Microwave-Assisted Synthesis of Heterocycles by Rhodium(III)-Catalyzed Annulation of N-Methoxyamides with α-Chloroaldehydes

Article abstract of DOI:10.1002/anie.201710776

α-Chloroaldehydes have been used as alkyne equivalents in rhodium-catalyzed syntheses of isoquinolones and 3,4-dihydroisoquinolins starting from N-methoxyamides. Compared to the existing technology, a complementary regioselectivity is achieved. Mechanistic investigations have been performed, and it was found that steric effects of both substrate and additive determine the product selectivity. Various other heterocycles, such as isoquinolines and lactones, can be prepared by transformation of the obtained products.

Full text of DOI:10.1002/anie.201710776

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Microwave-Assisted Synthesis of Heterocycles by Rh(III)-
Catalyzed Annulation of N-Methoxyamides with α-
Chloroaldehydes
Authors: Ji-Rong Huang and Carsten Bolm
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710776
Angew. Chem. 10.1002/ange.201710776
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10.1002/anie.201710776
Angewandte Chemie International Edition
COMMUNICATION
Microwave-Assisted Synthesis of Heterocycles by Rh(III)-
Catalyzed Annulation of N-Methoxyamides with α-Chloro-
aldehydes
Ji-Rong Huang and Carsten Bolm*
Abstract: α-Chloroaldehydes have been used as alkyne equivalents
in rhodium-catalyzed syntheses of isoquinolones and 3,4-
dihydroisoquinolins starting from N-methoxyamides. Compared to
were known to be reactive towards transition metals,[9] which could
lead to deleterious reactions here. Second, α-chloroaldehydes had
two electrophilic sites and both the chloro and the carbonyl group
could compete in reactions with an intermediately formed
nucleophilic rhodacycle resulting in product mixtures.[10] Third,
compared to α-halo or pseudohaloketones, aldehydes exhibited a
lower coordination ability with metal centers,[11] and forth, a rather
sterically congested tertiary carbon center would result from the
initially required formal SN-type substitution (of the chloro group).[12]
The overcoming of these issues and the success of our approach is
presented here [Scheme 1, Eq. (2)].
the existing technology,
a
complementary regioselectivity is
achieved. Mechanistic investigations have been performed, and it
was found that steric effects of both substrate and additive
determine the product selectivity. Various other heterocycles such as
isoquinolines and lactones can be prepared via the products.
In recent years, transition metal-catalyzed oxidative annulation has
emerged as a viable tool for the assembly of heterocycles.[1]
Rhodium complexes, which exhibit high efficiency in C−H bond
activations, have been recognized as effective catalysts for diverse
transformations. Among them, annulations with alkynes represent a
practical approach for the synthesis of pharmacologically important
heterocycles.[2] The regioselective insertion of unsymmetrical internal
alkynes, however, has remained a challenge in such reactions as it
is largely determined by the inherent electronic and steric factors of
the substrates. To reverse the intrinsic regioselectivity, tether-
mediated intramolecular cyclizations have been introduced.[3a]
Alternatively, 2-acetylenic ketones with weakly coordinated carbonyl
groups could be applied.[3b] As internal alkyne equivalents, diazo
compounds led to annulated heterocycles with specific regio-
selectivities.[4] In general, annulations with terminal alkynes proved
difficult due to competing alkyne dimerizations (Glaser coupling). To
solve this restraint, Guimond et al. developed a rhodium-catalyzed
redox-neutral synthesis of isoquinolones.[5] The exclusive
regioselectivity of the insertion was achieved by a substitution at the
3-position. Furthermore, allyl carbonates[6a-d] and 1,3-dienes[6e] have
been utilized as equivalents of terminal alkynes. Recently, Glorius
and co-workers introduced the C(Sp3)-based electrophiles α-halo or
pseudohaloketones as equivalents of preoxidized terminal
alkynes.[7a] Subsequently, others utilized such formal SN-type
reactions for constructing different heterocycles.[7b-d] In each case a
pronounced regioselectivity was observed leading to products with
the substituent located next to the nitrogen directing group [Scheme
1, Eq. (1)].[8] After analyzing mechanistic details we hypothesized
that using α-chloroaldehydes could reverse the regioselectivity.
