Stereocontrolled photodimerization with congested 1,8-Bis(4′-anilino) naphthalene templates

Article abstract of DOI:10.1021/jo101547w

Suzuki cross-coupling of a 1,8-dihalonaphthalene with 4-methoxy-3- methylphenylboronic acid or 4-acetamidophenylboronic acid and subsequent functional group transformation gave 1,8-bis(3′-methyl-4′-anilino) naphthalene, 16, and 1,8-bis(4′-anilino)naphthalene, 21, in 65% and 90% overall yield, respectively. These congested compounds exhibit two cofacial aniline rings that favor a proximate, parallel arrangement of covalently attached cinnamoyl units suitable for stereoselective photodimerization. The [2 + 2]cycloaddition was found to proceed with high yield and exclusive formation of cis,trans,cis-cyclobutane-1,2-dicarboxylic acids. Amide formation with cinnamoyl chloride and template 21 followed by photochemical dimerization and acidic hydrolysis gave β-truxinic acid, 10, in 69% overall yield. Coupling of 21 and (E)-3-(3,4-dimethylphenyl)acrylic acid in the presence of EDC, UV irradiation, and cleavage gave cis,trans,cis-3,4-bis(3,4-dimethylphenyl) cyclobutane-1,2-dicarboxylic acid, 26, in 60% yield. In both cases, the template was quantitatively recovered.

Full text of DOI:10.1021/jo101547w

pubs.acs.org/joc
Stereocontrolled Photodimerization with Congested
1,8-Bis(40-anilino)naphthalene Templates
Marwan W. Ghosn and Christian Wolf*
Department of Chemistry, Georgetown University, Washington, D.C. 20057
cw27@georgetown.edu
Received August 6, 2010
Suzuki cross-coupling of a 1,8-dihalonaphthalene with 4-methoxy-3-methylphenylboronic acid or 4-acet-
amidophenylboronic acid and subsequent functional group transformation gave 1,8-bis(30-methyl-
40-anilino)naphthalene, 16, and 1,8-bis(40-anilino)naphthalene, 21, in 65% and 90% overall yield,
respectively. These congested compounds exhibit two cofacial aniline rings that favor a proximate,
parallel arrangement of covalently attached cinnamoyl units suitable for stereoselective photodimeriza-
tion. The [2 þ 2]cycloaddition was found to proceed with high yield and exclusive formation of cis,trans,
cis-cyclobutane-1,2-dicarboxylic acids. Amide formation with cinnamoyl chloride and template 21
followed by photochemical dimerization and acidic hydrolysis gave β-truxinic acid, 10, in 69% overall
yield. Coupling of 21 and (E)-3-(3,4-dimethylphenyl)acrylic acid in the presence of EDC, UV irradiation,
and cleavage gave cis,trans,cis-3,4-bis(3,4-dimethylphenyl)cyclobutane-1,2-dicarboxylic acid, 26, in 60%
yield. In both cases, the template was quantitatively recovered.
Introduction
to polysubstituted cyclobutanecarboxylic acids, a common
structural motif in natural products and an important com-
ponent in many pharmaceuticals.2 Despite the biomedical signifi-
cance and natural abundance of analogues of truxillic and
truxinic acids, which are obtained via photodimerization of
cinnamic acid, the stereoselective photoaddition of unsaturated
carboxylic acids and amides remains challenging.3
The photodimerization of olefinic compounds has attracted
considerable interest in recent years.1 Several strategies to
control the regio- and stereochemical outcome of the [2þ2]-
cycloaddition of fumaric acid, cinnamic acid, and a few other
substrates have been developed. This reaction provides access
Many efforts have been directed toward solid-state synth-
esis with molecular templates, hosts, and large frameworks
to control the reaction topology.4 A parallel substrate align-
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generally accepted requirements for the photodimerization
of unsaturated compounds.5 The advance of supramolecular
chemistry has fueled the development of intriguing templates
that utilize noncovalent interactions such as hydrogen bond-
ing, halogen bonding, π-π interactions, cation-π interactions,
(3) (a) Russell, W. R.; Hanley, A. B.; Burkitt, M. J.; Chesson, A. Bioorg.
Chem. 1999, 27, 339–350. (b) Ito, Y.; Hosomi, H.; Ohba, S. Tetrahedron 2000,
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DOI: 10.1021/jo101547w
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JOCArticle
and transition metal coordination to affect the relative orienta-
tion of R,β-unsaturated compounds.6 This approach generally
exploits the distinguished regularity and molecular orientation
provided by a crystal lattice to control the stereo- and regio-
chemical selectivity during reaction in a solvent-free environment.7
For example, solid-state photodimerization of ammonium salts
of trans-cinnamic acid or cocrystals of trans-cinnamamide
and phthalic acid have been reported to produce truxinic acids
and truxinamides with high stereoselectivity.8 Several cases of
photochemical and γ-radiation-induced topochemical polymeriza-
tion of unsaturated ammonium carboxylates are also known.9
The use of 1,8-bis(40-pyridyl)naphthalene, 1, for template-
directed solid-state alignment of unsaturated dicarboxylic
acids has recently been reported from our laboratories.10
Through careful selection of cocrystallization parameters,
we obtained a series of four-component assemblies in which
SCHEME 1. Template-Directed Solid-State Photodimerization
of Fumaric Acid
two dipyridylnaphthalene molecules undergo OH N and
3 3 3
(4) (a) Koshima, H.; Ding, K.; Chisaka, Y.; Matsuura, T. J. Am. Chem.
