Efficient synthesis of isochromanones and isoquinolines via Yb(OTf) 3-catalyzed tandem oxirane/aziridine ring opening/Friedel-Crafts cyclization

Article abstract of DOI:10.1039/c2cc17836b

The first example of Yb(OTf)₃-catalyzed tandem ring opening/Friedel-Crafts cyclization of oxiranyl and aziridinyl ketones via selective C-C bond cleavage under mild conditions was developed. Isochromanones and isoquinolines are formed in reasonable yields, which often serve as building blocks for complex chemical synthesis. This journal is The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17836b

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COMMUNICATION
Efficient synthesis of isochromanones and isoquinolines via
Yb(OTf)3-catalyzed tandem oxirane/aziridine ring
opening/Friedel–Crafts cyclizationw
Lai Weia and Junliang Zhang*ab
Received 14th December 2011, Accepted 17th January 2012
DOI: 10.1039/c2cc17836b
The first example of Yb(OTf)3-catalyzed tandem ring opening/
Friedel–Crafts cyclization of oxiranyl and aziridinyl ketones via
selective C–C bond cleavage under mild conditions was developed.
Isochromanones and isoquinolines are formed in reasonable
yields, which often serve as building blocks for complex chemical
synthesis.
Isochromanones and isoquinolines are present in the core of
many natural products and medicinally active molecules,1,2 such
as the ajudazols, (4R)-hydroxyochratoxin A, acetoxy-geranyloxy-
mellein and so on. Furthermore, these ring-fused systems often
serve as building blocks for complex chemical synthesis. Because
of their growing popularity in the area of complex molecular
construction, organic chemists have been steadily exploring
efficient methods for their synthesis.3 One such method that
has been relatively underexplored is an acid-promoted ring
opening/cyclization of aryl oxiranes and aziridines.
Very recently, our group developed a novel strategy to
Scheme 1 Our previous work and the present work.
achieve carbon–carbon selective cleavage of oxiranes4 and
aziridines5 under the catalysis of Lewis acids and the resultant
intermediate reactive 1,3-dipole can easily undergo 1,3-dipolar
cycloadditions with dipolarophiles such as aldehydes, olefins
and alkynes, leading to highly substituted 1,3-dioxolanes,
1,3-oxazolidines, dihydrofurans, and pyrrolidines. With this
concept in mind, we envisaged that compound 1 might be able
to undergo tandem ring-opening/Friedel–Crafts cyclization
under mild Lewis acidic conditions by introducing electron-rich
aromatic systems or alkenes instead of the Ar group of A.
If successful, it will provide a facile and general access to
isochromanones and 1,2-dihydroisoquinolines 2. However,
one issue should be mentioned that this kind of substrates
may also easily undergo the reported Friedel–Crafts cyclization
reaction through intermediate C via the C–X bond cleavage,6
leading to 2,3-dihydro-1H-inden-1-one under the catalysis of
Brønsted acids or Lewis acids (Scheme 1).
We chose (Z)-ethyl 3-phenyl-2-(3,4,5-trimethoxy benzoyl)
oxirane-2-carboxylate 1a as a model substrate to test our
hypothesis (see Table S1 in ESIw). Initially, 1a was subjected
to the solution of 10 mol% of Sc(OTf)3 in CH2Cl2 at room
temperature. The reaction yielded the desired product 2a in
73% NMR yield after running the reaction for 10 h (Table S1,
entry 1, ESIw), and the product is not stable during the
purification, which exists as a mixture of ketone and enolate
forms (1 : 2). To improve the yield, a representative selection
of Lewis acids, including Cu(OTf)2, In(OTf)3, Yb(OTf)3,
Y(OTf)3, Sn(OTf)2, Fe(OTf)3, and Mg(OTf)2, in various
solvents were tested. Catalysts such as Sn(OTf)2, Cu(OTf)2,
Fe(OTf)3, Mg(OTf)2 have either low efficiency or no catalytic
activity. To our delight, the reaction worked very well in
CH2Cl2 at room temperature under the catalysis of 10 mol%
of Yb(OTf)3 to give the cyclized target in 99% yield. Solvents
other than DCE, toluene, THF, DMF failed to improve the
yield or shorten the reaction time. Performing the reaction
with a lower catalyst loading proved to be suboptimal. In the
absence of 4 A molecular sieves (MS), the reaction is sluggish,
indicating that the anhydrous conditions are essential for this
reaction.
a Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N, Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: jlzhang@chem.ecnu.edu.cn; Fax: +86 21-6223-3213
b State key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
P. R. China
w Electronic supplementary information (ESI) available: Representa-
tive experimental procedure and characterization of reaction products.
