Synthesis of two conformationally restricted piperazine scaffolds for combinatorial chemistry

Article abstract of DOI:10.1002/ejoc.200400358

Piperazines are widely used as central elements in the construction of bioactive molecules. Herein, the short synthesis of two chiral 2,6-bridged piperazines possessing orthogonally stable protecting groups from readily available starting materials is described. It is suggested that these molecules may be used as conformationally restricted scaffolds for the combinatorial synthesis of drug-like compounds. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400358

FULL PAPER
Synthesis of two Conformationally Restricted Piperazine Scaffolds for
Combinatorial Chemistry
Till Opatz[a]
Dedicated to Professor Johann Mulzer on the occasion of his 60th birthday
Keywords: Combinatorial chemistry / Nitrogen heterocycles / Piperazines / Protecting groups / Scaffolds
Piperazines are widely used as central elements in the con-
struction of bioactive molecules. Herein, the short synthesis
of two chiral 2,6-bridged piperazines possessing orthogon-
ally stable protecting groups from readily available starting
materials is described. It is suggested that these molecules
may be used as conformationally restricted scaffolds for the
combinatorial synthesis of drug-like compounds.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
The piperazine ring is a common pharmacophore found
in a large number of drugs for the treatment of disorders
of the central nervous system associated with imbalances in
dopaminergic, cholinergic or serotonergic signal trans-
mission. Among these CNS active agents are antipsychotics
such as trifluoperazine (1), antidepressants such as clozapin
(2) and anticonvulsants such as ropizine (3) (Figure 1).
The piperazine moiety is also contained in antihyperten-
sive agents such as prazosine, calcium channel blockers
such as flunarizine (4), H1-blockers such as oxatomide, and
the anti-ulcer agent esaprazole (5).[1] Because of its preva-
lence in the field of pharmacologically active compounds,
it is regarded as a privileged structural element for the con-
struction of drug-like molecules.[2Ϫ5] Whereas the synthesis
of simple 1,4-disubstituted piperazines has received con-
siderable attention, only a comparatively small number of
C-substituted derivatives have been prepared and evaluated
for their pharmacological properties. Nevertheless, the syn-
thesis of conformationally restricted bicyclic piperazines
could be an interesting approach to gain insight into the
influence of ring conformation on biological activity.[6]
The preparation of hexahydro-1,5-imino-3-benzazocines
from dipeptide aldehyde acetals by N-acyliminium ion
chemistry has been reported by Kurihara and Mishima and
has recently been taken up by Hiemstra et al., but there
have not yet been any reports on the construction of diam-
ine scaffolds for combinatorial chemistry based on this ef-
Figure 1. Some drugs containing the piperazine ring
ficient method.[7Ϫ10] Therefore, the preparation of the selec-
tively deprotectable chiral non-racemic piperazines 6 and
7 from FmocϪ-phenylalanine and FmocϪ-tyrosine tert-
butyl ether was undertaken (Figure 2).
Apart from its general use as a rigid scaffold for the con-
struction of potentially bioactive products, a more specific
application for the silyloxy-iminobenzazocine 7 could be
the synthesis of opioid mimetics. Various cyclic 2-phenyl-
alkylamines possessing a phenolic hydroxy group in meta-
[a]
Institut für Organische Chemie, Johannes Gutenberg-
Universität Mainz,
Duesbergweg 10Ϫ14, 55128 Mainz, Germany
Fax: (internat.) ϩ 49-6131-39-24786
E-mail: opatz@uni-mainz.de
Eur. J. Org. Chem. 2004, 4113Ϫ4118
DOI: 10.1002/ejoc.200400358
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4113

T. Opatz
FULL PAPER
ure 3), exhibit analgesic activity through a morphine-like
mechanism.[1,16]
Since scaffold 7 shares this structural feature with the
drugs described, its derivatives might possess an affinity to
opioid receptors.
