Catalyst-Controlled Regioselective Chlorination of Phenols and Anilines through a Lewis Basic Selenoether Catalyst

Article abstract of DOI:10.1021/acs.joc.0c01917

We report a highly efficient ortho-selective electrophilic chlorination of phenols utilizing a Lewis basic selenoether catalyst. The selenoether catalyst resulted in comparable selectivities to our previously reported bis-thiourea ortho-selective catalyst, with a catalyst loading as low as 1%. The new catalytic system also allowed us to extend this chemistry to obtain excellent ortho-selectivities for unprotected anilines. The selectivities of this reaction are up to >20:1 ortho/para, while the innate selectivities for phenols and anilines are approximately 1:4 ortho/para. A series of preliminary studies revealed that the substrates require a hydrogen-bonding moiety for selectivity.

Full text of DOI:10.1021/acs.joc.0c01917

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Article
Catalyst-Controlled Regioselective Chlorination of Phenols and
Anilines through a Lewis Basic Selenoether Catalyst
Andrew N. Dinh, Sean M. Maddox, Sagar D. Vaidya, Mirza A. Saputra, Christopher J. Nalbandian,
and Jeffrey L. Gustafson*
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ABSTRACT: We report a highly efficient ortho-selective electro-
philic chlorination of phenols utilizing a Lewis basic selenoether
catalyst. The selenoether catalyst resulted in comparable selectivities
to our previously reported bis-thiourea ortho-selective catalyst, with a
catalyst loading as low as 1%. The new catalytic system also allowed us
to extend this chemistry to obtain excellent ortho-selectivities for
unprotected anilines. The selectivities of this reaction are up to >20:1
ortho/para, while the innate selectivities for phenols and anilines are
approximately 1:4 ortho/para. A series of preliminary studies revealed
that the substrates require a hydrogen-bonding moiety for selectivity.
secondary ammonium chlorides can affect the chlorination of
protected anilines and phenols in excellent ortho-selectivity
with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) (Scheme
1A).33,34 Additionally, Yeung has demonstrated that bifunc-
tional urea catalysts are able to affect the regio- and
enantioselective halogenation of bisphenol scaffolds.35
To better understand the mechanism of action for catalyst 1,
we synthesized isotopically labeled catalyst analogues and
followed the reaction under optimal conditions via 15N and
13C NMR (see the Supporting Information). We were
somewhat surprised to observe that 1 converted to a new
species during the reaction. Isolation and analysis of the
observed byproduct led us to identify it as a guanidinium salt
1a (Scheme 1B),36 which we found to be catalytically inactive.
We hypothesized that this catalyst degradation attenuated the
observed catalyst activities, perhaps limiting the scope of
chemistry that could be affected. This led us to explore the
development of a second-generation ortho-selective catalyst.
We hypothesized that replacing one of the thioureas with
another Lewis basic moiety such as a chalcogenide ether would
lead to a longer-lived catalyst that would not undergo the
intramolecular cyclization we observed with 1.
INTRODUCTION
■
Halogenation of aromatics via aromatic electrophilic sub-
stitution (SEAr) is one of the most ubiquitous reactions in
modern synthesis, largely because halogenated aromatics are
among the most utilized precursors in modern cross-coupling
chemistry and other common reactions.1−6 Furthermore, the
incorporation of halogen atoms is commonly used to modulate
the physicochemical properties of small-molecule drug leads.7
While SEAr has been extensively studied for over a century,8−13
it often yields mixtures of constitutional isomers, representing a
major synthetic challenge. For example, electron-rich aromatic
scaffolds such as phenols and anilines yield a mixture of para-
and ortho-functionalized products, with the para-constitutional
isomer typically favored due to innate electronic proper-
ties.12,14−17
While there are synthetic strategies to access ortho-
halogenated phenols and anilines, these strategies usually
involve low regioselectivities, utilize multistep processes, or
contain harsh conditions that restrict the chemistry to a narrow
substrate scope.18−25 Recently, we and others have demon-
strated that catalysts can control the regiochemical outcome of
SEAr on both simple aromatics and complex natural
products.26 Gnaim and Snider have shown that secondary
ammonium chlorides and SO2Cl2 provide chlorinated phenols
in high ortho-selectivity.27,28 We have reported a highly ortho-
selective chlorination of phenols utilizing Nagasawa’s bis-
thiourea catalyst 1 and N-chlorosuccinimide (NCS). We
hypothesize that one of the thiourea moieties activates NCS
via a Lewis basic mechanism,11,29−31 while the other thiourea
interacts with the phenol via hydrogen bonding, leading to the
ortho direction of chlorination (Scheme 1A).32 Yeung and co-
workers have also demonstrated that the catalytic quantities of
Received: August 14, 2020
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© XXXX American Chemical Society
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Scheme 1. Catalyst Controlled Regioselective Methodologies
thioether with a selenoether in catalyst 10, observing a notable
increase in ortho-selectivity and conversion (Table 1, entry 9).
Finally, lowering the catalyst loading of 10 from 10 to 1 mol %
yielded significantly improved conversion and regioselectivity
(70% conversion; 2b/2c > 20:1; Table 1, entry 10). This result
is in line with the observations from the Seidel group,44
wherein they observed that at higher concentrations thioureas
can aggregate, attenuating their catalytic efficiency. To put
these selectivities in perspective, the difference in energy
between a catalyst such as 3 that yields 1:4 ortho/para and a
catalyst such as 10 that yields 20:1 ortho/para (defined as
ΔΔΔG‡; see Table 1, footnoted for definition) is 2.58 kcal/
mol.
We next sought to define the substrate scope of this
chemistry across simple phenols (Scheme 2). Each reaction
was repeated two times on an NMR scale (0.03 mmol) in
CDCl3 to obtain conversions and regioselectivities and then
repeated two more times on a preparative scale (1 mmol) in
CHCl3 to obtain the yield of the major constitutional isomer
after purification. Spot checking of the crude NMRs revealed
minimal variance in regioselectivity between the NMR scale
and preparative scale reactions. To avoid the formation of
dichlorinated products, which could lead to an overestimation
of regioselectivity via a “secondary resolution”, we ran each
reaction with 1.2 equiv of NCS, resulting in conversions
typically in the 50−70% range of the major constitutional
isomer with minimal to no observation of dichlorination.
Electron-poor-substituted phenols yielded excellent ortho-
selectivities in line with phenol. For example, 10 affected the
chlorination of 2-phenyl- and 2-cyano-substituted phenols
(11a and 12a) exclusively at the ortho-position to provide 11b
RESULTS AND DISCUSSION
■
Zhao and co-workers have developed a series of chiral
bifunctional Lewis base chalcogenides derived from the 1-
amino indanol scaffold and have successfully implemented
them in the context of diverse electrophilic olefin functional-
izations.37−43 Inspired by this work, we initially synthesized
and evaluated a series of thioether catalysts based on Zhao’s
scaffold that possessed varying directing groups of the 1-amino
group and evaluated their selectivity on phenol 2a. However,
these catalysts offered little perturbation from the “innate”
regioselectivity observed with triphenylphosphine sulfide 3
(Table 1, entries 2−6). We chose catalyst 3 and NCS as a
control for “innate” selectivity as our previous work has
demonstrated that these catalyst conditions result in
regioselectivities that match a noncatalyst system for phenols
at an accelerated rate. Interestingly, 10 mol % of indanol
catalyst 7, which possesses an electron-poor thiourea and is
perhaps a direct analogue of our original ortho-selective
catalyst 1, displayed preliminary levels of ortho-selectivity
(1.5:1.0 of 2b/2c), albeit with modest conversion. To increase
conversion, we kept the thiourea functional group constant and
began varying the Lewis base moiety. When the aryl
substitution of the thioether was made more electron-rich as
in catalyst 8, we observed increased conversion, albeit with
equal amounts of constitutional isomers (85% conversion,
1.0:1.0 of 2b/2c (Table 1, entry 7)). Incorporating a sterically
bulky 2,4,6-trimethyl substitution of the thioether aryl, as in
catalyst 9, increased the ortho-selectivity to 2.5:1.0 2b/2c,
albeit with a decrease in conversion to 49% (Table 1, entry 8).
