Pd-catalyzed sequential C-C and C-N bond formations for the synthesis of N-heterocycles: Exploiting protecting group-directed C-H activation under modified reaction conditions

Article abstract of DOI:10.1002/asia.201100024

Easy & efficient: A Pd-catalyzed domino olefination/conjugate addition reaction of N-Ts-2-arylanilines with activated olefins has been achieved at ambient temperature under the newly defined reaction conditions. This process highlighted the directing effect of the N-protecting group in C-H activation, displayed broad substrate scope with wide functional group compatibility; thus rendering a straightforward entry to a wide variety of N-heterocycles such as dihydrophenanthridines.

Full text of DOI:10.1002/asia.201100024

COMMUNICATION
DOI: 10.1002/asia.201100024
À
À
Pd-Catalyzed Sequential C C and C N Bond Formations for the Synthesis
À
of N-Heterocycles: Exploiting Protecting Group-Directed C H Activation
under Modified Reaction Conditions
Byung Seok Kim,[a] Sun Young Lee,[b] and So Won Youn*[a]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
In the search for an atom economical and eco-friendly
chemical process, direct activation and subsequent function-
in stark contrast to acetyl- or benzoyl-protected anilines,
aryl sulfonamides underwent an analogous Fujiwara–Mori-
tani reaction with an activated olefin to afford dihydrophe-
nanthridines as the sole product. This observation can be
À
alization of C H bonds in aromatic compounds have attract-
ed significant attention as the method of choice and impli-
cated wide spread synthetic applications.[1] In particular, oxi-
dative cross-coupling reactions between arenes and olefins,
commonly known as the Fujiwara–Moritani reaction,[1c,g,2] is
a powerful variant of the classical Mizoroki–Heck reaction[3]
that obviates the need for the use of aryl halides and allevi-
ates the generation of salt waste. In general, regioselectivity
of the Fujiwara–Moritani reaction can be achieved either
through the introduction of a coordinative functionality,[4] or
by the use of external ligands.[5]
À
mechanistically rationalized through an initial C H activa-
tion at the C2’-position, followed by a subsequent palladi-
um-catalyzed olefination and an intramolecular conjugate
addition reaction (Scheme 1, route B).[7] Although a closely
related process has been previously reported by Miura and
co-workers, however, the prolonged reaction time at elevat-
ed temperature under a basic reaction medium could pres-
ent limitations to the substrate scope and practicality.[7a]
More recently, related examples of PdII-[8] and RhIII-cata-
lyzed[9] domino intermolecular olefination/intramolecular
cyclization reactions of amides or benzoic acids with activat-
ed olefins have also appeared in the literature, which further
vindicates the importance and growing interest of this con-
stantly evolving synthetic technology.
Recently, we reported a highly effective palladium-cata-
lyzed ortho-olefination reaction of acetanilides with unpre-
cedented substrate scope.[6] When 2-arylacetanilides were
used as the substrate, reactions with activated olefins pro-
ceeded smoothly at room temperature to afford a variety of
2-alkenyl-6-arylacetanilides in moderate to good yields. In
Transition-metal catalyzed domino annulation reactions
are powerful methods to synthesize a variety of cyclic com-
pounds, in which a single catalyst serves to promote multiple
bond-forming events in a one-pot operation.[10] In parallel
with our efforts towards developing efficient synthetic meth-
ods for the preparation of heterocycles,[10g–h,11] we became
À
this process, the initial C H activation at the C2-position
was well tolerated in spite of the high steric hindrance
around the reaction center (Scheme 1, route A). During the
course of our earlier investigations, we also uncovered the
effect of N-protecting groups in directing the regiochemical
outcome of the Fujiwara–Moritani reaction. In this context,
À
À
interested in processes that involve sequential C C and C
N bond formations to afford nitrogen-containing cyclic
structures. In view of the prevalence of N-heterocyclic
motifs in both natural and designed bioactive substances,[12]
such synthetic methodology is particularly valuable. Here,
we report a palladium-catalyzed domino reaction of N-Ts-2-
arylanilines with activated olefins that involves a directed
[a] B. S. Kim, Prof. Dr. S. W. Youn
Department of Chemistry and Research Institute
for Natural Sciences
Hanyang University
Seongdong-Gu, Seoul 133-791 (Korea)
Fax : (+82)2-2299-0762
E-mail: sowony73@hanyang.ac.kr
À
À
C H activation, C C bond formation, and intramolecular
conjugate addition reaction to generate dihydrophenanthri-
dines as a privileged structural motif. In particular, the
modified reaction conditions described herein significantly
improved the efficiency and practicality of this transforma-
tion, and could prove complementary to the earlier report[7a]
[b] S. Y. Lee
Department of Chemistry
Pukyong National University
Nam-Gu, Busan 608-737 (Korea)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100024.