However, a number of challenges had to be addressed with α-
chloroaldehydes as coupling partners: First, aldehyde C−H bonds
Standard regioselectivity observed with terminal alkynes or equivalents:
[Rh]
NR
R1
NHR
R1
(1)
+
H
or alkyne equivalents (such as
allyl carbonates, 1,3-dienes,
α-halo or pseudohaloketones)
Complementary regioselectivity achieved here with α-chloroaldehydes
O
O
O
OMe
OMe
R1
[Rh]
N
N
(2)
H
+
H
H
Cl
R1
Scheme 1. Rhodium-catalyzed annulations with alkynes and equivalents
thereof.
The annulation studies were initiated by taking N-methoxy-
benzamide (1a) and 2-chloro-3-phenylpropanal (2a) as starting
materials, which we expected to result in heterocycle 3aa (Table 1).
After an extensive screening (see Supporting Information),
a
microwave-assisted coupling catalyzed by [RhCp*(MeCN)3][SbF6]2 in
the presence of NaOAc and NaHCO3 was found to be optimal
leading to 3aa in 72% yield after 5 h (Table 1, entry 1). The heating
mode largely affected the reaction outcome, as revealed by a
Table 1. Screening of the reaction conditions.[a]
O
O
[RhCp*(MeCN)3][SbF6]2
(5 mol %)
Bn
OMe
OMe
O
N
Ph
N
H
+
Cl
NaOAc (3.0 equiv),
NaHCO3 (1.0 equiv)
MeOH, Ar, 60 °C, MW, 5 h
Bn
3aa
1a
2a
Entry
1
2
3
4
5
6
7
8
Variable
-
Yield [%][b]
72
65
58
49
38
57
56
47
55
76
Use of a preheated oil bath for 60 h
Reaction time of 3 h
[*]
Dr. J.-R. Huang,# Prof. Dr. C. Bolm
Institute of Organic Chemistry
Reaction time of 3 h at 100 °C
Use of Cs2CO3 instead of NaHCO3
Use of K3PO4 instead of NaHCO3
Use of TEA instead of NaHCO3
Use of 1.5 equiv of NaOAc
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail:carsten.bolm@oc.rwth-aachen.de
Homepage: http://bolm.oc.rwth-aachen.de/
New address:
[#]
9
10
Use of 0.5 equiv of NaHCO3
Use of 2.0 equiv of NaHCO3
School of Pharmacy
Huazhong University of Science and Technology
Wuhan, Hubei 430030 (China)
[a]
A mixture of 1a (30.2 mg, 0.2 mmol), 2a (100.8 mg, 0.6 mmol),
[RhCp*(MeCN)3][SbF6]2 (8.1 mg, 5 mol %), NaOAc (49.2 mg, 3.0 equiv) and
NaHCO3 (16.8 mg, 1.0 equiv) in dry MeOH (1.0 mL) was stirred under Ar at
60 °C for 5 h under microwave irradiation. [b] After column chromatography.
Supporting information for this article is given via a link at the end of
the document
This article is protected by copyright. All rights reserved.

10.1002/anie.201710776
Angewandte Chemie International Edition
COMMUNICATION
O
O
O
catalysis performed in a preheated oil bath, which provided 3aa in
only 65% yield after 60 h (Table 1, entry 2). Thus, microwave
irradiation was applied when the effects of time, temperature, and
additives were evaluated (Table 1, entries 3-10). As a result, the
yield of 3aa could be improved to 76% by increasing the amount of
NaHCO3 from the commonly used 1 equiv to 2 equiv (Table 1, entry
10).
Method (A)
or (B)
OMe
OH
OMe
or
R1
OMe
N
N
O
N
+
Ar
Ar
Ar
H
Cl
R1
R1
1
2
3
4
Method (A): As described in Table 1, entry 10.
Method (B): As method (A) but with NaOPiv instead of NaOAc.
