Diastereoselective Copper-Mediated Conjugate Addition of Functionalized Magnesiates for the Preparation of Bisaryl Nrf2 Activators

Article abstract of DOI:10.1021/acs.joc.0c02639

A two-step metal-halogen exchange and diastereoselective copper-mediated Michael addition onto a complex α,β-unsaturated system has been developed and applied toward the synthesis of bisaryl Nrf2 activators. Optimization of metal-halogen exchange using (n

Full text of DOI:10.1021/acs.joc.0c02639

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Diastereoselective Copper-Mediated Conjugate Addition of
Functionalized Magnesiates for the Preparation of Bisaryl Nrf2
Activators
Michal P. Glogowski,* Jay M. Matthews, Brian G. Lawhorn, and Kevin P. C. Minbiole
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ABSTRACT: A two-step metal−halogen exchange and diastereoselective copper-mediated Michael addition onto a complex α,β-
unsaturated system has been developed and applied toward the synthesis of bisaryl Nrf2 activators. Optimization of metal−halogen
exchange using (n-Bu)3MgLi allowed for the preparation of custom aryl-functionalized magnesiate reagents at noncryogenic
temperatures. Following transmetalation, these reagents were used in highly diastereoselective Michael addition reactions.
synthetic steps from an aryl bromide and a common late-stage
intermediate (Scheme 1; bottom). In this sequence, the bisaryl
chiral center is forged via copper-mediated conjugate addition
of an arylmagnesium species. While a chiral variant of Rh-
catalyzed conjugate addition would be an attractive approach
for synthesis, such conditions typically require optimization of
catalyst and ligand for each substrate in order to obtain
excellent selectivity. Therefore, we sought to develop a method
of high selectivity for a broad array of analogues. The
complexity of the Nrf2 bisaryl system necessitated the
development of a robust procedure for the generation of an
organometallic species which could not be achieved via
traditional Grignard reagent formation using magnesium
metal or metal−halogen exchange with organolithium reagents.
For this reason, herein we describe results of optimization of
metal−halogen exchange with various magnesium complexes
and the associated substrate scope to generate species for late-
stage Michael addition with >95:5 diastereomeric ratio.
INTRODUCTION
■
Michael additions to α,β-unsaturated systems allow for facile
synthesis of complex chiral molecules and remain as some of
the most well-studied and robust C−C and C−heteroatom
bond-forming reactions.1 Since the simultaneous discovery of
̈
copper-mediated conjugate additions (CA) by Naf and Corey
in 1972, development of various other metal catalysts and
ligands as well as chiral auxiliaries led to ease of control of the
regio- and stereochemical outcome of these reactions.2−12 To
date, Michael addition reactions have seen extensive utilization
for the synthesis of complex natural products as well as
pharmaceuticals (Figure 1).13−18
In particular, multiple routes for the synthesis of the 3,3-
bisarylpropionic acid series of noncovalent Nrf2 activators
developed via a collaboration of GlaxoSmithKline and Astex
Pharmaceuticals featured a key step of racemic rhodium-
catalyzed conjugate addition.19,20 Originally synthesized
utilizing these methods, GSK ‘419 (419) and relative
compounds were identified as leads of interest possessing
favorable physicochemical property profiles.21,22 In an effort to
expand the structure−activity relationship (SAR) in this series,
a study of the steric and electronic contributions of the aryl
group exemplified by the benzotriazole moiety was undertaken.
However, the legacy synthetic routes were not amenable to
such rapid SAR exploration; in all cases, the point of diversity
would be introduced early on in the sequence and the shortest
route required six steps, including a chiral HPLC separation to
isolate the desired enantiomer (Scheme 1; top).
RESULTS AND DISCUSSION
■
Examples of 1,4-additions affording chiral centers with
excellent diastereoselectivity and high yields have been
Received: November 5, 2020
Published: February 8, 2021
In this paper, we present a shortened synthesis of 419, as
well as other analogues in the bisaryl series, requiring only two
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Figure 1. Examples of compounds of pharmaceutical interest where marked centers (red dot) were established via Michael addition reactions.
Scheme 1. Synthesis of Bisaryl Propionic Acid Nrf2 Activators
Scheme 2. Synthesis of Chiral N-Enoyloxazolidin-2-one 2
a
b
Acryloyl chloride, DIPEA, THF, then (S)-(+)-4-phenyl-2-oxazolidinone, LiCl, 1 h, 81%. Aryl bromide A, DIPEA, Pd(OAc)2/P(o-tol)3, DMF,
120 °C, 7 h, 33%.
reported on simple systems employing Grignard reagents in
the presence of copper(I) bromide dimethylsulfide complex
(CuBr·DMS) and a 4-phenyl-2-oxazolidinone chiral auxiliary,
and encouraged our attempts on a more complex, late-stage
intermediate.23−26 As a model system we chose to investigate
Michael additions onto chiral N-enoyloxazolidin-2-one 2,
which was synthesized in two steps from acrylic acid (Scheme
2).
Scheme 3. Asymmetric 1,4-Addition of Classic
Organocuprates to Chiral N-Enoyloxazolidin-2-one 2
Treatment of acrylic acid with acryloyl chloride in the
presence of DIPEA afforded the corresponding anhydride (not
shown). Subsequent nucleophilic attack by (S)-(+)-4-phenyl-
2-oxazolidinone in the presence of LiCl afforded chiral
acryloyl-4-phenyloxazolidin-2-one 1 in 81% yield. Aryl bro-
mide A, synthesized via a previously published procedure,21
was coupled via a Heck reaction to afford 2 in 33% yield. To
test whether conjugate addition chemistry would produce
acceptable selectivity on the Nrf2 bisaryl scaffold, 2 was treated
with cuprates generated from commercially available phenyl-
and 2-methylphenylmagnesium bromide reagents and CuBr·
DMS at −40 °C (Scheme 3).
a
b
Isolated yields after preparative HPLC. Determined by chiral
HPLC.
The reaction proceeded well in the presence or absence of
the o-methyl group, and in fact, the steric bulk at the ortho
position led to a notable improvement in diastereoselectivity
(95:5 to 97:3 dr for products 3a and 3b, respectively). Since
the Michael addition was successful on this model system, we
sought to employ the approach on an advanced N-
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Scheme 4. Synthesis of Advanced N-Enoyloxazolidin-2-one 5
a
b
c
DDQ, DCM/H2O, 1 h, 94%. SOCl2, CHCl3, 16 h, quant. Oxazepine B, DIPEA, MeCN, 60 °C, 16 h, 82%.
Table 1. Substrate Scope of Conjugate Addition (CA) with Various Commercially Available Grignard Reagents and
Subsequent Hydrolysis
a
b
c
d
e
Isolated after flash chromatography. Determined by chiral HPLC. Determined by 1H NMR. Isolated yields after preparative HPLC. Isolated
as the benzophenone following aq HCl workup.
enoyloxazolidin-2-one 5 that would provide an ideal two-step
route to prepare the desired analogues. For this purpose,
benzylic oxazepine 5 was prepared in three steps from PMB
ether 2 (Scheme 4).
