Efficient catalytic, oxidative lactonization for the synthesis of benzodioxepinones using thiazolium-derived carbene catalysts

Article abstract of DOI:10.1021/ol101854r

An efficient, oxidative carbene-catalyzed lactonization reaction has been developed. Using thiazolium precatalysts, a variety of benzodioxepinone products are accessible in good to excellent yields under mild and operationally simple conditions. The react

Full text of DOI:10.1021/ol101854r

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4552-4555
Efficient Catalytic, Oxidative
Lactonization for the Synthesis of
Benzodioxepinones Using
Thiazolium-Derived Carbene Catalysts
Christopher A. Rose and Kirsten Zeitler*
Institut fu¨r Organische Chemie, UniVersita¨t Regensburg, UniVersita¨tsstrasse 31,
D-93053 Regensburg, Germany
kirsten.zeitler@chemie.uni-regensburg.de
Received August 7, 2010
ABSTRACT
An efficient, oxidative carbene-catalyzed lactonization reaction has been developed. Using thiazolium precatalysts, a variety of benzodioxepinone
products are accessible in good to excellent yields under mild and operationally simple conditions. The reaction does not require high dilution
conditions and proceeds via mild and selective oxidation with azobenzene, which can easily be recovered and reused applying inexpensive
FeCl3 as a formal terminal oxidant.
Lactones are ubiquitous motifs in organic chemistry and
constitute the core of many biologically active compounds
and natural products. As a consequence, the mild and efficient
preparation of these cyclic systems, particularly via new
strategies, remains an important objective. Thus, a variety
of powerful methods for the “carbonyl-centered”1 ring
closure has been developed, including numerous approaches
of coupling preformed or in situ activated acyl species, such
as mixed anhydrides, thioesters, acyl halides, or activated
esters, amenable for the subsequent C-O bond formation
with the nucleophilic alcohol species.2 However, such
classical lactonization protocols starting from the parent acid
(Scheme 1, path A) require the (super)stoichiometric use of
an activation reagent and often depend on non-“step-
economical”3 protection/deprotection sequences to ensure
chemoselectivity and to avoid potential side reactions. In
contrast, there are only few catalytic reactions to achieve
the desired ring closure. On the basis of Cannizzaro-type,
respectively, Tishchenko-type, disproportionation of di-
aldehydes, only recently a number of elegant transition-
metal-catalyzed intramolecular ketone hydroacylation pro-
cesses4,5 have been developed; general organocatalytic
lactonization approaches are rather rare.6 Additionally, in the
context of valuable alternative transformations, oxidative
(1) Especially for the synthesis of macrolides, alternative methods
targeting other positions to achieve ring closure, such as ring closing
metathesis or (Suzuki) cross coupling, have gained in importance during
the last years; for corresponding reviews, see, for RCM: (a) Rouge dos
Santos, A.; Kaiser, C. R.; Fe´re´zou, J.-P. Quim. NoVa 2008, 31, 655. (b)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4490. For cross coupling: (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4442.
(2) (a) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. ReV. 2006,
106, 911. (b) Shiina, I.; Fukui, H.; Sasaki, A. Nat. Protoc. 2007, 2, 2312,
and references cited therein.
(3) (a) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc.
Chem. Res. 2008, 41, 40. (b) Young, I. S.; Baran, P. S. Nat. Chem. 2009,
1, 193. (c) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. ReV.
2009, 38, 3010.
10.1021/ol101854r  2010 American Chemical Society
Published on Web 09/23/2010

only accessible via internal redox reactions employing
R-functionalized aldehyde precursors (Scheme 1, path B)11
but can, in principle, also be obtained from unfunctionalized
aldehydes upon carbene attack via external oxidation (Scheme
1, path C)12,13 of the corresponding initial intermediate.
