Synergistic catalysis: Highly diastereoselective benzoxazole addition to Morita-Baylis-Hillman carbonates

Article abstract of DOI:10.1039/c4cc00728j

An expedited method has been developed for the diastereoselective synthesis of highly functionalized alkyl-azaarene systems with good yields and high diastereoselectivities (>15:1 dr). The methodology includes a synergistic catalysis event involving organometallic (10 mol% AgOAc) activation of an alkyl azaarene and Lewis base (10 mol% DABCO) activation of a Morita-Baylis-Hillman carbonate. The structure and relative configuration of a representative product were confirmed by X-ray analysis. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00728j

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Synergistic catalysis: highly diastereoselective
benzoxazole addition to Morita–Baylis–Hillman
carbonates†
Cite this: Chem. Commun., 2014,
50, 7447
Received 29th January 2014,
Accepted 16th May 2014
Victor Ceban,a Piotr Putaj,ab Marta Meazza,a Mateusz B. Pitak,a Simon J. Coles,a
Jan Veselyb and Ramon Rios*a
DOI: 10.1039/c4cc00728j
www.rsc.org/chemcomm
An expedited method has been developed for the diastereoselective
synthesis of highly functionalized alkyl-azaarene systems with good
yields and high diastereoselectivities (415 : 1 dr). The methodology
includes a synergistic catalysis event involving organometallic
(10 mol% AgOAc) activation of an alkyl azaarene and Lewis base
(10 mol% DABCO) activation of a Morita–Baylis–Hillman carbonate.
The structure and relative configuration of a representative product
were confirmed by X-ray analysis.
Synergistic catalysis,1 in which two catalytic cycles involving
two separate catalysts work in a concerted fashion to create a
single new bond, has emerged as a powerful approach for the
development of new reactions. The concurrent activation of both
nucleophile and electrophile using distinct catalytic species
facilitates the enhancement of inherent chemical reactivity and
allows for the synthesis of complex scaffolds that might be
difficult to obtain otherwise (Fig. 1). While synergistic catalysis
is more prevalent in nature, the principle has now begun to
emerge as a recognized and valued approach to bond-forming
processes in organic chemistry.
Fig. 1 Suggested mechanism.
Based on our previous experience in organocatalysis and
organometallic chemistry,2 we envisioned that a system in photoredox-mediated a-alkylations, as developed by MacMillan.5
which an organometallic catalyst and organocatalyst operate in However, the use of a simple metallic Lewis acid and organic Lewis
synergy could provide further opportunities for the development base as a synergistic catalytic system has been less extensively
of new reaction.
explored, probably due to the presumption that self-quenching
Several examples of synergistic catalyst systems mixing organo- would occur, which renders both catalysts inactive. The first
catalytic and organometallic processes can be found in the literature; example was reported by Corey and Wang in 1993, who applied
for example, Cordova demonstrated the b-arylation3 or b-silylation4 this method to the cyanation of aldehydes;6 they developed a dual
of enals by combining iminium and Pd catalytic processes with catalytic system wherein a chiral Lewis base creates a chiral
excellent results; further representative procedures include cyanide nucleophile, while a chiral Lewis acid activates the
aldehyde. More recently, several research groups developed Lewis
a Chemistry, Faculty of Natural & Environmental Sciences,
base-catalyzed cycloadditions and cyclizations using Cinchona
alkaloids or N-heterocyclic carbenes and a metallic Lewis acid.7
Concurrently, Lectka and coworkers developed a synthesis of
b-lactams based on this concept.8
Recently, we became interested in studying the reactivity of
Morita–Baylis–Hillman (MBH) carbonates;9 however, one of the
drawbacks of their use in nucleophilic additions is the need for
University of Southampton, Highfield Campus, Southampton, SO17 1BJ, UK.
