An efficient synthesis of novel fused cycloheptatrienes through Mn(II)-mediated formal intermolecular [2 + 2 + 2 + 1] cycloaddition

Article abstract of DOI:10.1021/ol500202q

A new method for manganous acetate tetrahydrate mediated formal intermolecular [2 + 2 + 2 + 1] cycloaddition was developed for the synthesis of fused cycloheptatriene derivatives from N-(acylmethyl)pyridinium iodides and naphthoquinone. This method provides an innovative route for the efficient and convenient construction of fused seven-membered carbocycles from simple starting materials.

Full text of DOI:10.1021/ol500202q

Letter
pubs.acs.org/OrgLett
An Efficient Synthesis of Novel Fused Cycloheptatrienes through
Mn(II)-Mediated Formal Intermolecular [2 + 2 + 2 + 1] Cycloaddition
Wen-Ming Shu, Jun-Rui Ma, Yan Yang, and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University
Hubei, Wuhan 430079, P. R. China
S
* Supporting Information
ABSTRACT: A new method for manganous acetate tetrahy-
drate mediated formal intermolecular [2 + 2 + 2 + 1]
cycloaddition was developed for the synthesis of fused
cycloheptatriene derivatives from N-(acylmethyl)pyridinium
iodides and naphthoquinone. This method provides an
innovative route for the efficient and convenient construction
of fused seven-membered carbocycles from simple starting
materials.
he development of new strategies for the synthesis of
biologically active compounds, natural products, and non-
sequential process than others.10b−e In 2003, Barluenga’s group
reported a novel nickel-mediated [2 + 2 + 2 + 1] cyclization for
the construction of the cycloheptatriene chromium complexes
by the reaction of Fischer carbene complexes and alkynes
(Scheme 1a).9 Ojima and co-workers subsequently reported a
T
natural products with interesting molecular structures is of great
importance in organic chemistry.1 Much effort has therefore
been devoted to this activity, and considerable advances have
been made in the development of cycloaddition reactions.2,10c
Cycloaddition is widely regarded as one of the most efficient
means for the construction of cyclic compounds on account of
its ability to form at least two bonds in one operation.3 The
transition-metal-catalyzed cycloaddition reactions are the most
useful processes for the rapid construction of a complex ring
system.4,10 Various transition metals have been commonly used
to promote these processes, such as nickel, ruthenium, cobalt,
rhodium, palladium, and so on.5,10c
Scheme 1. Protocols for [2 + 2 + 2 + 1] Cycloaddition
Reactions
Trimeric naphthoquinone derivatives have widely existed in
various natural products and pharmaceutical molecules, which
exhibited good biological activity. For example, conocurvone
shows good HIV-inhibitory activity;6 cyclotrisjugnone has been
used to treat cardiovascular disease;7 and trimeric compound 5,
as an organic pigment and vat dye, has wide applications in
organic materials (Figure 1).8 Therefore, it is very intresting
and useful for the efficient construction of trimeric analogue 3
by cycloadditions. Among the various types of cycloadditions,
the [2 + 2 + 2 + 1] cycloaddition is rarely reported for the
synthesis of cycloheptatriene derivatives, since it is a higher self-
novel Rh-catalyzed intramolecular [2 + 2 + 2 + 1] cycloaddition
reaction for the synthesis of fused tropones from triyne
substrates and CO (Scheme 1b).10 Herein, a Mn(II)-mediated
formal intermolecular [2 + 2 + 2 + 1] cycloaddition reaction is
described for the efficient construction of novel fused
cycloheptatriene derivatives from easily available N-(acyl-
methyl)pyridinium iodides and naphthoquinone (Scheme 1c).
This new formal [2 + 2 + 2 + 1] cycloaddition provides a
Received: November 23, 2013
Published: February 24, 2014
Figure 1. Examples of trimeric naphthoquinone derivatives.
© 2014 American Chemical Society
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Organic Letters
Letter
powerful method for the convenient synthesis of complex fused
seven-membered ring systems. To the best of our knowledge,
this is the first report on the use of transition-metal
manganese(II) as a promoter for a formal cycloaddition
reaction.
Initially, the reaction of N-phenacylpyridinium iodide (1a)
and naphthoquinone (2a) was explored under the conditions
shown in Table 1. Interestingly, the desired product 3aa was
decreases in the amount of Mn(OAc)2·4H2O (entries 15 and
16). Moreover, yields were decreased when the reaction was
performed at a lower or higher temperature (entries 17 and
18). The screening of various solvents revealed that the choice
of solvent had great influence on the reaction (entries 19−22).
