A series of two oxidation reactions of ortho-alkenylbenzamide with hypervalent iodine(III): A concise entry into (3 R,4 R)-4-hydroxymellein and (3 R,4 R)-4-hydroxy-6-methoxymellein

Article abstract of DOI:10.1021/ol502225p

A sequence of oxidation reactions of alkenamides with hypervalent iodine is described. Oxidation of ortho-alkenylbenzamide substrates selectively gave isochroman-1-imine products. The products underwent further oxidation in the presence of a Pd salt catal

Full text of DOI:10.1021/ol502225p

Letter
pubs.acs.org/OrgLett
A Series of Two Oxidation Reactions of ortho-Alkenylbenzamide with
Hypervalent Iodine(III): A Concise Entry into (3R,4R)‑4-
Hydroxymellein and (3R,4R)‑4-Hydroxy-6-methoxymellein
Takuya Takesue, Morifumi Fujita,* Takashi Sugimura, and Hiroki Akutsu†
Graduate School of Material Science, University of Hyogo, Kohto, Kamigori, Hyogo 678-1297, Japan
S
* Supporting Information
ABSTRACT: A sequence of oxidation reactions of alkenamides
with hypervalent iodine is described. Oxidation of ortho-
alkenylbenzamide substrates selectively gave isochroman-1-
imine products. The products underwent further oxidation in
the presence of a Pd salt catalyst leading to regioselective C−H
acetoxylation at the 8-position. A series of oxidations was applied
to the crucial steps of asymmetric synthesis of 4-hydroxymellein
derivatives.
cyclizations of alkenamides have been investigated, hypervalent
iodine(III) reagents mainly gave lactam products via the N-
attack pathway.11−13 Thus, we have to find suitable conditions
for selective formation of the desired imidate product via the O-
attack pathway.5,14
A sequence of oxidations would be applied for concise
synthesis of 4-hydroxymellein and related natural products.15,16
Most of the isochromanone natural products possess the 8-
hydroxy group originating in polyketide biosynthesis.17 The 8-
oxy group is regioselectively introduced in the late stage using
the imidate as a scaffold for Pd-catalyzed C−H activation
(Scheme 1a). In our previous approach,18 the oxy group was
introduced on the alkenylbenzoate substrate beforehand
(Scheme 1b). Dispensing with the oxy group in the early
stage (Scheme 1a) would increase the availability of aromatic
starting compounds and avoid undesirable side products due to
oxidation on the electron-rich aromatic part.
N-Tosyl 2-vinylbenzamide (1a) was used as a model
substrate in screening tests to determine optimal conditions
for obtaining an isochroman-1-imine (Scheme 2 and Table 1).
Pleasingly, reaction with (diacetoxyiodo)benzene (DIB) in the
presence of BF3·OEt2 gave imidate products, 2a and 3a (entries
1−5). The isomeric structure of these lactone imines was
established by X-ray crystal analysis (Figure 1). The imine
moiety of 2a and 3a had Z-geometry, probably owing to the
steric repulsion between the tosyl group and the aromatic part.
The ratio of 2a increased with an increase in the equivalent of
BF3·OEt2, and isochroman-1-imine 2a was isolated in 50% yield
in the reaction using 8 equiv of BF3·OEt2 (entry 5).19 The yield
of a six-membered lactone imine 4a was not improved when
[bis(trifluoroacetoxy)iodo]benzene (BTI) was used instead of
DIB (entries 6 and 7). The reaction with BTI accelerated in the
presence of trifluoroacetic acid and proceeded at 0 °C (entry
ypervalent iodine compounds have been shown to effect
1,2
Hnumerous useful chemical oxidations.
The oxidation is
accelerated under acidic conditions in the presence of a
Brønsted or Lewis acid.3 In addition, transition metal salts and
complexes catalyze various oxidations with hypervalent iodine.4
The reactivity of hypervalent iodine reagents is characterized by
electrophilicity because of the electron-deficient polyvalent
iodine atom and also by the capability for a ligand transfer
reaction toward organic substrates. Taking advantage of the
diversity of hypervalent-iodine-mediated oxidations, it is
possible to achieve a highly oxidized but well controlled
product, using a sequence of oxidations that increase the
oxidation state of substrates step by step.