O
O
O
O
OMe
OMe
OMe
OMe
N
Under the optimized conditions, the scope of the cross coupling
was explored (Schemes 2 and 3). First, the N-methoxybenzamide
structure was varied. 2-Chloro-3-phenylpropanal (2a) was kept as
coupling partner. In general, para-substituted N-methoxybenzamides
reacted well providing 4-substituted N-methoxyisoquinolones (3aa-
3ga) in moderate to good yields. With benzamide 1h having a bromo
substituent in the meta position of the arene, only 3ha was obtained
as exclusive product in 56% yield. In contrast, starting from
compound 1i with the same molecular scaffold but bearing a meta-
methoxy group gave a mixture of isomeric isoquinolones 3ia and
3i'a in yields of 68% and 24%, respectively. N-Methoxyiso-
quinolones 3ja and 3ka remained inaccessible presumably due to
formation of unreactive chelates of rhodium intermediates with the
heterocylic cores of the furanyl- and thiophenyl-based starting
materials. An entirely different reaction behavior was observed with
ortho-substituted N-methoxybenzamides, and those results will be
presented in Scheme 3.
N
N
N
F3C
F
Bn
Bn
Bn
Bn
3aa, 76% (A)
3ba, 83% (A)
3ca, 55% (A)
3da, 73% (A)
O
O
O
O
OMe
OMe
Br
OMe
OMe
N
N
N
N
Cl
I
Br
Bn
Bn
Bn
Bn
3ga, 93% (A)
3ha, 56% (A)
3ea, 49% (A)
3fa, 62% (A)
O
O
O
O
OMe
OMe
MeO
OMe
OMe
O
S
N
N
N
N
+
Bn
Bn
3ka, n. o. (A)
Bn
3ia, 68% (A)
OMe Bn
3i’a, 24% (A)
3ja, n. o. (A)
O
O
OMe
OH
OMe
N
N
O
3ab,
3ac,
3ad,
3ae,
3af,
R = oct, 45% (A)
R = pent, 55% (A)
R = Bu, 65% (A)
R = Pr, 59% (A)
R = Et, 62% (A)*
R = H, 40% (A)
OMe
N
+
R
O
3ag,
4ah, 10%, dr = 3:1 (A)
The substrate scope was further evaluated by studying couplings
between various 2-chloroaldehydes and N-methoxybenzamide 1a.
Unbranched alkyl-substituted substrates afforded isoquinolones 3ab-
3af and 3ai in yields ranging from 45% to 65% (Scheme 2).
Commercial available 2-chloroacetaldehyde (50 wt % in water) could
directly be applied (in the presence of MS 4 Å) leading to 3ag in 40%
yield. An unexpected observation was made in the reaction of 1a
with 2-chloro-3-cyclohexyl propanal (2h). Besides N-methoxyiso-
quinolone 3ah (55% yield), 3,4-dihydroisoquinolin 4ah was isolated
in 10% yield (as a 3:1 mixture of diastereomers as determined by 1H
NMR spectroscopy). The latter product type was also observed in
couplings of 2-aryl-substituted 2-chloroaldehydes. Those substrates,
however, did not react under the standard reaction conditions
(Method A), but required changing the base from NaOAc to NaOPiv
(Method B). Accordingly, 4aj and 4ak were accessed in yields of
40% and 89% yield, respectively. The diastereomeric ratios were 8:1
(for 4aj) and 5:1 (for 4ak). The structure of 4aj was further confirmed
by methylation of the hydroxyl group. The attempt to prepare 3al
from 1a and 2-chloropent-4-enal (2l) failed, presumably due to
coordination tendency of the terminal double bond of the aldehyde.
Also 4am and 4an remained inaccessible [from chloral (2m) and 2-
chloro-2-cyclohexylethanal (2n), respectively] revealing that the
presence of an α-hydrogen at the aldehyde was critical for the
catalysis to occur.
3ah, 55% (A)
O
OMe
N
O
O
OMe
N
OMe
N
OMe
N
OH
OH
R
R
(CH2)4Cl
4am, R = Cl, n. o.
(A or B)
4an, R = -(CH2)5-, n. o.
(A or B)
R
3al, n.o. (A or B)
3ai, 50% (A)
4aj, R = H, n. o. (A)
40%, dr = 8:1 (B)
4ak, R = Cl, 89%, dr = 5:1 (B)
Scheme 2. Scope of the rhodium-catalyzed annulations (part 1); n.o. = not
observed; * use of 0.4 mmol of 1a and 0.2 mmol of 2f.
