Lewis acid-catalyzed diastereoselective hydroarylation of benzylidene malonic esters

Article abstract of DOI:10.1021/jo900367g

(Chemical Equation Presented) Herein we report that simple Lewis acids catalyze the hydroarylation of benzylidene malonates with phenols. Ultimately, 3,4-disubstituted dihydrocoumarins are obtained via a hydroarylation- lactonization sequence. Moreover, t

Full text of DOI:10.1021/jo900367g

SCHEME 1
Lewis Acid-Catalyzed Diastereoselective
Hydroarylation of Benzylidene Malonic Esters
Shaofeng Duan, Ranjan Jana, and Jon A. Tunge*
Department of Chemistry, 1251 Wescoe Hall DriVe,
2010 Malott Hall, and the KU Chemical Methodologies and
Library DeVelopment Center of Excellence, The UniVersity
of Kansas, Lawrence, Kansas 66045-7582
tunge@ku.edu
ReceiVed February 18, 2009
SCHEME 2
SCHEME 3
Herein we report that simple Lewis acids catalyze the
hydroarylation of benzylidene malonates with phenols.
Ultimately, 3,4-disubstituted dihydrocoumarins are obtained
via a hydroarylation-lactonization sequence. Moreover, the
dihydrocoumarins are formed with a high degree of diaste-
reoselectivity favoring the trans stereoisomer.
Hydroarylation of cinnamic acid derivatives is a powerful
method for the formation of synthetically versatile dihydrocou-
marin derivatives.1-3 However, such hydroarylations are com-
monly carried out in highly acidic media and the substrate scope
can be limited.2 For example, the CF3CO2H-catalyzed hydroary-
lation of cinnamic acids is limited to electron-rich cinnamic
acids.2b Thus, we are interested in developing methods for the
hydroarylation of electron-deficient cinnamic acid derivatives.
First, it was necessary to explain why electron-deficient cin-
namates, which are inherently more electrophilic than electron-
rich cinnamates, are much less reactive toward acid-catalyzed
arylation with phenols. We reasoned that while electron-deficient
cinnamates are inherently more reactive toward nucleophilic
attack by phenols, they are poorly activated by acid catalysts
due to their low basicity (Scheme 1). In other words, the slow
rates of hydroarylation of electron-deficient cinnamates are likely
attributed to the inability to activate the cinnamic acid/ester via
protonation.
With this in mind, we reasoned that the degree of protonation
could be increased by appending another donor group that would
stabilize the protonated intermediate via intramolecular hydrogen
bonding (Scheme 2). A pendant carboxyl group was seen as ideal
since it can activate the substrate toward catalytic hydroarylation,
yet can be easily removed by decarboxylation.4 Thus, we began
by examining the hydroarylation of electron-deficient benzylidene
malonates under our previously reported conditions for
hydroarylation.2b Related catalytic hydroarylation of benzylidene
malonates with good nucleophiles like indole are known;5 however,
that chemistry has not been extended to the use of phenols, which
are significantly less nucleophilic than indoles.
(1) (a) Neugebauer, R. C.; Uchiechowska, U.; Meier, R.; Hruby, H.; Valkov,
V.; Verdin, E.; Sippl, W.; Jung, M. J. Med. Chem. 2008, 51, 1203–1213. (b) Li,
K.; Tunge, J. A. J. Comb. Chem. 2008, 10, 170–174. (c) Srinivas, K.; Srinivasan,
N.; Reddy, K. S.; Ramakrishna, M.; Reddy, C. R.; Arunagiri, M.; Kumari, R. L.;
Venkataraman, S.; Mathad, V. T. Org. Proc. Res. DeV. 2005, 9, 314–318. (d)
Awale, S.; Tezuka, Y.; Wang, S.; Kadota, S. Org. Lett. 2002, 4, 1707–1709.
(2) (a) Rodrigues-Santos, C. E.; Echevarria, A. Tetrahedron Lett. 2007, 48,
4505–4508. (b) Kelin, L.; Foresee, L. N.; Tunge, J. A. J. Org. Chem. 2005, 70,
2881–2883. (c) Majumder, P. L.; Chatterjee, S.; Mukhoti, N. J. Indian Chem.