Guided by Zhao’s recent work on the activation of a weakly
electrophilic SCF3 reagent with selenoethers,38 we replaced the
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Table 1. Catalyst Evaluation for Ortho-Selective
Chlorination of Phenol
Scheme 2. Expanded Scope for Ortho-Selective
Chlorination of Substituted Phenols
a
Optimized reaction conditions were used with respect to the catalyst.
Only the major product is shown. Yields were determined on a 1
b
c
mmol scale, using CHCl3 as the solvent, and represent an average of
d
two trials. Reactions were run on a 0.03 mmol scale in CDCl3;
1
conversions and isomeric ratios were determined by H NMR with a
TMS internal standard and represent an average of two trials.
e
ΔΔΔG‡ = ΔΔGentry#‡ − ΔΔGentry2‡, with ortho-selectivity defined as
a
All reactions were performed with 0.03 mmol of 2a, stirred with
positive ΔΔG‡ and para-selectivity defined as negative ΔΔG‡. ΔΔG‡
is derived from the Eyring equation, where ΔΔG‡ = −RT ln[para]/
[ortho] based on our previous definition. The following substrates
CDCl3 and catalyst, followed by addition of 0.036 mmol of NCS.
b
Conversion is the sum of both regioisomers 2b and 2c and
f
represents an average of three trials using tetramethylsilane (TMS) as
g
required a 5% catalyst loading. Substrate provided exclusively the
c
1
the internal standard. Regioisomeric ratios were determined by H
ortho regioisomer; 20:1.0 is the estimated ratio used to calculate the
d
‡
NMR and represent an average of three trials. ΔΔΔG‡ = ΔΔGentry#
h
ΔΔΔG‡ value. Ratios hold for small and large scales.
− ΔΔGentry2‡, with ortho-selectivity defined as ΔΔG‡ and para-
selectivity defined as negative ΔΔG‡. ΔΔG‡ is derived from the
Eyring equation, where ΔΔG‡ = −RT ln[para]/[ortho] based on our
previous definition.
some halogenation at the more hindered ortho-position was
also observed. Despite a general decrease in ortho-selectivity
for 3-substituted phenols compared to other substitution
patterns, the ortho-preference of catalyst 10 over the “innate”
furnished by triphenylphosphine sulfide 3 is still significant,
with ΔΔΔG‡ ranging from 1.03 to 1.83 kcal/mol. The
terpenoid thymol (19a) also provided ortho-selectivity (2.6:1.0
19b/19c). Finally, α-naphthol (20a) afforded ortho-selectivity
(9.5:1.0 20b/20c) to give (20b) with a moderate yield of 50%.
Overall, we show that this chemistry can be applied for a
diversity of substituted phenols. For the most part, 1 mol %
catalyst 10 yielded results comparable to 10 mol % catalyst 1;
however, it should be noted in some examples that there was a
notable loss in regioselectivity when compared to catalyst 1
(i.e., 14a and 15a). It should also be noted that Yeung’s
aforementioned work on phenols provides an efficient route
toward ortho-chlorinated phenols and is likely the superior
route from a cost perspective.
We next evaluated whether Lewis base catalysts could affect
ortho-selective chlorination on anilines. Anilines are typically
more reactive substrates for SEAr than phenols; indeed, no
catalyst is needed to affect the chlorination of anilines.
Furthermore, anilines typically display innate para-selectivities
on par with that of phenols. To overcome these issues, the
Yeung group has studied ortho-selective halogenation on
protected anilines;34 however, unprotected anilines have
and 12b in yields of 44 and 71%, respectively, significantly
overriding the para-selectivity observed with triphenylphos-
phine sulfide 3. On the other hand, we observed a decrease in
ortho-selectivities once we introduced bulkier substituents at
the 2-position; nonetheless, there was still a significant
overriding of the innate para-selectivity. For example, 2-
bromophenol (13a), 2-tert-butylphenol (14a), and 2-iodophe-
nol (15a) all provided the ortho-substituted regioisomers as
the major product (13b, 14b, 15b), affording ortho/para ratios
between 1.8:1.0 and 7.2:1.0. One possible explanation for this
decrease may be due to steric hindrance of the bulky
substituents, interfering with the hydroxy group forming
hydrogen bonds with the thiourea moiety.
Catalyst 10 also directed chlorination to the least hindered
ortho (6)-position of 3-substituted phenols. For example, the
chlorination of 3-fluorophenol (16a) yielded exclusive ortho-
selectivity at the 6-position to give 16b in a 70% yield. 3-
Bromophenol (17a) resulted in lower ortho-selectivities with 5
mol % 10 (3.5:1.0 17b/17c); nonetheless, 17b was furnished
as the major product in good yields. Phenyl-substituted 18a
was also predominantly chlorinated at the least hindered
position (3.5:1.0:1.7 18b/18c/18d); however, in this case,
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proven recalcitrant to catalyst-controlled regioselectivity. Initial
attempts for chlorination of unprotected anilines with
Nagasawa’s catalyst 1 provided no discernible chlorinated
products. On the other hand, chlorination of several simple
anilines in the presence of 1 mol % of catalyst 10 resulted in
nearly exclusive ortho chlorination (Scheme 3). For example,
the para innate selectivity in the absence of catalyst) is similar
to that observed for phenols, with ΔΔΔG‡ ranging from 1.08
to 2.82 kcal/mol.
To gain insight into the catalytic mechanism, we first
completed a series of control experiments utilizing 2a under
1
optimal conditions and followed conversion via H NMR.
Stirring 1 equiv of phenol and NCS in the absence of catalyst
provided no reaction (Scheme 4, reaction 1). A mixture of
Scheme 3. Expanded Scope of Ortho-Selective Chlorination
of Substituted Unprotected Anilines
Scheme 4. Preliminary Mechanistic Studies
phenol with 1 equiv of 10 also showed no change in NMR
spectrum (Scheme 4, reaction 2). On the other hand,
subjecting 10 to 20 equiv of NCS under reaction conditions
resulted in marked shifts of the resonances of several key
catalyst hydrogens and the formation of a new intermediate;
quenching with phenol after 30 min provides the observed
ortho-selectivities of 2a. This reaction was then repeated on a 1
g scale of phenol, wherein the ortho-chlorinated product was
obtained in a 65% yield with regeneration of the catalyst in a
52% yield (Scheme 4, reaction 3). These results differ from
what we observed with Nagasawa’s bis-thiourea 1, wherein
prestirring with NCS resulted in the formation of the
catalytically inactive guanidinium and thus no conversion
after the addition of phenol. Finally, the chlorination of anisole
with 10 provided exclusively the para-regioisomer in a 57%
yield (Scheme 4, reaction 4), implying that there is a
substrate−catalyst interaction via the hydrogen bond handle
of the phenol.
