Aryl Ether Syntheses via Aromatic Substitution Proceeding under Mild Conditions

Article abstract of DOI:10.1021/acs.joc.0c01250

In this study, mild conditions for aromatic substitutions during the syntheses of aryl ethers were developed. In the reaction conditions, the choices of solvent, base, and the sequence for the addition of the reagents proved important. A wide variety of alcohols were used directly as nucleophiles and smoothly reacted with aryl chlorides that possessed either a nitro or a cyano group at either the ortho- or para-position. Controlled experiments we performed suggested that the reaction underwent a charge-transfer process mediated by a combination of DMF and tert-BuOK.

Full text of DOI:10.1021/acs.joc.0c01250

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Article
Aryl ether syntheses via aromatic substitution
proceeding under mild conditions
Shin Ando, Marina Tsuzaki, and Tadao Ishizuka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01250 • Publication Date (Web): 11 Aug 2020
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Aryl ether syntheses via aromatic substitution proceeding under mild conditions
Shin Ando,* Marina Tsuzaki, and Tadao Ishizuka*
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Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi Chuo-ku, Kumamoto 862-0973,
Japan
ando@gpo.kumamoto-u.ac.jp (S.A), tstone@gpo.kumamoto-u.ac.jp (T.I.)
Abstract
In this study, mild conditions for aromatic substitutions during the syntheses of aryl ethers were
developed. In the reaction conditions, the choices of solvent, base, and the sequence for the addition of
the reagents proved important. A wide variety of alcohols were used directly as nucleophiles and
smoothly reacted with aryl chlorides that possessed either a nitro or a cyano group at either the o- or p-
position. Controlled experiments we performed suggested that the reaction underwent a charge transfer
process mediated by a combination of DMF and tert-BuOK.
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Introduction
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Aryl ether is one of the most fundamental functional groups and is ubiquitous in biologically
active compounds such as pharmaceuticals and agrochemicals. Therefore, chemical transformations to
reconstruct this functionality are continuously studied, and many effective methodologies have been
reported to date. The transition metal catalyzed cross-coupling reactions between alcohols and aryl
halides are representative and powerful methodologies. This type of transformation is widely used and
includes a copper mediated/catalyzed reaction that is widely known as Ullman-type coupling1 and a
palladium-catalyzed version that is referred to as Buchwald-Hartwig type coupling.2 Under these
metal-catalyzed processes, the reactivity trends usually depend on a leaving group of aryl halides, I >
Br > Cl > F, and aryl bromides are the most commonly used. These catalytic processes are applicable to
a wide variety of substrates, but the requirement of a metal catalyst, which is often expensive and toxic,
is a drawback. For an alternative to these metal-catalyzed processes, aromatic nucleophilic substitution
reactions such as SNAr are used for the aryl ether syntheses from aryl halides (Figure 1).3 Under these
traditional catalyst-free reaction conditions, an inverted order of reactivities, compared with the
metal-catalyzed reactions, is usually observed depending on the order of the leaving groups: F > Cl >
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Br > I. Although some relevant studies in this decade have introduced the possibility of other concerted
mechanisms among the reactions that occur in this class,4 the SNAr has commonly been recognized as
the reaction that will form “Meisenheimer complexes”.5 This reaction is useful in the synthesis of aryl
ethers from aryl fluorides or chlorides, but heating under high temperature in the presence of either
sodium or potassium alkoxide, which serves as both a nucleophile and a strong base, is a typical
reaction condition. In addition to these harsh conditions, a necessity for the electronic activation of aryl
halides with EWGs such as nitro, cyano, and acyl groups is a general limitation. In particular, for the
SNAr reactions of aryl chlorides, only highly activated aryl substrates with plural EWGs are applicable.
Here, we report the development of aromatic substitutions for aryl ether syntheses, which can be
performed either at 0 or 25 °C. Under the conditions we developed, aryl chlorides activated by a nitro
or a cyano group can be coupled with a wide variety of alcohols.
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Traditional SNAr reactions
OR
O
X
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X
OR
NO2
NO2
NO2
MOR

nucleophilic addition
(rate determining step)
N
NO2
NO2
O
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Meisenheimer complex
Strongly basic alkoxides are generally used.
Relatively high temperature is often required.
Reactivity trends depend on leaving groups: F ≫ Cl ≈ Br > I.
This work
Cl
OR
KOtBu in THF
EWG
EWG
+ HOR
DMF, 0 °C or 25 °C
EWG = NO2 or CN at the o- or p- position
Alcohols are used directly.
≫
≫
≫
≫
Reactions proceeded at 0 °C in most cases.
A wide variety of alcohols including phenol are applicable.
Arylchlorides are effectively transformed.
Figure 1. Representative features of traditional SNAr reactions and the reaction reported in this study.