Figure 2. Selectively deprotectable iminobenzazocine scaffolds
Results and Discussion
Amide 12 was prepared from FmocϪ-phenylalanine by
condensation with commercially available N-(methylami-
or para-position, such as the partial µ-opioid agonists no)acetaldehyde dimethyl acetal, using isobutyl chloro-
dezocine (8, Dalgan),[11,12] metazocine (9),[13] profadol formate as the coupling reagent and N-methylmorpholine
(10)[14] and meptazinol (11, Meptid, Nestan;[15] Fig- as an activating base.[17] A low reaction temperature was
Scheme 1. Preparation of the iminobenzazocine scaffolds
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Eur. J. Org. Chem. 2004, 4113Ϫ4118

Synthesis of two Conformationally Restricted Piperazine Scaffolds for Combinatorial Chemistry
FULL PAPER
argon from suitable drying agents (CH2Cl2 from calcium hydride,
THF from Na/benzophenone). Analytical TLC was performed on
aluminium-backed TLC plates coated with silica 60 F254 (E.
Merck). Compounds were viewed under UV light (254 nm) and/or
by dipping the plates into an alkaline KMnO4 solution and heat-
ing. Column chromatography was performed on silica gel (40Ϫ63
µm, E. Merck). Optical rotations were measured with
a
PerkinϪElmer 241 polarimeter. NMR spectra were recorded with
Bruker AC 300, AMX 400 or DRX 600 spectrometers; chemical
Figure 3. Opioid receptor ligands
shifts were referenced to the residual solvent peak (CHCl3, δH
ϭ
7.24 ppm, δC,central ϭ 77.0 ppm). ESI-MS spectra were measured
with a Navigator instrument (ThermoQuest) at a cone voltage of
70 V with a flow rate of 0.75 mL/min acetonitrile/water (70:30 v/v)
and a nitrogen flow of 300 L/h. A Basic-Marathon autosampler
was employed for sample injection (20 µL at 0.1 g/L in acetonitrile).
ESI-HMRS analyses were performed with a Micromass Q-TOF
Ultima-III with a Lockspray interface and sodium formate as an
external reference, FD-MS spectra were recorded with a Finnigan
MAT 95 (desorption voltage 5 kV, heater current 10 mA/min). IR
spectra were measured with a PerkinϪElmer 1760X FTIR spec-
trometer.
kept to suppress racemization in this step.[18] TFA-catalysed
cyclization of amide 12 to iminobenzazocinone 16 pro-
ceeded through intermediate formation of 3-benzyl-3,4-di-
hydro-2-pyrazinone 13, yielding the bicyclic product 16
upon heating at reflux in neat TFA (97% from FmocϪ-
Phe).[7,8,19,20] This reaction proceeds via the cyclic acylimin-
ium ion 14, the result of protonation at C6. Although pro-
tonation at C5 to afford the isomeric acyliminium ion 15 is
possible, no cyclization occurs in this case.
The tertiary amide moiety of 16 can be reduced in a fast
and clean reaction with boraneϪTHF without affecting the
carbamate group.[21] Surprisingly, the hydrolytic destruction
of the borane complex of the resulting tertiary amine took
much longer than the reduction itself, which was complete
after less than one hour. The obtained N-methylamine 17
was then subjected to N-demethylation with allyl chloro-
formate and Hünig’s base in benzene at reflux to furnish
the doubly protected scaffold 6 in 85% yield.[22,23] The pro-
ton and carbon NMR spectra of 6 revealed the presence of
four conformers, due to slow rotation about both COϪN
bonds.[24] The triply protected phenol 7, the hydroxy deriva-
tive of scaffold 6, was prepared from FmocϪ-tyrosine tert-
butyl ether in an analogous sequence, the tert-butyl group
being cleaved under the conditions used for the cyclization
of dimethyl acetal 18 to iminobenzazocinone 19. Although
no trapping reagent for the generated tert-butyl cations
could be added, realkylation at the ortho position of the
phenol ring occurred only to a small extent as judged by
TLC. After borane reduction of the amide moiety and acid
hydrolysis of the resulting borane complex, the hydroxy
group of the resulting N-methylamine 20 was protected as
the TBDPS ether. Finally, N-demethylation with allyl
chloroformate furnished the triply protected scaffold 7.
