An efficient one-pot synthesis of functionalized azamacrocycles from methyl 2-siloxy-2-vinylcyclopropanecarboxylates

Article abstract of DOI:10.1055/s-2001-9706

The (N)-benzylamine substituted 2-siloxy-2-vinylcyclopropanecarboxylates 5, 7, 9, 10, 13, 15, and 17 upon desilylation-ring opening induced by cesium fluoride and subsequent intramolecular Michael addition-ring closure, afford azamacrocycles 18-22 and 24-26 in moderate to good yields in a one-pot operation. The aromatic spacer in amine precursor 12 does not allow formation of ring 23 due to ring strain. Except in the case of 5, dimers or higher oligomers are not observed.

Full text of DOI:10.1055/s-2001-9706

LETTER
33
An Efficient One-Pot Synthesis of Functionalized Azamacrocycles from
Methyl 2-Siloxy-2-vinylcyclopropanecarboxylates
Pranab K. Patra, Hans-Ulrich Reissig*
Institut für Chemie, Organische Chemie, Freie Universität Berlin, Takustr. 3, D-14195 Berlin, Germany
Fax +49 30 838 55367; E-mail: Hans.Reissig@chemie.fu-berlin.de
Received 4 October 2000
ligands for metal ions,8 renal calculi dissolving agents9
and as linkers for monoclonal antibodies and radiometal
ions in cancer treatment.10 In this communication we re-
port our preliminary contribution to this exciting field of
Abstract: The (N)-benzylamine substituted 2-siloxy-2-vinylcyclo-
propanecarboxylates 5, 7, 9, 10, 13, 15, and 17 upon desilylation-
ring opening induced by cesium fluoride and subsequent intramo-
lecular Michael addition-ring closure, afford azamacrocycles 18-22
and 24-26 in moderate to good yields in a one-pot operation. The ar- chemistry. 11
omatic spacer in amine precursor 12 does not allow formation of
The 2-siloxy-2-vinylcyclopropanecarboxylate
3 was
ring 23 due to ring strain. Except in the case of 5, dimers or higher
deprotonated and alkylated with E-1,4-dibromobutene to
furnish the corresponding bromide 4.5a Treatment of bro-
mide 4 with an excess of benzylamine in dichloromethane
afforded the corresponding (N)-benzylamine 5 in 68%
yield (Scheme 2) along with the dialkylated product in 9%
yield. We also prepared the long chain amine 7 by N-alky-
lation of ammonium salt 612 with bromide 4 in the pres-
ence of a suitable base (K2CO3 or TEA). The expected
substrate 7 was obtained in 52% yield (Scheme 2) togeth-
er with the inevitable formation of the corresponding di-
alkylated product in low yield.
oligomers are not observed.
Key words: siloxycyclopropane, benzylamination, intramolecular
Michael addition, one-pot synthesis, azamacrocycle
2-Siloxy-2-vinylcyclopropanecarboxylates 3 are versatile
intermediates for a variety of chemical transformations.1-4
The key feature of their chemistry is the hidden enone unit
which can be demasked by desilylation and ring opening
thereby releasing the inherent strain. Thus, siloxycyclo-
propanes 1 supplemented by substitution reactions with a
spacer group and a suitable terminal pronucleophilic unit
activated by two acceptor groups Acc, serve as key inter-
mediates for a one-pot synthesis5 of medium to large car-
bocyclic rings 2 (Scheme 1). This concept uses building
block 3 as equivalent of the dipolar synthon A.
Scheme 1
Our present work has extended this strategy. By changing
the pronucleophilic unit to a suitable nitrogen nucleophile,
we have successfully carried out sequential ring opening
and ring closing operations for the construction of highly
functionalized macroheterocycles. Medium and large het-
erocyclic ring systems have been the subject of contempo-
rary interest due to their intriguing biological, chemical
and physical properties.6 Azamacrocycles are used for
molecular recognition (host molecules for inclusion of
neutral organic molecules),7 as selectively coordinating
a, PhCH2NH2 / CH2Cl2, rt, 3 h
b, K2CO3 / CH3CN / rt to reflux, 24 h
Scheme 2
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34
P. K. Patra, H.-U. Reissig
LETTER
The next experiment followed our previously described concentration in view of getting an increased yield of 19,
repetitive alkylation process5b affording bromide 8, which however, we were left with only a lower yield of 18 along
was conveniently converted to its benzylamine derivative with polymerized material. It should be mentioned here
9 in 78% yield. Compound 10 was prepared in 50% yield, that the related (N)-tosyl derivative14 of 5 under similar re-
upon reaction of 8 with ammonium salt 6 in the presence action conditions did not afford the corresponding (N)-to-
of K2CO3 in refluxing acetonitrile for 24 h (Scheme 2).
syl azecine, presumably due to the lower nucleophilicity
of a sulfonamide over a dialkylamine. The related primary
amine also had the similar fate of not providing us with the
related ring.