Scheme 1. Overview of Stoichiometric and (NHC) Catalytic
Lactonization Approaches via Activated Acyl Species
Recently, we reported on the NHC-mediated synthesis of
3,4-dihydrocoumarins following the intramolecular redox
strategy starting from o-hydroxycinnamaldehydes.14
The obvious benefits of a related oxidation/esterification
sequence using heterazolium-derived carbenes as catalytic
acyl transfer agents for the synthesis of lactones and the
significant potential of merging this approach with an
operationally trivial recycling method for the oxidant prompted
us to evaluate the feasibility of this concept (Scheme 2).
lactonization reactions7 have recently attracted a revived
interest.8
Scheme 2. Catalytic Oxidative Lactonization Using NHCs
Apart from the versatile chemistry of N-heterocyclic
carbene (NHC)-catalyzed C-C bond formations,9 NHCs also
allow for the catalytic generation of activated acyl azolium
species which can undergo subsequent C-O or C-N bond
formation.10 In general, these activated carboxylates are not
(4) For selected examples, see, for aldehyde C-H activation with Rh
catalysts: (a) Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc.
2009, 131, 15608. (b) Shen, Z.; Khan, H. A.; Dong, V. M. J. Am. Chem.
Soc. 2008, 130, 2916. (c) Shen, Z.; Dornan, P. K.; Khan, H. A.; Woo, T. K.;
Dong, V M. J. Am. Chem. Soc. 2009, 131, 1077. Rh-catalyzed oxidative
process: (d) Ye, Z.; Lv, G.; Wang, W.; Zhang, M.; Cheng, J. Angew. Chem.,
Int. Ed. 2010, 49, 3671. Pd catalysts: (e) Ye, Z.; Qian, P.; Lv, G.; Luo, F.;
Cheng, J. J. Org. Chem. 2010, 75, 6043. (f) Li, Y.; Jardine, K. J.; Tan
R.; Song, D.; Dong, V. M. Angew. Chem., Int. Ed. 2009, 48, 9690.
(g) Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am.
Chem. Soc. 2006, 128, 9032. Ru catalysts: (h) Omura, S.; Fukuyama, T.;
Murakami, Y.; Okamoto, H.; Ryu, I. Chem. Commun. 2009, 6741, and
references cited therein.
Herein, we disclose the successful development of a simple
carbene-catalyzed oxidative lactonization protocol for the
efficient synthesis of benzodioxepinone derivatives.
Macrocyclic benzolactones such as the marine salicyli-
halamides and structurally related salicylic acid lactones
exhibit attractive biological properties;15 also, the lichen and
endophytic fungi-derived class of depsidones with their
characteristic seven-membered benzo[e]1,4-dioxepan-5-one
(5) For an NHC-catalyzed intramolecular hydroacylation yielding a
phthalide scaffold, see: Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2006,
128, 4558.
(6) For selected recent examples, see: (a) Whitehead, D. C.; Yousefi,
R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132, 3298.
(b) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang, W.
J. Am. Chem. Soc. 2010, 132, 3664. (c) Zhang, H.; Zhang, S.; Liu, L.; Luo,
G.; Duan, W.; Wang, W. J. Org. Chem. 2010, 75, 368.
(7) Potential complications arise from overoxidation, especially in the
case of electron-rich substrates and as well from missing selectivity if non-
meso-diols are used. For a general review on oxidative esterifications, see:
Ekoue-Kove, K.; Wolf, C. Chem.sEur. J. 2008, 14, 6302.
(11) Representative recent examples: (a) Reynolds, N. T.; de Alaniz,
J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518. (b) Chow, K. Y.-K.;
Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126. (c) Chan, A.; Scheidt,
K. A. Org. Lett. 2005, 7, 905. (d) Sohn, S. S.; Bode, J. W. Angew. Chem.,
Int. Ed. 2006, 45, 6021. (e) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2010,
132, 2860. (f) Zeitler, K. Org. Lett. 2006, 8, 637.
(8) Representative recent examples: (a) Ebine, M.; Suga, Y.; Fuwa, H.;
Sasaki, M. Org. Biomol. Chem. 2010, 8, 39. (b) Ito, M.; Osaku, A.; Shiibashi,
A.; Ikariya, T. Org. Lett. 2007, 9, 1821. (c) Hansen, T. M.; Florence, G. J.;
Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett.
2003, 44, 57. (d) Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. Org. Lett.
2002, 4, 2361.
