Enantioselective Palladium-Catalyzed Carbene Insertion into the N?H Bonds of Aromatic Heterocycles

Article abstract of DOI:10.1002/anie.201611845

C3-substituted indoles and carbazoles react with α-aryl-α-diazoesters under palladium catalysis to form α-(N-indolyl)-α-arylesters and α-(N-carbazolyl)-α-arylesters. The products result from insertion of a palladium-carbene ligand into the N?H bond of the aromatic N-heterocycles. Enantioselection was achieved using a chiral bis(oxazoline) ligand, in many cases with high enantioselectivity (up to 99 % ee). The method was applied to synthesize the core of a bioactive carbazole derivative in a concise manner.

Full text of DOI:10.1002/anie.201611845

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201611845
German Edition: DOI: 10.1002/ange.201611845
Synthetic Methods
À
Enantioselective Palladium-Catalyzed Carbene Insertion into the N H
Bonds of Aromatic Heterocycles
Vanessa Arredondo, Stanley C. Hiew, Eugene S. Gutman,
Ilandari Dewage Udara Anulal Premachandra, and David L. Van Vranken*
Abstract: C3-substituted indoles and carbazoles react with a-
aryl-a-diazoesters under palladium catalysis to form a-(N-
indolyl)-a-arylesters and a-(N-carbazolyl)-a-arylesters. The
products result from insertion of a palladium-carbene ligand
pounds to generate electrophilic metal carbene intermedi-
ates.[5] These insertion reactions may be highly diastereose-
lective or enantioselective. Zhu and co-workers demonstrated
that a palladium(II) precatalyst was more effective than other
À
À
into the N H bond of the aromatic N-heterocycles. Enantio-
metals for enantioselective carbene insertion into the O H
selection was achieved using a chiral bis(oxazoline) ligand, in
many cases with high enantioselectivity (up to 99% ee). The
method was applied to synthesize the core of a bioactive
carbazole derivative in a concise manner.
bonds of phenols, using a-aryl-a-diazoesters as palladium
carbene precursors and a chiral spiro-bis(oxazoline) ligand
(Scheme 2a).[6] Sun and co-workers used palladium(0) pre-
catalysts and chiral a-aryl-a-diazoesters to insert into aniline
N H bonds, obtaining a-aminoesters. Similarly, Feng and
co-workers reported the reaction of anilines and a-alkyl-a-
[7]
À
N
-Alkylindoles with stereocenters adjacent to the indole
nitrogen, such as human norepinephrine reuptake inhibitor 1,
are pharmacophores for important biological targets
(Scheme 1).[1] Such N-substituted indoles are commonly
diazoesters using a chiral guanidine co-catalyst (Sche-
me 2b).[8] Recently, Zhou and co-workers reported insertion
À
into the C3 H bonds of N-substituted indoles, but it was
À
unclear whether such insertions could be applied to the N H
bonds of indoles and related heterocycles (Scheme 2c).[9]
Herein, we report the first example of a palladium-catalyzed
À
carbene insertion into the N H bonds of aromatic hetero-
cycles, C3-substituted indoles and carbazoles, to obtain a-(N-
indolyl)-a-arylesters and a-(N-carbazolyl)-a-arylesters, using
a-aryl-a-diazoesters as palladium carbene precursors. Enan-
tioselection was achieved using
(Scheme 2d).
a
PyBOX ligand
Scheme 1. Biologically active N-alkylindoles with stereocenters adja-
cent to nitrogen.
accessed through inefficient and challenging substitution
reactions, requiring enantioenriched starting material[2] or
chiral resolution to obtain products with the desired stereo-
chemistry.[3] Alternatively, N-substituted carbazoles such as 5-
HT6 receptor antagonist 2 may be synthesized through
enantioselective reductive amination, but require a late-
stage Fischer indolization to construct the heterocycle.[4]
Carbene insertion processes are an attractive alternative
to substitution reactions to form sp3 carbon–heteroatom
À
À
bonds (e.g., C O and C N). Rhodium-, copper-, ruthenium-,
iron- and palladium-catalyzed insertion reactions have been
demonstrated with phenols and anilines using diazo com-
[*] V. Arredondo, S. C. Hiew, E. S. Gutman, I. D. U. A. Premachandra,
Dr. D. L. Van Vranken
Department of Chemistry, University of California, Irvine
1102 Natural Sciences II, Irvine, CA 92697 (USA)
E-mail: david.vv@uci.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611845.
Scheme 2. Comparison of previously reported palladium-catalyzed car-
bene insertions with this work.
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We first studied the intrinsic regioselectivity of the
palladium-catalyzed reaction of unsubstituted indole with
Higher yield was obtained by bolus addition of excess
diazo (1.5 equiv), although in slightly lower ee (entry 1 vs. 3).