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Tetrahedron Lett. 1997, 38, 6063–6066. (c) Koshima, H.; Ding, K.; Chisaka,
Y.; Matsuura, T.; Miyahara, I.; Hirotsu, K. J. Am. Chem. Soc. 1997, 119,
10317–10324. (d) Ito, Y.; Hosomi, H.; Ohba, S. Tetrahedron 2000, 56, 6833–
6844. (e) MacGillivray, L. R.; Reid, J. L.; Ripmeester, J. A. J. Am. Chem. Soc.
2000, 122, 7817–7818. (f) Amirsakis, D. G.; Garcia-Garibay, M. A.; Rowan,
S. J.; Stoddart, J. F.; White, A. J. P.; Williams, D. J. Angew. Chem., Int. Ed.
2001, 40, 4256–4261. (g) Friscic, T.; MacGillivray, L. R. Chem. Commun.
2003, 1306–1307. (h) Ouyang, X.; Fowler, F. W.; Lauher, J. W. J. Am. Chem.
Soc. 2003, 125, 12400–12401. (i) Gao, X.; Friscic, T.; MacGillivray, L. R.
Angew. Chem., Int. Ed. 2004, 43, 232–236. (j) Varshney, D. B.; Gao, X.;
Friscic, T.; MacGillivray, L. R. Angew. Chem., Int. Ed. 2006, 45, 646–650.
(k) Yang, J.; Dewal, M. B.; Shimizu, L. S. J. Am. Chem. Soc. 2006, 128, 8122–
8123. (l) MacGillivray, L. R. J. Org. Chem. 2008, 73, 3311–3317. (m) Yang,
J.; Dewal, M. B.; Profeta, S., Jr.; Smith, M. D.; Li, Y.; Shimizu, L. S. J. Am.
Chem. Soc. 2008, 130, 612–621.
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CH O hydrogen bonding with two bridging molecules of
3 3 3
2-5, Scheme 1. The cocrystal obtained with fumaric acid, 2,
places two dicarboxylic acid molecules in close proximity with a
separation between the superimposed olefinic bonds of less than
˚
4.0 A. As expected, photochemical irradiation gave quantitative
amounts of cis,trans,cis-cyclobutanetetracarboxylic acid, 6, and
the template was fully recovered by extraction with dichloro-
methane. Unfortunately, numerous attempts to produce a co-
crystal with trans-cinnamic acid that would afford a similar
double bond arrangement suitable for stereoselective photo-
addition were unsuccessful. When a cocrystal was obtained by slow
evaporation of an ethanol solution containing equimolar amounts
of template 1and the acid, we found that only one pyridyl ring of
1 would participate in hydrogen bonding, resulting in an offset
head-to-tail packing arrangement of the cinammic acid mole-
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FIGURE 1. Structure of the cocrystal of 1 and trans-cinnamic acid.
The cocrystallization experiment with 1 and trans-cinnamic
acid clearly revealed an important limitation of this solid state
approach. Despite the overall success with solid-state photo-
dimerizations, the packing motif and the relative orientation of
(10) Mei, X.; Liu, S.; Wolf, C. Org. Lett. 2007, 9, 2729–2732.
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olefinic substrates in the presence of 1or other templates remain
difficult to control. As a result, the application spectrum of
template-assisted solid-state photodimerization is often rather
narrow and may not be extended to a wide range of substrates.
In most cases, a reaction does not occur if the crystallization
efforts do not provide a perfect cofacial orientation of proxi-
mate substrates unless this can be manipulated by heating of the
crystal or by other means.11
This result encouraged us to develop a rigid template for
in-solution photoaddition of covalently attached substrates
that would overcome the limitations of 1 and provide synthetic
access to polysubstituted cyclobutanes other than 6. Initially, we
rationalized that a template should exhibit two parallel func-
˚
tionalities within less than 4.0 A combined with a certain degree
of rigidity. On the basis of our experience with the structure and
conformational flexibility of 1,8-diarylnaphthalenes,18 we began
our study with the synthesis of 1,8-bis(30-methyl-40-anilino)-
naphthalene, 16, Scheme 3. Suzuki coupling of boronic acid 11
and 1,8-dibromonaphthalene gave 1,8-bis(30-methyl-40-methoxy-
phenyl)naphthalene, 12, in 96% yield. Deprotection with boron
tribromide and treatment of 13 with trifluoromethanesulfonic
anhydride provided 14 in almost quantitative amounts. We first
used 14 to make template 16 via palladium-catalyzed amidation
and subsequent hydrolysis of 1,8-bis(30-methyl-40-acetamido-
phenyl)naphthalene, 15. As a result, 16 was prepared in 5 steps
from 11 with an overall yield of 65%. Attachment of two
cinnamoyl units followed by photodimerization of 1,8-bis-
(30-methyl-40-cinnamamidophenyl)naphthalene, 17, and cleavage
of the cycloadduct from the template gave β-truxinic acid, 10, in
high yields while 16 was quantitatively recovered. The [2 þ 2]-
photodimerization apparently proceeds with excellent stereo-
control, and the formation of configurational isomers of 10 was
not observed. We then realized that trans-cinnamamide can be
used to prepare 17 directly from 14 in 90% yield, which
eliminates two steps and further enhances the efficiency of the
template-assisted stereoselective synthesis of 10.
