substitutions on the benzene ring, including both electron-
donating and -withdrawing groups. Notably, chlorine-
substituted isoquinolines can be prepared taking advantage
of the higher reactivity of nonaflates than chlorides in Pd-
catalyzed cross-couplings (Table 1, entry 4).
Scheme 1. Pd-Catalyzed Cross-Coupling Reactions with Tosylhy-
drazones: (a) Synthesis of Enol Ethers and Enamines; (b) This Work
Variations at position 4 of the isoquinoline can be
achieved starting from a different alkoxyketone and includes
aromatic and heteroaromatic substituents (Table 1, entries
10À12). Interestingly, the employ of the hydrazone derived
from R-diethoxy acetophenone led to the 3-ethoxy substi-
tuted isoquinoline (Table 1, entry 7), while the reaction with
the hydrazone obtained from R-methoxy-R-phenylaceto-
phenone enabled the synthesis of a 3,4-diphenyl isoquinoline
(Table 1, entry 8). Both examples show the ability of this
methodology in the synthesis of 3,4-disubstituted isoquino-
lines. Finally, the reaction with the hydrazone of benzylox-
yacetaldehyde led to the preparation of isoquinolines
unsubstituted in the heterocyclic ring (Table 1, entry 9).
In order to achieve the synthesis of 1-substituted isoqui-
nolines, we examined a similar reaction starting from the
corresponding ketone; however, although the cross-coupling
reaction proceeded with moderate yields, we were not able
to promote the cyclization efficiently. For this reason, we
turned our attention to o-cyano nonaflates 5 with the idea
that the same type of cross-coupling reaction would lead
to o-cyanoalkenes 6, which could be transformed into
1-substituted isoquinolines by addition of an organometal-
lic reagent, as previously described by Kobayashi et al.12 As
expected, the cross-coupling reaction proceeded smoothly
under the reaction conditions developed for the formyl
substituted derivatives 1, leading to the cross-coupling prod-
ucts in high yields. Then, treatment with organolithium de-
rivatives afforded the 1-substituted isoquinolines (Scheme 3).
It is noteworthy that, as in the preceding reaction, it is not
necessary to isolate the intermediate enol ether 6, and the
process can be conducted in one pot. The best experimental
conditions found included evaporation of the dioxane once
the cross-coupling has finished, followed by dilution in THF
and addition of the organolithium derivative at À78 °C, to
afford the 1-substituted isoquinolines with good yields.
In summary, we have reported that the cross-coupling
of o-functionalized nonaflates, readily available from
salicyl aldehydes or o-cyanophenols, with functionalized
conditions previously described for the couplings of aryl
nonaflates produced the desired product 3a in only moderate
yield (Scheme 2, conditions A) probably due to the severe
steric requirements of this particular nonaflate. For this
reason, a reoptimization study was conducted. After some
experimentation we discovered that the coupling could be best
accomplished employing LiOH as a base (1.5 equiv) and in the
presence of 3 equiv of LiCl, leading to 3a in excellent yield as a
3:1 mixture of Z/E isomers (Scheme 2, conditions B). Re-
markably, the reaction proceeds nicely in the presence of the
unprotected aldehyde functionality.
Compound 3a, an unprecedented structure, is indeed a
masked 1,5-dicarbonyl derivative that can be envisioned as a
platform for the synthesis of a large variety of condensed
heterocycles and carbocycles. As a proof of concept, we initially
focused on one of the simplest transformations, the reaction
with ammonium hydroxide, which should lead to polysubsti-
tuted isoquinolines.9,10 Although the cyclization can be accom-
plished simply by adding a solution of ammonium hydroxide
to the reaction mixture, better yields are obtained if the mixture
is concentrated by evaporation of the dioxane prior to the
addition of the ammonium hydroxide solution. In this manner,
a set of isoquinolines 4 was prepared by combining nonaflates
derived from substituted salicylaldehydes 1 with tosylhydra-
zones derived from R-alkoxycarbonyls 211 (Table 1).
(10) For some recent leading references on the synthesis of isoquino-
lines: (a) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc.
2008, 130, 1558. (b) Wang, B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma, D. Org.
Lett. 2008, 10, 2761. (c) Hui, B. W.-Q.; Chiba, S. Org. Lett. 2009, 11, 729.
(d) Niu, Y.-N.; Yan, Z.-Y.; Gao, G.-L.; Wang, H.-L.; Shu, X.-Z.; Ji,
K.-G.; Liang, Y.-M. J. Org. Chem. 2009, 74, 2893. (e) Guimond, N.;
Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050. (f) Roy, S.; Roy, S.;
Neuenswander, B.; Hill, D.; Larock, R. C. J. Comb. Chem. 2009, 11,
1061. (g) Dell’Acqua, M.; Abbiati, G.; Rossi, E. Synlett 2010, 2672. (h)
Liu, C.-C.; Parthasarathy, K.; Cheng, C.-C. Org. Lett. 2010, 12, 3518. (i)
Zhang, X.; Chen, D.; Zhao, M.; Zhao, J.; Jia, A.; Li, X. Adv. Synth.
Catal. 2011, 353, 719. (j) Si, C.; Myers, A. G. Angew. Chem., Int. Ed.
2011, 50, 10409.
Scheme 2. Pd-Catalyzed Cross-Coupling between the Tosylhy-
drazone 2a and Nonaflate 1a
(11) For the synthesis of R-alkoxy carbonyl compounds: (a) Muthu-
samy, S.; Babu, S. A.; Gunanathan, C. Tetrahedron Lett. 2002, 43, 3133.
(b) Tudjarian, A. A.; Minehan, T. G. J. Org. Chem. 2011, 76, 3576.
(12) (a) Kobayashi, K.; Shiokawa, T.; Morikawa, O.; Konishi, H.
Chem. Lett. 2004, 33, 236. (b) Kobayashi, K.; Hayashi, K.; Miyamoto,
K.; Morikawa, O.; Konishi, H. Synthesis 2006, 2934. (c) Kobayashi, K.;
Shiokawa, T.; Omote, H.; Hashimoto, K.; Morikawa, O.; Konishi, H.
Bull. Chem. Soc. Jpn. 2006, 79, 1126.
The reaction can be employed very efficiently for the
preparation of 4-substituted isoquinolines with different
(9) Alajarın, R.; Burgos, C. Modern Heterocyclic Chemistry; Wiley-
VCH: Weinheim, 2011; p 1527.
2324
Org. Lett., Vol. 14, No. 9, 2012
Florentino, Lucia
