Fluorous benzaldehyde-based synthesis of biaryl-substituted oxazabicyclo[3.3.1]nonanes

Article abstract of DOI:10.1039/c0gc00725k

Fluorous benzaldehyde-based synthesis of biaryl-substituted oxazabicyclo[3.3.1]nonanes is accomplished by a three-step synthesis including multicomponent reaction (MCR) to form tetrahydroquinoline, followed by cycloaddition with coumarin to form oxazabicy

Full text of DOI:10.1039/c0gc00725k

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Fluorous benzaldehyde-based synthesis of biaryl-substituted
oxazabicyclo[3.3.1]nonanes†
Shan Ding, Minhgiao Le-Nguyen, Tao Xu and Wei Zhang*
Received 24th October 2010, Accepted 16th February 2011
DOI: 10.1039/c0gc00725k
Fluorous benzaldehyde-based synthesis of biaryl-
substituted oxazabicyclo[3.3.1]nonanes is accomplished
by
a three-step synthesis including multicomponent
reaction (MCR) to form tetrahydroquinoline, followed
by cycloaddition with coumarin to form oxazabicycles,
and then a Suzuki coupling to introduce the biaryl group.
Microwave irradiation and fluorous solid-phase extraction
(F-SPE) are employed to speed up reactions and simplify
product purification.
As part of our continuous effort in the development of
microwave-assisted fluorous synthesis for the preparation of
heterocyclic compound libraries,10 we have demonstrated that
perfluorooctanesulfonyl benzaldehydes are a feasible synthon
for MCRs to assemble heterocyclic scaffolds.11 The reaction
intermediates can be purified by simple fluorous solid-phase
extraction (F-SPE)12 The fluorous linker can be removed
by microwave-promoted coupling reactions to introduce new
functional groups.13 In the current project, the fluorous ben-
zaldehydes 6 were used as a key component to react with
four other building blocks 7 to 10 to prepare diaryl-substituted
oxazobicyclo[3.3.1]nonanes 5 (Scheme 1).
The cleft-shaped biaryl-fused heterobicyclo[3.3.1]nonanes are a
well-studied scaffold in molecular recognition.1 They have also
been investigated as host molecules in enzymatic inhibition2
and DNA interaction,3 as well as catalysts for asymmetric
synthesis.4 One of the best known heterobicyclo[3.3.1]nonanes
is Troger’s base 1 which has a central diazabicycle fused with
two benzene rings.5 Other nitrogen- and oxygen-containing
heterobicyclo[3.3.1]nonanes, such as 2 and 3, have been incor-
porated in the design of functionalized materials6 and molecules
with biological interest.7 The Yang group recently reported
the utility of diazobicyclo- and oxazobicyclo[3.3.1]nonanes
4 as photochromic colorants.8 The compound libraries were
prepared by a two-step synthesis including a multicomponent
reaction (MCR) to form tetrahydroquinoline, followed by a
cycloaddition with a 1,3-diketone or an enamine derivative.8d
Described in this paper is a modified method for the preparation
of biaryl-substituted oxazobicyclo[3.3.1]nonanes 5 by using: 1)
microwave irradiation to speed up the reactions; 2) fluorous
linker to facilitate intermediate purifications and reduce the
amount of waste solvent; and 3) Suzuki coupling to remove
the fluorous linker and introduce the biaryl-functionality to the
bicyclic system. The new method has high synthetic efficiency,
provides additional molecular diversity, and also has green
chemistry advantages.9
Scheme 1
We have developed a three-step synthetic sequence for the
preparation of diaryl-substituted oxazobicyclo[3.3.1]nonanes
5. The first step was a three-component reaction of fluorous
benzaldehyde 6 with aniline 7 and isobutyraldehyde 8 to
form tetrahydroquinoline 11 (Scheme 2).14 The reactions were
catalysed by 0.4 eq. of Yb(OTf)3 under microwave irradiation
Department of Chemistry, University of Massachusetts Boston, 100
Morrissey Boulevard, Boston, MA, 02125, USA.
E-mail: wei2.zhang@umb.edu
† This publication is part of the web themed issue on fluorine chemistry.
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All the non-fluorous components went into the MeOH–H2O
fraction and compound 11 was collected in the MeOH fraction.
