Cyclopentadiene-phosphine/palladium-catalyzed cleavage of C-N bonds in secondary amines: Synthesis of pyrrole and indole derivatives from secondary amines and alkenyl or aryl dibromides

Article abstract of DOI:10.1021/ja308950d

An efficient Pd-catalyzed cleavage of C(sp³)-N bonds in secondary amines and a consequent C(sp²)-N and C(sp³)-N coupling process was developed. Various secondary amines could be used to react with alkenyl or aryl dibromide

Full text of DOI:10.1021/ja308950d

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Communication
Cyclopentadiene-Phosphine/Palladium Catalyzed Cleavage of C-
N Bonds in Secondary Amines: Synthesis of Pyrrole and Indole
Derivatives from Secondary Amines and Alkenyl or Aryldibromides
Weizhi Geng, Wen-Xiong Zhang, Wei Hao, and Zhenfeng Xi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja308950d • Publication Date (Web): 03 Dec 2012
Downloaded from http://pubs.acs.org on December 3, 2012
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Cyclopentadiene-Phosphine/Palladium Catalyzed Cleavage of
C-N Bonds in Secondary Amines: Synthesis of Pyrrole and
Indole Derivatives from Secondary Amines and Alkenyl or
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Aryldibromides
,†,‡
Weizhi Geng,† Wen-Xiong Zhang,† Wei Hao †
,
Zhenfeng Xi
*
Beijing National Laboratory for Molecular Sciences (BNLMS), and Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China;
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry (SIOC), Shanghai
200032, China
Supporting Information Placeholder
Abstract: An efficient Pd–catalyzed cleavage of C(sp3)–
N bonds in secondary amines and consequent C(sp2)–N
and C(sp3)–N coupling process was developed. Various
secondary amines could be used to react with alkenyl or
aryl dibromides affording pyrroles and indoles in high
yields. Cyclopentadiene-phosphine ligands, a new type of
P–olefin ligands, were found to be able to remarkably
promote the efficiency of this Pd–catalyzed process. A
reactive Pd complex coordinated with a cyclopentadiene-
phosphine ligand was successfully isolated and
structurally characterized.
Table 1. Optimization of Reaction Conditions
entry
ligand
base
yield of
2a (%)a
0
1
LiOt-Bu
LiOt-Bu
–
PPh3
2
32
0
3
Xantphos
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
4
Xphos
Sphos
Davephos
L1
18
29
16
75 (62)
52
0
The cleavage of carbon–nitrogen (C–N) bonds is of
significant synthetic interest, because such bonds are
5
6
common in organic chemistry and usually unreactive 1-8
.
7
The cleavage of such C–N bonds in tertiary amines have
been reported leading to various important N-
heterocycles by using a stoichiometric amount3 or a
catalytic amount of transition-metal complexes.4-6
However, to the best of our knowledge, there is no report
in the literature on transition-metal catalyzed cleavage
and synthetic applications of C(sp3)–N bonds in
secondary amines.1b,7,8 Since a secondary amine contains
one N–H bond and two C–N bonds, their efficient
selective cleavage and further synthetic applications are
very attractive for both mechanistic study and synthetic
chemistry. Herein, we report the first example of
catalytic cleavage of the C(sp3)–N bonds in secondary
amines and consequent C(sp2)–N and C(sp3)–N coupling
process, which results in high-yield formation of pyrroles
and indoles. In addition, cyclopentadiene-phosphine
ligands, a new type of mixed P-olefin ligands,9,10 were
synthesized and found to be able to remarkably promote
the efficiency of this catalytic process.
8
L2
9
L3
LiOt-Bu
LiOt-Bu
NaOt-Bu
KOt-Bu
K3PO4
10
11
12
13
14
L4
38
0
L1
L1
0
L1
14
0
L1
Cs2CO3
a GC yields. Isolated yields are in parenthesis.
After various reaction conditions being screened, we
found that our newly designed and synthesized
phosphine–cyclopentadiene ligands (L1, L2, see SI for
detailed synthetic procedure) were the best for this
reaction (entries 7, 8). Many other ligands, including
those commonly used ones such as PPh3, Xantphos,
Xphos, Sphos, and Davephos gave low yields or totally no
As shown in Table 1, when the dibromide 1a11 was
treated with piperidine, an unexpected pyrrole derivative
2a was obtained. Obviously, an unprecedented coupling
process involving amination, C–N bond cleavage and C–
N bond formation took place.
