N -acylsulfonamide assisted tandem C-H olefination/annulation: Synthesis of isoindolinones

Article abstract of DOI:10.1021/ol200093f

A tandem C-H olefination/annulation sequence directed by N-acylsulfonamides affords a variety of isoindolinones. This transformation is compatible with aliphatic alkenes as well as conjugated alkenes. Notably, molecular oxygen can be used as the sole, eco-friendly oxidant.(Figure Presented)

Full text of DOI:10.1021/ol200093f

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1214–1217
N-Acylsulfonamide Assisted Tandem
C-H Olefination/Annulation: Synthesis
of Isoindolinones
Chen Zhu* and J. R. Falck
Departments of Biochemistry and Pharmacology, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
chen.zhu@utsouthwestern.edu
Received January 12, 2011
ABSTRACT
A tandem C-H olefination/annulation sequence directed by N-acylsulfonamides affords a variety of isoindolinones. This transformation
is compatible with aliphatic alkenes as well as conjugated alkenes. Notably, molecular oxygen can be used as the sole, eco-friendly
oxidant.
Pd(II)-mediated aromatic C(sp2)-H olefinations
(Fujiwara-Moritani reactions) have emerged as a power-
ful tool for C-C bond formation.1,2 Indeed, the utility and
unique characteristics of this reaction have been cogently
demonstrated in the total synthesis of polyfunctional
natural products of current interest and for the efficient
construction of bioactive scaffolds.3 Generally, nitrogen-
or oxygen-containing directing groups are required for
acceptable reactivity and selectivity using the Fujiwara-
Moritani reaction.4,5 Hence, it is apparent that both
synthetic efficiency and atom economy would be greatly
extended if the heteroatom served as both the directing
group and precursor to a C-X bond (X = N, O). An early
example of this concept was provided by Miura and co-
workers who revealed benzoic acid could direct tandem
C-H olefination and C-O formation, albeit in unsatisfy-
ing yields;6 more recently, the Yu group demonstrated
that a triflamide and tertiary hydroxyl were competent
(1) For initial reports, see: (a) Moritani, I.; Fujiwara, Y. Tetrahedron
Lett. 1967, 8, 1119. (b) Fujiwara, Y.; Moritani, I.; Matsuda, M.;
Teranishi, S. Tetrahedron Lett. 1968, 9, 633.
(2) For reviews, see: (a) Moritani, I.; Fujiwara, Y. Synthesis 1973,
524. (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34,
633. (c) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.
Chem. Rev. 2007, 107, 5318. (d) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (e) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147.
^
(3) (a) Trost, B. M.; Godleski, S. A.; Genet, J. P. J. Am. Chem. Soc.
1978, 100, 3930. (b) Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M.
J. Am. Chem. Soc. 1993, 115, 9323. (c) Baran, P. S.; Corey, E. J. J. Am.
Chem. Soc. 2002, 124, 7904. (d) Garg, N. K.; Caspi, D. D.; Stoltz, B. M.
J. Am. Chem. Soc. 2004, 126, 9552. (e) Beck, E. M.; Hatley, R.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2008, 47, 3004.
(4) For examples of Pd(II) catalyzed C-H olefination with directing
groups, see: (a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries,
A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J.
Am. Chem. Soc. 2002, 124, 1586. (b) Zaitsev, V. G.; Daugulis, O. J. Am.
Chem. Soc. 2005, 127, 4156. (c) Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J.
Am. Chem. Soc. 2007, 129, 7666. (d) Cho, S. H.; Hwang, S. J.; Chang, S.
J. Am. Chem. Soc. 2008, 130, 9254. (e) Houlden, C. E.; Bailey, C. D.;
(5) For examples of Pd(II) catalyzed C-H olefinations without
directing groups, see: (a) Fujiwara, Y.; Maruyama, O.; Yoshidomi,
M.; Taniguchi, H. J. Org. Chem. 1981, 46, 851. (b) Itahara, T.; Ikeda, M.;
Sakakibara, T. J. Chem. Soc., Perkin Trans. 1 1983, 1361. (c) Ferreira,
E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578. (d) Beccalli,
E. M.; Broggini, G. Tetrahedron Lett. 2003, 44, 1919. (e) Ma, S.; Yu, S.
Tetrahedron Lett. 2004, 45, 8419. (f) Liu, C.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2004, 126, 10250. (g) Grimster, N. P.; Gauntlett, C.;
Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44,
3125. (h) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.;
Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506.
