Synthesis of enantioenriched 5,6-dihydrophenanthridine derivatives through retro-carbopalladation of chiral o-bromobenzylamines

Article abstract of DOI:10.1002/anie.201411276

Retro-carbopalladation of aldimines in the presence of a suitable β-hydrogen atom has been observed in the Pd-catalyzed homocoupling reactions of o-bromobenzylamines, providing an expeditious synthetic route to 5,6-dihydrophenanthridine derivatives. Furthermore, a highly enantioselective synthesis of 6-aryl-substituted 5,6-dihydrophenanthridines was achieved in a one-pot manner by taking advantage of Rh and Pd catalysis.

Full text of DOI:10.1002/anie.201411276

Angewandte
Chemie
DOI: 10.1002/anie.201411276
b-Carbon Elimination
Synthesis of Enantioenriched 5,6-Dihydrophenanthridine Derivatives
through retro-Carbopalladation of Chiral o-Bromobenzylamines**
Juntao Ye, Aurore Limouni, Sonia Zaichuk, and Mark Lautens*
Abstract: Retro-carbopalladation of aldimines in the presence
of a suitable b-hydrogen atom has been observed in the Pd-
catalyzed homocoupling reactions of o-bromobenzylamines,
providing an expeditious synthetic route to 5,6-dihydrophe-
nanthridine derivatives. Furthermore, a highly enantioselective
synthesis of 6-aryl-substituted 5,6-dihydrophenanthridines was
achieved in a one-pot manner by taking advantage of Rh and
Pd catalysis.
P
alladium-catalyzed CÀC bond cleavage through b-carbon
elimination, or retro-carbopalladation, has emerged as an
effective strategy for the activation of carbon–carbon single
bonds as well as for the development of novel synthetic
[
1]
approaches over the last few decades. Being thermodynami-
cally unfavorable, this process usually occurs when there is no
syn-b-hydrogen atom or in cyclic systems in which a significant
release of ring strain is possible. Retro-carbopalladation has
rarely been observed in the presence of a suitable b-hydrogen,
[1,2]
especially in acyclic systems (Scheme 1).
Recently, Satyanarayana and co-workers reported a Pd-
catalyzed homocoupling reaction of tertiary o-bromobenzyl
alcohols 1 for the preparation of chromenes 2 via the
Scheme 2. Previous work and proposal of this work.
intermediacy of palladium species A and B [Eq. (1),
Scheme 2], which delivered the final product through a mech-
IV
anism involving a Pd intermediate and b-carbon elimina-
[
3]
tion. It should be noted that when primary or secondary o-
bromobenzyl alcohols were employed, b-H elimination of the
palladacycle A occurred to give the carbonyl products 3
[
3a]
[
Eq. (1), Scheme 2]. Based on these interesting observa-
[4]
tions and our previous work on the Catellani reaction, in
which formation of Pd intermediate and retro-carbopalla-
dation of norbornene are two of the key steps, we
Scheme 1. Pd-catalyzed b-hydride elimination versus b-carbon elimina-
tion.
IV
[5]
anticipated that 5,6-dihydrophenanthridine derivatives 7,
which are prevalent structural units in natural products and
[
*] Dr. J. Ye, A. Limouni, S. Zaichuk, Prof. Dr. M. Lautens
Davenport Laboratories, Department of Chemistry
University of Toronto
[
6,7]
biologically active molecules,
might be accessible if o-
bromobenzylamines 6 undergo a similar Pd-catalyzed homo-
coupling reaction as that of o-bromobenzyl alcohols
8
0 St. George Street, Toronto, ON, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
**] We thank the Natural Sciences and Engineering Research Council
NSERC), the University of Toronto, and Alphora Research Inc for
1
[Eq. (2), Scheme 2]. However, when compared with tertiary
[
alcohols 1, a major obstacle is that the palladacycle C as well
as the key intermediate D contain a b-hydrogen at the
benzylic position, which might form the undesired imine
products 8a and/or 8b instead of the desired product 7.