We then extended the precursor compounds using aromat-
ic and heteroaromatic spacer units. Thus, benzylamina-
tion of the reported5d benzyl bromide substituted
siloxycyclopropane 11 afforded the corresponding amine
12 in 81% yield (Scheme 3). Similarly, bromide 11, when
treated with 6 in the presence of K2CO3 afforded the cor-
responding long chain amine 13 in 55% yield. In order to
introduce a heteroaromatic spacer such as a pyridine ring,
we started with the already known bromide 14.5d The cor-
responding benzylamine 15 was provided in 49% yield,13
when ammonium salt 6 was alkylated with bromide 14.
Finally, amine 17 was synthesized in 78% yield when
benzylamine was monoalkylated (Scheme 3) with the cor-
responding bromide 16.5d
a, CsF / TEBA, DMF, 90 °C, 22-25 h
Scheme 4
a, PhCH2NH2 / CH2Cl2, rt, 3 h
b, K2CO3 / CH3CN / rt to reflux, 24 h
Interestingly, when amine 7 was exposed to cesium fluo-
ride under similar reaction conditions, the corresponding
diazamacrocycle 20 was obtained in 31% yield as sole
product (Scheme 4). Also the benzylamine derivative 9
was cyclized to the 15-membered azacycle 21 under the
conditions mentioned above in 19% yield as the only
characterized product. The rest of the material may be oli-
gomers and polymers. On the other hand, amine 10 was
readily cyclized under standard reaction conditions to a
20-membered macrocycle 22 in a delighting yield of 62%
(Scheme 4).
Scheme 3
Having the precursors in hand, we started with the
azamacrocycle synthesis. Thus, from cyclopropane 5,
when slowly subjected to a hot suspension of CsF in dry
DMF (200 mL/mmol) in the presence of phase transfer
catalyst (TEBA), the corresponding azecine 18 (Scheme
4) was obtained in 24% yield along with a low quantity of
dimer 19 (4% yield). Our experience with similar car-
bocycles prompted us to attempt the reaction in higher
Synlett 2001, No. 1, 33–36 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Efficient One-Pot Synthesis of Functionalized Azamacrocycles
35
The reaction was then extended to azacyclophanes and
pyridinophanes using the corresponding amine precursors
(Scheme 5). Fluoride induced desilylation of 12 in the
presence of phase transfer catalyst in hot DMF, did not
yield the corresponding cyclophane 23, nor higher oligo-
mers, which we experienced during our carbocycle syn-
thesis.5 The failure may be due to its geometrical
restriction. However, its longer chain derivative 13 af-
forded the diazacyclophane 24 as the sole product in 33%
yield. Our extension of this process to similar pyridine
containing precursors 15 and 17, provided the correspond-
ing pyridinophanes 2513 and 26 as single products in 54%
and 49% yields, respectively (Scheme 5).
Acknowledgement
PKP thanks the Alexander-von-Humboldt Foundation for a rese-
arch fellowship. We are grateful to the Fonds der Chemischen Indu-
strie for financial support.
References and Notes
(1) Review: Reissig, H.-U. Top. Curr. Chem. 1988, 144, 73-135.
(2) Syntheses of heterocycles: (a) Hofmann, B.; Reissig, H.-U.
Chem. Ber. 1994, 127, 2337-2339. (b) Böttcher, G.; Reissig,
H.-U. Synlett 2000, 725-727.
(3) Michael additions: (a) Grimm, E. L.; Zschiesche, R.; Reissig,
H.-U. J. Org. Chem. 1985, 50, 5543-5545. (b) Zschiesche, R.;
Reissig, H.-U. Liebigs Ann. Chem. 1988, 1165-1168.
(c) Schnaubelt, J.; Zschiesche, R.; Reissig, H.-U.;
Lindner, H. J.; Richter, J. Liebigs Ann. Chem. 1993, 61-70.
(4) Intramolecular Diels-Alder reactions: (a) Frey, B.;
Schnaubelt, J.; Reissig, H.-U. Eur. J. Org. Chem. 1999, 1377-
1384. (b) Schnaubelt, J.; Frey, B.; Reissig, H.-U. Helv. Chim.
Acta 1999, 82, 666-676. (c) Frey, B.; Reissig, H.-U. J. Prakt.
Chem. 1999, 341, 173-177.
(5) (a) Schnaubelt, J.; Ullmann, A.; Reissig, H.-U. Synlett 1995,
1223-1225. (b) Ullmann, A.; Schnaubelt, J.; Reissig, H.-U.
Synthesis 1998, 1052-1066. (c) Ullmann, A.; Reissig, H.-U.;
Rademacher, O. Eur. J. Org. Chem. 1998, 2541-2549.