E-mail: R.Rios-Torres@southampton.ac.uk
b Department of Organic Chemistry, Faculty of Science, Charles University in Prague,
Hlavova 2030, 128 43 Praha 2, Czech Republic
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data. CCDC 978247. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4cc00728j
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 7447--7450 | 7447

View Article Online
Communication
ChemComm
Table 1 Reaction optimizationa
strong nucleophiles such as malonates, amines, or alcohols for
suitable reactivity. Some less active nucleophiles, such as alkyl
azaarenes, are unreactive.
Based on the idea of synergistic catalysis, we devised the
addition of alkyl azaarenes (specifically, benzoxazoles and
pyridines) to MBH carbonates by the use of two different
catalysts (metal Lewis acid and organic Lewis base).
Lewis
acid
T
(1C)
Lewis
base
Conv.b
(%)
Entry
Solvent
d.r.c
Shibata and coworkers reported one of the rare examples of
the simultaneous use of a metal Lewis acid and organic Lewis
base using this kind of substrate.10 They reported that the use
of FeCl2 or Ti(OiPr)4 increase the enantioselectivity of their
reaction but it was not crucial for reactivity.
Alkyl benzoxazoles are an interesting class of heterocycle
that have found wide use in the fields of agro- and medicinal
chemistry. Several methods have been developed for their syn-
thesis and functionalization. Despite growing attention from the
chemical community directed at these compounds, the synthesis
of alkyl benzoxazoles remains unexplored. To the best of our
knowledge, just a single example exists in the literature regarding
the addition of alkyl benzoxazoles to imines catalyzed by
Pd–bisoxazolidinone complexes with excellent results, as reported
by Lam and coworkers in 2012 (Scheme 1).11
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Pd(OAc)2
Cu(OAc)2
YbTf3
CuTf2
PdCl2
AgOBz
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgSbF6
AgOAc
—
50
50
50
50
50
50
50
50
50
50
r.t.
0
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
—
71
Traces
9
9
50
43
50
50
n.r.
25
100
100
100
n.r.f
n.r.f
Traces
2 : 1
n.d.e
2.5 : 1
4 : 1
2 : 1
8 : 1
15 : 1
1 : 1
9
CHCl3
THF
—
10
11d
12d
13d
14d
15d
16d
5 : 1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
415 : 1
415 : 1
415 : 1
—
r.t.
r.t.
r.t.
r.t.
DABCO
DMAP
—
AgOAc
n.d.e
a
In a small vial, 1.0 equiv. of benzoxazole 1a, 2 equiv. of MBH
carbonate 2a were added in 1 mL of the corresponding solvent in the
presence of 10% Lewis acid and 10% Organic base. The reaction was
b
In this work we report the first example of alkyl-azaarene
addition to MBH carbonates using synergistic catalysis. This
methodology provides highly functionalized alkyl azaarenes
and may potentially lead to the development of new scaffolds
of interest to the agrochemical and pharmaceutical industries.
stirred at the temperature shown in the table for 14 h. Determined by
1H NMR of the crude mixture. Determined by 1H NMR of the crude
c
d
mixture. Reaction carried out with 4 equiv. of MBH carbonate 2a.
e
f
n.d. = not determined. n.r. = no reaction.
As shown in Fig. 1, we envisioned that a metal Lewis acid different solvents. DMF gave good conversions, but without any
could interact with the alkyl azaarene via nitrogen coordination, diastereoinduction (entry 8), CHCl3 yielded only traces of the final
thus increasing the acidity of the a-carbon. Simultaneous reaction adduct after 14 h (entry 9), and THF gave lower conversions and
of an organic Lewis base with the MBH carbonate via SN20 addition diastereoselectivities than that observed for toluene (entry 10). Next,
with release of carbonic acid yields highly reactive intermediate 6, the reaction was performed at different temperatures while
which reacts with the previously activated nucleophile 5 to form simultaneously increasing the equivalents used of MBH carbonate
the product (3) after release of the organic catalyst.
