Syntheses of 3,4-benzotropolones by ring-closing metatheses

Article abstract of DOI:10.1021/ol400510j

Ortho-lithiated styrenes or ortho-lithiated benzaldehyde dimethyl acetals were added to 2,2-dimethoxypent-4-enals 7. The resulting alcohols were carried on to the aromatic dienones 10. These were ring-closed by olefin metathesis. Hydrolysis of the dimethyl ketal moiety and enolization provided the 3,4-benzotropolones 5. Overall, this access comprises 4-6 steps and totaled a 22-81% yield.

Full text of DOI:10.1021/ol400510j

ORGANIC
LETTERS
2013
Vol. 15, No. 11
2582–2585
Syntheses of 3,4-Benzotropolones
by Ring-Closing Metatheses
€
Deniz Arican and Reinhard Bruckner*
€
Institut fu€r Organische Chemie, Albert-Ludwigs-Universitat, Albertstraβe 21, 79104
Freiburg im Breisgau, Germany
reinhard.brueckner@organik.chemie.uni-freiburg.de
Received February 27, 2013; Revised Manuscript Received May 3, 2013
ABSTRACT
Ortho-lithiated styrenes or ortho-lithiated benzaldehyde dimethyl acetals were added to 2,2-dimethoxypent-4-enals 7. The resulting alcohols were
carried on to the aromatic dienones 10. These were ring-closed by olefin metathesis. Hydrolysis of the dimethyl ketal moiety and enolization
provided the 3,4-benzotropolones 5. Overall, this access comprises 4À6 steps and totaled a 22À81% yield.
In 1945 Dewar deduced the correct structure of the
fungal metabolite stipitatic acid (Figure 1) and named its
hydroxycycloheptatrienone core tropolone (1).1 This as-
signment was confirmed by Todd et al.2 The latter also
demonstrated that the mold product puberulic acid is
hydroxystipitatic acid.3 β-Thujaplicin was described as a
naturallyoccurringtropoloneatthattimeaswell.4 Figure1
shows stipitatic and puberulic acid as single tautomers
arbitrarily, and β-thujaplicin is depicted as a mixture of
tautomers,5 because tropolone tautomerizes quickly.6
Benzannulation to the tropolone scaffold gives rise to
3,4- (3) and 5,6-benzotropolones (4) but not to 6,7-
(tautom-3) or 4,5-benzotropolones (tautom-4). The latter
gain a Clar electron sextet7 if they isomerize to give the
Figure 1. Tropolones (red), 3,4-benzotropolones (blue), and 6,7-
former. Only a few 5,6-benzotropolones (4) occur in nature,8
(tautom-3), 4,5- (4), and 5,6-benzotropolone (tautom-4).
but various 3,4-benzotropolones (3) do, e.g. purpurogallin9
(Figure 1). In nature 3,4-benzotropolones are found in
(1) Dewar, M. J. S. Nature 1945, 155, 50–51.
(2) Corbett, R. E.; Johnson, A. W.; Todd, A. R. J. Chem. Soc. 1950,
147–149.
plants10 and fungi.11 In industry 3,4-benzotropolones have
gained patent protection as antimicrobial, antiretroviral, and
(3) Corbett, R. E.; Johnson, A. W.; Todd, A. R. J. Chem. Soc. 1950, 6–9.
(4) Erdtman, H.; Gripenberg, J. Nature 1948, 161, 719–719.
(5) Two phenols cocrystallized with a given tautomer of β-thujaplicin,
and a third phenol cocrystallized with the other tautomer: Tanaka, K.;
Nagahiro, R.; Ohba, S.; Eishima, M. Tetrahedron Lett. 2001, 42, 925–929.
(6) Redington, R. L. J. Chem. Phys. 2000, 113, 2319–2335.
(9) Barltrop, J. A.; Nicholson, J. S. J. Chem. Soc. 1948, 116–120.
