Nickel-catalyzed cross-coupling of chromene acetals and boronic acids

Article abstract of DOI:10.1021/ol300364s

A modular and highly efficient protocol for the synthesis of 2-aryl- and heteroaryl-2H-chromenes is described. Under base-free conditions, readily accessible 2-ethoxy-2H-chromenes undergo C_sp3-O activation and C _sp3-C bond formation in the presence of an inexpensive nickel catalyst and boronic acids. This new strategy enables broad access to 2-substituted-2H-chromenes and has been applied to the late-stage incorporation of complex molecules, including the pharmaceuticals loratidine and indomethacin methyl ester.

Full text of DOI:10.1021/ol300364s

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1616–1619
Nickel-Catalyzed Cross-Coupling of
Chromene Acetals and Boronic Acids
Thomas J. A. Graham and Abigail G. Doyle*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544,
United States
agdoyle@princeton.edu
Received February 14, 2012
ABSTRACT
A modular and highly efficient protocol for the synthesis of 2-aryl- and heteroaryl-2H-chromenes is described. Under base-free conditions, readily
accessible 2-ethoxy-2H-chromenes undergo Csp3ÀO activation and Csp3ÀC bond formation in the presence of an inexpensive nickel catalyst and
boronic acids. This new strategy enables broad access to 2-substituted-2H-chromenes and has been applied to the late-stage incorporation of
complex molecules, including the pharmaceuticals loratidine and indomethacin methyl ester.
2-Substituted 2H-chromenes and their analogs are per-
vasive molecular structures in chemistry, biology, and
medicine. Examples include fungicidal agents,1 potent
antioxidants (e.g., Vitamin E),2 and pharmaceuticals that
possess antitumor,3 antibacterial,4 and antiviral activity.5
The heterocycle is also used extensively as a photochromic
material6 and a precursor to flavylium dyes7 (Figure 1).
Accordingly, the availability of efficient and modular
methods for the preparation of this privileged motif is of
paramount importance.8
Numerous synthetic approaches have been devised to
access2-substituted 2H-chromenes(Scheme 1).9 Routinely
employed protocols rely on benzopyran construction from
phenol or salicylaldehyde derivatives by oxaÀMichael-type
or olefin metathesis annulations.10 These approaches
typically involve multistep sequences, incorporate the
C-2 group early in the synthesis, or lack broad generality.
Alternatively, nucleophilic substitution of chromene ace-
tals, prepared by reduction of readily available coumarins,
potentially offers a versatile solution to the synthesis of this
scaffold where the C-2 group is introduced in the final step.
Reactions with Grignard reagents are frequently used;
while these obviate the need for prefunctionalized frag-
ment synthesis,11 they often produce regioisomeric pro-
duct mixtures and are intolerant of many functional
groups.12 Schaus recently reported a related approach that
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Guimaraes, E. F.; Young, M. C. M.; Kato, M. J. J. Nat. Prod. 2004, 67,
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Caldwell, I. C.; Young, D. A. B. Nature 1981, 292, 369–370.
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Technol. 2009, 125, 249–261. (b) Bamfield, P.; Hutchings, M. G. Chromic
Phenomena: The Technological Applications of Colour Chemistry; The
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Soc. 2000, 122, 9939–9953.
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2012, 134, 1357–1362 and references therein.