Results and Discussion
In comparison with the numerous reports of stereoselective
photoaddition of olefinic compounds in the solid state,
there are relatively few examples that have been accom-
plished in solution. In these cases, substrate alignment has
been controlled by inclusion in cucurbiturils, cyclodextrins,
and organometallic hosts,12 association with biomolecules,13
in micellar environments,14 self-assembly of substrates designed
for complementary cation-π-interactions and rotaxane forma-
tion,15 or with small molecular templates.16 A prime example of
the use of a template for stereoselective photodimerization in
solution has been presented by Hopf and co-workers.17 They
prepared 4,15-diamino[2.2]paracyclophane, 7, from [2.2]para-
cyclophane in 8 steps with 14% overall yield. Diamide forma-
tion with cinnamoyl chloride then allowed photochemical cyclo-
addition to the corresponding cyclobutane 9 with 76% yield.
Acidic cleavage gave β-truxinic acid, 10, and the free template in
almost quantitative amounts, Scheme 2.
A closer look at the cycloaddition product by NMR
analysis revealed the presence of two diastereomers that
apparently vary by the orientation of the methyl groups in
the template. We were able to separate the syn- and anti-
isomers of 18 by chromatography and found that both form
the desired product upon UV irradiation. Slow evaporation
of a solution of 18 in chloroform gave single crystals of the
anti-isomer suitable for X-ray diffraction. Crystallographic
analysis proved that 18 has a cis,trans,cis-cyclobutane ring and
opposite orientation of the carbonyl groups of the neighboring
amide functionalities, Figure 2. Both NMR and X-ray analysis
suggest that the bridging of the cofacial 2-methylaniline rings in
18 by the cyclobutane moiety generates a congested framework
that does not show rotation about the aryl-aryl bonds, thus
SCHEME 2. Hopf’s Synthesis of β-Truxinic Acid with
Template 7
SCHEME 3. Synthesis of β-Truxinic Acid via Template 16
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SCHEME 4. Synthesis of 10 and 26 with Template 21
and thus generate the C2-symmetric δ-truxinic acid. However,
crystallographic analysis of 18 and the exclusive formation of
β-truxinic 10 after hydrolysis of the photodimer suggested
thatthe presence of the methyl groups in the templatedoes not
affect the stereochemical outcome of the cycloaddition. We
therefore decided to prepare 1,8-bis(40-anilino)naphthalene, 21,
in two high-yielding steps from 4-acetamidophenylboronic
acid, 19, Scheme 4. This readily available template then gave
access to cyclobutane 10 in just 3 steps with an overall yield of 69%.
We then applied our template-assisted cycloaddition strategy
in the stereoselective synthesis of cis,trans,cis-3,4-bis(3,4-dimethyl-
phenyl)cyclobutane-1,2-dicarboxylic acid, 26. Coupling of 21
and (E)-3-(3,4-dimethylphenyl)acrylic acid in the presence of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) gave
1,8-bis(40-(3,4-dimethylcinnamido)phenyl)naphthalene, 24,
(14) (a) Takagi, K.; Suddaby, B. R.; Vadas, S. L.; Backer, C. A. J. Am.
Chem. Soc. 1986, 108, 7865–7866. (b) Nakamura, T.; Takagi, K.; Itoh, M.;
Fujita, K.; Katsu, H.; Imae, T.; Sawaki, Y. J. Chem. Soc., Perkin Trans. 2
1997, 2751–2755.
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2003, 42, 1126–1132. (b) Yamada, S.; Uematsu, N.; Tokugawa, Y. J. Am.
Chem. Soc. 2007, 129, 12100–12101.
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2006, 4, 3694–3702. (b) Selig, P.; Bach, T. J. Org. Chem. 2006, 71, 5662–5673.
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FIGURE 2. Crystal structure of anti-18.
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giving rise to syn/anti-atropisomers that can be separated at
room temperature (see the Supporting Information).
Originally, we assumed that template 16 and its diamide
analogue 17 would favorably populate the anti-conformation
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13, 1153–1156. (b) Wolf, C.; Tumambac, G. E. J. Phys. Chem. A 2003, 107,
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2005, 7, 4045–4048. (i) Mei, X.; Martin, R. M.; Wolf, C. J. Org. Chem. 2006,
71, 2854–2861. (j) Mei, X.; Wolf, C. Tetrahedron Lett. 2006, 47, 7901–7904.
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Pestano, J. P. C.; Wolf, C. J. Org. Chem. 2008, 73, 4267–4270. (n) Ghosn,
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Natarajan, A.; Ramamurthy, V. Langmuir 2006, 22, 7605–7609. (c) Karthikeyan,
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in 80% yield. As expected, photochemical cycloaddition
and hydrolysis with concentrated HCl gave cyclobutane-1,2-
dicarboxylic acid 26 in excellent yields.
1,8-Bis(30-methyl-40-trifluoromethanesulfonatophenyl)naphthalene
(14). To a solution of 1,8-bis(30-methyl-40-hydroxyphenyl)-
naphthalene (13) (1.33 g, 3.9 mmol) and triethylamine (2.2 mL,
15.7 mmol) in 25 mL of toluene was added trifluoromethane-
sulfonic anhydride (6.6 mL, 39.2 mmol) at 0 °C. The tempera-
ture was gradually increased to 95 °C over a period of 1 h, and
the reaction mixture was then allowed to stir for 14 h. The
mixture was cooled to room temperature, quenched with water,
and extracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and concentrated in vacuo. Purification by
flash chromatography on silica gel (hexanes:CH2Cl2 4:1) afforded
2.30 g of 14 (3.8 mmol, 98%) as a yellow oil.
