 mmol) in 131.0, 128.6, 128.2 (s, 3 d, Ph), 132.0 (d, C-3), 126.9, 126.6, 125.5
DMF (250 mL) for 22 h. Workup and purification by silica gel col-
umn chromatography (EtOAc/hexane, 1:9) afforded 19 (50 mg,
24%) as a thick, colourless liquid, along with dimer 20 (4 mg, 4%,
colourless liquid, one diastereomer) as the second fraction. Ϫ IR
(3 d, C-9, C-4, C-8), 60.3 (s, C-6), 58.6, 55.8 (2 t, CH2Ph, C-2),
49.5 (t, C-15), 41.9, 41.5 (2 t, C-5, C-7), 39.3 (d, C-11), 35.2, 35.1
(2 t, C-12, C-10), 33.7 (t, C-14). Ϫ MS (EI, 80 eV): m/z (%) ϭ 485
(7) [Mϩ], 454 [Mϩ Ϫ 31] (18), 394 [Mϩ Ϫ 91] (59), 106 (100). Ϫ
(film): ν˜ ϭ 3085Ϫ2910 cmϪ1 (ϭC-H, CϪH), 1735 (CO2Me), 1705 HRMS: calcd. for C27H35NO7: 485.24135; found 485.24069.
(CϭO), 1640 (CϭC). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
Trimethyl (3E,8E,13E)-1,6-Dibenzyl-18-oxo-1,6-diazacycloeicosa-
7.32Ϫ7.23 (m, 5 H, Ph), 5.59 (mc, 1 H, 8-H), 5.25 (mc, 1 H, 9-H),
3,8,13-triene-11,11,16-tricarboxylate (23): Following general pro-
3.69 (s, 3 H, CO2Me), 3.65 (s, 2 H, CH2Ph), 3.45Ϫ3.34 (m, 2 H,
cedure C, diamine 10 (495 mg, 0.65 mmol) was cyclized in the pres-
10-H), 2.94Ϫ2.52 (m, 7 H, CH, CH2), 2.47Ϫ2.26, 2.06Ϫ1.94 (2 m,
ence of CsF (297 mg, 1.95 mmol) and TEBA (223 mg, 0.98 mmol)
in dry DMF (450 mL) for 25 h, followed by workup and column
1 H each, CH2). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ 208.8 (s,
CϭO), 174.6, 51.9 (s, q, CO2Me), 138.0, 128.8, 128.3, 127.1 (s, 3 d,
chromatography using silica gel (EtOAc/hexane, 3:7) to yield 23
Ph), 134.4, 130.2 (2 d, C-9, C-8), 62.2, 58.9 (2 t, CH2Ph, C-10),
˜
(258 mg, 62%) as a colourless liquid. Ϫ IR (film): ν ϭ 3060Ϫ2800
50.0, 45.3, 45.0 (3 t, C-2, C-5, C-3), 44.8 (d, C-6), 36.5 (t, C-7). Ϫ
MS (EI, 70 eV): m/z (%) ϭ 301 (14) [Mϩ], 210 [Mϩ Ϫ CH2Ph] (46),
91 (100). Ϫ C18H23NO3 (301.4): calcd. C 71.73, H 7.69, N 4.65;
found C 71.48, H 7.48, N 4.71.
cmϪ1 (ϭCϪH, CϪH), 1735 (CO2Me), 1640 (CϭC). Ϫ 1H NMR
(250 MHz, CDCl3): δ ϭ 7.32 (mc, 10 H, 2 Ph), 5.74 (mc, 2 H,
ϭCH), 5.68Ϫ5.19 (m, 4 H, ϭCH), 3.71, 3.68 (2 s, 9 H, 3 CO2Me),
3.57 (mc, 4 H, 2 CH2Ph), 3.20Ϫ2.78, 2.66Ϫ2.52, 2.49Ϫ2.22 (3 m,
10 H, 6 H, 3 H, CH2, CH). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ
Dimethyl (3E,13E)-1,11-Dibenzyl-8,18-dioxo-1,11-diazacycloeicosa-
3,13-diene-6,16-dicarboxylate (20): 1H NMR (300 MHz, CDCl3): 208.3 (s, CϭO), 174.7, 171.2, 171.1, 52.5, 51.9 (3 s, 2 q, CO2Me),
δ ϭ 7.35Ϫ7.24 (m, 10 H, Ph), 5.63 (mc, 2 H, 3-H, 13-H), 5.50 (mc,
139.2, 138.8 (2 s, Ph), 132.1, 130.8, 130.7, 128.9, 128.7, 128.2, 127.8,
2 H, 4-H, 14-H), 3.79, 3.41 (AB system, JAB ϭ 13.0 Hz, 2 H each, 127.6, 127.0, 126.9, 126.8 (11 d, Ph, ϭCH), 58.7, 58.7, 55.5, 54.9,
CH2Ph), 3.72 (s, 6 H, CO2Me), 3.36Ϫ3.26, 3.14Ϫ3.02, 2.86Ϫ2.44, 54.5 (5 t, 2 CH2Ph, 3 CH2), 57.0 (s, C-11), 48.8, 42.1, 41.0 (3 t, 3
4202
Eur. J. Org. Chem. 2001, 4195Ϫ4206

Functionalized Azamacrocycles and Large-Ring α-Amino Esters
CH2), 39.3 (d, C-16), 35.3, 35.0, 34.4 (3 t, 3 CH2). Ϫ MS (EI,
FULL PAPER
38.7 (3 t, C-14, C-12, C-10), 39.7 (d, C-13). Ϫ MS (EI, 80 eV): m/
z (%) ϭ 511 (4) [Mϩ], 480 [Mϩ Ϫ 31] (1), 420 [Mϩ Ϫ 91] (4), 91
80 eV): m/z (%) ϭ 644 (7) [Mϩ], 613 [Mϩ Ϫ 31] (13), 553 [Mϩ
Ϫ
91] (52), 91 (100). Ϫ HRMS: calcd. for C38H48N2O7: 644.34615;
(100).
