Facile synthesis of isochromanones and isoquinolones by AuCl3 catalyzed cascade triggered by an internal nucleophile

Article abstract of DOI:10.1021/ol4011129

Synthesis of isochromanones and isoquinolones comprising a quaternary center with high diastereoselectivity was realized via a AuCl₃ catalyzed tandem intramolecular exo-dig heterocyclization/enol isomerization/Claisen rearrangement sequence in

Full text of DOI:10.1021/ol4011129

ORGANIC
LETTERS
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Vol. XX, No. XX
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Facile Synthesis of Isochromanones and
Isoquinolones by AuCl3 Catalyzed
Cascade Triggered by an Internal
Nucleophile
Kavirayani R. Prasad* and Chinta Nagaraju
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
prasad@orgchem.iisc.ernet.in
Received April 22, 2013
ABSTRACT
Synthesis of isochromanones and isoquinolones comprising a quaternary center with high diastereoselectivity was realized via a AuCl3 catalyzed
tandem intramolecular exo-dig heterocyclization/enol isomerization/Claisen rearrangement sequence in excellent yields. The reaction is general
and amenable for the synthesis of structurally diverse analogues.
The advent of gold catalysis in organic synthesis has
seen a virtual rush in recent years in developing synthetic
strategies based on gold complexes. A variety of gold
catalysts with a number of substrates that include a
combination of alkene, alkyne, and heteroatoms leading
to the evolution of diverse reactions for the construction of
carbo- and heterocyclic compounds were developed.1
Claisen rearrangement [in general 3,3-sigmatropic rear-
rangements], a reaction that has a profound impact in
organic synthesis,2 was also a subject of investigation with
gold catalysts. Dean Toste’s group disclosed the first
successful gold catalyzed Claisen rearrangement of
vinyl propargyl ethers for the synthesis of homoallenic
alcohols.3 Similarly, 3,3-sigmatropic rearrangement of
allenyl vinyl ethers was also reported by the Kraft and
Xu groups.4 Herein we report a novel strategy, hitherto
unexplored, involving a combination of tandem exo-dig
heterocylizationÀenol isomerizationÀClaisen rearrange-
ment triggered by an internal nucleophile to yield isochro-
manones and isoquinolones (Figure 1), which were
important scaffolds present in a number of natural
products.
(1) For selected reviews on gold-catalyzed cyclizations, see: (a)
Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (b) Gorin, D. J.; Sherry,
B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351. (c) Li, Z.; Brouwer, C.;
He, C. Chem. Rev. 2008, 108, 3239. (d) Corma, A.; Leyva-Perez, A.;
Sabater, M. J. Chem. Rev. 2011, 111, 1657. (e) Huang, H.; Zhou, Y.; Liu,
~~
H. Beilstein J. Org. Chem. 2011, 7, 897. (f) Nunez, E. J.; Echavarren,
A. M. Chem. Rev. 2008, 108, 3326.
(2) (a) Claisen, L. Ber. 1912, 45, 3157. (b) For a review on Claisen
rearrangement see: Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
(3) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
Figure 1. Isochromanone and isoquinolone.
~
(b) Mauleon, P.; Krinsky, J. L.; Toste, F. D. J. Am. Chem. Soc. 2009, 131,
4513. (c) Horino, Y.; Luzung, M. R.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 11364. (d) For theoretical treatment of gold mediated Claisen re-
arrangement, see: Vidhani, D. V.; Cran, J. W.; Krafft, M. E.; Manoharan,
M.; Alabugin, I. V. J. Org. Chem. 2013, 78, 2059.
(4) (a) Krafft, M. E.; Hallal, K. M.; Vidhani, D. V.; Cran, J. W. Org.
Biomol. Chem. 2011, 9, 7535. (b) Wei, H.; Wang, Y.; Yue, B.; Xu, P.-F.
Adv. Synth. Catal. 2010, 352, 2450.
r
10.1021/ol4011129
XXXX American Chemical Society