Based on these preliminary experiments, a plausible catalytic
mechanism for 10 is shown in Scheme 5. First, the Lewis basic
selenium in 10 will nucleophilically attack NCS to form a
selenium-bound halenium adduct A, perhaps aided by NCS
activation via H-bonding with the thiourea. The formed
succinimide anion will then coordinate with the urea N−H
bonds to give B. It should be noted that control experiments
with the addition of excess succinimide yielded no
perturbations in conversion or selectivity of the reaction (see
the Supporting Information). At this point, the succinimide
can deprotonate the phenol or aniline, and the new anion will
now hydrogen-bond to the thiourea to provide C. This
interaction will position the Se−halenium adduct adjacent to
the ortho-position of the substrate, explaining the observed
selectivity. Canonical SEAr completes the cycle and the
regeneration of the selenoether catalyst 10.
a
b
Reactions were quenched with vinyl ether after completion. Only
c
the major product is shown. Yields were determined on a 1 mmol
scale, using CHCl3 as the solvent, and represent an average of two
trials. Reactions were run on a 0.03 mmol scale in CDCl3;
conversions and isomeric ratios were determined by H NMR with a
d
1
TMS internal standard and represent an average of two trials.
e
ΔΔΔG‡ = ΔΔGentry#‡ − ΔΔGentry2‡, with ortho-selectivity defined as
positive ΔΔG‡ and para-selectivity defined as negative ΔΔG‡. ΔΔG‡
is derived from the Eyring equation, where ΔΔG‡ = −RT ln[para]/
f
[ortho] based on our previous definition. The following substrates
g
required a 5% catalyst loading. Substrate provided exclusively the
ortho regioisomer. 20:1.0 is the estimated ratio used to calculate the
h
i
ΔΔΔG‡ value. Ratios hold for small and large scales. Only
conversion is reported due to impurity of the starting material in the
scale-up.
alkyl-substituted anilines such as 2-methylaniline and 2-
isopropylaniline (21a and 22a) gave significant ortho-
selectivities at greater than 20:1, allowing for isolation of the
product in good yields. For comparison, each of these
substrates yielded primarily para-chlorinated products in the
absence of catalyst (1.0:2.7 and 1.0:2.4 o/p, respectively). As
with phenols, ortho tert-butyl substitution (23a) is met by a
decrease in the ortho-selectivity at 6.2:1.0 o/p (compared to
1.0:1.0 o/p in the absence of catalyst). 2-Bromoaniline (24a)
also provided reduced ortho-selectivity, giving an o/p ratio of
4.3:1.0 at a moderate conversion of 60%. 3-Fluoroaniline (25a)
provided excellent ortho-selectivities for 25b with trace
amounts of the other two regioisomers in a 70% yield.
However, 3-bromoaniline and 3-phenylaniline (26a and 27a)
resulted in lower yields and selectivity for the less hindered
ortho-substituted product (26b and 27b). Overall, the ortho
bias demonstrated by 10 for substituted anilines (compared to
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Scheme 5. Proposed Catalytic Cycle
(FCC) was performed using grade 60 silica gel (230−400 mesh)
purchased from Fisher Scientific. All thin-layer chromatography
(TLC) preparatory plates were performed using grade 60 silica gel
with fluorescent indicator F254 and were purchased from Fisher
Scientific. All reactions that required elevated temperatures were
heated with an oil bath.
Syntheses of Guanidinium Intermediate and Verification.
N-(Hexahydro-1H-benzo[d]imidazol-2(3H)-ylidene)-3,5-bis-
(trifluoromethyl)aniline (1a). The guanidinium intermediate was first
isolated in the chlorination of phenol following the optimized
procedure from our previously reported manuscript.32 The crystal
structure was obtained from material from the chlorination. We then
synthesized and isolated the intermediate on a preparatory scale using
two different methodologies. The second synthesis was used to isolate
15N labeled 1a, which was used to confirm that the observed
In conclusion, we have developed a second-generation Lewis
base selenoether catalyst, which can regioselectively chlorinate
phenols in an ortho fashion. Our new catalyst 10 provides
comparable selectivity relative to our previously reported
catalyst 1 at significantly lower catalyst loading. Catalyst 10
also enabled us to achieve high ortho-selectivities to
unprotected anilines, which possess a significant para-selective
background reaction. We hope this strategy can be applied for
other catalyst-controlled functionalizations, including the late-
stage functionalization of complex pharmaceutical intermedi-
ates.
EXPERIMENTAL SECTION
■
1
General Information. H and 13C NMR spectra were recorded
byproduct from regioselective chlorination was indeed the guanidi-
nium salt.
on a Varian VNMRS 400 MHz, Bruker Avance III 400 MHz, and
Varian Inova 500 MHz at room temperature (r.t.). High-resolution
mass spectra of new compounds were recorded on an Agilent 6530
Accurate-Mass Q-TOF LC/MS. All chemical shifts were reported in
parts per million (δ) and were internally referenced to residual protio
solvents, unless otherwise noted. All spectral data were reported as
follows: chemical shift (multiplicity [singlet (s), doublet (d), triplet
(t), quartet (q), and multiplet (m)], coupling constants [Hz],
integration). Carbon spectra were recorded with complete proton
decoupling. Fluorine spectra were recorded with internal fluorine
standards (i.e., trifluoroacetic acid). Some proton NMR spectra were
taken in an aprotic solvent (dimethyl sulfoxide (DMSO)-d6) to
prevent proton exchange and improve signal resolution. Conventional
mass spectra were obtained using Advion expressions CMS APCI/
ASAP. For the chlorination of substrates, purchased (N)-chlorosucci-
nimide was recrystallized from water before use. CDCl3 was run
through basic alumina before use in NMR experiments. All other
chemicals used were purchased from Sigma-Aldrich, TCI, Frontier
Scientific, Acros Organics, Strem, Oakwood, Cambridge Isotope
Laboratories, or Fisher and were used as received without further
purification or recrystallization. All flash column chromatography
Synthesis from Chlorination Conditions. Nagasawa’s bis-thiourea
(compound 1, 100 mg, 0.15 mmol, 1 equiv) was dissolved in CHCl3
(0.1 M). Then, N-chlorosuccinimide (20 mg, 0.15 mmol, 1 equiv)
was added to the mixture and the reaction was stirred for 12 h. The
reaction was concentrated down and purified by FCC (95:5::Hex/
EtOAc) to give 1a.
Synthesis from Diamine. This procedure is adapted from the
following literature.45 A solution of 3,5-bis(trifluoromethyl)phenyl
isothiocyanate (745 mg, 5 mmol) in 10 mL dichloromethane (DCM)
was added dropwise to a solution of a (1S,2S)-cyclohexane-1,2-
diamine (570 mg, 5 mmol). The reaction was stirred overnight for 12
h, concentrated, and purified by FCC (30:70::Hex/DCM) to give 1-
[(1S,2S)-2-aminocyclohexyl]-3-[3,5-bis(trifluoromethyl)phenyl] thio-
urea.
Next, the following procedure is adapted from the following
literature.36 420 mg of the thiourea (1.1 mmol, 1.0 equiv) was
dissolved in toluene (0.1 M). 224 mg of DCC (1.1 mmol, 1.0 equiv)
in 5 mL toluene was added to the solution, and the reaction was
brought to reflux. The reaction was stirred for 24 h. The solid was
E
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filtered, and filtrate was collected, concentrated, and purified by FCC
(50:50::Hex/EtOAc) to give 1a in a 62% yield, 240 mg, as a white
flaky solid. 1H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.40 (s, 2H),
3.19-3.06 (m, 2H), 2.06−1.92 (m, 2H), 1.87−1.77 (m, 2H), 1.54−
1.22 (m, 4H). 13C{1H} NMR (126 MHz, CDCl3) δ 159.0, 150.9,
132.3 (q, J = 32.7 Hz), 125.6 (d, J = 272.7 Hz), 123.0 (d, J = 13.2
Hz), 121.2 (d, J = 272.7 Hz), 115.0, 61.7, 29.4, 23.8. 19F NMR (376
MHz, CDCl3) δ −61.72. High-resolution mass spectrometry
(HRMS): calcd for C15H15F6N3 [M + H]+ = 352.1248. Found
352.1254.