Ϫ
HRMS: calcd. for C32H37N3O3: 511.28349; found
found 644.34375.
511.28333.
Methyl
3-Benzyl-6-oxo-3,14-diazabicyclo[8.3.1]tetradeca-
Trimethyl
(E)-3-Benzyl-6-oxo-3,19-diazabicyclo[13.3.1]nonadeca-
1(13),10(14),11-triene-8-carboxylate (25): According to general pro- 1(18),10,15(19),16-tetraene-8,13,13-tricarboxylate (28): According
cedure C, amine 15 (320 mg, 0.69 mmol) was cyclized in the pres-
to general procedure C, amine 18 (590 mg, 0.90 mmol) was cyclized
ence of CsF (315 mg, 2.07 mmol) and TEBA (236 mg, 1.03 mmol)
in the presence of CsF (413 mg, 2.72 mmol) and TEBA (309 mg,
in dry DMF (450 mL) for 22 h, followed by workup and column 1.36 mmol) in dry DMF (450 mL) for 22 h, followed by workup
chromatography using silica gel (EtOAc/hexane, 1:1) to yield 25 and column chromatography using silica gel (EtOAc/hexane, 3:7)
˜
˜
(79 mg, 33%) as a colourless liquid. Ϫ IR (film): ν ϭ 2955Ϫ2850 to yield 28 (236 mg, 49%) as a colourless liquid. Ϫ IR (film): ν ϭ
1
cmϪ1 (ϭCϪH, CϪH), 1730 (CO2Me), 1710 (CϭO). Ϫ H NMR 3060Ϫ2845 cmϪ1 (ϭCϪH, CϪH), 1740 (CO2Me), 1700 (CϭO),
(250 MHz, CDCl3): δ ϭ 7.47 (t, J ϭ 7.5 Hz, 1 H, pyr-H), 1640 (CϭC), 1590, 1580 (pyridine). Ϫ 1H NMR (250 MHz,
7.40Ϫ7.22 (m, 5 H, Ph), 7.02, 6.76 (2 d, J ϭ 7.5 Hz, each 1 H, pyr- CDCl3): δ ϭ 7.48 (t, J ϭ 7.7 Hz, 1 H, pyr-H), 7.24 (m, 5 H, Ph),
H), 3.83 (mc, 2 H, CH2Ph), 3.80 (s, 2 H, 2-H), 3.75 (s, 3 H, 6.94 (d, J ϭ 7.7 Hz, 1 H, pyr-H), 6.83 (d, J ϭ 7.7 Hz, 1 H, pyr-
CO2Me), 3.34 (dd, J ϭ 16.0, 3.7 Hz, 1 H, 9-H), 3.58Ϫ3.49,
H), 5.68Ϫ5.48 (m, 2 H, 10-H, 11-H), 3.72, 3.71, 3.70 (3 s, 9 H, 3
3.20Ϫ2.98, 2.55Ϫ2.35 (3 m, 1 H, 4 H, 2 H, CH2, CH), 2.77 (dd, CO2Me), 3.70, 3.66 (AB system, JAB ϭ 13.2 Hz, 2 H, CH2Ph), 3.57
J ϭ 16.0, 1.5 Hz, 1 H, 9-H). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ (s, 2 H, 2-H), 3.44 (br. s, 2 H, 14-H), 3.06Ϫ2.46 (m, 10 H, 4-H, 5-
207.3 (s, CϭO), 175.8, 52.0 (s, q, CO2Me), 157.9, 153.6 (2 s, C-1, H, 7-H, 9-H, 12-H), 2.32Ϫ2.21 (m, 1 H, 8-H). Ϫ 13C NMR
C-10), 139.3 (d, C-12), 136.8, 128.9, 128.2, 126.9 (s, 3 d, Ph), 121.5,
(62.9 MHz, CDCl3): δ ϭ 208.2 (s, CϭO), 175.0, 171.0, 170.9, 52.4,
120.5 (2 d, C-11, C-13), 59.5, 58.9 (2 t, C-2, CH2Ph), 50.4 (t, C-4), 51.7 (3 s, 2 q, CO2Me), 157.4, 156.5 (2 s, C-pyr), 138.7, 128.9, 128.1,
44.6, 42.5, 38.3 (3 t, C-9, C-7, C-5), 39.6 (d, C-8). Ϫ MS (EI, 127.0 (s, 3 d, Ph), 136.3, 131.6 (2 d, C-11, C-10), 126.6, 122.5, 121.9
80 eV): m/z (%) ϭ 352 (55) [Mϩ], 261 [Mϩ Ϫ 91] (31), 91 (100). Ϫ (3 d, C-pyr), 58.5, 58.0 (2 t, C-2, CH2Ph), 58.2 (s, C-13), 48.9, 42.3,
HRMS: calcd. for C21H24N2O3: 352.17869; found 352.17462.
