PdII-catalyzed C-H olefination of N-(2-pyridyl)sulfonyl anilines and arylalkylamines

Article abstract of DOI:10.1002/anie.201105611

Flexible friend: The N-(2-pyridyl)sulfonyl group acts as a removable directing group in the Pd^II-catalyzed aryl C-H ortho alkenylation of N-alkyl aniline, benzylamine, and phenethylamine derivatives with electron-poor alkenes. The products were obtained in high yields (70-90 %) and with complete regiocontrol. The mild reductive N-sulfonyl removal enables the construction of a variety of nitrogen heterocycles. EWG=electron-withdrawing group.

Full text of DOI:10.1002/anie.201105611

DOI: 10.1002/anie.201105611
ꢀ
C H activation
II
ꢀ
Pd -Catalyzed C H Olefination of N-(2-Pyridyl)sulfonyl Anilines and
Arylalkylamines**
Alfonso Garcꢀa-Rubia, Beatriz Urones, Ramꢁn Gꢁmez Arrayꢂs,* and Juan C. Carretero*
ꢀ
The metal-catalyzed direct C H olefination (Fujiwara–Mor-
itani reaction) has emerged as a powerful method for the
introduction of functional diversity and structural complexity
into arene compounds because of its chemical versatility and
its environmental advantages.[1,2] In spite of the tremendous
progress made in this field,[3–7] some important challenges still
remain. Very often the directing groups[1,8] used for promoting
substrates, most notably to N-alkylated and ortho-substituted
anilines, and also enabling a double ortho-alkenylation
process. The flexibility with regard to the tether length of
the directing group allows the extension of this method to the
ꢀ
C H olefination of benzylamines and b-arylethylamines.
At the outset we focused on finding a catalyst system for
the olefination of protected N-methyl aniline, as a model
substrate (Table 1). A set of potentially coordinating protect-
ing groups (PG)[10] were examined in the reaction of
ꢀ
the carbometallation of a proximal C H bond are difficult to
remove, thus compromising the synthetic usefulness of the
procedures. In addition, the tether length of the directing
group is typically found to be crucial for reactivity. A tether
that is one or two atoms longer frequently leads to insufficient
or no reactivity.
ꢀ
Table 1: Screening of a suitable directing group for the direct C H
alkenylation of N-methyl aniline derivatives with butyl acrylate.
Nitrogen-containing products are especially attractive
since they are found in a myriad of natural products and
biologically active molecules. In this regard, NH-acetanilides
and their derivatives have proven to be very effective in
directing Rh-[3] and Pd-catalyzed[4] oxidative olefination. In
the latter case, the reaction is usually restricted to the use of
acrylates as alkene partners and the carbopalladation step
exhibits marked electronic and steric sensitivity, which limit
its applicability. For instance, low yields are usually obtained
from NH-anilides substituted with electron-withdrawing
groups as well from ortho-substituted anilides.[4] Also disfa-
vored for steric reasons are the ortho alkenylation of N-
substituted anilides (instead of NH-anilides), for which a
Entry
PG
Aniline
Product
Yield [%][a]
[b]
1
2
3
4
5
6
Boc
Ts
p-Ns
(8-quinolyl)SO2
(2-pyridyl)SO2
(3-pyridyl)SO2
1
2
3
4
5
6
–
–
–
–
7
–
–
[c]
–
[c]
–
[c]
–
87
[c]
–
[a] Yield of the isolated product after chromatography on silica gel. [b] A
complex mixture was observed (1H NMR spectroscopy). [c] Only starting
material was detected (1H NMR spectroscopy). Boc=tert-butyloxycar-
bonyl ,DCE=dichloroethane, Ns=p-nitrobenzenesulfonyl, Ts=p-tolue-
nesulfonyl.
ꢀ
general protocol is still required, and the double ortho C H
alkenylation to produce bisolefinated anilines.[3a] Examples of
[5]
ꢀ
direct C H alkenylation of benzylamine derivatives are
even scarcer, in spite of their great synthetic value.
