Chromium-Catalyzed Asymmetric Dearomatization Addition Reactions of Halomethyl Heteroarenes

Article abstract of DOI:10.1021/acs.orglett.6b00559

The first asymmetric dearomatization addition reaction of halomethyl arenes including benzofuran and benzothiophene was enabled by chromium catalysis. A variety of aldehydes served as suitable electrophiles under mild reaction conditions. Molecular complexities are quickly increased in a highly diastereo- and enantioselective manner.

Full text of DOI:10.1021/acs.orglett.6b00559

Letter
pubs.acs.org/OrgLett
Chromium-Catalyzed Asymmetric Dearomatization Addition
Reactions of Halomethyl Heteroarenes
Qingshan Tian, Jing Bai, Bin Chen, and Guozhu Zhang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: The first asymmetric dearomatization addition
reaction of halomethyl arenes including benzofuran and
benzothiophene was enabled by chromium catalysis. A variety
of aldehydes served as suitable electrophiles under mild
reaction conditions. Molecular complexities are quickly
increased in a highly diastereo- and enantioselective manner.
earomatization reactions are attractive methods to quickly
build complex and diverse molecular architectures from
most powerful synthetic methods for carbon−carbon bond
formation.5 In line with our own interests in chromium-
catalyzed asymmetric transformations with functionalized
carbohalides,6 we envisioned the feasibility of dearomatization
of halomethyl arenes upon chromium catalysis for two reasons.
First, the fact that allyl-chromium reagents prefer to react at its
γ end might offer a chance to overcome the aromaticity of
halomethyl arenes.5f Second, the fixed E olefin geometry of
halomethyl arenes leads to the favored configuration of
allylchromium species for anti-products through a cyclic
Zimmermann−Traxler-type chair transition state.11c Herein,
we wish to report our preliminary results on chromium-
catalyzed highly stereoselective dearomatization addition
reactions of halomethyl hetereoarenes with aldehydes (Scheme
2).
D
simple, flat aromatic molecules.1 More importantly, the
resulting alicyclic systems are frequently observed in bioactive
natural products and pharmaceuticals. In recent years, catalytic
asymmetric dearomatization (CADA) reactions have drawn
broad research interest and have become a powerful synthetic
method.2,3 Thanks to efforts from many research groups,
excellent enantiomeric excess values have been achieved
through substrate design and exquisite subtle control of the
stereoselectivities in many elegant catalytic dearomatization
reactions such as hydrogenation of heteroarenes,2b oxidative
dearomatizations,3a,c,d,f,i,j,m and alkylative3g,l and arylative
dearomatizations.3b,h,n,o
Among various aromatic materials, halomethyl arenes are one
class of important building blocks which are widely utilized in
alkylation related transformations. However, to the best of our
knowledge, catalytic dearomative addition occurring at its γ
position, i.e. electrophile added on arenes, has been rarely
investigated, not to mention the enantioselective version.4 The
major challenge to realize this dearomative reactivity is to
circumvent the direct benzylic addition upon metal activation
(Scheme 1).Undoubtedly, a new strategy to address this issue
Scheme 2. CADA Addition of Halomethyl Arenes with
Aldehydes
Scheme 1. Reactions of Halomethyl Arenes
At the outset, 2-(chloromethyl)benzofuran was selected as a
model substrate to test this hypothesis; we chose benzofuran
not only because of its relatively weak resonance stabilization
which facilitates the dearomatization but also because of the
fact that 5-membered hetereoarenes represent one class of
privileged structural units in organic syntheses. We first
investigated the reaction of 2-(chloromethyl)benzofuran and
dihydrocinnamaldehyde under standard NHK conditions
without a ligand, i.e. a catalytic amount of CrCl2, stoichiometric
would be synthetically useful and mechanistically interesting,
not only opening new possibilities for these stock chemicals but
also adding a valuable variant to the fast growing asymmetric
dearomatization research field.
Chromium mediated Grignard-type addition of carbohalides
to aldehyde, well-known as the NHK (Nozaki−Hiyama−Kishi)
reaction when Ni salt cocatalyzes, has proven to be one of the
Received: February 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
amount of Mn as reductant, and TMSCl as dissociating
reagent.7 To our delight, a small amount of desired
dearomatized coupling compound 3a did form together with
benzylic adduct 2 as a major product (Table 1, entry 1).
reported by Nakada9 and L6 by Guiry10 were both tested,
providing 3a in 80% yield with 91% ee and 68% yield with 82%
ee, respectively (Table 1, entries 7 and 8). The above results
indicated the rigid ligand backbone benefits the overall
efficiency.11 Using L4 as the ligand, a few solvents were then
examined. DME gave the best result, affording 3a in 92% yield
with 95% ee; notably, the formation of 2 was minimized to a
negligible amount (Table 1, entry 10). Air-stable CrCl3 was also
tested, giving the product in 80% yield with comparable 92% ee
(Table 1, entry 11). Lowering the temperature to −10 °C
further improved the reaction; the product 3a was obtained in
90% yield with 98% ee, and 2 was not detected by crude NMR
(Table 1, entry 12). A significant amount of aldehyde remained
unreacted when the reaction occurred at −20 °C, but the
enantioselectivity was essentially the same (Table 1, entry 14).