41.0 (3 t, C-4, C-14, C-12), 39.2 (d, C-8), 39.1 (t, C-9), 34.3, 33.7
(2 t, C-5, C-7). Ϫ MS (EI, 80 eV): m/z (%) ϭ 536 (23) [Mϩ], 505
[Mϩ Ϫ 31] (10), 445 [Mϩ Ϫ 91] (7), 91 (100). Ϫ HRMS: calcd. for
C30H36N2O7Si: 536.25225; found 536.25177.
Methyl (E)-3,8-Dibenzyl-11-oxo-3,8-diazabicyclo[13.3.1]nonadeca-
1(18),5,15(19),16-tetraene-13-carboxylate (26): According to gen-
eral procedure C, diamine 13 (520 mg, 0.83 mmol) was cyclized in
the presence of CsF (379 mg, 2.49 mmol) and TEBA (283 mg,
Synthesis of Amino Ester 30: Ester 29 (1.42 g, 5.78 mmol) was ad-
1.24 mmol) in dry DMF (450 mL) for 22 h, followed by workup ded, at Ϫ78 °C under argon atmosphere, to LDA (5.78 mmol) in
and column chromatography using silica gel (EtOAc/hexane, 2:3)
THF (20 mL), and the reaction mixture was stirred for 1.5 h at this
to yield 26 (139 mg, 33%) as a colourless liquid. Ϫ IR (film): ν˜ ϭ
temperature. Cyclopropyl bromide 2 (1.50 g, 3.75 mmol) in THF
3085Ϫ2800 cmϪ1 (ϭCϪH, CϪH), 1735 (CO2Me), 1710 (CϭO), (20 mL) was slowly added to the reaction mixture over a period of
1
1640 (CϭC). Ϫ H NMR (250 MHz, CDCl3): δ ϭ 7.41Ϫ6.99 (m, 10 min and the mixture was allowed to stir at Ϫ78 °C for 3 h. It was
14 H, Ar), 5.75Ϫ5.54 (m, 2 H, 5-H, 6-H), 3.74Ϫ3.42 (m, 6 H, allowed to warm to room temperature and poured into saturated
CH2Ph, 2-H), 3.72 (s, 3 H, CO2Me), 3.25Ϫ2.75, 2.68Ϫ2.42 (2 m, 9 aqueous NH4Cl solution (200 mL). The aqueous phase was ex-
H, 4 H, CH2, CH). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 208.9
tracted with ethyl acetate (3 ϫ 20 mL) and the combined organic
(s, CϭO), 175.0, 51.8 (s, q, CO2Me), 140.3, 139.4, 138.8, 138.3 (4 extracts were washed with brine (3 ϫ 20 mL), dried (Na2SO4), and
s, Ar), 131.1, 129.3, 129.0, 128.9, 128.7, 128.4, 128.2, 128.1, 127.6, concentrated. Purification by flash chromatography using hexane/
126.9, 126.9, 126.2 (12 d, Ar, C-5, C-6), 59.5, 58.6, 57.7, 55.7, 53.9 EtOAc (1:1) afforded 30 (1.36 g, 88%) as a colourless liquid (1:1
(5 t, C-2, CH2Ph, C-4, C-7), 48.4, 41.8 (2 t, C-9, C-14), 41.3 (d, C-
13), 41.2, 32.2 (2 t, C-12, C-10). Ϫ MS (EI, 80 eV): m/z (%) ϭ 510
mixture of diastereomers). Ϫ IR (film): ν˜ ϭ 3380 cmϪ1 (NϪH),
3095Ϫ2860 (ϭCϪH, CϪH), 1730 (CO2Et, CO2Me), 1640 (CϭC).
1
(12) [Mϩ], 479 [Mϩ Ϫ 31] (8), 453 [Mϩ Ϫ 57] (11), 419 [Mϩ Ϫ 91] Ϫ H NMR (300 MHz, CDCl3): δ ϭ 5.70 (dd, J ϭ 17.0, 10.5 Hz,
(100).
510.28824.
Ϫ
HRMS: calcd. for C33H38N2O3: 510.28702; found
1 H, 2-H), 5.45, 5.29 (2 mc, 2 H, 7-H, 8-H), 5.14 (dd, J ϭ 17.0,
1.0 Hz, 1 H, 1-H), 4.98 (dd, J ϭ 10.5, 1.0 Hz, 1 H, 1-H), 4.05 (q,
J ϭ 7.2 Hz, 2 H, CO2CH2), 3.50 (s, 3 H, CO2Me), 3.36 (t, J ϭ
5.5 Hz, 1 H, 10-H), 2.75 (dd, J ϭ 15.0, 6.0 Hz, 1 H, 6-H),
2.34Ϫ2.19 (m, 2 H, 9-H), 2.09 (dd, J ϭ 15.0, 6.0 Hz, 1 H, 6-H),
1.70 (d, J ϭ 6.5 Hz, 1 H, 4-H), 1.50 (br. s, 2 H, NH2), 1.15 (t, J ϭ
7.2 Hz, 3 H, CO2CH2CH3), 0.89 (d, J ϭ 6.5 Hz, 1 H, 4-H), 0.79
(s, 9 H, tBu), 0.00, Ϫ0.02 (2 s, 6 H, SiMe2). Ϫ 13C NMR
(75.5 MHz, CDCl3): δ ϭ 175.1, 51.8 (s, q, CO2Me) 171.8, 60.7,
14.2 (s, t, q, CO2CH2CH3), 136.6, 131.7, 126.1 (3 d, C-2, C-7, C-
8), 115.1, 115.0 (2 t, C-1), 65.0, 64.9 (2 s, C-3), 54.0 (d, C-10), 37.9,
31.9, 31.8 (3 t, C-6, C-9), 37.4 (s, C-5), 18.1 (t, C-4), 25.7, 14.2 (q,
s, tBu), Ϫ3.5, Ϫ3.7 (2 q, SiMe2). Ϫ C21H37NO5Si (411.6): calcd. C
61.27, H 9.06, N 3.40; found C 60.93, H 9.38, N 3.41.