3,4-dihydroisoquinolin 4la, which was isolated in 86% yield as an 8:1
mixture of diastereomers (Scheme 3). Other ortho-substituted
benzamides reacted analogously, and the yields of the
corresponding 3,4-dihydroisoquinolins were high (reaching 96% for
ortho-bromo-substituted 4na; Scheme 3). A few observations shall
be highlighted: First, scaling-up the catalysis towards 4ma
proceeded well, and on a 2 mmol scale, the product was obtained in
88% yield.[13] Second, initially, an unprotected phenolic substrate
was used for the synthesis of 4qa. Although the coupling occurred,
the yield was low (20%). Using the O-acetyl-protected N-methoxy-
benzamide (1r) proved beneficial leading to 45% of 4qa with a dr of
15:1 after direct hydrolysis. Third, applying method A in the coupling
of 2-methoxy N-methoxybenzamide 1s with 2a gave a 1:1 mixture of
isoquinolone 4sa and 3,4-dihydroisoquinolin 3sa (as determined by
1H NMR spectroscopy). Following method B, led to 4sa exclusively
(in 77% yield). Testing the sodium salt of N-Boc leucine in this
coupling (instead of NaOAc or NaOPiv, method C) gave 86% of a
2:1 mixture of 4sa and 3sa, which was separated by preparative
TLC. Finally, also couplings of 2a with 2,4-disubstituted N-methoxy
benzamides afforded mixtures of the corresponding 3,4-dihydro-
isoquinolins (4ta and 4ua) and isoquinolones (3ta and 3ua). Testing
As mentioned above, the reaction behavior of ortho-substituted
N-methoxybenzamides differed from the one observed with
substrates having other substitution patterns (which, for example, led
to 3aa-ha). This was first found in the attempt to couple ortho-iodo
N-methoxybenzamide 1l with 2-chloro-3-phenylpropanal (2a) which,
to our suprise, did not proceed under the aforementioned standard
reactions conditions (method A, with NaOAc as base). However, as
observed in the aldehyde variation study, a reaction occurred when
NaOPiv was used instead of NaOAc (method B). Also in this case,
the product was not the initially expected isoquinolone, but
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10.1002/anie.201710776
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COMMUNICATION
substituents were obtained in yields of up to 75%. Thus, for product
formation, the presence of a substituent at C2 was essential, and
overall, method B proved superior over method A.[14]
Br
O
F
O
I
O
Cl
O
OMe
OH
OMe
OH
OMe
OH
OMe
OH
N
N
N
N
Further experiments were conducted to investigate mechanistic
Bn
Bn
Bn
Bn
details (Scheme
5
and Supporting Information).[15] The kinetic
4la
4ma
89%, dr = 11:1 (B)
88%, dr = 12:1 [2 mmol scale; (B)]
OMe O
4oa, 91%, dr = 4:1 (B)
4na, 96%, dr = 8:1 (B)
isotope effect (KH/D = 1:1, after 1 h) observed in parallel reactions
using N-methoxyamide 1a and 1a-d5 indicated that the C−H
cleavage was not rate-determining (Scheme 5, top). Intermolecular
competition reaction between 2a and substrates 1b and 1g revealed
that the aryl moiety with lower electron density facilitated the C−H
bond activation (Scheme 5, middle). Performing the coupling of 1m
and 2a in CD3OD (following method B) led to 73% of 4ma (dr = 11:1)
with 79% deuterium incorporation in the α-position of the benzyl
group. This result suggested the involvement of an enolic
intermediate in the process, which was further supported by the the
coupling of 1m with enantioenriched 2a (79% ee), providing 84% of
(essentially) racemic 4ma (dr = 11:1, 1% ee). Finally, also enol
acetate 6 (Z/E = 5:1) reacted with N-methoxyamide 1a providing 3aa
in 64% yield (following method A).