Results and Discussion
During the course of our study to develop a mild and useful method for the syntheses of aryl
ethers, we serendipitously found that the sequence used for the addition of reagents drastically changed
the reactivities (Scheme 1). In the first trial, the ethoxylation of 1-chloro-4-nitrobenzene 1 with the use
of sodium ethoxide in DMF was attempted at 0 °C, and 1-ethoxy-4-nitrobenzene 2 was isolated in a
24% yield after 2h with a 49% recovery of starting material 1 (Scheme 1a).6 When we mixed
tert-BuOK with ethanol to form KOEt in situ prior to an addition of 1-chloro-4-nitrobenzene 1, we
isolated1-ethoxy-4-nitrobenzene 2 in a 50% yield with a 36% recovery (Scheme 1b). In contrast to
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these results, a dropwise addition of tert-BuONa solution in THF over 5 min to a solution of
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1-chloro-4-nitrobenzene
1
and EtOH in DMF resulted in
a
much higher yield of
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1-ethoxy-4-nitrobenzene 2 (Scheme 1c; 86% yield with 13% recovery). As we added tert-BuOK
instead of tert-BuONa, a complete conversion was observed in 10 min and 1-ethoxy-4-nitrobenzene 2
was isolated in a 97% yield (Scheme 1d), whereas the use of tert-BuOLi resulted in a poor yield
(Scheme 1e). When etherification with tert-BuOK was attempted on a 10 mmol scale, 1.60 g of
1-ethoxy-4-nitrobenzene 2 was obtained (95%). Based on these preliminary results, we decided to
investigate these unique phenomena more carefully to gain insight into the nature of this
transformation.
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Scheme 1. Drastic change in reactivity during an ethoxylation of 1-chloro-4-nitrobenzene 1
Results from the experiments to test the effects of reaction solvents are summarized in Table
1. With the use of a commercially available tert-BuOK solution in THF as a base, we screened aprotic
polar solvents because of the polar characteristics of the reaction (entries 1 to 6). In addition to DMF,
DMAc (entry 3), DMPU (entry 4), and DMSO (entry 6) were found to be usable solvents; DMF and
DMSO were particularly effective and converted 1-chloro-4-nitrobenzene 1 completely. The reaction in
DMSO included some intractable side products and the yield of the substituted product 2 (74%) was
somewhat lower than in DMF. The use of ethanol as a solvent, which also serves as a nucleophile, was
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fruitless (entry 7), and the reaction in THF gave us only a trace amount (<5%) of
1-ethoxy-4-nitrobenzene 2 (entry 8). The ratio of DMF to THF also affected the reactivity (entries 1, 9,
and 10), and the reactivity was lowered when we used less than 50 v/v% of DMF as a solvent. Based
on the results of these experiments, we selected DMF as a solvent for further investigations.
Table 1. Effects of reaction solvents
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entry
solvent
yield (%) recovery of 1 (%)
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DMF/THF (1.0 mL/0.3 mL)
DMI/THF (1.0 mL/0.3 mL)
DMAc/THF (1.0 mL/0.3 mL)
97a
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0
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DMPU/THF (1.0 mL/0.3 mL) 19
NMP/THF (1.0 mL/0.3 mL)
DMSO/THF (1.0 mL/0.3 mL) 74
0
EtOH/THF (1.0 mL/0.3 mL)
THF (1.3 mL)
0
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trace
DMF/THF (0.65 mL/0.65 mL) 86
DMF/THF (0.25 mL/0.75 mL) 41
a Data from Scheme 1d.
We next tested a form of reactivity that depended on a leaving group of 4-nitrohalobenzenes
(Table 2), and a trend in reactivity that was the same as that of the general SNAr reaction. Although the
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reactivities of 1-bromo-4-nitrobenzene 3b and 1-iodo-4-nitrobenzene 3c under these mild conditions
were somewhat higher than our expectations based on literature searches, some undesired side products
were observed during the reaction using these substrates. These results indicated that the
rate-determining step would not be a cleavage of the C–X bond.
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Table 2. Effects of leaving groups
entry
substrate
yield (%)
quant.
97a
recovery of S.M. (%)
1
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4
3a (X = F)
1 (X = Cl)
3b (X = Br)
3c (X = I)
0
0
68
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a Data from Scheme 1d.
To investigate the scope of the aromatic components, chlorobenzene derivatives with an
EWG at the p- or o- position and some N-heterocycles were applied to the ethoxylation conditions we
found (Figure 2). Regardless of the requirement of the reaction at 25 °C in the case of cyano-substituted
chlorobenzene, nitro- and cyano-substituted aryl chlorides were effectively ethoxylated (4a – 4c). A
trifluoromethyl group at the ortho position was ineffective for activating the aryl chlorides. Acyl groups
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such as benzoyl and pivaloyl showed less reactivity and resulted in the recovery of large amount of the
starting materials (4e and 4f), but the reaction of benzophenone with a fluoride leaving group at 0 °C
resulted in an excellent yield. It should be emphasized that two similar N-heterocycles, pyridine and
quinoline, showed contrasting results. Although the alkoxylation of 2-chloropyridine is aptly known to
be a practical reaction under the typical SNAr conditions, ethoxylation under the presented method at
25 °C gave no pyridyl ether (4g). On the other hand, ethoxylation at the 2- or 4- position of quinoline
smoothly proceeded at 0 °C and produced ethyl ethers in excellent yields (4h and 4i). An important
intermediate to a bidentate ligand, 4,7-dichloro-1,10-phenanthroline, was applicable to access a novel
diethoxy derivative 4j in a quantitative yield.