(12) Representative recent examples using MnO2: (a) Maki, B. E.; Chan,
A.; Phillips, E. M.; Scheidt, K. A. Tetrahedron 2009, 65, 3102. (b) Maki,
B. E.; Scheidt, K. A. Org. Lett. 2008, 10, 4331. (c) Maki, B. E.; Chan, A.;
Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007, 9, 371.
(9) For recent reviews, see: (a) Phillips, E. M.; Chan, A.; Scheidt, K. A.
Aldrichimica Acta 2010, 42, 55. (b) Moore, J. L.; Rovis, T. Top. Curr.
Chem. 2010, 291, 77. (c) Zeitler, K. E. Schering Found. Symp. Proc. 2007,
2, 183. (d) Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107,
5606. (e) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506.
(13) Representative examples using organic oxidants: (a) De Sarkar, S.;
Studer, A. Org. Lett. 2010, 12, 1992. (b) De Sarkar, S.; Grimme, S.; Studer,
A. J. Am. Chem. Soc. 2010, 132, 1190. (c) Noonan, C.; Baragwanath, L.;
Connon, S. J. Tetrahedron Lett. 2008, 49, 4003. (d) Guin, J.; De Sarkar,
S.; Grimme, S.; Studer, A. Angew. Chem., Int. Ed. 2008, 47, 8727.
(e) Miyashita, A.; Suzuki, Y.; Nagasaki, I.; Ishiguro, C.; Iwamoto, K.-I.;
Higashino, T. Chem. Pharm. Bull. 1997, 45, 1254. (f) Tam, S. W.; Jimenez,
L.; Diederich, F. J. Am. Chem. Soc. 1992, 114, 1503. (g) Inoue, H.;
Higashiura, K. J. Chem. Soc., Chem. Commun. 1980, 549. (h) Shinkai, S.;
Yamashita, T.; Kusano, Y.; Manabe, O. J. Org. Chem. 1980, 45, 4947.
(i) Castells, J.; Pujol, F.; Llitjo´s, H.; Moreno-Man˜as, M. Tetrahedron 1982,
38, 337. (j) Castells, J.; Llitjo´s, H.; Moreno-Man˜as, M. Tetrahedron Lett.
(10) For selected related, recent preparations of lactones via NHC
catalysis, see: (a) Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P.; Bode,
J. W. J. Am. Chem. Soc. 2010, 132, 8810. (b) Ryan, S. J.; Candish, L.;
Lupton, D. W. J. Am. Chem. Soc. 2009, 131, 14176. (c) Phillips, E. M.;
Wadamoto, M.; Roth, H. S.; Ott, A. W.; Scheidt, K. A. Org. Lett. 2009,
11, 105. (d) Wang, L.; Thai, K.; Gravel, M. Org. Lett. 2009, 11, 891. (e)
Wang, X.-N.; Shao, P.-L.; Lv, H.; Ye, S. Org. Lett. 2009, 11, 4029. (f) Li,
G.-Q.; Dai, L.-X.; You, S.-L. Org. Lett. 2009, 11, 1623. (g) Sohn, S. S.;
Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370. (h) Glorius,
F.; Burstein, C. Angew. Chem., Int. Ed. 2004, 43, 6205. (i) See also
references cited in ref 14.
1977, 18, 205, and references cited therein
.
(14) Zeitler, K.; Rose, C. A. J. Org. Chem. 2009, 74, 1759.
(15) Yet, L. Chem. ReV. 2003, 103, 4283.
Org. Lett., Vol. 12, No. 20, 2010
4553

Table 1. Optimization of Reaction Conditions for Oxidative Lactonization
entry
variation of standard condition
yielda A (%)
yielda B (%)
1
2
none
95(94)b
84
<5
<5
1 equiv of MnO2 instead of azobenzene
1 instead of 5d, 5 mol % of DMAP instead of NEt3, toluene
(0.5 M) instead of THF
3c
10
49
<5
<5
4
2 instead of 5d
5d
3 instead of 5d, 1.2 equiv of DBU instead of NEt3, 5 equiv of
MnO2 instead of azobenzene, toluenec
4 instead of 5d
5a instead of 5d
5b instead of 5d
5c instead of 5d
0 mol % of 5d
0 mol % of 5d; 1 equiv of MnO2 instead of azobenzene
41
93
27
91
93
0
<5
7
<5
<5
<5
0
6
7
8
9
10
11
0
0
a Yields determined by 1H NMR using 1,1,2-trichloroethylene as internal standard. b Isolated yield. c Reaction conditions according to ref 11f. d Reaction
conditions related to ref 12a. e c ) 0.2 M.
