Cu(I)-Catalyzed domino reactions: Efficient and selective synthesis of 4h-chromenes and naphthalenes

Article abstract of DOI:10.1021/ol200347g

Depending on the ratio of the substrates and the reaction conditions, the Cu(I)-catalyzed domino reaction between bromobenzyl bromides and β-ketoesters exclusively yields either 4H-chromenes or naphthalenes.

Full text of DOI:10.1021/ol200347g

ORGANIC
LETTERS
2011
Vol. 13, No. 8
1972–1975
Cu(I)-Catalyzed Domino Reactions:
Efficient and Selective Synthesis of
4H-Chromenes and Naphthalenes
€
Chandi C. Malakar, Dietmar Schmidt, Jurgen Conrad, and Uwe Beifuss*
€
Institut fu€r Chemie, Universitat Hohenheim, Garbenstr. 30, 70599 Stuttgart, Germany
ubeifuss@uni-hohenheim.de
Received February 7, 2011
ABSTRACT
Depending on the ratio of the substrates and the reaction conditions, the Cu(I)-catalyzed domino reaction between bromobenzyl bromides and
β-ketoesters exclusively yields either 4H-chromenes or naphthalenes.
Over the past years remarkable progress has been achieved
in the field of Cu(I)-catalyzed C-, N-, O-, and S-arylations.1
In contrast, few examples of the combination of such
arylations with other transformations into new domino
processes have been developed.1,2 Predictably, these domino
processes will be more and more important for the synthesis
of carbocycles and heterocycles. Most known examples are
related to the synthesis of N-heterocycles such as indoles,3
isoindoles,4 benzimidazoles,5 and isoquinolines.6 In addition,
benzofurans,7 benzothiazoles,8 benzoxazoles,9 and phe-
nothiazines10 can also be obtained using this strategy.
Here we report on two new and efficient Cu(I)-cata-
lyzed domino reactions between readily available and
inexpensive 2-bromobenzyl bromides and β-ketoesters.
Depending on the ratio of the substrates and the reaction
conditions employed, either 4H-chromenes or naphtha-
lenes are formed exclusively.
Due to their diverse biological activities, chromenes
have attracted considerable attention.11 Some prominent
examples of biologically active 4H-chromenes are the
antibiotic rhodomyrtone,12a the R-glucosidase inhibitor
myrtucommolone-E,12b and the apoptosis inducing agent
sHA 14-1.12c
(1) Reviews: (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed.
2009, 48, 6954–6971. (b) Evano, G.; Blanchard, N.; Toumi, M. Chem.
Rev. 2008, 108, 3054–3131. (c) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41,
1450–1460. (d) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400–5449. Some examples: (e) Marcoux, J.-F.; Doye, S.; Buchwald,
S. L. J. Am. Chem. Soc. 1997, 119, 10539–10540. (f) Kiyomori, A.;
Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657–2660.
(g) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3,
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(2) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(9) Viirre, R. D.; Evindar, G.; Batey, A. J. Org. Chem. 2008, 73, 3452–
3459.
(3) (a) Chen, Y.; Wang, Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625–
628. (b) Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844–4850. (c) Minatti,
A.; Buchwald, S. L. Org. Lett. 2008, 10, 2721–2724. (d) Tanimori, S.;
Ura, H.; Kirihata, M. Eur. J. Org. Chem. 2007, 3977–3980.
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11, 1309–1312.
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2008, 73, 7841–7844. (b) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int.
Ed. 2007, 46, 2598–2601.
(6) Wang, B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma, D. Org. Lett. 2008,
10, 2761–2763.
(7) (a) Lu, B.; Wang, B.; Zhang, Y.; Ma, D. J. Org. Chem. 2007, 72,
5337–5341. (b) Hang, H. C.; Drotleff, E.; Elliott, G. I.; Ritsema, T. A.;
Konopelski, J. P. Synthesis 1999, 398–400.
(10) Ma, D.; Geng, Q.; Zhang, H.; Jiang, Y. Angew. Chem., Int. Ed.
2010, 49, 1291–1294.
(11) (a) Keay, B. A. In Comprehensive Heterocyclic Chemistry, 2nd
ed.; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 2, p 395. (b) Nicolaou, K. C.; Pfefferkorn, J. A.;
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Soc. 2000, 122, 9939–9953.
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M. I.; Rahman, A.-U. Eur. J. Org. Chem. 2006, 2371–2377. (c) Tian, D.;
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r
10.1021/ol200347g
Published on Web 03/16/2011
2011 American Chemical Society

