Diastereoselective synthesis of 1,3-disubstituted isoindolines and sultams via bronsted acid catalysis

Article abstract of DOI:10.1039/C8CC04946G

The bis(trifluoromethane)sulfonimide (Tf₂NH) catalyzed intramolecular hydroamidation of terminal alkynes is reported. The combination of Et₃SiH and Tf₂NH provides cis-1,3-disubstituted isoindolines and sultams in high yield (up to 98%) and high diastereoselectivity (up to 99?:?1 d.r.).

Full text of DOI:10.1039/C8CC04946G

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Diastereoselective Synthesis of 1,3-disubstituted
Isoindolines and Sultams via Bronsted Acid Catalysis
Ye Tao and Scott R. Gilbertson,*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The Bis(trifluoromethane)sulfonimide (Tf2NH) catalyzed catalyze hydroamination.20-26 Using related conditions we
intramolecular hydroamidation of terminal alkynes is report the formation of both isoindolines and sulfams by
reported. The combination of Et3SiH and Tf2NH provide cis- Bronstead acid catalyzed intramolecular hydroamidation.
1,3-disubstituted isoindolines and sultams in high yield (up
to 98%) and high diastereoselectivity (up to 99:1 dr).
Isoindolines are a common structural motif in a variety of
pharmaceuticals and bio-active compounds such as mariline A,
petalachloride A, pagoclone and isoindoline dicarboxylic acid
(Figure 1).27-31 Although, there are reported methods to
synthesize chiral 1,3-disubstituted isoindolines from
hydroamidation of active alkenes (Scheme 2), the asymmetric
synthesis of chiral 1,3-disubstituted isoidolines from
unactivated unsaturated groups remains underdeveloped.32-35
Isoindolines and sultams are important building blocks that
are found in a number of biologically active molecules. 1, 2 They
have been synthesized by
a variety of different bond
connections, including carbon-carbon bond and nitrogen-sulfur
bond formation. One other approach that has been utilized is
via transition metal catalyzed intramolecular hydroamination of
alkynes. (Scheme 1). Various metals, including rhodium,3
8
14
iridium,4-6, copper,7, silver,9 gold,10-12 palladium,13,
and
ruthenium15, 16 complexes, have been used to promote such
reactions.17-19 In addition to the metal catalyzed approaches,
Shibuya has illustrated that Bronsted acids can effectively
The first example of diastereoselective hydroamidation we
report is of terminal alkynes to construct chiral 1,3-
disubstituted isoindoline. Initially, copper catalysis with a
hydride source, Et3SiH, at room temperature was examined
(Table 1). However, the reaction with terminal alkynes did not
proceed (entry 1-2). Increasing the temperature and changing
ligands provided exocyclic alkenes (14) instead of reduced
a.Department of Chemistry, University of Houston, Houston TX 77204.
srgilbertson@uh.edu.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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withdrawing groups (F 22i and 22j) exhibited good yields and
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DOI: 10.1039/C8CC04946G
products (13) (entry 3-4). Attempting acid catalysis with
trifluoromethanesulfonic acid (TfOH) resulted in only recovered
starting material (entry 5). Using the stronger acid,
trifluoromethanesulfonimide (Tf2NH) resulted in the isolation of
chiral cis-1,3-disubstituted pyrrolidine (entry 6). Reaction with
20% Tf2NH and 2 equivalent Et3SiH at room temperature gave
the 1,3-disubstituted isoindoline in 95% yield and >99:1
diastereoselectivity (entry 7).
Table 1. Reaction Conditions for Cyclization
selectivities (Scheme 4).
Attempts for use other groups on the nitrogen such as
carbamates (Boc or Cbz) as well as simple amides did not
provide the desired product. The reaction with internal
alkynes provided only unreacted starting material.
Positioning the sulfone group at an internal position next
the aromatic ring provides sultam products upon cyclization.
Entr
y
cat
ligand
T
% Yield
oC
rt
rt
13
--
--
14
1
Cu(OTf)2
Cu(OTf)2•
C6H6
PPh3
PPh3
2
3
CuSO4•
5H2O
1,10-
phenanthrolin
e
80
80
--
--
--
60b
73b
4
CuBr
1,10-