Our strategy for the synthesis of isochromanones and
isoquinolones is depicted in Scheme 1. We anticipated that
the propargyl-allyl ethers of type 1 should undergo AuCl3
catalyzed intramolecular nucleophilic exo-dig heterocycli-
zation reaction, leading to the intermediate vinyl gold
complex 2a which on protodeauration should form the
exocyclic enol ether 2b. Double bond isomerization of 2b
should afford the enol ether 3, which is appropriately
arranged to undergo the Claisen rearrangement, resulting
in the product isochromanones or isoquinolones.
Table 1. Synthesis of Isochromanones 4aÀh by AuCl3
Catalyzed Reaction of Allyl Propargyl Ethers 1aÀha
Scheme 1. Retrosynthesis for Isochromanones and
Isoquinolones Involving Gold Mediated Tandem Process
With this hypothesis, at the outset, propargyl allyl ether
1a was prepared from phthalyl alcohol (see Supporting
Information for preparation) and was subjected to the
reaction with a catalytic amount (2 mol %) of AuCl3 in
MeOH. We were pleased to find that the expected iso-
chromanone 4a was formed in 80% yield (Scheme 2).
a All reactions were performed with 2 mol % AuCl3 in refluxing
MeOH. b Reaction was performed with a scalemic mixture of diaste-
reomers. c Major diastereomer was shown in the product (4e dr 83:17; 4f
dr 88:12; 4g dr 77:23). d Relative stereochemsitry of the product 4f was
established by X-ray crystal structure determination.7
Scheme 2. Formation of the Isochromanones 4a from 1a
and 1f comprising a secondary alcohol group [possessing
alkyl and aryl substitution at the benzylic position] also
underwent the facile tandem sequence to yield the product
isochromanones 4e and 4f in 95% and 91% yield respec-
tively (entries 4À5, Table 1).6 The relative stereochemistry
at both stereocenters of the product was assigned by X-ray
crystal structure determination of one of the isochroma-
nones 4f.7 The presence of a vinyl group R to the hydroxy
group did not alter the outcome of the reaction, and the
The reaction was found tobe general, and a series of allyl
ethers underwent an efficient tandem sequence to yield the
product isochromanones in excellent yields. As evident
from Table 1, reaction of the crotyl propargyl ether 1c
afforded the product isochromanone 4c (dr 92:8) (entry 2,
Table 1) in 89% yield.5 Similarly, the cinnamyl propargyl
ether 1d also rendered the product isochromanone 4d
(dr 92:8) in 90% yield (entry 3, Table 1). Substrates 1e
(6) The diastereomeric ratio was estimated with the aid of 1H NMR
within detectable limits.
(5) Commercially available crotylbromide which is a scalemic mix-
ture of E/Z isomers was employed to prepare the propargyl-crotylether
1c. No efforts were made to determine the relative/absolute stereochem-
istry of the major diastereomer obtained in the reaction.
(7) Crystallographic data were deposited with The Cambridge Crys-
tallographic Data Centre. CCDC No. 932987. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
B
Org. Lett., Vol. XX, No. XX, XXXX