Conclusion
We have introduced 1,8-bis(40-anilino)naphthalene templates
for stereoselective photodimerization of R,β-unsaturated carbo-
xylic acids. The template design affords two cofacial aniline rings
that favor a proximate, parallel arrangement of covalently
attached cinnamoyl units. The [2 þ 2]cycloaddition proceeds
with high yield and excellent stereoselectivity and the cis,trans,
cis-cyclobutane-1,2-dicarboxylic acid formed is easily cleaved by
acidic hydrolysis, which also allows quantitative recovery of
the template. This approach overcomes limitations experienced
with 1,8-bis(40-pyridyl)naphthalene which proved useful for the
template-directed solid-state dimerization of fumaric acid while
cocrystals obtained with cinnamic acid were not suitable for
[2þ2]cycloaddition toward β-truxinic acid.
1H NMR δ 2.09 (s, 3H), 2.18 (s, 3H), 6.70-7.00 (m, 6H), 7.34
(dd, J = 1.1, 7.1 Hz, 2H), 7.52 (dd, J = 7.2, 8.1 Hz, 2H), 7.98
(dd, J = 1.1, 8.2 Hz, 2H). 13C NMR δ 15.8, 16.0, 118.5 (q, JC-F
=
320.0 Hz), 120.0, 123.3, 125.3, 127.8, 128.5, 128.8, 129.2, 129.3,
129.5, 131.1, 133.1, 133.5, 135.3, 137.9, 143.0, 146.5. Anal. Calcd
for C26H18F6O6S2: C, 51.66; H, 3.00. Found: C, 51.51; H, 2.98.
1,8-Bis(30-methyl-40-acetamidophenyl)naphthalene (15). To acet-
amide (0.26 g, 4.4 mmol), tris(dibenzylideneacetone)dipalladium
(0.20 g, 0.22 mmol), potassium phosphate (0.69 g, 3.3 mmol), and
2-di-tert-butylphosphino-20,40,60-triisopropylbiphenyl (0.46 mg,
1.1 mmol) was added a solution of 14 (0.65 g, 1.1 mmol) in 15 mL of
nitrogen-purged isopropyl alcohol, and the mixture was stirred at
90 °C for 19 h. The resulting mixture was allowed to come to room
temperature, quenched with water, and extracted with CH2Cl2.
The combined organic layers were dried over MgSO4 and con-
centrated in vacuo. Purification by flash chromatography on silica
gel (EtAOc to EtOAc:EtOH 90:10) afforded 0.35 g (0.84 mmol,
78%) of 15 as a yellow paste. This material was used in the
following step without further purification.
Experimental Section
1. General Synthetic Procedures. All reagents and solvents
were used without further purification. Reactions were carried
out under nitrogen atmosphere and under anhydrous condi-
tions. Products were purified by flash chromatography on SiO2
(particle size 0.032-0.063 mm). NMR spectra were obtained at
400 (1H NMR) and 100 MHz (13C NMR), using CDCl3 as
solvent unless otherwise specified. Chemical shifts are reported
in ppm relative to TMS. UV irradiation experiments were
conducted with a 400 W Mercury lamp positioned 1 cm away
form the quartz reaction vessel. A fan was used to keep the
solution at room temperature.
2. Synthesis of β-Truxinic Acid 10 with Template 16. 1,8-Bis-
(30-methyl-40-methoxyphenyl)naphthalene (12). A solution of
1,8-dibromonaphthalene, (1.20 g, 4.2 mmol), 3-methyl-4-methoxy-
phenylboronic acid (11) (2.10 g, 12.7 mmol), Pd(PPh3)4 (0.74 g, 0.64
mmol), and K3PO4, (4.05 g, 19.1 mmol) in 40 mL of toluene was
stirred at reflux for 24 h. The resulting mixture was allowed to come
to room temperature, quenched with water, and extracted with
CH2Cl2. The combined organic layers were dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography on
silica gel (hexanes:CH2Cl2 3:1) afforded 1.50 g (4.1 mmol, 96%) of
12 as off-white crystals.
1H NMR δ 1.87 (s, 3H), 1.97 (s, 3H), 2.15 (s, 6H), 6.40 (s, 1H),
6.66-6.84 (m, 2H), 7.04-7.11 (m, 2H), 7.38 (d, J = 7.0 Hz, 2H),
7.50 (dd, J = 7.3, 7.9 Hz, 2H), 7.70 (s, 1H), 7.86 (s, 1H), 7.92
(d, J = 8.1 Hz, 2H). 13C NMR δ 17.5, 17.9, 23.6, 23.7, 124.6,
125.1, 125.4, 126.6, 127.5, 128.7, 129.4, 129.5, 130.4, 131.1,
132.2, 132.4, 132.6, 133.0, 133.0, 135.3, 135.4, 139.7, 141.0,
141.4, 169.3.
1,8-Bis(30-methyl-40-anilino)naphthalene (16). To a solution
of 1,8-bis(30-methyl-40-acetamidophenyl)naphthalene (15) (0.27 g,
0.64 mmol) in 8 mL of ethanol was added 3 M HCl (4.3 mL,
12.7 mmol) and the mixture was stirred at 95 °C for 24 h. The
resulting mixture was allowed to come to room temperature,
basified with a stoichiometric amount of 28% NH4OH, and
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4 and concentrated in vacuo. Purification by flash
chromatography on silica gel (EtOAc:EtOH 97.5:2.5) afforded
0.20 g (0.59 mmol, 92%) of 16 as a yellow powder.
