Direct prenylation of aromatic and α,β-unsaturated carboxamides via iridium-catalyzed C-H oxidative addition-allene insertion

Article abstract of DOI:10.1021/ol901759t

Exposure of aromatic carboxamides 1e-1m, heteroaromatic carboxamides 1n-1p, and α,β-unsaturated carboxamides 1q-1s to 1,1-dimethylallene in the presence of the a cationic iridium complex derived from [Ir(cod) ₂]BAr₄^F and r

Full text of DOI:10.1021/ol901759t

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4248-4250
Direct Prenylation of Aromatic and
r,ꢀ-Unsaturated Carboxamides via
Iridium-Catalyzed C-H Oxidative
Addition-Allene Insertion
Yong Jian Zhang, Eduardas Skucas, and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received July 30, 2009
ABSTRACT
Exposure of aromatic carboxamides 1e-1m, heteroaromatic carboxamides 1n-1p, and r,ꢀ-unsaturated carboxamides 1q-1s to 1,1-
dimethylallene in the presence of the a cationic iridium complex derived from [Ir(cod)2]BArF4 and rac-BINAP results in direct C-H prenylation
to furnish adducts 2e-2m, 2n-2p, and 2q-2s, respectively, in good isolated yields as single isomers.
Enzymatic prenyl transfers are heavily trafficked biosynthetic
pathways,1 yet synthetic catalysts for C-H prenylation are
unknown.2-4 Having recently developed protocols for cata-
lytic carbonyl prenylation employing 1,1-dimethylallene as
the prenyl donor,5 catalytic ortho-C-H insertion of 1,1-
dimethylallene was viewed as a potential strategy for the
direct prenylation of aryl C-H bonds. Due largely to the
pioneering efforts of Murai,6 Lewis base-directed catalytic
C-H activation initiated olefin insertions, and alkyne inser-
(3) For selected reviews of catalytic C-C bond formation via C-H
activation initiated arylation, see: (a) Campeau, L.-C.; Fagnou, K. Chem.
Commun. 2006, 1253. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.;
Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382. (c) Yu, J.-Q.; Giri, R.; Chen,
X. Org. Biomol. Chem. 2006, 4, 4041. (d) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174. (e) Campeau, L.-C.; Stuart, D. R.;
Fagnou, K. Aldrichimica Acta 2007, 40, 35. (f) Ackermann, L. Top.
Organomet. Chem. 2007, 24, 35.
(1) For selected reviews on enzymatic prenyl transfer, see: (a) Poulter,
C. D.; Rilling, H. C. Acc. Chem. Res. 1978, 11, 307. (b) Sacchettini, J. C.;
Poulter, C. D. Science 1997, 277, 1788. (c) Ogura, K.; Koyama, T. Chem.
ReV. 1998, 98, 1263. (d) Liang, P.-H.; Ko, T.-P.; Wang, A. H. J. Eur.
J. Biochem. 2002, 269, 3339.
(4) For selected reviews of catalytic C-C bond formation via carbenoid
insertion, see: (a) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
(b) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861. (c)
Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45, 6422. (d) Davies,
H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(2) For selected reviews on catalytic C-C bond formation via C-H
activation initiated π-bond insertion, see: (a) Kakiuchi, F.; Murai, S. Top.
Organomet. Chem. 1999, 3, 47. (b) Dyker, G. Angew. Chem., Int. Ed. 1999,
38, 1698. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102,
1731. (d) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (e)
Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (f) Park,
Y. J.; Jun, C.-H. Bull. Korean Chem. Soc. 2005, 26, 871. (g) Godula, K.;
Sames, D. Science 2006, 312, 67. (h) Kakiuchi, F. Top. Organomet. Chem.
2007, 24, 1. (i) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem.
Res. 2008, 41, 1013. (j) Kakiuchi, F.; Kochi, T. Synlett 2008, 3013. (k)
(5) For carbonyl reverse prenylation via iridium-catalyzed hydrogenative
and transfer hydrogenative coupling of 1,1-dimethylallene, see: (a) Skucas,
E.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12678. (b)
Bower, J. F.; Skucas, E.; Patman, R. L.; Krische, M. J. J. Am. Chem. Soc.
2007, 129, 15134. (c) Kim, I. S.; Han, S.-B.; Krische, M. J. J. Am. Chem.
Soc. 2009, 131, 6916. (d) For the reverse prenylation of carboxylic acids
employing 1,1-dimethylallene, see: Kim, I. S.; Krische, M. J. Org. Lett.
2008, 10, 513.
(6) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529.
Kitamura, T. Eur. J. Org. Chem. 2009, 1111
.
10.1021/ol901759t CCC: $40.75
Published on Web 08/17/2009
 2009 American Chemical Society