Herein, we report a general procedure for the Pd-
ꢀ
catalyzed C H olefination of aniline derivatives with elec-
substrates 1–6 with butyl acrylate under Pd(OAc)2 catalysis
(10 mol%)[11] using N-fluoro-2,4,6-trimethylpyridinium tri-
flate (2.0 equiv) as an oxidant[12] in DCE[13] at 1108C. The N-
Boc derivative 1 led to a complex mixture of products
(entry 1). Switching to an N-Ts group (2) or an N-Ns group (3)
led to the recovery of the starting material, even after
24 hours (entries 2 and 3), and an identical disappointing
result was obtained with the N-(8-quinolyl)sulfonyl aniline 4
(entry 4). Pleasingly, the N-(2-pyridyl)sulfonyl[9] group (5)
provided complete conversion and ortho regiocontrol, thus
affording 7 in 87% yield upon isolation (entry 5). The absence
of any reaction in the case of the N-(3-pyridyl)sulfonyl
derivative 6, an isomer of 5, highlights the key role of the 2-
pyridylsulfonyl group likely involved in the formation of the
presumed palladated intermediate.[14]
tron-poor alkenes that relies on the use of the 2-pyridylsul-
fonyl group as a protecting and directing group,[9] thus
expanding the scope of this reaction to difficult-to-activate
[*] A. Garcꢀa-Rubia, B. Urones, Dr. R. Gꢁmez Arrayꢂs,
Prof. Dr. J. C. Carretero
Departamento de Quꢀmica Orgꢂnica, Facultad de Ciencias
Universidad Autꢁnoma de Madrid (UAM)
Cantoblanco 28049 Madrid (Spain)
E-mail: ramon.gomez@uam.es
juancarlos.carretero@uam.es
[**] This work was supported by the Ministerio de Ciencia e Innovaciꢁn
(MICINN; projects CTQ2006-01121 and CTQ2009-07791) and the
Consejerꢀa de Educaciꢁn de la Comunidad de Madrid (programme
AVANCAT; S2009/PPQ-1634). A.G.-R. and B.U. thank the MICINN
for a predoctoral fellowship. We also thank Johnson Matthey PLC for
a generous supply of Pd(OAc)2.
The structural versatility of the N-alkyl group (R) and of
the alkene component was next explored (Scheme 1). Other
N-alkyl groups such as n-butyl (substrate 8) or the function-
alized N-CH2CO2Me group (substrate 9) are equally well
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105611.
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Scheme 1. Versatility of the N-alkyl group and olefin scope in the
ortho alkenylation of N-(2-pyridyl)sulfonyl anilines. Reaction conditions:
substrate (0.15 mmol), Pd(OAc)2 (10 mol%), N-fluoro-2,4,6-trimethyl-
pyridinium triflate (2 equiv), alkene (1-2 equiv), DCE, 1108C, 12 h.
[b] 5 equiv of methyl acrylate were used. EWG=electron-withdrawing
group, [F+]=N-fluoro-2,4,6-trimethylpyridinium triflate.
tolerated, leading to the corresponding olefinated products in
high yields (10 and 11 in 86% and 91% yield, respectively).[15]
Regarding the olefin scope, not only acrylates but also a
variety of monosubstituted electrophilic alkenes including
acrylic acid, vinyl sulfones, vinyl phosphonates, and vinyl
nitriles (1–2 equiv) reacted efficiently with N-(2-pyridyl)sul-
fonyl anilines 5 (N-Me) and 9 (N-CH2CO2Me), leading to the
corresponding monoalkenylated products in high yields upon
isolation (typically ꢁ 80%). Unfortunately, nonactivated
alkenes such as styrene failed to provide high conversions.