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Brimble, M.; Jay-Smith, M.; Furkert, D.; Sperry, J. Synlett 2011, 2011,
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r
10.1021/ol300364s
Published on Web 03/02/2012
2012 American Chemical Society

selectively affords C-2 substituted chromenes.13,14 This
organocatalytic Petasis-like reaction uses functional group
tolerant boronate esters but is only effective for intrinsi-
cally nucleophilic partners such as cinnamyl and π-rich
arenes. For these reasons, a concise, efficient, and general
method for the synthesis of chromenes is still in demand.
of quinoline-derived N,O-acetals20 and styrenyl epoxides.21
Our preliminary mechanistic data indicated that in these
systems Csp3ÀO oxidative addition is promoted by Lewis
acid complexation of the boronic acid to the Lewis basic
oxygen of the electrophile. Inspired by these findings, we
decided to pursue the possibility that boronic acid
activation22 of an allylic acetal in the absence of a base
would encourage selective oxidative addition and trans-
metalation. A particularly attractive aspect of this ap-
proach is that it would afford a neutral method for the
synthesis of allylic ethers from widely available and stable
precursors.23
Scheme 1. Synthetic Strategies for Chromene Synthesis
Figure 1. Pharmacologically active and photochromic chro-
mene derivatives.
Herein, we report such a method: a nickel-catalyzed
cross-coupling reaction of aryl- and heteroarylboronic
acids with chromene acetals. The method represents a
mechanistic alternative to nucleophilic acetal substitution
that enables access to a broad range of previously inacces-
sible C-2 substituted chromenes by late-stage diversifica-
tion of a common scaffold. To our knowledge, it also
represents the first example of a SuzukiÀMiyaura cross-
coupling reaction with allylic acetals.
Although recent reports have described SuzukiÀ
Miyaura reactions with allylic phenoxides, acetates, and
carbonates,15 the use of allylic acetals in cross-coupling has
been limited to Kumada16 and Negishi17 reactions. Slow
oxidative addition of electron-rich Csp3ÀO bonds to a
transition metal18 and the preponderance of such bonds
in the substrate as well as the product of acetal cross-
coupling are two likely causes for this comparative lack of
success.19 We recently reported SuzukiÀMiyaura reactions
In an initial demonstration of this hypothesis, we chose
to evaluate chromene-based acetals for the preparation of
2-substituted 2H-chromenes (Scheme 1). Subjecting
2-ethoxy-2H-chromene 1a to 10 mol % Ni(cod)2, 10 mol %
PPh3, and 2 equiv of p-fluorophenyl boronic acid at rt in
dioxane/t-AmOH as solvent afforded the desired cross-
coupled heterocycle 3 in 92% yield (Figure 2). In the
absence of the Ni catalyst, 3 was not observed, even when
the reaction was conducted at elevated temperatures
(<5% yield). Furthermore, it was found that the type of
organoboron nucleophile employed significantly affected
the reaction outcome. The use of boronate esters or
potassium aryltrifluoroborate salts also did not afford
the desired product. Since these boronates are less Lewis
acidic than boronic acids the results provide circumstantial
support for the role of the boronic acid in activating the
acetal toward oxidative addition. Notably, the chromene
acetals possess two distinct ethereal leaving groups, but
selective activation of the more Lewis basic exocyclic ether
is observed. The reaction is also regioselective, delivering
(13) Moquist, P. N.; Kodama, T.; Schaus, S. E. Angew. Chem., Int.
Ed. 2010, 49, 7096–7100.
(14) For a related approach, see: Doodeman, R.; Rutjes, F. P. J. T.;
Hiemstra, H. Tetrahedron Lett. 2000, 41, 5979–5983.
(15) For a review, see: (a) Pigge, F. Synthesis 2010, 2010, 1745–1762.
For specific examples, see: (b) Nishikata, T.; Lipshutz, B. H. J. Am.
Chem. Soc. 2009, 131, 12103–12105. (c) Chung, K.-G.; Miyake, Y .;
Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000, 15–18. (d) Kobayashi,
Y.; Mizojiri, R.; Ikeda, E. J. Org. Chem. 1996, 61, 5391–5399.
(16) (a) Wenkert, E.; Ferreira, T. W. Organometallics 1982, 1, 1670–
1673. (b) Sugimura, H.; Takei, H. Chem. Lett. 1985, 351–354. (c)
Moineau, C.; Bolitt, V.; Sinou, D. Chem. Commun. 1995, 1103–1104.