(d) Ullmann, A.; Gruner, M.; Reissig, H.-U. Chem. Eur. J.
1999, 5, 187-197.
(6) (a) Kranemann, C. L.; Costisella, B.; Eilbracht, P.
Tetrahedron Lett. 1999, 40, 7773-7776. (b) Izatt, R. M.;
Pawlak, K.; Bradshaw, J. S. Chem. Rev. 1995, 95, 2529-2586.
(c) Schmidtchen, F. P.; Berger, M. Chem. Rev. 1997, 97,
1609-1646. (d) Denat, F.; Brandes, S.; Guilard, R. Synlett
2000, 561-574. (e) Kranemann, C. L.; Eilbracht, P. Eur. J.
Org. Chem. 2000, 2367-2377. (f) Pidwell, A. D.; Collinson, S.
R.; Coles, S. J.; Hursthouse, M. B.; Schröder, M.; Bruce, D.
W. Chem. Commun. 2000, 955-956.
(7) (a) Diederich, F. “Cyclophanes” The Royal Society of
Chemistry, London 1991. (b) Bencini, A.; Burguete, M. I.;
Garcia-Espana, E.; Luis, S. V.; Miravet, J. F.; Soriano, C. J.
Org. Chem. 1993, 58, 4749-4753.
(8) (a) Turonek, M. L.; Moore, P.; Clase, H. J.; Alcock, N. W. J.
Chem. Soc., Dalton Trans. 1995, 3659-3666. (b) Kimura, E.;
Koike, J. Chem. Commun. 1998, 1495-1500. (c) Graubaum,
H.; Costisella, B.; Dambowsky, R. J. Prakt. Chem. 1998, 340,
165-170.
(9) Kimura, E. Top. Curr. Chem. 1985, 128, 113-141.
(10) (a) Parker, D. Chem. Soc. Rev. 1990, 19, 271-291.
(b) Norman, T. J.; Parker, D.; Royle, A. L.; Harrison, A.;
Antoniw, P.; King, D. J. Chem. Soc., Chem. Commun. 1995,
1877-1878.
(11) (a) Ramaseshan, M.; Robitaille, M.; Ellingboe, J. W.; Dory,
Y. L.; Deslongschamps, P. Tetrahedron Lett. 2000, 41, 4737-
4742. (b) Soucy, P.; Dory, Y. L.; Deslongschamps, P. Synlett
2000, 1123-1126.
a, CsF / TEBA, DMF, 90 °C, 22-25 h
Scheme 5
(12) De Rose, A. F.; Weston, A. W. German Patent 1016265, 1959;
Chem. Abstr. 1958, 52, 6413.
The above results demonstrate again the efficacy of our
ring enlargement process which proceeds through fluo-
ride promoted cyclopropane cleavage and intramolecular
Michael addition. As the importance of polyazamacrocy-
cles increases, the search for convenient preparation fol-
lows. In view of this, our method would be an important
contribution to such an area as it is very flexible and al-
lows a wide variation of highly functionalized ring sizes,
polyazacyclophanes and pyridinophanes. We are now in-
troducing more advanced connectors like amino esters
and peptides to construct biologically relevant systems.
(13) Typical procedure, preparation of 15 and its cyclization to
25: To a well stirred suspension of anhyd. K2CO3 (2.35 g,
17.0 mmol) in 20 mL of dry acetonitrile was added
ammonium salt 6 (2.30 g, 6.80 mmol) followed by fast
addition of bromide 14 (1.50 g, 3.40 mmol) in 5 mL of
acetonitrile. The reaction mixture was stirred for 12 h at r.t.