Methyl (E)-3,8-Dibenzyl-11-oxo-3,8,19-triazabicyclo[13.3.1]nona-
deca-1(18),5,15(19),16-tetraene-13-carboxylate (27): According to
general procedure C, diamine 16 (240 mg, 0.38 mmol) was cyclized
in the presence of CsF (175 mg, 1.15 mmol) and TEBA (130 mg,
0.57 mmol) in dry DMF (500 mL) for 22 h, followed by workup
and column chromatography using silica gel (EtOAc/hexane, 2:3)
˜
to yield 27 (104 mg, 54%) as a colourless liquid. Ϫ IR (film): ν ϭ
3085Ϫ2800 cmϪ1 (ϭCϪH, CϪH), 1735 (CO2Me), 1700 (CϭO),
1640 (CϭC). Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ 7.54 (t, J ϭ
7.7 Hz, 1 H, pyr-H), 7.42Ϫ7.17 (m, 11 H, Ph, pyr-H), 6.98 (d, J ϭ
7.7 Hz, 1 H, pyr-H), 5.73Ϫ5.62, 5.54Ϫ5.43 (2 m, 2 H, 5-H, 6-H),
3.75 (mc, 4 H, 2 CH2Ph), 3.67 (s, 3 H, CO2Me), 3.52 (s, 2 H, 2-H),
3.48Ϫ2.84 (m, 9 H, CH, CH2), 2.74 (mc, 2 H, 12-H), 2.58 (mc, 2 Synthesis of N-Benzylated Amino Ester 31: Freshly distilled benzal-
H, 10-H). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 208.8 (s, CϭO), dehyde (335 mg, 3.16 mmol) was added to the amino ester 30
174.9, 51.8 (s, q, CO2Me), 159.1, 157.8 (2 s, C-pyr), 139.3, 138.9 (2
(1.30 g, 3.16 mmol) in dry methanol (20 mL), followed by MgSO4
s, Ph), 136.6, 131.9 (2 d, C-5, C-6), 128.9, 128.7, 128.2, 128.1, 126.9, (0.5 g). The reaction mixture was stirred for 1 h (monitored by
126.9 (6 d, Ph), 128.6, 121.6, 120.7 (3 d, C-pyr), 59.5 (t, C-2), 58.6, TLC). After complete consumption of 30, the reaction mixture was
58.1 (2 t, CH2Ph), 55.8, 54.2, 48.5 (3 t, C-4, C-7, C-9), 42.6, 40.9, filtered and the filtrate was cooled to 0 °C. NaBH4 (120 mg,
Eur. J. Org. Chem. 2001, 4195Ϫ4206
4203

P. K. Patra, H.-U. Reißig
FULL PAPER
1
3.16 mmol) was added gradually over a period of 30Ϫ45 min. After
stirring at room temperature for 2Ϫ3 h, the reaction mixture was
poured into water and extracted with dichloromethane (3 ϫ
1640 (CϭC). Ϫ H NMR (250 MHz, CDCl3): δ ϭ 5.69 (dd, J ϭ
16.7, 11.0 Hz, 1 H, 2-H), 5.48Ϫ5.09 (m, 4 H, 7-H, 8-H, 12-H, 13-
H), 5.10 (dd, J ϭ 16.7, 1.5 Hz, 1 H, 1-H), 4.95 (dd, J ϭ 11.0,
20 mL), washed with brine, dried (MgSO4), and concentrated. The 1.5 Hz, 1 H, 1-H), 4.07Ϫ3.92 (m, 2 H, CO2CH2), 3.55, 3.54, 3.48
residue, after purification by flash chromatography using hexane/
EtOAc (3:7), afforded 31 (1.17 g, 74%, 3:2 mixture of diastereo-
(3 s, 9 H, 3 CO2Me), 3.32 (t, J ϭ 6.6 Hz, 1 H, 15-H), 2.69 (dd, J ϭ
15.0, 6.6 Hz, 1 H, 6-H), 2.40 (br. d, J ϭ 6.5 Hz, 4 H, 9-H, 11-H),
mers) as a colourless liquid. Ϫ IR (film): ν˜ ϭ 3340 cmϪ1 (NϪH), 2.33Ϫ2.15 (m, 2 H, 14-H), 2.02 (dd, J ϭ 15.0, 6.6 Hz, 1 H, 6-H),