(2a; from 2 to 3). The reactions gave full conversions after 14 h and
In our preliminary experiments, we investigated the reaction with total diastereoselectivity when conducted at room temperature
of MBH carbonate 2a with 2-ethyl-6-nitrobenzoxazole (1a) in the (r.t.) or 0 1C (entries 11 and 12); this increase in the final conversion
presence of different metal Lewis acids, solvents, organic Lewis is likely due the decreased MBH carbonate decomposition at the
bases, etc. As shown in Table 1, the reaction is quite flexible in low temperatures used. AgSbF6 was used as a catalyst to determine
the nature of the metal Lewis acid. Satisfactorily, Pd(OAc)2 and whether acetate plays a role in the reaction (entry 13); a similar
DABCO were able to catalyze the reaction, affording (after 14 h result was observed as that with AgOAc. Finally, the reactions were
at 50 1C) a 2 : 1 diastereomeric mixture of adduct 3a in 71% performed without Lewis acid or Lewis base to prove that synergistic
conversion.
catalysis indeed promotes this reaction; no reaction was observed in
We next tested several metal Lewis acids; copper and ytterbium both cases, showing that activation of both compounds is necessary
salts gave low conversions after 14 h, with only moderate diastereo- (entries 14 and 15). Using DMAP as Lewis base instead of DABCO
selectivities (Table 1; entries 2–4); PdCl2 exhibited similar reactivity did not provide any product (entry 16).
to that of Pd(OAc)2 (entry 5). Fortunately, upon switching to silver
Once the optimal conditions were identified, we next examined
salts, the reaction provided moderate to good conversions with the scope of the reaction in terms of the MBH carbonate. As shown
excellent diastereoselectivities (entries 6–7). Once the optimal Lewis in Scheme 2, the reaction provides the final adducts in excellent
acid (AgOAc) was determined, the reaction was next examined with yields and diastereoselectivities in almost all examples; the reac-
tion did not work only when aliphatic MBH carbonates or bulky
di-ortho-substituted MBH carbonates (3h and 3i) were employed.
We also studied the effect of the ester substituent; tert-butyl
derivatives only gave traces of 3j, likely due to the higher steric
hindrance. The reaction tolerates para- (3c, 3d, and 3g),
meta- (3f), and ortho- (3i) halogen substitution on the aromatic
Scheme 1 Organometallic methodology for the synthesis of azaarenes
developed by Lam (2012).
ring, giving the final compounds in very good yields and
7448 | Chem. Commun., 2014, 50, 7447--7450
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
Table 2 Catalyst loadinga
Entry
Ag(OAc) (%)
DABCO (%)
Conv.b (%)
d.r.c
1
2
3
4
5
6
7
20
10
5
1
5
1
10
10
10
10
10
5
1
5
100
100
62
35
50
20
Traces
415 : 1
415 : 1
415 : 1
415 : 1
415 : 1
415 : 1
—
a
In a small vial, 1.0 equiv. of benzoxazole 1a, 4 equiv. of MBH
carbonate 2g were added in 1 mL of toluene in the presence of Lewis
acid and organic base. The reaction was stirred at room temperature for
14 h. Determined by 1H NMR of the crude mixture. Determined by
b
c
1H NMR of the crude mixture.
substituents were present on the aromatic ring (3s). These results
suggest that an electron-withdrawing group is needed to lower the
pKa of the benzoxazole. Next, we decided to study the scope of the
reaction with benzoxazoles bearing different alkyl chains. Increas-
ing the length of the alkyl chain did not affect the outcome of the
reaction (3m). However, the use of tertiary carbons in the a-position
(3u) rendered the benzoxazole unreactive under the reaction con-
ditions. Finally, we employed a highly reactive benzoxazole bearing
a labile group in the alkyl chain; adduct 3p was produced in
excellent diastereoselectivities, albeit in low yields, probably due the
decomposition of the starting benzoxazole in the reaction.
Encouraged by the excellent results obtained with benzoxazoles,
we tested the reaction with different heterocycles. Oxazolopyridine
reacted with MBH carbonates to give adduct 3m in excellent
yield and in diastereopure form. Pyridine derivatives (4-methyl-
3-nitropyridine) were also applicable in the reaction. However
the reaction gave the alkyl azaarene derivatives in low yields
(3q and 3t).