n. o. (A)
86%, dr = 8:1 (B)
OMe O
X
O
NO2
O
OMe
N
OMe
OH
N
OMe
OH
OMe
OH
+
N
N
Bn
Bn
4sa
Bn
4qa
Bn
3sa
33%, 4sa (dr = 3:1) + 3sa; ratio = 1:1 (1H NMR) (A)
77%, 4sa (dr = 5:1) + 3sa; ratio = >20:1 (1H NMR) (B)
86%, 4sa (dr = 6:1) + 3sa; ratio = 2:1 (isolated) (C)
4pa, 85%, dr = 5:1 (B)
20%, dr = 6:1 (X = OH) (B)
45%, dr = 15:1 (X = OAc)* (B)
Me
O
Me
O
Me
O
Me
O
OMe
OH
OMe
OMe
OH
OMe
N
N
N
N
+
+
Me
Br
Me
Br
Bn
Bn
Bn
Bn
4ta, 69%, dr = 8:1 (B)
3ta, 22% (B)
3ua, 31% (B)
4ua, 15%, dr = 16:1 (B)
Cl
O
Cl
O
Cl
O
Cl
O
As generally accepted, most coupling reactions proceed by direct
coordination of both reaction partners at the metal center. Explaining
the influence of the anions (OAc or OPiv) on both the product
formation and the regioselectivity of the process has, however,
remained difficult. Although the mechanistic details of the coupling
reported here are still unclear, two scenarios involving the anions
can be envisaged. In the first one, the combination of aldehyde and
anion (OAc or OPiv) generates an ester enolate (such as enol
acetate 6), which then completes the coupling reaction by alkene
insertion.[6] Alternatively, the protonated form of the anion acts as
ligand assisting the approach of the aldehyde towards the rhodium
species by hydrogen bonding interaction (TS-II) (see Supporting
Information).[16] In any case, the steric factors induced by both the
substrate and the anion (OAc or OPiv) will account for the product
generation.
OMe
N
OMe
OH
OMe
N
OMe
OH
N
N
OH
OH
COOMe
Bu
4md, 80%, dr = 15:1 (B)
4mh, 84%, dr = 14:1 (B)
4mo, 78%, dr = 7:1 (B)
4mj, 43%, dr = 11:1 (B)
Scheme 3. Scope of the rhodium-catalyzed annulations (part 2); methods (A)
and (B) as described in Scheme 2; method (C): as method (A), but with the
sodium salt of N-Boc-Leu instead of NaOAc; n.o. = not observed; * use of 2-
(methoxycarbamoyl)phenyl acetate (1r); after work-up 4qa with X = OH was
isolated.
other α-chloro aldehydes (than 2a) in reactions with 2-chloro-N-
methoxybenzamide (1m) gave 3,4-dihydroisoquinolins 4md, 4mh,
4mj, and 4mo as the only products in yields ranging from 43% to
84%.
To further expand the substrate scope, indole-2-carboxamide (1v)
was applied (Scheme 4). Reacting 1v with 2a gave 4va in yields of
98% (dr = 6:1) and 81% (dr = 9:1) following method A and method B,
respectively. Heating of 4va in CDCl3 to 100 °C for 2 h led
quantitatively to 3va.
O
2a
O
OMe
[RhCp*(MeCN)3][SbF6]2 (5 mol %)
N
OMe
N
H/D
NaHCO3 (2.0 equiv)
NaOAc (3.0 equiv)
Ar, 60 °C, MeOH, MW, 1 h
KH/D = 1:1
H
H/D
Bn
3aa, 42%
3aa-d4, 42%
1a
1a-d5
O
Bn
Bn
OH
O
HN OMe
OMe
2a
100 °C
N
OMe
N
N
N
OMe
OMe
CDCl3
2 h, quant
N
Me
O
Method A or B
H
2a
N
N
[RhCp*(MeCN)3][SbF6]2 (5 mol %)
98%, dr = 6:1 (A)
81%, dr = 9:1 (B)
O
O
Bn
Me
3va
Me
4va
1b
+
O
3ba, 29%
+
1v
NaHCO3 (2.0 equiv)
NaOAc (3.0 equiv)
Ar, 60 °C, MeOH, MW, 1 h
O
O
OMe
OMe
O
O
O
N
N
H
OMe
N
Me
OMe
Ph
OMe
OMe
N
N
N
I
I
1g
R
Bn
3ga, 76%
Bn
Bn
Bn
Bn
5wa, R = H
5xa, R = Ph
} n. o. (A or B)
O
5ya
5za
75% (B)
5aaa
21% (B)
Cl
O
trace (A), 22% (B)
OMe
N
OMe
OH
Cl
Cl
N
Rh Cp*
O
OAc
Bn
Scheme 4. Couplings of 2a with indole-2-carboxamide (1v) and N-methoxy-
acrylamides.