3085Ϫ2860 (ϭCϪH, CϪH), 1730 (CO2Me, CO2Et), 1640 (CϭC). 1.67 (d, J ϭ 5.8 Hz, 1 H, 4-H), 1.51 (br. s, 2 H, NH2), 1.57Ϫ1.07
Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ 7.31Ϫ7.13 (m, 5 H, Ph), 5.75 (m, 3 H, CO2CH2CH3), 0.86 (d, J ϭ 5.8 Hz, 1 H, 4-H), 0.78 (s, 9
(dd, J ϭ 17.2, 10.3 Hz, 1 H, 2-H), 5.59Ϫ5.31 (m, 2 H, 7-H, 8-H),
H, tBu), Ϫ0.02, Ϫ0.04 (2 s, 6 H, SiMe2). Ϫ 13C NMR (62.9 MHz,
5.22 (dd, J ϭ 17.2, 1.0 Hz, 1 H, 1-H), 5.07 (dd, J ϭ 10.3, 1.0 Hz, CDCl3): δ ϭ 174.8, 171.5, 170.8, 60.4, 52.0, 51.6, 53.7, 14.0 (3 s, t,
1 H, 1-H), 4.13 (q, J ϭ 7.2 Hz, 2 H, CO2CH2), 3.78, 3.62 (AB 4 q, CO2Me, CO2Et), 136.5, 132.2, 129.3, 127.9, 124.7 (5 d, C-2,
system, JAB ϭ 12.9 Hz, 2 H, CH2Ph), 3.52 (s, 3 H, CO2Me), 3.27
(br. t, J ϭ 6.5 Hz, 1 H, 10-H), 2.83 (dd, J ϭ 15.5, 6.0 Hz, 1 H, 6-
C-7, C-8, C-12, C-13), 114.9 (t, C-1), 64.8 (s, C-3), 60.6 (d, C-15),
57.7 (s, C-10), 37.7 (s, C-5), 37.1, 35.3, 35.2 (3 t, C-6, C-9, C-11),
H), 2.35 (mc, 2 H, 9-H), 2.15 (dd, J ϭ 15.5, 6.0 Hz, 1 H, 6-H), 1.84 31.5 (t, C-14), 25.6, 17.9 (q, s, tBu), 23.4 (t, C-4), Ϫ3.7, Ϫ3.9 (2 q,
(br. s, 1 H, NH), 1.77 (d, J ϭ 6.0 Hz, 1 H, 4-H), 1.23 (t, J ϭ 7.2 Hz, SiMe2). Ϫ MS (EI, 80 eV): m/z (%) ϭ 595 (13) [Mϩ], 564 [Mϩ
Ϫ
3 H, CO2CH2CH3), 0.96 (d, J ϭ 6.0 Hz, 1 H, 4-H), 0.90 (s, 9 H, 91] (19), 522 [Mϩ Ϫ 73] (100). Ϫ C30H49NO9Si (595.8): calcd. C
tBu), 0.10, 0.06 (2 s, 6 H, SiMe2). Ϫ 13C NMR (75.5 MHz, CDCl3): 66.43, H 7.74, N 4.30; found C 65.54, H 7.36, N 4.23.
δ ϭ 174.3, 171.8, 60.4, 51.9, 51.7, 14.3 (2 s, t, 3 q, CO2Me, CO2Et),
Synthesis of N-Benzylated Amino Ester 34: Freshly distilled benzal-
dehyde (0.10 g, 0.92 mmol) was added to the amino ester 33 (0.55 g,
0.92 mmol) in dry methanol (15 mL), followed by MgSO4 (0.25 g).
The reaction mixture was stirred for 1 h (monitored by TLC). After
complete consumption of 33, the reaction mixture was filtered and
the filtrate was cooled to 0 °C. NaBH4 (40 mg, 1.00 mmol) was
added gradually over a period of 30Ϫ45 min. After stirring at room
temperature for 2Ϫ3 h, the reaction mixture was poured into water
and extracted with dichloromethane (3 ϫ 20 mL), washed with
brine, dried (MgSO4), and concentrated. The residue, after puri-
139.8, 128.2, 128.1, 126.9 (s, 3 d, Ph), 136.7, 130.8, 126.4 (3 d, C-
2, C-7, C-8), 115.1 (t, C-1), 65.0 (s, C-3), 60.5 (d, C-10), 51.8 (t,
CH2Ph), 37.4 (s, C-5), 36.5, 31.7 (2 t, C-6, C-9), 25.8, 18.1 (q, s,
tBu), 23.5 (t, C-4), Ϫ3.5, Ϫ3.7 (2 q, SiMe2). Ϫ MS (EI, 80 eV):
m/z (%) ϭ 501 (3) [Mϩ], 428 [Mϩ Ϫ 73] (4), 91 (100). Ϫ HRMS:
calcd. for C28H43NO5Si: 501.29105; found 501.29003.