To examine the concept of a series of oxidations with
hypervalent iodine, we focused on oxidative cyclization of
alkenamides5 and oxidative replacement of the C−H bond
catalyzed by a Pd salt.6,7 The first oxidation is expected to yield
an imidate, which will be utilized as a removable directing
group8−10 for the second oxidation catalyzed by Pd salt, as
illustrated in Scheme 1a. Although a number of oxidative
Scheme 1. Proposed Strategy Leading to 4-Hydroxymellein
Derivatives
Received: July 28, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502225p | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Oxidation of N-Tosyl 2-Vinylbenzamide (1a)
Scheme 3. Oxidative Cyclization of Alkenylbenzamides
Table 1. Optimization of Oxidative Cyclization of N-Tosyl 2-
Vinylbenzamide (1a)
a
entry
conditions
crude 2a/3a
(isolated yield)
b
c
1
2
3
4
5
6
7
8
DIB, BF3·OEt2 (0.5 equiv)
DIB, BF3·OEt2 (0.8 equiv)
DIB, BF3·OEt2 (1.5 equiv)
DIB, BF3·OEt2 (4.0 equiv)
DIB, BF3·OEt2 (8.0 equiv)
45:55
57:43
66:34
71:29
81:19
2a/3a = 44:56 (64%)
2a/3a = 50:50 (84%)
2a/3a = 67:33 (63%)
2a/3a = 72:28 (60%)
2a (50%)
d
e
BTI, reflux, 18 h
62:38
4a (31%), 5a (22%)
4a (24%), 5a (19%)
5a (35%), 6a (46%)
d
BTI, TFA, 0 °C, 4 h
f
m-CPBA (3 equiv), rt, 28 h
g
a
gave the corresponding lactone imine 3k as a result of exo
cyclization, but the yield was low under the conditions in the
presence of BF3·OEt2 (Scheme 4). The yield was improved in
the reaction with BTI.
1a (0.1 mmol), DIB (0.15 mmol), and AcOH (0.2 mL) in CH2Cl2 (4
b
c
mL) at −40 °C for 3 h, unless otherwise noted. For 14 h. At −80 °C
for 1.5 h. BTI (0.15 mmol) was used instead of DIB and AcOH.
Crude reaction mixtures were hydrolyzed in aqueous methanol
containing K2CO3. Ratio of 4a/5a. A five-membered lactone product
d
e
f
g
5a′ was also observed (4a/5a/5a′ = 44/31/25). A mixture of imine
Scheme 4. Oxidative Cyclization of Alkenamide 1k
5a and lactam 6a was obtained (5a/6a = 41/59).
The lactone imines 2a−2d were used for Pd-catalyzed
acetoxylation with DIB, as shown in Scheme 5. The N-methoxy
Figure 1. Structure of 2a and 3a in solid state.
Scheme 5. Regioselective Acetoxylation of 2
7); unfortunately, the ratio of 4a decreased compared with that
obtained in entry 6. Oxidation with m-CPBA did not yield 4a;
however, five-membered lactone imine 5a and lactam 6a were
obtained (entry 8). The structure of lactam 6a was also
established by X-ray crystal analysis (Supporting Information
(SI)).
With optimized conditions established for the isochroman-1-
imine 2a (Table 1, entry 5), we examined a range of
alkenamides in the oxidative cyclization (Scheme 3). Methoxy,
acetoxy, benzamide, and phthalimido N-substituted substrates
also selectively gave the corresponding isochroman-1-imine
product 2.20 A relatively good yield was observed in the
reaction of the N-methoxy (1b) and N-acetoxy (1c) substrates.
