Synthesis of Tetrahydroisoquinolines through an Iron-Catalyzed Cascade: Tandem Alcohol Substitution and Hydroamination

Article abstract of DOI:10.1021/acs.orglett.9b02353

Rapid assembly of saturated nitrogen heterocycles - the synthetically more challenging variants of their aromatic relatives - can expedite the synthesis of biologically relevant molecules. Starting from a benzylic alcohol tethered to an unactivated alkene, an iron-catalyzed tandem alcohol substitution and hydroamination provides access to tetrahydroisoquinolines in a single synthetic step. Using a mild iron-based catalyst, the combination of these operations forms two carbon-nitrogen bonds and provides a unique annulation strategy to access this valuable core.

Full text of DOI:10.1021/acs.orglett.9b02353

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Tetrahydroisoquinolines Through an Iron-Catalyzed
Cascade: Tandem Alcohol Substitution and Hydroamination
Paul T. Marcyk and Silas P. Cook*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States
S
* Supporting Information
ABSTRACT: Rapid assembly of saturated nitrogen hetero-
cyclesthe synthetically more challenging variants of their
aromatic relativescan expedite the synthesis of biologically
relevant molecules. Starting from a benzylic alcohol tethered
to an unactivated alkene, an iron-catalyzed tandem alcohol
substitution and hydroamination provides access to tetrahy-
droisoquinolines in a single synthetic step. Using a mild iron-
based catalyst, the combination of these operations forms two
carbon−nitrogen bonds and provides a unique annulation strategy to access this valuable core.
etrahydroisoquinoline represents a common heterocyclic
motif occurring in natural products, drug candidates, and
T
bioactive compounds.1−3 This scaffold has been the focus of
numerous synthetic methods, including classic annulation
chemistry.4,5 Of the methods developed, the venerable Pictet−
Spengler reaction remains a frequent method to prepare
diverse structures with the tetrahydroisoquinoline core.6,7
More recent strategies have included intramolecular hydro-
amination,8−11 amino-functionalization of alkenes,12−14 elec-
trophilic aromatic substitution reactions,15−17 or the nucleo-
philic displacement of allyl alcohols.18−20 Modern annulation
approaches rely on transition-metal-mediated directed C−H
activation and cyclization onto π-systems.21,22 In all of these
examples, the existing chemistry requires the preinstallation of
the nitrogen prior to the key ring-forming stepwhich only
forms a single C−N bond.
Figure 1. Iron-catalyzed tandem alcohol substitution and hydro-
amination (TASH) provides a unique disconnection for the synthesis
of tetrahydroisoquinolines.
Recently, we described an iron-based catalyst that performs
as an unusually powerful and mild Lewis acid that can activate
both alcohols and alkenes for functionalization with
sulfonamide nucleophiles.23,24 Given that both alcohol and
alkene activation proceed with the same catalyst system, and
under similar reaction conditions, we postulated that these two
methods could be merged into a valuable reaction cascade. By
tethering an alcohol to an alkene, the tandem functionalization
of this scaffold with a sulfonamide nucleophile would afford a
unique annulation reaction (Figure 1). This strategy would
leverage readily accessible functional groups and allow rapid
entry to nitrogen-containing saturated heterocycles. This
operation would form two carbon−nitrogen bondsavoiding
the preinstallation of nitrogen. For example, by utilizing
substituted allyl benzenes with an o-benzyl alcohol, the target
cascade could, in one step, produce tetrahydroisoquinolines
(Figure 1).
activation of this substrate with the powerful combination of
FeCl3 with AgSbF6 failed to produce substantial annulation
product (18% yield). Unfortunately, intramolecular hydro-
etherification eclipsed the target reaction and formed
substituted tetrahydrofuran product 3a.25,26 In order to
outcompete the intramolecular process, the rate of intermo-
lecular substitution of the alcohol with the sulfonamide
nucleophile required acceleration. Substitution of benzylic
alcohols with sulfonamides proceeds rapidly with a range of
mild catalysts.27,28 Consequently, we hypothesized that a
benzylic alcohol substrate would expedite intermolecular
alcohol substitution and enable the overall annulation.
Designing these two operations into a substrate tethers a
benzylic alcohol to allyl benzenea system primed for the
synthesis of tetrahydroisoquinolines (Figure 1).
The initial studies of an iron-catalyzed tandem alcohol
substitution and hydroamination (TASH) focused on an
unactivated alcohol/alkene (1a) combination to target the
synthesis of pyrrolidine rings, such as 2a, (eq 1). Catalytic
Received: July 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02353
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
idine (Table 1, entry 14) were added to the reaction. The
addition of either base inhibited the hydroamination reaction,
while activity for alcohol substitution remained. These results
are inconsistent with “hidden Brønsted acid catalysis” as the
sole promotor of the reaction. Moreover, the TASH proceeds
most effectively with the privileged combination of FeX3 with
AgSbF6, regardless of the potential contribution of “hidden
Brønsted acid catalysis” toward hydroamination.
With substrate 1b designed to test TASH with a sulfonamide
nucleophile, various catalysts could be evaluated (Table 1).
Table 1. Evaluation of Acid Catalysts
With suitable conditions for TASH, we next evaluated the