CCDC 842104 (4a). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc17836b
c
2636 Chem. Commun., 2012, 48, 2636–2638
This journal is The Royal Society of Chemistry 2012

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Table 1 Cascade ring opening/cyclization of oxiranesa
With the optimized conditions in hand, a variety of aryl
oxiranes with different electronic and steric properties were
examined to determine the reaction scope and limitation. The
cascade ring opening/cyclization of 1a–1j could give the
corresponding isochromanones 2a–2j in good to excellent
yields with high diastereoselectivities, but all suffered somewhat
enolization issue as mentioned in ESI.w In order to demonstrate
the synthetic application and to avoid the enolization issue,
further methylation reaction of 2a–2j was carried out leading
to 3a–3j in moderate to good yields with excellent diastereo-
selectivities (Table 1, entries 1–10). Bulky tert-butyl ester is
compatible under Lewis acidic conditions and 3b can be
isolated in 69% yield (Table 1, entry 2). Gratifyingly, sub-
strates 1c–1h bearing aryl groups of different nature proceeded
smoothly to provide the corresponding cycloadducts 3c–3h in
40–79% total yields after two steps, albeit 1c with a strong
electron-withdrawing CN group required higher temperature
(DCE, 80 1C) to accomplish cyclization (Table 1, entries 3–8).
Substrate 1g with a poor electron-donating group (–CH3)
afforded 2g in 99% yield, whereas it can only afford 3g in 68%
yield along with some decomposition during the methylation
step (Table 1, entry 7). In contrast, a strong electron-donating
methoxy group made the substrate 1h too reactive to give 3h in
low yield (40%) (Table 1, entry 8). The 1-naphthyl group is also
compatible with the present transformation (Table 1, entry 9).
Similarly, substrate 1j with a strong electron-rich aromatic system
gave 3j in 85% yield as a single isomer (Table 1, entry 10). What is
more, it is interesting to find substrates 1k–1m with electron-
rich systems such as 2-substituted, 3-substituted indole and
3,4-dihydro-2H-pyranyl ring afforded 2k–2m in good to
excellent yields as ketone forms, albeit with moderate diastereo-
selectivities as mentioned in ESI.w7 Further methylation reaction
of 2k–2m was carried out leading to 3k/3k0–3m/3m0 in
moderate to good yields with moderate diastereoselectivities.
It is noteworthy that only isolated examples of indoles and
pyrans fused to pyrans were reported in the literature.8
Compound 1a0 is less reactive than its diastereoisomer 1a
and requires higher temperature to make the reaction
occur. After the further methylation reaction, the same
product 3a was isolated in 74% yield (Table 1, entry 14).
The structure of the product was further confirmed by the
single-crystal X-ray analysis9 of the product 4a, which was
prepared from the ethylation of 2a. Additionally, synthetically
useful triflate 5a can be easily prepared in 66% yield via the
sequential tandem ring opening/cyclization and triflation
reaction (eqn (1)).
Entry
Substrate 1
Product, yield, dr
1
2
Et (1a)
t-Bu (1b)
Et (3a), 86%, >50 : 1
t-Bu (3b), 69%, >50 : 1
3b
4
5
6
7
8
9
4-NCC6H4 (1c)
4-FC6H4 (1d)
4-NCC6H4 (3c), 75%, >50 : 1
4-FC6H4 (3d), 74%, >50 : 1
4-ClC6H4 (3e), 78%, >50 : 1
4-BrC6H4 (3f), 79%, >50 : 1
4-MeC6H4 (3g), 68%, >50 : 1
4-MeOC6H4 (3h), 40%, >50 : 1
1-Naphthyl (3i), 66%, >50 : 1
4-ClC6H4 (1e)
4-BrC6H4 (1f)
4-MeC6H4 (1g)
4-MeOC6H4 (1h)
1-Naphthyl (1i)
10
11c
12
13d
14e
(1)
a
The reaction was carried out at RT with 1 (racemic, 0.3 mmol), 4 A
MS (120 mg), 10 mol% Yb(OTf)3 in CH2Cl2 at 25 1C and completed
within 15 h, and after filtration to remove the catalyst and solvent, the
crude product 2 was treated with 5 eq. CH3I with t-BuOK (1.2 eq.) and
Next, we attempted to extend the scope of this tandem ring
opening/cyclization to the aziridines under the optimized reaction
conditions (Table 2). Aziridines 1o–1r with aryl groups (Ar) of
different electronic properties could give the corresponding
products 2o–2r, which were then further converted to 6a–6e
under the basic conditions in high yields. Aziridine 1o with
b
t-BuOH (a drop) in THF at RT. Reaction performed in 1,2-dichloro-
c
ethane at 80 1C. Flash chromatography with a short pad of silica gel.