Four tetrahydroquinolines 11 were prepared in 74–89% yields.17
The cycloaddition of tetrahydroquinoline11 with coumarin or
4-hydroxy-1-methylquinolin-2(1H)-one was carried out under
microwave irradiation using 0.2 eq. of p-TsOH as a catalyst
(Scheme 3). Compound 9 was used in excess (1.5 eq.) to promote
the reaction completion. Eight oxazabicycles 12 were prepared
in 48–77% yields after F-SPE purification.18
The removal of the fluorous linker and introduction of the
biaryl functional group to oxazabicycle was accomplished by
a microwave-promoted Suzuki coupling reaction (Scheme 4).19
The aryl perfluorooctanesulfonyl group is a triflate equivalent
which can be used for Pd-catalyzed cross-coupling reactions.
The reaction was carried out using Pd(dppf)Cl2 as a catalyst,
4 : 1 : 4 acetone : H2O : HFE7200 (C4F9OC2H5) as a co-solvent,
and Cs2CO3 as a base under microwave heating at 100 ◦C
for 30 min. Fluorous solvent HFE7200 was used to increase
the solubility of the fluorous sample. Eight compounds 5 were
prepared in 26–65% yields after F-SPE followed by flash chro-
matography purification.20 The structures of the final products
Scheme 2
◦
at 50 C for 20 min.15 Fluorous component 6 was used as the
limiting agent, while compounds 7 and 8 were used in excess
(1.5 eq.) to ensure 6 was consumed. It was interesting to find that
under these reaction conditions, the product was the O-ethylated
ether 11 generated by the reaction of the initial MCR product
with solvent ethanol. The reaction mixture was purified by F-
SPE, eluted with 80 : 20 MeOH–H2O and then 100% MeOH.16
Scheme 3
Scheme 4
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were characterized by LC-MS, 1H and 13C NMR analyses. The
cleaved fluorous linker as C8F17SO2H was collected in the MeOH
fraction of F-SPE. This compound can be converted to active
linkers C8F17SO2F or C8F17SO2Cl for reuse.21
13 (a) W. Zhang, in Microwave Methods in Organic Synthesis; Topics
Curr. Chem., vol. 266, ed. M. Larhed and K. Olofsson, Springer,
2006, pp. 145–166; (b) W. Zhang, Y. Lu and C. H.-T. Chen, Mol.
Diversity, 2003, 7, 199–202; (c) W. Zhang, T. Nagashima, Y. Lu and
C. H.-T. Chen, Tetrahedron Lett., 2004, 45, 4611–4613; (d) W. Zhang
and T. Nagashima, J. Fluorine Chem., 2006, 127, 588–591.
In summary, a fluorous benzaldehyde-based method for the
preparation of biaryl-substituted oxazabicyclo[3.3.1]nonanes
has been developed. High synthetic efficiency with green chem-
istry advantages are realized by conducting multicomponent
reactions for atom economy, microwave reactions for short
reaction times, F-SPE for easy purification of intermediates
and reducing the amount of waste solvent, and Suzuki coupling
reaction to remove the fluorous linker and introduce the biaryl
functional group. This synthetic protocol can be applied to
prepare a big compound library by using an expanded number
of building blocks.
14 Synthesis of fluorous benzaldehydes, see ref. 11a.
15 For a Zn(OTf)2-promoted synthesis of tetrahydroquinoline, see: S.
Yamazaki, M. Takebayashi and K. Miyazaki, J. Org. Chem., 2010,
75, 1188–1196.
16 Fluorous SPE cartridges are available from Fluorous Technologies,
Inc. (www.fluorous.com) and Silicycle (www.silicycle.com).
17 A representative procedure for the synthesis of compounds 11b. To
a solution of fluorous benzaldehyde 6a (1.2 g, 2.0 mmol) in ethanol
(4 mL) was added aniline 7 (272 mL, 3.0 mmol), isobutyraldehyde 8
(273 mL, 3.0 mmol) and Yb(OTf)3 (496 mg, 0.8 mmol). The mixture
was heated under microwave (Biotage Initiator 8) at 50 ◦C for 20 min.