General Synthesis of Selenoether Catalyst Precursor.
(1S,2R)-1-((tert-Butoxycarbonyl)amino)-2,3-dihydro-1H-inden-2-yl
methanesulfonate. To a round-bottom flask and dry stir bar was
added 5 g of (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (5 g, 33.5
mmol, 1.0 equiv) into a solution of tetrahydrofuran (THF)/H2O
(∼70 mL of both, 0.5 M). NaHCO3 (4.2 g, 50.3 mmol, 1.5 equiv) was
added to the solution and stirred for 5 min. Boc2O (8.0 g, 36.8 mmol,
1.1 equiv) was then added to the solution. The reaction was then
stirred at r.t. for 24 h and then diluted with EtOAc (2 × 30 mL). The
organic layer was separated, washed with brine, and dried with
Na2SO4, filtered, and concentrated under reduced pressure to give
tert-butyl ((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate
as a viscous brown oil. No further purification was needed. The
NMR spectra match the literature precedence.46
dihydro-1H-inden-2-yl methanesulfonate (1 equiv) in anhydrous
THF (0.6 M) was slowly added. The resulting mixture was stirred at
reflux for 12 h. The reaction was quenched with aqueous saturated
NH4Cl. The organic phase was extracted with DCM (20 mL × 2).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification through flash
column chromatography (hexanes/EtOAc::100:0−85:15) afforded
the desired product.
tert-Butyl ((1S,2S)-2-(Mesitylthio)-2,3-dihydro-1H-inden-1-yl)-
carbamate. Prepared and purified according to the general procedure
A: To an oven-dried round-bottom flask with a stir bar were added
300 mg of (1S,2R)-1-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-
inden-2-yl methanesulfonate and 379 mg of K2CO3. The flask was
sealed with a rubber stopper, evacuated, and back-filled with an inert
nitrogen gas. Then, 4.5 mL of anhydrous DMF was syringed into the
flask and stirred for 10 min. 112 mg of 2,4,6-trimethylthiophenol was
added to the flask, and the reaction was stirred at 100 °C for 12 h.
Purification through flash column chromatography (hexanes/
EtOAc::100:0−85:15) afforded the desired product in a 75% yield,
264 mg, as a white flaky solid. 1H NMR (500 MHz, CDCl3) δ 7.21−
7.11 (m, 4H), 6.94 (s, 2H), 5.06 (t, J = 7.8 Hz, 1H), 4.60 (d, J = 7.8
Hz, 1H), 3.42 (q, J = 7.8 Hz, 1H), 3.15 (dd, J = 7.5 Hz, 7.8 Hz, 1H),
2.90−2.84 (m, 1H), 2.51 (s, 6H), 2.27 (s, 3H), 1.47 (s, 9H). 13C{1H}
NMR (126 MHz, CDCl3) δ 155.4, 143.2, 129.0, 128.0, 127.1, 124.4,
124.0, 61.9, 54.4, 37.9, 28.3, 22.1, 21.0. HRMS: calcd for
C23H29NO2S: [M + H]+ = 384.1997. Found 422.1762 m/z, which
is [M + H + K]+.
tert-Butyl ((1S,2S)-2-(Mesitylselanyl)-2,3-dihydro-1H-inden-1-yl)-
carbamate. Prepared and purified according to the general procedure
B: To an oven-dried round-bottom flask with a stir bar was added 589
mg (1.37 mmol) of 1,2-dimesityldiselane in 9 mL (0.15 M) of EtOH
under an inert atmosphere. 104 mg of NaBH4 (2.74 mmol) was
added, and the mixture was stirred at r.t. for 10 min. Then, a solution
of 900 mg (2.74 mmol) of (1S,2R)-1-((tert-butoxycarbonyl)amino)-
2,3-dihydro-1H-inden-2-yl methanesulfonate in 6 mL anhydrous THF
(0.6 M) was slowly added. Purification through flash column
chromatography (hexanes/EtOAc::100:0−85:15) afforded the de-
sired product in a 45% yield, 532 mg, as a flaky white solid. 1H NMR
(500 MHz, CDCl3) δ 7.26−7.12 (m, 4H), 6.94 (s, 2H), 5.11 (t, J =
7.8 Hz, 1H), 4.61 (d, J = 7.8 Hz, 1H), 3.48 (q, J = 7.8 Hz, 1H), 3.18
(dd, J = 7.5 Hz, 7.8 Hz, 1H), 2.89−2.84 (m, 1H), 2.54 (s, 6H), 2.27
(s, 3H), 1.47 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) δ 155.4,
143.7, 141.3, 128.5, 128.0, 127.0, 124.3, 123.9, 47.3, 38.3, 28.3, 24.7,
20.9. HRMS: calcd for C23H29NO2Se: [M + H]+ = 431.1365. Found
452.1267 m/z plus multiplets from selenium isotopes, which is [M +
H + Na]+.
The product was dissolved in anhydrous DCM (∼50 mL, 0.5 M).
Et3N was syringed (4.8 mL, 34.5 mmol, 1.5 equiv) into the solution,
and the reaction was cooled down to 0 °C. MsCl (1.96 mL, 25.3
mmol, 1.1 equiv) was syringed slowly into the reaction, warmed to r.t.,
and stirred for 12 h. The reaction was quenched with 1 M NaHCO3
solution and then extracted with DCM (2 × 30 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure to give
(1S,2R)-1-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-inden-2-yl
methanesulfonate, as a brownish-white solid. No further purification
was needed. The NMR spectra match the literature precedence.47
1,2-Dimesityldiselane. N-Bromosuccinimide (2.2 g, 1 equiv) and
selenium metal powder (1.2 g 1.2 equiv) were added to a round-
bottom flask, and then MeCN (∼60 mL, 0.2 M) was added to the
mixture and stirred at 60 °C for 10 min. Mesityl boronic acid (2.0 g, 1
equiv) was added followed by the addition of pyridine (2.5 mL, 22.5
equiv). The reaction turns an orange color immediately after addition.
The reaction was left stirring in open air at 60 °C for 12 h. The
reaction was concentrated under reduced pressure, dissolved in
EtOAc, washed with 1 M HCl (30 mL × 3) and brine (30 mL × 3),
dried with Na2SO4, filtered, and concentrated under reduced pressure.
Purification through flash column chromatography (hexanes/EtOAc
= 100:0−99:1) afforded the desired product in a 55% yield, 1.3 g, as
1
an orange crystalline solid. H NMR (500 MHz, CDCl3) δ 6.85 (s,
4H), 2.27 (s, 6H), 2.25 (s, 12H). 13C{1H} NMR (126 MHz, CDCl3)
δ 143.4, 138.8, 128.1, 128.0, 23.9, 20.8. HRMS: calcd for C18H22Se2
[M + H]+ = 399.0133. Found 399.0046 m/z plus multiplets from
selenium isotopes.