[(9H-Fluoren-9-yl)methyl] (1R,9S)-11-Methyl-10-oxo-11,13-diaza-
tricyclo[7.3.1.02,7]trideca-2,4,6-triene-13-carboxylate (16): N-Meth-
ylmorpholine (3.41 mL, 31.0 mmol) was added to a stirred suspen-
sion of FmocϪ-phenylalanine (10 g, 25.8 mmol) in dry CH2Cl2
(50 mL) and the resulting clear solution was cooled to Ϫ20 °C in an
ice/NaCl bath. Isobutyl chloroformate (3.68 mL, 28.4 mmol) was
added, and the mixture was stirred at Ϫ20 °C for 5 min. N-(Methyl-
amino)acetaldehyde dimethyl acetal (4.97 mL, 38.7 mmol) was ad-
ded to the turbid mixture, and the reaction mixture was warmed
up to 0 °C. After stirring for 3 h at that temperature, the mixture
was poured into a saturated aqueous solution of NaHCO3
(200 mL) and the product was extracted twice with CH2Cl2
(50 mL). The combined organic layers were dried over Na2SO4 and
the solvent was evaporated in vacuo. The resulting viscous yellow-
ish oil was passed over a column of silica with ethyl acetate contain-
ing 1% ethyldimethylamine. Evaporation of the eluent in vacuo
gave the tertiary amide 12 (13.07 g, not completely dry) as a colour-
less, viscous oil sufficiently pure for the subsequent cyclization. A
portion of amide 12 (12.84 g) was dissolved in trifluoroacetic acid
(130 mL), and the mixture was heated at reflux until TLC indicated
complete conversion (ca. 6 h). The reaction mixture was poured
onto ice (1 L) and the acid was neutralised by portionwise addition
of NaHCO3 (150 g). The product was extracted with CH2Cl2 (3 ϫ
100 mL), the combined organic layers were dried over Na2SO4, and
the solvent was evaporated in vacuo to afford iminobenzazocinone
16 (10.47 g, 97%) as a slightly pinkish foam. [α]2D5 ϭ Ϫ24.2 (c ϭ
1.0, CHCl3). Rf (EtOAc) ϭ 0.38. 1H NMR, COSY (400 MHz,
x
y
CDCl3): δ ϭ 2.77 (s, 1.2 H, NCH3 ), 2.82 (s, 1.8 H, NCH3 ),
2.96Ϫ3.20 (m, 3 H, H2-8xϩy, H12bxϩy), contained in this multiplet:
3.17 (d, Jgem ϭ 11.5 Hz, 0.6 H, H12by), 3.67 (dd, Jgem ϭ 11.5,
Jvic ϭ 4.7 Hz, 0.4 H, H12ax), 3.91 (dd, Jgem ϭ 11.5, Jvic ϭ 4.7 Hz,
0.6 H, H12ay), 4.18Ϫ4.24 (br. m, 1 H, FmocϪCHxϩy), 4.43Ϫ4.53
Conclusion
In summary, a short synthesis of the divalent scaffold 6
and the trivalent scaffold 7 from simple starting materials
through ring closure of cyclic acyliminium ions has been
achieved. The protecting groups chosen are orthogonally
stable, and so their selective removal and the subsequent
introduction of substituents in any order is possible.
(m, 1.6 H, OCH2-bxϩy, OCH2-ay), 4.65 (dd, Jgem ϭ 10.8, Jvic
ϭ
5.9 Hz, 0.4 H, OCH2-ax), 4.78Ϫ4.83 (m, 0.6 H, H9y), 4.93 (br.
pseudo-d, J ϭ 6.0 Hz, 0.4 H, H9x), 4.99 (br. pseudo-d, J ϭ 4.7 Hz,
0.4 H, H1x), 5.38 (br. pseudo-d, J ϭ 4.7 Hz, 0.6 H, H1y), 6.98Ϫ7.77
(several m, 12 H, ArϪHxϩy) ppm. 13C NMR (75.4 MHz, CDCl3),
HMQC, HMBC (100.6 MHz, CDCl3): δ ϭ 31.47 (C8x), 32.11
(C8y), 34.01 (NMex), 34.20 (NMey), 47.20 (FmocϪC9y), 47.30
(FmocϪC9x), 49.04 (C1y), 49.89 (C1x), 52.51 (C9x), 53.26 (C9y),
Experimental Section
x
y
General Remarks: All reactions were carried out in dried glassware
under argon unless stated otherwise. Solvents were distilled under
56.10 (C12y), 56.36 (C12x), 66.93 (OCH2 ), 67.60 (OCH2 ), 119.78,
119.94, 120.03 (FmocϪC4,5xϩy), 124.61, 124.69, 124.78
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T. Opatz
FULL PAPER
(FmocϪC1,8xϩy), 126.07, 126.40, 126.51, 126.66, 126.90, 127.03,
C30H28N2O4 ϩ Na: 503.1947, found 503.1958. IR (film): ν˜ ϭ 3018,
127.60, 127.73, 127.81, 127.89 (C3 Ϫ C5xϩy, FmocϪC2,3,6,7xϩy), 2899, 1698, 1451, 1428, 1325, 1310, 1251, 1113, 759, 740 cmϪ1
.
