Complementary regioselectivity in Rh(III)-catalyzed insertions of potassium vinyltrifluoroborate via C-H activation: Preparation and use of 4-trifluoroboratotetrahydroisoquinolones

Article abstract of DOI:10.1021/ol400307d

Potassium vinyltrifluoroborate was found to be an efficient partner with benzamide derivatives for Rh(III)-catalyzed annulations. 4- Trifluoroboratotetrahydroisoquinolones were generated under mild conditions, affording a regioisomerically complementary substitution pattern to other alkenes in related reactions. These new boron-containing building blocks were derivatized by N-arylations, retaining the boron substituent for further elaboration.

Full text of DOI:10.1021/ol400307d

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Complementary Regioselectivity in
Rh(III)-Catalyzed Insertions of Potassium
Vinyltrifluoroborate via CꢀH Activation:
Preparation and Use of 4‑Trifluoro-
boratotetrahydroisoquinolones
Marc Presset,†,‡ Daniel Oehlrich,‡ Frederik Rombouts,*,‡ and Gary A. Molander*,†
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States, and Neuroscience
Medicinal Chemistry, Research & Development, Janssen Pharmaceutical Companies,
Turnhoutseweg 30, 2340 Beerse, Belgium
frombout@its.jnj.com; gmolandr@sas.upenn.edu
Received February 2, 2013
ABSTRACT
Potassium vinyltrifluoroborate was found to be an efficient partner with benzamide derivatives for Rh(III)-catalyzed annulations.
4-Trifluoroboratotetrahydroisoquinolones were generated under mild conditions, affording a regioisomerically complementary substitution
pattern to other alkenes in related reactions. These new boron-containing building blocks were derivatized by N-arylations, retaining the boron
substituent for further elaboration.
During the past decade, Rh(III)-catalyzed CꢀH bond
functionalizations have emerged as a powerful tool in
organic synthesis.1 Their success is due in large part to
their atom economy and to selectivity achieved by the use
of a directed CꢀH activation. Indeed, such reactions have
been successfully used for the formation of CꢀC,2 CꢀN,3
and CꢀX (X = halogen)4 bonds5 as well as heterocycles6
through the use of a co-oxidant. Among such transforma-
tions, the insertion of unsaturated compounds in benza-
mide derivatives has received much attention.7,8 Guimond
† University of Pennsylvania.
‡ Janssen Pharmaceutical Companies.
(1) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624. (b) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A.
Acc. Chem. Res. 2012, 45, 814. (c) Zhu, C.; Wang, R.; Falck, J. R. Chem.
Asian J. 2012, 7, 1502. (d) Patureau, F. W.; Wencel-Delord, J.; Glorius,
F. Aldrichim. Acta 2012, 45, 31.
(2) Recent selected references: for nucleophilic additions, see: (a)
Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2011, 133, 1248. (b) Shi, X.; Li, C.-J. Adv. Synth. Catal. 2012, 354,
2933. For acylations, see: (c) Sharma, S.; Park, E.; Park, J.; Kim, S. Org.
Lett. 2012, 14, 906. (d) Yang, Y.; Zhou, B.; Li, Y. Adv. Synth. Catal.
2012, 354, 2916. For cross-dehydrogenative coupling, see: (e) Wencel-
Delord, J.; Nimphius, C.; Wang, H.; Glorius, F. Angew. Chem., Int. Ed.
2012, 51, 13001 and references cited therein. For insertions in
R-diazomalonates, see: Chan, W.-W.; Lo, S.-F.; Zhou, Z.; Yu, W.-Y.
J. Am. Chem. Soc. 2012, 134, 13565.
(3) (a) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang,
S. J. Am. Chem. Soc. 2012, 134, 9110. (b) Ryu, J.; Shin, K.; Park, S. H.;
Kim, J. Y.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 9904. (c)
Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2012, 14, 656.
€
(4) Schroder, N.; Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc.
2012, 134, 8298.
(5) For a review, see: Song, G.; Wang, F.; Li, X. Chem. Soc. Rev.
2012, 41, 3651.
(6) Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212.
(7) For a seminal paper with benzoic acids, see: Ueura, K.; Satoh, T.;
Miura, M. Org. Lett. 2007, 9, 1407.
(8) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565.