Surprisingly, DMSO was identified as the only solvent so far
suitable for the formation of 3aa (entry 14). The desired
product was not obtained with other solvents (C2H5OH, THF,
DMF, and toluene) (entries 19−22).
a
With the optimized conditions in hand, the scope of the
reaction was further investigated, as shown in Table 2. To our
Table 1. Optimization of the Reaction Conditions
a
Table 2. Synthesis of Fused Cycloheptatriene Derivatives
b
entry
solvent
addictive
temp (°C)
yield (%)
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
C2H5OH
THF
−
HOAc
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
80
100
78
66
90
90
45
41
38
0
b
2
entry
Ar
product
yield (%)
3
TFA
1
Ph
3aa
3ba
3ca
3da
3ea
3fa
85
86
72
75
65
71
64
73
76
71
68
74
0
4
K2CO3
2
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
3,4-(CH2O)2C6H3
4-NO2C6H4
2-ClC6H4
5
Cs2CO3
0
3
6
CrCl3·6H2O
FeCl3
40
42
78
47
20
48
82
35
85
4
7
5
8
Co(OAc)2·4H2O
Ni(NO3)2·6H2O
Cu(OAc)2·H2O
ZnCl2
6
9
7
3ga
3ha
3ia
10
11
12
13
14
15
16
17
18
19
20
21
22
8
9
4-ClC6H4
Pd(OAc)2
10
11
12
13
14
15
2,4-Cl2C6H3
3-BrC6H4
3ja
AgNO3
3ka
3la
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
4-BrC6H4
c
66
2-furyl
3ma
3na
3oa
d
84
2-thienyl
81
75
78
83
0
2-naphthyl
a
Reaction conditions: N-(acylmethyl)pyridinium iodides 1 (1.0 mmol,
1.0 equiv) with naphthoquinone 2a (3.0 mmol, 3.0 equiv) and
Mn(OAc)2·4H2O (0.5 mmol, 0.5 equiv) was stirred in DMSO (20
0
b
DMF
0
mL) at 90 °C for 18 h. Isolated yields.
Toluene
0
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.3 mmol, 3.0
equiv), addictive (0.05 mmol, 0.5 equiv), and solvent (2 mL) for 18 h.
Isolated yields. 0.3 equiv of Mn(OAc)2·4H2O was used. The
delight, various N-(acylmethyl)pyridinium iodides 1 proceeded
smoothly to afford the corresponding products in good to
excellent yields (64−86%), regardless of their electronic or
steric properties. Moreover, electron-neutral (H, 4-Me),
electron-donating (3-OMe, 4-OMe, 3,4-2OMe, 3,4-2OCH2),
and electron-withdrawing (4-NO2) substrates attached to the
benzene ring were smoothly transformed into their correspond-
ing products in good to excellent yields (64−86%; entries 1−
7). Much to our satisfaction, good yields were also obtained for
halo-substituted substrates (68−76%; entries 8−12). Hetero-
aryl groups were also investigated. Unfortunately, the desired
product was not detected with 2-furyl as the substituted group
(entry13). However, the 2-thienyl substituted substrate
proceeded to obtain the target product in 81% yield (entry
14). In addition, even when the substrate contained a sterically
hindered 2-naphthyl group, the corresponding product was
obtained in 75% yield (entry15). The structure of 3ia was
further determined by X-ray crystallographic analysis (see
Supporting Information (SI)).
b
c
d
amount of Mn(OAc)2·4H2O was 1.0 equiv.
obtained in 45% yield when the reaction was performed in
DMSO at 90 °C for 18 h without any additives (Table 1, entry
1). The influence of acid and base in the reaction was
subsequently examined. HOAc and TFA were shown to have
little significant effect on the reaction (entries 2 and 3).
Moreover, the desired product was not detected in the presence
of K2CO3 or Cs2CO3 (entries 4 and 5). The effect of additives
was then examined in the reaction. To our delight, Mn(OAc)2·
4H2O, Co(OAc)2·4H2O, and Pd(OAc)2 were all found to
promote the reaction in varying degrees. Mn(OAc)2·4H2O was
the most effective one, and the product was obtained in 85%
yield (entry 14). Other additives, such as CrCl3·4H2O, FeCl3,
Ni(NO3)2·6H2O, Cu(OAc)2·H2O, ZnCl2, and AgNO3, were
found to be ineffective for the reaction (entries 6−7, 9−11, and
13). Next, the influences of temperature and additive quantitiies
were investigated. The yield was not improved with increases or
We next investigated the scope of quinones in the standard
conditions. To our disappointment, when 1,4-benzoquinone,
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Letter
juglone, and 1,4-anthracenedione were employed, their
corresponding products were not afforded. The reason may
be the difficulty in forming the corresponding trimeric
intermediate, due to the intramolecular hydrogen bond,
solubility, and other factors of quinones.