1H NMR δ 1.91 (s, 3H), 2.02 (s, 3H), 3.73 (s, 6H), 6.30-6.90
(m, 6H), 7.38 (dd, J = 1.2, 7.0 Hz, 2H), 7.48 (dd, J = 7.3, 7.9 Hz,
2H), 7.89 (dd, J = 1.0, 8.0 Hz, 2H). 13C NMR δ 15.9, 55.3, 108.6,
108.9, 124.8, 124.9, 127.6, 127.9, 128.2, 130.3, 130.5, 132.4,
132.8, 135.4, 135.4, 135.4, 135.5, 140.4, 155.7. Anal. Calcd for
C26H24O2: C, 84.75; H, 6.57. Found: C, 84.74; H, 6.61.
1,8-Bis(30-methyl-40-hydroxyphenyl)naphthalene (13). To a solu-
tion of 1,8-bis(30-methyl-40-methoxyphenyl)naphthalene (12) (1.50 g,
4.1 mmol) in 40 mL of anhydrous CH2Cl2 at 0 °C was added BBr3
(24.4 mL, 24.4 mmol) dropwise and the mixture was stirred for
6 h. The reaction was carefully quenched with isopropyl alcohol
followed by addition of water and extraction with CH2Cl2.
The combined organic layers were dried over MgSO4 and con-
centrated in vacuo. Purification by flash chromatography on silica
gel (CH2Cl2:EtOAc 7:1) afforded 1.33 g of 13 (3.92 mmol, 97%) as
a white solid.
1H NMR δ 1.85 (s, 3H), 1.98 (s, 3H), 3.18 (s, 4H), 6.20-6.90
(m, 6H), 7.39 (dd, J = 1.2, 7.0 Hz, 2H), 7.49 (dd, J = 7.2, 8.0 Hz,
2H), 7.87 (dd, J = 1.2, 8.1 Hz, 2H). 13C NMR δ 17.1, 17.7, 113.4,
114.1, 120.8, 124.9, 126.5, 127.9, 129.7, 130.3, 132.1, 134.2,
135.5, 140.8, 142.0. Anal. Calcd for C24H22N2: C, 85.17; H, 6.55;
N, 8.28. Found: C, 85.08; H, 7.13; N, 7.87.
1,8-Bis(30-methyl-40-cinnamamidophenyl)naphthalene (17): (A)
From 14: To trans-cinnamamide (0.75 g, 5.1 mmol), tris-
(dibenzylideneacetone)dipalladium (0.22 g, 0.24 mmol),
potassium phosphate (0.81 g, 3.82 mmol), and 2-di-tert-
butylphosphino-20,40,60-triisopropylbiphenyl (0.54 mg, 1.3 mmol)
was added a solution of 14 (0.77 g, 1.3 mmol) in 35 mL
of nitrogen-purged isopropyl alcohol, and the mixture was
stirred at 90 °C for 19 h. The resulting mixture was allowed
to come to room temperature, quenched with water, and
extracted with THF. The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The material was
suspended in 10 mL of CH2Cl2 and filtered to isolate the
precipitate (0.39 g, 0.65 mmol). The filtrate was subjected
to flash chromatography on silica gel (CH2Cl2:EtOAc 15:1) to
1H NMR δ 1.98 (s, 3H), 2.10 (s, 3H), 4.95 (s, 2H), 6.35-6.90
(m, 6H), 7.39 (dd, J = 1.3, 7.0 Hz, 2H), 7.51 (dd, J = 7.1, 8.1 Hz,
2H), 7.91 (dd, J=1.3, 8.2 Hz, 2H). 13C NMR δ 15.44, 15.61,
113.3, 113.9, 121.8, 122.0, 125.0, 127.8, 128.3, 129.7, 130.4, 132.6,
132.8, 135.4, 136.1, 140.1, 151.6. Anal. Calcd for C24H20O2:
C, 84.68; H, 5.92. Found: C, 84.69; H, 5.92.
J. Org. Chem. Vol. 75, No. 19, 2010 6657

Ghosn and Wolf
JOCArticle
afford another 0.30 g (0.50 mmol, 40%) of 17 as a white
powder, which was combined with the precipitate to give a
total of 0.69 g (1.15 mmol, 90%).
(0.57 g, 1.4 mmol), 4-acetamidophenylboronic acid (19) (0.64 g,
3.6 mmol), Pd(PPh3)4 (0.41 g, 0.36 mmol), and K2CO3 (0.89 g,
6.5 mmol) in 21 mL of nitrogen-purged ethanol:toluene:water
(1:1:1) was stirred at 95 °C for 20 h. The resulting mixture was
allowed to come to room temperature, quenched with water, and
extracted with EtOAc and THF (1:1). The combined organic layers
were washed with brine, dried over MgSO4, and concentrated in
vacuo. Purification by flash chromatography on silica gel (EtOAc:
EtOH 95:5 to 4:1) afforded 0.51 g (1.3 mmol, 90%) of 20 as a light
brown powder.
(B) From 16: To 16 (0.20 g, 0.59 mmol) in 18 mL of THF was
added a solution of cinnamoyl chloride (0.24 g, 1.4 mmol) in
5 mL of THF at 0 °C, then the solution was allowed to stir for
24 h at room temperature. The resulting mixture was quenched
with 1 M NaOH and extracted with THF. The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The
residue was suspended in 10 mL of CH2Cl2 and filtered to isolate
the precipitate (0.22 g. 0.38 mmol). The filtrate was then sub-
jected to flash chromatography on silica gel (CH2Cl2:EtOAc
95:5) to afford another 0.11 g (0.17 mmol, 29%) of 17 as a white
powder, which was combined with the precipitate to give a total
of 0.33 g (0.55 mmol, 94%).