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Chem. Asian J. 2011, 6, 1952 – 1957

whereas a control experiment
employing pTsOH as the sole
source of acid in dichlorome-
thane only afforded recovered
starting material. These results
suggest that pTsOH serves as
an additive to enhance either
the catalytic activity of the pal-
ladium species or the efficiency
of the catalytic cycle,[14] whereas
TFA is essential for product
À
formation through a C H acti-
vation-coupling reaction. An
optimal reaction condition was
established that consisted of a
TFA/CH2Cl2 (1:3) solvent mix-
ture and one equivalent of
pTsOH; reducing either the
amount of TFA or pTsOH is
compensated with a longer re-
action time (ꢀ10 h for 2a) in
order for the reaction to reach
À
Scheme 1. Pd-catalyzed oxidative cross-coupling between 2-arylanilines and activated olefins: C H activation
at the C2- versus C2’-position.
in the case of base-sensitive substrates. The unique directing
completion with acceptable yields. Lastly, Pd
to be the most effective palladium catalyst for this reaction,
and no reaction was observed in the absence of Pd(OAc)2.
ACHTUNGRTENUN(NG OAc)2 proved
À
effect of the N-protecting group in C H activation is equally
noteworthy.
ACHTUNGTRENNUNG
In our preliminary studies, free and protected 2-phenyla-
nilines were subjected to our standard reaction conditions
(PdACHTUNGTRENNUNG(OAc)2, K2S2O8 in CF3CO2H (TFA) at ambient tempera-
Table 1. Pd-catalyzed domino olefination-conjugate addition reaction of
2-arylanilines with activated olefins.
ture) in the presence of methyl acrylate, and the results are
shown in Table 1. As expected based on our earlier observa-
tions, the effectiveness of the sulfonyl protecting group was
immediately apparent. The para-toluenesulfonyl (Ts) group
was revealed as the protecting group of choice for the pro-
posed transformation (Table 1, entries 1–8).[6,13] Considering
the previously reported work that generally required high
reaction temperatures under basic conditions,[7] our initial
result was particularly encouraging, as product 2a was af-
forded at ambient temperature albeit in low yield (45%
yield by 1H NMR spectroscopy). Prompted by this initial
result, we set out to identify optimal conditions, and this
began with a systematic examination of the reaction param-
eters.
Entry
PG
R
R’
t [h]
Yield [%][a]
[b]
1
2
3
4
5
6
7
8
Ac
Bz
Boc
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
36
36
36
36
36
36
36
36
4
5
3
9
6
–
–
–
–
[b]
[c]
[c]
Ts (1a)
PhSO2
p-ClC6H4SO2
Ms
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
(45)[d] (2a)
(35)[d]
(40)[d]
(25)[d]
9
79 (2a)
95 (2b)
88 (2c)
60 (2d)
56[e] (2e)
80[f] (2f)
Our studies revealed K2S2O8 as an inexpensive and easy-
to-handle oxidant for this transformation, and a low concen-
tration (0.02m) was preferred presumably by favoring the in-
tramolecular process (for details, see the Supporting Infor-
mation). Among all the acids examined either as a solvent/
co-solvent or as an additive, TFA proved the most superior
with its strong acidity that could enhance the electrophilicity
of the palladium center, thereby accelerating the electrophil-
10
11
12
13
14
CO2nBu
CO2Me
CONMe2
COMe
6
Reaction conditions for entry 1–7: 1 (1 equiv), olefin (2 equiv), Pd
(5 mol%), and K2S2O8 (1 equiv) in TFA (0.1m) at 258C. Reaction condi-
tions for entry 8–13: 1 (1 equiv), olefin (2 equiv), Pd(OAc)2 (5 mol%),
K2S2O8 (3 equiv), and pTsOH (1 equiv) in TFA/CH2Cl2 (1:3, 0.02m) at
258C, unless otherwise noted. [a] Isolated Yields. [b] Olefination products
at the C2-position were obtained in 40–60% yield. [c] Some by-products
were observed, but their structures could not be determined. [d] Deter-
mined by 1H NMR spectroscopy using trichloroethylene as an internal
ACHTUNGTRENNUNG(OAc)2
AHCTUNGTRENNUNG
[1c,2f,6]
À
ic metalation of the aromatic C H bond.