Under the reaction conditions shown in Scheme 1, in
some cases the formation of a minor amount of the
Scheme 3. Structural variations to the aniline counterpart. Reaction
conditions: substrate (0.15 mmol), Pd(OAc)2 (10 mol%), N-fluoro-
2,4,6-trimethylpyridinium triflate (2-3 equiv), alkene (1-2 equiv), DCE,
1108C, 12 h. [a] 5 equiv of methyl acrylate were used.
ing result as such substituents are versatile handles for further
transformations by cross-coupling. In some cases, under the
optimal reaction conditions the monoolefination product was
accompanied by roughly 5% of the ortho-diolefinated
product, which could be readily separated by flash chroma-
tography. High regiocontrol was observed in meta-substituted
1
diolefinated product was detected by H NMR spectroscopy.
Interestingly, increasing the amount of both the alkene and
the oxidant to 3 equivalents resulted in a clean diolefination
reaction (products 19 and 20 in 81% and 75% yield,
respectively; Scheme 2).[16]
ꢀ
anilines, in favor of the C H functionalization at the sterically
less-hindered ortho-position (products 27–29, 67–73% yield).
Notably, 1- and 2-naphthalenamine derivatives were also
amenable to the olefination reaction, which proceeded with
high selectivity at the more-accessible position (products 30–
32, 84–89% yield). Excellent catalyst performance was noted
with especially challenging aniline substrates, including those
bearing a strong electron-withdrawing substituent[18] (e.g. CF3
and CO2Me; products 25 and 26 in 70% and 73% yield,
respectively) and ortho-substituted products (33–35, 81–91%
yield), although for products 34 and 35 3 equivalents of
oxidant were required for complete conversion.
Scheme 2. ortho-Dialkenylation of aniline derivative 5.
ꢀ
This C H olefination protocol was then tested on a
variety of N-(2-pyridyl)sulfonyl aniline derivatives, having
either a N-Me or a N-CH2CO2Me group, with butyl or methyl
acrylate (Scheme 3). A broad range of para-, meta-, and
ortho-substituted aryl rings with diverse steric and electronic
properties (ether, alkyl, halide, and ester groups) can be
readily exploited in this procedure, thus affording the
corresponding olefinated products in yields typically above
70%.[17] Halides, such as chloride and bromide, survived
under the reaction conditions; this is a synthetically interest-
The high reactivity of this method prompted us to test its
ꢀ
applicability to the C H alkenylation of arylalkylamine
derivatives. The reaction of N-methyl-N-(2-pyridyl)sulfonyl
benzylamine (38) and N-methyl-N-(2-pyridyl)sulfonyl phe-
nethylamine (42) with butyl acrylate under the optimized
reaction conditions occurred cleanly to give the correspond-
ing alkenylated products 39 and 43 in good yield (81% and
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87%, respectively; Scheme 4). The higher reactivity displayed
by substrates 38 and 42 compared to that of the aniline
derivatives made it necessary to adjust the amount of butyl
withdrawing (F) nature of the attached groups and the
substitution pattern, including ortho-substituted arenes.
The easy reductive removal of the N-(2-pyridyl)sulfonyl
directing group under acidic conditions (Zn powder, 1:1 THF/
sat. aq NH4Cl) enables access to different nitrogen-containing
skeletons (Scheme 6).[19] The treatment of sulfonyl aniline
olefinated adducts 7 and 15 with Zn powder led to the
Scheme 4. Extension to arylalkylamine derivatives.
acrylate to 1.1 equivalents to minimize the formation of the
diolefinated product. At this point we confirmed again the
key directing role of the 2-pyridylsulfonyl unit, as demon-
strated by the lack of reactivity of the related N-tosyl
protected substrates 36 and 40.