GENERAL SYNTHESIS OF BOC-DEPROTECTION
■
The following synthesis is adapted from a general procedure
from the published literature.40 A solution of 6 M HCl (10
equiv) was added to a solution of dioxane (0.1 M) and Boc-
protected reagent. The mixture was stirred at 60 °C for 6 h and
then quenched with 1 M NaOH solution until pH 14. Then,
the solution was extracted with EtOAc (20 mL × 3). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification through
flash column chromatography (DCM/MeOH::100:0−80:20)
afforded the desired product.
General Synthesis of Lewis Base Substitution. Substitution
of Benzenethiols. To an oven-dried round-bottom flask with a stir bar
were added (1S,2R)-1-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-
inden-2-yl methanesulfonate (1 equiv) and K2CO3 (3 equiv). The
flask was sealed with a rubber stopper, evacuated, and back-filled with
inert nitrogen. Then anhydrous dimethylformamide (DMF) (0.2 M)
was syringed into the flask and stirred for 10 min. Benzenethiol (1
equiv) was added to the flask, and the reaction was stirred at 100 °C
for 12 h. The reaction was cooled to r.t., quenched with 1 M HCl,
extracted with EtOAc (20 mL × 3), dried with Na2SO4, filtered, and
concentrated under reduced pressure. Purification through flash
column chromatography (hexanes/EtOAc::100:0−85:15) afforded
the desired product.
Substitution of Diselenides. The following synthesis is adapted
from a general procedure from the published literature.40 To an oven-
dried round-bottom flask with a stir bar was added a solution of
diselenide (0.5 equiv) in EtOH (0.15 M) under an inert atmosphere.
NaBH4 (2 equiv) was added, and the mixture was stirred at r.t. for 10
min. Then, a solution of (1S,2R)-1-((tert-butoxycarbonyl)amino)-2,3-
(1S,2S)-2-(Phenylthio)-2,3-dihydro-1H-inden-1-amine
(4). A solution of 6 M HCl (480 μL) was added to a solution
of 2.9 mL dioxane and 100 mg (0.29 mmol) of tert-butyl
((1S,2S)-2-(phenylthio)-2,3-dihydro-1H-inden-1-yl) carba-
mate. The mixture was stirred at 60 °C for 6 h. The synthesis
and spectral data are in agreement with the literature.42
(1S,2S)-2-(Mesitylthio)-2,3-dihydro-1H-inden-1-
amine. A solution of 6 M HCl (650 μL) was added to a
solution of 3.9 mL dioxane and 150 mg (0.39 mmol) of tert-
F
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butyl ((1S,2S)-2-(mesitylthio)-2,3-dihydro-1H-inden-1-yl)-
carbamate. The mixture was stirred at 60 °C for 6 h.
Purification through flash column chromatography (DCM/
MeOH::100:0−80:20) afforded the desired product in an 81%
through flash column chromatography (Hex/EtOAc::100:0−
85:15) afforded the desired product in a 67% yield, 171 mg, as
a pale white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s,
1H), 8.79 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 1.6 Hz, 2H), 7.75
(s, 1H), 7.56−7.43 (m, 2H), 7.38−7.14 (m, 7H), 6.02 (s, 1H),
4.07 (q, J = 8.0 Hz, 1H), 3.43 (dd, J = 16.0, 7.6 Hz, 1H), 2.85
(dd, J =16.0, 8.2 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3)
δ 181.1, 161.6, 140.7, 133.1, 129.4, 128.2, 127.7, 124.9, 124.2,
124.1, 121.4, 119.5, 113.1, 65.8, 54.1, 38.0. HRMS: calcd for
C24H18F6N2S2 [M + H]+: 513.0894. Found 513.0893 m/z.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S,2S)-2-((4-
methoxyphenyl)thio)-2,3-dihydro-1H-inden-1-yl)-
thiourea (8). One hundred and fifty milligrams (0.28 mmol, 1
equiv) of (1S,2S)-2-((4-methoxyphenyl)thio)-2,3-dihydro-1H-
inden-1-amine was dissolved in 1.4 mL (0.2 M) of anhydrous
THF under an inert atmosphere. Then, 76 mg (0.28 mmol, 1
equiv) of 3,5-bis(trifluoromethyl)phenyl isothiocyanate was
added to the reaction. The mixture was stirred at r.t. for 4 h
and then immediately concentrated under reduced pressure.
Purification through flash column chromatography (Hex/
EtOAc::100:0−85:15) afforded the desired product in a 65%
1
yield, 89 mg, as a brown oil. H NMR (400 MHz, CDCl3) δ
7.31 (d, J = 7.0 Hz, 1H), 7.24−7.17 (m, 2H), 7.13 (d, J = 6.6
Hz, 1H), 6.96 (s, 2H), 4.24 (d, J = 7.8 Hz, 1H), 3.24 (dd, J =
16.7, 7.5 Hz, 1H), 3.15 (dd, J = 15.5, 7.5 Hz, 1H), 2.85 (dd, J
= 15.5, 9.0 Hz, 1H), 2.56 (s, 6H), 2.27 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 145.2, 143.1, 140.6, 138.4, 129.1, 129.0,
127.6, 126.9, 124.2, 123.4, 63.6, 58.5, 38.0, 22.2, 21.0. HRMS:
calcd for C18H21NS [M + H]+: 284.1473. Found 267.1205 m/
z, which is [M + H − NH2]+.
(1S,2S)-2-(Mesitylselanyl)-2,3-dihydro-1H-inden-1-
amine. A solution of 6 M HCl (940 μL) was added to a
solution of 5.6 mL dioxane with 244 mg (0.56 mmol) of tert-
butyl ((1S,2S)-2-(mesitylselanyl)-2,3-dihydro-1H-inden-1-yl)-
carbamate. The mixture was stirred at 60 °C for 6 h.
Purification through flash column chromatography (DCM/
MeOH::100:0−80:20) afforded the desired product in a 78%
1
yield, 144 mg, as a brown oil. H NMR (500 MHz, CDCl3) δ
1
7.32 (d, J = 7.1 Hz, 1H), 7.23−7.17 (m, 2H), 7.14 (d, J = 7.1
Hz, 1H), 6.96 (s, 2H), 4.26 (d, J = 7.8 Hz, 1H), 3.30 (dd, J =
16.8, 7.6 Hz, 1H), 3.21 (dd, J = 15.7, 7.6 Hz, 1H), 2.91−2.85
(m, 1H), 2.59 (s, 6H), 2.28 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 145.4, 143.5, 141.3, 138.5, 128.6, 127.5, 126.9,
126.7, 124.1, 123.4, 64.1, 52.2, 38.2, 24.9, 21.0. HRMS: calcd
for C18H21NSe [M + H]+: 332.0918. Found 315.0635 m/z plus
multiplets from selenium isotopes, which is [M + H − NH2]+.
4-Methyl-N-((1S,2S)-2-(phenylthio)-2,3-dihydro-1H-
inden-1-yl)benzenesulfonamide (5). To a solution of 250
mg (1S,2S)-2-(phenylthio)-2,3-dihydro-1H-inden-1-amine
(0.63 mmol, 1 equiv) in 3.1 mL DCM (0.2 M) were added
132 μL Et3N (0.95 mmol, 1.5 equiv) and 136 μL TsCl (0.95
mmol, 1 equiv) at r.t. The solution was stirred for 12 h and
then quenched with water and extracted with DCM (10 mL ×
3). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification
through flash column chromatography (Hex/EtOAc::100:0−
90:10) afforded the desired product. The spectral data are in
agreement with the literature.42
1,1,1-Trifluoro-N-((1S,2S)-2-(phenylthio)-2,3-dihydro-
1H-inden-1-yl)methanesulfonamide (6). N,N-Diisopropy-
lethylamine (DIPEA) (250 μL, 1.5 mmol) was added to a
solution of (1S,2S)-2-(phenylthio)-2,3-dihydro-1H-inden-1-
amine in 15 mL dry DCM (0.1 M) under an inert atmosphere.