X-ray crystallographic analysis confirmed the isochroman-1-
imine structure of 2b and 2d (SI). Trans-alkenyl substrates led
to cis-isochroman-1-imine products. The cis configuration was
definitively established by X-ray crystal analysis of 2g and 2j
(SI). Remarkably, an aliphatic alkenamide 1k also selectively
and N-acetoxy imidates, 2b and 2c, led to regioselective
acetoxylation at the peri-position of the imidates. The position
of the acetoxy substitution was determined by NOESY NMR
analysis (SI). The regioselectivity can be explained by directing
C−H activation using the imidate as a scaffold for the Pd
catalyst. The electron-withdrawing tosyl-substituted substrate
2a resulted in no reaction. In the case of N-benzamide 2d,
hydrolysis of the imine moiety proceeded to give the lactone
compound of 2d.
B
dx.doi.org/10.1021/ol502225p | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
An enantioselective variant of the oxidative imino lactoniza-
tion was examined prior to its application in the synthesis of
natural products. We have previously reported the enantiose-
lective oxidation of methyl alkenylbenzoates using a chiral
lactate-based hypervalent iodine reagent 8.21,22 Based on the
results of the ester substrates, the amide substrates 1a−1j were
reacted with (R)-8, as summarized in Table 2.23 The
enantioselectivity of these amide substrates was similar to that
of the corresponding methyl ester,21 and it was not significantly
affected by the type of N-substituent.
yield rac-9 without isomerization to a phthalide compound.
1
The H and 13C NMR data of synthetic rac-9 were consistent
with those in the literature.15 Preparation of rac-9 in a 1 g scale
was also performed (SI) as a demonstration of the advantage of
this methodology. In order to synthesize the (3R,4R)-isomer of
9, we chose the (S)-isomer of the lactate-based hypervalent
iodine reagent 8 for the imino lactonization. The obtained
optically active 2l was converted to 9 using the same
procedures. The enantiomeric sample of 9 was able to be
recrystallized from dichloromethane−hexane. The recrystalliza-
tion resulted in enrichment of ee to 98% ee and provided a
single crystal for X-ray analysis (SI). Optical rotation of 9
a
Table 2. Enantioselective Oxidation
20
([α]D = −41 (c = 0.17, MeOH)) agreed well with the
reported value ([α]D = −39.2 (c = 0.25, MeOH)).15c
20
Moreover, (3R,4R)-4-hydroxy-6-methoxymellein (10) was
synthesized according to similar procedures using a methoxy-
substituted substrate 1m. The absolute stereochemistry of 10
was confirmed by comparison with the circular dichroism
spectrum16 (SI).
In conclusion, we found suitable reaction conditions for the
regio- and stereoselective synthesis of lactone imines during the
oxidation of alkenamides with hypervalent iodine(III). The
obtained imidate was utilized as a removable directing group for
oxidative C−H acetoxylation catalyzed by a Pd salt in the
presence of hypervalent iodine(III). Both oxidations provided
appropriate selectivity for the synthesis of 4-hydroxymellein
and related natural products.
b
entry
1
1
2 (yield)
2a (66%)
2, ee (%)
1a
1a
1b
1c
1d
1e
1f
2a (81) [83]
c
2
2a (24%), 3a (35%)
2b (62%)
2c (79%)
2a (71), 3a (31)
d
3
2b (78)
4
2c (84)
5
2d (70%)
2e (53%)
2d (83)
6
2e (74)
7
2f (73%)
2f (82)
8
1g
1h
1i
2g (71%)
2h (50%)
2i (61%)
2g (90)
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
9
2h (88) [98]
2i (82) [97]
S
10
11
1j
2j (42%)
2j (80)
b
a
In the presence of 8 equiv of BF3·OEt2 at −80 °C. Determined by
HPLC analysis on a chiral stationary phase. The values in brackets
correspond to ee after crystallization. In the presence of 0.5 equiv of
BF3·OEt2 at −40 °C. (S)-3a was the major enantiomer. (S)-2b was
the major enantiomer.
c
d
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fuji@sci.u-hyogo.ac.jp.