(d) Gomez-Bengoa, E.; Heron, N. M.; Didiuk, M. T.; Luchaco, C. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 7649–7650. (e) Guagnano,
V.; Lardicci, L.; Malanga, C.; Menicagli, R. Tetrahedron Lett. 1998, 39,
2025–2026. (f) Moineau, C.; Bolitt, V.; Sinou, D. J. Org. Chem. 1998, 63,
582–591.
(17) Chatterjee, S.; Negishi, E. J. Org. Chem. 1985, 50, 3406–3408.
(18) Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F. J. Am. Chem.
Soc. 2007, 129, 7508–7509.
(21) Nielsen, D. K.; Doyle, A. G. Angew. Chem., Int. Ed. 2011, 50,
6056–6059.
(19) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346–
1416.
(20) Graham, T. J. A.; Shields, J. D.; Doyle, A. G. Chem. Sci. 2011, 2,
980–984.
(22) (a) Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, 2005. (b)
Zheng, H.; Lejkowski, M.; Hall, D. G. Chem. Sci. 2011, 2, 1305–1310.
(23) (a) Vo, C.-V. T.; Mitchell, T. A.; Bode, J. W. J. Am. Chem. Soc.
2011, 133, 14082–14089. (b) Mitchell, T. A.; Bode, J. W. J. Am. Chem.
Soc. 2009, 131, 18057–18059.
Org. Lett., Vol. 14, No. 6, 2012
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Figure 2. Scope of Ni-catalyzed coupling of aryl- and heteroarylboronic acids with 2-ethoxy-2H-chromene 1a.a
the aryl group to the C-2 rather than the C-4 position with
greater than 20:1 rr (regioisomeric ratio). Overall, the
method displays an expansive scope with respect to both
coupling partners, is scalable, and requires short reaction
times (vida infra). Moreover, the catalyst and ligand are
both inexpensive and purification of the products is
straightforward because the only side products arise from
acetal hydrolysis and protodeboronation.24
the outlined conditions (Figure 2, 18, 95% yield) more
sterically encumbered boronic acids were generally not
reactive. This limitation was overcome by employing a
higher reaction temperature (100 °C); at this temperature,
a PPh3/Ni ratio of 3:1 was necessary to prevent the
formation of nickel black. Under these modified condi-
tions sterically encumbered (e.g., 2,6-(CH3)2 21, 2-Ph 22)
and strongly deactivated (e.g., 2,4-(CF3)2 23) aryl boronic
acids reacted smoothly.
The reaction proved general for a broad range of aryl
boronic acids, with yields ranging from 51 to 97%
(Figure 2). High efficiency was observed regardless of the
electronic nature of the para- or meta-substituted aryl
boronic acid employed (e.g., π-neutral boronic acids
2À7, 16, 17 and π-deficient boronic acids 8À15). In this
regard, thestrategyholds a distinctadvantage overPetasis-
type reactions as its success is not governed by the intrinsic
reactivity of the nucleophile. In fact, competition studies
indicate that electron-deficient aryl boronic acids display
higher reactivity than electron-rich ones (4-CF3 > 4-H >
4-MeO).25 Notably, the reaction proceeded with similar effi-
ciency and high regioselectivity (8:1 rr) on a gram scale using
a reduced catalyst loading and an elevated concentration,
indicating that it should be a viable approach for the prepa-
rative scale synthesis of chromene derivatives (Figure 2, 2).
For ortho-substituted boronic acids, we found that the
reaction is sensitive to the steric properties of the arene.