(10) For example: (a) Watanabe, N.; Sekine, T.; Takagi, M.; Iwasaki,
J.-i.; Imamoto, N.; Kawasaki, H.; Osada, H. J. Biol. Chem. 2009, 284, 2344–
ꢀ
(7) Inferred from: Randic, M. Chem. Rev. 2003, 103, 3449–3605.
ꢀ
ꢀ
2353. (b) Mesa-Siverio, D.; Estevez-Braun, A.; Ravelo, A. G.; Murguia,
(8) (a) Ginda, H.; Kusumi, T.; Ishitsuka, M. O.; Kakisawa, H.;
Weijie, Z.; Jun, C.; Tian, G. Y. Tetrahedron Lett. 1988, 29, 4603–4606.
(b) Kabouche, A.; Boutaghane, N.; Kabouche, Z.; Seguin, E.; Tillequin,
F.; Benlabed, K. Fitoterapia 2005, 76, 450–452 (CAN 144:167135). (c)
Seephonkai, P.; Sangdee, A.; Bunchalee, P.; Pyne, S. G. J. Nat. Prod.
2009, 72, 1892–1894.
J. R.; Rodrıguez-Afonso, A. Eur. J. Org. Chem. 2003, 4243–4247.
´
€
(11) For example: (a) Kerschensteiner, L.; Lobermann, F.; Steglich,
W.; Trauner, D. Tetrahedron 2011, 67, 1536–1539. (b) Klostermeyer, D.;
Knops, L.; Sindlinger, T.; Polborn, K.; Steglich, W. Eur. J. Org. Chem.
2000, 603–609.
r
10.1021/ol400510j
Published on Web 05/13/2013
2013 American Chemical Society

Scheme 1. Our Retrosynthetic Analysis of 3,4-Benzotropolones
Scheme 2. Syntheses of 2,2-Dimethoxypent-4-enals 7a and b
Accordingly, a synthetic plan targeting diketones keto-5
should conclude with 3,4-benzotropolones enol-5. We
traced back these diketones keto-5 to their monoketals 6.
Constituting cycloheptenes of sorts we envisaged accessing
them by ring-closing metatheses (“RCM”) of benzannu-
lated dienes 10. The latter are aromatic ketones. This
indicated that 10 could stem from the acylation20;or an
equivalent hydroxyalkylation/oxidation sequence starting
with the incorporation of 2,2-dimethoxypent-4-enals 7;
of ortho-metalated styrenes or ortho-metalated precursors
of styrenes. Such reagents seemed accessible from ortho-
bromostyrenes 8 (by Br/Li exchange) or benzaldehyde
dimethyl acetals 9 (by ortho-lithiation), respectively.
Our syntheses of 2,2-dimethoxypent-4-enals 7a and b
began with the dimethoxyacetate 11 (available from glyoxylic
acid in one step;21 Scheme 2). Allylating the 11-enolate by
modifying the procedure from Conia et al.22 delivered the
ester 12a in 74% yield (ref 22, 50%). Methallylating the
11-enolate analogously furnished ester 12b readily. Esters 12a
and b were reduced with iBu2AlH23 to provide aldehydes 7a
(74% yield) and b (95%).
antiobesity agents, for stabilizing household, cosmetic, and
nutritional products, and as UV-absorbers in sunscreens.12
Several 3,4-benzotropolones inhibit a regulator of our im-
mune system.13
A one-step synthesis of 3,4-benzotropolones from cate-
chols and pyrogallols has been known since the 19th
century.14 It is still being used15 but entails limited varia-
bility of the substitution pattern. Multistep routes to 3,
4-benzotropolone comprise the functionalization of
benzocycloheptenones16 and ring expansions.17 A route
to ether-annulated 3,4-benzotropolones by an intra-
molecular 1,3-dipolar cycloaddition18 was extended to
making polycyclic 3,4-benzotropolones by hetero-DielsÀ
Alder reactions.19
In our retrosynthetic analysis (Scheme 1) we perceived
3,4-benzotropolones 5 as thermodynamically favored enol
tautomers enol-5 of much less stable 1,2-diketones keto-5.