129.21 (C6y), 129.45 (C6x), 132.70 (C7y), 133.13 (C7x), 134.05 Note: The complete assignment of all signals in the NMR spectra
(C2x), 134.27 (C2y), 141.21, 141.27, 141.33 (FmocϪC4a,bxϩy),
143.34, 143.48, 143.57, 143.64 (FmocϪC8a,9axϩy), 153.18
(FmocϪCOx), 153.58 (FmocϪCOy), 167.65 (COy), 167.93 (COx)
ppm. Note: The indices x and y denote the minor and the major
rotamer, respectively. ESI-MS: m/z (%) ϭ 488.27 (21) [M ϩ Na ϩ
MeCN]ϩ, 447.23 (100) [M ϩ Na]ϩ, 179.08 (49) [fluorenylmethyl]ϩ.
ESI-HRMS: calcd. for C27H24N2O3 ϩ Hϩ: 425.1865, found
425.1853. IR (film): ν˜ ϭ 3016, 2947, 1705, 1656, 1452, 1427, 1324,
was not undertaken due to the presence of two pairs of rotamers.
(9H-Fluoren-9-yl)methyl
(1R,9S)-4-Hydroxy-11-methyl-10-oxo-
11,13-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene-13-carboxylate
(19): N-Methylmorpholine (341 µL, 3.10 mmol) was added to a
stirred suspension of FmocϪ-tyrosine tert-butyl ether (1.19 g,
2.59 mmol) in dry dichloromethane (5 mL) and the resulting clear
solution was cooled to Ϫ20 °C in an ice/salt bath. Isobutyl chloro-
formate (368 µL, 2.84 mmol) was added dropwise to yield a milky
1298, 1230, 1124, 1030, 757, 742 cmϪ1
.
11-Allyl 13-[(9H-Fluoren-9-yl)methyl] (1R,9S)-11,13-Diazatricyclo- suspension. After the mixture had been stirred at Ϫ20 °C for 5
[7.3.1.02,7]trideca-2,4,6-triene-11,13-dicarboxylate (6):
A
stirred
min, (methylamino)acetaldehyde dimethyl acetal (497 µL,
3.87 mmol) was added and the reaction mixture was warmed up to
0 °C. After the mixture had been stirred for 1.5 h, TLC indicated
complete conversion and the reaction mixture was quenched with
aq. NaHCO3 (50 mL). The resulting mixture was extracted with
CH2Cl2 (2 ϫ 50 mL), and the organic layer was washed with brine
and dried over Na2SO4. Evaporation of the solvent in vacuo gave
solution of 16 (1 g, 2.36 mmol) in dry THF (30 mL) was cooled to
0 °C in an ice bath. A solution of borane in THF (1 , 9.4 mL,
9.4 mmol) was added, and the mixture was stirred at 0 °C for
20 min. The solution was warmed up to 25 °C and stirring was
maintained until TLC indicated complete conversion (ca. 25 min).
