New heteroannulation reactions of N-Alkoxybenzamides by Pd(II) Catalyzed C-H activation

Article abstract of DOI:10.1021/ol202187h

A new palladium(II) catalyzed methodology for the direct synthesis of alkylidene isoindolinones from N-alkoxybenzamides is presented. Isoindolinone formation proceeds through a highly efficient and E-selective C-H activation/Heck/Aza-Wacker sequence. Subs

Full text of DOI:10.1021/ol202187h

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5326–5329
New Heteroannulation Reactions of
N-Alkoxybenzamides by Pd(II) Catalyzed
CꢀH Activation
Joe W. Wrigglesworth,† Brian Cox,‡ Guy C. Lloyd-Jones,*,† and
Kevin I. Booker-Milburn*,†
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K., and
Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, RH12 5AB,
U.K.
k.booker-milburn@bristol.ac.uk; guy.lloyd-jones@bristol.ac.uk
Received August 11, 2011
ABSTRACT
A new palladium(II) catalyzed methodology for the direct synthesis of alkylidene isoindolinones from N-alkoxybenzamides is presented.
Isoindolinone formation proceeds through a highly efficient and E-selective CꢀH activation/Heck/Aza-Wacker sequence. Substoichiometric
amounts of benzoquinone can be employed in a cooperative oxidation system with O2, leading to facile purification of products. Modification of the
reaction conditions provides a general route to substituted phthalimides by carbonylation with CO. Both systems were found to tolerate a wide
range of functionality.
New efficient methods for the synthesis of highly sub-
stituted heterocycles continue to be an area of intense
activity, especially in the context of natural product related
substructures and medicinal chemistry.1 Recently, transi-
tion metal catalyzed CꢀH activation has become a domi-
nant theme for the synthesis of heterocyclic systems as it
avoids the requirement of (pseudo)halide heteroaryl sub-
strates in conventional Pd(0) catalyzed sequences.2 We
recently reported the development of a palladium(II)-cata-
lyzed indoline synthesis proceeding via a urea directed CꢀH
activation/1,2 carboamination sequence (Scheme 1) .3
Scheme 1. Urea Directed CꢀH Carboamination of 1,3-Dienes
† University of Bristol.
‡ Novartis Institutes for Biomedical Research.
(1) Phthalimide natural products: (a) Zhang, X.; Ye., W.; Zhao, S.;
Che, C.-T. Phytochemistry (Elsevier) 2004, 65, 929–932. (b) Chang,
L. C.; Bhat, K. P. L.; Pisha, E.; Kennelly, E. J.; Fong, H. H. S.; Pezzuto,
J. M.; Kinghorn, A. D. J. Nat. Prod 1998, 61, 1257–1262. (c) Phuwa-
praisirisan, P.; Rangsan, J.; Tip-Pyang, S.; Siripong, P. Nat. Prod. Res.
2009, 23, 1063–1071. Isoindolinone natural products:(e) Sener, B.;
Goezler, B.; Minard, R. D.; Shamma, M. Phytochemistry (Elsevier)
1983, 22, 2073–6. (f) Efdi, M.; Fujita, S.; Inuzuka, T.; Koketsu, M. Nat.
Prod. Res. 2010, 24, 657–662.
(2) Recent review on Pd(II) CꢀH activation: (a) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169. (b) Chen, X.; Engle,
K. M.; Wang, D.-L.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094–
5115. Other TM catalyzed CꢀH activation:(c) Colby, D. A.; Bergman,
R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (d) Stuart, D. R.;
Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326–
18339. (e) Satoh, T.; Ueura, K.; Miura, M. Pure Appl. Chem. 2008, 80,
1127–1134.
We have now elaborated this concept so as to generate
isoquinolones from dienes and benzamides. Initial tests
with simple benzamides resulted in no diene addition
products, even at elevated temperatures and with high
catalyst loadings. The ability of N-methoxyamides to facil-
itateCꢀH activation on sp3 and sp2 centers hasbeenamply
ꢀ
(3) Houlden, C. E.; Bailey, C. D.; Ford, G.; Gagne, M.; Lloyd-Jones,
G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066–10067.
r
10.1021/ol202187h
Published on Web 09/12/2011
2011 American Chemical Society

