Synthesis of a novel chemotype via sequential metal-catalyzed cycloisomerizations

Article abstract of DOI:10.3762/bjoc.8.153

Sequential cycloisomerizations of diynyl o-benzaldehyde substrates to access novel polycyclic cyclopropanes are reported. The reaction sequence involves initial Cu(I)-mediated cycloisomerization/nucleophilic addition to an isochromene followed by diastereoselective Pt(II)-catalyzed enyne cycloisomerization.

Full text of DOI:10.3762/bjoc.8.153

Synthesis of a novel chemotype via sequential
metal-catalyzed cycloisomerizations
Bo Leng, Stephanie Chichetti, Shun Su, Aaron B. Beeler
and John A. Porco Jr.*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1338–1343.
Department of Chemistry and Center for Chemical Methodology and
Library Development (CMLD-BU), Boston University, 590
Commonwealth Avenue, Boston, Massachusetts 02215, USA
doi:10.3762/bjoc.8.153
Received: 24 May 2012
Accepted: 13 July 2012
Published: 20 August 2012
Email:
John A. Porco Jr.* - porco@bu.edu
This article is part of the Thematic Series "Recent developments in
chemical diversity".
* Corresponding author
Keywords:
Associate Editor: D. Spring
chemical diversity; cycloisomerization; cyclopropane; diyne;
isochromene; π-acid
© 2012 Leng et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Sequential cycloisomerizations of diynyl o-benzaldehyde substrates to access novel polycyclic cyclopropanes are reported. The
reaction sequence involves initial Cu(I)-mediated cycloisomerization/nucleophilic addition to an isochromene followed by dia-
stereoselective Pt(II)-catalyzed enyne cycloisomerization.
Introduction
Our laboratory has an ongoing interest in discovering transfor- using alkynyl o-benzaldehyde scaffolds, which revealed a
mations that afford novel chemotypes [1-4]. To this end, we number of reactions affording novel polycyclic scaffolds,
have developed a reaction screening paradigm that enables the including Au(III)-catalyzed addition of diethyl malonate to 1 to
discovery of new reaction processes and chemotypes [5]. For afford isochromene 2 (Scheme 1). The chemotypes discovered
example, we have conducted multidimensional reaction screens in initial pilot studies have been further developed into library
Scheme 1: Cycloisomerization/nucleophilic addition of alkynyl benzaldehyde 1 to isochromene 2.
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Beilstein J. Org. Chem. 2012, 8, 1338–1343.
scaffolds and identified as biologically interesting structures [6].
Herein, we report the expanded utility of alkynyl o-benzalde-
hydes through a sequential metal-catalyzed cycloisomerization
process to afford a novel polycyclic cyclopropane chemotype.
Results and Discussion
In an effort to further explore the utility of alkynyl o-benzalde-
hydes as scaffolds for reaction screening, we designed a focused
reaction screen with diynyl benzaldehyde [7] substrate 3. Based
on the cycloisomerization/addition reactions previously studied
(Scheme 1), it was not clear at the outset of our study whether
an o-alkynyl benzaldehyde containing an additional alkynyl
moiety (3) would react to form an isochromene derivative or
whether additional polycyclization would occur [8]. Accord-
ingly, a reaction screen was conducted, evaluating a number of
metal catalysts in the presence of diethyl malonate. From this
focused reaction screen we identified three types of reactivity:
(1) no reaction; (2) alkyne hydration (4); and (3) cycloisomer-
ization leading to isochromene (5) (Figure 1). Many catalysts
resulted in no reaction, including ones that might have been
expected to catalyze cycloisomerization, such as AgOTf. Two
catalysts, Cu(OTf)2 and Pd(MeCN)2Cl2, afforded only hydra-
Figure 1: Reaction screen with diynyl benzaldehyde 3.
tion of the alkyne. Interestingly, hydration was regioselective, to explore this manifold of reactivity. Based on reports by
which is possibly due to direction from the ether oxygen. We Echavarren and co-workers [14,15], we treated enyne 5 with
were most interested in metal catalysts that effected cycloiso- PtCl2 at 80 °C in toluene [16,17]. The reaction afforded poly-
merization of 3 to alkynyl isochromene 5, which is an interest- cyclic cyclopropane 6 in good yield (65%) as a single diastereo-
ing enyne substrate with potential for further reactivity [9,10]. mer (Scheme 2a). Interestingly, reaction of 3 in the presence of
In the reaction screen of alkynyl benzaldehyde substrate 3, we only PtCl2 afforded exclusively isochromene 5 in low yield.
found that in the absence of optimization Cu(MeCN)4PF6 [11- Further studies revealed that a multicatalytic reaction system
13] afforded the highest isolated yield of 5 (60%) (Scheme 2). [18] utilizing both Cu(I) and Pt(II) [19] catalysts afforded the
desired cyclopropane 6 in moderate yield (40%) along with
As the production of isochromene 5 offered a unique opportu- ketone 7 (45%), derived from [4 + 2] cycloaddition of the
nity for additional cycloisomerization processes, we elected benzopyrylium intermediate with the pendent alkyne [20]
Scheme 2: Sequential cycloisomerizations of substrate 3. Condition A: PtCl2 (10 mol %), Cu(MeCN)4PF6 (10 mol %), toluene, 80 °C, 8 h (40%).