Moreover, whereas retro-carbopalladation reactions of
(
financial support. M.L. thanks the Canada Council for the Arts for
a Killam Fellowship. Dr. Alan Lough (Department of Chemistry,
University of Toronto) is acknowledged for X-ray analysis. We also
thank D. Petrone and Dr. L. Zhang from our group for helpful
discussions.
[
16]
ketones and alkenes are well documented, retro-carbopal-
ladation of aldimines, to the best of our knowledge, has not
been uncovered to date.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411276.
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[
a]
Table 1: Optimization of reaction conditions.
Table 2: Substrate scope of the Pd-catalyzed homocoupling reaction of
o-bromobenzylamines.
[
a]
[
b]
Entry
[Pd]
Base
T [8C]
Yield [%]
[
[
c]
c]
1
2
3
4
5
6
7
8
9
1
1
Pd(OAc) /PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
120
120
120
120
110
130
120
120
120
120
120
64 (62)
72
72
2
Pd(dba) /PPh3
2
Pd(PPh3)4
–
[
d]
n.r.
[
[
e]
f]
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
72
76
12
68
86
60
Na CO3
2
Cs CO3
2
K3PO4
K3PO4
K3PO4
[
g]
h]
0
1
[
(86)
[a] The reaction was performed using 6aa (0.1 mmol), [Pd] (10 mol%),
and base (2 equiv) in toluene (1 mL) in a microwave vial at the indicated
1
temperature for 24 h unless otherwise noted. [b] Determined by H NMR
analysis of the crude reaction mixture. Value in the parentheses is the
yield of isolated 7aa. [c] PPh (10 mol%) was added. [d] No palladium
3
catalyst was used, n.r.=no reaction. [e] 90% conversion. [f] 16%
conversion. [g] K PO (1 equiv) was used. [h] Pd(PPh ) (5 mol%) was
3
4
3 4
used. Ts=4-toluenesulfonyl, dba=dibenzylideneacetone.
With these challenges in mind, o-bromobenzylamine 6aa
was chosen as a model substrate to test the feasibility of our
proposal (Table 1). After some screening, we were pleased to
find that the desired product 7aa, whose structure was
[8]
confirmed by X-ray crystallographic analysis, was isolated in
2% yield using Pd(OAc) (10 mol%), PPh (10 mol%), and
6
2
3
K CO3 (2 equiv) in toluene at 1208C for 24 h (entry 1,
2
Table 1). The imine 9a and its decomposition product 10a
[
9]
were observed as the by-products of this reaction. Encour-
aged by these results, a range of reaction parameters was
examined and representative results are shown in Table 1.
Better results were obtained with Pd(dba)2 and PPh3 or
Pd(PPh ) (entries 2 and 3) and Pd(PPh ) was chosen for
[a] The reaction was performed using 6 (0.3 mmol), Pd(PPh
and K PO (2 equiv) in toluene (1.5 mL) at 1208C for 24 h unless
otherwise noted. Yields of isolated product 7 were given. [b] Pd(PPh3)4
3 mol%) was used. [c] Reaction conducted at 1308C. [d] Reaction time:
8 h. [e] Reaction time: 28 h. 4-Ns=4-nitrobenzenesulfonyl.
3 4
) (5 mol%),
3
4
(
4
3
4
3 4
further optimization. A control experiment was carried out in
the absence of the palladium catalyst and no reaction
occurred (entry 4). Changing the temperature did not lead
to an appreciable improvement (entries 5 and 6). Among the
bases surveyed, K PO proved to be the best (entries 7–9).
study for its relative ease of purification. The reactivity of o-
bromobenzylamines 6 with different aromatic substituents at
the benzylic position (Ar) was then evaluated. Monosubsti-
tuted electron-rich (7ad–7af) or electron-poor aryl groups
(7ag–7ai), a disubstituted aryl group (7aj), and 1- or 2-
naphthyl (7ak and 7al) were all tolerated, furnishing the
homocoupling products in moderate to excellent yields. o-
Bromobenzylamines with a heteroaromatic substituent such
as 2-methoxyquinolin-3-yl and 2- or 3-thienyl also reacted at
elevated temperature and/or with prolonged reaction time
(7am–7ao). Substitution effects on the brominated aromatic
3
4
Whereas reducing the amount of K PO to 1.0 equivalent
3
4
resulted in a lower yield (entry 10), decreasing the loading of
Pd(PPh ) to 5 mol% maintained the yield of 7aa at 86%
3
4
upon isolation (entry 11). These conditions were used in the
remainder of the study.