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products (entries 2-6). Ligands such as L3 and L4 also
the indole derivatives 2h-m were obtained in good to
showed very low or totally no efficiency (entries 9, 10).
These results demonstrated that both the P moiety and
the cyclopentadiene moiety were necessary for high
efficiently realizing this Pd-catalyzed coupling process.
In addition, base was very sensitive for this
transformation and LiOt-Bu was found most effective.
An excess amount of piperidine (more than 5 equivalents)
is required to achieve a clean reaction. The optimal
reaction condition was realized as follows (see SI for
details): Pd(OAc)2 (2 mol%), L1 (5 mol%), LiOt-Bu (3
equiv), in piperidine/toluene = 1/9 (2 mL) solvent, 110
oC, 12 h (entry 7). With this optimized condition, the
pyrrole derivative 2a was obtained in 62% isolated yield.
excellent isolated yields. In addition, acyclic secondary
amines including Et2NH, Pr2NH, Bu2NH and i-Pr2NH
were investigated and results are summarized in Table 3.
No reaction took place when i-Pr2NH was used (the
dibromide 1a was unreacted), probably due to the steric
effect. It should be noted that formation of R″3N was
observed in all these reactions. For example, when 1a
was treated with Pr2NH, Pr3N was formed in 85% GC
yield, along with 3b in 69% isolated yield. The formation
of R″3N sheds clue on the reaction mechanism.
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Table 3. Palladium-Catalyzed Reaction of Dibromides 1
with Dialkylamines (R″2NH)
Table 2. Palladium-Catalyzed Reaction of Dibromides 1
with Cyclic Amines
R
R
Pd(OAc)2 (2 mol%)
H
N
R
R
L1 (5 mol%)
Br
Br
N Q
N
X
+
LiOt-Bu (3 equiv)
in toluene
R'
R'
X
R'
R'
Q = (CH2)2X(CH2)2
110 °C, 12 h
1
2
dibromide 1
cyclic amine
product 2
R
R
H
N
R
R
Br
N
Q
N
X
Br
R'
R'
X
R'
R'
1a: R = R' = Et
1b: R = R' = Pr
1c: R = Et, R' = Ph
2a: R = R' = Et, X = CH2, 62%
2b: R = R' = Et, X = O, 76%
2c: R = R' = Pr, X = CH2, 85%
X = CH2, O
2d: R = Et, R' = Ph, X = CH2, 84%
R
R
Br
Br
X = CH2, O
N Q
N
X
R
R
2e: R = Et, X = CH2, 77%
2f: R = Pr, X = CH2, 90%
2g: R = Pr, X = O, 82%
1d: R = Et
1e: R = Pr
R
R'
R
R'
X = CH2, O,
N Q
N
X
CHCH3
We then applied acyclic secondary amines possessing
two different groups (R1R2NH), with the aim to
investigate the chemoselective cleavage of C(sp3)–N
bonds. As given in Table 4, when the dibromide 1a was
treated with Me(Et)NH, the N-Et pyrrole derivative 3a
was obtained in 65% isolated yield as the only pyrrole
derivative product. Obviously, a selective cleavage of the
Me-N bond in Me(Et)NH took place. In the case of
Et(Pr)NH, a mixture of two pyrrole derivatives 3a and
3b was formed in 2:3 ratio. When Me(Ph)NH was used,
the cleavage took place exclusively at the weaker Me-N
bond (71.4 kcal/mol for the bond energy of Me-N, 100.1
kcal/mol for the bond energy of Ph-N),12a,b affording the
corresponding N-Ph pyrrole derivative 3j in 57% isolated
yield. In addition, the tertiary amine Me2NPh was
formed in 75% GC yield. In contrast, when Et(Ph)NH
was used, no remarkable reaction took place. These
results demonstrate that the bulkiness of the N-
substituent and the C-N bond energy determine which C-
N bond in R1R2NH is more readily cleaved.12 The
formation of Me2NPh again sheds clue on the reaction
mechanism.
