Toward a Catalytic Atroposelective Synthesis of Diaryl Ethers Through C(sp 2)-H Alkylation with Nitroalkanes

Article abstract of DOI:10.1055/s-0037-1609581

We report studies toward a small-molecule-catalytic approach to access atropisomeric diaryl ethers that proceeds through a C(sp ²)-H alkylation using nitroalkanes as the alkyl source. A quaternary ammonium salt derived from quinine, containing

Full text of DOI:10.1055/s-0037-1609581

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© Georg Thieme Verlag Stuttgart · New York
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A. N. Dinh et al.
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Toward a Catalytic Atroposelective Synthesis of Diaryl Ethers
Through C(sp2)–H Alkylation with Nitroalkanes
Andrew N. Dinh
R2
R2
Cat. C2 (10 mol %)
Cs2CO3 (10 equiv)
NO2Me (10 equiv)
0.1 M PhMe, 36 h
O
Ryan R. Noorbehesht
Sean T. Toenjes
Br
H
CF3
N
O
O
Amy C. Jackson
R1
R1
NH
- Up to 80% yield
- Up to 85:15 er
99:1 via trituration
Mirza A. Saputra
Sean M. Maddox
Jeffrey L. Gustafson*
H
O
Me
O
O
O
N
NH
CF3
O
0
0
0
0
0-
0
0
1
7-
0
5
4
7-
5
9
5
Cat. C2
Department of Chemistry and Biochemistry, San Diego State
University, 5500 Campanile Drive, San Diego, CA, 92182-1030,
6 examples
USA
Jgustafson@sdsu.edu
Published as part of the Cluster Atropisomerism
Received: 10.05.2018
Accepted after revision: 21.06.2018
Published online: 31.07.2018
Diaryl ethers are a type of atropisomer that have been
largely overlooked by the enantioselective catalysis com-
munity, despite the prevalence of these functional groups
in natural products as exemplified by the macrocyclic diaryl
ether moieties present in vancomycin. Furthermore, atrop-
isomerically unstable diaryl ethers are common motifs in
drug discovery (Figure 1). To date, the literature involving
diaryl ethers is highlighted by some elegant diastereoselec-
tive examples en route to vancomycin21 and by several ex-
cellent studies by Clayden and co-workers22–26 wherein
they characterized the stereochemical stabilities of various-
ly substituted diaryl ethers and developed diastereoselec-
tive routes to atropisomeric diaryl ethers. Notably, in col-
laboration with Turner, they disclosed the only catalytic at-
roposelective route towards diaryl ethers currently in the
literature; this route employs oxidase or reductase enzymes
to desymmetrize prochiral diaryl ethers (Scheme 1A).
DOI: 10.1055/s-0037-1609581; Art ID: st-2018-d0300-c
Abstract We report studies toward a small-molecule-catalytic ap-
proach to access atropisomeric diaryl ethers that proceeds through a
C(sp2)–H alkylation using nitroalkanes as the alkyl source. A quaternary
ammonium salt derived from quinine, containing a sterically hindered
urea at the C-9 position, was found to effect atroposelective C(sp2)–H
alkylation with moderate to good enantioselectivities across several
naphthoquinone-containing diaryl ethers. Products could then be iso-
lated in >95:5 er after one round of trituration. For several substrates
that were evaluated, we obtained nitroethylated products in similar
yields and selectivities.