Considering the selective synthesis of 4H-chromenes D
we assumed that a domino C-benzylation/O-arylation
between a 2-halobenzyl halide A and a 1,3-dicarbonyl
B could serve this purpose (Scheme 1). However, a
domino O-benzylation/C-arylation with formation of
2H-chromenes F seemed to be possible, too.
°C for 24 h.13 Control experiments verified that the
reaction does not proceed in the absence of a Cu source.
With optimized reaction conditions at hand it was de-
monstrated that 1a could be reacted with numerous β-
ketoesters 2 in DMF or DMA to produce the correspond-
ing 4H-chromenes 3a-k with yields ranging from 65% to
88% (Table 1). In no case did we observe the formation of
a 2H-chromene.
Scheme 1. Possible Domino Processes upon Reaction of a
2-Halobenzyl Halide A and a 1,3-Dicarbonyl B
Table 1. Cu(I)-Catalyzed Synthesis of 4H-Chromenesa
Thisiswhyitwas a great pleasurewhenthe reactionsof 1
equiv 2-bromobenzyl bromide (1a) with 1 equiv of the β-
keto esters 2a,b in the presence of 10 mol % CuI and with 3
equiv of Cs2CO3 exclusively yielded the corresponding 4H-
chromenes 3a and 3b in 55% and 58% yield, respectively
(Scheme 2).13 Not even traces of the corresponding
2H-chromenes were isolated. It seems that the C-benzyla-
tion/O-arylation is more favorable than the O-benzylation/
C-arylation. It should be emphasized that the formation
of 4H-chromenes 3 not only is highly selective but also can
be performed under ligand-free conditions which are typical
of many other Cu(I)-catalyzed transformations.1
a All reactions were performed using 1 mmol of 1 and 2 mmol of 2 in a
sealed vial.
Scheme 2. Initial Experiments for the Cu(I)-Catalyzed Synthesis
of 4H-Chromenes
Also, the 4-hydroxy-6-methyl-pyrone (4) was reacted
with 1a to afford the expected cyclization product 5 in
45% yield along with the benzyl ether 6 in 19% yield
(Scheme 3). So far this has been the only example of the
additional formation of an O-benzylated product.
Our experiments have clearly established that 4H-
chromenes 3 and related skeletons can be synthesized in
a highly efficient and selective one-pot process by reacting
2-bromobenzyl bromide (1a) and a β-ketoester 2. There-
fore, the new domino process is a valuable alternative to
the intramolecular O-arylation of R-(2-bromobenzyl)-β-
ketoesters of type C since it does not require the separate
synthesis and isolation of the R-(2-bromobenzyl)-β-
ketoesters.14a It is also a valuable supplement to the
Fe(III)-catalyzed reaction between 2-(hydroxymethyl)
Optimizing the reaction conditions with regard to Cu
source, base, additive, solvent, reaction temperature, and
time revealed that the highest yield of 3b was obtained
when 1 equiv of 1a and 2 equiv of 2b were reacted with 20
mol % CuI and 4 equiv of K3PO4 in DMF or DMA at 110
(13) For details see Supporting Information.
(14) (a) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427–6431. (b) Fan,
J.; Wang, Z. Chem. Commun. 2008, 5381–5383. (c) Bunce, R. A.; Rogers,
D.; Nago, T.; Bryant, S. A. J. Heterocycl. Chem. 2008, 45, 547–550.
Org. Lett., Vol. 13, No. 8, 2011
1973