1H NMR (DMSO) δ 1.97 (s, 5.2 H), 2.03 (s, 0.8 H), 6.82 (d,
J = 8.2 Hz, 4H), 7.17 (d, J = 8.3 Hz, 4H), 7.33 (d, J = 6.8 Hz,
2H), 7.56 (dd, J = 7.4, 7.8 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 9.69
(s, 1.8 H), 9.97 (s, 0.2H). 13C NMR (DMSO) δ 24.5, 117.9, 119.8,
125.7, 126.8, 128.6, 129.0, 129.9, 131.1, 134.7, 135.7, 137.6,
137.7, 138.8, 140.1, 168.3, 168.7. Anal. Calcd for C26H22N2O2:
C, 79.16; H, 5.62; N, 7.10. Found: C, 79.42; H, 5.96; N, 7.19.
1,8-Bis(40-anilino)naphthalene (21). To a solution of 1,8-bis-
(40-acetamidophenyl)naphthalene (20) (0.31 g, 0.79 mmol) in
12 mL of ethanol was added 3 M HCl (2.4 mL, 7.1 mmol) and
the mixture was stirred at 95 °C for 24 h. The resulting mixture
was allowed to come to room temperature, basified with 28%
NH4OH, and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography on silica gel (EtOAc:
EtOH 97.5:2.5 to 95:5) afforded 0.25 g (0.79 mmol, 100%) of
21 as an off-white powder.
1H NMR δ 2.02 (s, 3.7H), 2.16 (s, 2.3H), 6.47 (s, 1H), 6.60-
6.85 (m, 4H), 6.95 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H),
7.20-7.58 (m, 16H), 7.70 (s, 1H), 7.78 (d, J = 6.6 Hz, 1H), 7.82
(d, J = 6.6 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H). 13C NMR δ 17.7,
18.1, 121.2, 123.9, 125.1, 126.7, 127.6, 127.9, 128.7, 128.8, 128.9,
129.5, 130.3, 130.5, 132.3, 132.7, 132.9, 133.0, 134.7, 134.8,
135.4, 139.8, 140.8, 141.4, 141.8, 164.8. Anal. Calcd for
C42H34N2O2: C, 84.25; H, 5.72; N, 4.68. Found: C, 84.43; H,
6.07; N, 4.49.
Cycloadduct (18). A suspension of 17 (0.53 g, 0.88 mmol) in
120 mL of nitrogen-purged acetone was placed in a quartz vessel
and subjected to 48 h of irradiation from a 400 W medium
pressure wide band mercury lamp placed 1 cm away. A fan was
used to maintain the solution at room temperature. The solvent
was then removed, and purification by flash chromatography on
silica gel (CH2Cl2) afforded 0.45 g (0.77 mmol, 86%) of 18 as a
white solid (mixture of two isomers that can be isolated).
1H NMR δ 2.76 (br s, 4H), 6.33 (d, J = 8.2 Hz, 4H), 6.74 (d,
J = 8.2 Hz, 4H), 7.38 (d, J = 7.0 Hz, 2H), 7.50 (dd, J = 7.3, 7.8
Hz, 2H), 7.87 (d, J = 8.1 Hz, 2H). 13C NMR δ 114.0, 125.0,
127.9, 129.6, 130.5, 130.7, 134.1, 135.6, 140.7, 144.2. Anal. Calcd
for C22H18N2: C, 85.13; H, 5.85; N, 9.03. Found: C, 85.39; H,
6.12; N, 8.77.
1
First eluting isomer (anti-18): H NMR δ 2.09 (s, 3H), 2.16
1,8-Bis(40-cinnamamidophenyl)naphthalene (22). To 21 (0.049 g,
0.16 mmol) in 5 mL of THF was added a solution of cinnamoyl
chloride (0.05 g, 0.33 mmol) in 2 mL of THF at 0 °C, and the
solution was stirred for 22 h at room temperature. The resulting
mixture was quenched with 1 M NaOH and extracted with EtOAc.
The combined organic layers were dried over MgSO4 and concen-
trated in vacuo. The residue was suspended in 10 mL of CH2Cl2 and
filtered twice to recover the desired product (0.05 g. 0.10 mmol), and
the filtrate was then subjected to flash chromatography on silica gel
(hexanes:THF 2:1) to afford a total of 0.074 g (0.15 mmol, 93%) of
22 as a white powder.
(s, 3H), 3.75 (dd, J = 2.0, 9.6 Hz, 1H), 4.32-4.48 (m, 2H), 4.60
(dd, J = 2.0, 9.6 Hz, 1H), 6.41 (d, J = 8.1 Hz, 2H), 6.95-7.20
(m, 13H), 7.45-7.58 (m, 5H), 7.94 (d, J = 8.0 Hz, 2H), 8.17
(d, J = 8.3 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H). 13C NMR δ 17.2,
17.4, 43.9, 45.0, 48.4, 49.4, 117.2, 117.4, 124.6, 124.7, 125.0, 126.7,
126.8, 127.3, 128.2, 128.4, 128.5, 128.7, 129.8, 129.9, 130.0, 132.5,
134.5, 135.6, 137.5, 137.7, 138.9, 139.7, 168.5, 169.8.