The PMB protecting group was removed under oxidative
conditions (DDQ) to afford benzyl alcohol 4 in 94% yield.
Subsequent conversion to a benzyl chloride and its displace-
ment with oxazepine B21 afforded 5 in 82% yield over the two
steps. Pleasingly, 5 proved to be a competent substrate for the
cuprate-based 1,4-addition despite featuring complexing agents
in the form of tertiary amine and pyridine nitrogen atoms.
We subjected 5 to Michael addition with cuprates prepared
from various commercially available Grignard reagents and
subsequently hydrolyzed the products to their corresponding
carboxylic acids (Table 1). We were pleased to see that most
CA products were isolated in high yields of 52−81% and
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Scheme 5. Synthesis of Custom Aryl- and Heteroaryl Bromides
a
b
c
3,4-Dihydro-2H-pyran, PTSA, DCM, 16 h, 93%. Ethylene glycol, PTSA monohydrate, toluene, Dean−Stark apparatus, 56 h, 75%. 2-Bromo-1,1-
d
e
diethoxyethane, 48% aq HBr, EtOH, 60 °C, 48 h, 77%. 2-Bromo-1,1-dimethoxypropane, 48% aq HBr, EtOH, 80 °C, 48 h, 51%. Acetic anhydride,
f
KOAc, 18-crown-6, t-BuONO, chloroform, 75 °C, 16 h, 90%. NaH, MeI, DMF, room temperature, 16 h, 38 and 21% of 11 and 12, respectively.
g
Formic acid, 37% aq HCl, 65 °C, 16 h, quantitative.
exhibited excellent diastereomeric ratios of >95:5 (Table 1,
entries 1−10). The product of conjugate addition with (2-
chlorophenyl)magnesium bromide suffered from a low yield of
23% which was attributed to side reactions due to generation
of a benzyne intermediate (Table 1, entry 5). In this instance,
several products were detected by LC/MS with masses
corresponding to the desired product + phenyl ring suggesting
electrophilic quenching with benzyne following Michael
addition. The conjugate addition products were subsequently
hydrolyzed using H2O2 and LiOH at low temperature to afford
their corresponding carboxylic acids 6a−6j in 22−66% yields.
Given the success of conjugate addition chemistry with
commercially available Grignard reagents, we sought to
prepare other organomagnesium reagents from aryl- and
heteroaryl bromides that would further modulate physico-
chemical properties in the Nrf2 bisaryl series. While several of
the necessary aromatic bromides were commercially available,
we have synthesized additional custom aryl- and heteroaryl
bromides as shown in Scheme 5.
Given the anionic character of the cuprate-mediated
conjugate addition chemistry, the phenol and benzophenone
substrates were protected with THP and ketal protecting
groups to afford 7 and 8 in 93 and 75% yield, respectively.
Condensation of a commercially available aminopyridine with
either 2-bromo-1,1-diethoxyethane or 2-bromo-1,1-dimethox-
ypropane under acidic conditions (HBr) afforded the
corresponding imidazopyridines 9 and 10, respectively, in
adequate yields. The indazole was prepared in one step from
its corresponding aniline, and its methylation afforded
separable regioisomeric methyl indazoles 11 and 12 in 38
and 21% yield, respectively. Phenylenediamine C21 was
condensed with formic acid to afford imidazole 13 in excellent
yield.
MS to monitor for the formation of the deuterated product
14b.
Table 2. Grignard Reagent Forming Conditions Using Mg
and Different Initiators
a
b
b
entry
cat. initiator
14a (%)
14b (%)
1
2
3
1,2-dibromoethane
iodine
DIBAL-H, LiCl
0
23
75
0
0
13
a
b
Reactions performed under inert atmosphere over 2 h. Conversions
by LC/MS relative to % D remaining.
Overall, traditional approaches did not successfully promote
the desired organomagnesium forming reaction. While 1,2-
dibromoethane and iodine failed to produce any detectible 14b
(Table 2, entries 1 and 2), both iodine and DIBAL-H resulted
in 23 and 75% conversion to the protodehalogenated product
14a (Table 2, entries 2 and 3), which presumably arises
through quench of a transient Grignard species by an in situ
proton source.
In the case where catalytic iodine was used as initiator,
protons could only be introduced from adventitious water or
solvent; however, given the rigorous drying procedures as well
as the measured 0.35% water content of the bromobenzo-
triazole D (coulometric Karl Fischer analysis), the 23%
conversion to 14a (Table 2, entry 2) was unlikely a result of
residual water (water content of at least 1% would be needed
to quench 25% of the desired Grignard reagent). Therefore, we
postulated that one pathway for the formation of the 14a could
be through deprotonation of solvent (THF) following
successful Grignard formation, which is analogous to THF
decomposition by organolithium reagents.30,31 To test this
hypothesis, the Grignard reagent forming reaction employing
iodine as initiator (entry 2) was repeated with THF-d8 as the
solvent (Scheme 6).
To further expand the scope of the 1,4-addition reaction and
access additional analogues of interest from the variety of aryl-
and heteroaryl bromides, a robust method to generate other
organomagnesium reagents was investigated. As a model
system, we chose to resynthesize 419 using this newly
developed 1,4-addition route beginning with the bromobenzo-
triazole D.21 To generate the desired organomagnesium we
first investigated known methods of Grignard reagent
preparation from bromobenzotriazole D using catalytic
amounts of initiators and magnesium metal at refluxing
conditions (Table 2).27−29 Aliquots of reaction mixtures
were quenched with water-d2 (D2O) and analyzed by LC/
Following a quench with saturated ammonium chloride
solution, a 1:2 mixture of products 14a and 14b, respectively,
was isolated in 49% yield, confirming THF is a major source of
protodehalogenation. We suspect that deprotonation of THF
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Scheme 6. Formation of an Organomagnesium of D with
Mg and cat. Iodine in THF-d8 at Reflux
Table 3. Metal−Halogen Exchange of D with Magnesium
Complexes
b
b
14a
14b
a
entry
Mg complex
equiv
conditions
(%)
(%)
observed for derivatives of D may be a feature of slowly
forming Grignard reagents resulting from prolonged reaction
times at reflux. To our knowledge, this observation has not
been previously appreciated as shown by the lack of literature
precedents for a reaction of this kind.
Given the inefficiency in Grignard reagent formation with
magnesium metal under high temperatures, we investigated
metal−halogen exchange with n-BuLi at low temperature
(Scheme 7).