Present Address
†Current address: Department of Chemistry, Graduate School
of Science, Osaka University.
Use of this series of oxidations was demonstrated by its
application to the concise entry into (3R,4R)-4-hydroxymellein
(9) and (3R,4R)-4-hydroxy-6-methoxymellein (10), as illus-
trated in Scheme 6. A racemic sample of isochroman-1-imine
rac-2l was synthesized in 78% yield in the oxidation of 1l with
DIB in the presence of BF3·OEt2, and it was converted to the 8-
acetoxy compound rac-7l. The two acetoxy groups and the N-
methoxyimidate moiety of 7l were readily hydrolyzed at rt to
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by the Japan Society for
the Promotion of Science (JSPS) through Grant-in-Aids for
Scientific Research (C) (23550059 and 26410057). We thank
Prof. Hiroshi Yao (Hyogo) for his assistance with CD spectrum
measurement.
Scheme 6. Synthesis of 4-Hydroxymellein Derivatives 9 and
10
REFERENCES
■
(1) (a) Varvoglis, A. The Organic Chemistry of Polycoordinated Iodine;
VCH: New York, 1992. (b) Varvoglis, A. Hypervalent Iodine In Organic
Synthesis; Academic Press: San Diego, 1997. (c) Hypervalent Iodine
Chemistry; Wirth, T., Ed.; Springer: Berlin, 2003. (d) Zhdankin, V. V.
Hypervalent Iodine Chemistry; John Wiley & Sons: Chichester, 2014.
(2) For recent reviews, see: (a) Moriarty, R. M. J. Org. Chem. 2005,
70, 2893−2903. (b) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656−
3665. (c) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299−
5358. (d) Ochiai, M.; Miyamoto, K. Eur. J. Org. Chem. 2008, 4229−
4239. (e) Uyanik, M.; Ishihara, K. Chem. Commun. 2009, 2086−2099.
(f) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052−
C
dx.doi.org/10.1021/ol502225p | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
9070. (g) Ngatimin, M.; Lupton, D. W. Aust. J. Chem. 2010, 63, 653−
658. (h) Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185−1197. (i) Silva,
L. F., Jr.; Olofsson, B. Nat. Prod. Rep. 2011, 28, 1722−1754. (j) Liang,
H.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2011, 50, 11849−11851.
(k) Kita, Y.; Dohi, T.; Morimoto, K. J. Synth. Org. Chem., Jpn. 2011, 69,
1241−1250. (l) Parra, A.; Reboredo, S. Chem.Eur. J. 2013, 19,
17244−17260. (m) Brown, M.; Farid, U.; Wirth, T. Synlett 2013, 24,
424−431. (n) Dohi, T.; Kita, Y. ChemCatChem 2014, 6, 76−78.
(o) Singh, F. V.; Wirth, T. Chem.Asian J. 2014, 9, 950−971.
(p) Romero, R. M.; Woste, T. H.; Muniz, K. Chem.Asian J. 2014, 9,
Kock, I.; Elsasser, B.; Florke, U.; Schulz, B.; Draeger, S.; Pescitelli, G.;
̈
̈
Antus, S.; Kurtan
(16) Takenaka, Y.; Hamada, N.; Tanahashi, T. Heterocycles 2011, 83,
́
, T. Eur. J. Org. Chem. 2007, 1123−1129.
2157−2164.
(17) (a) Hertweck, C. Angew. Chem., Int. Ed. 2009, 48, 4688−4716.
(b) Buntin, K.; Weissman, K. J.; Muller, R. ChemBioChem 2010, 11,
̈
1137−1146. (c) Axford, L. C.; Simpson, T. J.; Willis, C. L. Angew.
Chem., Int. Ed. 2004, 43, 727−730.
(18) Fujita, M.; Mori, K.; Shimogaki, M.; Sugimura, T. Org. Lett.
2012, 14, 1294−1297.