Key words atropisomerism, alkylation, phase-transfer catalysis, asym-
metric catalysis, chirality
Atropisomerism is a type of chirality that occurs when
there is hindered rotation about a bond, typically between
two sp2 atoms, wherein the rotational isomers are enantio-
meric.1–5 Although molecules that do not possess adequate
barriers to rotation are not considered atropisomeric,6 they
possess the potential to be atropisomeric when engaging a
chiral receptor (e.g., in protein binding or when interacting
with a chiral catalyst).7–12
R3
Sa
O
NH
R1
R2
H2N
O
NH
R4
Cl
O
NH
N
Previous work from our group and others has demon-
strated that atropisomer conformation can be leveraged to
improve various properties of biologically active small mol-
ecules.13–16 This work, in part, serves as a call to action for
the development of new synthetic methods toward atrop-
isomeric compounds. Whereas there have been several ex-
cellent examples of atroposelective catalysis over the past
few decades,17–20 the vast majority of examples have in-
volved biaryl scaffolds. Examples of atroposelective cataly-
sis on nonbiaryl atropisomers have largely focused on ben-
zamides and anilides.2,8,9
O
R3
O
O
N
O
R4
R2
R1
O
O
NH2
F3C
Lenvatinib
(Thyroid Cancer)
Tafenoquine
(Malaria)
Atropisomeric
Diaryl Ether
Figure 1 Illustrative examples of diaryl ethers
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
A. N. Dinh et al.
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loid C-9 position gave almost no observable selectivities
[see Supporting Information (SI) for details]. On the other
hand, catalyst C1, which has a C-9 stereochemically invert-
ed Boc-protected amine (Table 1, entry 2), gave reasonable
levels of enantioselectivity, albeit with low conversions into
2a. The selectivity could be further improved to an enantio-
meric ratio (er) of 85:15 when the tert-butyl urea-contain-
ing catalyst C2 was used.
A. Previous Work:
ketoreductase
O
O
OH
OHC
CHO
CHO
H
H
Clayden and Turner's biocatalytic atroposelective
synthesis of diaryl ethers
B. This Work:
Table 1 Optimization of C(sp2)–H Methylation of 1aa
R2
R2
Cl
Cl
O
O
R1
R1
R-NO2
NO2Me
Base
R
O
O
O
O
O
bifunctional
organocatalyst
Cl
Cl
Me
O
O
O
O
Cat. (10 mol%)
3Å sieves, r.t., 24 h
O
Atroposelective organocatalytic synthesis of diaryl ethers
Scheme 1 (A) Previous catalytic atroposelective route towards diaryl
1a
2a
ethers. (B) Proposed atroposelective alkylation of diaryl ethers.
Cat.:
O
O
C1, R =
O
N
Br
O
N
H
H
CF3
N
Other than these groundbreaking examples, work on
the catalytic atroposelective synthesis of diaryl ethers has
been scarce. Perhaps the major reason for this is that diaryl
ethers possess two axes (Figure 1), which can complicate
reaction development, analysis, and, in some cases, result in
racemization at a lower-than-expected energy through a
concerted gearing mechanism.23,27 When defining the chi-
rality of diaryl ethers, Clayden and others have made an
analogy to atropisomeric biaryl systems, defining chirality
based on the orientation of the substituents across both
aryl planes when the molecule is viewed along one aryl
ether axis (see Figure 1; the priority in the example is as-
signed according to the R group number).
Recent work from our group has focused on the atro-
poselective synthesis of naphthoquinone-based biaryls by
rigidification of a rapidly interconverting axis through a
1,4-nucleophilic addition to the quinone.28 As there was a
lack of enantioselective routes towards atropisomeric diaryl
ethers, we decided to test whether this approach could be
extended to this scaffold (Scheme 1B). We chose to evaluate
naphthoquinones such as 1a, in which the aryl group bears
a large tert-butyl group and a second smaller substituent
ortho to the ether axis, as Clayden has shown that the pres-
ence of one large quaternary substituent is often a prereq-
uisite for the formation of stereochemically stable diaryl
ethers.