1
2
3
4
5
6
7
8
iPrMgBr
1
1
1
1
1
1
1
1
rt, 4 h
3
6
0
6
14
0
0
10
0
0
0
1
14
30
4
26
48
60
65
62
3
iPrMgBr·LiCl
s-BuMgCl·LiCl
t-BuMgCl·LiCl
iPrMgCl·LiCl
iPrMgCl·LiCl
iPrMgCl·LiCl
iPrMgCl·LiCl
(s-Bu)2Mg
Me3MgLi
(s-Bu)3MgLi
(n-Bu)2iPrMgLi 0.35 −10 °C, 30 min
(n-Bu)3MgLi
rt, 4 h
rt, 4 h
rt, 4 h
rt, 4 h
TMEDA, rt, 4 h
1,4-dioxane, rt, 4 h
15-crown-5, rt, 4 h
rt, 4 h
9
0.5
10
11
12
13
14
0.35 −10 °C, 30 min
0.35 −10 °C, 30 min
Scheme 7. Metal−Halogen Exchange of D with n-BuLi
42
51
63
100
0
0
0
0.35 −10 °C, 30 min
0.5 −10 °C, 5 min
(n-Bu)3MgLi
a
b
All reactions performed under inert atmosphere. Conversions by
LC/MS relative to % D remaining.
ingly, treatment of iPrMgCl·LiCl with TMEDA, 1,4-dioxane,
or 15-crown-5 nearly doubled conversion to 14b (Table 4, 48,
60, and 65%, entries 6−8) while direct use of commercially
available (s-Bu)2Mg yielded similar results (Table 4, entry 9,
62% conversion).
Triorganomagnesiate complexes are known to exhibit an
increased reactivity due to the larger electron density on
magnesium from the presence of an additional organic ligand.
Similar results were observed with (s-Bu)3MgLi, (n-
Bu)2iPrMgLi, and (n-Bu)3MgLi complexes, where the reaction
times to reach peak conversion were drastically shortened from
4 h to 30 min, yielding 42, 51, and 63% 14b, respectively
(Table 4, entries 11−13). Only the Me3MgLi complex
performed poorly, with a 3% conversion to 14b (Table 4,
entry 10).
Since increasing reaction times for each of these complexes
resulted in protodehalogenation and decomposition, modu-
lation of reagent equivalents was explored. Triorganomagnesi-
ate complexes feature three ligands, and thus, 0.35 equiv of
each was used in an initial attempt to exchange all organic
ligands to produce a triarylmagnesiate lithium complex upon
complete metal−halogen exchange. However, this was not
observed for any of the reagents investigated, and even in the
case of the most reactive (n-Bu)3MgLi, 37% of bromobenzo-
triazole D remained, suggesting an exchange of only two n-Bu
ligands and formation of an n-BuAr2MgLi complex (Table 4,
entry 13). Steric considerations do not explain this finding as
the literature reports a (2,4,6-trimethylphenyl)3MgLi complex
which been isolated and structurally confirmed by X-ray
crystallography.37 On the other hand, various procedures in the
literature report using between 0.35 and 3 equiv of
triorganomagnesiate lithium reagents in metal−halogen
exchange reactions, presumably due to different energetic
demands arising from a wide range of electronic properties of
diverse aryl halides.38,39 We found that by increasing the
equivalents of (n-Bu)3MgLi from 0.35 to 0.5 complete metal−
Complete consumption of starting material D was observed
by LC/MS within 5 minutes following the addition of n-BuLi
at −78 °C. However, the reaction produced a mixture of the
desired 14a and the alkylated side product 14c. Given the 4:1
mixture of products 14a and 14c, it was postulated that the
benzotriazole organolithium reagent deprotonated the N-
methyl group, generating a highly nucleophilic species that
was alkylated by the 1-bromobutane byproduct of metal−
halogen exchange.
It was evident that metal−halogen exchange of bromoben-
zotriazole D must be carried out under milder conditions to
suppress undesired reactions. Therefore, bromobenzotriazole
D was subjected to various mono- and diorganomagnesium
species as well as triorganomagnesiate complexes with
additives that have been shown to be effective for metal−
halogen exchange conditions (Table 3).32−36
Metal−halogen exchange of the bromobenzotriazole D
proceeded at room temperature with all magnesium com-
plexes, albeit with a high variability in yield. Monoorgano-
magnesium complexes caused decomposition with reaction
times >4 h. Addition of stoichiometric LiCl to iPrMgBr
improved the conversion to 14b from 1 to 14% (Table 4,
entries 1 and 2); however, the commercial Turbo Grignard
(iPrMgCl·LiCl) afforded a greater conversion to 14b and the
undesired 14a (Table 4, 26 and 14%, respectively, entry 5).
Increasing the electron density around the metal center by
utilizing a bulkier s-Bu group suppressed protodehalogenation
and resulted in marginal improvement of the desired reaction
over iPrMgCl·LiCl (Table 4, 30% 14b, entry 3), while a t-Bu
group showed only 4% conversion (Table 4, entry 4).
As demonstrated by Knochel et al., stochiometric chelators
of MgCl2 in the presence of iPrMgCl·LiCl enhanced the rate of
metal−halogen exchange by shifting the Schlenk equilibrium
toward production of diorganomagnesium species.33 Accord-
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Table 4. Substrate Scope with Various Aryl and Heteroaryl Bromides and Subsequent Hydrolysis
a
b
Metal−halogen exchange (MHE); percent conversions by LC/MS after quenching aliquots with D2O or CD3OD. Conjugate addition (CA);
c
d
e
1
isolated yields after flash chromatography (silica gel). Determined by chiral HPLC. Determined by H NMR. Isolated yields after preparative
HPLC. Isolated as the deprotected compound following aq HCl workup.
f
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Scheme 8. Michael Addition of D onto Advanced N-Enoyloxazolidin-2-one 5
Figure 2. Proposed mechanism of the formation of homo- and heterocuprate reagents with the Ar2AlkMgLi complex.
halogen exchange and 100% conversion to 14b was observed
within 5 min (Table 4, entry 14). This procedure was adopted
to test the full sequence of organomagnesiate formation
followed by transmetalation with CuBr·DMS and conjugate
addition (Scheme 8).
Heterocyclic aryl bromides proved to be difficult partners in
this reaction sequence. Pyridyl bromide (Table 4, entry 10) did
not afford its 1,4-addition product despite complete metal
halogen exchange. We observed that the presence of a methyl
group in the 5-membered ring of imidazopyridines improved
the outcome of Michael addition from 0 to 21% (Table 4,
entries 11 and 12), likely due to blocking a potential site of
metalation. Interestingly, isomeric dimethyl indazoles showed
remarkably different reactivity, as one regioisomer underwent
full metal−halogen exchange and resulted in 51% yield of
conjugate addition while the other regioisomer was resistant to
metal−halogen exchange, with only 15% conversion (Table 4,
entries 13 and 14). Similarly, benzimidazole 13 was found to
be nearly inert to metal−halogen exchange under the
magnesiate (Table 4, entry 15, 2% conversion) as well as
traditional n-BuLi conditions (not shown).
It was noted that most substrates subjected to the newly
developed two-step procedure afforded their products in <50%
yield (Table 4). While limited studies have been done to
elucidate the true mechanism of this reaction sequence, we
surmise that upon transmetalation with 0.5 equiv of CuBr·
DMS, the presence of a 2:1 ratio of Ar to n-Bu ligands results
in formation of mixtures of homo- and heteroleptic organo-
cuprates: the diaryl and dialkyl homocuprates as well as the
mixed heterocuprate (Figure 2).