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Figure 2. Ethoxylation of aryl chlorides; a 2.0 eq. of EtOH and 2.0 eq. of KOtBu were used. b 3.0 eq. of
EtOH and 3.0 eq. of KOtBu were used.
We then tested the scope of an alcoholic nucleophile for this transformation (Figure 3). For
an aromatic substrate, 1-chloro-4-nitrobenzene 1 was tested first (5a–t). Primary alcohols such as
methanol, n-butanol, and allyl alcohols smoothly reacted and gave the corresponding ethers in excellent
yields (5a–d). The reaction with isopropanol, a secondary alcohol, required warming to 25 °C and
resulted in a slightly decreased yield (5e; 76%). Benzyl and p-methoxybenzyl protected ethers were
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obtained in good yields (5f; 80% and 5g; quantitative yield), and a cyclopropane ring was installed with
no problem (5h; 95%). Regardless of the requirement of a longer reaction time at 25 °C, diaryl ether
(5i) was also accessible in an efficient manner (86%). At 25 °C, 2,2,2-trifluoroethanol gave us
trifluoroethyl ether 5j in good yield, whereas heptafluorobutanol was only mildly reactive (5k, 29%
after stirring for 24 h at 25 °C). Linear alkyl structures with unsaturated bond(s) were also applicable,
and geraniol and (-)--citronellol showed good reactivity at 0 °C (5l in 84% and 5m in 86%,
respectively). Some secondary alcohols with chiral centers were used for etherification. (-)-Menthol
and diacetone-D-glucose were highly reactive under the presented conditions at 0 °C (5n in 83% and
5o in 90%, respectively), but cholesterol diminished the reactivity and resulted in a decreased yield (5p
in a 65% yield). In some cases, we noticed that nitrophenol 7 was generated as a side product. During a
session of tert-butoxylation, nitrophenol was obtained as a major product (35% yield) with
tert-butylether 5q (23%) and 1-chloro-4-nitrobenzene was recovered (30%). The reaction with
homoallyl alcohols such as 3-buten-1-ol and cis-3-hexen-1-ol gave nitrophenol 7 and yields of coupled
ethers 5r and 5s were moderate (54% and 65%, respectively), which was also the case for the reaction
with 2-butyn-1-ol (5t in 37% with 33% of nitrophenol 7). The isolated homoallyl ether 5s was treated
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under the reaction conditions to examine pathways leading to nitrophenol, and we isolated nitrophenol
7 in a 69% yield (Scheme 2a). The use of H2O instead of alcohols would not produce nitrophenol 7 at
all, however, which suggested that the cleavages of the alkyl groups to generate nitrophenol 7 occurred
after the substitution reactions. We then found that the etherification of 4-chlorobenzonitrile was
amenable to reaction with secondary alcohols and 2,2,2-trifluoroethanol to afford the ethers in
moderate to good yields (6a, 6c–f) at 25 °C. Unfortunately, a diaryl ether 6b was not formed via the
reaction with phenol at 25 °C. Additionally, a chiral secondary alcohol at the benzylic position was
reacted with 1-chloro-4-nitrobenzene to examine the possibility of racemization, and this resulted in a
good yield with a complete retention of the chirality (Scheme 2b). To demonstrate the arylation of an
alcohol, we reacted 0.2 mmol of (-)-menthol 10 with 1.5 eq. of 1-chloro-4-nitrobenzene 1via the slow
addition of 1.5 eq. of tert-BuOK solution in THF at 0 °C (Scheme 2c). The coupled product 5n was
obtained in a quantitative yield based on (-)-menthol, which indicated that the presented conditions
could be useful for the arylations of alcohols.
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a
Figure 3. The aromatic substitution with varied alcoholic nucleophiles. 3.0 eq. of alcohol was used.
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b2.0 eq. of alcohol was used. cTwice the amount of DMF was used.
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Scheme 2. a) Cleavage of a homoallyl group under the presented conditions. b) An aromatic
substitution with a chiral secondary alcohol at a benzylic position. c) An arylation of (-)-menthol with
the use of an excess amount of 1-chloro-4-nitrobenzene 1.