R
C2, R =
CF3
N
H
N
H
Entry Solvent
Catalyst Base
MS
Yield (%) erb
1
2
toluene
TBAB
C1
C2
C2
C2
C2
C2
C2
C1
C2
C2
C2
Cs2CO3
–
–
–
–
–
–
–
18
18
17
40
20
15
60
51
36
68
38
71
-
toluene
toluene
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
62:38
85:15
50:50
60:40
65:35
80:20
75:25
64:36
81:19
68:32
73:27
3
4
toluene–H2O
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
5
6
7
8
4 Å
9
4 Å
3 Å
3 Å
3 Å
10
11
12
MTBE
aReactions were performed on a 0.028 mmol scale with 10 equiv of both
base and nitromethane in 0.1 M solvent.
b Calculated by HPLC; the results are reported as an average from at least
two trials. See the SI for more details.
The addition of water, or the use of other carbonate
bases, resulted in a loss in selectivity with a minimal in-
crease in yield (Table 1, entries 4–6); however, the use of
tribasic potassium phosphate (Table 1, entry 7) resulted in
an increase in yield to 60% with only a slight drop in selec-
tivity (er 80:20) when compared with Cs2CO3. Finally, in
line with Mukherjee’s work, we found that the addition of
3 Å molecular sieves (MS) resulted in yields of 2a that
While evaluating nucleophiles for the addition into 1a,
we observed that the use of nitromethane in the presence
of excess Cs2CO3 and tetrabutylammonium bromide (TBAB)
resulted in the isolation of the C(sp2)–H methylated product
2a (Table 1, entry 1), in line with seminal work reported by
Mukherjee and co-workers.29,30 Quinine-derived quaterna-
ry amines with hydroxy substitution at the cinchona alka-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
A. N. Dinh et al.
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approached 70% with a small increase in selectivity to
81:19 er (Table 1, entry 10). Whereas these selectivities can
be considered moderate, 1a was further enantioenriched
through trituration with isopropanol to provide 2a in great-
er than 97:3 er. Product 2a proved to be moderately stable,
with an experimentally determined barrier to rotation at
65 °C of 26.6 kcal/mol, likely resulting in what LaPlante
refers to as a ‘Type-II atropisomer” that would be expected
to display significant racemization at room temperature
over the course of a few weeks.
Extensive experimentation failed to achieve an increase
in er. Nonetheless, we decided to evaluate the conditions in
Table 1, entry 10 across several variously substituted sub-
strate analogues (Scheme 2).31–33 Substrate 1b, in which the
aryl group bore a 6-methyl substituent, resulted in a
decrease in yield and enantioselectivity in the isolated
product 2b to 54% yield with 71:29 er. Substrate 1c, which
contained 4-phenyl and 6-methyl substituents, gave 2c
with similar selectivities. These results can be explained by
an increase in electron density on the ether, reducing the
electrophilicity of the quinone. Diaryl ether 1d, which
possesses an electron-deficient para-aryl ring, reinforced
this hypothesis, as its reaction proceeded with a significant
increase in the yield of 2d, while retaining moderate enantio-
selectivity (er 71:29).
Substrate 1e, which contained 4-phenyl and 2-chloro
substituents on the aryl ring, also gave moderate selectivi-
ties and yields of 2e (47% yield; 72:28 er); however, we also
obtained small amounts of the nitroethylated product 3e
(see below). Substrate 1f, which contained a 6-bromo sub-
stituent, gave a 1:3 mixture of methylated 2f (10% yield) to
nitroethylated 3f (30% yield). Interestingly, whereas 2f was
obtained in 78:22 er, 3f was obtained in only 60:40 er. Sur-
prisingly, one round of trituration with hexanes permitted
the isolation of 3f in 99:1 er, albeit in low overall yield. Sub-
strate 1g, which possesses 4,6-diphenyl substitution, gave
the nitroethylated product 3g exclusively with a 75:25 er.
We observed similar results with 1h and 1i, which gave
nitroethylated 3h and 3i with similar yields and selectivi-
ties.
