Direct Access to Furoindolines by Palladium-Catalyzed Intermolecular Carboamination

Article abstract of DOI:10.1021/acscatal.6b02238

A versatile Pd-catalyzed intermolecular syn-carboamination of dihydrofurans giving access to the ubiquitous furoindoline motif is described. The efficiency of the process relies on the use of Buchwald-type biarylphosphines and the perfect control for site-selectivity of Pd insertion across the C=C bond. A catalytic sequence consisting of Heck and carboamination cross-coupling reactions from readily available dihydrofurans affords - in usually high chemical yields and high levels of diastereocontrol - poly(hetero)cyclic compounds that would be difficult to access by established methods. Encouraging preliminary results for the enantioselective carboamination of 2,3-dihydrofurans are also disclosed.

Full text of DOI:10.1021/acscatal.6b02238

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Article
Direct Access to Furoindolines by Palladium-
Catalyzed Intermolecular Carboamination
Vincent Bizet, Gustavo M. Borrajo-Calleja, Celine Besnard, and Clément Mazet
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02238 • Publication Date (Web): 14 Sep 2016
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†
†
‡
*,†
Vincent Bizet, Gustavo M. Borrajo-Calleja, Céline Besnard, Clément Mazet
†
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva, Switzerland.
Laboratory of Crystallography, University of Geneva, 24 quai Ernest Ansermet, 1211 Geneva, Switzerland.
‡
ABSTRACT: A versatile Pd-catalyzed intermolecular syn-carboamination of dihydrofurans giving access to the ubiquitous
furoindoline motif is described. The efficiency of the process relies on the use of Buchwald-type biarylphosphines and the
perfect control for site-selectivity of Pd insertion across the C=C bond. A catalytic sequence consisting of Heck and carbo-
amination cross-coupling reactions from readily available dihydrofurans affords - in usually high chemical yields and high
levels of diastereocontrol - poly(hetero)cyclic compounds that would be difficult to access by established methods. En-
couraging preliminary results for the enantioselective carboamination of 2,3-dihydrofurans are also disclosed.
KEYWORDS: palladium catalysis, cross-coupling, intermolecular carboamination, furoindolines, enantioselective catalysis,
diastereoselective catalysis
Indole alkaloids constitute an endless source of inspira-
tion and attention for synthetic chemists, medicinal
chemists and biologists because of their elaborated archi-
strategy affords valuable poly(hetero)cyclic structures
with high levels of diastereocontrol.
1
tectures and their broad range of biological activities. The
furoindoline motif is no exception to the rule and natural
products or derivatives of this structural subclass not only
pose intellectual challenges to researchers in academia
but their established anti-cancer, anti-bacterial, anti-
inflammatory or anti-malarial activity render them intrin-
2
sically attractive (Figure 1). To date, two types of ap-
proaches constitute the state-of-the-art to access the fu-
roindoline motif: (1) interrupted Fischer-indole syntheses
(usually starting from hydrazines) and (2) dearomative
3
,4
5
,6
cascade reactions (usually starting from tryptophol).
Although these methods are often efficient and have
permitted the synthesis of a number of highly complex
natural products, they typically provide limited diversity
with respect to the furoindoline core structure. We envi-
sioned that the development of a general catalytic inter-
molecular cross-coupling reaction based on the combina-
tion of readily available elementary building blocks would
facilitate structural diversification and add a novel dimen-
sion to the existing strategies to generate furoindoline
derivatives
Figure 1. Representative examples of biologically active
compounds possessing a furoindoline core structure.
For our approach to be successful, we speculated that
the pKa of the 2-haloanilines to be cross-coupled with 2,3-
dihydrofuran should approximate the pKa of the 2-
bromophenols employed in the related carboetherifica-
9
tion reaction recently reported by our group. Therefore
our study commenced by subjecting 2,3-dhf 1a and N-(2-
bromophenyl)methanesulfonamide 2a to the reaction
conditions optimized for carboetherification (2.5 mol%
As part of our efforts on the development of Pd-
catalyzed C‒C and C‒X bond forming reactions, we re-
cently disclosed a highly chemo-, regio- and stereoselec-
tive intermolecular carboetherification of olefins enabling
access to a broad array of tetrahydrofurobenzofurans.