R2
H
O
Bn D/H
6 (Z/E = 5:1)
O
R1
TS-II
4ma, 73%, dr = 11:1, 79% D
(from a reaction in CD3OD)
Next, N-methoxyacrylamides were tested in reactions with 2a
(Scheme 4). To our disappointment, neither method A nor method B
led to products 5wa and 5xa. In contrast, 2-pyridones 5ya-5aaa
derived from N-methoxyacrylamides with α-alkyl or α-phenyl
Scheme 5. Mechanistic investigations.
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10.1002/anie.201710776
Angewandte Chemie International Edition
COMMUNICATION
To demonstrate the synthetic value of the products, various
functionalizations were studied (Scheme 6). The N-methoxy group of
Acknowledgements
3aa was removed by treatment with NaH in DMF at 120 °C under
microwave irradiation leading to benzolactam 7 in 77% yield. Upon
reaction of 7 with triflic anhydride, 8 was obtained in 90% yield. The
latter product proved useful for the synthesis of isoquinolines 9-11,
which were accessed by reductive deoxygenation and cross-
couplings (for details see Supporting Information). 3,4-Dihydro-
isoquinolin 4ma could readily be converted into N-methoxy-
benzamide 3ma by treatment with a mixture of mesyl chloride and
triethylamine. The ease of this dehydration providing the product in
97% yield after 2 h at 0 °C was unexpected because the starting
material was stable at ambient conditions for weeks. Also surprising
was the reaction of 4ma with PDC, which led to 12 in 68% yield.
Apparently, oxidation had occurred at two positions, the hydroxyl
group and the benzylic C–H.[17] Product 12 proved valuable because
under basic conditions, lactones 13a-c were formed. While the first
product resulted from deprotonation of the hydroxyl group followed
by intramolecular carbonyl addition, lactones 13b and 13c were
obtained by the aforementioned process and a subsequent inter-
molecular esterification with MeOH or EtOH, respectively.
J.-R.H. acknowledges support by the Alexander von Humboldt
Foundation.
Keywords: rhodium catalysis • α-chloroaldehyde • hydrogen
bonding • isoquinolone
[1]
For recent reviews: a) C−H Bond Activation and Catalytic
Functionalization (Eds.: P. H. Dixneuf, H. Doucet), Springer
I
International Publishing, Cham, 2016; b) J. Wencel-Delord, F. W.
Patureau, F. Glorius, Top. Organomet. Chem. 2016, 55, 1; c) J. G. Kim,
K. Shin, S. Chang, Top. Organomet. Chem. 2016, 55, 29; d) T. Gensch,
M. N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc. Rev. 2016,
45, 2900; e) S.-S. Li, L. Qin, L. Dong, Org. Biomol. Chem. 2016, 14,
4554; f) R.-Y. Zhu, M. E. Farmer, Y.-Q. Chen, J.-Q. Yu, Angew. Chem.
Int. Ed. 2016, 55, 10578; Angew. Chem. 2016, 128, 10734; g) M.
Gulías, J. L. Mascareñas, Angew. Chem. Int. Ed. 2016, 55, 11000;
Angew. Chem. 2016, 128, 11164.
[2]
[3]
For selected review: Rh-Catalyzed Synthesis of Nitrogen-Containing
Heterocycles (Eds.: X.-F. Wu), Wiley-VCH, Weinheim, 2016.
a) X. Xu, Y. Liu, C.-M. Park, Angew. Chem. Int. Ed. 2012, 51, 9372;
Angew. Chem. 2012, 124, 9506; b) K. K. Gollapelli, S. Kallepu, N.
Govindappa, J. B. Nanubolu, R. Chegondi, Chem. Sci. 2016, 7, 4748.
For selected examples: a) W.-W .Chan, S.-F .Lo, Z. Zhou, W.-Y .Yu, J.
Am. Chem. Soc. 2012, 134, 13565; b) Y. Cheng, C. Bolm, Angew.
