Free-amine-directed alkenylation of C(sp2)-H and cycloamination by palladium catalysis

Article abstract of DOI:10.1002/chem.201202672

A new protocol for the palladium-catalyzed free-amine-directed alkenylation of C(sp²)-H bonds and cycloamination is described. Substituted biaryl-2-amines react with various alkenes, including electron-deficient alkenes, aryl alkenes and alkyl alkenes, to give the corresponding phenanthridines with exclusive regioselectivity. The use of α-branched styrenes leads to the formation of tricyclic compounds with a seven-membered amine ring. The method operates through a free-amine-directed alkenylation and a subsequent hydroamination cyclization reaction. Seven-membered cycloamination: A new protocol for the palladium-catalyzed free-amine-directed alkenylation of C(sp²)-H bonds and subsequent cycloamination is described (see scheme). Substituted biaryl-2-amines react with various alkenes to give the corresponding phenanthridines with exclusive regioselectivity. The use of α-branched styrenes leads to the formation of tricyclic compounds with a seven-membered amine ring. Copyright

Full text of DOI:10.1002/chem.201202672

DOI: 10.1002/chem.201202672
2
À
Free-Amine-Directed Alkenylation of CACTHNUTRGNEU(GN sp ) H and Cycloamination by
Palladium Catalysis
Zunjun Liang,[a] Long Ju,[a] Yongju Xie,[a] Lehao Huang,[a] and Yuhong Zhang*[a, b]
Abstract: A new protocol for the palladium-catalyzed free-amine-directed alkeny-
2
À
lation of C
N
amines react with various alkenes, including electron-deficient alkenes, aryl
alkenes and alkyl alkenes, to give the corresponding phenanthridines with exclu-
sive regioselectivity. The use of a-branched styrenes leads to the formation of tri-
cyclic compounds with a seven-membered amine ring. The method operates
through a free-amine-directed alkenylation and a subsequent hydroamination cyc-
lization reaction.
Keywords: alkenylation
·
amina-
À
tion · C H activation · cyclization ·
palladium · phenanthridines
2
À
Introduction
amine-directed alkenylation of CACHUTNGTRENNUNG
À
Transition-metal-catalyzed C H functionalization reactions
have emerged as one of the most efficient and straightfor-
À
À
ward methods for the construction of C C and C N bonds
in organic synthesis.[1] Among these transformations, the re-
gioselectivity can be controlled by the use of directing
groups (DGs), which commonly have a lone pair of elec-
trons, to precomplex the metal and direct it to the desired
position. As well as the oxygen-containing groups,[2–5] a vari-
ety of nitrogen-containing groups, including pyridines,[6]
amides,[7] imines,[8] oximes,[9] alkyl amines,[10] and other nitro-
gen-containing heterocycles,[11] have been intensively investi-
gated as DGs under palladium, ruthenium, or rhodium cat-
alysis. Amines are the most prevalent of the N-containing
compounds and are ubiquitous in natural products and phar-
maceuticals. Although free amines have been successfully
employed as assisting groups in asymmetric catalysis, the ap-
plication of this simple functional group as a DG in direct
À
À
C H activation/C C-coupling processes remains a chal-
lenge.[12] Advances in this field have focused primarily on
approaches to convert amines into amides, anilides, or
imines that act as DGs [Eq. (1)]. The use of free amines as
À
simple and cheap DGs in C H bond-activation processes is
a highly desirable goal, particularly from an industrial point
of view. Herein, we report a palladium-catalyzed free-
Results and Discussion
At the outset of our study, we examined the reaction be-
tween biphenyl-2-amine (1a) and methyl acrylate (2a) by
the use of PdACTHNUGRTENNUG(OAc)2 as catalyst with CuACHTUNTGERN(NUGN OAc)2 as an oxi-
[a] Dr. Z. Liang, L. Ju, Y. Xie, L. Huang, Prof. Y. Zhang
Department of Chemistry, Zhejiang University
Hangzhou 310027 (P.R. China)
dant at 908C for 6 h in acetic acid. Surprisingly, the reaction
resulted in the formation of phenanthridine (3a) in 40%
yield. After intensive investigation of the reaction conditions
(for details, see the Supporting Information), it was found
that CuCO3·Cu(OH)2 can promote this PdCl2-catalyzed
transformation in the presence of HOAc (10 equiv) by the
use of trifluoroethanol (TFEtOH) as solvent. The reaction
proceeded in a regio- and chemoselective manner to give
Fax : (+86)571-87953244
E-mail: yhzhang@zju.edu.cn
[b] Prof. Y. Zhang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202672.