R2
R2
R2
NO2Me
Cat. C2 (10 mol%)
O
O
O
R1
R1
R1
+
O2N
Me
O
O
O
K3PO4, 0.1 M PhMe
3 Å sieves, r.t., 36 ha,b,c
O
O
O
1
2
3
Cl
Cl
Ph
Ar1
Ph
Ph
O
O
O
O
O
Cl
Me
Me
Me
Cl
O
Cl
Me
O
Me
O
Me
O
Me
O
Me
O
O
O
O
O
O
O2N
O
+
O
2a
2b
2c
2d
2ee
3e
<3%
54%, er = 71:29
46%, er = 70:30
68%, er =71:29
68%, er = 82:18
41%, erd = 97:3
47%, er = 72:28
Ar1 = 3,5-(CF3)2-C6H3
Ph
Me
Me
Me
Me
O
O
O
O
O
Br
Ph
Ph
Cl
Br
O2N
O2N
O2N
O
O2N
Me
O
O
O
O
O
+
O
O
O
O
2f
3f
3g
3h
3i
10%, er =78:22
65%, er = 75:25
49%, er =74:26
68%, er = 69:31
30%, er = 60:40
5%, erf = 99:1
Scheme 2 a Reactions were performed on a 0.028 mmol scale with 10 equiv of both base and nitromethane in 0.1M toluene. b The formation of both
products was observed for substrates 1a–i. The major product is shown above together with its yield and er. More information about product ratios can
be found in the SI. c The er was determined by HPLC from at least two trials. d 2a was triturated with HPLC-grade isopropanol. e A mixture of the methyl-
ated and ‘nitroethylated’ products was detected by mass spectroscopy; only the methylated product 2e was isolated and characterized. f 3f was triturat-
ed with HPLC-grade hexanes. See SI for more details.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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A. N. Dinh et al.
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O
O
O
O
O
O
O
O
t-Bu
t-Bu
t-Bu
t-Bu
O
O
O
O
– HNO2
R1
Me
R1
R1
R1
R2
R2
R2
R2
H
H
NO2
(Sa)-exo 1a
(Sa)-endo 2a
O2N
B
2nd addition
N
O
O
N
H
H
N
H
H
O
O
O
O
t-Bu
O
BzN
t-Bu
t-Bu
O
O
HBr
R1
Ox.
R1
R1
R2
R2
R2
O
NO2
O
N
O
NO2
O
(Sa)-endo 3a
(Sa)-exo
Scheme 3 Proposed mechanism for nucleophilic methylation. The key intermediate involves a quinone methide that is heavily affected by electronic
effects of the aryl ring. Stabilization of the intermediate can induce subsequent addition of nitromethane, forming the nitroethylated product. We
hypothesize that the urea catalyst interacts with both the diaryl ether and the carbonyl oxygen of the substrate, thereby locking the substrate into an
(Sa)-exo conformation. Subsequent tautomerization or second addition of nitronate, followed by oxidation, provides the diaryl ether products 2a and
3a, respectively.
Referring back to Mukherjee’s hypothesized mechanism
of C(sp2)–H alkylation with nitroalkanes, we postulate that
our diaryl ether substrates react via a quinone methide in-
termediate.29 If this intermediate is sufficiently long-lived,
then another equivalent of nitronate anion can add in a 1,4-
fashion to the quinone methide to give the nitroethylated
product (Scheme 3). Although the exact mechanism of qui-
none methide stabilization is unknown, we suspect that it
is due to a subtle electronic effect, as nitroethylation is only
observed with substrates that possess electron-neutral or
electron-donating substituents para to the ether group.
We next sought to define the stereochemical induction
of this reaction. As we were unable to obtain suitable crys-
tals, we compared experimental and computational circular
dichroism (CD) spectra, a method that is gaining acceptance
in the stereochemical community.34–36 We obtained a CD
spectrum of highly enantioenriched 2a (er > 97:3) and we
compared this to computed CD spectra of 2a in all possible
stable conformations about both ether axes (Scheme 4).
This analysis suggests that the major product is in the Sa
configuration with the proximal quinone carbonyl endo to
the aryl ring, (Sa)-endo.