Scheme 2 Reaction scope using MBH carbonate.12
overall diastereoselectivities. Only in the case of 2-bromo sub-
stitution (3i) were the yields observed to drop slightly. A para-
electron-withdrawing nitro group gave the final adduct 3e in
almost quantitative yield and in diastereopure form; para-methyl-
substituted MBH carbonate gave 3b in excellent yield and
diastereoselectivity.
The scope of the reaction in terms of the alkyl azaarene
employed was next examined, as shown in Scheme 3. Different
substituents on the benzoxazole ring were first investigated; an
electron-withdrawing substituent was found to be a requirement
for reactivity. Nitro derivatives 3e, 3l, 3n, 3o, and 3r provided
adducts in good yields and overall diastereoselectivity. The
benzoxazole with ester substitution gave final compound 3w in
low yield, but with the same diastereoselectivity. Unfortunately,
the reaction did not take place when no electron-withdrawing
Catalyst loading was next examined. As shown in Table 2,
decreasing the AgOAc loading gave successively poorer con-
versions after 14 h; however, the diastereoselectivity remained
the same (entries 1–6). In terms of DABCO, the reaction with
5 mol% DABCO and 10 mol% AgOAc only renders traces of the
expected product.
The relative configuration of the products was ascertained
by X-ray diffraction analysis of a single crystal of 3i. The major
Fig. 2 Molecular structure of compound 3i. Displacement ellipsoids are
drawn at the 50% probability level.13
Scheme 3 Reaction scope using alkyl azaarenes.12
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 7447--7450 | 7449

View Article Online
Communication
ChemComm
(Channel) – England cross-border cooperation Programme.
J.V. thanks GAUK No. 427011. Publication is co-financed by
the European Social Fund and the state budget of the Czech
Republic (Project CZ.1.07/2.3.00/30.0022) This work was done
under the auspices of COST Action CM0905 (ORCA).
Notes and references
Fig. 3 Proposed transition state.
1 A. E. Allen and D. W. C. MacMillan, Chem. Sci., 2012, 3,
633–658.
2 (a) X. Companyo, A. Zea, A.-N. R. Alba, A. Mazzanti, A. Moyano and
R. Rios, Chem. Commun., 2010, 46, 6953–6955; (b) S. Cihalova, G. Valero,
J. Schimer, M. Humpl, M. Dracinsky, A. Moyano, R. Rios and J. Vesely,
Tetrahedron, 2011, 67, 8942–8950; (c) C. Jimeno, R. Rios, P. J. Carroll and
P. J. Walsh, Tetrahedron, 2004, 60, 4543–4548.
3 I. Ibrahem, G. Ma, S. Afewerki and A. Cordova, Angew. Chem., Int. Ed.,
2013, 52, 878–882.
4 I. Ibrahem, S. Santoro, F. Himo and A. Cordova, Adv. Synth. Catal.,
2011, 353, 245–252.
5 C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013,
113, 5322–5363 and references there in.
6 E. J. Corey and Z. Wang, Tetrahedron Lett., 1993, 34, 4001–4004.
7 For example, see: (a) D. E. A. Raup, B. Cardinal-David, D. Holte and
K. A. Scheidt, Nat. Chem., 2010, 2, 766–771; (b) M. A. Calter, O. A.
Tretyak and C. Flaschenriem, Org. Lett., 2005, 7, 1809–1812.
8 (a) A. E. Taggi, H. Wack, A. M. Hafez, S. France and T. Lectka, Org.
Lett., 2002, 4, 627–629; (b) T. Dudding, A. M. Hafez, A. E. Taggi, T. R.
Wagerle and T. Lectka, Org. Lett., 2002, 4, 387–390; (c) A. M. Hafez,
A. E. Taggi, T. Dudding and T. Lectka, J. Am. Chem. Soc., 2001, 123,
10853–10859; (d) A. M. Hafez, A. E. Taggi, H. Wack, W. J. Drury III
and T. Lectka, Org. Lett., 2000, 2, 3963–3965.