Since the high reactivity under the presented conditions deviated from the typical reactivity
of the SNAr reaction, we decided to conduct some controlled experiments (Scheme 3a and 3b). Under
the presented conditions, some reactions seemed to deviate from the typical reactivity of the SNAr
reaction: 1) low reaction temperature, 2) inferior yields using premixed ethanol and KOtBu (see
Scheme 1b), 3) unsatisfactory reactivity toward acylated aryl chlorides, and, 4) extreme differences in
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the reactivities between 2-chloropyridine and 2-chloroquinoline. Based on these observations, the
reagents we used, and discussions found in the literature concerning the mechanisms of SNAr
reactions,7 we hypothesized that the substitutions under the presented conditions would include a
charge transfer process via a combination of DMF and KOtBu.8 To test this hypothesis, we added
compound 11, which had been reported as an electron donor precursor by Tuttle and Murphy,8a,9 to the
conditions shown in entry 10 of Table 1. In contrast to the moderate yield without 11, the yield was
significantly increased in the presence of 10 mol% of compound 11 (83%, Scheme 3a), which supports
the involvement of a charge transfer process. We then performed the reaction in the presence of 1.0 eq.
of TEMPO as a radical scavenger (Scheme 3b), but the yield of the product was unaffected. The
reaction under an oxygen atmosphere was also attempted, but the yield was the same level as that under
an argon atmosphere. Although dissociation of C–X bond after the formation of “charge-transfer
complex” 12 would generate an aryl radical 13, based on the above observations, the SRN1 pathway10
seemed unreasonable (Scheme 3c). A trend wherein reactivity depended on the halogen leaving groups
(see Table 2) would also support this explanation.11 With respect to the inferior yield when using
premixed ethanol and KOtBu (Scheme 1b), the premixing would have generated potassium ethoxide
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and tert-butanol in situ, which would result in an inefficient SET process. In a similar manner, when
the reaction was performed using a larger amount of an alcohol than tert-BuOK, it would not proceed,
which was likely due to changes in the equilibrium between alcohols and tert-BuOK. Single-electron
captures by the carbonyl moieties of acylated aryl chlorides 4e and 4f would have caused the low yields.
Since the reduction potential of pyridine is lower than that of quinoline,12 the SET to 2-chloropyridine
was expected to be less effective than that to 2-chloroquinoline, which caused the significant difference
in their reactivities. Ultimately, we became convinced that the charge-transfer complex 12 generated by
a combination of DMF and KOtBu played a key role in the formation of the Meisenheimer complex 14
at low temperature,7a,13 although more detailed mechanistic studies are required to understand the
mechanisms of all processes. During the formation of the Meisenheimer complex 14, the electron
donors L would regenerate and could work as a catalyst.
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Scheme 3. The reaction in the presence of a) compound 11 as an electron donor precursor and b)
TEMPO or O2 as a free radical scavenger. c) A possible reaction pathway.
Conclusion
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In conclusion, we developed mild conditions for the etherification of aryl chlorides activated
with either a nitro or a cyano group. The addition of a solution of KOtBu in THF into a solution of aryl
chloride and an alcoholic nucleophile in DMF enabled ether formations with the use of a wide variety
of alcohols that included chiral secondary alcohols. With this method, the pre-formation of either
potassium or sodium alkoxide, which is generally highly exothermic, was not required, and the reaction
proceeded at either 0 or 25 °C. Additionally, the use of a commercial solution of KOtBu in THF
avoided the need to handle the hygroscopic and air- and moisture-sensitive KOtBu powder, which
made the process more user-friendly.14 Preliminary controlled experiments indicated that this ether
formation involves a charge-transfer complex generated by a combination of DMF and KOtBu.
Investigations are underway in our laboratory to further explain the mechanisms involved and to
develop more useful aromatic substitution methods.
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Experimental Section
General Information. CAUTION. Although we did not notice any exothermic phenomena, explosion
hazards of strong base in DMSO or in DMF had been reported.14 A safety evaluation must be conducted prior to
a large scale synthesis. All reactions were carried out under an argon atmosphere with freshly distilled
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solvents under anhydrous conditions, unless otherwise noted. Anhydrous DMSO and THF were
purchased and used without further distillation. Ethanol and methanol were distilled from either sodium
ethoxide or methoxide. Other reagents were used without further purification. Compound 11 was
prepared according to the literature.8a Yields refer to chromatographically and spectroscopically (1H
NMR) homogeneous materials unless otherwise noted. 1H and 13C NMR spectra were recorded at 600
and 151 MHz, respectively. Chemical shifts are reported in δ ppm and reference either an internal
tetramethylsilane or solvent peaks. The following abbreviations are used to indicate the multiplicities: s
= singlet; d = doublet; t = triplet; q = quartet; qt = quintet; sex = sextet; sept = septet dd = doublet of
doublets; ddd = doublet of doublet of doublets; dddd = doublet of doublet of doublet of doublets; dt =
doublet of triplets; app = apparent; m = multiplet; br = broad. Melting points were uncorrected.
High-resolution mass spectra were recorded on a double-focusing magnetic-sector mass analyzer
operating in a fast atomic bombardment (FAB) mode.
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Typical experimental procedures and data of ether compounds obtained in this study. A two-neck
round-bottom flask was charged with an aryl/heteroaryl chloride (0.2 mmol) and a magnetic stir bar. The flask
was evacuated and backfilled with argon (three times), and DMF (0.8 mL) was added using a syringe. An
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alcohol in DMF (0.3 mmol in 0.2 mL) was added to the resultant flask, then the flask was cooled to 0 °C in an
ice bath. 1.0 M tert-BuOK solution in THF (0.3 mL) was added dropwise over 5 min by a syringe with stirring at
0 °C. After stirring at 0 °C or 25 °C until TLC monitoring indicated the completion of the reaction, the reaction
was quenched by an addition of sat. NH4Cl aq. at 0 °C. The mixture was then transferred to a separatory funnel
and extracted with Et2O or CH2Cl2 (×3), and the combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by a column
chromatography on silica gel (amino-functionalized silica gel was used for compound 4j) to afford the desired
product.