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Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J.
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Am. Chem. Soc. 2008, 130, 10066. (f) Garcıa-Rubia, A.; Arrayas, R. G.;
Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, 6511. (g) Wang, D.-H.;
Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315. (h) Shi, B. F.;
Zhang, Y.-H.; Lam, J. K.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 460. (i) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2010, 49, 6169. (j) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010,
(6) (a) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J.
Org. Chem. 1998, 63, 5211. Also see: (b) Ueura, K.; Satoh, T.; Miura, M.
Org. Lett. 2007, 9, 1407. (c) Ueura, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2007, 72, 5362.
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r
10.1021/ol200093f
Published on Web 02/08/2011
2011 American Chemical Society

directing groups for the cascade process of C-H olefina-
tion/C-X bond formation resulting in six-membered
heterocycles.7,8 However, in those cases, the annulation
was strictly limited to electron-deficient olefins. Herein, we
disclose tosyl amide as a new directing group that affords
the isoindolinone motif via a sequence of C-H olefination
followed by C-N bond formation. Another notable fea-
ture is the use of molecular oxygen as the sole oxidant and
shows the preference for the PdII/Pd0 redox cycle. Impor-
tantly, this transformation is broadly compatible with
aliphatic alkenes as well as activated alkenes; the specific
type of adduct formed is dictated by the electronic proper-
ties of the alkene (eq 1).
Scheme 1. Reaction Scope Using Various N-Tosylbenzamidesa,b
a 1 (0.1 mmol), alkene (0.12 mmol), Pd(OAc)2 (0.01 mmol), ligand
(0.012 mmol) and O2 (1 atm). bIsolated yield. c72 h. dPerformed for 80 h
using 20 mol % Pd(OAc)2 and 24 mol % bathophenanthroline.
For the initial survey of reaction conditions and optimi-
zation, N-tosylbenzamide and tert-butyl acrylate were
selected as model substrates since they were commercially
available and amenable to deprotection and/or manipula-
tion following annulation. Subsequent screening cam-
paigns established some important reaction parameters:9
(i) Pd(OAc)2 performed as well or better than other
commercial Pd(II)-catalysts, (ii) bathophenanthroline was
much superior to other intermediaries of the catalytic PdII/
Pd0 redox cycle, and (iii) toluene furnished better yields than
THF, CH3CN, DMSO, and other common solvents. While
benzoquinone (BQ) is one of the most commonly used
oxidants for Pd(II)-catalyzed C-H activations, and also
works in our reaction, we were delighted to discover eco-
friendly molecular oxygen had a higher turnover number
than BQ and could function as the sole oxidant in the
absence of other co-oxidants.10 Indeed, the anticipated
annulation adduct 3a was isolated in good chemical yield
when the optimized conditions were employed (eq 2).
of the electronic properties of the aryl substituent(s). For
instance, the electron-donating methoxy (3c) and methyl
group (3d) as well as fluoride (3f) all furnished their
respective adducts in high yields. The chemoselective for-
mation of 3g, without a competitive Heck reaction by the
aryl bromide, is noteworthy, as the latter provides func-
tionality for subsequent Pd(0)-mediated cross-coupling
reactions. Acceptable yields of adduct when strong elec-
tron-withdrawing groups were present, e.g., CF3, generally
required prolonged reaction times (3e). The facile annula-
tion of 3h compared with the somewhat sluggish closure of
the regioisomeric 3i is also of interest and can be attributed
to the torsional hindrance from the ortho-methoxy in 3i,
which prevents the amide from achieving optimum overlap
with the aromatic ring. To confirm this hypothesis, a
comparable experiment was carried out by replacing the
bulky ortho-methoxy withanortho-fluorogroup. As might
be anticipated from the foregoing discussion, the annula-
tion of 3j proceeded with an obviously better reaction rate
and in higher yield than 3i.