phenanthrolin
e
5
6
7
TfOH
Tf2NH
Tf2NH
--
--
--
50
50
rt
42 c --
95 d --
aReaction conditions: 0.1 M solution of alkyne (0.15
mmol) in DCE, with 15 mol% metal catalyst or 20 mol%
organocatalyst, 2 equiv Et3SiH, overnight. bisolated yield
with no reduced product formed. Cisolated yield of
desired product, 1 hour reaction time. disolated yield of
desired cis-1,3-disubstituted isoindoline.
When this chemistry is combined with the use of Ellman’s
tert-butanesulfinamide, a chiral immine is obtained (18).
Addition of Grignard reagent proceeds in high
diastereoselectivity (19).36 Attempted cyclization with the the
tert-butanesulfinamide failed so that group was exchanged for
p-toluenesulfonamide which upon cyclization provided chiral
22a. The chiral center set by addition to Ellman’s chiral auxillary
results in cyclization giving chiral products in high selectivity.
With these optimized conditions the substrate scope was
investigated. Aromatic, saturated and unsaturated alkyl groups
on R3-position displayed good to excellent reactivity and
excellent diastereoselectivity. Functionality on aromatic ring,
electron donating groups (OMe 22g and 22h) and electron
2 | J. Name., 2012, 00, 1-3
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Sultams have been valuable structures in antiviral, anticancer, group being removed under the reaction conditions after the
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antimicrobial
, antimalarial agents. Using the reaction initial sultam has formed. So by running the reaction at room
conditions developed for the synthesis of isoindolines, sultam temperature the product with a protected nitrogen is obtained
products were obtained in high yield. Interestingly, this while running the reaction at 50 ˚C provides the product with a
transformation only requires a reaction time of 10 minutes at free amine NH. This compliments the observation that the
reaction fails with primary sulfonamides.
Table 2. Cyclization with loss of nitrogen group
Entr
y
SM
product
yield
98%b
1
2
67%b
76%b
82%b
3
4
5
96%b
90%b
6
room temperature. Using these conditions, the substrate scope
was investigated. Substrates with benzyl groups and alkyl
groups in the R-position, as well as functionality on aromatic
ring proceeded in good yield (Scheme 5). All attempts to
perform this reaction with simple internal alkynes failed to
provide significant product.
When the reaction was run at 50 oC with substrates that have
a electron rich benzyl and furan protected amine, or a group of
similar functionality, on the nitrogen the product where that
group has been removed, resulting in free sulfonamides, is
obtained (Table 2). Presumably this is due to the reactivity of
the CH2 group next to the aromatic ring. To determine how this
type of product formed 24f was heated to 50 oC in
dichloroethane (Scheme 6). These conditions did not produce
the free sulfonamide 30. However when isolated 24f was
subjected to the reaction conditions, 20 mol% Tf2NH and two
equivalent Et3SiH (same conditions as Table 2), free sulfonamide
product 30 was obtained. This is consistent with the benzyl
In summary, we have achieved the catalytic synthesis of chiral
cis-1,3-disubstituted isoindolines and sultams through Tf2NH,
Et3SiH combination approach, by utilizing terminal alkynes as
starting materials. This chemistry is currently being developed
for the synthesis of biologically active molecules with a SO2N
group representing an amide pharmacophore.
Conflicts of interest
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J. Name., 2013, 00, 1-3 | 3
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“There are no conflicts to declare”.
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Acknowledgements
This work was supported in part by NSF CHE-0953083 and the
University of Houston
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DOI: 10.1039/C8CC04946G
R3
NTs
R3
20 mol% Tf2NH
Et3N
R1
R2
R1
R2
NHTs
DCE, rt, 1h
O
O
O
20 mol% Tf2NH
Et3SiH
R1
R2
R1
R2
S
R
O
S
N
N R
H
DCE, rt, 10min
Isoindolines and Sultams formed under mild condictions