2-Ethyl 7-Methyl (E)-1-Benzyl-9-oxo-1-azacycloundec-4-ene-2,7-di-
carboxylate (32): According to general procedure C, amine 31
(220 mg, 0.44 mmol) was cyclized in the presence of CsF (200 mg,
1.31 mmol) and TEBA (150 mg, 0.66 mmol) in dry DMF (250 mL) fication by flash column chromatography using hexane and EtOAc
for 30 h, followed by workup and column chromatography using (1:1), afforded 34 (0.51 g, 81%, 3:2 mixture of diastereomers) as a
silica gel (EtOAc/hexane, 1:3) to yield 32 (71 mg, 42%) as a colour-
colourless liquid. Ϫ IR (film): ν˜ ϭ 3365 cmϪ1 (NϪH), 3030Ϫ2860
less liquid (1:1 mixture of isomers). Ϫ IR (film): ν ϭ 3065Ϫ2850 (ϭCϪH, CϪH), 1740 (CO2Me), 1640 (CϭC). Ϫ 1H NMR
˜
cmϪ1 (ϭCϪH, CϪH), 1730 (CO2Me, CO2Et), 1725 (CϭO), 1640
(250 MHz, CDCl3): δ ϭ 7.37Ϫ7.23 (m, 5 H, Ph), 5.80 (dd, J ϭ
1
(CϭC). Ϫ H NMR (250 MHz, CDCl3): δ ϭ 7.41Ϫ7.22 (m, 5 H, 17.3, 10.6 Hz, 1 H, 2-H), 5.59Ϫ5.25 (m, 4 H, 7-H, 8-H, 12-H, 13-
Ph), 5.51Ϫ5.45, 5.38Ϫ5.29 (2 m, 1 H each, ϭCH), 5.02 (mc, 1 H,
ϭCH), 4.27Ϫ4.20 (m, 2 H, CO2CH2), 3.95, 3.89 (AB system, JAB ϭ
H), 5.25 (dd, J ϭ 17.3, 1.4 Hz, 1 H, 1-H), 5.09 (dd, J ϭ 10.6,
1.4 Hz, 1 H, 1-H), 4.17 (q, J ϭ 7.1 Hz, 2 H, CO2CH2), 3.87, 3.65
14.0 Hz, 1 H, CH2Ph), 3.75, 3.74 (2 s, 3 H, CO2Me), 3.59, 3.52 (AB system, JAB ϭ 13.2 Hz, 2 H, CH2Ph), 3.67, 3.62 (2 s, 9 H,
(AB system, JAB ϭ 13.2 Hz, 1 H, CH2Ph), 3.42Ϫ2.57 (m, 7.5 H, CO2Me), 3.28 (t, J ϭ 6.6 Hz, 1 H, 15-H), 2.84 (dd, J ϭ 15.4,
CH2), 2.36Ϫ1.57 (m, 4.5 H, CH, CH2), 1.30, 1.28 (2 t, J ϭ 7.7 Hz
6.6 Hz, 1 H, 6-H), 2.54 (br. d, J ϭ 6.5 Hz, 4 H, 9-H, 11-H), 2.36
each, 3 H, CH3). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 210.0, (mc, 2 H, 14-H), 2.16 (dd, J ϭ 15.4, 6.6 Hz, 1 H, 6-H), 1.82 (br. s,
208.1 (2 s, CϭO), 175.6, 172.8, 172.5, 60.3, 60.2, 51.9, 14.5, 14.4 (3 1 H, NH), 1.80 (d, J ϭ 6.6 Hz, 1 H, 4-H), 1.27 (t, J ϭ 7.1 Hz, 3
s, 2 t, 3 q, CO2Me, CO2Et), 139.5, 138.6 (2 s, Ph), 130.6, 130.3, H, CO2CH2CH3), 0.99 (d, J ϭ 6.6 Hz, 1 H, 4-H), 0.91 (s, 9 H,
130.0, 129.5, 129.3, 128.6, 128.5, 127.6, 127.2, 126.9 (10 d, Ph, tBu), 0.11, 0.08 (2 s, 6 H, SiMe2). Ϫ 13C NMR (62.9 MHz, CDCl3):
ϭCH), 64.5 (d, C-2), 56.8, 55.7 (2 t, CH2Ph, C-11), 47.2, 46.3, 44.3, δ ϭ 174.4, 171.8, 171.1, 60.6, 52.2, 51.9, 14.3 (3 s, t, 3 q, CO2Et,
43.2, 41.9 (5 t, CH2), 38.3, 38.1 (2 d, C-7), 36.1, 32.9, 32.4 (3 t,
CO2Me), 139.8, 128.3, 128.2, 127.4 (s, 3 d, Ph), 136.7 (d, C-2),
CH2). Ϫ MS (EI 80 eV): m/z (%) ϭ 387 (2) [Mϩ], 356 [Mϩ Ϫ 31] 132.2, 129.9, 127.0, 125.1 (4 d, C-7, C-8, C-12, C-13), 115.2 (t, C-
(2), 314 [Mϩ Ϫ 73] (30), 91 (100). Ϫ HRMS: calcd. for C22H29NO5: 1), 65.1 (s, C-3), 60.4 (d, C-15), 58.0 (s, C-10), 51.8 (t, CH2Ph), 37.4
387.204573; found 387.20843.
(s, C-5), 36.5, 35.6, 35.5 (3 t, C-14, C-9, C-11), 31.8 (t, C-6), 25.8,
18.2 (q, s, tBu), 23.6 (t, C-4), Ϫ3.5, Ϫ3.6 (2 q, SiMe2). Ϫ MS (EI,
80 eV): m/z (%) ϭ 686 (1) [Mϩ ϩ 1], 685 (3) [Mϩ], 654 [Mϩ
Ϫ
Synthesis of Amino Ester 33: Ester 29 (1.89 g, 3.23 mmol) was ad-
ded, at Ϫ78 °C under argon atmosphere, to LDA (4.83 mmol) in
THF (20 mL), and the reaction mixture was stirred for 1.5 h at the
same temperature. The cyclopropyl bromide 7 (927 mg, 1.61 mmol)
in THF (20 mL) was slowly added to the reaction mixture over a
period of 10 min and the mixture was allowed to stir at Ϫ78 °C
for 3 h. It was allowed to warm to room temperature and poured
31] (1), 612 [Mϩ Ϫ 73] (100). Ϫ HRMS: calcd. for C37H55NO9Si:
685.36461; found 685.36408. Ϫ C30H49NO9Si (685.9): calcd. C
64.79, H 8.08, N 2.04; found C 64.26, H 7.54, N 1.84.