core shows a broad range of interesting biological activities.16
Moreover, in perfumery, so-called marine notes mainly stem
from benzodioxepinone compounds.17
Our initial experiments began with simple test substrates,
such as 6, which could be conveniently prepared from
salicylaldehyde derivatives.18 At the outset of our study, we
investigated the efficacy and selectivity of various hetera-
zolium salt/base combinations (Table 1). As we envisioned
the “reactivation” of the oxidizing agent, we focused on mild
organic oxidants, such as azobenzene,13c,g,i which previously
had proven to also work successfully without the general
requirement of being applied in excess.
Figure 1. Evaluated heterazolium-derived carbene precursors.
limitations and ethyl acetate proved ineffective. Changing
the oxidant to MnO2 resulted in diminished but still very
good yield (entry 2).21
After examining a number of common NHC precursors
(Figure 1 and Table 1), we found that sterically hindered
Mes-substituted thiazolium perchlorate 5d in combination
with NEt3 and azobenzene indeed promotes the desired
cyclization, providing lactone 7A in excellent yield (94%,
entry 1).19 Gratifyingly, our initial concerns centered on a
potential concurrent competing dimerization2a of the start-
ing material were not confirmed as even at 1 M sub-
strate concentration we could only detect traces of the
14-membered diolide 7B.20 In a brief solvent screen, toluene
and dichloromethane in addition to THF gave best yields,
while the use of chloroform and acetonitrile showed some
This study also revealed marked effects on reactivity and
performance of the heterazolium carbene precursors, em-
phasizing the importance of the employment of thiazolium-
derived carbenes for this process (entries 6-9 vs entries
3-5). In the presence of imidazolium precatalyst 1, lactone
7A was obtained in poor yield, while triazolium salts 2 and
3 only showed moderate activity for the desired conversion
(including versatile conditions developed by Scheidt et al.,
entry 5). Within the group of thiazolium precatalysts, simple
commercially available benzyl-substituted precatalyst 4
demonstrated an excellent performance for this transforma-
tion, albeit with a slightly diminished selectivity (entry 6).
However, N-phenyl thiazolium catalyst 5a only displayed
minor lactonization reactivity, providing further evidence for
(16) (a) Pittayakhajonwut, P.; Dramae, A.; Madla, S.; Lartpornmatulee,
N.; Boonyuen, N.; Tanticharoen, M. J. Nat. Prod. 2006, 69, 1361. (b)
Khumkomkhet, P.; Kanokmedhakul, S.; Kanokmedhakul, K.; Hahnvajana-
wong, C.; Soytong, K. J. Nat. Prod. 2009, 72, 1487. (c) Zheng, Y.; Zhao,
B.; Lu, C.; Lin, X.; Zvheng, Z.; Su, W. Nat. Prod. Commun. 2009, 4, 501.
(17) (a) Kraft, P.; Popaj, K.; Mu¨ller, P.; Scha¨r, M. Synthesis 2010, 3029.
(b) Hu¨gel, H. M.; Drevermann, B.; Lingham, A. R.; Marriott, P. J. Chem.
BiodiV. 2008, 5, 1034.
(21) Attempts to use air or O2 (balloon) as terminal oxidant did not
provide satisfactory yields (11 resp. 21%); however, for reports on strongly
electron-deficient substrates that could be converted to their corresponding
esters/acids without additional oxidant, see: (a) Goswami, S.; Hazra, A.
Chem. Lett. 2009, 38, 484. (b) Yoshida, M.; Katagiri, Y.; Zhu, W.-B.;
Shishido, K. Org. Biomol. Chem. 2009, 7, 4062.
(18) He, J.; Zheng, J.; Liu, J.; She, X.; Pan, X. Org. Lett. 2006, 8, 4637.
(19) In addition, benzimidazolium and N-Mes triazolium salts were
evaluated, but provided much lower yields than 5d.