tions are well developed. To our knowledge, analogous C-H
actiVation-initiated insertions of allenes remain unex-
plored.2-4,6,7 Here, we report that cationic iridium complexes
catalyze the coupling of 1,1-dimethylallene to aromatic
carboxamides, heteroaromatic carboxamides, and R,ꢀ-
unsaturated carboxamides to furnish the products of C-H
prenylation in good isolated yield as single isomers.8
To avoid potential overprenylation, initial studies focused
on amides derived from ortho-methoxybenzoic acid. To our
delight, the cationic iridium complex assembled from
[Ir(cod)2]BArF4 and rac-BINAP8f was found to catalyze the
coupling of N-benzyl amide 1a and 1,1-dimethylallene in
THF solvent at 120 °C in 78% isolated yield. Neutral iridium
complexes did not promote coupling. One complication,
however, is that N-benzyl amide 1a delivers a 3:1 mixture
of olefin regioisomers 2a and 3a, respectively (Table 1, entry
1,1-dimethylallene under the aforementioned conditions, the
desired product of C-H prenylation 2a was obtained in 70%
isolated yield as a single isomer (Table 1, entry 5).
To evaluate the scope of this process, these conditions were
applied to aromatic carboxamides 1e-1m. In each case, good
to excellent yields of the desired aryl C-H prenylation
products were obtained. Remarkably, ortho-substituted aryl
carboxamides are not required to suppress isomerization or
overprenylation (Figure 1, adducts 2g, 2i, 2j-m). Indeed,
Table 1. Selected Examples Revealing the Influence of the
Amide Directing Group in Iridium-Catalyzed Aryl C-H
Prenylationa
entry
1a-1e
R1
benzyl
R2
yield 2a:3a
1
2
3
4
5
1a
1b
1c
1d
1e
H
78% (3:1)
benzyl
benzyl
H
---
recovered 1a
80% (2.4:1)
recovered 1a
70% (>20:1)
cyclohexyl
morpholinyl
pyrrolidinyl
---
a In all cases, cited yields are of isolated material. See Supporting
Information for detailed experimental procedures.
1). On the basis of the notion that isomerization occurs by
way of amide-directed allylic C-H insertion of 2a, it was
reasoned that tertiary amides may suppress isomerization by
twisting out of plane upon introduction of the prenyl moiety,
which should attenuate the amides directing influence.
Consistent with this hypothesis, primary amides provide good
yields of prenylation product, but as mixtures of olefin
regioisomers 2a and 3a, whereas tertiary amides, such the
dibenzyl amide 1b and amide 1d derived from morpholine,
do not participate in the coupling (Table 1, entries 2 and 3).
Presumably, amides 1b and 1d are too large, and nonbonded
interactions twist the amide out of plane and prohibit
coupling. It was postulated that amide 1e derived from
pyrrolidine should be smaller and more Lewis basic,
potentially providing an ideal combination of steric and
electronic features. Indeed, upon exposure of amide 1e to
Figure 1. Iridium-catalyzed C-H prenylation of aryl carboxamides
1e-1m. In all cases, cited yields are of isolated material and
represent the average of two or more runs. See Supporting
b
Information for detailed experimental procedures. A 5:1 ratio of
2f to iso-2f was obtained. For iso-2f, prenylation occurs at the
alternate ortho-position.
the parent benzamide 1m is monoprenylated under these
conditions in 84% isolated yield. Only in the case of the
meta-methoxy derivative 1f was a mixture of isomeric
adducts obtained, yet the corresponding meta-nitro derivative
1k undergoes prenylation to furnish a single isomeric product
2k.9 Additionally, the naphthoic amide 1l prenylates at the
(7) For reviews of metal-catalyzed reactions of allenes, see: (a) Zimmer,
R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. ReV. 2000, 100, 3067.
(b) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590. (c) Ma, S.
Chem. ReV. 2005, 105, 2829. (d) Ma, S. Aldrichimica Acta 2007, 40, 91
.
Org. Lett., Vol. 11, No. 18, 2009
4249

more hindered position. These data suggest electronic
features of the substrate strongly influence regioselectivity.
To further evaluate the scope of this process, catalytic aryl
C-H prenylation of heterocyclic aromatic carboxamides
1n-1p was attempted.10 In each case, the prenylated adducts
2n-2p are obtained in good isolated yields as single isomers.
The conversion of indole 3-carboxamide 1p to the 2-prenyl
derivative 2p is significant given the abundance of prenylated
indoles in Nature (Figure 2).11 R,ꢀ-Unsaturated carboxamides
Scheme 1. Iridium-Catalyzed C-H Prenylation of deuterio-2ma
a As described in Figure 1 footnotes.
oxidative addition followed by allene hydrometalation to
furnish an aryl-allyl iridium complex, which upon C-C
reductive elimination from the primary σ-allyliridium hap-
tomer delivers the product of prenylation with regeneration
of cationic iridium(I). Incomplete levels of deuterium
incorporation may arise Via ꢀ-hydride elimination from the
tertiary σ-allyliridium haptomer of the aryl-allyl iridium
intermediate (Scheme 1).
In summary, we report the first catalytic C-H activation
initiated C-C coupling of allenes, as demonstrated by the
direct C-H prenylation of aromatic, heteroaromatic, and R,ꢀ-
unsaturated carboxamides. Future studies will focus on the
development of related transformations that promote C-C
bond formation in the absence of premetalated reagents and,
consequently, in the absence of stoichiometric metallic
byproducts.
Figure 2. Iridium-catalyzed C-H prenylation of heterocyclic
aromatic carboxamides 1n-1p. As described in Figure 1 footnotes.
bTwo equivalents of 1,4-cyclooctadiene was added to suppress olefin
isomerization.
1q-1s also were examined.12 The desired adducts 2q-2s
were generated in good isolated yields as single isomers
(Figure 3).
Acknowledgment. The following agencies are acknowl-
edged for their support of our research: the Robert A. Welch
Foundation, the American Chemical Society Green Chem-
istry Institute Pharmaceutical Roundtable, and the NSF
(CHE-0749016).
Supporting Information Available: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 3. Iridium-catalyzed C-H prenylation of R,ꢀ-unsaturated
carboxamides 1q-1s. As described in Figure 1 footnotes.
OL901759T
(9) Stoichiometric ortho-cyclometallation of iridium centers onto m-
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131, 6916, and ref 5c.
To corroborate the catalytic mechanism, deuterio-1m was
subjected to standard conditions for C-H prenylation. As
anticipated, deuterium was transferred to the vinylic position
of the adduct deuterio-2m (Scheme 1). This result is
consistent with a catalytic mechanism involving ortho-C-H
(10) See ref 2i and literature cited therein.
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