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1-ethoxy-4-nitrobenzene (2).15 Eluent for column chromatography: 1–3% EtOAc/n-hexane; Yield: 32.3 mg
1
(97%), 1.60 g (95% on a 10 mmol scale); State of the product: pale yellow solid; H NMR (600 MHz, 300 K,
CDCl3, Figure S3)  = 8.20 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2
Hz, 3H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S4)  = 164.0, 141.4, 125.9, 114.4, 64.4, 14.5
ppm. Other spectroscopic properties were identical to those previously reported.
1-ethoxy-2-nitrobenzene (4a).15 Eluent for column chromatography: 1–3% EtOAc/n-hexane; Yield: 31.9 mg
(95%); State of the product: yellow liquid; 1H NMR (600 MHz, 300 K, CDCl3, Figure S5)  = 1H-NMR (CDCl3)
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7.81 (dd, J = 1.8, 7.8 Hz, 1H), 7.51 (ddd, J = 1.2, 7.2, 8.4 Hz, 1H), 7.07 (dd, J = 1.2, 8.4 Hz, 1H), 7.01 (ddd, J =
1.2, 7.2, 7.8 Hz, 1H), 4.19 (q, J.=.6.6 Hz, 2H), 1.48 (t, J = 6.6 Hz, 3H) ppm; 13C{1H} NMR(151 MHz, 300 K,
CDCl3, Figure S6)  = 152.3, 140.2, 133.9, 125.5, 120.1, 114.5, 65.4, 14.5 ppm. Other spectroscopic properties
were identical to those previously reported.
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4-ethoxybenzonitrile (4b).15 Eluent for column chromatography: 2–5% EtOAc/n-hexane; Yield: 24.8 mg
(84%); State of the product: colorless solid; 1H NMR (600 MHz, 300 K, CDCl3, Figure S7)  = 7.58 (d, J = 9.0
13
Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.08 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H) ppm; C{1H} NMR(151
MHz, 300 K, CDCl3, Figure S8)  = 162.3, 134.0, 119.3, 115.2, 103.7, 63.9, 14.5 ppm. Other spectroscopic
properties were identical to those previously reported.
2-ethoxybenzonitrile (4c).15 Eluent for column chromatography: 2–5% EtOAc/n-hexane; Yield: 28.8 mg (98%);
State of the product: colorless solid; 1H NMR (600 MHz, 300 K, CDCl3, Figure S9)  = 7.56 (dd, J = 1.2, 7.2 Hz,
1H), 7.51 (ddd, J = 1.2, 7.2, 8.4 Hz, 1H), 6.99 (ddd, J = 0.6, 7.2, 7.2 Hz, 1H), 6.95 (dd, J = 0.6, 8.4 Hz, 1H), 4.16
(q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S10)  = 160.6,
134.2, 133.8, 120.5, 116.5, 112.2, 102.1, 64.6, 14.5 ppm. Other spectroscopic properties were identical to those
previously reported.
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(4-ethoxyphenyl)(phenyl)methanone (4e).15 Eluent for column chromatography: 10–30% CH2Cl2/n-hexane;
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Yield: 44.9 mg (99% from Ar-F); State of the product: pale yellow oil; H NMR (600 MHz, 300 K, CDCl3,
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Figure S11)  = 7.83 (d, J = 9.0 Hz, 2H), 7.76 (dd, J = 1.2, 8.4 Hz, 2H), 7.57 (dddd, J = 1.2, 1.2, 7.2, 7.2 Hz, 1H),
7.48 (dd, J = 7.2, 7.2 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H) ppm;
13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S12)  = 195.5, 162.6, 138.3, 132.5, 131.8, 129.9, 129.6, 128.1,
114.0, 63.7, 14.6 ppm. . Other spectroscopic properties were identical to those previously reported.
1-(4-ethoxyphenyl)-2,2-dimethylpropan-1-one (4f).15 Eluent for column chromatography: 1–5%
1
EtOAc/n-hexane; Yield: 1.6 mg (4%); State of the product: pale brown liquid ; H NMR (600 MHz, 300 K,
CDCl3, Figure S13)  = 7.85 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H), 1.44 (t, J =
7.2 Hz, 3H), 1.38 (s, 9H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S14)  = 206.2, 161.4, 130.9,
129.9, 113.7, 63.6, 43.8, 28.4, 14.7 ppm.. Other spectroscopic properties were identical to those previously
reported.