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FULL PAPER
Table 1. Reaction of various biarylamines with acrylates.
2-amine (1h), and 2-(thiophen-2-yl)aniline (1k)
were used as substrates. 2-Naphthyl aniline (1 f)
also reacted with methyl acrylate (2a) to provide
the annulated polycyclic product in moderate yield
(3h). Importantly, the reaction was compatible with
the heteroaromatic compound 1k, giving the corre-
sponding fused heterocyclic compounds (3m/3m’).
The steric hindrance played an important role in
this transformation. For example, when 2’-methylbi-
phenyl-2-amine (1m) was used as the substrate, the
corresponding phenanthridine 3o (for X-ray crystal-
lography, see the Supporting Information) was ob-
tained in only 33% yield, and the aza-Michael-addi-
tion product 3o’ of amine 1m and methyl acrylate
(2a) was generated in 60% yield. When a methyl
group was ortho to the amino group (1n), the corre-
sponding phenanthridine product was not observed
and the aza-Michael-addition compounds became
the major products (3p and 3p’).
The substrate scope of aryl alkenes was also eval-
uated with biphenyl-2-amine (1a) as the reaction
partner (Table 2). We were pleased to find that the
aryl alkenes showed very good reactivity. In com-
parison to the reactions of a,b-unsaturated esters,
only one equivalent of the aryl alkene was con-
sumed to give the corresponding phenanthridines 5.
Both electron-rich and electron-poor aryl alkenes
were accommodated with good efficiency. A variety
of useful functional groups were tolerated, includ-
ing methyl (5a, 5b, and 5c), methoxy (5e), chloride
(5 f), fluoride (5g; for X-ray crystallography, see
the Supporting Information), and nitryl (5h) func-
tional groups. Aryl alkenes with substituents at the
ortho position were found to be equally active, illus-
trating that steric encumbrance on the aryl ring of
aryl alkenes played a poor role in the transforma-
tion (5d). 2-Vinylnaphthalene also participated in
the reaction to give the corresponding phenathri-
Reaction conditions: 1 (0.5 mmol), 2 (5.0 mmol), PdCl2 (10 mol%, 0.05 mmol), Cu-
CO3·Cu(OH)2 (1.0 mmol, 221 mg), AcOH (10 mmol), TFEtOH (1 mL), 20 min at RT,
then heated at 908C with stirring for 6 h. Yields of isolated product based on biphenyl-
amine (1).
exclusively 3a (Table 1). The aza-Michael-addition product
of amine and methyl acrylate was not observed. Thus, an
atom- and step-economical synthesis of fused nitrogen-con-
taining heterocycles has been developed, in which the free-
amine (DG) is simultaneously involved in the construction
of the product.
Under the optimized reaction conditions, we explored the
scope of the reaction and the results were summarized in
Table 1. This new alkenylation and cycloamination transfor-
mation displayed good functional-group tolerance. The elec-
tron-deficient alkenes, such as 2a, 2b, and 2c, were subject-
ed to the reaction and the desired products 3a, 3b, and 3c
were obtained in good yields. The electronic properties of
substituents on the arenes exerted a dramatic effect on the
reaction. Arenes with electron-donating groups presented
higher reactivity (3d, 3i/3i’, 3j/3j’, and 3n) than arenes with
electron-withdrawing groups (3e–g, 3k, 3l/3l’, and 3q). The
decarboxylation products 3i’, 3j’, and 3m’ were observed
when 3’-methylbiphenyl-2-amine (1g), 3’-methoxybiphenyl-
dine 5i. Notably, alkenyl phosphonates, such as dimethyl vi-
nylphosphonate (4j), participated in the alkenylation and
cyclization reaction smoothly to give dimethyl phenanthri-
din-6-yl-methylphosphonate 5j in 77% yield. This protocol
might be useful for the synthesis of natural products that
contain a phosphonate moiety.[22] Importantly, alkyl alkenes
(4k and 4l), which are commonly less reactive in oxidative
[23]
À
C H Heck-type couplings,
were compatible with this
newly developed protocol and gave the desired phenanthri-
dine products in moderate yields under the reaction condi-
tions (5k and 5l).