The homocuprates transfer one of their groups while
retaining the other as a sacrificial ligand. On the other hand,
the heterocuprate delivers the alkyl group preferentially and
the aryl group is effectively lost. Upon metal−halogen
exchange with (n-Bu)3MgLi and transmetalation with the
specified equivalents of CuBr, two possible mixtures of
cuprates may be formed. If the transmetalation reaction
proceeds at equal rates and leads to a random distribution of
cuprate species, the net outcome results in an equal availability
for aryl as well as alkyl 1,4-addition. The 1:1 ratio of the
benzotriazole 15 and n-Bu addition 16 products supports this
hypothesis, and the results of optimization of metal−halogen
Gratifyingly, 1,4-addition of the cuprate of D to 5 was
successful and afforded the desired product 15 in 43% yield
and >95:5 dr. As expected, the n-Bu addition product 16,
which resulted from the presence of the residual n-Bu ligand in
the magnesiate complex, was also isolated (37% yield, dr =
90:10). This procedure translated well on gram scale and
afforded 611 mg of the desired product in a 43% yield. The
chiral auxiliary was subsequently removed under previously
described conditions to afford 419 in a 38% yield and 98:2 dr
after reversed-phase HPLC, eliminating four steps and the
need for chiral chromatography from the original synthesis.
Given the results obtained with the bromobenzotriazole D,
the scope of this procedure was tested using various aryl and
heteroaryl bromides to synthesize additional analogues (Table
4).
It was observed that a majority of both electron-rich and
electron-deficient phenyl rings underwent full metal−halogen
exchange and afforded their respective 1,4-addition products in
24−62% yields with excellent diastereoselectivity (dr >95:5).
As noted previously with the model system which afforded 3a
and 3b as well as conjugate addition products leading to 6a
and 6b (Table 1, entries 1 and 2), the presence of the o-methyl
group enhanced the diastereoselectivity under these conditions
presumably due to increased steric bulk (Table 4, entries 1 and
2). As suspected, a substrate bearing a halogen at the ortho
position (Table 4, entry 7) proved to be problematic and did
not afford a Michael addition product, despite achieving
complete metal−halogen exchange; again, benzyne intermedi-
ates are suspected. Interestingly, even the most sterically
encumbered aryl bromide (Table 4, entry 8) underwent
complete metal−halogen exchange and afforded its respective
conjugate addition product in a 33% yield.
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extract was dried (Na2SO4), filtered, concentrated, and subjected to
flash chromatography (30% EtOAc-heptane) to afford the desired
product as a white, crystalline solid (10.8 g, 49.7 mmol, 81% yield).
1H NMR (400 MHz, DMSO-d6) δ = 7.47−7.35 (m, 3H), 7.35−7.25
(m, 3H), 6.31 (dd, J = 2.0, 17.2 Hz, 1H), 5.95 (dd, J = 2.0, 10.6 Hz,
1H), 5.52 (dd, J = 3.9, 8.5 Hz, 1H), 4.78 (t,J = 8.7 Hz, 1H), 4.20 (dd,
J = 3.9, 8.7 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 164.3,
154.2, 140.1, 131.8, 129.3, 128.5, 128.2, 126.3, 70.8, 57.6. HRMS
(ESI) m/z: [M + H]+ calcd for C12H12NO3 218.0812, found
exchange on the bromobenzotriazole D substrate support the
postulated formation of the n-BuAr2MgLi complex as the
active magnesiate species.
To complete the synthesis of Nrf2 analogs, the CA products
were subsequently hydrolyzed using a previously described
procedure to afford their corresponding carboxylic acids 6k−6r
in 33−62% yields (Table 4). Biological characterization of
these analogues will be reported separately.
20
218.0812. [α]D +170 (c 1.0, DCM). mp 87 °C.
CONCLUSION
(S,E)-3-(3-(3-(((4-Methoxybenzyl)oxy)methyl)-4-methylphenyl)-
acryloyl)-4-phenyloxazolidin-2-one (2). A solution of A (20.70 g,
64.4 mmol) in N,N-dimethylformamide (200 mL) was purged with
N2 for 30 min, then tri-o-tolylphosphine (3.92 g, 12.89 mmol),
palladium(II) acetate (1.447 g, 6.44 mmol), DIPEA (33.8 mL, 193
mmol), and 1 (14 g, 64.4 mmol) were added, and the mixture was
stirred at 110 °C for 7 h before being cooled to room temperature.
The mixture was diluted with EtOAc, washed (water, brine), dried
(Na2SO4), filtered, concentrated, and subjected to flash chromatog-
raphy (30% EtOAc-heptane) to give a yellow solid, which was
triturated in Et2O (200 mL) and collected by filtration to afford 12 g
of a yellow solid which was subjected to flash chromatography (30%
EtOAc-heptane) to afford the desired product as a pale yellow solid
(9.7 g, 21.20 mmol, 32.9% yield). 1H NMR (400 MHz, DMSO-d6) δ
= 7.81 (d, J = 16.0 Hz, 1H), 7.65 (d, J = 15.7 Hz, 1H), 7.62 (d, J = 1.5
Hz, 1H), 7.49 (dd, J = 1.8, 7.9 Hz, 1H), 7.43−7.36 (m, 2H), 7.36−
7.22 (m, 6H), 6.97−6.89 (m, 2H), 5.58 (dd, J = 3.8, 8.6 Hz, 1H), 4.80
(t, J = 8.6 Hz, 1H), 4.57−4.43 (m, 4H), 4.21 (dd, J = 4.1, 8.9 Hz,
1H), 3.74 (s, 3H), 2.28 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-
d6) δ = 164.5, 159.2, 154.4, 145.3, 140.3, 140.0, 137.8, 132.2, 131.2,
130.6, 129.8, 129.3, 128.5, 128.2, 128.0, 126.3, 117.1, 114.2, 71.9,
70.7, 69.7, 57.7, 55.5, 18.9. HRMS (ESI) m/z: [M + H]+ calcd for
C28H28NO5 458.1967, found 458.1965.
■
In conclusion, a shortened two-step synthesis of bisaryl Nrf2
activators was developed using late-stage functionalization via
Michael addition of metalated aryl substituents. Asymmetric
cuprate-based 1,4-addition was achieved on a complex system
featuring both sp2- and sp3-hybridized basic nitrogen centers.
Several methods for the preparation of a Grignard reagent of
bromobenzotriazole D were investigated and led to utilization
of a mild and rapid metal−halogen exchange procedure using
(n-Bu)3MgLi. This procedure allowed for a novel, accelerated
synthesis of 419 as well as a number of diverse analogues with
excellent diastereoselectivity. A mechanism involving forma-
tion of homo- and heterocuprate mixtures resulting in 1:1 aryl
to alkyl conjugate addition products was postulated. It is hoped
that these investigations will stimulate further exploration of
high-valent organomagnesium species in organic synthesis.