9 (a) X. Companyo, A. Mazzanti, A. Moyano, A. Janecka and R. Rios,
Chem. Commun., 2013, 49, 1184–1186; (b) B. Wang, X. Companyo,
J. Li, A. Moyano and R. Rios, Tetrahedron Lett., 2012, 53, 4124–4129;
(c) X. Companyo, G. Valero, V. Ceban, T. Calvet, M. Font-Bardia,
A. Moyano and R. Rios, Org. Biomol. Chem., 2011, 9, 7986–7989;
Scheme 4 Asymmetric addition of benzoxazole 1a to MBH carbonate 2e.
diastereomer of the addition possessed an (R,R) relative con-
figuration (Fig. 2).
Based on the configuration of 3i, we propose the following
transition state in which the aromatic ring of the benzoxazole,
organic Lewis base, and aryl substituent of the MBH carbonate
are on opposite sides to avoid steric interactions (Fig. 3).
Initial experiments have been done in order to develop an
enantioselective version of the present reaction. As shown in
Scheme 4, the use of b-ICD instead DABCO, we get the final
compound in moderate yields and enantioselectivities. We also
explored the use of chiral ligands such as (R)-BINAP obtaining
the final compound, in good yields but low enantioselectivities.
For
a review, see: (d) R. Rios, Catal. Sci. Technol., 2012, 2,
267–278.
10 T. Furukawa, J. Kwazoe, W. Zhang, T. Nishimine, E. Tokunaga,
T. Matsumoto, M. Shiro and N. Shibata, Angew. Chem., Int. Ed., 2011,
50, 9684–9688.
Remarkably in both cases the diastereoselectivity of the reaction 11 D. Best, S. Kujawa and H. W. Lam, J. Am. Chem. Soc., 2012, 134,
18193–18196.
remains excellent. This initial data open a gate for the develop-
ment of a chiral version of the present reaction.
12 Experimental procedure: in small vial, benzoxazole 1a (0.1 mmols),
MBH carbonate 2a (0.4 mmols), AgOAc 2 mg (10 mol%) and DABCO
In summary we have developed a new reaction based on
synergistic catalysis between alkyl azaarenes and MBH carbonates.
The reaction provides the final adducts in excellent yields and total
1 mg (10 mol%) were added in 1 mL of toluene, the reaction was
stirred at room temperature for 14 h. Next the crude reaction
was purified by column chromatography to afford compound 3a
(see ESI†).
diastereoselectivity. Mechanistic studies, synthetic applications, 13 Crystal data for 3i: C20H17BrN2O5, Mr = 445.26, colourless plate,
3
%
0.24 ꢀ 0.20 ꢀ 0.04 mm , Triclinic, P1, a = 8.9971(4) Å, b = 10.0949(4) Å,
development of a suitable chiral version of this new methodology,
and the discovery of new reactions based on this concept are
currently ongoing in our laboratory.
V.C, M.M and R.R acknowledge the European Regional
Development Fund (ERDF) for co-financing the AI-CHEM-
Chem project (No. 4061) through the INTERREG IV A France
c = 11.5631(8) Å, a = 70.132(5)1, b = 68.095(5)1, g = 80.935(6)1, V =
915.83(9) Å3, Z = 2, Dc = 1.615 g/cm3, m = 2.280 mmꢁ1, T = 100 K,
12120 collected reflections, 4167 unique reflections (Rint = 0.0244),
3969 reflections with F2 4 2, R(F2 4 2) = 0.0257, wR2 = 0.0684,
GoF = 1.082. Crystallographic data (excluding structure factors) for
the structure 3i have been deposited with the Cambridge Crystallo-
graphic Data Centre with CCDC number 978247.
7450 | Chem. Commun., 2014, 50, 7447--7450
This journal is ©The Royal Society of Chemistry 2014