Chem. Int. Ed. 2015, 54, 12349; Angew. Chem. 2015, 127, 12526; c) H.
Wang, L. Li, S. Yu, Y. Li, X. Li, Org. Lett. 2016, 18, 2914; d) J. Jie, H. Li,
S. Wu, Q. Chai, H. Wang, X. Yang, RSC Adv. 2017, 7, 20548; e) B. Li,
B. Zhang, X. Fan, Chem. Commun. 2017, 53, 1297.
O
OTf
O
[4]
OMe
N
N
NH Tf2O, py
DCM, 0 °C
NaH, DMF
120 °C, Ar, MW, 2 h
Bn
Bn
Bn
Me
3aa
7, 77%
8, 90%
O
diverse
transfor-
mations
[5]
[6]
N. Guimond, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2011, 133,
6449.
H
N
N
N
N
a) N. J. Webb, S. P. Marsden, S. A. Raw, Org. Lett. 2014, 16, 4718; b)
H. Chu, S. Sun, J.-T. Yu, J. Cheng, Chem. Commun. 2015, 51, 13327;
c) M. Zhang, H.-J. Zhang, T. Han, W. Ruan, T.-B. Wen, J. Org. Chem.
2015, 80, 620; d) J. Wen, D. P. Tiwari, C. Bolm, Org. Lett. 2017, 19,
1706; e) D. Zhao, F. Lieb, F. Glorius, Chem. Sci. 2014, 5, 2869.
a) D.-G. Yu, F. de Azambuja, F. Glorius, Angew. Chem. Int. Ed. 2014,
53, 2754; Angew. Chem. 2014, 126, 2792; b) Z.-J. Wu, Y.-Q. Li, Z.-Z.
Huang, Eur. J. Org. Chem. 2016, 5399; c) J. Li, Z. Zhang, M. Tang, X.
Zhang, J. Jin, Org. Lett. 2016, 18, 3898; d) C. Yang, F. Song, J. Chen,
Y. Huang, Adv. Synth. Catal. 2017, 359, 3496.
Bn
O
Bn
10, 67%
Bn
9, 97%
11, 46%
Cl
Cl
O
OMe
OH
OMe
N
N
MsCl, NEt3
[7]
DCM, 0 °C, 2 h
Bn
4ma
Bn
3ma, 97%
PDC
DCM
RT, 20 h
Cl
O
Cl
O
Cl
O
OMe
N
[8]
[9]
3,3-Disubstituted cyclopropenes have been employed to realize the
reverse regioselective annulation: T. K. Hyster, T. Rovis, Synlett 2013,
24, 1842.
NEt3
NaH
O
O
H
DMF, RT
ROH
80 °C
N
O
Bn
COOR
Bn
OMe
Bn OH
O
13a, 37%
12, 68%
a) K. Kokubo, K. Matsumasa, M. Miura, M. Nomura, J. Org. Chem.
1997, 62, 4564; b) K. Kokubo, K. Matsumasa, Y. Nishinaka, M. Miura,
M. Nomura, Bull. Chem. Soc. Jpn. 1999, 72, 303; c) R. T. Stemmler, C.
Bolm, Adv. Synth. Catal. 2007, 349, 1185; d) M. Shimizu, H. Tsurugi, T.
Satoh, M. Miura, Chem. Asian J. 2008, 3, 881; e) F. Xiao, Q. Shuai, F.
Zhao, O. Baslé, G. Deng, C.-J. Li, Org. Lett. 2011, 13, 1614; f) H.-J.
Zhang, C. Bolm, Org. Lett. 2011, 15, 3900; g) M. Gao, M. C. Willis, Org.
Lett. 2017, 19, 2734.
13b, R = Me,
13c, R = Et,
46%
66%
Scheme 6. Product derivatizations.
In conclusion, α-chloroaldehydes have been used as equivalents
of terminal alkynes allowing to access isoquinolones and 2-
pyridones with complementary regioselectivity compared to known
processes. With sterically crowded amides or aldehydes, 3,4-
dihydroisoquinolins are formed as sole products. Presumably the
added sodium salt participates in the reaction by generating an ester
enolate species or by acting as ligand stabilizing the association of
the aldehyde to the metal by hydrogen bonding interactions. Finally,
both isoquinolones and 3,4-dihydroisoquinolins were converted to
other molecular scaffolds demonstrating their synthetic value.