The substrate scope of the Pd-catalyzed homocoupling
reaction of o-bromobenzylamines
6
was investigated
(
Table 2). In addition to 4-toluenesulfonyl (Ts), other N-
1
sulfonyl protecting groups such as benzenesulfonyl, meth-
anesulfonyl, and 4-nitrobenzenesulfonyl can also be utilized
for this transformation. Although the 4-toluenesulfonyl and
benzenesulfonyl substituent gave comparable yields of the
corresponding products (7aa vs. 7ba, 7ab vs. 7bb, 7ac vs.
moiety of o-bromobenzylamines 6 (R ) were also explored.
Both electron-rich and electron-poor substrates underwent
the reaction smoothly to give highly substituted 5,6-dihydro-
phenanthridine derivatives 7ea–7ja in moderate to good
yields. It is worth mentioning that the chlorine counterpart of
o-bromobenzylamine 6aa also afforded the desired product
7
bc), the 4-toluenesulfonyl group was chosen for further
2
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t
7
aa in a 75% yield when Pd(P Bu ) (10 mol%) was used as
overall yield of (S)-7aa with 99% ee was obtained when the
first step was conducted with rhodium/diene complex
3
10]
2
[
the catalyst instead of Pd(PPh ) .
3
4
[12b,c]
Having realized the Pd-catalyzed synthesis of 6-aryl-5,6-
dihydrophenanthridine derivatives 7 from o-bromobenzyl-
amines 6, we turned our attention to the enantioselective
synthesis of these compounds. Although optically active 6-
substituted 5,6-dihydrophenanthridine derivatives have ex-
hibited interesting biological activities, no catalytic asym-
metric approach has been reported. Based on Hayashiꢀs
pioneering work on the asymmetric arylation of imines using
[RhCl((R)-11)]2
as the catalyst, phenyl boroxine
(1.2 equiv of B) as the nucleophile, and 40 mol% of KOH
solution (3.0m) as the base followed by the addition of
Pd(PPh ) (5 mol%), K PO (2 equiv), and 4 ꢁ molecular
3
4
3
4
sieves in the second step. Under these conditions, the
generality of this enantioselective one-pot reaction was
explored (Table 3). Arylboroxines containing an electron-
donating or -withdrawing group all afforded the correspond-
ing products (S)-7ab–(S)-7ai in moderate to good overall
yields with excellent enantioselectivity (ꢀ 99% ee). A disub-
stituted arylboroxine worked as well to give the enantiomer-
ically pure product (S)-7aj in 64% yield. The reduced yields
in the cases of (S)-7ac and (S)-7ak may be attributable to the
sluggish arylation of imine with sterically bulky 2-methyl-
phenylboroxine and 1-naphthylboroxine in the first step.
Highly oxygenated 5,6-dihydrophenanthridine derivatives
[
6e]
[11]
[
12,13]
Rh/chiral dienes
and our previous studies on multimetal-
[14]
catalyzed one-pot/domino reactions, we envisioned that the
implementation of Rh and Pd catalysis might enable a one-
pot enantioselective synthesis of 5,6-dihydrophenanthridines
from o-bromobenzaldimines 4 and aryl boronic acids or
boroxines. However, compatibility issues and potential race-
mization of the sensitive benzylic stereocenter were the major
7
[
15]
concerns. Fortunately, after extensive screening,
a 70%
(
(S)-7ea, (S)-7ei, and (S)-7 fa), which are common scaffolds
[
6]
in natural products, were also obtained in good overall yield
with excellent enantioselectivity. o-Bromobenzaldimine sub-
stituted with an electron-donating group such as 5-OMe or 4-
Me are also suitable substrates for this reaction, furnishing the
corresponding products (S)-7ga, (S)-7ha, and (S)-7hh in
synthetically useful yields with > 99% ee. Dichloro-substi-
tuted 5,6-dihydrophenanthridine (S)-7ja was also obtained in
moderate yield with high enantiopurity. The absolute config-
uration of the enantiopure products 7 was unambiguously
determined to be S by X-ray diffraction analysis of (S)-7ea
Table 3: Substrate scope of enantioselective one-pot syntheses of 5,6-
dihydrophenanthridines 7 through Rh/Pd catalysis.