Second eluting isomer (syn-18): 1H NMR δ 2.03 (s, 3H), 2.17
(s, 3H), 3.70 (dd, J = 9.2 Hz, 11.1 Hz, 1H), 3.96 (m, 1H), 4.10
(dd, J = 7.8 Hz, 9.9 Hz, 1H), 4.60 (m, 1H), 6.38 (s, 1H), 6.43
(s, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.90 (s, 1H), 6.96 (d, J = 8.4 Hz,
1H), 7.27-7.51 (m, 15H), 7.64 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H),
7.92 (m, 1H), 8.18 (d, J = 8.4 Hz, 1H). 13C NMR δ 17.3, 17.4, 44.8,
46.4, 49.7, 51.9, 116.6, 118.4, 124.5, 124.6, 124.9, 125.0, 126.5, 126.6,
126.8, 127.5, 128.3, 128.6, 129.0, 129.7, 129.9, 130.1, 132.2, 132.3, 134.1,
134.8, 135.5, 138.7, 138.9, 139.4, 139.7, 140.8, 167.7, 168.9.
1H NMR (DMSO) δ 6.73 (d, J = 15.7 Hz, 2H), 6.87 (d, J =
8.0 Hz, 4H), 7.25-7.60 (m, 20H), 8.0 (d, J = 7.8 Hz, 2H), 9.99
(s, 2H). 13C NMR (DMSO) δ 122.9, 125.8, 128.0, 128.8, 129.1,
129.3, 130.0, 130.1, 131.1, 135.2, 135.7, 137.6, 138.1, 140.1,
140.2, 163.7. Anal. Calcd for C40H30N2O2: C, 84.19; H, 5.30;
N, 4.91. Found: C, 84.56; H, 5.60; N, 4.80.
Cyclobutane Derivative (23). A suspension of 22 (0.22 g,
0.39 mmol) in 54 mL of nitrogen-purged acetone was placed
in a quartz vessel and subjected to 48 h of UV irradiation with a
400 W, medium pressure wide band mercury lamp placed 1 cm
away. A fan was used to maintain the solution at room tem-
perature. The solvent was then removed. Purification of the
residue by flash chromatography on silica gel (CH2Cl2) afforded
0.18 g (0.32 mmol, 82%) of 23 as a white solid.
Anal. Calcd for C42H34N2O2 (syn/anti-mixture of 18): C, 84.25;
H, 5.72; N, 4.68. Found: C, 83.90; H, 6.04; N, 4.46.
β-Truxinic Acid (10)17. A suspension of a mixture of syn- and
anti-18 (0.050 g, 0.084 mmol) in 5 mL of 30% aqueous hydro-
chloric acid was stirred at 110 °C for 24 h in a closed vessel. The
resulting mixture was allowed to come to room temperature,
basified with NH4OH, and extracted with chloroform to quanti-
tatively recover 16. The aqueous layer was then acidified to pH 2
with concentrated hydrochloric acid, and extracted with EtOAc.
The combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was then
crystallized from acetic acid, filtered, washed with 10% hydro-
chloric acid, and freeze-dried to afford 0.020 g of 10 (0.068 mmol,
81%) as a white powder.
1H NMR δ 3.78 (d, J = 9.7 Hz, 1H), 4.36 (dd, J = 10.6, 11.2
Hz, 1H), 4.50-4.64 (m, 2H), 6.31 (d, J = 7.8 Hz, 2H), 6.48 (d,
J = 7.1 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 7.6 Hz,
2H), 7.05-7.20 (m, 10H), 7.42 (br s, 1H), 7.50-7.60 (m, 5H),
7.82 (d, J = 7.4 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.97 (dd, J =
1.4, 7.8 Hz, 2H). 13C NMR δ 43.4, 44.8, 47.4, 48.4, 119.2, 119.4,
119.5, 119.8, 125.1, 126.7, 127.3, 128.2, 128.4, 128.8, 129.0, 129.8,
130.1, 130.4, 130.9, 131.2, 135.6, 135.8, 137.6, 138.0, 139.1, 139.2,
139.4, 139.5, 168.9, 170.4. Anal. Calcd for C40H30N2O2: C, 84.19;
H, 5.30; N, 4.91. Found: C, 84.42; H, 5.59; N, 4.76.
1H NMR (DMSO) δ 3.77 (d, J=5.9 Hz, 2H), 4.18 (d, J=
5.8 Hz, 2H), 6.94-7.09 (m, 10H), 12.38 (s, 2H). 13C NMR (DMSO)
δ 43.0, 44.9, 126.3, 128.1, 128.3, 139.7, 174.4.
3. Synthesis of 10 and 26 with Template 21. 1,8-Bis(40-acet-
amidophenyl)naphthalene (20). A solution of 1,8-diiodonaphthalene
6658 J. Org. Chem. Vol. 75, No. 19, 2010

Ghosn and Wolf
JOCArticle
β-Truxinic Acid (10). A suspension of 23 (0.054 g, 0.094
mmol) in 6 mL of 30% aqueous hydrochloric acid was stirred
at 110 °C for 24 h in a closed vessel. The resulting mixture was
allowed to come to room temperature, basified with NH4OH,
and extracted with chloroform to quantitatively recover 21. The
aqueous layer was then acidified to pH 2 with concentrated
hydrochloric acid, and extracted with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was then crystallized from
acetic acid, filtered, washed with 10% hydrochloric acid, and
freeze-dried to afford 0.025 g of 10 (0.085 mmol, 90%) as a white
powder.
away. A fan was used to maintain the solution at room tem-
perature. The solvent was then removed, and the residue was
purified by flash chromatography on silica gel (CH2Cl2) to give
0.08 g (0.13 mmol, 82%) of 25 as a white solid.