Br
Br
1f: R = TMS, R' = Me
1g: R = R' = Et
2h: R = TMS, R' = Me, X = CH2, 64%
2i: R = R' = Et, X = CH2, 81%
2j: R = R' = Et, X = O, 86%
2k: R = R' = Et, X = CHCH3, 79%
2l: R = R' = Pr, X = CH2, 85%
Et
1h: R = R' = Pr
Et
Et
Et
H
N
N
Br
Br
N
1g
2m: 58%
The scope of the above Pd-catalyzed coupling process
was investigated under the optimized reaction conditions.
Results are summarized in Tables 2-4. A variety of
dibromides 1a-h were applied. Shown in Table 2 are
results obtained from the reaction of dibromides 1a-h
with various cyclic secondary amines, including
piperidine, 4-methyl piperidine, morpholine, and
pyrrolidine. A wide variety of the pyrrole derivatives 2a-
d, the 4,5,6,7-tetrahydro-isoindole derivatives 2e-g, and
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represents an unprecedented way for the synthesis of a
Table 4. Investigation into the Selectivity of Amines
wide variety of pyrrole and indole derivatives with useful
N-substitution.17 Further study on the reaction
mechanism and synthetic applications is in progress.
with Two Different Substituents (R1R2NH)
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Scheme 1. Proposed Key Intermediates
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Scheme 2. Mechanistic Study
Et
Pd(OAc)2 (2 mol%)
Et
N
H
N
Et
Et
It is obvious that the new type of mixed P-olefin
ligands is very effective for this Pd-catalyzed coupling
process. However, it is not clear yet how this ligand
works together with the palladium. Given in Scheme 1
are proposed key intermediates. The intermediate I
would be formed from a dibromide 1 and a secondary
amine, via oxidative addition/amination/oxidative
addition process.13 Nucleophilic attack of piperidine
anion on intermediate I would generate a 6-membered
palladacycle III, which could then reductively eliminate
to form the product. Although this mechanism is readily
acceptable, however, the path via intermediates IV and
V is also possible,14,15 since the compound 4, which might
be formed via reductive elimination of IV,15 was obtained
when less amount of morpholine was used (Scheme 2).
Under the same reaction condition, the compound 5, a
precursor of I, could give 2i in 90% isolated yield with
piperidine. In sharp contrast, no formation of 2i was
observed without piperidine; A trace amount of de-
iodination product and a small amount (<3%) of 6 were
observed. When Et2NH was used, the indole derivative 7
was obtained. These results indicate that the proposed
intermediate IV is possible, but its formation is a slow
step and its following reaction with amine would
facilitate its formation.
Et
Et
O
L1 (5 mol%)
Br
Br
2b
+
+
LiOt-Bu (3 equiv)
in toluene
110 °C, 12 h
O
Br
Et
Et
1a
n equiv.
4
morpholine
n equivalents
yield of 2b
yield of 4
n = 5
n = 2
n = 1
76%
52%
27%
trace
11%
19%
with
piperidine
2i: 90%
Et
Et
Pd(OAc)2 (2 mol%)
without
Et
L1 (5 mol%)
Et
piperidine
N
I
LiOt-Bu (3 equiv)
in toluene
N
(CH2)4CH3
6: < 3%
Et
110 °C, 12 h
5
with Et2NH
Q: (CH2)5
Et
N
Q
NEt2
7: 88%
Further, as shown in Eq. 1, a Pd-L1 complex 8 was
obtained and structurally characterized (see SI for
details). The complex 8 is a dimer with two bridging
chloride atoms. The five-membered cyclometallated ring
is puckered and the bite angle of Cσ–Pd–P is 84.7(3)°.
The bond length of the Pd–Cσ bond is 2.090(10)
Å,
ASSOCIATED CONTENT
similar to other five-membered azapalladacycles.16
Supporting Information. Experimental details, X-ray
data for L1, 8 and scanned NMR spectra of all new products
(PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Notably, this complex 8 (2 mol%) could catalyze
efficiently the coupling process of 1a or 1g with
piperidine to give 2a and 2i in 62% and 83% isolated
yields, respectively.
AUTHOR INFORMATION
Corresponding Author
zfxi@pku.edu.cn
In summary, we have developed the first transition-
metal catalyzed cleavage of C(sp3)–N bonds in secondary
amines.
A new type of cyclopentadiene-phosphine
ligands were found to be able to remarkably promote the
efficiency of this catalytic process. This finding
3
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ACKNOWLEDGMENT
This work was supported by the Natural Science Foundation
of China, and the 973 Program (2012CB821600).
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