(12) (a) Bieler, K.; Ochs, D.; Wagner, B. WO2011048011 (A2), April 28,
2011 (CAN 154:524103). (b) Wagner, B. et al. WO2011042423 (A2), April 14,
2011 (CAN 154:443987). (c) Fukui, Y.; Asami, S.; Maeda, M. WO2010134595
Scheme 3. ortho-Lithiostyrene Approach to Benzotropolone 5d
€
(A1), November 25, 2010 (CAN 153:634903). (d) Wagner, B.; Ohrlein, R.;
Herzog, B.; Eichin, K.; Baisch, G.; Portmann, S. WO2009156324 (A2), December
30, 2009 (CAN 152:97724). (e) Romanov, A. N. et al. RU2359954 (C2), June 27,
2009 (CAN 151:100921). (f) Romanov A. N. et al. RU2359955 (C2), June 27,
2009 (CAN 151:100922).
(13) (a) Cheng, K.; Wang, X.; Zhang, S.; Yin, H. Angew. Chem., Int.
Ed. 2012, 51, 12246–12249.
(14) (a) First chemical synthesis of purpurogallin (Figure 1): Girard,
M. A. C. R. Hebd. Seꢀances Acad. Sci. 1869, 69, 865–868. (b) First enzymatic
synthesis of purpurogallin: Bertrand, M. G. C. R. Hebd. Seꢀances Acad. Sci.
1895, 120, 267–269. Isolations of analogues of the putative 1,9-dihydroxy-
4a,5-dihydro-9H-5,9-methanobenzocycloheptene-2,8,10-trione and 3,4,
5-trihydroxy-5,9-dihydro-5,9-methanobenzocycloheptene-6,10-dione inter-
€
mediates, respectively: (c) Durckheimer, W.; Paulus, E. F. Angew. Chem.,
A Br/Li exchange reaction of ortho-bromostyrene (8a)
followed by the addition of aldehyde 7a24 gave the benzylic
alcohol 13a (Scheme 3). Oxidation with Dess-Martin
periodinane25 led to the benzannulated dienone 10a. In
the presence of 1 mol % of the second generation Grubbs
Int. Ed. Engl. 1985, 24, 224–225. (d)Yanase, E.;Sawaki, K.; Nakatsuka, S.-i.
Synlett 2005, 17, 2661–2663.
(15) For example: (a) Kawabe, Y.; Aihara, Y.; Hirose, Y.; Sakurada,
A.; Yoshida, A.; Inai, M.; Asakawa, T.; Hamashima, Y.; Kan, T. Synlett
2013, 479–482. (b) Reference 11a. (c) Huang, C.; Bai, H.; Li, C.; Shi, G.
Chem. Commun. 2011, 47, 4962–4964. (d) Das, D.; Roy, S.; Debnath, S.;
Das, P. K. Chem.;Eur. J. 2010, 16, 4911–4922. (e) Li, Y.; Shibahara, A.;
Matsuo, Y.; Tanaka, T.; Kouno, I. J. Nat. Prod. 2010, 73, 33–39. (f)
Baisch, G.; Wagner, B.; Ohrlein, R. Tetrahedron 2010, 66, 3742–3748.
(16) (a) Synthesis of 3: Cook, J. W.; Somerville, A. R. Nature 1949,
€
163, 410–410. (b) Recent example: Das-tan, A.; Guney, M.; Balci, M.
€
(20) Attempted acylations of ortho-lithiostyrene (obtained from
bromostyrene 8a like in step 1 of Scheme 3) or 2-lithio-3,4-dimethoxy-
benzaldehyde dimethyl acetal (obtained from acetal 9a like in step 1 of
Scheme 5) failed with ester 12a or the corresponding Weinreb amide.
They also did not proceed cleanly with the corresponding acid chloride.