EXPERIMENTAL SECTION
■
General Information. Compounds A, B, C, and D were prepared
according to known procedures.21 Grignard as well as other reagents
were commercially available and were used without further
purification. All reactions were monitored by liquid chromatog-
raphy−mass spectrometry (LC/MS) using Waters Acquity UPLC and
(S)-3-((R)-3-(3-(((4-Methoxybenzyl)oxy)methyl)-4-methylphenyl)-
3-phenylpropanoyl)-4-phenyloxazolidin-2-one (3a). To an oven-
dried glass vessel with a magnetic stirrer was transferred copper(I)
bromide−dimethyl sulfide complex (0.063 g, 0.306 mmol) followed
by dimethyl sulfide (0.162 mL, 2.186 mmol), and the mixture was
stirred until dissolved. Next, anhydrous tetrahydrofuran (1.46 mL)
was added, and the solution was cooled on a regular ice/water bath. A
3 M solution of phenylmagnesium bromide in diethyl ether (0.204
mL, 0.612 mmol) was added, and the reaction mixture was stirred
over 10 min on the regular ice/water bath. Next, the reaction mixture
was cooled to −40 °C on an MeCN/dry ice bath, solid 2 (0.100 g,
0.219 mmol) was added under a stream of nitrogen gas, and the
reaction mixture was stirred over 1 h at −40 °C. The reaction was
quenched with saturated NH4Cl solution and combined with
additional water and EtOAc. The aqueous layer was extracted three
times with EtOAc, and the combined organic portions were dried
over MgSO4, filtered, and concentrated to afford the crude product
mixture. The crude product mixture was purified via flash
chromatography on silica gel (10−30% EtOAc/heptane, 12 g RediSep
Rf Gold column) to the desired product as a white amorphous solid
(86 mg, 0.153 mmol, 69.8% yield, 90% de by chiral HPLC). 1H NMR
(400 MHz, DMSO-d6) δ = 7.29−7.02 (m, 13H), 6.94−6.87 (m, 2H),
5.37 (dd, J = 3.7, 8.5 Hz, 1H), 4.68 (t, J = 8.6 Hz, 1H), 4.49−4.43 (m,
1H), 4.41 (s, 2H), 4.40 (s, 2H), 4.08 (dd, J = 3.8, 8.9 Hz, 1H), 3.86
(dd, J = 7.6, 16.7 Hz, 1H), 3.74 (s, 3H), 3.50 (dd, J = 8.0, 16.6 Hz,
1H), 2.57−2.43 (m, 2H), 2.17 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ = 170.6, 159.2, 154.3, 144.5, 141.6, 140.0, 136.8, 134.6,
130.7, 130.5, 129.8, 129.1, 128.8, 128.2, 128.1, 128.0, 127.0, 126.6,
125.9, 114.1, 71.7, 70.6, 70.1, 57.3, 55.5, 46.1, 40.7, 18.4. HRMS
(ESI) m/z: [M + H]+ calcd for C34H33NO5Na 558.2256, found
Waters QDa or thin layer chromatography (TLC). 1H NMR and 13
C
NMR spectra were recorded on Bruker UltraShield Plus (101, 126,
400, 501 MHz) spectrometers, using DMSO-d6 as a solvent and
tetramethylsilane (TMS) as an internal standard. HRMS spectra were
determined on an Orbitrap (QE Plus) or Waters Xevo G2-S (ESI-
Tof) mass spectrometers in positive-ion mode. Compounds 6a−6r
and 419 were isolated via preparative mass directed auto purification
(MDAP) system using XSELECT CSH C18 column with a mobile
phase of 10 mM ammonium bicarbonate in H2O and MeCN.
Synthesis. 4-Bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-meth-
ylbenzene (A).21 13C NMR{1H} (101 MHz, DMSO-d6) δ = 158.80,
139.26, 135.32, 132.01, 130.08, 130.06, 130.00, 129.30, 118.50,
113.70, 71.54, 68.73, 55.04, 17.78. HRMS (ESI) m/z: [M + H]+ calcd
for C16H18BrO2 321.0485, found 321.0313.
(R)-2-Ethyl-2,3,4,5-tetrahydropyrido[2,3-f ][1,4]oxazepine dihy-
drochloride (B).21 13C{1H} NMR (101 MHz, DMSO-d6) δ =
155.72, 144.34, 141.77, 132.45, 126.70, 80.80, 51.59, 48.46, 26.28,
10.14. HRMS (ESI) m/z: [M + H]+ calcd for C10H15N2O 178.1184,
found 178.1183.
4-Bromo-N-1,3-dimethylbenzene-1,2-diamine (C).21 13C{1H}
NMR (101 MHz, DMSO-d6) δ = 136.58, 134.92, 120.49, 118.99,
112.35, 108.82, 30.81, 17.78. HRMS (ESI) m/z: [M + H]+ calcd for
C8H12BrN2 215.0178, found 215.0178.
5-Bromo-1,4-dimethyl-1H-benzo[d][1,2,3]triazole (D).21 13C{1H}
NMR (101 MHz, DMSO-d6) δ = 146.32, 132.80, 131.04, 129.39,
118.36, 110.01, 34.85, 17.01. HRMS (ESI) m/z: [M + H]+ calcd for
C8H9BrN3 225.9974, found 225.9975.
(S)-3-Acryloyl-4-phenyloxazolidin-2-one (1). A mixture of acrylic
acid (5.46 mL, 80 mmol) in tetrahydrofuran (200 mL) at 25 °C was
treated with DIPEA (32.1 mL, 184 mmol) and acryloyl chloride (7.47
mL, 92 mmol) and stirred for 1 h (off-white precipitate formed)
before being treated with lithium chloride (2.86 g, 67.4 mmol) and
(S)-4-phenyloxazolidin-2-one (10 g, 61.3 mmol). The mixture was
stirred for an additional 1 h before being quenched with saturated
aqueous ammonium chloride and extracted with EtOAc. The organic
20
558.2258. [α]D +62 (c 1.0, DCM).