2-ethoxyquinoline (4h).15 Eluent for column chromatography: 2–5% EtOAc/n-hexane; Yield: 34.8 mg (quant.);
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State of the product: pale yellow oil ; H NMR (600 MHz, 300 K, CDCl3, Figure S15)  = 7.98 (d, J = 8.4 Hz,
1H), 7.83 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 1.2, 7.8 Hz, 1H), 7.62 (ddd, J = 1.2, 7.2, 8.4 Hz, 1H), 7.37 (ddd, J =
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1.2, 7.2, 8.4 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 4.55 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H) ppm; 13C{1H}
NMR(151 MHz, 300 K, CDCl3, Figure S16)  = 162.1, 146.7, 138.5, 129.4, 127.4, 127.2, 125.0, 123.8, 113.3,
61.6, 14.6 ppm.. Other spectroscopic properties were identical to those previously reported.
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7-chloro-4-ethoxyquinoline (4i).15 Eluent for column chromatography: 10–30% EtOAc/n-hexane; Yield: 38.3
mg (92%); State of the product: colorless solid ; 1H NMR (600 MHz, 300 K, DMSO-d3, Figure S17)  = 8.87 (d,
J = 5.4 Hz, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.70 (dd, J = 1.8, 9.0 Hz, 1H), 7.17 (d, J =
5.4 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.60 (3H, t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3,
Figure S18)  = 161.5, 152.5, 149.7, 135.6, 127.8, 126.3, 123.5, 119.9, 100.8, 64.3, 14.4 ppm.. Other
spectroscopic properties were identical to those previously reported.
4,7-diethoxy-1,10-phenanthroline (4j). Eluent for column chromatography (amino functionalized silica gel):
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1–3% MeOH/CH2Cl2; Yield: 53.7 mg (quant.); State of the product: colorless solid; mp 184–186 °C; H NMR
(600 MHz, 300 K, CDCl3, Figure S19)  = 8.97 (d, J = 5.2 Hz, 2H), 8.18 (s, 2H), 6.95 (d, J = 5.2 Hz, 2H), 4.31 (q,
13
J = 7.0 Hz, 4H), 1.60 (t, J = 7.0 Hz, 6H) ppm; C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S20)  = 161.5,
151.0, 146.9, 120.9, 118.8, 103.2, 64.2, 14.4 ppm; HRMS(FAB+) m/z calcd for C16H16O2N2 [M + H]+: 269.1290;
found: 269.1306.
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1-methoxy-4-nitrobenzene (5a).15 Eluent for column chromatography: 1–3% EtOAc/n-hexane; Yield: 28.8 mg
(94%); State of the product: pale yellow solid ;1H NMR (600 MHz, 300 K, CDCl3, Figure S21)  = 8.22 (d, J =
9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 3.92 (s, 3H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S22) 
= 164.6, 141.6, 125.9, 114.0, 55.9 ppm.. Other spectroscopic properties were identical to those previously
reported.
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1-butoxy-4-nitrobenzene (5b).15 Eluent for column chromatography: 1–3% EtOAc/n-hexane; Yield: 34.3 mg
(88%); State of the product: yellow oil ; 1H NMR (600 MHz, 300 K, CDCl3, Figure S23)  = 8.20 (d, J = 9.2 Hz,
2H), 6.95 (d, J = 9.0 Hz, 2H), 4.06 (t, J = 6.5 Hz, 2H), 1.82 (tt, J = 6.5, 7.2 Hz, 2H), 1.52 (tq, J = 7.2, 7.2 Hz,
2H), 1.00 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S24)  = 164.2, 141.3, 125.9,
114.4, 68.6, 31.0, 19.1, 13.7 ppm.. Other spectroscopic properties were identical to those previously reported.
1-(prop-2-enoxy)-4-nitrobenzene (5c).15 Eluent for column chromatography: 1–3% EtOAc/n-hexane; Yield:
34.9 mg (95%); State of the product: yellow oil ; 1H NMR (600 MHz, 300 K, CDCl3, Figure S25)  = 8.20 (d, J
= 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.05 (tdd, J = 5.3, 10.2, 17.4 Hz, 1H), 5.44 (tdd, J = 1.2, 1.2, 17.4 Hz,
1H), 5.36 (tdd, J = 1.2, 1.2, 10.2 Hz, 1H), 4.64 (ddd, J = 1.2, 1.2, 5.4 Hz, 2H) ppm; 13C{1H} NMR(151 MHz,
300 K, CDCl3, Figure S26)  = 163.6, 141.6, 131.9, 125.9, 118.6, 114.7, 69.4 ppm.. Other spectroscopic
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(E)-1-(hex-2-enoxy)-4-nitrobenzene (5d).15 Eluent for column chromatography: 1–3% EtOAc/n-hexane; Yield:
37.7 mg (84%); State of the product: yellow oil ; 1H NMR (600 MHz, 300 K, CDCl3, Figure S27)  = 8.20 (d, J
= 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 5.88 (dt, J = 7.2, 15.6 Hz, 1H), 5.69 (ttd, J=1.2, 6.0, 15.6 Hz, 1H), 4.58
(d, J = 6.0 Hz, 2H), 2.10 (td, J = 7.2, 7.2 Hz, 2H), 1.45 (tq, J = 7.2, 7.2 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm;
13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S28)  = 163.8, 141.4, 136.7, 125.8, 123.6, 114.7, 69.5, 34.3,
22.0, 13.6 ppm.. Other spectroscopic properties were identical to those previously reported.