1H NMR δ 2.13 (s, 12H), 3.72 (d, J = 10.2 Hz, 1H), 4.36 (dd,
J = 10.2, 10.8 Hz, 1H), 4.40-4.54 (m, 2H), 6.31 (d, J = 7.8 Hz,
2H), 6.48 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 7.4 Hz, 1H), 6.69 (d,
J = 7.6 Hz, 1H), 6.76 (br s, 1H), 6.82-6.94 (m, 4H), 7.06 (d, J =
8.2 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.46-7.58 (m, 6H), 7.82
(d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.96 (dd, J = 1.4,
7.8 Hz, 2H). 13C NMR δ 19.3, 19.7, 43.0, 44.4, 48.0, 48.5, 119.3,
124.7, 125.0, 125.7, 128.5, 129.0, 129.4, 129.6, 129.8, 130.0,
130.8, 131.0, 134.8, 135.2, 135.5, 136.2, 136.3, 139.0, 139.6,
169.3, 170.1. Anal. Calcd for C44H38N2O2: C, 84.31; H, 6.11; N,
4.47. Found: C, 84.00; H, 6.28; N, 4.80.
1H NMR (DMSO) δ 3.77 (d, J = 5.9 Hz, 2H), 4.18 (d, J =
5.8, 2H), 6.94-7.09 (m, 10H), 12.38 (s, 2H). 13C NMR (DMSO)
δ 43.0, 44.9, 126.3, 128.1, 128.3, 139.7, 174.4.
1,8-Bis(40-(3,4-dimethylcinnamido)phenyl)naphthalene (24). A
solution of 21 (0.12 g, 0.38 mmol), (E)-3-(3,4-dimethylphenyl)-
acrylic acid (0.14 g, 0.81 mmol), 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide (0.16 g, 0.85 mmol), and DMAP (0.07 g,
0.58 mmol) was stirred in 6 mL of toluene for 23 h at room
temperature. The resulting suspension was filtered twice to
collect the desired product (0.05 g. 0.10 mmol), and the filtrate
was subjected to flash chromatography on silica gel (hexanes:
THF 2:1) to afford a total of 0.19 g (0.31 mmol, 80%) of 24 as a
white powder.
3,4-Bis(3,4-dimethylphenyl)cyclobutane-1,2-dicarboxylic Acid
(26). A suspension of 25 (0.06 g, 0.096 mmol) in 6 mL of 30%
aqueous hydrochloric acid was stirred at 110 °C for 24 h in a
closed vessel. The resulting mixture was allowed to come to
room temperature, basified with NH4OH, and extracted with
chloroform to quantitatively recover 21. The aqueous layer was
then acidified to pH 2 with concentrated hydrochloric acid, and
extracted with EtOAc. The combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo. The
residue was then crystallized from acetic acid, filtered, washed with
10% hydrochloric acid, and freeze-dried to afford 0.031 g of 26
(0.088 mmol, 92%) as a white solid.
1H NMR (DMSO) δ 2.11 (s, 6H), 2.17 (s, 6H), 6.33 (d, J =
15.7 Hz, 2H), 6.84 (d, J = 8.4 Hz, 4H), 7.02 (d, J = 7.6 Hz, 2H),
7.14 (d, J = 8.0 Hz, 2H), 7.17 (s, 2H), 7.28 (d, J = 8.4 Hz, 4H),
7.37 (d, J = 15.5 Hz, 2H), 7.37 (d, J = 7.0 Hz, 2H), 7.57 (dd, J =
7.4, 7.6 Hz, 2H), 7.99 (d, J = 8.0 Hz, 2H), 9.86 (s, 2H). 13C NMR
(DMSO) δ 19.7, 118.1, 121.7, 125.6, 125.7, 128.8, 128.9, 129.1,
130.1, 130.3, 131.0, 132.8, 135.6, 137.0, 137.7, 137.9, 138.5,
140.1, 140.2, 163.9. Anal. Calcd for C44H38N2O2: C, 84.31; H,
6.11; N, 4.47. Found: C, 84.67; H, 6.16; N, 4.82.
Cyclobutane Derivative (25). A suspension of 24 (0.10 g,
0.16 mmol) in 54 mL of nitrogen-purged acetone was placed
in a quartz vessel and subjected to 48 h of UV irradiation, using a
400 W, medium pressure wide band mercury lamp placed 1 cm
1H NMR (CDCl3) δ 2.10 (s, 6H), 2.11 (s, 6H), 3.85 (d, J =
6.1 Hz, 2H), 4.31 (d, J = 6.1 Hz, 2H), 6.60-6.90 (m, 6H). 13
C
NMR (CDCl3) δ 19.3, 19.7, 44.0, 44.4, 125.2, 129.2, 129.3, 134.5,
135.7, 136.0, 179.7. Anal. Calcd for C22H24O4: C, 74.98; H, 6.86.
Found: C, 75.11; H, 7.05.
Acknowledgment. This material is based upon work sup-
ported by the NSF under CHE-0910604. We thank Dr. Travis
Holman for help with the crystallographic analyses.
Supporting Information Available: Experimental procedures,
crystallographic data, and NMR spectra of all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Kunio, S.; Hiroshi, T.; Eiko, N. Nihon Daigaku Seisankogakubu
Kenkyu Hokuku, A: Rikokei 2003, 36, 49–60.
J. Org. Chem. Vol. 75, No. 19, 2010 6659