naphthalenes is of general interest.17 Optimizing the reac-
tion conditions with regard to Cu source, base, additive,
solvent, reaction temperature, and time13 revealed that
naphthalene 9b could be isolated in 68% yield when 1 equiv
of 1a was reacted with 3 equiv of 2b in the presence of 10 mol
% of CuI, 30 mol % of 2-picolinic acid (8), and 4 equiv of
Cs2CO3 in N-methyl pyrrolidine at 100 °C for 24 h. In the
absence of CuI the naphthalene 9b did not form.
Scheme 3. Cu(I)-Catalyzed Reaction of Pyrone 4
The scope of the three-component reaction was
then studied. It was found that numerous substituted
Table 2. Cu(I)-Catalyzed Synthesis of Naphthalenes 9a
phenols and β-ketoesters14b and the synthesis of 4H-
chromenes by a domino SN2/SNAr reaction.14c
After having successfully developed the domino C-
benzylation/O-arylation, the question was whether the
intramolecular O-arylation of C to D (Scheme 1) could be
suppressed in favor of an intermolecular C-arylation of C
with a second equivalent of a β-keto ester. To this purpose
1 equiv of 2-bromobenzyl bromide (1a) was reacted with 2
equiv of ethyl acetoacetate (2b) in the presence of 2-pico-
linic acid (8), an additive which has recently proven to be
highly efficient for promoting the C-arylation of malo-
nates with aryl iodides.15 And indeed, 33% of the
naphthalene 9b, which can be regarded as a product
resulting from a C-benzylation/C-arylation process, were
isolated (Scheme 4). Under these conditions the corre-
sponding 4H-chromene 3b was formed in traces only.
Scheme 4. Cu(I)-Catalyzed Synthesis of Naphthalene 9ba
a In addition, traces of 3b were observed.
We decided to study this transformation in more detail
as it represents not only a new domino reaction but also a
new method for the synthesis of polysubstituted
naphthalenes.16 Naphthalenes are important building
blocks in organic synthesis; they occur in natural products
and other bioactive products and play a significant role in
the field of material sciences. Thus, the development of
new and efficient synthetic approaches to polysubstituted
(15) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett.
2007, 9, 3469–3472.
(16) de Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L.
Tetrahedron 2003, 59, 7–36.
(17) Mason, R. T.; Talukder, M.; Kates, C. R. In Kirk-Othmer
Encyclopedia of Chemical Technology; Kirk, R. E., Ed.; Wiley: New York,
1995; p 963.
a All reactions were performed using 0.5 mmol of 1 and 1.5 mmol of 2.
Org. Lett., Vol. 13, No. 8, 2011
1974

2-bromobenzyl bromides 1 can be successfully reacted
with a range of β-keto esters 2 (Table 2). It was also
established that the annulation is not restricted to the
synthesis of naphthalenes 9 but also allows for the synth-
esis of polycyclic aromatic hydrocarbons and heteroaro-
matics (Scheme 5).
Scheme 6. Possible Reaction Mechanism
Scheme 5. Cu(I)-Catalyzed Synthesis of Phenanthrene 11 and
Benzo[b]thiophene 13
Scheme 7. Differentiation of the Ester Functionalitiesa
We assume that the annulation of aromatics starts
with the intermolecular C-benzylation of a β-keto ester
(A þ B f C) (Scheme 6). After intermolecular
C-arylation of a second β-keto ester moiety (C þ B f
D) an intramolecular 1,2-addition takes place (D f E).
The final steps of the sequence including the cleavage of a
carboxylic acid (E f F f G) and aromatization lead to
the desired product (G f H).
In accordance with this mechanistic proposal it was
anticipated that the method would allow for the synthesis
of naphthalenes with two different ester functionalities
when an R-(2-halobenzyl)-β-ketoester C is reacted with a
β-keto ester B carrying a different alcohol component.
Thus, it was no surprise when the trisubstituted naphtha-
lene 9j with two different ester functionalities was formed
upon reaction of 7 and 2e (Scheme 7).
a In addition, 5% of 3b were isolated.
Cu(I)-catalyzed domino reaction between bromobenzyl
bromides and β-ketoesters exclusively yields either
4H-chromenes or naphthalenes.
Acknowledgment. We thank S. Mika for NMR spectra
and Dr. H. Leutbecher, Dipl.-Chem. H.-G. Imrich, Dipl.
-Chem. C. Asta, and Dr. T. Tolasch (all affiliated with the
University of Hohenheim) for mass spectra.
To conclude, two new, easy-to-perform, and efficient
Cu(I)-catalyzed domino processes using readily available
and cheap substrates are presented. Depending on the
ratio of the substrates and the reaction conditions, the
Supporting Information Available. Experimental de-
tails and spectra of all new compounds are included in the
Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 8, 2011
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