We further explored the facile acetylation of products (3aa as
example), shown in Scheme 4. We expect that these acetylated
a
Scheme 4. Acetylation of Trimeric Derivatives
To gain an insight into the reaction mechanism, a control
experiment was performed (Scheme 2). When the reaction was
carried out under an argon atmosphere, 3aa was afforded only
in 10% yield. The result clearly shows that air is playing a vital
role in this reaction.
a
Scheme 2. Control Experiment
a
Reaction conditions: 3aa (1.0 mmol, 587 mg) with Zn dust (25.0
mmol, 1.625 g) and NaOAc (25.0 mmol, 2.05 g) was stirred in Ac2O
(15 mL) at 40 °C for 6 h. Isolated yields.
a
Isolated yields.
derivatives could have potential applications in medicine or
materials chemistry. The product 3aa readily underwent
reductive acetylation6 to give a peracetylated derivative 6a in
78% yield with NaOAc and Zn dust in acetic anhydride at 40
°C for 6 h.
On the basis of the results described above, a plausible
mechanism is proposed as outlined in Scheme 3 (3aa as
In conclusion, a novel Mn(II)-mediated formal intermolec-
ular [2 + 2 + 2 + 1] cycloaddition reaction has been developed
for the construction of fused cycloheptatriene derivatives. This
transformation provides a direct and efficient method for the
construction of seven-membered carbocyclic rings from easily
available N-(acylmethyl)pyridinium iodides and naphtho-
quinone under mild conditions. Further investigations into
the mechanism and applications of this reaction are currently
underway in our laboratory.
Scheme 3. A Plausible Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterization, crystallo-
1
graphic data, and copies of the H and 13C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chwuax@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of
China (Grants 21032001 and 21272085).
■
example). Initially, naphthoquinone 2a is reduced by
manganous acetate to form 1,4-naphthalenediol 4a. At the
same time, the dihydroxy(oxo)manganese and acetate acid are
generated in the process, which trigger the oxidation of iodide
ions to iodine.11 The 1,4-naphthalenediol 4a easily reacts with
2a to form the dimeric intermediate A via a Michael
addition,12d,e which subsequently reacts with another molecule
of 2a via another Michael addition to afford the trimeric
intermediate B.12e Then, the intermediate B is oxidized to
another trimeric intermediate C.12 (Intermedate C was
detected by MS: see the SI). Next, 1a is converted to the N-
phenacylpyridinium ylide (1a′),13 which reacts with C via a
cyclocondensation reaction leading to the intermediate D.
Finally, the intermediate D is oxidized by air leading to the
desired product 3aa (see SI).
REFERENCES
■
(1) For selected reviews, see: (a) Lautens, M.; Klute, W.; Tam, W.
Chem. Rev. 1996, 96, 49−92. (b) Battiste, M. A.; Pelphrey, P. M.;
Wright, D. L. Chem.Eur. J. 2006, 12, 3438−3447. (c) Ylijoki, K. E.
O.; Stryker, J. M. Chem. Rev. 2013, 113, 2244−2266.
(2) For selected reviews, see: (a) Harmata, M. Adv. Synth. Catal.
2006, 348, 2297−2306. (b) Harmata, M. Chem. Commun. 2010, 46,
8886−8903.
(3) For selected reviews, see: (a) Pellissier, H. Adv. Synth. Catal.
2011, 353, 189−218. (b) Shu, X.-Z.; Li, X.; Shu, D.; Huang, S.;
Schienebeck, C. M.; Zhou, X.; Robichaux, P. J.; Tang, W. J. Am. Chem.
Soc. 2012, 134, 5211−5221. (c) Schienebeck, C. M.; Robichaux, P. J.;
Li, X.; Chen, L.; Tang, W. Chem. Commun. 2013, 49, 2616−2618.
1288
dx.doi.org/10.1021/ol500202q | Org. Lett. 2014, 16, 1286−1289

Organic Letters
Letter
(4) For examples of transition-metal-catalyzed cycloadditions, see:
(a) Schore, N. E. Chem. Rev. 1988, 88, 1081−1119. (b) Rigby, J. H.
Acc. Chem. Res. 1993, 26, 579−585. (c) Fruhauf, H.-W. Chem. Rev.