(S)-3-((S)-3-(3-(((4-Methoxybenzyl)oxy)methyl)-4-methylphenyl)-
3-(o-tolyl)propanoyl)-4-phenyloxazolidin-2-one (3b). To an oven-
dried glass vessel with a magnetic stirrer was transferred copper(I)
bromide−dimethyl sulfide complex (0.063 g, 0.306 mmol) followed
by dimethyl sulfide (0.162 mL, 2.186 mmol), and the mixture was
stirred until dissolved. Next, anhydrous tetrahydrofuran (1.45 mL)
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was added, and the solution was cooled on a regular ice/water bath. o-
Tolylmagnesium bromide (2 M, 0.306 mL, 0.612 mmol) was added,
and the reaction mixture was stirred over 10 min on the regular ice/
water bath. Next, the reaction mixture was cooled to −40 °C on an
MeCN/dry ice bath, solid 2 (0.100 g, 0.219 mmol) was added under
a stream of nitrogen gas, and the reaction mixture was stirred over 1 h
at −40 °C. The reaction was quenched with saturated NH4Cl solution
and combined with additional water and EtOAc. The aqueous layer
was extracted three times with EtOAc, and the combined organic
portions were dried over MgSO4, filtered, and concentrated to afford
the crude product mixture. The crude product mixture was purified
via flash chromatography on silica gel (10−30% EtOAc/heptane, 12 g
RediSep Rf Gold column) to afford the desired product as a white
amorphous solid (89 mg, 0.154 mmol, 70.4% yield, 94% de by chiral
layers were washed once with water and then once with brine, dried
over MgSO4, filtered, and concentrated to afford the crude product
mixture. The crude product mixture was purified via flash
chromatography on silica gel (30−55% EtOAc/heptane, 220 g
RediSep Rf Gold column) to afford the desired product as a white,
1
crystalline solid (5.441 g, 10.39 mmol, 82% yield). H NMR (400
MHz, DMSO-d6) δ = 8.18 (dd, J = 1.5, 4.9 Hz, 1H), 7.79 (d, J = 15.6
Hz, 1H), 7.63 (d, J = 15.6 Hz, 1H), 7.53−7.49 (m, 1H), 7.46 (dd, J =
2.0, 7.8 Hz, 1H), 7.42−7.29 (m, 6H), 7.28−7.21 (m, 2H), 5.58 (dd, J
= 3.7, 8.6 Hz, 1H), 4.80 (t, J = 8.6 Hz, 1H), 4.20 (dd, J = 3.7, 8.6 Hz,
1H), 3.95 (d, J = 14.2 Hz, 1H), 3.92−3.87 (m, 1H), 3.84 (d, J = 14.2
Hz, 1H), 3.61 (s, 2H), 3.01 (d, J = 13.2 Hz, 1H), 2.89 (dd, J = 9.8,
13.7 Hz, 1H), 2.30 (s, 3H), 1.68−1.54 (m, 1H), 1.54−1.41 (m, 1H),
1.00 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ =
164.5, 1545.0, 154.3, 152.8, 145.5, 143.7, 141.3, 140.3, 137.9, 132.0,
131.4, 129.7, 129.3, 129.2, 128.5, 128.3, 127.9, 126.5, 126.3, 123.9,
116.9, 81.7, 70.7, 62.2, 60.0, 57.7, 56.8, 26.8, 19.3, 10.6. HRMS (ESI)
m/z: [M + H]+ calcd for C30H32N3O4 498.2393, found 498.2392.
1
HPLC). H NMR (400 MHz, DMSO-d6) δ = 7.36−7.16 (m, 7H),
7.15−7.00 (m, 7H), 6.93−6.87 (m, 2H), 5.38 (dd, J = 3.8, 8.6 Hz,
1H), 4.67 (t, J = 8.7 Hz, 1H), 4.62 (t, J = 7.7 Hz, 1H), 4.44−4.34 (m,
4H), 4.07 (dd, J = 3.8, 8.9 Hz, 1H), 3.91 (dd, J = 8.5, 16.9 Hz, 1H),
3.75 (s, 3H), 3.39 (dd, J = 7.1, 17.0 Hz, 1H), 2.17 (s, 3H), 2.16 (s,
3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 170.7, 159.2, 154.3,
142.0, 141.0, 134.0, 136.8, 136.1, 134.5, 130.8, 130.7, 130.5, 129.7,
129.1, 128.2, 128.2, 127.4, 126.6, 126.5, 126.5, 125.8, 114.1, 71.6,
70.6, 70.0, 57.4, 55.5, 41.9, 41.3, 19.9, 18.4. HRMS (ESI) m/z: [M +
H]+ calcd for C35H35NO5Na 572.2413, found 572.2419. [α]D20 +98 (c
1.0, DCM).
20
[α]D −22 (c 1.0, DCM). Mp: 136 °C.
General Procedure 1 (Michael Addition Using Solutions of
Commercially Available Grignard Reagents). To an oven-dried glass
vessel with a magnetic stirrer was transferred copper(I) bromide−
dimethyl sulfide complex (1.4 equiv) followed by dimethyl sulfide (10
equiv), and the mixture was stirred until dissolved. Next, anhydrous
tetrahydrofuran (0.15 mol/L) was added, and the solution was cooled
on a regular ice/water bath. A commercially available solution of
Grignard reagent (2.8 equiv) was added and the reaction mixture was
stirred over 10 min on the regular ice/water bath. Next, the reaction
mixture was cooled to −40 °C on an MeCN/dry ice bath, 5 (1 equiv)
was added under a stream of nitrogen gas, and the reaction mixture
was stirred over 1 h at −40 °C. The reaction was quenched with
saturated NH4Cl solution and combined with additional water and
EtOAc. The aqueous layer was extracted three times with EtOAc, and
the combined organic portions were dried over MgSO4, filtered, and
concentrated to afford the crude product mixture. The crude product
mixture was purified via flash chromatography on silica gel to afford
the desired product.
(S,E)-3-(3-(3-(Hydroxymethyl)-4-methylphenyl)acryloyl)-4-phe-
nyloxazolidin-2-one (4). To a biphasic mixture of 2 (5.827 g, 12.74
mmol) in dichloromethane (87 mL) and water (4.33 mL) was added
DDQ (4.34 g, 19.10 mmol), and the resulting mixture was stirred over
1 h at room temperature. Next, the mixture was diluted with DCM
and saturated NaHCO3 solution, and the system was transferred to a
separatory funnel. After the layers separated, the organic layer was
drained. Over time, the aqueous layer showed formation of insoluble
solids. The aqueous layer was filtered, and the leftover solids were
washed with DCM. The filtrate was then placed back in the separatory
funnel and extracted with DCM once again. The combined organic
portions were washed once with brine, dried over MgSO4, filtered,
and concentrated to afford the crude product mixture was a yellow,
brown, oil. The crude product mixture was purified via flash
chromatography on silica gel (20−60% EtOAc/heptane, 330 g
RediSep Rf Gold column) to afford the desired product as an
General Procedure 2 (Hydrolysis of Chiral Auxiliary under Basic
Conditions). To a solution of starting material in 3:1 tetrahydrofuran
and water (0.025 mol/L) at 0 °C (water/ice) was added 30% aqueous
H2O2 solution (5 equiv) followed by 2 M aqueous LiOH solution (3
equiv), and the reaction mixture was stirred until completion (15 min
to 1 h) at 0 °C. The reaction mixture was quenched with 10% sodium
metabisulfite solution and diluted with water. The resulting mixture
was extracted with EtOAc three times, and the combined organic
portions were dried over MgSO4, filtered, and concentrated to afford
the crude product mixture. The crude product was purified via
preparative HPLC (MDAP), and the desired fractions were combined
and lyophilized to afford the desired product as a white amorphous
solid.
(R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-phenylpropanoic Acid (6a).