We extended this new transformation to the internal
alkene bonds and the desired products were not found, pre-
sumably due to the steric encumbrance. Surprisingly, a varie-
ty of tricyclic compounds with seven-membered amine rings
were obtained from the corresponding a-branched styrenes
in all cases, as shown in Table 3. This kind of tricyclic amine
core is an important substructure unit of arginine vasopres-
sin antagonists, and has a substantial effect on their antago-
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Y. Zhang et al.
Table 2. Reaction of biarylamines with various styrenes and alkyl al-
kenes.
Table 3. Reaction of biarylamines with a-branched styrenes.
Reaction conditions:
1
(0.5 mmol),
6
(2.0 mmol), PdCl2 (10 mol%,
Reaction conditions: 1a (0.5 mmol),
4 (2.0 mmol), PdCl2 (10 mol%,
0.05 mmol), Cu(OAc)2·H2O (1.0 mmol, 200 mg), AcOH (1.0 mmol), TFEtOH
AHCTUNGTRENNUNG
0.05 mmol), CuCO3·Cu(OH)2 (1.0 mmol, 221 mg), AcOH (10 mmol),
TFEtOH (1.0 mL), 20 min at RT, then heated at 908C with stirring for
12 h. Yields of isolated product based on biphenylamine (1).
(1.0 mL), 20 min at RT, then heat at 908C with stirring for 12 h. Yields of iso-
lated product based on biarylamine (1).
nistic activity for the V1a and V2 receptors.[24] In addition,
compounds containing a fused, seven-membered central ring
are potent phototherapeutic agents.[25]
Thus, this reaction results in the efficient synthesis of tricy-
clic compounds with a seven-membered amine ring.[26]
À
To understand the mechanism of this new C H cleavage
We tested the generality of this protocol by applying it to
the synthesis of diverse tricyclic compounds with a seven-
membered amine ring (Table 3). Electron-rich arenes
showed a better reactivity than electron-deficient arenes
(products 7d, 7e, and 7g) and delivered the desired prod-
ucts in moderate yields (7a–c and 7 f; for X-ray crystallogra-
phy of 7b, see the Supporting Information). 2-(Naphthalen-
2-yl)aniline participated successfully in the reaction at the
less hindered position to give the product 7h. When the sub-
stituent was at the meta position, the major products were
formed at the less hindered ortho position of the amino
group, accompanied by minor products that were functional-
ized at the more hindered ortho position (7i/7i’ and 7j/7j’).
The substituents on the aryl ring of a-methylstyrenes influ-
enced the efficiency of the reaction and substrates with elec-
tron-donating groups gave higher yields (7k) than those
with electron-withdrawing groups (7l and 7m). Moreover,
2-(prop-1-en-2-yl)naphthalene participated smoothly in the
reaction to give the desired product (7n) in 70% yield.
reaction, we took note of the reactions between various al-
kenes and N-(biphenyl-2-yl)acetamide (8a), which might be
formed in situ under our reaction conditions (Scheme 1). In
Scheme 1. The performance of N-(biphenyl-2-yl)acetamide.
all of the cases, no target products were detected, showing
À
that the amide-directed C H cleavage pathway is unlikely.
By the use of bulky alkene 3,3-dimethylbut-1-ene 9a, we
obtained the alkenylated products 10a and 11a (Table 4).
The reaction afforded 10a as the major alkenylated product.
When excess 9a was used, the dialkenylated product 11a
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2
À
Alkenylation of CACHTUNGTRENNUNG(sp ) H and Cycloamination by Palladium Catalysis
FULL PAPER
Table 4. Alkenylation reaction of biaryl-2-amine.
yl-2-amine (1a) with 4a (for details, see the Supporting In-
formation). These results support the proposed reaction
pathway of, first, an alkenylation and a subsequent cycloa-
mination step.
The key six-membered palladacycle, intermediate A, was
synthesized[28] and subjected to a reaction with tert-butyl-
ethylene (9a) under standard reaction conditions in the ab-
sence of Cu salts. Indeed, we obtained the alkenylated prod-
uct 10a (Scheme 3), the formation of which provides solid
À
evidence for the proposed free-amine-directed C H-activa-
tion mechanism.
Substrate ([mmol])
Product ([%])
R=H
1a (0.5)
1a (0.5)
1a (0.5)
R=OMe
1c (0.5)
R=F
9a (0.5)
9a (1.0)
9a (3.0)
10a (45)
10a (50)
10a (43)
11a (tr)
11a (5)
11a (15)
12a (tr)
12a (tr)
12a (tr)
9a (3.0)
10b (28)
11b (41)
12b (tr)
1e (0.5)
9a (3.0)
10c (30)
11c (7)
12c (tr)
Scheme 3. Study of the key palladacycle intermediate.