(21) (a) Cameron, A. G.; Hewson, A. T. J. Chem. Soc., Perkin Trans.
1 1983, 2979–2983. (b) Griesbaum, K.; Meister, M. Chem. Ber. 1987,
120, 1573–1580.
Helv. Chim. Acta 2005, 88, 830–838.
(17) For example: (a) Fukui, N.; Ohmori, K.; Suzuki, K. Helv. Chim.
Acta 2012, 95, 2194–2217. (b) Iwaya, K.; Tamura, M.; Nakamura, M.;
Hasegawa, E. Tetrahedron Lett. 2003, 44, 9317–9320.
€
(18) Plug, C.; Friedrichsen, W.; Debaerdemaeker, T. J. Prakt. Chem.
1997, 339, 205–216.
(19) Baldwin, J. E.; Mayweg, A. V. W.; Neumann, K.; Pritchard,
G. J. Org. Lett. 1999, 1, 1933–1935.
(22) Huet, F.; Pellet, M.; Conia, J. M. Synthesis 1979, 33–34.
(23) Reduction protocol: Trost, B. M.; Fettes, A.; Shireman, B. T.
J. Am. Chem. Soc. 2004, 126, 2660–2661.
Org. Lett., Vol. 15, No. 11, 2013
2583

catalyst26 (“Grubbs II catalyst”) the benzocycloheptad-
ienedione monoketal 6a resulted in nearly quantitative yield.
Hydrolysis of 6a with excess pTsOH in aqueous acetoni-
trile required heating at 75 °C for 4 h. This sluggishness
reflects the destabilization of the carboxonium ion, which
precedes the hemiacetal intermediate, through the benzoyl
group. Completion of hydrolysis and ketoÀenol tautomer-
ism furnished the unsubstituted 3,4-benzotropolone 5a.
Altogether our synthesis comprised four steps and gave
71% of 5a. This resembles the best previous synthesis of 5a,
which required four steps as well and totaled a 68% yield.16b
5b in 32% yield from styrene 8b. Inthe presence of 2 mol %
Grubbs II catalyst26 the dienones 10c and d ring-closed at
110 °C (3 h) and 100 °C (90 min), whereupon the respective
hydrolyses provided the known28 benzotropolone 5c (45%
overall yield) and the hitherto unknown benzotropolone
5d (52% overall yield). In the latter the RCM had estab-
lished a trisubstituted CdC bond.
Scheme 5. Accessing Benzotropolone 5e Upon Ortho-Lithiation
of the Benzaldehyde Dimethyl Acetal 9aa
Scheme 4. Synthesis of 3,4-Benzotropolones 5bÀd: Embellish-
ing the ortho-Lithiostyrene Approach of Scheme 3,a
a Prepared from Ph3MePx BrQ and sodium hexamethyldisilazide.
b From 9a.
The sequence in Scheme 5 shows a modified entry into
our benzotropolone synthesis. It warrants consideration
when proceeding similarly to Scheme 3 or 4 would require
an ortho-bromostyrene substrate, which is neither com-
mercially available nor readily synthesized. In the first step
benzaldehyde dimethyl acetal 9a29 and n-BuLi gave an
ortho-lithioacetal, which was added to the aldehyde 7b.
The resulting benzylic alcohol 13e was oxidized with the
Dess-Martin reagent25 in the presence of pyridine.30 Hy-
drochloric acid selectively cleaved the benzylic acetal of the
crude product, furnishing ketoaldehyde 14e (71% yield
from 9a). 14e was dimethylenated under “salt-free” Wittig
conditions, providing 78% of the benzannulated dienone
10e. This substrate required the harshest RCM conditions
of the present study: Within 7 h at 100 °C, 5 mol % of the
Grubbs II catalyst26 led to the bicyclic monoketal 10e in
91% yield. Hydrolysis afforded the benzotropolone 5e
(49% overall yield for the five steps).
a Over the two steps.