The impact of various deviations from the standard reaction
conditions was also evaluated. A lower catalyst loading (CrCl2 5
mol %, L4 7 mol %) resulted in a decreased yield and ee (82%
yield, 97% ee, Table 1, entry 15). No extra additives are
necessary for this reaction, which significantly simplified the
reaction setup. Notably, the reaction scale could be increased to
1 mmol with maintenance of the efficiency, giving 3a in 99% ee
(Table 1, entry 16).
Table 1. Optimization of the Reaction Conditions
b
b
c
yield
yield
ee (%)
a
entry ligand
solvent
temperature (%) of 2 (%) of 3a
of 3a
d
1
−
−
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
DME
DME
DME
DME
DME
DME
DME
rt
40
55
9
5
−
−
2
rt
20
81
66
79
85
80
68
75
92
80
93
90
74
82
89
3
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
L4
L4
L4
rt
89
30
69
95
91
82
86
95
92
96
98
97
97
99
4
rt
12
6
5
rt
6
rt
10
9
7
rt
8
rt
14
10
−
−
−
−
−
−
−
9
rt
10
11
12
13
14
15
16
rt
e
rt
The absolute configuration of the product 3a (>97% ee) was
unambiguously identified to be (R,R) by single crystal X-ray
diffraction analysis.12 Based on this experimental result, a
possible transition state was suggested to account for the
preferential formation of the (R,R)-enantiomer of the product
(Figure 2).
0 °C
−10 °C
−20 °C
−10 °C
−10 °C
f
g
h
a
The reactions were carried out at 0.2 mmol scale; ZrCp2Cl2 was
b
1
employed unless noted otherwise. Measured by H NMR analysis
using 1,1,2,2-tetrabromoethane as internal standard. Determined by
c
d
chiral HPLC analysis. TMSCl instead of ZrCp2Cl2 was employed.
e
f
CrCl3 was employed. 5 mol % CrCl2 and 7 mol % L4 were
g
h
employed. 1 mmol of aldehyde was used. Isolated yield. TMS =
trimethylsilane; Cp = cyclopentadienyl; PS = proton sponge
(N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine).
Figure 2. Proposed transition state.
Notably, only one diastereomer of 3a was observed. TMSCl
was changed to well-behaved ZrCp2Cl2, and a much improved
yield of 3a was obtained (Table 1, entry 2).8 Encouraged by
this result, we tested asymmetric catalysis of the coupling
reaction using modified Nakata ligand L1 (Figure 1).6,9
With the optimized reaction conditions in hand, the substrate
scope was promptly investigated. We first checked the
dearomative coupling of 2-(chloromethyl)benzofuran with
various aldehydes; moderate to good yields (65%−91%) and
excellent diastereoselectivity (>99/1) and enantioselectivity
(92−98% ee) were obtained (Scheme 3). Aliphatic aldehydes
including cyclopropyl carboxyaldehyde and 5-chloropentanal
participated in the coupling reaction efficiently; the correspond-
ing dearomative products 3b and 3c were isolated in good yield
with excellent enantiomeric excess (96% and 95% ee
respectively). A range of α,β-unsaturated aldehydes such as
cinnamaldehyde, (E)-3-(4-fluorophenyl)acrylaldehyde, and
(E)-hex-2-enal also reacted well, providing dearomatized
products 3d−3f in high enantiomeric excess (97%−98% ee).
It is worth noting that this dearomatization addition protocol
works equally well with aryl aldehydes including benzaldehyde
and thiophene-2-carbaldehyde, producing the corresponding
arylated secondary alcohols 3g−3h in moderate yields with
excellent enantiomeric excess (92% ee and 96% ee). These
optimal conditions can also be expanded to reactions with 2-
(chloromethyl)benzothiophene, and an even higher enantiose-
lectivity ranging between 91% and 99% ee was observed
(Scheme 3). Aliphatic aldehydes including dihydro-
cinnamaldehyde, 5-chloropentanal, cyclohexyl carboxyaldehyde,
Figure 1. Tested ligands.