Reaction performed with 15 mol% Yb(OTf)3 within 21 h for the
d
e
first step. Refluxing DCM for the first step.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2636–2638 2637

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Table 2 Cascade ring opening/cyclization of aziridinesa,b
We are grateful to National Natural Science Foundation of
China (21172074), the National Basic Research Program of
China (973 Program: 2011CB808600) for financial support.
Notes and references
1 For some recent examples of naturally occurring or biologically active
fused pyrans, see: (a) R. Jansen, B. Kunze, H. Reichenbach and
G. Hofle, Eur. J. Org. Chem., 2002, 917; (b) H. J. Reichenbach, J. Ind.
Microbiol. Biotechnol., 2001, 27, 149; (c) B. Kunze, J. A. Rolf, G. Hofle
and H. J. Reichenbach, J. Antibiot., 2004, 57, 151; (d) H. Zepnik,
A. Pahler, U. Schauer and W. Dekant, Toxicol. Sci., 2001, 59, 59;
(e) G. Appendino, H. C. Ozen and J. Jakupovic, Phytochemistry, 1994,
36, 531; (f) T. Dethoup, L. Manoch, A. Kijjoa, M. Pinto, L. Gales,
A. M. Damas, A. M. S. Silva, G. Eaton and W. J. Herz, J. Nat. Prod.,
2007, 70, 1200; (g) H. Takahashi, M. Kosada, Y. Watanabe, K. Nakade
and Y. Fukuyawa, Bioorg. Med. Chem., 2003, 11, 1781.
Entry
1, Ar =, drc
Product 2d
Product 6
1
2
3
4
5
6
1n, Ph (1.1 : 1)
1n, Ph (3.0 : 1)
1o, 4-ClC6H4 (4.6 : 1)
1p, 4-BrC6H4 (2.4 : 1)
1q, 4-i-PrC6H4 (5.0 : 1)
1r, 4-NO2C6H4 (2.7 : 1)
2n, 80%
2n, 83%
2o, 85%
2p, 89%
2q, 71%
2r, 55%e
6a, 78%
/
6b, 84%
6c, 89%
6d,70%
6e, 42%
a
Reactions of substrates 1n–1r were run with 10 mol% Yb(OTf)3 and
120 mg of activated 4 A MS in DCM at RT within 15 h to afford
2 For some recent examples of naturally occurring or biologically
active isoquolines, see: A. Cappelli, M. Anzini, S. Vomero,
P. G. De Benedetti, M. C. Menziani, G. Giorgi and C. Manzoni,
J. Med. Chem., 1997, 40, 2910.
b
products 2n–2r. Further elimination of crude products 2n–2r was
c
carried out with 1.05 eq. of K2CO3 in DCM, reflux. The numbers in
3 For representative approaches to aromatic fused pyrans and pyridines,
see: (a) S. P. Runyon, L. E. Brieaddy, S. W. Mascarella, J. B. Thomas,
H. A. Navarro, J. L. Howard, G. T. Pollard and F. I. Carroll, J. Med.
Chem., 2010, 53, 5290; (b) W. M. Abdou, A. F. M. Fahmy and
A. A.-A. Kame, Eur. J. Org. Chem., 2002, 1696; (c) J. I. Trujillo and
M. J. Meyers, Bioorg. Med. Chem. Lett., 2007, 17, 4657; (d) R.
Aggarwal, A. A. Brikbeck, C. B. de Koning, R. G. F. Giles, I. R.
Green, S.-H. Li and F. J. Oosthuizan, Tetrahedron Lett., 2003, 44, 4535.