To circum-
vent the excessive use of TFA as a solvent, a co-solvent
system in the presence of dichloromethane was preferred, in
contrast to other solvents examined, and it had no detrimen-
tal effect on the reaction yield. Moreover, it has been dem-
onstrated that the use of pTsOH along with a TFA/dichloro-
methane solvent system further improved the reaction yield,
standard. [e] With PdACTHNUTRGNEUNG(OAc)2 (10 mol%) and N,N-dimethylacrylamide
(1.2 equiv) at 408C. [f] In TFA/CH2Cl2 (1:8, 0.02m). Ac=acetyl, Bz=
benzoyl, Boc=tert-butyloxycarbonyl, Ts=para-toluenesulfonyl, Ms=
methanesulfonyl.
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1953

S. W. Youn et al.
COMMUNICATION
With the optimized reaction conditions in hand, we set
out to explore the substrate scope of this process. A variety
of electron-deficient olefins could participate in this reac-
tion, thereby generating the corresponding dihydrophenan-
thridines 2 in moderate to excellent yields (Table 1, en-
tries 9–14). The structure of cyclized product 2a was unam-
biguously confirmed by X-ray crystallographic analysis.[15] In
addition to mono-substituted alkenes, 1,1-disubstituted
alkene was also well tolerated in this process (Table 1,
entry 12). When methyl vinyl ketone was employed as the
activated olefin coupling partner, a reduced amount of TFA
(TFA/CH2Cl2 =1:8) was required in order to prevent any
unwanted side reactions (Table 1, entry 14). Lastly, acryloni-
trile, (E)-ethyl crotonate, and 4-nitrostyrene were unsuccess-
ful under our standard reaction conditions, whereby the de-
sired products could neither be detected nor isolated. Next,
we proceeded to examine the substituent effect of the tosy-
lamide-bearing aromatic ring (Table 2, entries 1–4). It has
been documented that a subtle change in the acidity of the
NH moiety, as a result of substituent effect at the C4-posi-
tion of the tosylamide, can have a drastic effect on the
chemical reactivity.[7] Under our established reaction condi-
tions, the introduction of substituents including Me, NO2,
and CF3 at the C4- or C5-position resulted in a similar ob-
servation, thus leading to a notable reduction in chemical
yield in comparison with the parent substrate (Table 2, en-
tries 1–4). This observation is also consistent with the pro-
tecting group effect described earlier (Table 1, entries 1–8),
which further supports the influence of NH acidity on the
chemical reactivity. It is noteworthy that a delicately bal-
anced acidity of the NH group is required to achieve high
efficiency for this reaction.
The substituent effect of the 2-aryl moiety of substrate 1
was also explored. In this context, both electron-donating
and electron-withdrawing substituents were well tolerated
(Table 2, entries 5–15), with the exception that substrates
bearing a strongly electron-withdrawing group (e.g. NO2) at
the C3’-position required forced reaction conditions to
afford an acceptable yield (Table 2, entry 14). While the re-
action with 2’-OMe substituted substrate (1i) proceeded un-
eventfully with a lower catalyst loading (2n: 72% yield;
Table 2, entry 8), the 2’-NHTs substituted substrate (1j)
gave only the mono-olefination/intramolecular cyclization
product (2o: 57% yield) even when an excessive amount of
ethyl acrylate (1.5 equiv) was used (Table 2, entry 9). Sub-
jecting substrate 1j to the same reaction conditions with a
large excess of activated olefin (up to 6 equiv) also did not
favor the formation of a doubly alkylated product, and this
resulted in predominantly product 2o (~40%) together with
3-alkenylated 2o (~20%), which did not undergo further
cyclization. On the other hand, C3’-substituted substrates
participated in the domino reaction with remarkable regio-
selectivity, thus leading to products originating from the ac-
À
tivation of the less hindered C H bond (Table 2, entries 7,
11, 14-15, and 17-18). This
methodology
useful in the preparation of di-
hydrophenanthridines with
also
proved
Table 2. Pd-catalyzed domino olefination-conjugate addition reaction for the synthesis of various dihydrophe-
nanthridines.