demonstrated, most notably through studies by Yu.4 More
recently, the work of Fagnou,5 Glorius,6 and Li7 has
proven the generality of this moiety as a CꢀH activating
group.
Switching from simple benzamides to N-alkoxy benza-
mides 1 led to the desired reactivity, and a number of
isoquinolinones 3 were generated, albeit in low to moder-
ate yields. The best results were obtained by exploiting a
cooperative oxidation system,8 whereby only 20 mol % of
benzoquinone (BQ) was required when the reactions were
carried out under an atmosphere (balloon) of O2 (Table 1).
via an efficient aza-Wacker reaction,10 and Zhu and Falck11
have disclosed related findings concerning the formation of
saturated isoindolinones via efficient CꢀH activation/Heck
reactions of NTs benzamides. The formation of alkylidene
isoindolinone 4a is likely the result of a sequential CꢀH
activation/Heck/intramolecular aza-Wacker sequence, pro-
ceeding with exceptional E-selectivity.
After some optimization (Table 2), the isoindolinone 4a
was obtained in excellent yield. In the absence of O2, at
least 2 equiv of BQ were required (entries 1ꢀ6) indicating
that two distinct Pd(0)fPd(II) redox steps are involved in
the sequence. The use of the 20 mol % BQ/O2 system gave
Table 1. Methoxybenzamide Directed Carboamination of 1,3-
Dienes
Table 2. Methoxybenzamide Directed E-Selective Carboami-
nation of Butyl Acrylate: Optimization Study
yield of
entry
R
R0
Z
3 (%)
temp
yield
(%)b
1a
2a
3a
4a
5b
6b
7b
8b
9b
H
H
H
H
H
Me
Et
Ph
10
7
entry
(°C)
oxidant
Ph
1
120
120
110
90
BQ 1 equiv, N2
BQ 2.5 equiv, N2
BQ 2.5 equiv, N2
BQ 2.5 equiv, N2
BQ 1 equiv, air
BQ 3 equiv, N2
O2
32
67
76
55
63
79
21
85
90
95
74
9
iPr
Me
Me
Me
Me
Me
Me
Ph
6
2
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
3
3
64
35
49
50
52
4
6-Me
5
110
110
110
110
110
110
110
110
5-Mec
4-Me
6
7
5-OMed
8
BQ 3 equiv, O2
BQ 0.5 equiv, O2
BQ 0.2 equiv, O2
BQ 0.1 equiv, O2
HQ 0.2 equiv, O2
9
a (MeCN)2PdCl2 10 mol %, Oxone 0.7 equiv, 1,2-DCE, 80 °C, 24 h.
b Pd(OAc)2 10 mol %, BQ 20 mol %, O2, AcOH, 110 °C, 24ꢀ48 h. c 17:3
ratio of 5- vs 3-Me isomers. d 5:4 ratio of 5- vs 3-OMe isomers.
10
11
12
a Pd(OAc)2 5 mol %, N-methoxybenzamide (0.5 mmol), butyl acry-
Despite extensive studies, we were unable to expand the
scope or increase the yields outside of those described in
Table 1. To probe the CꢀH activation step, we tested an
oxidative Heck type coupling9 of N-methoxybenzamide 1a
with butyl acrylate instead of 1,3-diene 2. Surprisingly, this
led to generation of the annulated ring system 4a. We
recently described the formation of heterocyclic systems
late (1 mmol), AcOH (4 mL), 24 h. b Isolated yields
the best results (entry 10). Not only was the yield of 4a
highest with this procedure, but the product was also sig-
nificantly easier to purify. The reaction was highly tolerant
of solvent/reagent quality; indeed, laboratory grade re-
agents can be used without further purification, while
3
˚
addition of external desiccants (Ac2O or 4 A sieves) de-
creased catalyst turnover.
(4) Wang, D.-H.; Wasa, M.; Giri., R.; Yu, J.-Q. J. Am. Chem. Soc.
2008, 130, 7190–7191.
(5) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010,
132, 6908–9.
(6) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem.
Soc. 2011, 133, 2350–2353.
(7) (a) Wang, G.-W.; Tuan, T.-T. J. Org. Chem. 2010, 75, 476–479.
(b) Wang, G.-W.; Yuan, T.-T.; Li, D.-D. Angew. Chem., Int. Ed. 2011,
50, 1380–1383.
(8) (a) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010,
327, 315–319. (b) Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
14137–14151. (c) Decharin, N.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133,
5732–5735.
(9) (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. J. Am. Chem. Soc. 2002,
124, 1586–1587. (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318–5365.
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Booker-Milburn, K. I. Org. Lett. 2011, 13, 728–731.
With these optimized conditions in hand we explored the
scope of the reaction with a variety of substituted N-
alkoxybenzamides and alkenes (Scheme 2). With the par-
ent system 1a it was found that electron-deficient alkenes
made the bestcouplingpartners, althoughevenstyrenewas
found to give moderate yields of cyclized product 4g. For
example, 4u and 4v proved interesting cases as saturated
products, similar to Zhu and Falck, were obtained. In these
cases we suspect that ring closure proceeds via a Michael
addition, rather than via Pd(II) catalysis (vide infra). With
(11) Zhu, C.; Falck, J. R. Org. Lett. 2011, 13, 1214–1217.
Org. Lett., Vol. 13, No. 19, 2011
5327