We employed the strategy of Scheme 3 for synthesizing
the substituted benzotropolones 5bÀd (Scheme 4). None
of them nor their core 5a is substituted such that it could be
reached by the mentioned14 co-oxidation of a catechol and
a pyrogallol. By subjecting the ortho-bromostyrenes 8b27
Àd to Br/Li-exchange reactions, adding aldehyde 7a, and
oxidizing the resulting carbinols without prior purification
by the Dess-Martin reagent25 rendered the benzannulated
dienones 10bÀd in 39%, 59%, and 54% yield, respec-
tively. Dienone 10b needed 3 mol % Grubbs II catalyst and
90 °C (9 h) for an effective ring closure to the benzo-
cycloheptadienedione monoketal 10b (93% yield). Acidic
hydrolysis completed the unprecedented benzotropolone
The benzaldehyde dimethyl acetals 9a29 and b29 were the
starting materials for the benzotropolone syntheses in
Scheme 6. Following the course of our proof-of-principle
sequence 9a f 10e (Scheme 5) we advanced to the
(24) Recent Br/Li exchanges in ortho-bromostyrenes with ensuing
hydroxyalkylations: (a) Snyder, S. A.; Sherwood, T. C.; Ross, A. G.
Angew. Chem., Int. Ed. 2010, 49, 5146–5150. (b) Snyder, S. A.; Breazzano,
S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L. J. Am. Chem. Soc. 2009, 131,
1753–1765. (c) Kim, J.; Li, H. B.; Rosenthal, A. S.; Sang, D.; Shapiro,
T. A.; Bachi, M. D.; Posner, G. H. Tetrahedron 2006, 62, 4120–4127. (d)
Tietze, L. F.; Stewart, S. G.; Polomska, M. E.; Modi, A.; Zeeck, A.
Chem.;Eur. J. 2004, 10, 5233–5242.
(28) 5c was synthesized in 3 steps and 7% total yield by: Barltrop,
J. A.; Johnson, A. J.; Meakins, G. D. J. Chem. Soc. 1951, 181–185.
(29) Obtained by acetalization of the corresponding aldehyde as de-
scribed by: Napolitano, E.; Giannone, E.; Fiaschi, R.; Marsili, A. J. Org.
Chem. 1983, 48, 3653–3657.
(30) When the base was absent the benzylic acetal hydrolyzed
partially. Thereupon the OH and CHdO groups combined forming a
lactol, which was inert to the oxidant. The same kind of lactolization
thwarted our attempts of ortho-lithiating benzaldehydes rather than
benzaldehydedimethyl acetals by Comins in situ protection/ortho-lithia-
tion strategy (Comins, D. L. Synlett 1992, 615–625).
(25) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(26) [1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-
(phenylmethylene)(tricyclohexylphosphane)ruthenium.
(27) 8b had been obtained from 2-bromo-3,5-dimethoxybenzalde-
hyde: Broering, T. J.; Morrow, G. W. Synth. Commun. 1999, 29, 1135–
1142. However, we made 8b differently (see Supporting Information).
(31) The dimethylenation of ketoaldehyde 14g giving dienone 10g
afforded a 92% yield only under “salt-free” conditions. The ylide
resulting from MePh3Px BrQ and n-BuLi gave 10g in 45% yield at best.
2584
Org. Lett., Vol. 15, No. 11, 2013

Scheme 6. Benzotropolone Syntheses Based on the ortho-
Lithioacetal Approach of Scheme 5 (a Non-Hydrolytic
Ketoketal Cleavage of 6gf15g Is Included)a
Scheme 7. Synthesis of the Benzotropolone Methyl Ether 15i via
a Ring-Closing Enyne Metathesisa
a Over the 3 steps.
4-O (f15h).34 15h was di(demethylated) at rt giving 3,4-
dihydroxybenzotropolone (5h) in 77% yield.