A screen identified (S,S)-iPr-PyBOX L6 as the optimal ligand,
affording 3aa in 99% yield and 97% ee (entries 3–8). Lower
catalyst loadings led to longer reaction times, but still
generated product in high yield and ee (entries 8–10). Other
chlorinated solvents and toluene worked well for the reaction
(entries 11 and 12). The reaction did not proceed in THF
(entry 13).
À
methyl phenyldiazoacetate 2a. Applying Zhuꢀs O H inser-
tion conditions, using L1 (Table 1) and slow addition of the
Table 1: Reaction optimization for carbazole 1a.
With the optimized conditions (entry 8), we explored the
scope of the reaction with other diazo compounds and N-
heterocycles. Diazo compounds 2b–e, with substitution on the
aryl ring, reacted to form products 3ab–3ae (Figure 1). Para-
substitution with an electron-donating methoxy group accel-
Entry
Pd[c]
Pd
(mol%)
Solvent
Ligand
t [h]
Yield
[%][d]
ee
[%]
1[a]
2[b]
3
4
5
6
7
8
9
10
11
12
13
1
2
1
1
1
1
1
1
1
1
1
1
1
5
10
5
5
5
5
5
5
1
CHCl3
DCM
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCE
L1
L2
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
2
5
2
2
2
2
16
2
4
20
4
64
100
88
85
0
94
94
99
98
91
100
95
0
83
5
76
13
–
15
90
97
97
95
96
95
–
0.5
5
5
PhMe
THF
4
4
5
[a] See Scheme 3. [b] 2 equiv of diazo, no NaBArF, no MS. [c] 1=Pd-
(PhCN)2Cl2, 2=Pd2(dba)3. [d] Isolated yield.
Figure 1. Reaction scope with various carbazoles. Conditions: Table 1
entry 8. [a] 10 mol% Pd, 12 mol% L6, 24 mol% NaBArF, and 8 h slow
addition of diazo. [b] ee determined for the corresponding alcohol 3 fa-
OH (SI, page 10).
diazo compound, we observed alkylation at the indole C3, C2
erated the reaction, with carbazole 1a fully consumed in
30 minutes. In contrast, an electron-withdrawing para-nitro
group slowed the reaction significantly, affording a low yield
of 3ad after 24 h at 558C. Not surprisingly, the easily
enolizable para-nitro analogue 3ad was obtained as the
racemate. With an ortho-chloro substituent, product 3ae was
obtained in low yield, but good ee. a-Alkyl-a-diazoesters
were poor substrates due to palladium-catalyzed decomposi-
tion. For example, methyl a-diazobutanoate formed (E)- and
(Z)-methylcrotonate as major products (see Supporting
Information (SI), page 15).
À
and N1 positions in an 18:3:2 ratio, respectively. While C3 H
À
insertion was favored, N H insertion was also a viable
process (Scheme 3).
À
When Zhuꢀs O H insertion conditions were applied to
À
carbazole 1a, the N H insertion product a-(N-carbozolyl)-a-
phenylacetate 3aa was obtained in 64% yield and 83% ee
À
(Table 1, entry 1). Next, we applied Fengꢀs N H insertion
conditions using a palladium(0) precatalyst, L2, and bolus
addition of the diazo compound, yielding 3aa quantitatively,
but in substantially lower ee (entry 2).
The absolute stereochemistry of 3ab was secured by X-ray
crystallographic analysis of the corresponding alcohol 5
following DIBAL-H reduction (Figure 2). The absolute con-
figuration of alcohol 5 and analogous insertion products were
assigned (R) based on the X-ray structure.[10]
Halogen substituents on the diazo or carbazole substrate
are tolerated, but bromine substituents led to slightly lower
Scheme 3. Intrinsic regioslectivity of unsubstituted indole.
2
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Figure 2. Absolute stereochemistry assigned by X-ray analysis of alco-
hol 5.
yields and incomplete conversion, possibly due to catalyst
deactivation resulting from oxidative addition (3ab and 3ba).
1-Substituted carbazoles were challenging, affording products
3ea–3ga in yields below 30%, although higher temperatures,
higher catalyst loadings, and slow addition of the diazo led to
reasonable yields. Above 408C, competitive formation of
fumarate side products was observed. Slow addition of diazo
reduced fumarate formation, although up to two equivalents
were required. With hindered 1-methoxycarbazole 1 f, the
corresponding product 3 fa was accompanied by an insepa-
rable mixture of over-insertion products, presumably due to
reaction with the electron-rich aromatic ring. Indeed, when 9-
N-methylcarbazole 1h was subjected to the reaction condi-
À
tions, the C3 H insertion product was obtained in 51% yield
(Scheme 4).[11]
Figure 3. Indole substrate scope. [a] Yield of an inseparable N1/C2
product mixture. Ratio obtained by 1H NMR analysis. [b] (R,R)-iPr-
pybox. [c] No ligand.