Then, triflic anhydride (185 μL, 1.1 mmol) was added slowly.
The reaction was stirred at r.t. for 3 h. Then, a 1 M HCl
solution was added and the solution was extracted with DCM
(15 mL × 3). The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification through flash column chromatography (Hex/
EtOAc::100:0−90:10) afforded the desired product. The
spectral data are in agreement with the literature.42
yield, 98 mg, as a pale white solid. H NMR (400 MHz,
DMSO-d6) δ 10.10 (s, 1H), 8.74 (d, J = 8.5 Hz, 1H), 8.20 (s,
2H), 7.7.6 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.33−7.11 (m,
4H), 6.91 (d, J = 8.4 Hz, 2H), 5.97 (t, J = 8.4 Hz, 1H), 3.85 (t,
J = 8.4 Hz, 1H), 3.71 (s, 3H), 3.25 (dd, J = 16.1, 7.8 Hz, 1H),
2.79 (dd, J = 15.9, 8.8 Hz, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 181.1, 160.3, 140.7, 136.7, 132.5, 129.1, 127.6,
124.8, 124.3, 122.6, 121.4, 119.3, 114.9, 105.0, 65.3, 55.3, 55.0,
37.4. HRMS: calcd for C25H20F6N2OS2 [M + H]+: 543.0999.
Found 543.1001 m/z.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S,2S)-2-(mesi-
tylthio)-2,3-dihydro-1H-inden-1-yl)thiourea (9). One
hundred and twenty milligrams (0.42 mmol, 1 equiv) of
(1S,2S)-2-(mesitylthio)-2,3-dihydro-1H-inden-1-amine was
dissolved in 2.1 mL (0.2 M) of anhydrous THF under an
inert atmosphere. Then, 115 mg (0.42 mmol, 1 equiv) of 3,5-
bis(trifluoromethyl)phenyl isothiocyanate was added to the
reaction. The mixture was stirred at r.t. for 4 h and then
immediately concentrated under reduced pressure. Purification
through flash column chromatography (Hex/EtOAc::100:0−
85:15) afforded the desired product in a 72% yield, 167 mg, as
a dark yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s,
1H), 8.52 (s, 1H), 8.19 (s, 2H), 7.75 (s, 1H), 7.40−7.14 (m,
4H), 6.94 (s, 2H), 5.83 (s, 1H), 3.80 (q, J = 6.9 Hz, 1H), 3.18
(dd, J = 16.2, 7.3 Hz, 1H), 2.73 (dd, J = 16.1, 6.8 Hz, 1H),
2.44 (s, 6H), 2.17 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3)
δ 180.9, 143.5, 139.6, 129.5, 128.0, 125.1, 123.8, 121.7, 119.8,
110.0, 52.1, 37.4, 22.1, 20.7. 19F NMR (470 MHz, CDCl3) δ
−62.87 MS (atmospheric pressure chemical ionization
(APCI)): calcd for C27H24F6N2S2 [M + H]+: 555.1363.
Found 555.1363 m/z.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S,2S)-2-(mesi-
tylselanyl)-2,3-dihydro-1H-inden-1-yl)thiourea (10).
One hundred and thirty milligrams (0.33 mmol, 1 equiv) of
(1S,2S)-2-(mesitylselanyl)-2,3-dihydro-1H-inden-1-amine was
dissolved in 6.6 mL (0.2 M) of anhydrous THF under an inert
atmosphere. Then, 100 mg (0.37 mmol, 1 equiv) of 3,5-
bis(trifluoromethyl)phenyl isothiocyanate was added to the
reaction. The mixture was stirred at r.t. for 4 h and then
immediately concentrated under reduced pressure. Purification
through flash column chromatography (Hex/EtOAc::100:0−
85:15) afforded the desired product in a 67% yield, 133 mg, as
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S,2S)-2-(phe-
nylthio)-2,3-dihydro-1H-inden-1-yl)thiourea (7). One
hundred and twenty milligrams (0.50 mmol, 1 equiv) of
(1S,2S)-2-(phenylthio)-2,3-dihydro-1H-inden-1-amine was
dissolved in 2.5 mL (0.2 M) of anhydrous THF under an
inert atmosphere. Then, 136 mg (0.50 mmol, 1 equiv) of 3,5-
bis(trifluoromethyl)phenyl isothiocyanate was added to the
reaction. The mixture was stirred at r.t. for 4 h and then
immediately concentrated under reduced pressure. Purification
G
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1
a pale white solid. H NMR (400 MHz, DMSO-d6) δ 9.95 (s,
129.4, 129.2, 128.5, 128.3, 127.8, MS (APCI): calcd for
C12H10ClO [M + H]+: 205.0. Found 205.0 m/z. The data
matches references found in the literature.48
1H), 8.57 (s, 1H), 8.20 (s, 2H), 7.75 (s, 1H), 7.34 (s, 1H),
7.22 (bs, 3H), 6.94 (s, 2H), 5.89 (s, 1H), 3.87 (q J = 7.0 Hz,
1H), 3.20 (dd, J = 16.3, 7.4 Hz, 1H), 2.75 (dd, J = 15.8, 7.5
Hz, 1H), 2.46 (s, 6H), 2.16 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 180.8, 143.7, 142.1, 129.1, 129.0, 127.7, 125.2,
124.2, 121.5, 119.8, 45.0, 37.6, 24.6, 20.7. 19F NMR (470
MHz, CDCl3) δ −62.92 MS (APCI): calcd for C27H24F6N2SSe
[M + H]+: 603.0809. Found 603.0603 m/z plus multiplets
from selenium isotopes.
3-Chloro-2-hydroxybenzonitrile (12b). 12b was pre-
pared according to the general procedure on a 1 mmol scale
and obtained in a 71% yield, 109 mg, as a white solid. A 5%
catalyst loading was used. 1H NMR (500 MHz, CDCl3) δ 7.56
(dq, J = 8.0, 1.3 Hz, 1H), 7.48 (dq, J = 7.9, 1.4 Hz, 1H), 7.02−
6.93 (m, 1H), 6.25 (s, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 153.8, 133.7, 132.1, 121.5, 121.1, 115.0, 101.3. MS
(APCI): calcd for C7H4ClNO [M + H]+: 154.57. Found
154.57 m/z. The data matches references found in the
literature.32
GENERAL ORTHO-CHLORINATION SYNTHESIS OF
PHENOLS AND ANILINES
■
2-Bromo-6-chlorophenol (13b). 13b was prepared
according to the general procedure on a 1 mmol scale and
obtained in a 43% yield, 89 mg, as a clear oil. A 5% catalyst
loading was used. 1H NMR (500 MHz, CDCl3) δ 7.41 (dq, J =
8.1, 1.6 Hz, 1H), 7.30 (dq, J = 8.1, 1.6 Hz, 1H), 6.76 (ddd, J =
8.0, 2.0 Hz, 1H), 5.88 (s, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 148.7, 131.4, 129.0, 121.8, 120.8, 110.3. MS
(APCI): calcd for C6H4BrClO [M + H]+: 208.45. Found
208.45 m/z. The data matches references found in the
literature.33
2-(tert-Butyl)-6-chlorophenol (14b). 14b was prepared
according to the general procedure on a 1 mmol scale and
obtained in a 56% yield, 103 mg, as a light orange oil. 1H NMR
(400 MHz, CDCl3) δ 7.19 (t, J = 7.3 Hz, 2H), 6.80 (td, J = 8.0,
2.2 Hz, 1H), 5.85 (s, 1H), 1.41 (s, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 149.7, 137.6, 126.4, 125.7, 120.9, 120.3, 35.2,
29.3. MS (APCI): calcd for C10H13ClO [M + H]+: 185.66.
Found 185.66 m/z. The data matches references found in the
literature.32
Substrate (0.030 mmol, 1 equiv), catalyst (0.00030 mmol, 0.01
equiv unless specifically mentioned otherwise), and CDCl3
(0.05 M) were added to an NMR tube followed by the
addition of tetramethylsilane (TMS) as an internal standard.