As shown in Scheme 5, the range of electrophilic alkenes
amenable to the reaction with substrate 38 (R = H) includes
not only acrylates but also vinyl sulfones, vinyl sulfonates, and
vinyl phosphonates, and the corresponding monoolefinated
products are furnished with consistently good yields (products
44–46, 71–80% yield). Steric and electronic modifications to
the aryl substrate were also explored for the benzylamine
series, with butyl acrylate as the alkene counterpart
(Scheme 5; products 47–51). The olefination reaction
proved to be rather general (yields typically above 70%)
regardless of the electron-donating (Me, OMe) or electron-
Scheme 6. N-(2-pyridyl)sulfonyl removal.
corresponding free amino derivatives 52 and 53 in good yield
(72% and 65%, respectively). The deprotection of sulfon-
amide products possessing one or two carbons between the
nitrogen atom and the aryl moiety simultaneously triggers the
cyclization of the free amines under the reaction conditions,
thus allowing the rapid construction of isoindoline (54 and 55)
and tetrahydroisoquinoline (56) bicyclic frameworks in syn-
thetically useful yields (57–78%; Scheme 6).
Scheme 7 shows the three-step transformation of the
olefinated aniline products with an N-CH2CO2Me group into
functionalized indoles, thus exploiting the reactivity of a
functionalized N-alkyl substituent. The indoline skeleton was
assembled by an intramolecular Michael addition of the ester
enolate (LHMDS, THF, 08C) and subsequent reductive
desulfonylation (Mg turnings, MeOH, sonification). Aroma-
tization of the resulting NH-indoline with DDQ afforded the
corresponding indole in acceptable overall yields (57–60, 58–
63% yield). This Mg-promoted N deprotection is compatible
with sensitive functional groups (Cl and CO2Me, products 58
and 59, respectively). In the case of aniline 14, bearing an a,b-
unsaturated phenylsulfone moiety, the application of this
Scheme 5. Olefin scope and structural variations to the benzylamine
counterpart. Reaction conditions: substrate (0.15 mmol), Pd(OAc)2
(10 mol%), N-fluoro-2,4,6-trimethylpyridinium triflate (2.0 equiv),
alkene (1-2 equiv), DCE, 1108C, 12 h. [b] 3.0 equiv of oxidant were
required for complete conversion. [F+]=N-fluoro-2,4,6-trimethylpyridi-
nium triflate.
Scheme 7. Application to indole synthesis.
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ꢀ
[6] For selected references on metal-catalyzed C H olefination of
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both N and C desulfonylation with Mg/MeOH (63% overall
yield for the three steps).
In summary, a general and reliable method for the PdII-
ꢀ
catalyzed ortho C H olefination of N-alkyl aniline, benzyl-
amine, and phenethylamine derivatives enabling the gener-
ation of relevant nitrogen-containing architectures, such as
indoles, isoindolines or tetrahydroisoquinolines, is described.
This protocol relies on the N-(2-pyridyl)sulfonyl group as a
directing and removable protecting group and features
remarkable tolerance with regard to the tether length,
alkene partner, and steric and electronic substitution on the
arene, including electron deficient and ortho-substituted
arenes. In addition, the double ortho-alkenylated products
can be also obtained in good yields. Mechanistic studies, as
well as further exploration of the synthetic potential of this
ꢀ
[7] For other selected C H olefination protocols, see: a) K. M.
Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2010, 122, 6305;
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Wang, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 14137; c) Y. Lu, D.-
H. Wang, K. M. Engle, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132,
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2010, 327, 315; e) S. Mochida, K. Hirano, T. Satoh, M. Miura,
Org. Lett. 2010, 12, 5776; f) T.-J. Gong, B. Xiao, Z.-J. Liu, J. Wan,
J. Xu, D.-F. Luo, Y. Fu, L. Liu, Org. Lett. 2011, 13, 3235; g) S. H.
Park, J. Y. Kim, S. Chang, Org. Lett. 2011, 13, 2372; h) T.
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Brasse, R. G. Bergman, J. A. Ellman, Org. Lett. 2011, 13, 540.
[8] For a review on removable directing groups in synthesis and
catalysis, see: a) G. Rousseau, B. Breit, Angew. Chem. 2011, 123,
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ces [7e,i,j and 9].
ꢀ
novel C H bond functionalization platform are underway in
our laboratory.