have previously found, aryl nitro substitution has a detri-
mental effect on CꢀH activation.3,14 We have also found
that substitution ortho- to a urea CꢀH activating group
impairs the directing ability of that group;14 a similar
situation likely exists in the case of 4l. Finally, the use of
other N-alkoxybenzamides was much less successful (4r
and 4s), suggesting that the smaller, less sterically demand-
ing ꢀOMe group plays a key role in directing the CꢀH
insertion of Pd(II).
Scheme 2. Scope of N-Alkoxybenzamide Directed Synthesis of
E-Alkylidene Isoindolinones
Attention was then turned to the likely sequence of
events involved in the reaction (1f4). Hydrogenation of
4a gave 6a, which was inert when tested under the standard
heteroarylation conditions (Scheme 3) ruling out the inter-
mediacy of alkyl isoindolinones (6) during the catalytic
cycle. The putative CꢀH activation Heck product 7a was
prepared15 in order to assess its potential intermediacy in
the reaction sequence. N-Methoxybenzamide 1k was re-
acted with butyl acrylate for 15 min under the standard
conditions, to ensure that turnover had ensued, and then
7a was added (Scheme 3). This yielded both isoindolinones
4a and 4k, confirming the potential viability of 7a as an
intermediate in the sequence.
Scheme 3. Investigation of Possible Reaction Intermediates
t-Bu acrylate the major product was the decarboxylated
alkene 4t. This was also the only product isolated when
acrylic acid was used, suggesting that in the former case the
initial product 4c undergoes acid catalyzed t-Bu elimina-
tion followed by decarboxylation.12 The aryl ring proved
tolerant to substitution, and in most cases moderate to
excellent yields of heteroannulated product were formed.
In all examples only the E-alkene was observed.13 The
reactions also proceeded with complete regioselectivity as
evidenced by examples 4j and 4m.
On the basis of these preliminary experiments, a plau-
sible mechanism can be proposed (Figure 1) in which MeO
directed CꢀH insertion of Pd(II) leads to the palladacycle
I. This can then undergo a Heck type addition to II and
then a β-hydride elimination to generate 7. A second
Pd(II)-catalytic cycle effects an aza-Wacker sequence, in
which 7 is cyclized to III, followed by CꢀC rotation and
then β-hydride elimination to generate alkylidene isoindo-
linone 4. The overall E-selectivity of the reaction is con-
sistent with a stereospecific aza-Wacker reaction involving
the E-alkene intermediate 7and proceeding via the syn-amino
palladation mechanism described by Stahl.16 In the case of
4u and 4v (Scheme 2), intermediates 7u and 7v (Z = COMe
In the cases of 4l and 4n consistently low yields were
obtained, despite several repeat reactions. With 4n, as we
(12) A plausible decarboxylation mechanism is decribed below:
(15) See Supporting Information.
(16) (a) Ye, X.; Liu, G.; Popp, B. V.; Stahl, S. S. J. Org. Chem. 2011,
76, 1031–1044. (b) McDonald, R. I.; White, P. B; Weinstein, A. B.; Tam,
C. P.; Stahl, S. S. Org. Lett. 2010, 13, 2830–3. (c) Liu, G.; Stahl, S. S.
J. Am. Chem. Soc. 2007, 129, 6328–6335. (d) Rogers, M. M.; Kotov, V.;
Chatwichien, J.; Stahl, S. S. Org. Lett. 2007, 9, 4331–4334. (e) Wolfe,
J. P. Chem.;Eur. J. 2007, 4, 571–82.
€
(13) E-selectivity confirmed by nOe spectroscopy and X-ray crystal-
lography; e.g., see data for 4b and 4e in Supporting Information.
(14) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler,
ꢀ
S. N. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I.
Angew. Chem., Int. Ed. 2009, 48, 1830–1833.
5328
Org. Lett., Vol. 13, No. 19, 2011