(
Pd2(dba)3), 5 mol% RuPhos (L1), 80 ˚C, toluene; Entry 1,
7
Table 1). Even with an extended reaction time (24 h vs. 4 h
originally) no product was formed. Reactivity was ob-
served with a temperature of 110 ˚C under otherwise iden-
tical conditions. Unfortunately, an equimolar amount of
the dehydrobrominated mesylated aniline 3a accompa-
nied the formation of the targeted carboamination prod-
uct 4a (11% yield). Analysis of the crude reaction mixture
proved difficult, and only the relative ratio between 2a, 3a
and 4a could be determined with high fidelity; the isolat-
ed yield in 4a remaining the ultimate parameter for
7
e
Building on this discovery, we report herein a Pd-
catalyzed syn-carboamination of dihydrofurans (dhf) us-
ing 2-bromo-anilines which provides direct access to
complex furoindolines that would be otherwise difficult
8
to synthesize. When combined in sequence with an in-
termolecular Pd-catalyzed Heck reaction, this synthetic
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measuring the overall efficiency of the catalytic process.
After evaluation of other Buchwald-type biarylphosphine
fording furoindoline 4a as the sole product of the reaction
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in nearly quantitative yield (94%). When N-(2-
bromophenyl)-4-methylbenzenesulfonamide 6a or N-(2-
bromophenyl)-p-tolylsulfonamide 7a were tested as alter-
natives to 2a, the corresponding carboamination products
were formed along with the generic Heck-type cross-
coupling products 5a and 5a’, indicating a reduced site-
selectivity for Pd insertion across the C=C bond.
1
0
ligands (Entry 2-5,7), CPhos (L6) was identified as the
best candidate. Whereas with XPhos (L2), DavePhos (L3)
and SPhos (L4) low reactivity and selectivity were ob-
served, with L6, the carboamination product was ob-
tained exclusively and 4a was isolated in 63% yield after
purification by column c hromatography. Of note, no re-
action occurred with tri(o-tolyl)phosphine (L5; Entry 6).
Reasoning that the heterogeneous nature of the system
might affect the efficiency of the catalytic reaction, polar
solvents with a high boiling point were also surveyed - but
only with limited success (Entry 8-10). In contrast, the
effect of the alkali metal was quite pronounced. Whereas
no reaction was observed with KOtBu (Entry 11), a signifi-
cant improvement was noticed with the more soluble
LiOtBu (4a: 74%, Entry 12). As a side note, attempts to
lower the stoichiometry of dihydrofurans led to much
reduced yield in most cases.
The desired furoindoline 11a was isolated in 84% yield
using
N-(2-bromophenyl)-1,1,1-trifluoromethane-
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sulfonamide 8a, but its higher cost and reduced accessi-
12
bility prompted us to use 2a in all subsequent investiga-
tions.
The generality of the reaction was explored next using
the optimized conditions described in Entry 13 of Table 1
as a unified and practical protocol and N-(2-bromoaryl)-
methanesulfonamide derivatives 2a-o as coupling part-
ners (Table 2). Electronic variations, first investigated by
2
introducing various substituents in R (-OMe, -Me, -
a
Table 1. Reaction optimization
OCF3, -CF3, -Cl), were usually well-tolerated and yields
ranging from 55-81% were obtained. No reaction was ob-
served when a nitro substituent was present at this posi-
tion.
Table 2. Scope of the intermolecular carboamination
a
of 2,3-dihydrofuran
b
entry
ligand
L1
base
T (˚C) solvent
2a : 3a : 4a
c,d
1
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
80
110
110
110
110
110
110
110
110
110
110
110
110
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-dioxane
100 : 0 : 0 (0)
2
3
4
5
6
7
8
9
L1
0 : 47 : 53 (11)
25 : 28 : 47 (14)
28 : 31 : 41 (13)
37 : 8 : 55 (17)
100 : 0 : 0 (0)
0 : 0 : 100 (63)
16 : 48 : 25 (17)
5 : 65 : 30 (17)
0 : 60 : 40 (10)
100 : 0 : 0 (0)
0 : 6 : 94 (74)
0 : 0 : 100 (94)
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
e
DMA
f
1
0
NMP
11
Toluene
12
LiOtBu
LiOtBu
Toluene
g,h
1
3
Toluene:TAA
a
b
Reaction conditions: 1a (1.0 mmol), 2a (0.2 mmol). Rela-
a
Reaction conditions: 1a (1 mmol), 2a-o (0.2 mmol).