(20) We could observe a concentration effect: at 3 M, the ratio of 7A
to 7B was determined to be ca. 9:1.
4554
Org. Lett., Vol. 12, No. 20, 2010

the need of a distinct steric environment. We also performed
control experiments in order to verify the essential catalytic
role of the NHCs for this transformation and to exclude a
conceivable hemiacetal oxidation/lactonization process.22 In
the absence of a NHC catalyst, no conversion could be
observed (entries 10 and 11).
In an effort to further improve our conditions with respect
to the terminal oxidant, also being aware of the potential
drawbacks of the stoichiometric use of azobenzene, which
could significantly curtail the attractivity of our method, we
turned our attention to finding a useful, operationally trivial
recycling procedure. After separation of the reduced hydra-
zobenzene from the product via simple filtration over SiO2,
it was treated with FeCl3 × 6H2O in aqueous acetone under
reflux.23 After 5 min, the reoxidized, active oxidant azoben-
zene can be isolated by filtration, thus rendering this process
more attractive by employing FeCl3 as an inexpensive formal
oxidant.24
ditional hydroxy groups are tolerated without further protec-
tion (14, 74% yield). This method is also applicable to
secondary alcohol precursors, for example, providing access
to tricyclic lactone 16 with 78% isolated yield. Interestingly,
an illustrative survey of the olfactory properties of lactones
8, 9, and 10 evidenced their quite remarkable high intensity
as odorants (threshold values ) 250, 0.050, and 0.99 ng/L
air, respectively).
Taking advantage of MnO2’s12 ability to effectively
oxidize allylic and benzylic alcohols and having its usability
as alternative oxidant for the oxidative lactonization in mind,
we envisioned its application for a tandem sequence com-
bining benzylic oxidation with subsequent oxidative lacton-
ization.
As depicted in Scheme 4, this two-step transformation
could be performed as a single-flask procedure without the
Having developed optimal conditions for the oxidative
lactonization, we next examined the substrate scope of this
transformation. As shown in Scheme 3, a wide range of
differently substituted electron-rich as well as electron-
deficient aromatic hydroxyaldehydes can undergo catalytic
lactonization with good to excellent yields. Due to the mild
reaction conditions and the chemoselective oxidant, ad-
Scheme 4. Tandem One-Pot Oxidation/Lactonization Process
need of intermediate purification, providing lactone 7 in an
overall isolated yield of 58%.
Scheme 3. Substrate Scope of the Catalytic Lactonization
In conclusion, we have developed an NHC-catalyzed mild
oxidative lactonization protocol under non-high-dilution
conditions. Application of FeCl3 as recycling agent and thus
as formal terminal oxidant provides an efficient access to
interesting benzodioxepinone derivatives. Future studies will
explore the full scope of this method25 and its application.
Acknowledgment. Generous support from the DFG
(priority program “Organocatalysis” SPP1179) is gratefully
acknowledged. We also thank Dr. Philip Kraft (Givaudan,
Switzerland) for the olfactory evaluation and the determi-
nation of the corresponding odor threshold values of
compounds 8, 9, and 10.
Supporting Information Available: Experimental details
and spectroscopic and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL101854R
(22) Foot, J. S.; Kanno, H.; Giblin, G. M. P.; Taylor, R. J. K. Synthesis
2003, 1055.
(23) See Supporting Information for details: Wang, C.-L.; Wang, X.-
X.; Wang, X.-Y.; Xiao, J.-P.; Wang, Y.-L. Synth. Commun. 1999, 29, 3435.
Efforts for the concurrent use of FeCl3 for an in situ recycling process of
azobenzene have not proven successful so far.
(24) For a recent application of NHC-Fe complexes for an aerobic
esterification with boronic acids, see: Rosa, J. N.; Reddy, R. S.; Candeias,
N. R.; Cal, P. M. S. D.; Gois, P. M. P. Org. Lett. 2010, 12, 2686.
(25) Initial attempts to apply this methodology to the synthesis of the
most challenging eight-membered ring system2a affords the desired lactone
in only 14% yield. However, this is remarkable as a related Ru-catalyzed
approach only yielded 7% of the envisaged 8-ring. See ref 4h.
Org. Lett., Vol. 12, No. 20, 2010
4555