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1-(1-methylethoxy)-4-nitrobenzene (5e).15 Eluent for column chromatography: 1–3% EtOAc/n-hexane; Yield:
27.7 mg (76%); State of the product: yellow solid ; 1H NMR (600 MHz, 300 K, CDCl3, Figure S29)  = 8.19 (d,
J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 4.67 (sep, J = 6.0 Hz, 1H), 1.39 (d, J = 6.0 Hz, 6H) ppm; 13C{1H}
NMR(151 MHz, 300 K, CDCl3, Figure S30)  = 163.2, 141.0, 125.9, 115.2, 70.9, 21.7 ppm. Other spectroscopic
properties were identical to those previously reported.
1-benzyloxy-4-nitrobenzene (5f).15 Eluent for column chromatography: 1–3% EtOAc/n-hexane; Yield: 36.5 mg
(80%); State of the product: pale yellow solid; 1H NMR (600 MHz, 300 K, CDCl3, Figure S31)  = 8.22 (d, J =
13
9.0 Hz, 2H), 7.46–7.40 (m, 4H), 7.39–7.37 (m, 1H), 7.04 (2H, d, J = 9.0 Hz, 2H), 5.18 (s, 2H) ppm; C{1H}
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NMR(151 MHz, 300 K, CDCl3, Figure S32)  = 163.7, 141.7, 135.5, 128.8, 128.5, 127.5, 125.9, 114.9, 70.7
ppm. Other spectroscopic properties were identical to those previously reported.
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1-methoxy-4-(4-nitrophenoxymethyl)benzene (5g).15 Eluent for column chromatography: 5–10%
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EtOAc/n-hexane; Yield: 51.9 mg (quant.); State of the product: yellow solid ; H NMR (600 MHz, 300 K,
CDCl3, Figure S33)  = 8.21 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.95 (d, J =
9.0 Hz, 2H), 5.10 (s, 2H), 3.84 (s, 3H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S34)  = 163.8,
159.9, 141.6, 129.3, 127.5, 125.9, 114.8, 114.2, 70.5, 55.3 ppm. Other spectroscopic properties were identical to
those previously reported.
1-{(cyclopropyl)methoxy}-4-nitrobenzene (5h).15 Eluent for column chromatography: 1–3% EtOAc/n-hexane;
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Yield: 36.2 mg (94%); State of the product: yellow oil ; H NMR (600 MHz, 300 K, CDCl3, Figure S35)  =
8.20 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 3.91 (d, J = 7.2 Hz, 2H), 1.34-1.27 (m, 1H), 0.72-0.69 (m,
2H), 0.41–0.38 (m, 2H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S36)  = 164.1, 141.4, 125.9,
114.4, 73.5, 9.9, 3.3 ppm. Other spectroscopic properties were identical to those previously reported.
1-nitro-4-phenoxybenzene (5i).15 Eluent for column chromatography: 1–5% EtOAc/n-hexane; Yield: 37.1 mg
(86%); State of the product: pale yellow solid ; 1H NMR (600 MHz, 300 K, CDCl3, Figure S37)  = 8.21 (d, J =
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9.0 Hz, 2H), 7.45 (dd, J = 7.2, 9.0 Hz, 2H), 7.27 (ddd, J = 1.2, 1.2, 7.2 Hz, 1H), 7.10 (dd, J = 1.2, 9.0 Hz, 2H),
7.02 (d, J = 9.0 Hz, 2H)ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S38)  = 163.3, 154.7, 142.6,
130.3, 125.9, 125.4, 120.5, 117.1 ppm. Other spectroscopic properties were identical to those previously
reported.
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1-nitro-4-(2,2,2-trifluoroethoxy)benzene (5j).15 Eluent for column chromatography: 1–5% EtOAc/n-hexane;
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Yield: 43.6 mg (quant.); State of the product: pale yellow solid ; H NMR (600 MHz, 300 K, CDCl3, Figure
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S39)  = 8.25 (d, J = 9.0 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 4.47 (q, J = 7.8 Hz, 2H) ppm; C{1H} NMR(151
MHz, 300 K, CDCl3, Figure S40)  = 161.8, 142.9, 126.0, 122.8 (q, J = 277.6 Hz), 114.9, 65.8 (q, J = 36.2 Hz)
ppm. Other spectroscopic properties were identical to those previously reported.
1-(2,2,3,3,4,4,4-heptafluorobutoxy)-4-nitrobenzene (5k).15 Eluent for column chromatography: 1–3%
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EtOAc/n-hexane; Yield: 18.6 mg (29 %); State of the product: pale yellow solid ; H NMR (600 MHz, 300 K,
CDCl3, Figure S41)  = 8.27 (d, J = 9.27 Hz, 2H), 7.06 (2H, d, J = 9.0 Hz, 2H), 4.57 (t, J = 12.0 Hz, 2H) ppm;
13C{1H} NMR(151 MHz, 300 K, CDCl3, Figure S42)  = 161.8, 143.0, 126.0, 114.9, 65.1 (t, J = 27.9 Hz) ppm.