[10] a) K. Tanaka, G. C. Fu, Org. Lett. 2002, 4, 933; b) K. Tanaka, Y.
Hagiwara, K. Noguchi, Angew. Chem. Int. Ed. 2005, 44, 7260; Angew.
Chem. 2005, 117, 7426; c) B. Ye, N. Cramer, Synlett 2015, 26, 1490; d)
H. Jo, J. Park, M. Choi, S. Sharma, M. Jeon, N. K. Mishra, T. Jeong, S.
Han, I. S. Kim, Adv. Synth. Catal. 2016, 358, 2714.
[11] a) X.-H. Liu, H. Park, J.-H. Hu, Y. Hu, Q.-L. Zhang, B.-L. Wang, B. Sun,
K.-S. Yeung, F.-L. Zhang, J.-Q. Yu, J. Am. Chem. Soc. 2017, 139, 888;
b) D. Mu, X. Wang, G. Chen, G. He, J. Org. Chem. 2017, 82, 4497; c) S.
W. Youn, H. J. Yoo, Adv. Synth. Catal. 2017, 359, 2176 and references
therein.
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10.1002/anie.201710776
Angewandte Chemie International Edition
COMMUNICATION
[12] For the only example of a formal SN-type substitution involving an α-
halo or pseudohaloketone forming a tertiary carbon center, see ref. 7c.
[13] The couplings of 1a with 2a and 1m with 2a were also performed on a
gram scale (6 mmol). Because of the size restrictions of the microwave
reactor, those reactions were carried out using an oil bath for the
heating (to 60 °C in MeOH). Additional changes referred to the amount
of 2a, which was reduced to 2 equiv instead of the commonly applied 3
equiv., and the catalyst loading, which was changed from 5 mol % to
2.5 mol %. In contrast to the microwave-assited catalyses, extended
reaction times were required for achieving high conversions. Finally,
with NaHCO3 (2 equiv) and NaOAc (3 equiv) the reaction of 1a with 2a
led to a mixture of 57% of 3aa and 16% of 3,4-dihydroisoquinolin 4aa
.
(dr = 17:1) after 48 h. Analogously, but with NaOPiv instead of NaOAc,
the coupling of 1m with 2a gave 82% of 4ma (dr = 7:1) after 20 h.
[14] For a list of unreactive substrates, see the Supporting Information,
chapter 7.
[15] For previous studies along this line, see: a) L. Xu, Q. Zhu, G. Huang, B.
Cheng, Y. Xia, J. Org. Chem. 2012, 77, 3017; b) N. Kuhl, N. Schröder,
F. Glorius, Adv. Synth. Catal. 2014, 356, 1443.
[16] Y. Kuninobu, H. Ida, M. Nishi, M. Kanai, Nat. Chem. 2015, 7, 712.
[17] a) H. Heaney, M. O. Taha, A. M. Z. Slawin, Tetrahedron Lett. 1997, 38,
3051; b) K.-Q. Ling, J.-H. Ye, X.-Y. Chen, D.-J. Ma, J.-H. Xu,
Tetrahedron 1999, 55, 9185.
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10.1002/anie.201710776
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Ji-Rong Huang and Carsten Bolm*
O
R
O
R
O
OMe
OH
OMe
or
Cl
OMe
[Rh]
NaOR
N
N
N
Ar
+
O
Page No. – Page No.
H
R
Microwave-Assisted Synthesis of
Heterocycles by Rh(III)-Catalyzed
Annulation of N-Methoxyamides with
α-Chloroaldehydes
up to 93% yield
up to 96% yield
up to 16:1 dr
α-Chloroaldehydes are used as equivalents of terminal alkynes allowing to prepare
isoquinolone, 2-pyridone and 3,4-dihydroisoquinolins with complementary regio-
selectivity to known processes. Such products proved valuable for approaching
other heterocycles. The anion of an added sodium salt has a great impact on the
formation of the products, presumably by supporting an ester enolate generation or
stabilizing assemblies induced by hydrogen bond interactions.
This article is protected by copyright. All rights reserved.