2-Ethyl 7,7,12-Trimethyl (4E,9E)-1-benzyl-14-oxo-1-azacyclohexa-
deca-4,9-diene-2,7,7,12-tetracarboxylate (35): According to general
into saturated aqueous NH4Cl solution (200 mL). The aqueous procedure C, amine 34 (325 mg, 0.47 mmol) was cyclized in the
phase was extracted with ethyl acetate (3 ϫ 20 mL) and the com-
bined organic extracts were washed with brine (3 ϫ 20 mL), dried
presence of CsF (215 mg, 2.49 mmol) and TEBA (161 mg,
1.24 mmol) in dry DMF (500 mL) for 28 h, followed by workup
(Na2SO4), and concentrated. Purification by flash chromatography and column chromatography using silica gel (EtOAc/hexane, 1:3)
using hexane/EtOAc (1:1) afforded 33 (608 mg, 63%) as a colour-
less liquid (1:1 mixture of diastereomers). Ϫ IR (film): ν˜ ϭ 3380
cmϪ1 (NϪH), 2955Ϫ2860 (ϭCϪH, CϪH), 1740 (CO2Me, CO2Et),
to yield 35 (63 mg, 24%) as a colourless liquid (1:1 mixture of iso-
mers). Ϫ IR (film): ν˜ ϭ 3085Ϫ2850 cmϪ1 (ϭCϪH, CϪH), 1735
(CO2Me, CO2Et), 1730 (CϭO), 1640 (CϭC).
Ϫ
1H NMR
4204
Eur. J. Org. Chem. 2001, 4195Ϫ4206

Functionalized Azamacrocycles and Large-Ring α-Amino Esters
FULL PAPER
(250 MHz, CDCl3): δ ϭ 7.30Ϫ7.18 (m, 5 H, Ph), 5.59Ϫ5.35 (m, 2 3.28Ϫ3.05, 2.82Ϫ2.56, 2.20Ϫ1.71 (4 m, 6 H, 4 H, 4 H, 6 H CH2,
H, 4-H, 5-H), 5.27Ϫ5.05 (m, 2 H, 9-H, 10-H), 4.25Ϫ4.06 (m, 2 H, CH). Ϫ MS (EI, 80 eV): m/z (%) ϭ 493 (1) [Mϩ], 402 [Mϩ
OCH2), 3.97, 3.85 (AB system, JAB ϭ 13.2 Hz, 1 H, CH2Ph), 3.45,
CH2Ph] (1), 355 [Mϩ Ϫ C7H10N2O] (1), 91 (100). Ϫ HRMS: calcd.
Ϫ
3.37 (AB system, JAB ϭ 13.9 Hz, 1 H, CH2Ph), 3.72, 3.71, 3.70, for C31H35N5O: 493.28416; found 493.28420.
3.68, 3.67, 3.66 (6 s, 9 H, 3 CO2Me), 3.35Ϫ2.05 (m, 16 H, CH,
CH2), 1.31Ϫ1.23 (m, 3 H, CH3). Ϫ 13C NMR (62.9 MHz, CDCl3):
δ ϭ 208.1, 207.6 (2 s, CϭO), 175.1, 172.4, 172.0, 171.8, 171.5,
171.0, 60.2, 52.6, 52.6, 51.9, 14.5 (6 s, t, 4 q, CO2Me, CO2Et), 139.1,
138.9 (2 s, Ph), 132.0, 131.8, 131.3, 131.1 (4 d, C-4, C-10), 129.3,
Acknowledgments
Generous support by the Alexander von Humboldt Stiftung (re-
search fellowship for P. K. P.) and the Fonds der Chemischen Indu-
strie is most gratefully acknowledged. We thank Dr. M. Gruner
(Technische Universität Dresden) for numerous NMR measure-
ments and her assistance during their interpretation, and Dr. R.
Zimmer for his help during preparation of this manuscript.
128.9, 128.3, 128.2, 127.2, 126.7, 126.3, 124.6 (8 d, Ph, C-5, C-10),
62.7, 62.2 (2 d, C-2), 56.2, 55.9 (2 s, C-7), 55.7, 54.5 (2 t, CH2),
46.6, 45.5, 42.8, 42.7, 41.3 (5 t, CH2), 39.9, 38.7 (2 d, C-12), 35.0,
34.9, 34.8, 34.5, 33.7, 32.6, 32.0 (7 t, CH2). Ϫ MS (EI, 80 eV):
m/z (%) ϭ 571 (1) [Mϩ], 540 [Mϩ Ϫ 31] (11), 498 [Mϩ Ϫ 73] (100).
Ϫ HRMS: calcd. for C31H41NO9: 571.27813; found 571.27863.
Methyl 1-Benzyl-4-oxoazecane-6-carboxylate (36): PdϪC (100 mg,
10% Pd) was added to 19 (95 mg, 0.31 mmol) in MeOH (10 mL).
The reaction mixture was stirred under a hydrogen atmosphere for
48 h and then filtered through a pad of Celite. The filtrate was
concentrated under reduced pressure and the residue was purified
by flash chromatography using silica gel (hexane/EtOAc, 4:1) to
afford 36 (44 mg) in 47% yield. Ϫ IR (film): ν˜ ϭ 3065Ϫ2855 cmϪ1
(CϪH, ϭCϪH), 1735 (CO2Me), 1700 (CϭO). Ϫ 1H NMR
(250 MHz, CDCl3): δ ϭ 7.42Ϫ7.23 (m, 5 H, Ph), 3.88Ϫ3.65 (m, 2
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3 H, CO2Me), 3.53Ϫ3.11, 2.82Ϫ2.69,
1123Ϫ1126.