(9) For a highlight, see: Patureau, F. W.; Glorius, F. Angew. Chem.,
Int. Ed. 2011, 50, 1977.
r
10.1021/ol400307d
XXXX American Chemical Society

and Fagnou improved the original method by the use of a
combined directing group and internal oxidant,9,10 allow-
ing milder reaction conditions for the insertion of unsatu-
rated hydrocarbons in benzamide derivatives (Scheme
1.1).11 Since the emergence of this pioneering work, much
attention has been focused on its application to alkynes,12
and with the exception of a study on allenes,13 less effort
has been devoted to alkenes. Indeed, whereas a Heck-type
reaction with β-hydride elimination usually competes,7,11c,14
Rovis and Cramer have recently reported an asymmetric
version of this reaction.15
Glorius has reported the insertion of ethynyl-B(MIDA)
boronate using Cu(OAc)2 as a cocatalyst with the same
regioselectivity as for terminal alkenes (Scheme 1 (2)).22
Herein, we report the extension of Rh(III)-catalyzed
insertionreactions topotassium vinyltrifluoroborate, lead-
ing to a new class of tetrahydroisoquinolones that can sub-
sequently be bidirectionally functionalized (Scheme 1 (3)).
Scheme 1. Syntheses of Isoquinolones by Insertion Reactions
Owing to the importance of tetrahydroisoquinolines16
and to the increased demand for new organoboron
compounds,17 an annulative approach to these structures
utilizing alkenylboron components was sought. Indeed,
this would lead to novel boron-containing building blocks,
ready for further elaboration. However, such a strategy
would meet two main challenges or unknowns: (1) An
obvious issue of compatibility between the organoboron
species and the co-oxidant required in the desired trans-
formation could arise. (2) The potential participation
of the organoboron component in competing Rh(III)-
catalyzed reactions would also be of concern.18
To avoid these potential pitfalls and achieve the objec-
tive, attention was turned to organotrifluoroborates,
which have been shown to be much more stable than the
corresponding boronic acids and boronates.19 Thus, it has
been demonstrated that the trifluoroborato moiety is
capable of remaining intact in a broad range of reactions.20
Additionally, only rare examples of boryl-substituted sub-
strates have been reported in such insertion reactions, and
these have all been various alkynylborons.21 In particular,
In the strategy to use alkenyltrifluoroborates in Rh(III)-
catalyzed annulations, we were particularly interested in
utilizing an internal oxidant because it avoids the use of a
co-oxidant, which might be incompatible with an organo-
boron species. Therefore, investigations were begun using
the conditions originally reported for the reaction of
benzhydroxamate 1a with potassium vinyltrifluoroborate
2 using a slight excess of the arene substrate to ensure
complete conversion of the organoboron species. In an
initial effort, the desired tetrabutylammonium product 3a
was obtained (after salt metathesis to simplify the isolation
step),23 but only in 35% yield and as an 85:15 mixture of
regioisomers. Of interest is the unusual regiochemistry of
the major olefin insertion product, which provides tetra-
hydroisoquinolones that are regioisomeric to those formed
using other alkenes.11,15 Steric effects would not appear to
explain this reversal, and thus a substantial and unique
electronic effect seen previously in metal-mediated inser-
tion reactions of vinyltrifluoroborate appears to be the
major contributing factor.24 Thus, calculations (B3LYP
6-31G*) reveal that the dipole of the CdC bond in
vinyltrifluoroborate places enhanced negative charge at
the beta position of the double bond, in line with the
observed regiochemistry.
(10) For mechanistic studies, see: Xu, L.; Zhu, Q.; Huang, G.; Cheng,
B.; Xia, Y. J. Org. Chem. 2012, 77, 3017.
(11) (a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (b) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am.
Chem. Soc. 2011, 133, 6449. (c) Rakshit, S.; Grohmann, C.; Besset, T.;
Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350.
(12) Most recent publications: (a) Li, B.-J.; Wang, H.-Y.; Zhu, Q.-L.;
Shi, Z.-J. Angew. Chem., Int. Ed. 2012, 51, 3948. (b) Xu, X.; Liu, Y.;
Park, C.-M. Angew. Chem., Int. Ed. 2012, 51, 9372. (c) Pham, M.; Ye, B.;
Cramer, N. Angew. Chem., Int. Ed. 2012, 51, 10610.
(13) For Rh(III)-catalyzed annulations of allenes, see: Wang, H.;
Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 7318.
(14) Selected references: (a) Ueura, K.; Satoh, T.; Miura, M. Org.
Lett. 2007, 9, 1407. (b) Patureau, F. W.; Glorius, F. J. Am. Chem. Soc.
2010, 132, 9982. (c) Patureau, F. W.; Besset, T.; Glorius, F. Angew.