and COPh, respectively) would be R,β-unsaturated ketones,
rather than esters, and more susceptible to a non-Pd cata-
lyzed Michael addition, thus generating alkyl rather than
alkenylidene isoindolinones.
substitution or steric hindrance at the N-center decrease the
yield. Compared to the isoindolinones in Scheme 2, both the
m-methyl- and m-methoxy-N-methoxybenzamide examples
displayed a slight loss of regioselectivity. Although the yields
of the corresponding phthalimides were excellent, small
Scheme 4. Carbonylation of N-Alkoxybenzamides
Figure 1. CꢀH activation/Heck/aza-Wacker mechanism.
Previously we14 and others17 have demonstrated the via-
bility of carbonylation sequences for the synthesis of het-
erocycles and functionalization of arenes via CꢀH activa-
tion. We thus explored whether an analogous procedure
using N-methoxybenzamides would provide a direct route
to substituted phthalimides.
Initial tests using 1a and catalytic BQ under O2/CO gave
low conversions (18% by NMR), whereas using 2 equiv of
BQ under 1 atm of CO allowed the isolation of N-meth-
oxyphthalimide 8a in good yield (Scheme 4). Interestingly,
the reaction proved to be very sensitive to the solution-
phase CO concentration; increasing the CO pressure (2ꢀ4
atm) or diluting with N2 (1:1) resulted in reduced yields.
Even the mass-transfer rate had an impact, with lower
solution phase surface area giving better results; the “Re-
duced volume” Radleys tubes were found to be optimal,
whereas reactions in a standard round-bottom flask under
identical conditions resulted in consistently poor yields
of 8a.
amounts of the regioisomers 8b and 8j could be isolated.
This result would appear to indicate that different active Pd
species are involved in the CꢀH insertion step, as compared
to the reactions generating isoindolinones (Scheme 2).
In summary, we have demonstrated the efficacy of the
N-methoxyamide moiety as a CꢀH activating group in a
new synthesis of isoindolinones. The reaction is notable for
using low BQ loadings (20 mol %) and is E-selective. The
reaction conditions can also be modified to provide a general
route to substituted phthalimides by carbonylation with CO.
These optimized conditions were then applied to a variety
of substituted N-methoxybenzamides (Scheme 4). Once
again the general trend was that electron-donating groups
afford the products in highest yields, whereas aryl NO2
Acknowledgment. We would like to thank EPSRC and
Novartis for funding. G.C.L.J. is a Royal Society Wolfson
Research Merit Award holder.
(17) (a) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082.
(b) Giri, R.; Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 686.
(c) Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem.,
Int. Ed. 2010, 49, 7316. (d) Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 17378–80. (e) Haffermayer, B.; Gulias, M.; Gaunt, M. J.
Supporting Information Available. Detailed experimen-
tal procedures and spectral characterization of all pro-
ducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ
Chem. Sci. 2010, 2, 312–5. (f) Lopez, B.; Rodriguez, A.; Santos, D.;
Albert, J.; Ariza, X.; Garcia, J.; Granell, J. Chem. Commun. 2011, 47,
1054–6.
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