The range of acceptable alkenes was also investi-
gated. When subjected to the preceding reaction condi-
tions, electron-deficient alkenes, e.g., a conjugated ester
(4a), ketone (4b), and amide (4c), smoothly evolved
adducts 4 (Scheme 2). Even 2,4-pentadienoate and the
R-branched olefin methacrylate were suitable, afford-
ing 4d and 4e, respectively.
Despite the otherwise rare participation of simple ali-
phatic alkenes in C-H olefinations owing to their poor
reactivity, we found terminal aliphatic alkenes were readily
converted into annulated adducts (Table 1). Not only
simple alkene (5a) but also functionalized alkenes such as
aliphatic ester (5b), aliphatic chloride (5c), and aryl sub-
stituted alkene (5d) were suitable substrates for the annula-
tion cascade. An intriguing example of specificity
Encouraged by this result, we applied the method to a
variety of substituted N-tosylbenzamides (Scheme 1). The
tandem process readily provided isoindolinones regardless
(7) (a) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47,
6452. (b) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 5916.
(8) For an example of tandem C(sp3)-H olefination/C-N forma-
tion, see: Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
3680.
(9) See Supporting Information for details of reaction parameter
screening.
(10) For examples of using O2 as an oxidant in C-H olefination, see:
(a) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
5072. (b) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 14137.
Org. Lett., Vol. 13, No. 5, 2011
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Scheme 2. Reaction Scope with Activated Alkenesa,b
Scheme 3. Electronic Effects on Reaction Rate
a 1 (0.1 mmol), alkene (0.12 mmol), Pd(OAc)2 (0.01 mmol), ligand
(0.012 mmol), and O2 (1 atm). bIsolated yield. cReaction performed for
72 h using 20 mol % Pd(OAc)2 and 24 mol % bathophenanthroline. ddr
= 1.4:1, separated by preparative TLC.
Table 1. Reaction Scope with Nonconjugated Alkenesa
Additionally, a small amount of isoquinolinone 6 was also
produced. The overall process represents an unprece-
dented tandem C-H olefination/annulation involving
simple aliphatic alkenes.
While the mechanism of Pd(II)-mediated C(sp2)-H
cleavage has attracted considerable attention in past dec-
ades, the precise details remain controversial.11 However,
the data gained from the competitive reactions agree with
an electrophilic palladation mechanism as originally pro-
posed by Ryabov and co-workers (Scheme 3).11a Specifi-
cally, tosyl amides bearing substituents with various
electronicpropertiesweresubjected toparallel experiments
in which the conversion ratio was determined by 1H NMR.
Substrates with electron-donating groups, e.g., 1c, showed
the highest reaction rates while an unsubstituted case (1a) was
intermediate and the electron-deficient substrate (1e) had the
lowest reactivity. These results are consistent with the pathway
of an arenium (Wheland) intermediate of which the efficacy is
highly reliant on the electronic property of arene.11a
To further study the C-H cleavage step, we prepared
deuterium-labeled compound 7 and subjected it to compe-
titive, intermolecular experiments (eqs 3 and 4). An equi-
molar mixture of 1a and 7 was treated with 1 equiv of
electron-deficient alkene (or aliphatic alkene); the mea-
sured product isotope effect of 3.2 (or 3.0) might suggest
(11) For mechanistic studies of Pd(II)-mediated C-H cleavages,
see: (a) Ryabov, A. D.; Sakodinskaya, I. K.; Yatsimirsky, A. K. J.
Chem. Soc., Dalton Trans. 1985, 2629. (b) Canty, A. J.; van Koten, G.
a 1 (0.1 mmol), alkene (0.12 mmol), Pd(OAc)2 (0.01 mmol), ligand
(0.012 mmol), and O2 (1 atm). b Isolated yield. c Ratio of 5/6 calculated
from isolated yields. d Trace of 6e only detected by 1H NMR.