Chem., Int. Ed. 2010, 50, 1064. (d) Tsai, A. S.; Brasse, M.; Bergman,
R. G.; Ellman, J. A. Org. Lett. 2011, 13, 540. (e) Li, G.; Ding, Z.; Xu, B.
Org. Lett. 2012, 14, 5338. (f) Zhen, W.; Wang, F.; Zhao, M.; Du, Z.; Li,
X. Angew. Chem., Int. Ed. 2012, 51, 11819.
€
(15) (a) Hyster, T. K.; Knorr, L.; Ward, T. R.; Rovis, T. Science 2012,
338, 500. (b) Ye, B.; Cramer, N. Science 2012, 338, 504.
(16) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752.
(17) Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011.
(18) Karthikeyan, J.; Haridharan, R.; Cheng, C.-H. Angew. Chem.,
Int. Ed. 2012, 51, 12343. For Rh(III)-catalyzed oxidative coupling of
arylboronic acids and alkynes, see: Fukutani, T.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2009, 11, 5198.
An overview of the optimization process can be viewed
in the Supporting Information. Importantly, the reaction
conditions ultimately settled upon are easily scalable, and
(19) (a) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38,
49. (b) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288.
(20) (a) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (b)
Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240.
(21) (a) Miura, T.; Yamauchi, M.; Murakami, M. Org. Lett. 2008, 10,
(22) Wang, H.; Grohmann, C.; Nimphius, C.; Glorius, F. J. Am.
Chem. Soc. 2012, 134, 19592.
(23) Batey, R. A.; Quach, T. D. Tetrahedron Lett. 2001, 42, 9099.
(24) Molander, G. A.; Sandrock, D. L. J. Am. Chem. Soc. 2008, 130,
15792.
ꢀ
3085. (b) Geny, A.; Leboeuf, D.; Rouquie, G.; Vollhardt, K. P. C.;
Malacria, M.; Gandon, V.; Aubert, C. Chem.;Eur. J. 2007, 13, 5408.
B
Org. Lett., Vol. XX, No. XX, XXXX

the desired product 3a can be obtained in an even better
yield as either a tetrabutylammonium salt or, in a more
atom-economical way,25 as a potassium salt by modifying
the base and the workup (Scheme 2).
Scheme 3. Scope of the Insertion of Potassium
Vinyltrifluoroborate 2 in Benzhydroxamate Derivatives
Scheme 2. Preparative Scale
Attention was next turned to the scope of this reaction
(Scheme 3). Pleasingly, the reaction of 4-substituted hy-
droxamates 1aꢀe afforded the expected products 3aꢀe in
similarly good yields for both electron-withdrawing and
electron-donating groups. In the case of 3-substituted
substrates 1fꢀi, the regioselectivity of the CꢀH activation
is strongly influenced by steric factors, and the less hin-
dered CꢀH bond is the more reactive (e.g., providing 3g).
Interestingly, various types of heterocycles are suitable
substrates for these annulations. Indeed, pyridine, thio-
phene, and furan derivatives have been successfully used to
provide good yields of the desired products. Whereas
almost complete regioselectivity was observed in the for-
mation of 3k, the reaction was found to be less selective for
the thiophene system leading to 3l, but blocking the
2-position of furan 2m afforded a single trifluoroborate
3m in good yield. However, as already highlighted by the
results above, the present conditions are very sensitive to
steric hindrance, and the use of 2-substituted benzhydrox-
amates only led to traces of the expected compounds (e.g.,
3j), and furthermore no product was obtainedin the case of
substituted alkenyltrifluoroborates.
In addition to the regiocomplementary nature of the
olefin insertion, the reactivity of these new synthons was
found to be somewhat surprising. After unsuccessful at-
tempts to cross-couple the organotrifluoroborates using
Crudden’s conditions for benzylic boron species,26 the
cross-coupling of 3a with 4-bromobenzotrifluoride 5a
under palladium catalysis optimized for secondary alkyl
cross-coupling led,27 after purification, to the N-arylated
compound 6aa, where the boron had been oxidized
(Scheme 4). In a targeted synthesis, 6ab could be prepared
by formation of trifluoroborate 7ab via a quantitative
arylation, followed by its further oxidation to 6ab.28 This
completely chemoselective BuchwaldꢀHartwig coupling
in the presence of a boron derivative clearly demonstrates
the low reactivity of these secondary cyclic boron species in
cross-coupling29 and is a rare example of a selective
BuchwaldꢀHartwig coupling in preference to a Suzukiꢀ
Miyaura process.30 In these transformations, the vinyltri-
fluoroborate serves as an enol equivalent in the Rh-cata-
lyzed insertion reactions.
Owing to the importance of N-arylated isoquinolines
(and isoquinolones),31,32 the scope of the Buchwaldꢀ
Hartwig arylation/oxidation sequence was explored.