1
c
tive ratio as measured by H NMR. Relative stereochemistry
determined by NMR and X-ray analysis. In parenthesis,
d
Yields of isolated products after purification. Relative
b
steroechemsitry assigned by analogy with 4a. Using 1.05
yield of isolated product 4a after purification by column
c
d
e
f
equiv of LiOtBu.
No reaction.
Using 5 mol% of
chromatography.
Dimethylacetamide.
N-methyl-
g
h
Pd2(dba)3 and 10 mol% of CPhos (L6)
pyrrolidone. t-Amyl alcohol. Concentration was [0.1].
The carboamination products were isolated in moder-
ate to good yields when the nature of the substituent in
A homogeneous solution was obtained using a 2:1 mix-
1
1
ture of toluene and t-amyl alcohol (TAA; Entry 13), af-
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3
para position with respect to the bromine atom (R ) was
varied (50-68%). In line with observations made for the
carboetherification of olefins, no reaction occurred with
Subjecting these dhf derivatives to the optimized reac-
tion conditions for carboamination afforded the structur-
ally complex furoindolines 4p-4s (41-72%) with systemati-
cally excellent levels of diastereocontrol (from 19:1 to
49:1). In contrast to observations made in related dia-
stereoselective carboetherification reactions, in these
products the (hetero)aryl substituent and the cis-
hydrogen atoms at the ring junction are pointing towards
the same face of the furan core structure. To account for
this striking difference, we propose that the steric bulk
imposed by the N-Ms substituent may strongly influence
the diastereoselective outcome of these reactions. The
compatibility of both methods with O- and, more im-
portantly, N-containing heterocycles as well as the pre-
ferred chemoselectivity for the dihydrofuran ring over the
benzofuran unit in the reaction between 1e and 2a are
additional key features of this synthetic sequence.
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the
sterically
demanding
N-(2-bromo-3,5-
dimethylphenyl)-methane-sulfonamide 2l. Taking ad-
vantage of the substantial difference in basicity between a
mesylated aniline and an unprotected primary aniline,
furoindoline 4m could be prepared in 40% yield without
resorting to any protection/deprotection strategy. This
result clearly highlights the functional group tolerance of
the catalytic system. Remarkably, cross-coupling precur-
sors 2n and 20 enabled access to the structurally unique
pyridine-containing furoindolines 4n and 40 in very good
yields (75% and 69% respectively).
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To further assess the potential of the Pd-catalyzed syn-
carboamination reaction, a series of 2-substituted-2,3-
dihydrofurans was prepared by a Heck reaction between
2
,3-dhf and a representative selection of aryl and het-
Finally, aside from the excellent selectivities obtained,
it is interesting to note that with the same biar-
ylphosphine ligand (CPhos, L6) simple adjustment of the
reaction conditions enables to completely reverse site-
selectivity of [Pd‒C] insertion across the polarized C=C
13,14
eroaryl bromides 12b-e (Figure 2).
The isomerized
cross-coupled products were usually obtained predomi-
nantly over the product of direct cross-coupling (1b-e/1b’-
e’: 80:20 to 99:1) in moderate to very good yields (43-
16
78%).
bond of 2,3-dihydrofurans.
Preliminary efforts were also directed at developing an
enantioselective version of the carboamination reaction
(
Figure 3). A number of structurally and electronically
diversified chiral monodentate ligands and chiral hemila-
bile bis-phosphine mono-oxide ligands were inspected
1
7,18
(
see SI for details).
The most promising results were
19
obtained with a MOP-type ligand (L7) and the highest
enantioselectivity was measured for the cross-coupling
reaction between 1a and 2a (4a: 69% yield, 73% ee). Vari-
ation of the sulfonamide substituent had only minimal
impact on the reactivity and selectivity.
Figure 2. Synthetic sequence using 2,3-dhf: (1) Pd-
catalyzed Heck reaction of 2,3-dhf with aryl and heteroar-
yl bromides; (2) Pd-catalyzed carboamination of 2-
substituted-2,3-dhf (0.2 mmol scale). Yields are given for
isolated products. Site-selectivity and diastereomeric ratio
measured by H NMR of the crude reaction mixture. Rela-
tive stereochemistry assigned by NMR and X-ray analyses.