Other spectroscopic properties were identical to those previously reported.
(E)-1-(3,7-dimethylocta-2,6-dienoxy)-4-nitrobenzene (5l).15 Eluent for column chromatography: 1–3%
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EtOAc/n-hexane; Yield: 46.3 mg (84 %); State of the product: yellow oil ; 1H NMR (600 MHz, 300 K, CDCl3,
Figure S43)  = 8.20 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 5.47 (qt, J = 1.2, 6.6 Hz, 1H), 5.08 (tt, J = 1.2,
6.6 Hz, 1H), 4.64 (d, J = 7.2 Hz, 2H), 2.14–2.09 (m, 4H), 1.76 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H)ppm; 13C{1H}
NMR(151 MHz, 300 K, CDCl3, Figure S44)  = 164.0, 142.5, 141.3, 131.9, 125.8, 123.5, 118.2, 114.6, 65.7,
39.4, 26.2, 25.6, 17.6, 16.7 ppm. Other spectroscopic properties were identical to those previously reported.
(S)-1-(3,7-dimethyloct-6-enoxy)-4-nitrobenzene (5m).15 Eluent for column chromatography: 2–5%
EtOAc/n-hexane; Yield: 47.8 mg (86 %); State of the product: yellow oil ; 1H NMR (600 MHz, 300 K, CDCl3,
Figure S45)  = 8.20 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 5.11 (qdt, J = 1.2, 1.2, 7.2 Hz, 1H), 4.06–4.13
(m, 2H), 2.05 (tdd, J = 7.2, 7.2, 14.4 Hz, 1H), 2.00 (tdd, J = 7.2, 7.2, 14.4 Hz, 1H), 1.88 (qt, J = 4.8, 6.6 1H),
1.73–1.67 (m, 1H), 1.69 (d, J = 1.2 Hz, 3H), 1.68–1.63 (m, 1H), 1.62 (s, 3H), 1.40 (tdd, J = 6.0, 7.8, 9.6 Hz,
1H), 1.25 (ddd, J = 6.0, 7.8, 9.6 Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3,
Figure S46)  = 164.2, 141.3, 131.4, 125.8, 124.4, 114.4, 67.2, 37.0, 35.8, 29.4, 25.7, 25.4, 19.5, 17.6 ppm..
Other spectroscopic properties were identical to those previously reported.
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1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexoxy)-4-nitrobenzene (5n).15 Eluent for column chromatography:
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1–3% EtOAc/n-hexane; Yield: 46.0 mg (83 %); State of the product: yellow oil ; H NMR (600 MHz, 300 K,
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CDCl3, Figure S47)  = 8.19 (d, J = 9.6 Hz, 2H), 6.94 (d, J = 9.6 Hz, 2H), 4.17 (dt, J = 4.2, 10.6 Hz, 1H),
2.16–2.09 (m, 2H), 1.77–1.74 (m, 2H), 1.60–1.49 (m, 2H), 1.15–1.05 (m, 2H), 1.10–0.92 (m, 1H), 0.95 (d, J =
6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3,
Figure S48)  = 163.7, 141.0, 126.0, 115.0, 78.4, 47.8, 39.8, 34.3, 31.4, 26.2, 23.8, 22.0, 20.6, 16.6 ppm.. Other
spectroscopic properties were identical to those previously reported.
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(3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-(4-nitrophenoxy)tetrahydrofuro[2,3-d][
1,3]dioxole (5o).15 Eluent for column chromatography: 2–5% EtOAc/n-hexane; Yield: 68.8 mg (90 %); State of
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the product: pale yellow solid ; H NMR (600 MHz, 300 K, CDCl3, Figure S49)  = 8.24 (d, J = 9.6 Hz, 2H),
7.08 (2H, d, J = 9.6 Hz, 2H) 5.96 (d, J = 3.6 Hz, 1H), 4.83 (d, J = 3.0 Hz, 1H), 4.58 (d, J = 3.6 Hz, 1H), 4.42
(ddd, J = 4.8, 6.0, 8.4 Hz, 1H), 4.30 (dd, J = 3.0, 8.4 Hz, 1H), 4.16 (dd, J = 6.0, 8.4 Hz, 1H), 4.10 (dd, J = 5.4,
9.0 Hz, 1H), 1.57 (s, 3H), 1.44 (s, 3H), 1.33 (s, 3H), 1.30 (s, 3H) ppm; 13C{1H} NMR(151 MHz, 300 K, CDCl3,
Figure S50)  = 161.9, 142.2, 125.9, 115.4, 112.4, 109.4, 105.2, 82.2, 80.6, 80.3, 71.9, 67.2, 26.8, 26.6, 26.2,
25.1 ppm.. Other spectroscopic properties were identical to those previously reported.
(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-3-(4-nitrophenoxy)-2,3,4,7,8,9,10,1
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