Soc. 2001, 78, 743–755. (d) Dupin, J.-F. E.; Chenault, J. Heterocycles 1983, 20,
2401–2404. (e) Camps, F.; Coll, J.; Colomina, O.; Messeguer, A. J. Heterocycl.
Chem. 1985, 22, 363–368.
(3) (a) Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.; Khavasi,
H. R. Org. Lett. 2008, 10, 2581–2584. (b) Richardson, T. I.; Dodge, J. A.; Durst,
G. L.; Pfeifer, L. A.; Shah, J.; Wang, Y.; Durbin, J. D.; Krishnan, V.; Norman,
B. H. Biorg. Med. Chem. Lett. 2007, 17, 4824–4828. (c) Piao, C.-R.; Zhao, Y.-
L.; Han, X.-D.; Liu, Q. J. Org. Chem. 2008, 73, 2264–2269.
Initially, dimethyl (p-nitrobenzylidene)malonate was chosen
as a model electron-deficient olefin for hydroarylation (Scheme
3). Allowing the olefin 1a to react with 3,5-dimethoxyphenol
in CH2Cl2 in the absence of catalyst produced no product after
7 days at room temperature. When a catalytic amount of
(4) Patra, A.; Misra, S. K. Indian J. Chem., Sect. B 1988, 27B, 272–273.
(5) (a) Zhuang, W.; Hansen, T.; Jorgensen, K. A. Chem. Commun. 2001,
347–348. (b) Zhou, J.; Tang, Y. Chem. Commun. 2004, 432–433.
4612 J. Org. Chem. 2009, 74, 4612–4614
10.1021/jo900367g CCC: $40.75 2009 American Chemical Society
Published on Web 05/21/2009

TABLE 1. Catalysts for Hydroarylation
TABLE 2. Scope of Benzylidene Malonates
product
R1
R2
R3
dr
yield (%)a
2g
2h
2i
H
CF3
H
H
OMe
Br
H
H
OMe
H
H
H
H
H
H
H
H
OMe
H
H
Br
H
CO2Me
H
H
H
22:1
>20:1
>20:1
17:1
>20:1
>20:1
>20:1
17:1
78
72 (87)b
74
2j
85
90
67
95
63
78
2k
2l
2m
2n
2o
2p
2q
2r
H
OMe
OMe
Me
F
>20:1
>20:1
20:1
H
F
H
74 (85)b
95c
77c
NO2
NO2
10:1
a isolated yields, 0.25 mmol substrate. b 10 mol % TiCl4 c performed
on 3 mmol scale.
highly diastereoselective. Moreover, the phenol reacts regiose-
lectively at the least hindered ortho position (i.e., the 6-position)
of the phenol.6 Several other phenols were briefly investigated
and, in each case, TiCl4 was the most active catalyst and
hydroarylation always proceeded at the least hindered ortho
position of the phenol.7 One limitation is the requirement that
the phenol is electron rich; no reaction is observed between the
electron-deficient olefin 1a and phenol.
Having demonstrated that TiCl4 is the most active catalyst
for hydroarylation of benzylidene malonates with phenols, we
turned our attention to investigating the scope of benzylidene
malonates that will undergo hydroarylation (Table 2). Impor-
tantly, both electron-donating and electron-withdrawing func-
tional groups are tolerated on the benzylidene malonate.
Moreover, even highly electron-deficient benzylidene malonates
(2q, 2r) are excellent substrates for the catalytic hydroarylation.
There is also a fair degree of functional group tolerance, with
nitro groups, ethers, esters, and halogens all proving to be
compatible with the reaction conditions. Furthermore, the
functional groups can be incorporated in any of the ortho, meta,
or para positions of the benzylidene malonate. Taken together
these data show that the hydroarylation of benzylidene malonates
is not very sensitive to the sterics or electronics of the arene
rings of the benzylidene malonates.
a Isolated yields. b Isolated as a 1.5:1 mixture of 2a:3a.
trifluoroacetic acid (TFA) was added, then 29% conversion to
dihydrocoumarin 2a was realized after 30 h. Increasing the
amount of “catalyst” so that the reaction was run in neat TFA
did allow for 90% conversion of the starting material; however,
these conditions produced a 2.4:1 ratio of cyclic (2a) and acyclic
(3a) hydroarylation products. While TFA proved to be relatively
ineffective as a hydroarylation catalyst, the observation of any
hydroarylation products indicates that the use of benzylidene
malonic esters does indeed facilitate the acid-catalyzed hy-
droarylation of electron-deficient olefins.