Michael addition was carried out according to according to general
procedure 1 with 5 (100 mg, 0.165 mmol) and 3 M phenyl-
magnesium bromide in diethyl ether. The isolated product was
purified additionally via MDAP to afford the conjugate addition
product as a white amorphous solid (63 mg, 0.104 mmol, 51.7%
yield); 96.00% de by chiral HPLC (CHIRALPAK IA column, 95/05
Ethanol/Heptane +0.1% isopropylamine, 15 min run). 1H NMR (400
MHz, DMSO-d6) δ = 8.20 (dd, J = 1.5, 4.6 Hz, 1H), 7.39 (dd, J = 1.4,
8.0 Hz, 1H), 7.30−7.19 (m, 8H), 7.19−6.99 (m, 6H), 5.37 (dd, J =
3.7, 8.5 Hz, 1H), 4.63 (t, J = 8.6 Hz, 1H), 4.43 (t, J = 7.7 Hz, 1H),
4.07 (dd, J = 3.8, 8.9 Hz, 1H), 3.96 (d, J = 14.4 Hz, 1H), 3.90−3.76
(m, 3H), 3.60−3.46 (m, 3H), 2.88 (d, J = 13.2 Hz, 1H), 2.79 (dd, J =
9.4, 13.9 Hz, 1H), 2.19 (s, 3H), 1.61−1.45 (m, 1H), 1.44−1.30 (m,
1H), 0.98 (t, J = 7.4 Hz, 3H). LC/MS (ESI) m/z: [M + H]+ calcd for
C36H38N3O4 576.3, found 576.5. Hydrolysis was carried out according
to general procedure 2 (63 mg, 0.104 mmol) to afford the desired
product as a white amorphous solid (26 mg, 0.057 mmol, 52.4%
yield). 1H NMR (501 MHz, DMSO-d6) δ = 8.20 (dd, J = 1.3, 4.7 Hz,
1
amorphous solid (4.273 g, 12.03 mmol, 94% yield). H NMR (400
MHz, DMSO-d6) δ = 7.81 (d, J = 15.7 Hz, 1H), 7.65 (d, J = 15.7 Hz,
1H), 7.70−7.61 (m, 1H), 7.46−7.29 (m, 6H), 7.22 (d, J = 7.9 Hz,
1H), 5.58 (dd, J = 3.8, 8.6 Hz, 1H), 5.26−5.19 (m, 1H), 4.80 (t, J =
8.6 Hz, 1H), 4.51 (d, J = 5.6 Hz, 2H), 4.21 (dd, J = 3.8, 8.6 Hz, 1H),
2.26 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 164.5, 154.4,
145.7, 141.6, 140.3, 138.9, 132.1, 130.9, 129.3, 128.5, 127.7, 126.3,
126.0, 116.7, 70.7, 61.1, 57.7, 18.7. HRMS (ESI) m/z: [M + H]+
20
calcd for C20H20NO4 338.1392, found 338.1391. [α]D −20 (c 1.0,
DCM).
(S)-3-((E)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f ][1,4]-
oxazepin-4(5H)-yl)methyl)-4-methylphenyl)acryloyl)-4-phenyloxa-
zolidin-2-one (5). To a solution of 4 (4.273 g, 12.67 mmol) in
anhydrous chloroform (63.3 mL) was added SOCl2 (1.849 mL, 25.3
mmol) dropwise, and the resulting mixture was stirred at room
temperature over 64 h. Next, the mixture was concentrated, and the
resulting residue was reconcentrated from DCM three times and dried
under high vacuum to afford the intermediate benzyl chloride as a
sticky solid which was used directly without further purification. To
this residue was added B (3.82 g, 15.20 mmol) followed by
acetonitrile (63.3 mL) and DIPEA (11.06 mL, 63.3 mmol), and the
resulting solution was stirred for 16 h at room temperature. The
reaction was not complete at that time, and so the reaction mixture
was heated to 60 °C (heating block) and stirred over an additional 4
h. Next, the reaction mixture was then cooled back to room
temperature and quenched with saturated NH4Cl solution. Water and
EtOAc were added, and the biphasic system was transferred to a
separatory funnel. The organic layer was removed, and the aqueous
layer was extracted three times with EtOAc. The combined organic
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1H), 7.40 (dd, J = 1.3, 8.2 Hz, 1H), 7.31−7.18 (m, 5H), 7.16−7.11
(m, 2H), 7.11−7.06 (m, 1H), 7.03 (d, J = 7.9 Hz, 1H), 4.34 (t, J = 7.9
Hz, 1H), 3.95 (d, J = 14.2 Hz, 1H), 3.86 (d, J = 14.5 Hz, 1H), 3.89−
3.80 (m, 1H), 3.56−3.47 (m, 2H), 3.03−2.91 (m, 2H), 2.86 (d, J =
13.6 Hz, 1H), 2.77 (dd, J = 9.5, 13.6 Hz, 1H), 2.18 (s, 3H), 1.61−
1.47 (m, 1H), 1.43−1.32 (m, 1H), 0.98 (t, J = 7.4 Hz, 3H). 13C{1H}
NMR (126 MHz, DMSO-d6) δ = 173.3, 155.0, 153.1, 144.9, 143.6,
141.8, 136.9, 135.4, 130.6, 129.2, 128.7, 128.4, 127.9, 126.6, 126.5,
123.9, 81.4, 61.5, 60.6, 57.0, 46.8, 26.8, 18.7, 10.6. HRMS (ESI) m/z:
1.26 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ = 173.1, 155.0, 153.1, 143.6, 141.5, 140.4, 138.8, 136.9,
135.5, 130.9, 130.6, 130.2, 129.5, 128.5, 128.3, 126.9, 126.1, 123.9,
81.4, 61.6, 60.4, 56.8, 42.2, 40.9, 26.8, 19.6, 18.7, 10.6. HRMS (ESI)
m/z: [M + H]+ calcd for C28H32N2O3Cl 479.2101, found 479.2103.
20
[α]D +34 (c 0.50, MeOH).
(S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-(2-methoxyphenyl)propanoic
Acid (6d). Michael addition was carried out according to general
procedure 1 with 5 (250 mg, 0.413 mmol) and 1 M (2-
methoxyphenyl)magnesium bromide in THF to afford the conjugate
addition product an off-white amorphous solid (221 mg, 0.317 mmol,
20
[M + H]+ calcd for C27H31N2O3 431.2329, found 431.2327. [α]D
−7 (c 1.0, MeOH).
(S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-(o-tolyl)propanoic Acid (6b).