Condition B: Step 1: Cu(MeCN)4PF6 (10 mol %), rt, 1 h. Step 2: PtCl2 (10 mol %), 80 °C, toluene, 5 h (89%).
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Beilstein J. Org. Chem. 2012, 8, 1338–1343.
(Scheme 2b). However, better yields were observed when the We next focused on an evaluation of the general scope of the
initial cycloisomerization was carried out in the presence of reaction with regard to aryl and alkyne substitution. Reaction
Cu(MeCN)4PF6 followed by the addition of PtCl2 to the reac- utilizing an electron-poor trifluoromethyl-substituted diynyl
tion mixture (Scheme 2b). Optimization of the one-pot condi- benzaldehyde 8 was successful, producing product 9 in
tions afforded exclusively 6 in good yield (89%). X-ray crystal moderate yield (Table 1, entry 1). m-Methyl- and naphthyl-
analysis confirmed the structure and relative stereochemistry of containing substrates 10 and 12 afforded polycyclic cyclo-
polycyclic cyclopropane 6 (Figure 2, Supporting Information propanes 11 and 13 in 48 and 51% yields, respectively (Table 1,
File 1).
entries 2 and 3).
Table 1: Sequential cycloisomerizations of diynyl benzaldehyde substrates.
entry
aldehyde
product
yield entry
aldehyde
product
yield
62%
1
53%
5
9
16
18
20
8
17
2
48%
6
59%
11
19
10
3
51%
7
82%
13
21
12
4
60%
8
65%
23
14
15
22
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Beilstein J. Org. Chem. 2012, 8, 1338–1343.
benzaldehyde 3 and dimethyl malonate is catalyzed by Cu(I) to
afford isochromene 24 [20-22]. Pt(II) π-coordination of the
pendant alkyne of 24 followed by cyclization of the enol ether
affords the seven-membered-ring metal-“ate” intermediate 25.
The cyclization occurs at the face opposite the malonate
substituent (Nu, 24a) to minimize steric interactions relative to
24b, leading to the observed diastereoselectivity (Scheme 3,
inset) [23,24]. Subsequent cyclopropane formation through ad-
dition of the vinyl metal to the oxonium intermediate affords
metallocarbenoid 26, which may then undergo a 1,2-hydride
shift to intermediate 27 followed by elimination of the metal
catalyst [25] to afford the observed cyclopropane product 6.
An alternative reaction pathway may be invoked for the ethyl-
substituted substrate 22 leading to product 23 (Scheme 4). After
initial cyclization of the enol ether with the Pt-activated alkyne,
the resulting metal-“ate” intermediate 28 may undergo preferen-
tial elimination and proto-demetallation to afford 1,5-diene 29.
A second elimination results in the ring-opened triene 30.
Figure 2: X-ray crystal structure of cyclopropane 6.
We next explored substitution of the pendant alkyne. Reaction Subsequent 6π-electrocyclization affords alcohol 31, which
with cyclohexane diyne 14 afforded the fused cyclopropane 15 aromatizes through loss of water to afford the observed isochro-
in moderate yield (60%), while methyl ether 16 afforded cyclo- mane 23.
propane 17 in 62% yield. Phenyl substitution (18) also resulted
in a moderate yield (59%, Table 1, entry 6). Substituting the Conclusion
oxygen with N-tosyl (20) afforded N-tosyl cyclopropane 21 in We have described sequential cycloisomerizations of diynyl
good yield (82%). Substitution at the internal methylene (22) o-benzaldehyde substrates to access novel polycyclic cyclo-
resulted in a diverted reaction pathway (vida infra) affording propanes. The reaction sequence involves initial Cu(I)-
product 23 exclusively in moderate yield (65%).
mediated cycloisomerization/nucleophilic addition to an
isochromene followed by diastereoselective Pt(II)-catalyzed
A proposed mechanistic pathway for diastereoselective, sequen- enyne cycloisomerization. The chemistry reported herein
tial cycloisomerizations is shown in Scheme 3. We propose the illustrates the power of sequential cycloisomerization processes
initial cycloisomerization and nucleophilic addition of diynyl to provide access to novel chemotypes and chemical diversity
Scheme 3: Proposed reaction pathway for diastereoselective, sequential cycloisomerization.
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Beilstein J. Org. Chem. 2012, 8, 1338–1343.
Scheme 4: Proposed alternative reaction pathway affording 23.
from readily accessible building blocks [26]. Further transfor- benzaldehyde 3 (1.5 g, 7.1 mmol, 66%) as a viscous yellow oil.
mations of the novel polycyclic cyclopropanes as well as 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.91 (d, J =
additional studies employing reaction screening for metal- 7.6 Hz, 1H), 7.57 (m, 2H), 7.46 (m, 1H), 4.54 (s, 2H), 4.29 (q, J
mediated processes is ongoing and will be reported in future = 2.4 Hz, 2H), 1.89 (t, J = 2.4 Hz, 3 H); 13C NMR (100 MHz,
publications.