Delightfully, the coupling reaction proceeded even better with
much less formation of 2 (9% yield) and more of 3a (81%
yield), and the ee of 3a was determined to be 89% by chiral
HPLC analysis; again, only one diastereomer was observed
(Table 1, entry 3). The following ligand screening showed that
less-hindered L4 with the ethyl substitution was the most
effective one, giving 3a in 85% yield with 95% ee (Table 1,
entry 6). Ligand L2 with the sterically demanding tBu group
was not effective for this reaction; 3a was obtained in 66% yield
with 30% ee (Table 1, entry 5).
Ligand L3 with benzyl groups gave a much lower
enantioselectivity (69% ee). For more information, ligands L5
B
DOI: 10.1021/acs.orglett.6b00559
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a
a
Scheme 3. Substrate Scope Studies
Scheme 4. Substrate Scope Studies
a
a
All reactions carried out at 1 mmol scale under the standard
conditions; ligand (S)-L4 was used unless otherwise noted. The
absolute configurations of products were assigned by analogy.
All reactions carried out at 0.2 mmol scale under the standard
conditions; ligand (S)-L4 was used unless otherwise noted. The
absolute configurations of products were assigned by analogy.
the reactions of 3-(chloromethyl)-benzofuran with 5-chlor-
opentanal, cinnamaldehyde, and cyclohexyl carboxyaldehyde.
For comparison, 2-chloromethyl indene was also prepared
and subjected to the standard conditions; to our delight, the
coupling with dihydrocinnamaldehyde and 5-chloropentanal
proceeded smoothly to give highly functionalized benzene ring-
fused cyclopentane in good yields with excellent ee (97% and
99%).
heptaldehyde, and cyclopropyl carboxyaldehyde all reacted
well; the resulting 3i−3l were isolated in high yields with
excellent enantiomeric excess (91% ee to 99% ee). Again, both
benzaldehyde and thiophene-2-carbaldehyde are suitable
substrates for this reaction as well, giving products 3m and
3n in 76% yield with 94% ee and 65% yield with 97% ee,
respectively. Reaction of cinnamaldehyde proceeded smoothly
to give product 3o in 72% yield with 91% ee.
The highly functionalized products could be further
elaborated. As shown in Scheme 5, treatment of dearomatized
The benzene ring of 2-(chloromethyl)benzofuran could be
freely functionalized (Scheme 4). 2-(Chloromethyl)-5-
methylbenzofuran performed slightly better than its unmethy-
lated counterpart; the corresponding products 4a−4c by
coupling with 5-chloropentanal, dihydrocinnamaldehyde, and
cinnamaldehyde were obtained in moderate to good yields with
excellent ee (97%−98%). A stronger electron-donating group, a
methoxy group, was compatible under current reaction
conditions. Notably, changing the position of the methoxy on
the phenyl ring did not impose an evident influence on the
yield and enantioselectivity since 5- and 7-substituted substrates
offered the corresponding products 4d and 4e with the same
enantioselectivities (96% ee each). Halides including F, Cl, and
Br were well tolerated under the standard conditions; the
corresponding product 4f−4j were obtained in moderate to
good yields and high ee (95% −97%). A preinstalled bromo-
group on benzene ring allows further functionalization through
standard cross-coupling reactions. To our delight, 3-(chlor-
omethyl)-benzofuran proved to be a suitable substrate for this
dearomatization addition reaction as well. Excellent ee’s (92%
to 96%) of the elaborated products 4k−4m were obtained from
Scheme 5. Synthetic Utilities of Dearomatized Products
product 4k with trifluoroacetic acid gave the rearomatized
compound 5 with a disubstituted benzofuran segment which is
frequently present in bioactive natural products and synthetic
molecules.13 Compound 3c could undergo facile hydrogenation
in the presence of Wilkinson’s catalyst to produce compound 6
which contains three contiguous stereogenic centers; notably,
only one diastereomer was observed from this reaction.
C
DOI: 10.1021/acs.orglett.6b00559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In summary, the first asymmetric dearomatization addition
reaction of readily available halomethyl heteroarenes with a
broad range of aldehydes was realized under chromium-
catalyzed conditions, leading to optically pure elaborated
molecules with two adjacent stereogenic centers. Remarkable
features of the reaction include the mild reaction conditions
and excellent chemo-, regio-, diastereo-, and enantioselectiv-
ities. Future work will focus on expanding this catalytic system
to other halomethyl arene systems and applying this protocol to
the syntheses of complex molecules with biological and
medicinal significance.
ASSOCIATED CONTENT
* Supporting Information
■
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ACS Publications Web site. The Supporting Information is
available free of charge on the ACS Publications website at
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Experimetal procedures and characterization data for all
new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: guozhuzhang@sioc.ac.cn.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to NSFC-21421091, the “Thousand Plan”
Youth program, State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences.
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