Me
O
t-Bu
FAST
"gearing"
R1
O
O
O
f
q
f
q
R1
O
t-Bu
R2
Me
R2
O
(Ra)-endo
(Ra)-exo
0.001 (kcal/mol)
3.39 (kcal/mol)
Slow
Slow
DG = 26.6
DG = 26.6
kcal/mol
kcal/mol
O
Me
R1
t-Bu
O
O
O
f
q
f
q
R1
Me
t-Bu
O
R2
R2
FAST
O
"gearing"
(Sa)-endo
0.000 (kcal/mol)
(Sa)-exo
3.39 (kcal/mol)
Scheme 4 A dihedral-angle contour diagram, generated through a force-field molecular model, conveys an energetically favorable pathway towards
racemization via a concerted gearing mechanism (see SI for more details). Substrate–catalyst interactions can induce a high energy exo-conformation,
followed by immediate gearing to the respective endo-enantiomer.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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A. N. Dinh et al.
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When we generated these conformations for the com-
putational CD studies, we observed striking differences in
their predicted energies (Scheme 4). For example, the (Sa)-
endo-conformation of 2a is predicted to be significantly
more stable than the (Sa)-exo-conformation. Interestingly,
we observed the opposite trend for the starting material 1a,
with the exo-conformation being the more stable (see SI for
more details).
To investigate this further, we generated contour energy
maps of the rotational landscape about both axes of the di-
aryl ether (Scheme 4). In a manner consistent with results
from Clayden and co-workers,23 these maps demonstrate
that there is a low-energy pathway for interconversion be-
tween the exo- and endo-conformations of a given enantio-
mer that proceeds through a concerted gearing mechanism.
It is therefore likely that the exo-conformation of the start-
ing material is more stable and is likely to be the conforma-
tion that interacts with the catalyst. However, addition of
the methyl leads to an immediate conformational gear shift
to the endo-enantiomer.
Our working model for stereoinduction is shown in the
proposed transition state shown in Scheme 3, in which we
propose that the urea moiety of the catalyst forms a hydro-
gen bond with both the ether oxygen and one of the qui-
none carbonyls of the lower-energy exo-diaryl ether con-
formation. From here, the diaryl ether is preorganized into
the (Sa)-atropisomer to avoid steric interactions between
the tert-butyl group and the quinuclidinium that would be
present in the (Ra) atropisomer/catalyst complex. We pos-
tulate that the hydrogen bonding activates the diaryl ether
toward nucleophilic attack by the nitronate anion and that
the molecule subsequently undergoes HNO2 elimination
followed by tautomerism to give the alkylated quinone, or
subsequent attack by nitronate followed by oxidation to
give the nitroethylated byproduct. At this point, it is likely
that both products will rapidly relax to the endo-conforma-
tion, perhaps providing a release mechanism from the cata-
lyst.
In conclusion, we have disclosed the first example of a
small molecule catalytic synthesis of diaryl ethers.
Although our selectivities were moderate to good, highly
enantioenriched ethers can be accessed through trituration.
We also discuss several mechanistic aspects of this work.
We hope that these studies will serve as a starting point for
future efforts towards the enantioselective syntheses of di-
aryl ethers and related atropisomers.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609581.
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Funding Information
This work was supported by a grant from NIGMS (1R35GM124637).
A.N.D. and S.T.T. were supported by the SDSU University Graduate Fel-
lowship. A.C.J. is grateful for support from the NIH-funded Initiative
for Maximizing Student Development (IMSD) (5R25GMO58906).
N
oaitn
a
l
n
Itsu
i
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of
G
e
n
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e
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1(
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M
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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Moore, C. E.; Rheingold, A. L.; Gustafson, J. L. ACS Catal. 2018, 8,
5443.
(29) Manna, M. S.; Mukherjee, S. J. Am. Chem. Soc. 2015, 137, 130.