Finally we tested our benzotropolone strategy replacing
the ring-closing diene metathesis by a ring-closing enyne
metathesis (Scheme 7). The requisite substrate 17 was ob-
tained in a manner similar to that for the dienes 10aÀd by
our ortho-lithiostyrene route (Schemes 3 and 4), namely by
adding the lithioarene derived from (ortho-bromophenyl)-
acetylene 1635 to the aldehyde 7a. After oxidation and
deprotection we obtained the enyne 17 in 58% yield over
three steps. Ring-closing metathesis in the presence of
5 mol % of the Grubbs II catalyst26 delivered the vinyl-
substituted benzocycloheptadienedione monoketal 6i in
45% yield. Attempted ketal cleavage with pTsOH led to
decomposition rather than to the benzotropolone 5i. How-
ever, a DBU-induced β-elimination of methanol delivered
9-vinyl-3,4-benzotropolone methyl ether (15i) in 33% yield.
The fact that benzoid aromatics can emerge from ring-
closing metatheses may not be obvious but is well-
known.36 In the present study, it was established for the
first time that a nonbenzenoid aromatic such as a tropo-
lone can emerge from a ring-closing metathesis. This al-
lowed access to the 3,4-benzotropolones 5aÀh in 4À6 steps
with 22À81% overall yield and the 3,4-benzotropolone
methyl ethers 15gÀi in 5 steps with 8.6À69% overall yield.
a Over the three steps. b Over the two steps.
benzannulated dienones 10f and g uneventfully.31 Ring
closure by metathesis and ketal hydrolysis delivered
4-methoxybenzotropolone (5f) and 3,4-dimethoxybenzo-
tropolone (5g), respectively. Both compounds had not
been described. Optimizing their syntheses paid off by
overall yields of 48% (5f) and 81% (5g). Bis(demethyla-
tion) of 5g gave 75% of 3,4-dihydroxybenzotropolone
(5h). 50 years ago the latter compound was synthesized
by the mentioned14 co-oxidation of a catechol (in this case:
the catechol) and a pyrogallol (in this case: the pyrogallol)32
in a single step with a 47À50% yield. Remarkably, the
latter is less than the total yield of our six-step sequence:
61%. This underscores the efficiency of our strategy.33
A bypass for the ketal cleavage 6gf5g (Scheme 6,
middle), which we had performed at 75 °C under equally
acidic conditions as the analogous cleavages 6aÀf f5aÀf
(Schemes 3À6), deserves mentioning. An LDA-induced
β-elimination of methanol from the benzocycloheptadi-
enedione monoketal 6g provided 80% of 3,4-dimethoxy-
benzotropolone methyl ether (15g; Scheme 6, bottom).
The latterwas mono(demethylated) withBBr3 atÀ78°C at
Acknowledgment. The authors thank Clara Heimburger
€
(Institut fur Organische Chemie, Albert-Ludwigs-
€
Universitat Freiburg) for technical assistance, Dr.
Manfred Keller (Institut fur Organische Chemie, Albert-
€
€
Ludwigs-Universitat Freiburg) for NMR experiments,
and the IRTG 1038 (Deutsche Forschungsgemeinschaft)
for financial support.
€
€
(32) Horner, L.; Durckheimer, W.; Weber, K.-H.; Dolling, K. Chem.
Ber. 1964, 97, 312–324.
(33) Of course, this efficiency is more valuable when applied to the
generation of benzotropolones off the co-oxidation manifold.
(34) The triflate derived from phenol 15h suggests the possibility of
preparing 4-modified benzotropolones in the sequel of Pd-catalyzed
cross-coupling reactions.
(35) Compound 16 was prepared in 2 steps from 2-bromobenzalde-
hyde in 89% overall yield (see Supporting Information).
(36) van Otterlo, W. A. L.; de Koning, C. B. Chem. Rev. 2009, 109,
3743–3782.
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of NMR spectra,
and efficiency comparisons with previous syntheses of
benzotropolones 5aÀh (if existing). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 11, 2013
2585