The reaction mixture was purified by F-SPE eluted with 40 mL of
80 : 20 MeOH–H2O and then 40 mL of MeOH. The, MeOH fraction
was concentrated to give 11b (1.3 g, 89% yield). An analytical sample
was obtained by further purification by flash chromatography with
0–20% gradient of EtOAc–hexanes. 1H NMR (300 MHz, CDCl3) d
0.67 (s, 3H), 0.93 (s, 3H), 1.20 (t, J = 13.8 Hz, 3H), 3.44–3.50 (m,
1H), 3.62–3.69 (M, 2H), 4.15 (s, 1H), 4.61 (s, 1H), 6.61–6.71 (m, 2H),
This work was supported by the University of Massachussetts
Boston Healey grant. We thank Weiyi Li, Minh-Thu N. Huynh
and Min Lin for particitaing some experimental works of this
project.
7.10–7.17 (m, 2H), 7.24 (d, J = 8.1 Hz, 1H), 7.40–7.50 (m, 3H). 13
C
NMR (75 MHz, CDCl3) d 15.5, 19.1, 23.4, 36.2, 59.6, 64.4, 83.0,
114.3, 116.6, 119.9, 120.5, 122.0, 129.1, 129.2, 129.6, 131.0, 143.6,
144.1, 149.7. LC-MS (APCI+) m/z 734 [M + 1]+.
Notes and references
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18 A representative procedure for the synthesis of compounds 12e. To
a solution of 11a (469 mg, 0.6 mmol) in 1,2-dichloroethane (3 mL)
was added coumarin (146 mg, 0.9 mmol) and p-toluenesulfonic acid
(21 mg, 0.1 mmol). The mixture was heated under microwave (Biotage
Initiator 8) at 85 ◦C for 30 min. The reaction mixture was purified by
F-SPE eluted with 20 mL of 80 : 20 MeOH–H2O and then 20 mL of
MeOH. The, MeOH fraction was concentrated to give 12e (393 mg,
71% yield). An analytical sample was obtained by further purification
by flash chromatography with 0–10% gradient of EtOAc–hexanes. 1H
NMR (300 MHz, CDCl3) d 0.97 (s, 3H), 1.02 (s, 3H), 3.78 (s, 3H),
3.84 (s, 1H), 4.99 (s, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.65 (dd, J =
2.7 Hz, 3.0 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.24–7.32 (m, 2H),
7.42 (d, J = 7.8 Hz, 1H), 7.49–7.72 (m, 2H), 7.79 (s, 1H), 7.81 (d,
J = 4.8 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 22.2, 22.9, 33.4,
42.1, 55.9, 96.0, 106.1, 113.8, 114.3, 115.5, 116.9, 122.1, 122.4, 122.7,
124.1, 125.6, 128.8, 129.9, 131.9, 132.6, 141.5, 149.7, 152.4, 153.5.
LC-MS (APCI+) m/z 924 [M + 1]+.
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6, 1473–1476. See also ref. 11a.
20 A representative procedure for the synthesis of compounds 5d. To a
solution of 12h (92 mg, 0.1 mmol) in a co-solvent of 4 : 1 : 4 acetone:
H2O: HFE 7200 (3 mL) was added phenylboronic acid 10a (18 mg,
0.15 mmol), Cs2CO3 (81 mg, 0.25 mmol) and Pd(dppf)Cl2 (16 mg,
0.02 mmol). The mixture was heated under microwave (Biotage
Initiator 8) at 100 ◦C for 30 min. The reaction mixture was purified
by flash chromatography with 0–30% gradient of EtOAc–hexanes to
9 W. Zhang, Green Chem., 2009, 11, 911–920.
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give 5d (24 mg, 48% yield). H NMR (300 MHz, CDCl3) d 1.02 (s,
3H), 1.05 (s, 3H), 3.78 (s, 3H), 3.85 (s, 1H), 5.05 (s, 1H), 6.56 (d,
J = 8.7 Hz, 1H), 6.65 (dd, J = 2.4 Hz, 2.7 Hz, 1H), 7.10 (d, J =
2.7 Hz, 1H), 7.27–7.31 (m, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.50 (t,
J = 14.1 Hz, 3H), 7.66–7.72 (m, 4H), 7.81–7.90 (m, 4H). 13C NMR
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113.8, 115.8, 116.9, 123.0, 124.0, 125.5, 126.8, 127.3, 127.9, 129.1,
129.3, 131.7, 133.2, 137.3, 140.4, 142.0, 152.4, 153.1, 159.8, 162.5.
LC-MS (APCI+) m/z 502 [M + 1]+.
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This journal is
The Royal Society of Chemistry 2011
Green Chem., 2011, 13, 847–849 | 849
©