While ortho-tolyl boronic acid could be usedat40°C under
Given the importance of heterocyclic motifs within
biologically relevant molecules, our attention turned to
heteroarylboronic acids as reaction partners. Dibenzofu-
ran (19), dibenzothiophene (20), and indole (25) boronic
acids smoothly underwent coupling (Figure 2). However,
3-pyridylboronic acid failed to deliver product. Given our
success with electron-deficient aryl boronic acids, we as-
sumed that catalyst deactivation by the basic nitrogen,
rather than the electron-deficient nature of the heterocycle,
wasresponsibleforitsrelativelackof reactivity. Pleasingly,
we found that substituted pyridyl boronic acids (Figure 2,
26À28) were compatible with the reaction conditions. The
success of these substrates appears to be the result of steric
shielding, as both trifluoromethyl (28) and methoxy (26)-
substituted pyridyl boronic acids undergo coupling with
similar efficiency. However, the use of related heteroaryl
boronic acids bearing exposed Lewis basic nitrogens
(quinoline, pyrimidine, isoxazole, imidazole) remains an
important limitation of the methodology.
(24) Determined by LC/MS.
(25) Ratio of products for 4-CF3/4-H/4-MeO was 3:1:0.6. See Sup-
porting Information for details.
The scope of the chromene acetal component in this
cross-coupling protocol has also been studied (Figure 3).
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Org. Lett., Vol. 14, No. 6, 2012

described for heteroaryl substrates, the desired coupling
occurred in 26À79% yield (Figure 2, 29, and Scheme 2, 36
and 37). Importantly, these compounds would be impos-
sible to construct by methods that involved strong bases at
any stage of the chromene synthesis, including the addition
of Grignard reagents to chromene acetals.
Scheme 2. Late-Stage Chromene Acetal Couplinga
Figure 3. Scope of 2-ethoxy-2H-chromenes.a
a Conditions: (a) acetal 1a, 2 equiv of aryl boronic acid, Ni(cod)2
(10 mol %), PPh3 (30 mol %), dioxane/t-AmOH (10:1), 100 °C; see
Supporting Information for further details.
We found that chromene acetals substituted at the 5- and
6-positions with methoxy (30), methyl (31), fluoro (32),
and chloro (33) functionalities are suitable substrates.
Attempts to use sterically congested chromene acetals
resulted in low reactivity (3-Ph, 34), although a modest
yield could be achieved at 100 °C and a PPh3/Ni ratio of
3:1. Notably, aryl chlorides are well tolerated on both
reaction partners, allowing for a direct entry toward the
antiviral BW683C and providing handles for further func-
tionalization by metal-catalyzed cross-coupling (35).
Perhaps the most important demonstration of the capa-
city of the outlined method is late-stage functionalization
of molecules that possess functionality incompatible with
existing methods for chromene and ether syntheses. As a
validation of the principle, we selected the pharmaceutical
drugs loratadine and indomethacin methyl ester, in addi-
tion to a known furfuryl-benzotrifluoride, as test sub-
strates. Collectively, these substrates possess acidic CÀH
bonds, Lewis basicheteroatoms, nucleophilicheterocycles,
and an aldehyde. Utilizing Molander’s recently disclosed
method for the direct synthesis of aryl boronic acids from
aryl chlorides,26 we were able to successfully isolate the
requisite boronic acids. Under the reaction conditions
In conclusion, we have reported a modular synthesis of
2-aryl and 2-heteroaryl 2H-chromene derivatives from
readily available chromene acetals that is characterized
by a broad scope, mild conditions, and an inexpensive
metal/ligand system. The reaction also represents the first
example of a transition-metal-catalyzed cross-coupling
reaction between allylic acetals and boronic acids. Experi-
ments to delineate the generality of this acid and base-free
strategy for the construction of ethers will be the focus of
our future efforts.
Acknowledgment. Financial support was provided by
Princeton University and kind gifts from Eli Lilly and
Sanofi-Aventis. Allychem and Frontier Scientific are
acknowledged for generous donations of boronic acids.
BASF is acknowledged for a generous donation of
B2(OH)4.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(26) Molander, G. A.; Trice, S. L. J.; Dreher, S. D. J. Am. Chem. Soc.
2010, 132, 17701–17703.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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