4 For metal mediated C–C bond cleavage of oxiranes, see: (a) T. Wang
and J. Zhang, Chem.–Eur. J., 2011, 17, 86; (b) Z. Chen and L. Wei,
Org. Lett., 2011, 13, 1170; (c) T. Wang, C.-H. Wang and J. Zhang,
Chem. Commun., 2011, 47, 5578; (d) R. Liu, M. Zhang and J. Zhang,
Chem. Commun., 2011, 47, 12870; (e) J. Zhang, Z. Chen, H.-H. Wu
and J. Zhang, Chem. Commun., 2012, 48, 1817.
5 For Lewis acid mediated C–C bond cleavage of aziridines, see:
(a) L. Li, X. Wu and J. Zhang, Chem. Commun., 2011, 47, 5049;
(b) X. Wu, L. Li and J. Zhang, Chem. Commun., 2011, 47, 7824;
(c) L. Li and J. Zhang, Org. Lett., 2011, 13, 5940; (d) P. D. Pohlhaus,
R. K. Bowman and J. S. Johnson, J. Am. Chem. Soc., 2004, 126, 2294;
(e) M. Vaultier and R. Carrie, Tetrahedron Lett., 1978, 14, 1195.
6 For selective examples, see: (a) G.-X. Li and J. Qu, Chem. Commun.,
2010, 46, 2653; (b) S. Nagumo, T. Miura, M. Mizukami, I. Miyoshi,
M. Imai, N. Kawahara and H. Akita, Tetrahedron, 2009, 65, 9884;
(c) B.-F. Sun, R. Hong, Y.-B. Kang and L. Deng, J. Am. Chem. Soc.,
2009, 131, 10384; (d) R. Marcos, C. Rodrıguez-Escrich, C. Herrerıas
and M. A. Pericas, J. Am. Chem. Soc., 2008, 130, 16838; (e) Z.-J. Shi
and C. He, J. Am. Chem. Soc., 2004, 126, 5964.
parentheses refer to the diastereoselectivity of the substrates 2n–2r.
d
e
Isolated yields after column chromatography with 1% HOAc. The
reaction was performed at 40 1C.
different dr ratios (1.1 : 1 vs. 3.0 : 1) afforded 1,2-dihydroiso-
quinoline 2n in almost the same yield (Table 2, entries 1 and 2),
indicating that both diastereoisomers may proceed through
the same reaction pathway. Aziridines 1p–1q bearing weak
electron-withdrawing groups at the para position of the phenyl
ring yielded 1,2-hydroisoquinolines 2p and 2q in higher yields,
while electron-donating i-Pr groups decreased the yield of 2r,
probably owing to the more unstable substrate (Table 2,
entries 3–5). Furthermore, a strong electron-withdrawing
group (–NO2) made 1r less reactive and the corresponding
product 2r was obtained in 55% yield at 40 1C, while a much
higher temperature failed to improve the yield and resulted in
faster decomposition (Table 2, entry 6).
In summary, a general protocol for the first example of
catalytic ring opening/cyclization of aryl oxiranyl ketones and
aryl aziridinyl ketones through selective C–C bond cleavage
rather than the labile C–O/N bond cleavage under mild
conditions has been explored. Synthetically useful aromatic
ring-fused pyrans and isoquinolines can be easily prepared in
excellent yields, which can undergo further transformations
such as alkylation, triflation or elimination. Further studies
including asymmetric catalysis, mechanism and enlargement
of the scope are ongoing in our laboratory and will be reported
in due course.
7 Compounds 2a–2j were obtained with high diastereoselectivities but
have enol form issue, but compounds 2k–2m do not have enol form
issue but have low diastereoselectivities, this difference may be
caused by the different ring-fused system.
8 (a) K. Freter and V. Fuchs, J. Heterocycl. Chem., 1982, 19, 377;
(b) C. A. Demerson, L. G. Humber, T. A. Dobson and R. Martel,
J. Med. Chem., 1975, 18, 189; (c) D. J. Maloney and S. J. Danishefsky,
Angew. Chem., Int. Ed., 2007, 46, 7789.
9 CCDC 842104 (4a)w.
c
2638 Chem. Commun., 2012, 48, 2636–2638
This journal is The Royal Society of Chemistry 2012