substrate scope and found a range of simple substrates
compatible with the reaction (Table 2). 3-Methyl-2-tosylte-
Table 2. Iron-Catalyzed TASH for the Synthesis of
Tetrahydroisoquinolines
a
yield (%)
entry
catalyst
2b
3b
4b
1
2
3
4
5
6
7
8
FeCl3
FeBr3
0
0
55
68
28
0
0
24
0
0
0
0
0
0
0
9
10
4
0
0
ND
0
0
0
50
32
0
FeCl3 w/3 AgSbF6
FeBr3 w/3 AgSbF6
FeBr3 w/3 AgAsF6
FeBr3 w/3 AgPF6
FeBr3 w/3 AgBF4
FeBr3 w/3 AgOTf
FeBr2 w/2 AgSbF6
AgSbF6
HSbF6 (aq)
HCl (conc)
FeBr3 w/3 AgSbF6
FeBr3 w/3 AgSbF6
0
52
37
66
46
55
0
54
15
66
58
9
10
11
12
13
14
0
0
0
b
c
0
a
b
NMR yields with 1,3,5-trimethoxybenzene standard. Cs2CO3 (0.15
c
equiv) added. 2,6-Di-tert-butyl-4-methylpyridine (0.15 equiv) added.
Since iron(III) halide salts have been reported to catalyze both
the substitution of benzylic alcohols27 and the intramolecular
hydroamination of alkenes,25 mild Lewis acids FeCl3 (Table 1,
entry 1) and FeBr3 (Table 1, entry 2) provided obvious
starting points. These salts catalyzed the benzyl alcohol
substitution reaction but not the hydroamination, forming
benzyl sulfonamide side product 4b. To enhance the Lewis
acidity of the iron species, we surveyed silver salts containing
“non-coordinating” counterions (Table 1, entries 3−9).29 The
combination of FeCl3 with AgSbF6 (Table 1, entry 3) catalyzed
both the alcohol substitution and subsequent hydroamination
reaction with annulation compound 2b as the major product.
Switching to FeBr3 and AgSbF6 (Table 1, entry 4) improved
the yield to 68% of the tetrahydroisoquinoline product 2b
while also providing 10% yield of the regioisomeric isoindoline
product 3b. The five-membered side product 3b could arise
from a carbocation rearrangement to the more stabilized
benzylic carbocation.30 The combination of FeBr3 with other
“non-coordinating” silvers salts were inferior to AgSbF6,
affording primarily the benzyl sulfonamide side product 4b
(Table 1, entries 5−8).
While there exists precedent for iron promoting both
independent reactions,25,27 the influence of Brønsted acids
created in situ required evaluation. To investigate the
possibility of Brønsted acid catalysis, we attempted to catalyze
the reaction with HSbF6 and HCl (Table 1, entries 11 and 12).
While both HSbF6 and HCl catalyze the alcohol substitution
with p-toluenesulfonamide, the subsequent hydroamination
failed (Table 1, entries 11 and 12). Additionally, to test for
“hidden Brønsted acid catalysis,”31,32 bases Cs2CO3 (Table 1,
entry 13) or sterically hindered 2,6-di-tert-butyl-4-methylpyr-
trahydroisoquinoline (2b) could be synthesized in 62%
isolated yield as a 6:1 regioisomeric ratio (rr). Similar yield
of 2b was obtained when 1b was reacted on 1 mmol scale.
Trisubstituted olefin 1c was tolerated, but the yield of
tetrahydroisoquinoline product 2c was reduced due to
competitive formation of an isochroman through an intra-
molecular hydroetherification reaction. Placing an electron-
withdrawing fluorine at the 6-position (1d) had little effect on
the yield of the reaction but inhibited rearrangement, as 2d was
isolated in 18:1 rr. Placing an electron-withdrawing fluorine at
the 7-position (1e) inhibited alcohol substitution and favored
hydroetherification, with only a modest 21% of desired product
2d isolated. Electron-donating groups such as methyl (1f) or
methoxy (1e) placed at the 7-position were tolerated. Placing
an electron-donating at the 6-position, however, proved
problematic since this activates the benzylic alcohol and
B
DOI: 10.1021/acs.orglett.9b02353
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
leads to significant decompositionlikely through quinone
methide formation.16 For example, while trace amounts of 2h
could be isolated, replacing the methyl group of 1h with a
methoxy group led to complete decomposition of the product
(data not shown). While methyl proved general at the 3-
position (1b−1h), longer alkyl chains could be installed. For
example, internal alkenes were tolerated (1i, 1j) with the
tetrahydroisoquinoline isolated as the major products (2i, 2j).
However, the 7-membered ring products were also detected,
complicating analysis. Overall, the activating effect of the
aromatic ring needs to be carefully weighed against rearrange-
ments and side product formation.
step and does not require the preinstallation of nitrogen. The
aromatic backbone can be altered with varying substitution
patterns from the choice of building blocks used. This method
provides a simple approach to access 3-substituted tetrahy-
drosoquinolines and is complementary to classic approaches to
synthesize this valuable heterocycle.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02353.
We next investigated the composition of the sulfonamide
nucleophile (Table 3). o-Toluenesulfonamide (5a) gave yields
Experimental details, compound characterization and
NMR data (PDF)
Table 3. Evaluation of Sulfonamide Nucleophiles
AUTHOR INFORMATION
■
Corresponding Author
*Email: sicook@indiana.edu
ORCID
Silas P. Cook: 0000-0002-3363-4259
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge funds from Indiana University in partial
support of this work. Andrew P. Quest is acknowledged for his
reaction scale-up assistance. We also gratefully acknowledge
the NSF CAREER Award (CHE-1254783) and NIH
(GM121840) for partial support of this work. Eli Lilly & Co.
and Amgen supported this work through the Lilly Grantee
Award and the Amgen Young Investigator Award. P.T.M. was
supported by the Graduate Training Program in Quantitative
and Chemical Biology (T32GM109825). We acknowledge IU
mass spectrometry for HRMS (NSF Grant No. CHE1726633).
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