(30) Sarkar, R.; Mukherjee, S. Org. Lett. 2016, 18, 6160.
(31) Substituted Diaryl Ether Naphthoquinones 2; General Proce-
dure
(400 MHz, CDCl3): δ = 8.13 (dd, J = 7.7, 1.3 Hz, 1 H), 7.91 (dd, J =
7.5, 1.5 Hz, 1 H), 7.72 (td, J = 7.5, 1.5 Hz, 1 H), 7.66 (td, J = 7.5, 1.5
Hz, 1 H), 7.32 (d, J = 2.5 Hz, 1 H), 7.18 (d, J = 2.5 Hz, 1 H), 2.26 (s,
3 H), 1.38 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 185.01,
178.23, 154.23, 150.33, 142.76, 134.01, 133.37, 131.95, 130.49,
129.17, 128.39, 127.62, 126.47, 126.40, 126.29, 125.23, 35.85,
29.99, 9.73. MS (APCI): m/z [M + H]+ calcd for C21H18Cl2O3: 390.3;
found: 390.3.
A scintillation vial was charged with 3 Å powdered MS (10 mg)
and an oven-dried stirrer bar. The sieves were activated, and
toluene was syringed into the vial (0.1 M). The appropriate
diaryl ether naphthoquinone 1 (0.026 mmol, 1 equiv), K3PO4
(0.26 mmol, 10 equiv), quaternary ammonium salt catalyst C2
(.0026 mmol, 0.1 equiv), and NO2Me (0.26 mmol, 10 equiv)
were added sequentially. The mixture was stirred at r.t. for 36 h
then then diluted with toluene and filtered through Celite to
remove excess base and MS. Purification by flash column chro-
matography [silica gel, hexanes–CH2Cl2 (100:0 to 80:20)] gave
the desired methylated and nitroethylated products. (~3–68%
yield).
(33) 2-(2-Bromo-6-tert-butyl-4-methylphenoxy)-3-(2-nitro-
ethyl)naphthoquinone (3f)
Orange solid; yield: 3.8 mg (30%); mp 135 °C; 1H NMR (500
MHz, CDCl3): δ = 8.13 (dd, J = 7.6, 1.3 Hz, 1 H), 7.93 (dd, J = 7.7,
1.3 Hz, 1 H), 7.75 (td, J = 7.6, 1.4 Hz, 1 H), 7.68 (td, J = 7.5, 1.4 Hz,
1 H), 7.21 (d, J = 2.0 Hz, 1 H), 7.17 (d, J = 2.2 Hz, 1 H), 4.80–4.68
(m, 2 H), 3.59 (ddd, J = 13.2, 9.0, 6.9 Hz, 1 H), 3.43 (ddd, J = 13.2,
8.8, 6.0 Hz, 1 H), 2.35 (s, 3 H), 1.37 (s, 9 H). 13C NMR (126 MHz,
CDCl3): δ = 184.16, 177.98, 155.80, 149.75, 135.52, 134.29,
133.68, 131.66, 130.66, 128.41, 127.85, 127.48, 126.70, 126.41,
124.44, 71.98, 35.54, 30.32, 29.70, 22.44, 20.94. MS (APCI): m/z
[M + H]+ calcd for C23H22BrNO5: 473.3; found: 473.3.
(32) 2-[2-tert-Butyl-4,6-dichlorophenoxy]-3-methylnaphthoqui-
none (2a)
(34) Diedrich, C.; Grimme, S. J. Phys. Chem. A 2003, 107, 2524.
(35) Berova, N.; Di Bari, L.; Pescitelli, G. Chem. Soc. Rev. 2007, 36, 914.
(36) Li, X.-C.; Ferreira, D.; Ding, Y. Curr. Org. Chem. 2010, 14, 1678.
Bright-yellow solid; yield: 6.8 mg (68%); mp 123 °C. 1H NMR
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F