substitution on both aromatic
rings; this led to products 2v–y
in good yields (Table 2, en-
tries 16–19). The functional
group tolerance of the devel-
oped reaction conditions is
particularly noteworthy, in-
cluding but not limited to me-
thoxy, halogen, ketone, amino,
and nitro groups. As a conse-
quence, halogenated substrates
only afforded products that re-
sulted from olefination at the
C2’-position, thereby avoiding
any potential side reactions
that could lead to the forma-
tion of dehalogenated and/or
Heck-type products (Table 2,
entries 10–12 and 19). There-
fore, the highly functionalized
and halogenated dihydrophe-
nanthridines obtained from
this process are useful inter-
mediates for further elabora-
tion and structural diversifica-
tion.
Entry
R
R’
1
Pd
G
t [h]
2
Yield [%][a]
1
2
3
4
5
6
7
8
4-Me
4-NO2
5-NO2
4-CF3
H
H
H
H
H
H
H
H
H
H
H
4-Me
4-Me
5-NO2
4-Me
H
H
H
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
6
8
12
5
10
18
6
8
4
5
4
3
6
6
10
8
12
4
3
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
76
67
65
H
75
4’-Me
4’-OMe
3’-OMe
2’-OMe
2’-NHTs
4’-Cl
3’-Cl
4’-F
4’-Ac
3’-NO2
75
82[b]
90
72
9
57[c]
79
10
11
12
13
14
15
16
17
18
19
80
72
2s
2t
62
46[d]
85
G
2u
2v
2w
2x
2y
72[b]
83
3’-OMe
3’-OMe
4’-F
1s
1t
78
68
Reaction conditions: 1 (1 equiv), ethyl acrylate (2 equiv), PdACHTUNGTRNEGN(U OAc)2 (3–10 mol%), K2S2O8 (3 equiv), and
pTsOH (1 equiv) in TFA/CH2Cl2 (1:3, 0.02m) at 258C, unless otherwise noted. [a] Isolated Yields. [b] Per-
formed with TFA (30 equiv) in CH2Cl2 (0.02m). [c] Performed with ethyl acrylate (1.5 equiv). [d] Performed at
608C.
1954
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Chem. Asian J. 2011, 6, 1952 – 1957

À
À
C C and C N Bond Formation
As a further demonstration of the developed methodolo-
gy in the construction of structurally unprecedented polyhe-
terocyclic compounds, N-Ts-aniline 3 bearing 2’-thienyl
functionality at the C2-position furnished fused heterocycle
4 and noncyclized 4’ in excellent overall yield [Eq. (1)].
Ladder-type polyfused heterocycle 6 was also efficiently pre-
pared from 2,2’’-diamino-[1,1’;4’,1’’]terphenyl derivative 5,
which may find wide-spread applications in both physical
sciences and biological contexts
philic nature of this process was made available through ki-
netic isotope studies, whereby competition experiments
demonstrated modest but notable secondary intermolecular
(kH/kD =1.49) and intramolecular (kH/kD =1.50) kinetic iso-
tope effects [Eqs. (3)–(4)].[16]
By analogy with the mechanisms suggested for the related
processes,[7a,8] and on the basis of our preliminary studies, a
plausible mechanism for the palladium-catalyzed sequential
[Eq. (2)].