̈
̃
(19) Amount of BF3·OEt2 affected the product ratio of 2a/3a.
Selective decomposition of the minor product 3a might not be a major
factor of the product distribution, because ratio 2a/3a was unchanged
under treatment of an isolated mixture of 2a/3a (2:1) with BF3·OEt2
(2 equiv) for 1 h at −80 °C.
972−983.
(3) Kang, Y.-B.; Gade, L. H. J. Am. Chem. Soc. 2011, 133, 3658−3667.
(4) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924−1935.
(5) For a review for electrophilic cyclization of unsaturated amides,
see: Robin, S.; Rousseau, G. Tetrahedron 1998, 54, 13681−13736.
(6) (a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936−
946. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147−
1169.
(7) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 9542−9543. (b) Kalyani, D.; Dick, A. R.; Anani, W. Q.;
Sanford, M. S. Org. Lett. 2006, 8, 2523−2526.
(8) For imidate-directing C−H activation, see: (a) Yu, D.-A.; Suri,
M.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 8802−8805. (b) Shang,
M.; Zeng, S.-H.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. Org. Lett. 2013, 15,
5286−5289. (c) Sueki, S.; Guo, Y.; Kanai, M.; Kuninobu, Y. Angew.
Chem., Int. Ed. 2013, 52, 11879−11883.
(9) For a review of removable directing groups, see: Wang, C.;
Huang, Y. Synlett 2013, 24, 145−149.
(10) Imine was used as a removable directing group; see:
(a) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C. H. Angew.
Chem., Int. Ed. 2008, 47, 9462−9465. (b) Sun, C.-L.; Liu, N.; Li, B.-J.;
Yu, D.-G.; Wang, Y.; Shi, Z.-J. Org. Lett. 2010, 12, 184−187.
(c) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12, 532−535.
(d) Dubost, E.; Fossey, C.; Cailly, T.; Rault, S.; Fabis, F. J. Org. Chem.
2011, 76, 6414−6420. (e) Zhang, W.; Lou, S.; Liu, Y.; Xu, Z. J. Org.
Chem. 2013, 78, 5932−5948.
(20) Although the corresponding regioisomer 3 was not identified,
1
the ratio of 3/2 was estimated to be less than 1:9 by H NMR of the
crude mixture in the reactions of 1b and 1c. For the reactions of 1d
and 1e, it was less than 2:8. In the reactions of 1f−1j, it is difficult to
estimate the ratio in the crude mixture.
(21) (a) Fujita, M.; Yoshida, Y.; Miyata, K.; Wakisaka, A.; Sugimura,
T. Angew. Chem., Int. Ed. 2010, 49, 7068−7071. (b) Shimogaki, M.;
Fujita, M.; Sugimura, T. Eur. J. Org. Chem. 2013, 7128−7138.
(22) The lactate-based hypervalent iodine(III) reagents were used for
various asymmetric oxidations; see: (a) Fujita, M.; Okuno, S.; Lee, H.
J.; Sugimura, T.; Okuyama, T. Tetrahedron Lett. 2007, 48, 8691−8694.
(b) Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49,
2175−2177. (c) Fujita, M.; Wakita, M.; Sugimura, T. Chem. Commun.
2011, 47, 3983−3985. (d) Roben, C.; Souto, J. A.; Gonzal
́
ez, Y.;
̈
Lishchynskyi, A.; Muniz, K. Angew. Chem., Int. Ed. 2011, 50, 9478−
̃
9482. (e) Farid, U.; Wirth, T. Angew. Chem., Int. Ed. 2012, 51, 3462−
3465. (f) Kong, W.; Feige, P.; de Haro, T.; Nevado, C. Angew. Chem.,
Int. Ed. 2013, 52, 2469−2473. (g) Farid, U.; Malmedy, F.; Claveau, R.;
Albers, L.; Wirth, T. Angew. Chem., Int. Ed. 2013, 52, 7018−7022.