CDCl3) δ 191.6, 136.2, 133.8, 133.6, 129.0, 127.3, 126.1, 91.9,
83.7, 82.2, 74.2, 57.6, 57.1, 3.7; IR (thin film) νmax: 2920, 2852,
1697, 1594, 1477, 1450, 1350, 1274, 1244, 1193, 1138, 1076,
765 cm−1.
Experimental
General Information: All nuclear magnetic resonance spectra
were recorded on either a Varian or Bruker spectrometer.
1H NMR spectra were recorded at 400 MHz at ambient General one-pot procedure for sequential cycloisomeriza-
temperature with CDCl3 as solvent, unless otherwise stated. tion: To a flame-dried round-bottom flask was added 3 (10 mg,
13C NMR spectra were recorded at 100.0 MHz at ambient 0.046 mmol), dimethyl malonate (5.8 μL, 0.05 mmol) and
temperature with CDCl3 as solvent, unless otherwise stated. toluene (1.0 mL). To the reaction mixture was added
Chemical shifts are reported in parts per million relative to tetrakis(acetonitrile)copper(I) hexafluorophosphate (1.7 mg,
CDCl3 (1H, δ 7.27; 13C, δ 77.0) and acetone-d6 (1H, δ 2.05; 0.005 mmol), and the reaction mixture was stirred at room
13C, δ 30.8). Data for 1H NMR are reported as follows: chem- temperature for 1 h. Platinum(II) chloride (1.2 mg, 0.005 mmol)
ical shift, multiplicity (ovrlp = overlapping, s = singlet, d = was added and the reaction mixture was heated to 80 °C for 5 h.
doublet, t = triplet, q = quartet, qt = quintuplet, m = multiplet), The reaction mixture was concentrated in vacuo and purified by
coupling constant in hertz, and integration. All 13C NMR flash chromatography (SiO2, petroleum ether/EtOAc 9:1 to 4:1)
spectra were recorded with complete proton decoupling. to afford the desired cycloisomerization product 6 (14 mg,
Analytical LC was performed on a 2.1 × 50 mm, 1.7 μM C18 0.041 mmol, 89%) as a white solid. 1H NMR (400 MHz,
column. Analytical thin-layer chromatography was performed CDCl3) δ 7.25 (m, 2H), 7.08 (m, 1H), 6.98 (d, J = 4.2 Hz, 1H),
by using 0.25 mm silica gel 60-F plates. Otherwise, flash chro- 6.11 (d, J = 5.6 Hz, 1H), 5.28 (d, J = 10.4 Hz, 1H), 5.07 (d, J =
matography was performed by using 200–400 mesh silica gel. 5.6 Hz, 1H), 4.33 (d, J = 10.0 Hz, 1H), 3.92 (d, J = 10.8 Hz,
Yields refer to chromatographically and spectroscopically pure 1H), 3.83 (s, 3H), 3.66 (d, J = 10.0 Hz, 1H), 3.49 (s, 3H), 2.51
materials, unless otherwise stated. Acetonitrile, CH2Cl2, THF, (s, 1H), 0.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.3,
and toluene were purified by passing through two packed 166.4, 141.0, 135.8, 133.7, 130.8, 130.3, 128.9, 126.2, 111.1,
columns of neutral alumina. All reactions were performed under 75.0, 63.9, 62.7, 59.4, 53.2, 52.7, 30.5, 26.4, 12.2; IR (thin film)
an argon atmosphere in oven-dried or flame-dried glassware.
νmax: 2953, 2926, 2870, 1761, 1741, 1679, 1639, 1493, 1435,
1341, 1253, 1194, 1144, 1073, 1018, 912, 774, 749 cm−1;
General procedure for the synthesis of alkynyl o-benzalde- HRMS–ESI+ (m/z): [M + Na]+ calcd for C19H20O6, 367.1158;
hydes: 2-(3-(but-2-ynyloxy)prop-1-ynyl)benzaldehyde. To a found, 367.1189.
solution of 2-bromobenzaldehyde (2.0 g, 10.8 mmol) and
1-(prop-2-ynyloxy)but-2-yne (1.4 g, 13 mmol) in Et3N (68 mL),
Supporting Information
was added tetrakis(triphenylphosphine)palladium(0) (0.38 g,
0.32 mmol). The reaction mixture was stirred at room tempera-
Supporting Information File 1
ture for 5 min. Copper(I) iodide (0.075 g, 0.4 mmol) was added,
and the mixture was heated to 60 °C overnight. The mixture
was concentrated in vacuo and purified by flash chromatog-
raphy (SiO2, petroleum ether/EtOAc 4:1) to afford diynyl
Characterization data, spectra, and crystal structure data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-153-S1.pdf]
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Acknowledgements
Financial support from the NIGMS (P41 GM076263 and P50
GM067041) is gratefully acknowledged. We thank Professors
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