[
a]
[
8]
and (S)-7ha.
A possible mechanism for the formation of 5,6-dihydro-
phenanthridines 7 from o-bromobenzylamines 6 under palla-
[
3,16]
dium catalysis is shown in Scheme 3.
Oxidative addition of
0
o-bromobenzylamines 6 to Pd would form intermediate E,
[a] The reaction was performed on 0.3 mmol scale of 4 at 608C for 15 h
followed by the addition of Pd(PPh ) (5 mol%), 4 ꢀ molecular sieves
3
4
(
300 mg), and K PO (2 equiv) and stirred at 120 or 1308C for 24–48 h
3 4
unless otherwise noted (see the Supporting Information for details).
b] Yields of isolated product (S)-7. [c] ee was determined by HPLC using
[
a chiral stationary phase. [d] Reaction time of the first step: 48 h. [e] The
reaction was carried out on 1.0 mmol scale of 4. [f] [RhCl((R)-11)]2
(
1
5 mol%) was used, reaction time of the first step: 24 h. [g] [RhCl((R)-
1)] (1.5 mol%) and Pd(PPh ) (3 mol%) were used.
Scheme 3. A possible mechanism.
2
3 4
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Angewandte
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IV[16c]
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II
[17]
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a transmetalation-type reaction between palladacycle F and
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[
6]
5
,6-dihydrophenanthridine skeletons, in which an unprece-
dented retro-carbopalladation of aldimines was observed. By
taking advantage of Rh and Pd catalysis, a highly enantiose-
lective synthesis of 6-aryl-substituted 5,6-dihydrophenanthri-
dine derivatives was achieved in a one-pot manner. Further
studies on extending this strategy to related processes are
being pursued in our laboratory.
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CCDC 1021153 (7aa), 1026833 (7ak), 1021957 ((S)-7ea), and
[
1021729 ((S)-7ha) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
Received: November 20, 2014
Published online: && &&, &&&&
[9] Due to decomposition of the imine under the reaction conditions
and its instability on the silica gel column, only a low yield
(< 10%) of 9a was isolated. The formation of imine 9a and
benzaldehyde 10a was further confirmed by comparing the
Keywords: dihydrophenanthridines ·
.
enantioselective synthesis · palladium · b-carbon elimination
1
H NMR spectra of the crude reaction mixture with the
authentic samples. See the Supporting Information for details.
10] A very low yield was obtained under the optimized conditions,
see the Supporting Information for details.
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synthesis of 6-alkyl-substituted 5,6-dihydrophenanthridine
derivatives through asymmetric reduction of phenanthridines
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[
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Communications
b-Carbon Elimination
Retro-carbopalladation of aldimines in
the presence of a suitable b-hydrogen
atom is a key step in the Pd-catalyzed
homocoupling reactions of o-bromoben-
zylamines, providing an expeditious syn-
thetic route to 5,6-dihydrophenanthridine
derivatives. A highly enantioselective
synthesis procedure was also achieved in
a one-pot manner by taking advantage of
Rh and Pd catalysis.
J. Ye, A. Limouni, S. Zaichuk,
M. Lautens*
&&& — &&&
Synthesis of Enantioenriched 5,6-
Dihydrophenanthridine Derivatives
through retro-Carbopalladation of Chiral
o-Bromobenzylamines
6
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
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