(h) Wu, H.; He, Y.-P.; Xu, L.; Zhang, D.-Y.; Gong, L.-Z. Angew. Chem.,
Int. Ed. 2014, 53, 3466−3469. (i) Mizar, P.; Wirth, T. Angew. Chem.,
Int. Ed. 2014, 53, 5993−5997.
(11) Hypervalent-iodine-mediated oxidation of alkenamides led to
lactams; see: (a) Scartozzi, M.; Grondin, R.; Leblance, Y. Tetrahedron
Lett. 1992, 33, 5717−5720. (b) Serna, S.; Tellitu, I.; Domínguez, E.;
Moreno, I.; SanMartin, R. Tetrahedron 2004, 60, 6533−6539.
(c) Tellitu, I.; Urrejola, A.; Serna, S.; Moreno, I.; Herrero, M. T.;
Domínguez, E.; SanMartin, R.; Correa, A. Eur. J. Org. Chem. 2007,
437−444. (d) Tsukamoto, M.; Murata, K.; Sakamoto, T.; Saito, S.;
Kikugawa, Y. Heterocycles 2008, 75, 1133−1149. (e) Wardrop, D. J.;
Bowen, E. G.; Forslund, R. E.; Sussman, A. D.; Weerasekera, S. L. J.
Am. Chem. Soc. 2010, 132, 1188−1189. (f) Bowen, E. G.; Wardrop, D.
J. Org. Lett. 2010, 12, 5330−5333. (g) Wardrop, D. J.; Bowen, E. G.
Org. Lett. 2011, 13, 2376−2379. (h) Tellitu, I.; Domínguez, E. Trends
Heterocyclic Chem. 2011, 15, 23−32. (i) Wardrop, D. J.; Yermolina, M.
V.; Bowen, E. G. Synthesis 2012, 44, 1199−1207.
(23) Enantioselective oxidation of the aliphatic alkenamide 1k with
(R)-8 in the presence of TFA at 0 °C led to 5k in 87% yield, but only
to an enantiomeric excess of 6%. The enantiomers of 5k were
separated by GLC equipped with DEX-CB column; tR(major) = 11
min and tR(minor) = 12 min at column temperature of 130 °C.
(12) A mixture of lactam and lactone imine was obtained; see:
Nicolai, S.; Erard, S.; Gonzal
384−387.
́
ez, D. F.; Waser, J. Org. Lett. 2010, 12,
(13) Reactions of N-vinylamides and N-allylamides with DIB resulted
in the O-attack cyclization. (a) Zheng, Y.; Li, X.; Ren, C.; Zhang-
Negrerie, D.; Du, Y.; Zhao, K. J. Org. Chem. 2012, 77, 10353−10361.
(b) Moon, N. G.; Harned, A. M. Tetrahedron Lett. 2013, 54, 2960−
2963.
(14) A lactone imine product given by other electrophiles; see:
(a) Wang, C.; Lu, J.; Mao, G.; Xi, Z. J. Org. Chem. 2005, 70, 5150−
5156. (b) Ma, S.; Xie, H. J. Org. Chem. 2002, 67, 6575−6578. (c) Ma,
S.; Xie, H. Tetrahedron 2005, 61, 251−258. (d) Trabulsi, H.; Guillot,
R.; Rousseau, G. Eur. J. Org. Chem. 2010, 5884−5896. (e) Combettes,
L. E.; Schuler, M.; Patel, R.; Bonillo, B.; Odell, B.; Thompson, A. L.;
Claridge, T. D. W.; Gouverneur, V. Chem.Eur. J. 2012, 18, 13126−
13132.
(15) (a) Aldridge, D. C.; Galt, S.; Giles, D.; Turner, W. B. J. Chem.
Soc. (C) 1971, 1623−1627. (b) Garson, M. J.; Staunton, J.; Jones, P.
G. J. Chem. Soc., Perkin Trans. 1 1984, 1021−1026. (c) Krohn, K.;
D
dx.doi.org/10.1021/ol502225p | Org. Lett. XXXX, XXX, XXX−XXX