Received: July 13, 2011
Published online: September 22, 2011
ꢀ
Keywords: 2-pyridyl sulfonamides · aniline · C H activation ·
olefination · palladium
.
[1] For a recent review, see: a) The Mizoroki-Heck Reaction (Ed.:
M. Oestreich), Wiley, Chichester, 2009; for selected recent
ꢀ
reviews on direct C H functionalization, see: b) R. Giri, B. F.
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ꢀ
[9] For previous use of N-(2-pyridyl)sulfonyl group in the direct C
H functionalization of indoles and pyrroles, see: a) A. Garcꢁa-
Rubia, R. Gꢂmez Arrayꢃs, J. C. Carretero, Angew. Chem. 2009,
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ꢀ
[10] The use of the unprotected N-methyl aniline in the C H
olefination with butyl acrylate under various reaction conditions
failed to provide the desired product. Only decomposition
products were observed.
[11] Investigation of catalyst loading in the reaction of 5!7 under
the optimized reaction conditions shown in Table 1 revealed no
conversion in the absence of a Pd catalyst, while 57% and 90%
conversion was observed in the presence of 2 mol% and 5 mol%
of Pd(OAc)2, respectively.
[4] a) M. D. K. Boele, G. P. F. van Strijdonck, A. H. M. de Vries,
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[12] N-fluoro-2,4,6-trimethylpyridinium triflate has been used as an
ꢀ
oxidant in Pd-catalyzed C H fluorination, trifluoromethylation,
ˇ
Repic, T. J. Blacklock, Adv. Synth. Catal. 2005, 347, 1921; c) J.-R.
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b) X. Wang, T.-S. Mei, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131,
7520.
ꢀ
C H activation processes provided unpractical conversions,
whereas very low reactivity was observed with weaker oxidants
such as Cu(OAc)2, Cu(OTf)2, and benzoquinone.
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[13] Acetic acid was also a suitable solvent (100% conversion after
18 h). In contrast, a very low reactivity was observed in other
polar solvents such as CH3CN, N,N’-dimethylformamide, and
dimethylacetamide.
that substrates having electron-donating substituents are more
reactive than those substituted with electron-withdrawing
groups (see the scheme below, product ratio 21/25,
k
pꢀMe=kpꢀCF ¼12).
3
[14] For a recent example, in which the participation of seven-
[19] For the hydrolysis of ureas used as directing groups, see: C. E.
Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G. Tyler,
ꢀ
membered-palladacycle intermediates in Pd-catalyzed C H
functionalization is implicated, see: G.-W. Wang, T.-T. Yuan,
D.-D. Li, Angew. Chem. 2011, 123, 1416; Angew. Chem. Int. Ed.
2011, 50, 1380.
[15] The unsubstituted NH-N-(2-pyridyl)sulfonyl aniline proved to
be unreactive under the optimized Pd-catalyzed reaction
conditions.
[16] For the Pd-catalyzed diolefination reaction of benzylsulfona-
ꢀ
mides, see reference [6e]. For aryl C H diolefination of
carboxylic acid derivatives, see references [7a and b].
ꢀ
[17] This C H olefination protocol can be scaled up by 10 times
M. R. Gagnꢄ, G. C. Lloyd-Jones, K. I. Booker-Milburn, Angew.
Chem. 2009, 121, 1862; Angew. Chem. Int. Ed. 2009, 48, 1830. To
(from 0.15 mmol to 1.5 mmol scale) with similar efficiency. For
example, the reaction of 9 (459 mg, 1.5 mmol) with phenyl vinyl
sulfone afforded 16 (576 mg) in 81% yield (83% yield on
0.15 mmol scale).
ꢀ
the best of our knowledge, in previous reports on the C H
alkenylation of NH-acetanilides (references [3a and 4]), the final
N deprotection of the amide products, having a potentially
sensitive a,b-unsaturated ester, has not been described.
ꢀ
[18] As noted in previous Pd-catalyzed C H alkenylations of NH-
acetanilides (reference [4]), competition experiments showed
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