The reaction was stopped by slow addition of a saturated aqueous
solution of citric acid (10 mL), and the mixture was stirred for 18 h a viscous, colourless oil (1.61 g), which was purified by elution from
at 25 °C.[25] Since hydrolysis of the amine-borane complex was still
not complete, the mixture was heated at 45 °C for 2 h and was then
a short column of silica gel with ethyl acetate containing 1% of
ethyldimethylamine. Removal of the eluent in vacuo yielded the
stirred for 3d at 25 °C. The solution was made alkaline by addition tertiary amide 18 (1.37 g) as a viscous, colourless oil. A portion of
of a saturated aqueous NaHCO3, and the product was extracted
with CH2Cl2 (3 ϫ 20 mL). The combined organic layers were dried
over Na2SO4, and the solvent was evaporated in vacuo to afford
iminobenzazocine 17 (1.22 g, not completely dry) as a colourless
oil. Since 17 has an Fmoc group and a basic nitrogen, it was di-
rectly converted into the N-Aloc derivative. Amine 17 was dissolved
in dry benzene (50 mL), and after addition of allyl chloroformate
(2.5 mL, 23.4 mmol) the mixture was stirred for 15 h at 60 °C. Since
TLC still showed the presence of unchanged starting material,
ethyldiisopropylamine (404 µL, 2.36 mmol) was added and the mix-
ture was stirred for 6 h at 70 °C. The solvent was removed in vacuo
and the residue was coevaporated with benzene (2 ϫ 10 mL). The
residue was dissolved in diethyl ether (100 mL), and the solution
this product (1.33 g) was dissolved in trifluoroacetic acid (24 mL),
and the mixture was heated at reflux until TLC indicated complete
conversion (5 h). The reaction mixture was poured onto ice
(100 mL), and the resulting suspension was extracted with ethyl
acetate (100 mL). The organic layer was washed with aq. NaHCO3
and dried over Na2SO4, and the solvent was evaporated in vacuo
to furnish crude iminobenzazocinone 19 (1.14 g) as a tan-coloured
amorphous solid. Purification by silica gel column chromatography
with ethyl acetate/cyclohexane (2:1) gave 19 (670 mg, 60% from
FmocϪTyr(tBu)ϪOH) as a colourless foam. [α]2D5 ϭ Ϫ16.2 (c ϭ
1.0, CHCl3). Rf (EtOAc) ϭ 0.35. 1H NMR, COSY, ROESY
(600 MHz, CDCl3): δ ϭ 1.92 (br. s, 0.5 H, OH), 2.76 (s, 1.2 H,
NCH3 ), 2.82 (s, 1.8 H, NCH3 ), 2.92Ϫ3.06 (m, 2.4 H, H2-8xϩy
,
ϭ
x
y
was washed with water, saturated aq. NaHCO3, HCl (0.5 ) and H12bx), 3.15 (d, Jgem ϭ 11.7 Hz, 0.6 H, H12by), 3.61 (dd, Jgem
brine. The ethereal solution was dried over Na2SO4, and the solvent
was evaporated in vacuo to afford crude iminobenzazocine 6 as a
weakly brownish oil (1.38 g). The crude product was purified by
flash chromatography on silica gel with cyclohexane/ethyl acetate
(3:1) as the eluent to yield pure 6 as a colourless foam (959 mg,
85%). [α]2D5 ϭ Ϫ34.3 (c ϭ 1.0, CHCl3). Rf (EtOAc) ϭ 0.60. 1H
11.7, Jvic ϭ 4.7 Hz, 0.4 H, H12ax), 3.85 (dd, Jgem ϭ 11.7, Jvic
ϭ
4.7 Hz, 0.6 H, H12ay), 4.17Ϫ4.21 (br. m, 1 H, FmocϪCHxϩy),
4.42Ϫ4.46 (m, 1 H, OCH2-bxϩy), 4.50 (dd, Jgem ϭ 10.6, Jvic
ϭ
6.5 Hz, 0.6 H, OCH2-ay), 4.66 (dd, Jgem ϭ 10.9, Jvic ϭ 5.9 Hz, 0.4
H, OCH2-ax), 4.79Ϫ4.81 (m, 0.6 H, H9y), 4.88 (br. pseudo-d, J ϭ
4.7 Hz, 0.4 H, H1x), 4.92 (br. pseudo-d, J ϭ 5.9 Hz, 0.4 H, H9x),