tandem sequence proceeded smoothly to yield the isochro-
manone 4g in 92% yield. The formation of carbocycles
from the enyne-ene cyclizations8 that are normally domi-
nant under gold catalysis was not observed in this reaction.
The reactionwiththeallylpropargyl ether1hcomprising
a benzyloxymethyl substitution on the alkyne did undergo
the tandem reaction to yield the product isochromanone
4h, transforming the benzyl ether to the corresponding
methyl ether (entry 7, Table 1). This transformation, per-
haps, proceeds through the elimination of the benzyl ether
after the initial formation of the vinylgold complex (I)
leading to an allene intermediate (II) which undergoes sub-
sequent enol isomerizationÀClaisen rearrangement and
addition of MeOH affording the product 4h (Scheme 3).9
Scheme 4. Reaction of 1i and 1j with Catalytic AuCl3 in MeOH
Scheme 3. Proposed Pathway for the Formation of 4h from 1h
for synthesis). Reaction of the amines 7aÀb with 2 mol %
of AuCl3 proceeded in a facile manner to yield the iso-
quinolones 8aÀb in excellent yields. One of the formed
isoquinolones 8a was transformed to the tricyclic isoqui-
nolonoindolizidine 9 utilizing ring closing metathesis in
excellent yield (Scheme 5).
It was intriguing to find that the reaction of the prenyl
propargyl ether 1i with 2 mol % AuCl3 afforded the
product isochromanone 4i in 35% yield along with the
fused tetrahydrofuran 5 in 33% yield. Formation of the
tetrahydrofuran 5 can be explained by the pathway involv-
ing trapping of the oxo-carbonium 6 resulting from the
initial protodeauration, with an electron-rich nucleophilic
double bond (Scheme 4).
Scheme 5. Formation of the Isoquinolones 8aÀ8b from 7aÀ7b
To explore this pathway further, the reaction of the
geranyl ether 1j under similar reaction conditions was
performed with the expectation of a cascade capture of
the formed oxo-carbonium ion. However, treatment of 1j
with 2 mol % AuCl3 in MeOH furnished the rearranged
product 4j (dr 83:17) in 49% yield along with an unidentifi-
able mixture of products.
After successfully optimizing the conditions for the
synthesis of the isochromanones, we turned our attention
to the synthesis of corresponding amine analogues, the iso-
quinolones. The amine substrates 7aÀb required were syn-
thesized from the alcohol 1a (see Supporting Information
(8) (a) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962.
(b) For a review on gold and platinum catalysis of enyne cycloisomeri-
zation, see: Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006,
348, 2271.
(9) For a related reaction process with propargyl alcohols, see: (a)
Ghebreghiorgis, T.; Biannic, B.; Kirk, B. H.; Ess, D. H.; Aponick, A.
J. Am. Chem. Soc. 2012, 134, 16307. (b) Aponick, A.; Li, C.-Y.; Palmes,
J. A. Org. Lett. 2009, 11, 121. We thank one of the reviewers for
suggesting this alternate mechanism instead of a transetherification
reaction.
We also investigated the use of an aldehyde instead of
the alcohol/amine as an internal nucleophile in the above
cascade reaction. Accordingly, aldehyde 10 (prepared
by oxidation of the alcohol 1a) was subjected to the reac-
tion with catalytic AuCl3 in MeOH. We were pleased to
find that the isochromanone 11 was formed in 89% yield
(Scheme 6).
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 6. Formation of the Isochromanone 11 from the
Aldehyde 10
Scheme 7. Reaction of the Bis-propargyl Ether 12 with Catalytic
AuCl3
After the successful tandem sequence with the allyl
propargyl ethers, we focused our attention on the reaction
of analogous bis-propargyl ether under similar conditions.
This investigation would be interesting because the acet-
ylene functionality can act as a nucleophile in the reaction
leading to carbocylic structures, while the cascade reac-
tions described above will lead to the formation of the
allene. Numerous examples of diyne cyclizations to carbo-
cyclic compounds by gold catalysis10 were known in the
literature, while gold mediated transetherification11 and
aromatization of bis-propargyl ethers12 were also reported
with similar substrates.
Figure 2. X-ray crystal structure of compound 14.
Accordingly, treatment of the bis-propargyl ether 12
with 2 mol % AuCl3 in MeOH furnished the allene 13 in
48% yield (60% based on the recovered starting compound).
It was contemplated that a more electrophilic gold complex
such as AuPPh3Cl/AgBF4 might enhance the allene forma-
tion in the reaction. However, treatment of the bis-propargyl
ether 12 with AuPPh3Cl/AgBF4 led to the formation of the
allene 13 in 35% yield along with the unexpected formation
of the tricylic ketone 14 as a single diastereomer in 49% yield
(Scheme 7).13 The structure of the ketone 14 was further
confirmed by X-ray crystal structure analysis (Figure 2).14
In conclusion, facile synthesis of isochromanones and
isoquinolones possessing quaternary centers involving a
three-reaction cascade from easily accessible precursors
was presented. This was the first synthesis of isochroma-
nones and isoquinolones involving gold catalysis. Applica-
tion of this strategy was demonstrated in the synthesis of
isochromanones comprising allene substitution. Further
application of this strategy in the synthesis of bioactive
natural products is underway.
Acknowledgment. This paper is dedicated with warmth
and respect to Prof. Goverdhan Mehta FNA, FRS, National
Research Professor, University of Hyderabad, India, on the
occasion of his 70th birthday. We thank the Department of
Science and Technology (DST), New Delhi for funding of
this project. K.R.P. is Swarnajayanthi fellow of DST. C.N.
thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for a research fellowship. We thank
Prof. T. N. Gururow and Mr. K. Durgaprasad for their
help in X-ray crystal structure determination of com-
pounds 4f and 14.
(10) (a) Zhao, J.; Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 7436. (b) Rao, W.; Koh, M. J.; Kothandaraman, P.; Chan, W. H.
J. Am. Chem. Soc. 2012, 134, 10811.
(11) Georgy, M.; Boucard, V.; Campagne, J. M. J. Am. Chem. Soc.
2005, 127, 14180.
(12) (a) Lian, J.-J.; Chen, P.-C.; Lin, Y.-P.; Ting, H.-C.; Liu, R.-S.
J. Am. Chem. Soc. 2006, 128, 11372. (b) Lian, J.-J.; Liu, R.-S. Chem.
Commun. 2007, 1337.
(13) At this stage the mechanism for the formation of the tricylic
ketone 14 is unclear. Further investigations are underway to unravel the
exact sequence of events leading to 14.
(14) Crystallographic data were deposited with The Cambridge
Crystallographic Data Centre. CCDC No. 930207. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information Available. Full experimental
procedures and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX