Iron-Catalyzed Synthesis of Tetrahydronaphthalenes via 3,4-Dihydro-2H-pyran Intermediates

Article abstract of DOI:10.1021/acs.orglett.7b03367

The development of an iron(III)-catalyzed synthetic strategy toward functionalized tetrahydronaphthalenes is described. This approach is characterized by its operational simplicity and is distinct from currently available procedures that rely on [4 + 2]-cycloadditions. Our strategy takes advantage of the divergent reactivity observed for simple aryl ketone precursors to gain exclusive access to tetrahydronaphthalene products (23 examples). Detailed mechanistic investigations identified pyrans as reactive intermediates that afford the desired tetrahydronaphthalenes in high yields upon iron(III)-catalyzed Friedel-Crafts alkylation.

Full text of DOI:10.1021/acs.orglett.7b03367

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iron-Catalyzed Synthesis of Tetrahydronaphthalenes via
3,4-Dihydro‑2H‑pyran Intermediates
Rebecca B. Watson and Corinna S. Schindler*
Department of Chemistry, Willard Henry Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor,
Michigan 48109, United States
S
* Supporting Information
ABSTRACT: The development of an iron(III)-catalyzed syn-
thetic strategy toward functionalized tetrahydronaphthalenes is
described. This approach is characterized by its operational
simplicity and is distinct from currently available procedures
that rely on [4 + 2]-cycloadditions. Our strategy takes advantage
of the divergent reactivity observed for simple aryl ketone pre-
cursors to gain exclusive access to tetrahydronaphthalene pro-
ducts (23 examples). Detailed mechanistic investigations identified
pyrans as reactive intermediates that afford the desired tetrahydronaphthalenes in high yields upon iron(III)-catalyzed Friedel−
Crafts alkylation.
Consequently, diverse areas of research rely on efficient and eco-
nomical strategies to synthesize these important building blocks.
etrahydronaphthalenes are key structural motifs in molec-
1
Tules of interest such as biologically active natural products
and pharmaceuticals2 as well as precursors to functional mate-
rials, including optoelectronics3 and organic semiconductors.4
Table 1. Reaction Optimization for the Lewis Acid Catalyzed
Formation of Tetrahydronaphthalene 12
a
a
entry
Lewis acid
Fe(OTf)3
solvent time (h) yield (%) conversion (%)
1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
24
24
24
24
24
24
8
23
48
58
87
87
73
96
82
61
68
83
86
0
99
99
99
99
99
99
99
99
99
99
99
99
17
20
68
2
Bi(OTf)3
GaCl3
3
4
SnCl4
5
BF3·OEt2
AlCl3
6
b
7
FeCl3
8
FeCl3 (5 mol %)
24
4
9
FeCI3 (20 mol %) DCE
10
11
12
FeCl3
FeCl3
FeCl3
HCl
DCM
PhMe
NO2Me
DCE
4
4
4
c
13
24
24
24
d
14
e
HCl (100 mol %) DCE
HCl (500 mol %) DCE
0
15
0
a
1
Percent yield and percent conversion determined by H NMR using
b
c
dimethyl terephthalate as an internal standard. lsolated yield. 4%
d
(24% brsm) pyran 3 observed. 20% (100% brsm) pyran 3 observed.
e
f
35% (52% brsm) pyran 3 observed. All reactions were performed
using 0.113−0.189 mmol of aryl ketone.
Figure 1. (A) Divergent reactivity between Brønsted or Lewis acids.
(B) Literature procedures for the formation of tetrahydronaphthalenes
based on [4 + 2]-cycloadditions.
Received: October 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03367
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Organic Letters
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Scheme 1. Substrate Scope of Aryl and Alkyl Ketones*
*
a
Conditions: Ketone (1.0 equiv), FeCl3(10 mol %) in dichloroethane (0.1 M), room temperature, 1−71 h. Same conditions with two modifications:
b
1
FeCl3 (100 mol %) in nitromethane (0.1 M). Percent yield determined by H NMR using dimethyl terephthalate as an internal standard.
Existing reports to access this structural motif often utilize
Brønsted or Lewis acid catalyzed [4 + 2]-cycloaddition reactions
of o-alkynyl(oxo)-benzenes 5 with alkenes 6,5 or isochromene
acetals 8 with vinyl boronates 9 (Figure 1B).6 We herein present
a mild and efficient strategy for the synthesis of tetrahydronaph-
thalenes 4 which was inspired by mechanistic insights obtained
during our previous studies toward the synthesis of 3,4-dihydro-
2H-pyrans 2 from aryl ketones 1 bearing α-carbonyl substit-
uents.7 The corresponding α-arylated analogs of 1 exhibit diver-
gent reactivity upon Brønsted or Lewis acid catalysis resulting in
either the preferential formation of pyrans 3 or the exclusive
formation of tetrahydronaphthalenes 4 depending on the choice
of activation (Figure 1A). Divergent reactivity of the same
substrate upon Lewis acid or Brønsted acid catalysis has recently
been recognized as an attractive strategy to rapidly access
molecular diversity.8 Subsequent mechanistic investigations aimed
at the optimization of this transformation identified pyrans 3 as
reactive intermediates which undergo FeCl3-catalyzed9 Friedel−
Crafts alkylation resulting in the exclusive formation of tetrahy-
dronaphthalenes 4 in high yields. The strategy described herein
provides a mild reaction protocol to access functionalized tetrahy-
dronaphthalenes relying on iron as an environmentally benign
metal catalyst and complements current synthetic approaches.
Following the discovery of divergent reactivity utilizing FeCl3,
we then investigated the suitability of other Lewis acids. When
aryl ketone 11 was converted using catalytic amounts of Fe(OTf)3,
the corresponding tetrahydronaphthalene 12 was obtained in
23% yield with full conversion of the substrate (entry 1, Table 1).
The use of Bi(OTf)310 resulted in increased yields of 48% while
catalytic quantities of GaCl3 further improved the yield of 12
to 58% (entries 2 and 3, Table 1). Both SnCl4 and BF3·Et2O
resulted in the formation of tetrahydronaphthalene 12 in com-
parable yields of 87% while AlCl3, a more potent Lewis acid,
formed 12 in diminished yields of 73% (entries 4−6, Table 1).
Catalytic amounts of FeCl3 proved superior and gave rise to
the desired tetrahydronaphthalene in 96% yield in an overall
shorter reaction time of 8 h (entry 7). Furthermore, the evalua-
tion of various solvents with FeCl3 provided diminished reac-
tivity, as dichloromethane, toluene, and nitromethane resulted in
68%, 83%, and 86% yield, respectively (entries 10−12, Table 1).
Overall, 10 mol % of FeCl3 in dichloroethane provided optimal
reaction conditions. Importantly, orthogonal reactivity of aryl
ketone 11 was observed upon treatment with 10 mol %, 100 mol %,
and 500 mol % of HCl, which resulted in the exclusive for-
mation of the corresponding pyran product (3, Figure 1A)
(entries 13−15). The optimized reaction conditions for the syn-
thesis of tetrahydronaphthalenes proved applicable to a variety of
electronically differentiated aryl ketone substrates (Scheme 1).
Electron-deficient aryl ketones incorporating nitro, halogen and
nitrile functionalities were converted to the corresponding
products 17−18 and 21−22 in yields up to 96% (Scheme 1).
In comparison, electron-neutral substrates bearing phenyl (12)
and biphenyl (15) groups performed equally well and formed the
desired products in yields up to 96% (Scheme 1). Additionally,
B
DOI: 10.1021/acs.orglett.7b03367
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
electron-rich aryl ketones bearing hydroxyl, acetate, and methoxy
substitution were tolerated under the optimized reaction
conditions and gave rise to the corresponding tetrahydronaph-
thalenes 25, 26, and33 inup to 66% yield (Scheme 1). Thiophene-
and furan-containing substrates proved viable and resulted in the
formation of the desired products 19 and 23 in 64% and 56% yield,
respectively. Cinnamyl-derived aryl ketones were also identified as
suitable substrates for this transformation, tolerating a wide range
of electron-rich and electron-deficient substituents in up to 99%
yield (16, 20, 28, 29, and 34, Scheme 1). Importantly, aryl ketones
bearing bromine or triflate substituents, which would enable
subsequent functionalization via cross-coupling reactions, led to
the desired tetrahydronaphthalene products in excellent yields of
up to 98% (13 and 14, Scheme 1). Furthermore, the corre-
sponding tetrahydronaphthalene products such as 16 undergo
facile oxidation to the polyaromatic scaffold 35 in 82% yield upon
treatment with DDQ (Figure 2). Notably, this sequence provides
Figure 2. Oxidation of tetrahydronaphthalene 16 to give rise to
functionalized naphthalene 35.
an alternative synthetic strategy to current approaches toward
functionalized naphthalenes 35 which often rely on gold-catalyzed
benzannulation reactions of o-alkynyl(oxo)benzenes 5.11
Subsequent studies focused on the elucidation of the reaction
mechanism. During our evaluation of various Lewis acids, we
observed the formation of a new compound after short reaction
times. However, prolonged reaction times led to the isolation of
the corresponding tetrahydronaphthalenes as the sole products,
suggesting the intermediacy of this compound in the reaction.
Subsequent efforts focused on the isolation of this reactive inter-
mediate, which was later identified as the corresponding pyran 36.
To validate this result, pyran 36 was prepared independently and
subjected to the optimized reaction conditions (Figure 3). After
Figure 4. (A) Monitoring conversion of aryl ketone 11 to product 12 via
intermediate 36. (B) Distribution of 11, 12, and 36 as determined by
percent yield using 1H NMR with dimethyl terephthalate as an internal
1
standard. (C) Relevant sections of the H NMR spectra after 0 min,
30 min, 6 h, and 7 h.
12 was monitored at different time points when ketone 11 was
subjected to the optimized reaction conditions (Figure 4A,B).
Within the first 2 h of the transformation, the majority of starting
material 11 was consumed, and a high concentration of pyran 36
was observed. As the reaction progressed, the concentration of
pyran 36 decreased as the concentration of tetrahydronaph-
thalene 12 increased. Figure 4C shows the changing composition
of substrate 11, pyran 36 and product 12 in the reaction mixture
after 0 min, 30 min, 6 h, and 7 h. Based on these mechanistic
insights, we propose the following mechanism for the synthesis
of tetrahydronaphthalenes (Figure 5). Activation of aryl ketone
37 upon coordination of the Lewis acid leads to initial enolization
of the carbonyl to provide 38, which can subsequently protonate
the alkene subunit to form carbocation 39. The resulting carbocation
39 can either be trapped with the oxygen functionality of the
iron-enolate 39 to result in pyran 40 or undergo Friedel−Crafts
Figure 3. Evidence for intermediacy of 36. Conditions: (a) Percent yield
and percent conversion determined by 1H NMR using dimethyl
terephthalate as an internal standard. (b) 36 does not form 11 or 12
under 1.0 equiv of HCl in 0.1 M DCE after 24 h.
1 h, a mixture of aryl ketone 11 and tetrahydronaphthalene 12
was observed in a 2:1 ratio, respectively, suggesting that the
formation of pyran 36 is reversible under Lewis acid catalysis.
This hypothesis was further validated when the reaction was
quenched after 5 h, resulting in the formation of tetrahydronaph-
thalene 12 in 83% yield as the exclusive reaction product. Subsequent
NMR experiments provided additional support for the formation of
pyran 36 as a reactive intermediate (Figure 4). The distribution of
starting material 11, pyran 36, and tetrahydronaphthalene product
C
DOI: 10.1021/acs.orglett.7b03367
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ACKNOWLEDGMENTS
■
We thank the NIH/National Institute of General Medical
Sciences (R01-GM118644) and the Packard Foundation for
financial support. R.B.W. thanks the National Science Founda-
tion for a predoctoral fellowship (Grant No. 1256260). We thank
Dr. Jeff W. Kampf, University of Michigan, for X-ray crystallo-
graphic studies.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03367.
(7) Watson, R. B.; Golonka, A. N.; Schindler, C. S. Org. Lett. 2016, 18,
1310−1313.
Experimental details and spectroscopic data for all inter-
mediates, reactants, and products (PDF)
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Accession Codes
CCDC 1589086 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: corinnas@umich.edu.
ORCID
Corinna S. Schindler: 0000-0003-4968-8013
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b03367
Org. Lett. XXXX, XXX, XXX−XXX