N-Chlorosuccinimide (0.036 mmol, 1.2 equiv) was then added
1
to the NMR tube, and the reaction was monitored by H
NMR. The reaction was considered complete once the
substrate conversion had ceased. Isomeric ratios were
determined via integration of the aromatic peaks of each
product. Conversion to mono-Cl products represents the sum
of the conversions of all identified mono-chlorinated products,
and the value was determined via integration of mono-
chlorinated products with respect to TMS. Isomeric ratios
were determined by the analysis of nonobscure peaks. When
necessary, clear coupling patterns were partially integrated, and
full integration value was extrapolated from the partial
integration. If multiple peaks were clear, the average of those
peaks was used to determine the isomeric ratio. Each
experiment in Table 1 was performed in triplicate, and the
reported ratios are the average of the three trials.
Yields were determined on a 1 mmol scale using CHCl3; all
reagents and solvents were scaled equally, omitting TMS.
Phenols were stirred at room temperature, while anilines were
stirred at 0 °C. Upon reaction completion, as determined by
thin-layer chromatography (TLC), the reaction was filtered
through a short normal phase silica plug with DCM to remove
succinimide. The solvent was then removed by rotovap, and,
for almost all substrates, the resulting crude mixture was
purified by flash column chromatography (FCC) on normal
phase silica gel, eluting with hexanes and ethyl acetate
(hexanes/ethyl acetate::100:0 → 99:1 → 98:2 → 97:3 →
95:5), unless otherwise noted. Each experiment in Schemes 2
and 3 was done in duplicate, and the reported ratios,
conversions, and yields are the average of the two trials.
The relative energies are determined based on the
experimental constitutional isomeric ratios, finding the differ-
ence in energy between a reaction that is catalyst-controlled
versus one that possesses innate selectivity of the substrate.
2-Chloro-6-iodophenol (15b). 15b was prepared accord-
ing to the general procedure on a 1 mmol scale and obtained in
1
a 60% yield, 153 mg, as a white solid. H NMR (400 MHz,
CDCl3) δ 7.61 (dd, J = 8.0, 2.0 Hz, 1H), 7.31 (dd, J = 8.1, 1.8
Hz, 1H), 6.63 (td, J = 8.9, 8.5, 1.9 Hz, 1H), 5.94 (s, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 150.9, 137.8, 129.6,
122.8, 119.2, 83.5. MS (APCI): calcd for C6H4ClIO [M + H]+:
255.45. Found 255.45 m/z. The data matches references found
in the literature.32
2-Chloro-5-fluorophenol (16b). 16b was prepared
according to the general procedure on a 1 mmol scale and
1
obtained in a 70% yield, 102 mg, as a clear oil. H NMR (400
MHz, CDCl3) δ 7.29−7.23 (m, 1H), 6.76 (dd, J = 9.6, 2.9 Hz,
1H), 6.61 (ddd, J = 8.9, 8.0, 2.9 Hz, 1H), 5.66 (s, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 162.3 (d, J = 246 Hz),
152.3 (d, J = 12.7 Hz), 129.4 (d, J = 9.9 Hz), 115.0, 108.5 (d, J
= 23.3 Hz), 104.0 (d, J = 26.6 Hz) 19F NMR (376 MHz,
CDCl3) δ −112.46 (m) MS (APCI): calcd for C6H4ClFO [M
+ H]+: 147.55. Found 147.55 m/z. The data matches
references found in the literature.32
The equation for transition-state relative energy is derived
from the Eyring equation. ΔΔΔG‡ = ΔΔGcatalyst1
−
5-Bromo-2-chlorophenol (17b). 17b was prepared
according to the general procedure on a 1 mmol scale and
obtained in a 60% yield, 124 mg, as a dark brown oil. A 5%
‡
ΔΔGinnate‡, with ortho-selectivity defined as positive ΔΔG‡
and para-selectivity defined as negative ΔΔG‡. ΔΔG‡
−RT ln[para]/[ortho].
=
1
catalyst loading was used. H NMR (500 MHz, CDCl3) δ
3-Chloro-[1,1′-biphenyl]-2-ol (11b). 11b was prepared
according to the general procedure on a 1 mmol scale and
obtained in a 44% yield, 90 mg, as a pale white solid. 1H NMR
(500 MHz, CDCl3) δ 7.57−7.52 (m, 2H), 7.47 (t, 7.5 Hz,
2H), 7.41−7.38 (m, 1H), 7.33 (dd, J = 8.0, 1.5 Hz, 1H), 7.23
(d, J = 7.8 Hz, 1H), 6.95 (td, 7.8, 2.3 Hz, 1H), 5.71 (s, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 148.4, 137.1, 129.7,
7.20−7.17 (m, 2H), 7.01 (dt, J = 8.6, 1.9 Hz, 1H), 5.58 (s,
1H). 13C{1H} NMR (126 MHz, CDCl3) δ 152.0, 129.9, 124.5,
121.3, 119.6, 119.0. MS (APCI): calcd for C6H4BrClO [M +
H]+: 208.45. Found 208.45 m/z. The data matches references
found in the literature.32
4-Chloro-[1,1′-biphenyl]-3-ol (18b). 18b was prepared
according to the general procedure on a 1 mmol scale and
H
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obtained in a 35% yield as a white solid. A 5% catalyst loading
was used. 1H NMR (400 MHz, CDCl3) δ 7.56−7.53 (m, 2H),
7.45−7.41 (m, 4H), 7.38−7.35 (m, 2H), 7.11 (dd, J = 8.3, 2.1
Hz, 1H), 5.59 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ
151.5, 141.9, 139.8, 129.2, 129.1, 128.8, 128.1, 127.7, 127.0,
123.0, 120.1, 114.8. MS (APCI): calcd for C12H9ClO [M +
H]+: 205.65. Found 205.65 m/z. The data matches references
found in the literature.49
2-Chloro-6-isopropyl-3-methylphenol (19b). 19b was
prepared according to the general procedure on a 1 mmol scale
and obtained in a 37% yield, 68 mg, as a brownish-white solid.
1H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 7.8 Hz, 1H), 6.77
(d, J = 7.8 Hz, 1H), 5.69 (s, 1H), 3.28 (hept, J = 4.2 Hz, 1H),
2.34 (s, 3H), 1.24 (d, J = 9.6 Hz, 6H). 13C{1H} NMR (126
MHz, CDCl3) δ 148.5, 133.4, 133.2, 124.1, 121.9, 120.3, 27.6,
22.4, 19.9. MS (APCI): calcd for C10H13ClO [M + H]+:
185.66. Found 185.67 m/z. The data matches references found
in the literature.50
2-Chloronaphthalen-1-ol (20b). 20b was prepared
according to the general procedure on a 1 mmol scale and
obtained in a 50% yield, 89 mg, as a white solid. 1H NMR (400
MHz, CDCl3) δ 8.22 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 7.8 Hz,
1H), 7.55−7.47 (m, 2H), 7.37 (t, J = 1.3 Hz, 2H), 5.99 (s,
1H). 13C{1H} NMR (126 MHz, CDCl3) δ 147.0, 133.2, 127.6,
126.6, 126.1, 125.9, 124.4, 122.1, 120.9, 113.5. MS (APCI):
calcd for C10H7ClO [M + H]+: 179.61. Found 179.61 m/z.