NMR, COSY (400 MHz, CDCl3): δ ϭ 2.64Ϫ2.85 (m, 1 H, H8b), 5.27 (br. d, J ϭ 4.7 Hz, 0.6 H, H1y), 6.51 (d, Jgem ϭ 2.5 Hz, 0.4 H,
2.90Ϫ3.30 (m, 3 H, H8a, H10b, H12b), 3.87Ϫ4.62 (m, 8 H, H10a, H3x), 6.60 (d, Jgem ϭ 2.4 Hz, 0.6 H, H3y), 6.69Ϫ6.74 (m, 1 H,
H12a, 2 ϫ OCH2, FmocϪCH, H9), 4.81 (br. pseudo-d, Jtrans
ϭ
H5xϩy), 6.86Ϫ6.90 (m, 1 H, H6xϩy), 7.17Ϫ7.76 (several m, 8 H,
Fmoc) ppm. 13C NMR, HMQC, HMBC (150.9 MHz, CDCl3): δ ϭ
17.2 H, 0.7 Hz, CH2ϭ), 4.92Ϫ5.03 (m, 1.2 H, H1, CH2ϭ),
5.09Ϫ5.24 (m, 1.1 H, H1, CH2ϭ), 5.40Ϫ5.51 (m, 0.7 H, allyl ϭ 30.66 (C8x), 31.37 (C8y), 34.28 (NMex), 34.46 (NMey), 47.14
CHϪ), 5.68Ϫ5.81 (m, 0.3 H, allyl ϭCHϪ), 6.95Ϫ7.79 (several m, (FmocϪCHy), 47.29 (FmocϪCHy), 49.08 (C1y), 49.89 (C1x), 52.74
12 H, ArϪH) ppm. 13C NMR (75.4 MHz, CDCl3), HMQC
(C9x), 53.45 (C9y), 56.08 (C12y), 56.33 (C12x), 67.09 (OCH2 ),
x
(100.6 MHz, CDCl3): δ ϭ 30.93, 31.11, 31.47, 31.59 (C8), 45.98, 67.87 (OCH2 ), 112.71 (C3x), 112.91 (C3y), 115.68 (C5x), 115.76
y
46.36, 46.86 (C9), 47.23, 47.39 (FmocϪC9), 49.25, 49.45, 49.56,
50.07 (C10, C12), 50.95, 51.87 (C1), 65.69, 65.93 (AlocϪOCH2),
67.00, 67.10 (FmocϪOCH2), 116.71, 117.40 (CH2ϭ), 119.87,
119.95 (FmocϪC4,5), 124.66, 124.82 (FmocϪC1,8), 125.84,
(C5y), 119.85, 120.01, 120.07, 120.11 (FmocϪC4,5xϩy), 123.66
(C7y), 124.03 (C7x), 124.61, 124.73, 124.77, 124.87
(FmocϪC1,8xϩy), 126.95, 127.07, 127.13 (FmocϪC2,7xϩy), 127.67,
127.79, 127.82 (FmocϪC3,6xϩy), 130.24 (C6y), 130.40 (C6x), 134.89
125.89, 126.18, 126.21, 126.50, 126.91, 126.96, 127.00, 127.22, (C2x), 135.04 (C2y), 141.20, 141.26, 141.29, 141.39
127.40, 127.57, 127.61, 127.68, 128.08, 128.17, 128.48 (C3ϪC6,
(FmocϪC4a,bxϩy),
143.26,
143.42,
143.48,
143.56
FmocϪC2,3,6,7), 132.55, 132.78 (allyl ϪCHϭ), 134.03, 134.09, (FmocϪC8a,9axϩy), 153.32 (FmocϪCOx), 153.68 (FmocϪCOy),
134.59 (C2,7), 141.23, 141.31, 141.36 (FmocϪC4a,b), 143.59,
143.73, 143.79 (FmocϪC8a,9a), 154.09 (FmocϪCO), 155.06,
155.07 (C4x), 155.19 (C4y), 168.32 (C10y), 168.69 (C10x) ppm. ESI-
MS: m/z (%) ϭ 504.23 (17) [M ϩ Na ϩ MeCN]ϩ, 463.25 (76) [M
155.40 (Aloc-CO) ppm. ESI-MS: m/z (%) ϭ 503.25 (100) [M ϩ ϩ Na]ϩ, 179.07 (100) [fluorenylmethyl]ϩ. ESI-HRMS: calcd. for
Na]ϩ, 179.07 (78) [fluorenylmethyl]ϩ. ESI-HRMS: calcd. for
C27H24N2O4 ϩ Na: 463.1634, found 463.1635. IR (film): ν˜ ϭ 3279
4116
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Synthesis of two Conformationally Restricted Piperazine Scaffolds for Combinatorial Chemistry
FULL PAPER
(broad), 3017, 2932, 1705, 1640, 1504, 1451, 1429, 1339, 1300,
1222, 1122, 1032, 757, 742 cmϪ1
132.86 (allyl ϪCHϭ), 132.89 (2 ϫ PhϪC1), 134.81, 134.91 (C2),
135.44, 135.53 (2 ϫ PhϪC2,6), 141.26, 141.30, 141.33, 141.38
(FmocϪC4a,5a), 143.61, 143.77 (FmocϪC8a,9a), 153.45, 154.05,
155.03, 155.48 (C4, 2 ϫ CO) ppm. FD-MS: m/z (%) ϭ 735.5 [M
ϩ H]ϩ (100). ESI-HRMS: calcd. for C46H46N2O5 ϩ H: 735.3254,
found 735.3237. IR (film): ν˜ ϭ 3015, 2931, 2894, 2858, 1702, 1612,
1502, 1429, 1312, 1293, 1264, 1248, 1156, 1111, 966, 833, 757, 741,
702 cmϪ1. Note: The complete assignment of all signals in the
NMR spectra was not undertaken due to the presence of two pairs
of rotamers.