Reaction conditions:
1 (0.5 mmol), 9a (indicated amounts), PdCl2
(10 mol%), CuCO3·Cu(OH)2 (1.0 mmol, 221 mg), AcOH (10 mmol),
TFEtOH (1.0 mL), sealed tube, 20 min at RT, then heated at 908C with
stirring for 12 h. Yields of isolated product based on biphenylamine (1).
tr=trace.
An intermolecular kinetic isotope experiment was per-
formed by the treatment of equivalent biarylamine 1a and
its deuterated analogues 1a–d5 under the reaction conditions
(Scheme 4). A kinetic isotope effect (KIE) of 2.23 was dis-
À
and cycloamination product 12a were detected. In contrast,
anilide 8a was not observed. Arenes with electron-donating
groups showed better reactivity
closed, implying that the palladium-mediated C H cleavage
might be involved in the catalytic alkenylation.
than those with electron-with-
drawing groups (10b and 11b
compared with 10c and 11c).
These results offer compelling
evidence that the reaction pro-
ceeds through a free-amine-di-
À
rected C H cleavage mecha-
nism.
Scheme 4. Kinetic isotope experiment.
When 10a was subjected to
the above alkenylation reaction
conditions, the cycloamination product 12a was obtained
(Scheme 2). It is noteworthy that the cycloamination[27]
failed to occur in the absence of a palladium catalyst and
was very slow in the absence of copper salts. We also detect-
ed, by GC-MS analysis, the phenanthridine product of bi-
phenyl-2-amine (1a) with 2a before the aza-Michael addi-
tion and the alkenylated product in the reaction of biphen-
On the basis of other related work, there are two likely
À
pathways for the C H cleavage: one is the metallation/de-
protonation pathway,[29] the other is the electrophilic palla-
dation process.[30] Our experiments demonstrated that elec-
tron-rich substrates showed higher reactivity and gave
À
higher yields (Table 4). Therefore, we suppose that the C H
cleavage in this transformation might proceed through an
electrophilic palladation mechanism.[31] As shown in
Figure 1, the electrophilic palladation occurs preferentially
at the 2’-position of biphenyl-2-amine to form the palladacy-
cle intermediate A. The subsequent insertion reaction with
an alkene leads to the formation of intermediate B, which
undergoes b-hydride elimination to form the alkenylated
product C. In the case of a-branched styrenes, the b-hydride
elimination might occur at the methyl group, which contains
more hydrogen atoms, to form C’, which is in accordance
with a dynamic elimination process.[20,23a] The palladium(0)
that forms is reoxidized to palladium(II) by copper(II) salts
in the system to furnish the cycle. The Pd-catalyzed intramo-
Scheme 2. Intramolecular cycloamination and aromatization.
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Y. Zhang et al.
by flash column chromatography with ethyl acetate and petroleum ether
as the eluent to provide the corresponding products.
Acknowledgements
Funding from the National Basic Research Program of China (No.
2011CB936003) and the Natural Science Foundation of China (No.
21072169) is acknowledged.
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Figure 1. Plausible reaction mechanism.
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We have developed a palladium-catalyzed method for the
free-amine-directed alkenylation of C
2
À
(sp ) H and cycloami-
nation to prepare the corresponding functionalized phenan-
thridines. This new transformation is highly selective and
shows good functional-group tolerance. Moreover, seven-
membered nitrogen-containing-ring products, which are
often difficult to synthesize by other methods, were pro-
duced efficiently when a-branched styrenes were applied as
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À
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À
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À
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Experimental Section
General procedure: A 10 mL round bottom flask with a magnetic stir bar
and reflux condenser was charged with PdCl2 (9 mg, 0.05 mmol,
10 mol%), CuCO3·Cu(OH)2 (1.0 mmol, 221 mg), biphenylamine (1;
0.5 mmol, 1.0 equiv), acrylate (5.0 mmol), acetic acid (600 mg, 10 mmol)
and trifluoroethanol (1.0 mL). The mixture was stirred for 20 min at
room temperature, then heated at 908C and stirred for 6 h. After cooling
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Alkenylation of CACHTUNGTRENNUNG(sp ) H and Cycloamination by Palladium Catalysis
FULL PAPER
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Published online: October 10, 2012
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