and then under reflux for 12 h. The mixture was cooled and
diluted with 100 mL of ice cold water and extracted with
EtOAc (3 ¥ 20 mL). The combined organic layer was washed
with brine (3 ¥ 25 mL), dried over MgSO4 and the solvent was
Synlett 2001, No. 1, 33–36 ISSN 0936-5214 © Thieme Stuttgart · New York

36
P. K. Patra, H.-U. Reissig
LETTER
evaporated. The residue was purified by column chromato-
graphy (silica gel, hexane/EtOAc, 7:3) to afford the amine 15
(1.00 g, 49%) as light yellow liquid; IR (Film): n 3340 cm-1
(N-H), 3085-2800 ( =C-H, -C-H), 1725 (CO2Me), 1640
(-C=C-); 1HNMR (250 MHz, CDCl3): d 7.52 (t, J = 7.7 Hz,
1H, pyr-H), 7.39-7.17 (m, 11H, Ar-H, pyr-H), 7.01 (d, J = 7.7
Hz, 1H, pyr-H), 5.90 (dd, J = 17.3, 10.6 Hz, 1H, 1’’’-H), 5.72
(mc, 2H, 2’,3’-H), 5.33 (dd, J = 17.3, 1.4 Hz, 1H, cis-2’’’-H),
5.15 (dd, J = 10.6, 1.4 Hz, 1H, trans-2’’’-H), 3.76 (s, 3H,
CO2Me), 3.76, 3.69, 3.61 (3 br s, 6H, CH2), 3.76-3.52 (m, 2H,
CH2), 3.20-3.00 (m, 4H, 2 CH2), 1.93 (d, J = 5.8 Hz, 1H, cis-
3-H), 1.64 (br s, 1H, NH), 1.27 (d, J = 5.8 Hz, 1H, trans-3-H),
0.89 (s, 9H, tBu), 0.13, 0.11 (2s, 6H, SiMe2); 13CNMR (62.9
MHz, CDCl3): d 172.1, 51.8 (s, q, CO2Me), 159.4, 159.2 (2s,
C-pyr-2,6), 140.2, 139.5 (2s, C-Ar), 136.8, 136.3 (2d,
C-1’’’, C-Ar), 131.5, 129.5, 128.7, 128.3, 128.1, 126.8, 126.7
(7d, =CH, C-Ar), 120.3, 119.9 (2d, C-pyr-3,5), 115.1 (t,
C-2”’), 65.3 (s, C-2), 59.6, 57.9, 55.5, 53.2, 50.7 (5t, NCH2),
37.1 (s, C-1), 36.8 (t, C-1”), 25.8, 18.1 (q, s, tBu), 24.4 (t,
C-3), -3.5 (q, SiMe2); EA: Calcd for C38H51N3O3Si (625.9): C,
72.91%; H, 8.21%; N, 6.71%. Found: C, 72.66%; H, 7.57%;
N, 6.76%; MS (EI, 80 eV) m/z(%): 625.3 (M+, 22); HRMS
(EI, 80 eV): Calcd for C38H51N3O3Si: 625.36997; Found:
625.36933.
the same temperature for 2 h. After evaporation of all volatile
components (70 °C, 16 mbar), the residue was diluted with
150 mL of sat. aq. NH4Cl solution and extracted with EtOAc
(5 ¥ 30 mL). The combined organic layer was washed with
brine (2 ¥ 30 mL), dried over MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography
(silica gel, hexane/EtOAc, 8:2) to afford 25 (103 mg, 54%) as
colorless liquid; IR (Film): n 3085-2800 cm-1 ( =CH, -CH),
1735 (CO2Me), 1700 (-C=O); 1HNM (250 MHz, CDCl3):
d 7.54 (t, J = 7.7 Hz, 1H, pyr-H), 7.42-7.17 (m, 11H, Ar-H,
pyr-H), 6.98 (d, J = 7.7 Hz, 1H, pyr-H), 5.73-5.62, 5.54-5.43
(2m, 2H, 5,6-H), 3.75 (mc, 4H, 2 NCH2Ph), 3.67 (s, 3H,
CO2Me), 3.52 (s, 2H, 2-H), 3.48-3.38 (m, 1H, 13-H), 3.20-
2.84 (m, 8H, 4,7,9,14-H), 2.74 (mc, 2H, CH2, 12-H), 2.58 (mc,
2H, CH2, 10-H); 13CNMR (62.9 MHz, CDCl3): d 208.8 (s,
C=O), 174.9, 51.8 (s, q, CO2Me), 159.1, 157.8 (2s, C-15,1),
139.3, 138.9 (2s, C-Ar), 136.6, 131.9 (2d, C-5,6), 128.6,
121.6, 120.7 (3d, C-17,16,18), 128.9, 128.7, 128.2, 128.1,
126.9, 126.9 (6d, C-Ar), 59.5 (t, C-2), 58.6, 58.1 (2t, CH2Ph),
55.8, 54.2, 48.5 (3t, C-4,7,9), 42.6, 40.9, 38.7 (3t, C-14,12,10),
39.7 (d, C-13); MS (EI, 80 eV) m/z(%): 511 (M+, 4), 480
(M+-31, 1), 420 (M+-91, 4); HRMS (EI, 80 eV): Calcd for
C32H37N3O3: 511.28349; Found: 511.28333.
(14) Ullmann, A. Dissertation, Technische Universität Dresden,
1998.
A solution of amine 15 (240 mg, 0.38 mmol) in 50 mL of dry
DMF was slowly added through a syringe pump over 20 h to
a warm suspension (90 °C) of CsF (175 mg, 1.15 mmol) and
benzyltriethylammonium chloride (130 mg, 0.57 mmol) in
300 mL of DMF. The reaction mixture was further stirred at
Article Identifier:
1437-2096,E;2001,0,01,0033,0036,ftx,en;G21300ST.pdf
Synlett 2001, No. 1, 33–36 ISSN 0936-5214 © Thieme Stuttgart · New York