.
11-Allyl 13-[(9H-Fluoren-9-yl)methyl] (1R,9S)-4-[tert-Butyl(diphen-
yl)silyloxy]-11,13-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene-11,13-
dicarboxylate (7): A solution of borane in THF (1 , 3.64 mL,
3.64 mmol) was added at 0 °C to a stirred solution of 19 (320 mg,
726 µmol) in dry THF (15 mL). After 20 min, the solution was
warmed up to room temperature. When TLC indicated complete
conversion (40 min), the reduction was stopped by slow addition
of a saturated aqueous solution of citric acid (2 mL). The resulting
mixture was stirred for 4 d to destroy the rather stable amine bor-
ane adduct. The product was isolated by addition of aq. NaHCO3
(50 mL), extraction with CH2Cl2 (2 ϫ 25 mL), drying over Na2SO4
and removal of the solvent in vacuo. Amine 20 was obtained as
colourless oil (344 mg, not completely dry) and since it contains
both a sterically accessible amine and an Fmoc group, it was di-
rectly subjected to the subsequent silylation reaction without
further purification. Crude 20 was dissolved in dry CH2Cl2 (10 mL)
and after addition of tert-butyldiphenylsilyl chloride (570 µL,
2.18 mmol) and imidazole (74 mg, 1.09 mmol), the solution was
stirred for 20 h at room temperature. The reaction mixture was par-
titioned between CH2Cl2 (30 mL) and aq. NaHCO3 (50 mL), the
organic layer was dried over Na2SO4, and the solvent was removed
in vacuo to yield a colourless oil. The product was purified by silica
gel column chromatography with petroleum ether/ethyl acetate (4:1
to 3:1) containing 0.8% ethyldimethylamine to yield silyl ether 21
(400 mg) as a colourless foam, which was directly converted into
the N-Aloc derivative: ethyldiisopropylamine (515 µL, 3.01 mmol)
and allyl chloroformate (642 µL, 6.02 mmol) were added to a
stirred solution of 21 (400 mg) in dry benzene (15 mL), and the
resulting clear solution was heated at 80 °C. After 30 h, TLC indi-
cated a stagnating conversion, presumably due to complete de-
composition of the chloroformate. Further portions of ethyldiiso-
propylamine (258 µL, 1.51 mmol) and allyl chloroformate (321 µL,
3.01 mmol) were added and the solution was stirred at 80 °C for
12 h. To complete the conversion, two more portions of the re-
agents (1.51 mmol base and 3.01 mmol chloroformate each) were
added over a period of 5 h. The reaction mixture was concentrated
by evaporation of the solvent in vacuo. To remove volatile impurit-
ies, the resulting solid was coevaporated with benzene (2 ϫ 5 mL).
The residue was partitioned between ethyl acetate and aq.
NaHCO3, the organic layer was washed with KHSO4 (1 ) and aq.
NaHCO3 and, after drying over MgSO4, the solvent was removed
in vacuo. Purification of the crude product by flash chromatogra-
phy on silica gel with petroleum ether/ethyl acetate (3:1) yielded
iminobenzazocine 7 as a colourless foam (405 mg, 76% from 19).
[α]2D5 ϭ Ϫ35.9 (c ϭ 1.0, CHCl3). Rf (petroleum ether/EtOAc, 3:1) ϭ
0.13. 1H NMR, COSY (400 MHz, CDCl3): δ ϭ 1.10 (s, 4.1 H,
tBu), 1.14 (s, 4.9 H, tBu), 2.52Ϫ2.72 (m, 1 H, H8b), 2.85Ϫ3.22 (m,
3 H, H10b, H12b, H8a), 3.75Ϫ4.60 (m, 8 H, H10a, H12a, 2 ϫ
Acknowledgments
The author is grateful to H. Kolshorn for the 2D NMR spectro-
scopic analyses.
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4117

T. Opatz
FULL PAPER
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Received May 21, 2004
4118
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4113Ϫ4118