Scheme 4. Insertion reaction of 9-N-methylcarbazole 1h.
7a in 32% yield. The presence of unreacted starting material
suggests catalyst deactivation due to overligation by the
substrate. Aliphatic amines were briefly investigated. Piper-
idine afforded product 8a in 40% yield. Derivative 9a and
P2Y12 antagonist 9e ((Æ)-clopidogrel) were obtained in 59%
and 79% yield, respectively. Aliphatic amines are basic
enough to racemize the products; the ee of carbazole product
3aa declined to 25% after 2 h under the reaction conditions
with 50 mol% piperidine.
À
With 1-hydroxycarbazole 1g, the N H insertion product
3ga was obtained in up to 61% yield and 4:1 selectivity over
[5e]
À
the O H insertion product.
The ee for 3ga was highly
variable (0 to 49%) depending on reaction conditions.
Carbazole-like substrates such as phenoxazine also worked
well, affording 4a in 81% yield and 94% ee, but with some
over-insertion products.
À
We revisited unsubstituted indole using the conditions
optimized for carbazole. Once more, indole 6a gave primarily
We applied the N H insertion reaction towards the
synthesis of the core of 5-HT6 receptor antagonist 2
(Figure 4). Oxazinocarbazole 10 was synthesized by
DIBAL-H reduction of 3 fa to the alcohol, mesylation, and
a one-step thermal cyclization/dealkylation. This concise
À
C3 H insertion product, with double-insertion at the N1 and
C3 position as the major by-product (Figure 3). Blocking the
C3 position led to preferential insertion at N1. Increasing bulk
at the C3 position improved selectivity for N1 over C2
insertion (6aa < 6ba < 6ca < 6da). Indole substrates exhib-
ited lower ees than carbazole substrates. Ligands L1, L2, L4,
and L5 did not improve the ee of product 6ca. However, the
bulkier t-butyl phenyldiazoacetate improved the ee in the
reaction with indole 6c (see SI, page 15). Substituents with
hydrogen-bonding groups led to poorer ee (6ea and 6ga). A
crystal structure of tert-butyl indole 6db was obtained as the
racemate.[10]
À
synthesis highlights the powerful palladium-catalyzed N H
insertion reaction described herein, avoiding a lengthy syn-
thesis of oxazinocarbazoles that involves a late-stage Fischer
indolization.
Other aromatic heterocycles with sp2 lone pairs (e.g.
imidazole, indazole, and pyrazole) were poor substrates for
the reaction. For example, pyrazole afforded racemic product
Figure 4. Synthesis of the core of 5-HT6 receptor antagonist 2.
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À
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À
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À
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Experimental Section
A flask containing heterocycle (1 equiv), 5 mol% Pd(PhCN)2Cl2,
6 mol% (S,S)-iPr-PyBOX, 12 mol% NaBArF, 5 ꢁ MS and CHCl3
(200 mm in heterocycle) was heated at 308C for 5 min. Next, diazo
substrate (750 mm in CHCl3) and additional CHCl3 to obtain a final
75 mm heterocycle concentration was added. Upon completion, the
reaction was cooled, diluted with CHCl3, filtered through Celite,
concentrated, and purified (see SI, page 7 for full details).
Acknowledgements
V.A. and S.H. were supported by an NSF Graduate Research
Fellowships. We would like to acknowledge Dr. Joe Ziller (X-
Ray Crystallography Facility) and Mass Spectrometry Facility
personnel at UCI.
Conflict of interest
The authors declare no conflict of interest.
Keywords: diazo compounds · heterocycles · insertion ·
nitrogen heterocycles · palladium
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[10] CCDC 1519937 (5) and 1520167 (6db), respectively, contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
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À
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Manuscript received: December 5, 2016
Revised: February 16, 2017
Final Article published: && &&, &&&&
4
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Communications
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Synthetic Methods
V. Arredondo, S. C. Hiew, E. S. Gutman,
I. D. U. A. Premachandra,
D. L. Van Vranken*
&&&& — &&&&
Pharmacophores made easy: Palladium
catalyzes the insertion of a-arylester
esters and a-(N-carbazolyl)arylesters in
Enantioselective Palladium-Catalyzed
good yields and up to 99% ee. The
method enables a concise route to the
core of a bioactive carbazole derivative.
À
À
Carbene Insertion into the N H Bonds of
carbene ligands into the N H bonds of
Aromatic Heterocycles
heterocycles to afford a-(N-indolyl)aryl-
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