The data matches references found in the literature.51
2-Chloro-6-methylaniline (21b). 21b was prepared
according to the general procedure on a 1 mmol scale and
obtained in a 65% yield, 92 mg, as a dark brown oil. 1H NMR
(400 MHz, CDCl3) δ 7.14 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0
Hz, 1H), 6.63 (dd, J = 7.9, 2.5 Hz, 1H), 4.01 (bs, 2H), 2.20 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 141.1, 128.7, 127.0,
123.5, 119.1, 118.3, 17.9. MS (APCI): calcd for C7H8ClN [M
+ H]+: 142.60. Found 142.61 m/z. The data matches
references found in the literature.52
2-Chloro-5-fluoroaniline (25b). 25b was prepared
according to the general procedure on a 1 mmol scale,
obtained in a 70% yield, 101 mg, as a brown-orange oil. Five
1
percent of catalyst was used. H NMR (400 MHz, CDCl3) δ
7.17 (dd, J = 8.8, 5.7 Hz, 1H), 6.47 (dd, J = 10.1, 2.9 Hz, 1H),
6.40 (td, J = 8.4, 2.9 Hz, 1H), 4.14 (s, 2H). 13C{1H} NMR
(126 MHz, CDCl3) δ 162.2 (d, J = 244 Hz), 144.1 (d, J =11.3
Hz), 130.2 (d, J = 10.0 Hz), 114.1 (d, J = 2.9 Hz), 105.7 (d, J =
23.4 Hz), 102.5 (d, J = 26.4 Hz). 19F NMR (376 MHz,
CDCl3) δ −114.84 (m) MS (APCI): calcd for C6H5ClFN [M
+ H]+: 145.56. Found 145.56 m/z. The data matches
references found in the literature.54
5-Bromo-2-chloroaniline (26b). 26b was prepared
according to the general procedure on a 1 mmol scale and
obtained in a 30% yield, 62 mg, as a brown-orange oil. Five
1
percent of catalyst was used. H NMR (400 MHz, CDCl3) δ
7.08 (d, J = 8.4, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.79 (dd, J =
8.5, 2.2, 1H). 4.09 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3)
δ 144.1, 130.5, 121.7, 121.7, 118.3, 118.1. MS (APCI): calcd
for C6H5BrClN [M + H]+: 207.9350 Found 207.9352 m/z.
4-Chloro-[1,1′-biphenyl]-3-amine (27b). 27b was pre-
pared according to the general procedure on a 1 mmol scale,
obtained as a brown-orange oil. Five percent of catalyst was
used. 1H NMR (400 MHz, CDCl3) δ 7.47−7.38 (m, 5H), 7.30
(d, J = 8.2 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 8.2,
2.1 Hz, 1H), 4.12 (s, 2H). 13C{1H} NMR (126 MHz, CDCl3)
δ 143.0, 141.0, 140.4, 129.6, 129.3, 128.7, 127.9, 127.4, 127.0,
120.8, 118.0, 114.4. MS (APCI): calcd for C12H10ClN [M +
H]+: 204.0580. Found 204.0581 m/z.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01917.
■
sı
Crude NMR spectra for the determination of
regioselectivity NMR spectra of purified products;
crystal structure information; isotopically labeled experi-
ments; and preliminary mechanistic experiments with
catalyst 10 (PDF)
Crystallographic data file (CIF)
Guanidinium crystal structure (ZIP)
2-Chloro-6-isopropylaniline (22b). 22b was prepared
according to the general procedure on a 1 mmol scale and
1
obtained in a 66% yield, as a dark brown oil. H NMR (400
MHz, CDCl3) δ 7.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.05 (dd, J =
7.9, 1.4 Hz, 1H), 6.70 (t, J = 7.8 Hz, 1H), 4.11 (s, 2H), 2.90
(hept, J = 7.0 Hz, 1H), 1.27 (d, J = 6.8 Hz, 6H). 13C{1H}
NMR (126 MHz, CDCl3) δ 139.9, 133.8, 126.7, 123.7, 119.8,
118.6, 28.4, 22.1. HRMS: calcd for C9H12ClN [M + H]+:
170.0737. Found 170.0747 m/z.
2-(tert-Butyl)-6-chloroaniline (23b). 23b was prepared
according to the general procedure on a 1 mmol scale and
obtained in a 64% yield, 117 mg, as a dark brown oil. 1H NMR
(400 MHz, CDCl3) δ 7.16 (ddd, J = 10.7, 7.9, 1.4 Hz, 2H),
6.65 (t, J = 7.9 Hz, 1H), 4.35 (s, 2H), 1.43 (s, 9H). 13C{1H}
NMR (126 MHz, CDCl3) δ 140.9, 134.9, 127.3, 125.0, 121.2,
118.0, 34.7, 29.5. MS (APCI): calcd for C10H14ClN [M + H]+:
184.0893. Found 184.0895 m/z.
AUTHOR INFORMATION
Corresponding Author
■
Jeffrey L. Gustafson − Department of Chemistry and
Biochemistry, San Diego State University, San Diego, California
92182, United States; orcid.org/0000-0001-7054-7595;
Email: jgustafson@sdsu.edu
Authors
Andrew N. Dinh − Department of Chemistry and Biochemistry,
San Diego State University, San Diego, California 92182,
United States; orcid.org/0000-0002-9708-4583
Sean M. Maddox − Department of Chemistry and Biochemistry,
San Diego State University, San Diego, California 92182,
United States
2-Bromo-6-chloroaniline (24b). 24b was prepared
according to the general procedure on a 1 mmol scale and
obtained in a 40% yield, 82 mg, as a brownish-white solid. Five
1
percent of catalyst was used. H NMR (400 MHz, CDCl3) δ
7.33 (dd, J = 8.0, 1.4 Hz, 1H), 7.21 (dd, J = 8.0, 1.4 Hz, 1H),
6.55 (t, J = 8.0 Hz, 1H), 4.50 (s, 2H). 13C{1H} NMR (126
MHz, CDCl3) δ 141.1, 131.0, 128.5, 119.3, 118.7, 109.2. MS
(APCI): calcd for C6H5BrClN [M + H]+: 205.93. Found
205.93 m/z. The data matches references found in the
literature.53
Sagar D. Vaidya − Department of Chemistry and Biochemistry,
San Diego State University, San Diego, California 92182,
United States
Mirza A. Saputra − Department of Chemistry and Biochemistry,
San Diego State University, San Diego, California 92182,
United States
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Article
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Christopher J. Nalbandian − Department of Chemistry and
Biochemistry, San Diego State University, San Diego, California
92182, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01917
Author Contributions
The manuscript was written through the contributions of all
authors. All authors have given approval to the final version of
the manuscript.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
̈
(19) Schroder, N.; Wencel-Delord, J.; Glorius, F. High-Yielding,
A.N.D. is supported by the National Science Foundation
(Grant nos. Che-1664565 and Che-1955086) and the SDSU
Graduate Student Fellowship. We would like to thank Greg
Elliot, Dillon Stengel, and David Onofrei for their support with
NMR and HRMS instrumentation. We would also like to
thank Dr. Curtis Moore for his support with X-ray
crystallography.
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