At this point it was still unclear whether the major diastere-
omer was the cis or the trans isomer. The vicinal coupling
constants for products (JHH) are small (ca. 1-2 Hz), but this
coupling constant is ambiguous given the fact that these products
do not rigorously adopt chair conformations. In fact, simple
molecular modeling using the MM2 force field suggests that
the H-C-C-H dihedral angle for the trans diastereomer is
73°, while that in the cis isomer is 52°.8 Karplus analysis
suggests that the trans diastereomer should have a coupling
constant of 0.8 Hz, while the cis isomer should have a coupling
constant of 2.3 Hz.9 The observed coupling constant for 2a (J2a
) 1.5 Hz) does not clearly distinguish between these two
Next, we turned our attention to the use of Lewis acid catalysts
for hydroarylation of benzylidene malonates (Table 1). While
MgBr2 and ZnCl2 were not effective catalysts for the reaction,
stronger Lewis acids did indeed effect complete conversion to the
product dihydrocoumarin in a reasonable amount of time. Ulti-
mately, TiCl4, Cu(OTf)2, and Sc(OTf)3 were identified as
potentially practical catalysts. Each of these catalysts provided
the desired product in high yield as well as high diastereose-
lectivity. That said, transesterification to the dihydrocoumarins
was not as effective with Cu(OTf)2. Thus, while hydroarylation
products of 1a with 3,5-dimethoxyphenol were formed in 98%
combined yield, 39% of that mixture was the uncyclized
dimethylmalonate derivative 3a; this uncyclized product was
not observed when other Lewis acid catalysts were employed.
Further comparison of the catalysts with a less electron-rich
phenol (benzo[1,3]dioxol-5-ol) provided product 2b; however,
these studies revealed that TiCl4 is a more active catalyst than
either Cu(OTf)2 or Sc(OTf)3. Once again, the reactions are
(6) Ziegler, T.; Moehler, H.; Effenberger, F. Chem. Ber. 1987, 120, 373–
378.
(7) (a) Labaudiniere, L.; Burgada, R. Tetrahedron 1986, 42, 3521–3536. (b)
Bharate, S. B.; Khan, S. I.; Yunus, N. A. M.; Chauthe, S. K.; Jacob, M. R.;
Tekwani, B. L.; Khan, I. A.; Singh, I. P. Bioorg. Med. Chem. 2007, 15, 87–96.
(8) Using CambridgeSoft ChemBio3D.
(9) Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870–2871.
J. Org. Chem. Vol. 74, No. 12, 2009 4613

SCHEME 6
sense since phenols are much more nucleophilic than benzoate
derivatives like that present in 1f.
Next it was reasoned that, if C-C bond formation occurs before
formation of the lactone, it should be possible to observe the acyclic
“intermediate B” if one constrains the intermediate so it cannot
undergo the cyclization reaction. With this in mind, a constrained
coumarin electrophile (1s) was subjected to our conditions for
titanium-catalyzed hydroarylation (Scheme 6). Indeed, the relative
rigidity of the coumarin ring does not allow the substituents to
cyclize, and the acyclic phenol is formed exclusively. More
specifically, cyclization cannot take place because the trans-pseudo-
diaxial ester and phenol are not able to achieve a conformation
that would allow cyclization. Ultimately, the observation of 2s
supports the hypothesis that the formation of 2a-r takes place via
intermolecular hydroarylation followed by intramolecular transes-
terification (path B, Scheme 4).
FIGURE 1. Crystal structure of 2a.