̈
1997, 97, 523−596. (d) Yet, L. Chem. Rev. 2000, 100, 2963−3008.
(5) For selected reviews, see: (a) Schore, N. E. Chem. Rev. 1988, 88,
1081−1119. (b) Rigby, J. H. Acc. Chem. Res. 1993, 26, 579−585.
(c) Fruhauf, H.-W. Chem. Rev. 1997, 97, 523−596. (d) Wender, P. A.;
̈
Dyckman, A. J. Org. Lett. 1999, 1, 2089−2092. (e) Wender, P. A.;
Barzilay, C. M.; Dyckman, A. J. J. Am. Chem. Soc. 2001, 123, 179−180.
(f) Wegner, H. A.; de Meijere, A.; Wender, P. A. J. Am. Chem. Soc.
2005, 127, 6530−6531. (g) Yu, Z.-X.; Wang, Y.; Wang, Y. Chem.
Asian J. 2010, 5, 1072−1088.
(6) Decosterd, L. A.; Parsons, I. C.; Gustafson, K. R.; Cardellina, J.
H.; McMahon, J. B.; Cragg, G. M.; Murata, Y.; Pannell, L. K.; Steiner,
J. R. J. Am. Chem. Soc. 1993, 115, 6673−6679.
(7) Gu, G. Y.; Gui, Y. S.; Chen, L. R.; Yu, G.; Xu, X. J. J. Cheminform.
2013, 5, 51.
(8) For selected reviews, see: (a) Fierz-David, H. E.; Blangey, L.; Von
Krannichfeldt, W. Helv. Chim. Acta 1947, 30, 816−838. (b) Laatsch,
H. Liebigs Ann. Chem. 1990, 1990, 433−440.
(9) Barluenga, J.; Barrio, P.; Lop
́
ez, L. A.; Tomas
́
, M.; García-Granda,
S.; Alvarez-Rua, C. Angew. Chem., Int. Ed. 2003, 42, 3008−3011.
́
(10) (a) Ojima, I.; Lee, S.-Y. J. Am. Chem. Soc. 2000, 122, 2385−
2386. (b) Bennacer, B.; Fujiwara, M.; Ojima, I. Org. Lett. 2004, 6,
3589−3591. (c) Bennacer, B.; Fujiwara, M.; Lee, S. Y.; Ojima, I. J. Am.
Chem. Soc. 2005, 127, 17756−17767. (d) Kaloko, J. J.; Teng Gary, Y.-
H.; Ojima, I. Chem. Commun. 2009, 4569−4571. (e) Teng Gary, Y.-H.
Synthesis of Novel Fused Tropones and Colchicinoids Through Rh(I)-
Catalyzed [2 + 2 + 2 + 1] Cycloaddition of Triynes with Carbon
Monoxide, Ph.D Thesis, Stony Brook University, New York, 2011.
(11) (a) Engineering Chemistry; Sivasankar, B., Ed.; Tata McGraw-
Hill Education: Noida, 2008; Chapter 14. (b) Zhou, G. P.; Hui, Y. H.;
Wan, N. N.; Liu, Q. J.; Xie, Z. F.; De Wang, J. Chin. Chem. Lett. 2012,
23, 690−694. (c) Singh, M.; Bharty, M.; Singh, A.; Kashyap, S.; Singh,
U.; Singh, N. Transition Met. Chem. 2012, 37, 695−703.
(12) (a) Fierz-David, H. E.; Blangey, L.; Von Krannichfeldt, W. Helv.
Chim. Acta 1947, 30, 816−838. (b) Jurd, L. Aust. J. Chem. 1980, 33,
1603−1610. (c) Laatsch, H. Liebigs Ann. Chem. 1985, 1985, 605−619.
(d) Brockmann, H. Liebigs Ann. Chem. 1988, 1988, 1−7. (e) Laatsch,
H. Liebigs Ann. Chem. 1990, 1990, 433−440.
(13) (a) Yang, Y.; Gao, M.; Zhang, D.-X.; Wu, L.-M.; Shu, W.-M.;
Wu, A.-X. Tetrahedron 2012, 68, 7338−7344. (b) Liu, Y.; Sun, J.-W. J.
Org. Chem. 2012, 77, 1191−1197. (c) Osyanin, V. A.; Osipov, D. V.;
Klimochkin, Y. N. J. Org. Chem. 2013, 78, 5505−5520.
1289
dx.doi.org/10.1021/ol500202q | Org. Lett. 2014, 16, 1286−1289