All molecular structures have been represented using
Figure 3. Enantioselective carboamination of 2,3-dhf. Reac-
tion conditions: 1a (1 mmol), 2a-b,e or 6a-8a (0.2 mmol).
Yields of isolated product. Enantioselectivity determined by
HPLC using a chiral column.
1
In conclusion, we have developed a Pd-catalyzed in-
termolecular syn-carboamination of dihydrofurans which
1
5
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provides access to structurally complex furoindolines. The
Page 4 of 6
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Soc. 2016, 138, 1162─1165.
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method is very general, displays a high functional group
tolerance and the products are typically isolated in practi-
cal yields. When preceded by a Pd-catalyzed Heck reac-
tion, high levels of molecular complexity are readily ac-
cessible in only 2 steps from simple precursors and the
resulting poly(hetero)cyclic compounds are obtained with
excellent diastereoselectivity. Investigations aimed at im-
proving the promising levels of enantioselectivity already
obtained and mechanistic studies focused at understand-
ing the factors that govern site-, dia- and enantioselectivi-
ty are in progress.
(
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ASSOCIATED CONTENT
Supporting Information
7
492─7500; (e) Yang, W.; Huang, L.; Yu, Y.; Pflästerer,
D.; Rominger, F.; Hashmi, A. S. K. Chem. Eur. J. 2014, 20,
927─3931; (f) Zhang, X.; Liu, W. B.; Tu, H.-F.; You, S.-L.
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3
Experimental procedures, characterization of all new com-
pounds, spectral data and X-ray data for compounds 4a, 4p,
4q, 4r and 4s (CCDC 1490110, 1490109, 1490107, 1490106,
1
490108). This material is available free of charge via the In-
(
7) (a) Nareddy, P.; Mantilli, L.; Guénee, L.; Mazet, C. An-
gew. Chem. Int. Ed. 2012, 51, 3826─3831; (b) Franzoni, I.;
Guénée, L.; Mazet, C. Chem. Sci. 2013, 4, 2619─2624 ; (c)
Franzoni, I.; Guénée, L.; Mazet, C. Org. Biomol. Chem.
ternet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
2
015, 13, 6338─6343; (d) Borrajo-Calleja, G. M.; Bizet, V.;
Bürgi, T.; Mazet, C. Chem. Sci. 2015, 6, 4807─4811; (e)
Borrajo-Calleja, G. M.; Bizet, V.; Mazet, C. J. Am. Chem.
Soc. 2016, 138, 4014─4017.
Prof. Clément Mazet. University of Geneva, Organic Chemis-
try Department. Quai Ernest Ansermet 30, Geneva 1211 -
Switzerland. clement.mazet@unige.ch
(8) For reviews, see: (a) Wolfe, J. P. Top. Heterocycl. Chem.
2
013, 32, 1─38; (b) Stereoselective Synthesis of Drugs and
Natural Products; Ghorai, M. K.; Halder, S.; Samanta, S.
Eds., Wiley-Blackwell. 2013. For recent examples of relat-
ed carboaminations: (c) Hopkins, B. A.; Wolfe, J. P.
Chem. Sci. 2014, 5, 4840─4844; (d) Babij, N. R.; McKenna,
G. M.; Fornwald, R. M.; Wolfe, J. P. Org. Lett. 2014, 16,
3412─3415; (e) Faulkner, A.; Scott, J. S.; Bower, J. F. J. Am.
Chem. Soc. 2015, 137, 7224─7230; (f) White, D. R.; Hutt, J.
T.; Wolfe, J. P. J. Am. Chem. Soc. 2015, 137, 11246─11249;
g) Kindt, S.; Wicht, K.; Heinrich, M. R. Org. Lett. 2015,
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Chem. Eur. J. 2016, 22, 5919─5922; (i) Um, C.; Chemler, S.
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the University of Geneva and the
Swiss National Science Foundation. E. Acuna-Bolomey, R.
Miah, J. Pin and S. Rosset are warmly acknowledged for
technical and practical assistance. Johnson-Matthey is
acknowledged for a generous gift of palladium precursors.
(
1
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(
(
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16) Site selectivity of [Pd–C] insertion across a C=C bond can
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