SCHEME 4
In conclusion, the use of benzylidene malonates facilitates the
Brønsted and Lewis acid-catalyzed arylation by phenols. Titanium
tetrachloride was identified as the most practical catalyst for the
diastereoselective hydroarylation of benzylidene malonates to
produce trans-substituted dihydrocoumarins. Finally, mechanistic
studies suggest that the reaction proceeds via hydroarylation
followed by transesterification. Uses of these intermediates in the
synthesis of chemical libraries is being explored.
SCHEME 5
Experimental Section
General Procedure for the TiCl4-Catalyzed Hydroarylation
of Benzylidene Malonates with Phenols. Phenol (0.25 mmol) and
benzylidene malonate (0.25 mmol) were dissolved completely in
dry dichloromethane (2 mL) to form a clear solution that was then
cooled to 0 °C. To the solution was added TiCl4 via a syringe.
After reaction completion was indicated by TLC, 1 N HCl (10 mL)
was added and the mixture was extracted with dichloromethane (2
× 10 mL). The combined organic extracts were washed with water
(5 mL), saturated sodium bicarbonate (5 mL), and brine (5 mL)
and then dried over magnesium sulfate. Concentration under
reduced pressure gave a crude product that was purified via flash
chromatography.
possibilities. A further result of the molecular mechanics
simulations is that the trans diastereomer is favored by ca. 10
kcal/mol and is expected to adopt a half-chair structure where
the arene and the ester groups occupy pseudoaxial sites. To test
these predictions, and provide unambiguous evidence for the
stereochemistry of the diastereomer that is formed, X-ray quality
crystals of 2a were grown and analyzed. The crystal structure
confirms that the trans-diastereomer is the major product and
also confirms the trans-pseudo-diaxial structure predicted by the
MM2 simulations (Figure 1).10
Methyl 5,7-Dimethoxy-4-(4-nitrophenyl)-2-oxochroman-3-
The overall process for formation of dihydrocoumarins from
phenols and the benzylidene malonates involves two general
transformations: hydroarylation and transesterification. Thus, the
reaction could proceed by transesterification followed by
intramolecular hydroarylation (path A, Scheme 4) or by
intermolecular hydroarylation followed by intramolecular trans-
esterification (path B, Scheme 4). To gain a better mechanistic
understanding, ester 1f (intermediate A in Scheme 4) was
prepared. Subjecting ester 1f to 10 mol % of TiCl4 for 48 h
produced no dihydrocoumarin product; only E/Z isomerization
of the ester to a 1:1 E:Z mixture was observed (Scheme 5).
Since ester 1f is not a kinetically competent catalytic intermedi-
ate, path A can be ruled out. Thus, hydroarylation/transesteri-
fication (path B) is the most likely mechanism for the formation
of dihydrocoumarins. That path B is favored over path A makes
carboxylate (2a). Compound 2a was isolated as a white solid. IR
1
νmax (neat)/cm-1 1776, 1744, 1626, 1595, 1522, 1350; H NMR
(400 MHz, CDCl3) δ 3.72 (3H, s), 3.75 (3H, s), 3.83 (3H, s), 3.96
(1H, d, J ) 1.6 Hz), 5.08 (1H, s), 6.30 (1H, d, J ) 2.0 Hz), 6.37
(1H, d, J ) 2.4 Hz), 7.31 (2H, d, J ) 8.8 Hz), 8.14 (2H, d, J ) 8.8
Hz); 13C NMR (100 MHz, CDCl3) δ 38.6, 53.6, 53.6, 55.6, 55.9,
94.0, 95.6, 102.1, 124.3, 128.1, 147.1, 147.3, 152.5, 157.7, 161.6,
163.0, 166.7; HRMS (ESI) calcd for C19H17NO8Na (M + Na+)
410.0852, found 410.0857.
Acknowledgment. We acknowledge support of this work by
the National Institutes of Health (KU Chemical Methodologies
and Library Development Center of Excellence, P50 GM069663).
Supporting Information Available: General experimental
and complete compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) The aliphatic H-C-C-H dihedral angle is 81° in the crystal structure,
compared to 72° that was predicted based on MM2 calculations.
JO900367G
4614 J. Org. Chem. Vol. 74, No. 12, 2009