ꢀ
Acc. Chem. Res. 1995, 28, 406. (c) Gomez, M.; Granell, J.; Martinez,
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M. Organometallics 1997, 16, 2539. (d) Gomez, M.; Granell, J.;
Martinez, M. J. Chem. Soc., Dalton Trans. 1998, 37. (e) Biswas, B.;
Sugimoto, M.; Sakaki, S. Organometallics 2000, 19, 3895. (f) Davies,
D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005,
127, 13754. (g) Tunge, J. A.; Foresee, L. N. Organometallics 2005, 24,
6440.
(12) (a) Davidson, J. M.; Triggs, C. J. Chem. Soc. A 1968, 1324. (b)
Shue, R. S. J. Am. Chem. Soc. 1971, 93, 7116. (c) Lane, B. S.; Brown,
M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (d) Campeau,
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was found in 1,7-octadiene wherein one terminal alkene
underwent annulation while the other survived (5e). A
distinguishing feature ofthe adducts in Table 1, as opposed
to those in Scheme 2, is the retention and positional shift of
the olefin (exclusively E-configuration by H NMR) in-
dicating a significant variation in the termination step.
1
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Org. Lett., Vol. 13, No. 5, 2011

that the deprotonation was involved as the rate-limiting
step.4a,j,12
Scheme 5. Proposed Mechanism
To clarify the influence of the acidic N-H sulfonamide,
control experiments, utilizing the standard reaction con-
ditions, were conducted using benzamides in which the
tosyl group was replaced by H, Ph, or OMe.13 The results
cogently showed that the acid N-H was essential and
could dramatically improve the reactivity (Scheme 4).
subjecting 10 (mixture of Z/E-olefins) to the standard
annulation conditions (eq 5). The Wacker amination was
complete within a few hours and afforded the anticipated
product 5a irrespective of the original olefin configuration.15
If the parent nitrogen heterocycle is desired, the tosyl can
be conveniently removed in just 0.5 h using sodium
naphthalenide, e.g., 3a to isoindolinone 11 (eq 6).
Scheme 4. Dependency of Reactivity on N-H Acidity
In summary, a tandem process of C-H olefination/
annulation for heterocyclic synthesis is described. Tosyl
amides were employed as a novel directing group to afford
a series of isoindolinones. Impressively, this transforma-
tion is broadly compatible with electron-rich and -deficient
alkenes. For more eco-friendly transformations, molecular
oxygen or even atmospheric air could be used without the
need of other co-oxidants. From a practical point of view,
the only waste is water and thus this transformation meets
the goal of green chemistry. Further applications are on-
going in our group.
Illuminated by the preceding investigations, the postulated
mechanism is depicted in Scheme 5. We speculate that the
increased acidity of the N-H, a consequence of the
combined inductive effects of the carbonyl and tosyl,
facilitates the formation of the Pd-N bond that in turn
promotes the formation of a palladacycle (I). Alkene
insertion leads to intermediate II from which III is derived
via β-H elimination. The electronic properties of the alkenes
determines theultimatefateofIII. Electron-deficient alkenes
likely participate by a Michael addition (path A),6a,7a,8
while nonconjugated alkenes are annulated in a Wacker-type
amination (path B).14 Confirmation was obtained by
Acknowledgment. Financial support was provided by
the Robert A. Welch Foundation (GL625910) and the
NIH (GM31278, DK38226).
Supporting Information Available. Experimental pro-
cedures, characterization data, and spectra of new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) For examples of Pd(II)-mediated C-H activation involving
benzamides, see: (a) Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M.
Tetrahedron Lett. 2000, 41, 2655. (b) Shabashov, D.; Daugulis, O. Org.
Lett. 2006, 8, 4947. (c) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am.
Chem. Soc. 2008, 130, 7190. (d) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc.
2008, 130, 14058. (e) Yeung, C. S.; Zhao., X.; Borduas, N.; Dong, V. M.
Chem. Sci. 2010, 1, 331.
(15) Formation of byproduct isoquinolinone 6 was not observed in
the experiment. It presumably derived from intermediate II via reductive
elimination and subsequent dehydrogenation.
(14) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc.
2005, 127, 17778.
Org. Lett., Vol. 13, No. 5, 2011
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