Gratifyingly, under Buchwald’s conditions for the ami-
dation of aryl halides,33 a variety of aryl bromides 5 could
be introduced (Scheme 5). Even though a moderate yield
was observed in the case of the simple bromobenzene 5c,
(28) Molander, G. A.; Cavalcanti, L. N. J. Org. Chem. 2011, 76, 623.
(29) No traces of SuzukiꢀMiyaura coupling product was observed
with N-methylated 3a.
(30) For BuchwaldꢀHartwig couplings of inactive azaborine in
SuzukiꢀMiyaura couplings, see: Agou, T.; Kojima, T.; Kobayashi, J.;
Kawashima, T. Org. Lett. 2009, 11, 3534. The reverse selectivity is
ꢀ
usually observed; see, for example: (a) Sandrock, D. L.; Jean-Gerard, L.;
Chen, C.; Dreher, S. D.; Molander, G. A. J. Am. Chem. Soc. 2010, 132,
17108. (b) Treu, M.; Zahn, S. K.; Amouzegh, P.; Lecci, C.; Tye, H.
WO2012085126, 2011.
(25) Trost, B. M. Science 1991, 254, 1471.
(26) Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M.
J. Am. Chem. Soc. 2009, 131, 5024.
(31) Buckley, B. R.; Christie, S. D. R.; Elsegood, M. R. J.; Gillings,
C. M.; Bulman Page, P. C.; Pardoe, W. J. M. Synlett 2010, 939 and
references cited therein.
(32) Komoda, M.; Kakuta, H.; Takahashi, H.; Fujimoto, Y.; Kadoya,
S.; Kato, F.; Hashimoto, Y. Bioorg. Med. Chem. 2001, 9, 121.
(33) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(27) These conditions for cross-coupling have been found by high-
throughput experimentation; see: Dreher, S. D.; Dormer, P. G.;
Sandrock, D. L.; Molander, G. A. J. Am. Chem. Soc. 2008, 130, 9257.
Org. Lett., Vol. XX, No. XX, XXXX
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Scheme 4. Selective BuchwaldꢀHartwig Reactivity
Scheme 5. Scope of the BuchwaldꢀHartwig
Arylation/Oxidation Sequence
the reaction tolerated various electron-withdrawing and
electron-donating groups in the meta and para positions
(compounds 6aaꢀae).34 Moreover, the outcome of this
sequence is little influenced by the substitution of 3, as
both 3c and 3e work equally well. Additionally, 5-bromo-
2-trifluoromethylpyridine 5f afforded the desired biheter-
ocyclic compound 6af in 79% yield.
Scheme 6. Synthesis of Corydaldine 8 using a Rh(III)-Catalyzed
Annulation/Protodeborylation Strategy
Finally, we briefly studied the protodeborylation of this
new type of organotrifluoroborates as an alternative route
to the use of gaseous ethylene.11 Therefore, compound 3n
has been prepared under our standard conditions from the
benzhydroxamate 1n in a 54% yield as a 3:1 mixture in
favor of the desired regioisomer 3n0. Protodeborylation of
3n was achieved using AcOH in a toluene/water mixture at
120 °C, affording straightforward access to the natural
alkaloid corydaldine 835 in 56% isolated yield (Scheme 6).
In conclusion, we have developed mild and efficient
conditions for the Rh(III)-catalyzed annulations of benz-
hydroxamates with potassium vinyltrifluoroborate. The
vinyltrifluoroborate inserts with high regioselectivity in
most cases and in a manner that is regiocomplementary
to that of most terminal alkenes. Importantly, the resulting
building blocks can be functionalized on both the nitrogen
and boron position. In the simplest of these transforma-
tions, the vinyltrifluoroborate may serve as the synthetic
equivalent of the enol of acetaldehyde or as an ethylene
synthon.
Acknowledgment. This research was supported by the
Neuroscience Medicinal Chemistry Department of Janssen
and NIGMS (R01 GM035249). Michel Carpentier (Janssen)
is acknowledged for obtaining HRMS data. Dr. Floriane
Beaumard and Kaitlin Traister (University of Pennsylvania)
are acknowledged for performing HTS experiments and
MO calculations, respectively.
Supporting Information Available. Experimental de-
tails, characterization data, and NMR spectra of all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(34) As reported by Buchwald and Yin, no reaction was observed
with ortho-substituted aryl bromides under these conditions.
(35) For a recent synthesis, see: Oliva-Madrid, M.-J.; Garcia-Lopez,
J.- A.; Saura-Llamas, I.; Bautista, D.; Vicente, J. Organometallics 2012,
31, 3647.
The authors declare no competing financial interest.
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