2.48Ϫ1.91, 1.58Ϫ1.00 (4 m, 2 H, 2 H, 5 H, 6 H, CH2, CH). Ϫ 13C
NMR (75.5 MHz, CDCl3): δ ϭ 214.8 (s, CϭO), 174.4, 51.4 (s, q,
CO2Me), 139.8, 128.5, 128.0, 127.0 (s, 3 d, Ph), 56.0 (t, CH2Ph),
54.3, 52.2, 46.3, 46.2 (4 t, CH2), 40.4 (d, C-6), 35.3, 33.5, 29.8 (3 t,
CH2). Ϫ MS (EI, 80 eV): m/z (%) ϭ 303 (3) [Mϩ], 212 [Mϩ Ϫ 91]
(1), 91 (100). Ϫ HRMS: calcd. for C18H25NO3: 303.18343; found
303.18293.
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1(17),6,11-triene-9,9-dicarboxylate (37): Compound 22 (101 mg,
0.21 mmol) was added to a solution of 80% hydrazine hydrate
(14 mg, 0.28 mmol) in MeOH (5 mL). The reaction mixture was
stirred for 16 h at room temperature before removal of the solvent
under vacuum. Column chromatography using silica gel (hexane/
EtOAc, 7:3) afforded 37 (49 mg, 50%) as a viscous oil. Ϫ IR (film):
ν˜ ϭ 3240 cmϪ1 (NϪH), 3030Ϫ2850 (CϪH, ϭCH), 1730 (CO2Me),
1680 (CϭN, CϭO). Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ
7.38Ϫ7.20 (m, 5 H, Ph), 5.59Ϫ5.41 (m, 4 H, ϭCH), 3.71, 3.70 (2
s, 3 H each, 2 CO2Me), 3.72Ϫ3.57 (m, 2 H, CH2Ph), 2.99Ϫ2.20
(m, 11 H, CH2, NH), 2.18Ϫ1.71 (m, 5 H, CH2, CH). Ϫ 13C NMR
(75.5 MHz, CDCl3): δ ϭ 171.6, 171.5, 52.6, 52.5 (2 s, 2 q, CO2Me),
169.5 (s, CONH), 153.6 (s, CϭN), 140.8 (s, Ph), 130.6, 128.8, 128.7,
128.3, 127.8, 127.1, 126.9 (7 d, Ph, ϭCH), 58.5 (s, C-9), 57.6, 57.1,
56.5, 56.2, 51.1, 36.5, 36.1, 25.5 (8 t, CH2), 35.9 (d, C-14). Ϫ MS
(EI, 80 eV): m/z (%) ϭ 467 (6) [Mϩ], 436 [Mϩ Ϫ 31] (4), 376 [Mϩ
Ϫ 91] (34), 91 (100). Ϫ HRMS: calcd. for C26H33N3O5: 467.24202;
found 467.24533.
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R. Krämer, Angew. Chem. 2000, 112, 4641Ϫ4642; Angew.
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1165Ϫ1168.
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10,15-Dibenzyl-5,6,10,15,21-pentaazatricyclo[15.3.1.13,7]docosa-
1(21),6,12,17,19-pentaen-4-one (38): Compound 27 (69 mg,
0.13 mmol) was added to a solution of 80% hydrazine hydrate
(10 mg, 0.20 mmol) in MeOH (5 mL). The reaction mixture was
stirred for 16 h at room temperature before removal of the solvent
under vacuum. Column chromatography using silica gel (hexane/
EtOAc, 7:3) afforded 38 (29 mg, 46%) as a colourless solid (m.p.
[25]
[26]
[27]
[28]
˜
161Ϫ163 °C, recrystallized from MeOH). Ϫ IR (KBr): ν ϭ 3410
[29]
cmϪ1 (NϪH), 2930Ϫ2850 (CϪH, ϭCH), 1675 (CϭO, CϭN). Ϫ
1H NMR (250 MHz, CDCl3): δ ϭ 7.71Ϫ7.08 (m, 13 H, Ar),
6.33Ϫ6.15 (m, 1 H, ϭCH), 5.96 (mc, 1 H, ϭCH), 4.10Ϫ3.59,
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Eur. J. Org. Chem. 2001, 4195Ϫ4206
4205

P. K. Patra, H.-U. Reißig
FULL PAPER
[31]
[39]
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[41]
P. K. Patra, H.-U. Reißig, Synlett 2001, 33Ϫ36.
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Synthesis 1984, 786Ϫ787.
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1992, Part 2, Vol. 29, pp. 141.
[32]
I. Reichelt, H.-U. Reißig, Liebigs Ann. Chem. 1984, 531Ϫ551.
[33]
Compounds 4 and 9 are formed as 1:1 mixtures of diastereo-
mers that cannot be distinguished by spectroscopic methods,
due to the large distance between the corresponding ste-
reogenic centres.
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In ref. 30 we have discussed the possibility of a favourable ces-
[37]
[44]
ium effect, but we have found no clear evidence that this cation
is responsible for high-yield cyclizations.
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[38]
Received May 10, 2001
[O01235]
4206
Eur. J. Org. Chem. 2001, 4195Ϫ4206