To gain insight into this reac-
tion, we first performed compe-
tition experiments with a series
of 3’-substituted N-Ts-2-phenyl-
anilines, and the results are
shown in Table 3. This study re-
vealed a strong electronic de-
pendence, in which the elec-
tron-rich substrates reacted
considerably faster than their
electron-deficient counterparts,
an observation that is consistent
with the initial electrophilic cy-
clopalladation. Further evi-
dence in support of the electro-
olefination/conjugate addition
reaction was put forward as
shown in Scheme 2. Having un-
covered the connection be-
tween the acidity of the NH
moiety and the observed reac-
tivity, we speculated an initial
À
Pd N bond formation to take
place, thereby generating a PdII
species that is sufficiently elec-
trophilic for the subsequent sul-
À
fonamide-directed C H bond
activation. The electronic de-
pendence of this process is in
support of an electrophilic
attack at the palladium center;
this leads to the generation of
palladacycle A. Carbopallada-
tion of the activated olefin by
palladacycle A followed by b-
hydride elimination then com-
pletes the Fujiwara–Moritani
process, in which the resulting
cross-coupling product (B) un-
dergoes a subsequent intramo-
lecular conjugate addition reac-
tion to give the cyclized product
2. In parallel the so-obtained
Pd0 is reoxidized to the catalyti-
cally active PdII species using
K2S2O8 to complete the catalyt-
Table 3. Competition experiments of 3’-substituted N-Ts-2-phenylanilines.
Entry
R
R’
t [h]
1A [%][a]
1B [%][a]
2A [%][a]
2B [%][a]
1
2
3
4
H
H
H
OMe
OMe
Cl
NO2
NO2
2
3
3
3
50 (1a)
25 (1a)
40 (1a)
0 (1h)
10 (1h)
50 (1l)
90 (1o)
80 (1o)
40 (2b)
65 (2b)
45 (2b)
85 (2m)
80 (2m)
35 (2q)
0 (2t)
5 (2t)
Reaction conditions: 1A (0.5 equiv), 1B (0.5 equiv), ethyl acrylate (2 equiv), PdACHTUNGTRNEGN(U OAc)2 (5 mol%), K2S2O8
(3 equiv), and pTsOH (1 equiv) in TFA/CH2Cl2 (1:3, 0.02m) at 258C. [a] Determined by H NMR spectroscopy
using trichloroethylene as an internal standard.
1
Chem. Asian J. 2011, 6, 1952 – 1957
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www.chemasianj.org
1955

S. W. Youn et al.
COMMUNICATION
mixture was poured into water and basified with sat. NaHCO3, and then
the product was extracted with CH2Cl2 (three times), dried over MgSO4,
and concentrated in vacuo. The residue was purified by column chroma-
tography on silica gel to afford the corresponding product 2.
Acknowledgements
This work was supported by the Mid-career Researcher Program (No.
R01-2009-008-3940) and the Basic Science Research Program (Nos. 2010-
0017149 and 2010-0007737) through the National Research Foundation
of Korea (NRF) grant funded by the Ministry of Education, Science and
Technology (MEST). We thank Dr. Ji-Eun Lee (Central Instrument Fa-
cility, Gyeongsang National University) for X-ray crystallographic analy-
sis.
À
Keywords: C H activation
heterocycles · olefins · palladium
·
domino reactions
·
À
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Scheme 2. Proposed mechanism for the Pd-catalyzed domino olefination-
conjugate addition reaction.
ic cycle. While it is conceivable that this reaction takes place
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synergistic mechanistic proposal involving either a PdII/PdIII
or PdII/PdIV catalytic cycle[17] in the presence of a strong oxi-
dant (e.g. K2S2O8) could also be invoked.
In summary, we have developed an effective, palladium-
catalyzed domino olefination-conjugate addition reaction of
N-Ts-2-arylanilines with activated olefins that operates at
room temperature under acidic media in the presence of
K2S2O8 as an inexpensive and easy-to-handle oxidant. In
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À
parallel, the influence of N-protecting groups in directed C
H activation and the subsequent Fujiwara–Moritani olefina-
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offers a straightforward entry to a wide range of N-heterocy-
cles such as dihydrophenanthridines, a structural motif that
is prevalent in a variety of natural and designed compounds
with interesting physical and biological properties.[12] Func-
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leading to greater molecular complexity and structural di-
versity. Investigations along this direction and the applica-
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À
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À
tion of C H activation to construct other heterocyclic privi-
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Experimental Section
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Received: January 13, 2011
Published online: March 15, 2011
Chem. Asian J. 2011, 6, 1952 – 1957
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1957