Michael addition was carried out according to according to general
procedure 1 with 5 (100 mg, 0.165 mmol) and 2 M o-tolylmagnesium
bromide in diethyl ether. The isolated product was purified
additionally via MDAP to afford the conjugate addition product as
a white amorphous solid (70 mg, 0.113 mmol, 56.1% yield); 97.34%
de by chiral HPLC (CHIRALPAK IA column, 15/85 Ethanol/
1
63.2% yield). H NMR (400 MHz, DMSOd6) δ = 8.19 (dd, J = 1.5,
4.9 Hz, 1H), 7.39 (dd, J = 1.5, 8.3 Hz, 1H), 7.31−7.21 (m, 4H),
7.19−7.11 (m, 4H), 7.07 (s, 1H), 7.03−6.94 (m, 2H), 6.92−6.81 (m,
2H), 5.36 (dd, J = 3.7, 8.6 Hz, 1H), 4.77 (t, J = 7.8 Hz, 1H), 4.62 (t, J
= 8.8 Hz, 1H), 4.08 (dd, J = 3.4, 8.8 Hz, 1H), 3.96 (d, J = 14.2 Hz,
1H), 3.85 (d, J = 14.7 Hz, 1H), 3.83−3.76 (m, 1H), 3.73−3.64 (m,
4H), 3.62−3.44 (m, 3H), 2.88 (d, J = 13.2 Hz, 1H), 2.79 (dd, J = 9.3,
13.7 Hz, 1H), 2.18 (s, 3H), 1.63−1.45 (m, 1H), 1.38 (s, 1H), 0.98 (t,
J = 7.6 Hz, 3H). LC/MS (ESI) m/z: [M + H]+ Calc for C37H40N3O5
606.3, found 606.5. Hydrolysis was carried out according to general
procedure 2 (0.221 g, 0.317 mmol, 87 wt %) to afford the desired
product as a white amorphous solid (90 mg, 0.186 mmol, 58.5%
1
Heptane +0.1% isopropylamine, 15 min run). H NMR (400 MHz,
DMSO-d6) δ = 8.20 (dd, J = 1.5, 4.8 Hz, 1H), 7.39 (dd, J = 1.4, 8.0
Hz, 1H), 7.34−7.20 (m, 5H), 7.19−6.92 (m, 8H), 5.38 (dd, J = 3.7,
8.5 Hz, 1H), 4.65 (t, J = 8.6 Hz, 1H), 4.59 (t, J = 7.7 Hz, 1H), 4.07
(dd, J = 3.8, 8.6 Hz, 1H), 3.98−3.86 (m, 2H), 3.83 (d, J = 14.4 Hz,
1H), 3.81−3.73 (m, 1H), 3.54−3.44 (m, 2H), 3.40 (dd, J = 7.4, 17.0
Hz, 1H), 2.85 (d, J = 13.2 Hz, 1H), 2.77 (dd, J = 9.1, 13.7 Hz, 1H),
2.19 (s, 3H), 2.16 (s, 3H), 1.59−1.44 (m, 1H), 1.42−1.27 (m, 1H),
0.98 (t, J = 7.4 Hz, 3H). LC/MS (ESI) m/z: [M + H]+ calcd for
C37H40N3O4 590.3, found 590.6. Hydrolysis was carried out according
to general procedure 2 (70 mg, 0.113 mmol) to afford the desired
product as a white amorphous solid (19 mg, 0.041 mmol, 34.2%
1
yield). H NMR (400 MHz, DMSO-d6) δ = 11.58 (br s, 1H), 8.18
(dd, J = 1.5, 4.9 Hz, 1H), 7.38 (dd, J = 1.5, 7.8 Hz, 1H), 7.29−7.23
(m, 1H), 7.20 (dd, J = 1.5, 7.3 Hz, 1H), 7.17−7.11 (m, 1H), 7.11−
7.06 (m, 1H), 7.05−6.96 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 6.84 (dt,
J = 1.0, 7.8 Hz, 1H), 4.72 (t, J = 8.1 Hz, 1H), 3.95 (d, J = 14.2 Hz,
1H), 3.88 (d, J = 14.2 Hz, 1H), 3.85−3.77 (m, 1H), 3.73 (s, 3H),
3.51 (s, 2H), 2.96−2.82 (m, 3H), 2.77 (dd, J = 8.8, 13.7 Hz, 1H),
2.18 (s, 3H), 1.63−1.46 (m, 1H), 1.38 (s, 1H), 0.98 (t, J = 7.3 Hz,
3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 173.3, 156.8, 155.0,
153.0, 143.6, 141.2, 136.6, 135.1, 132.6, 130.3, 129.4, 128.3, 127.8,
127.6, 126.9, 123.9, 120.7, 111.4, 81.6, 61.6, 60.6, 57.2, 55.9, 39.6,
26.8, 18.7, 10.6. HRMS (ESI) m/z: [M + H]+ calcd for C28H33N2O4
1
yield). H NMR (501 MHz, DMSO-d6) δ = 12.02 (br s, 1H), 8.20
(dd, J = 1.4, 4.6 Hz, 1H), 7.39 (dd, J = 1.4, 8.0 Hz, 1H), 7.30 (d, J =
7.3 Hz, 1H), 7.26 (dd, J = 4.6, 8.0 Hz, 1H), 7.16−6.99 (m, 6H), 4.53
(t, J = 7.9 Hz, 1H), 3.93 (d, J = 14.5 Hz, 1H), 3.84 (d, J = 14.2 Hz,
1H), 3.82−3.74 (m, 1H), 3.55−3.46 (m, 2H), 2.96 (dd, J = 8.2, 15.8
Hz, 1H), 2.92−2.83 (m, 2H), 2.78 (dd, J = 9.5, 13.9 Hz, 1H), 2.25 (s,
3H), 2.19 (s, 3H), 1.60−1.46 (m, 1H), 1.42−1.29 (m, 1H), 0.98 (t, J
= 7.4 Hz, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ = 173.3,
155.0, 153.1, 143.6, 142.4, 141.0, 136.8, 136.1, 135.3, 130.7, 130.5,
129.5, 128.3, 126.9, 126.6, 126.5, 126.3, 123.9, 81.4, 61.7, 60.4, 56.9,
42.6, 41.1, 26.8, 19.9, 18.7, 10.6. HRMS (ESI) m/z: [M + H]+ calcd
20
461.2440, found 461.2444. [α]D −34 (c 1.0, MeOH).
(S)-3-(2-Chlorophenyl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-
f ][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic Acid
(6e). Michael addition was carried out according to general procedure
1 with 5 (250 mg, 0.413 mmol) and 0.5 M (2-chlorophenyl)
magnesium bromide in 2-MeTHF to afford the conjugate addition
product as an off-white amorphous solid (224 mg, 0.114 mmol,
22.65% yield) containing unreacted 5 (22% by weight by NMR) and
a byproduct of mass 685.3 (desired mass + Ph, 44% by weight by
NMR). LC/MS (ESI) m/z: [M + H]+ calcd for C36H37ClN3O4 610.3,
found 610.3. Hydrolysis was carried out according to general
procedure 2 (0.224 g, 0.114 mmol, 31% wt) to afford the desired
product as a white amorphous solid (12 mg, 0.025 mmol, 21.5%
20
for C28H33N2O3 445.2486, found 445.2484. [α]D +35 (c 1.0,
MeOH).
(S)-3-(4-Chloro-2-methylphenyl)-3-(3-(((R)-2-ethyl-2,3-
dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)methyl)-4-
methylphenyl)propanoic Acid (6c). Michael addition was carried out
according to general procedure 1 with 5 (600 mg, 0.990 mmol) and
0.5 M (4-chloro-2-methylphenyl)magnesium bromide in THF to
afford the conjugate addition product as an off-white amorphous solid
(625 mg, 0.951 mmol, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ
= 8.20 (br d, J = 2.9 Hz, 1H), 7.39 (dd, J = 1.5, 8.3 Hz, 1H), 7.32 (d, J
= 8.3 Hz, 1H), 7.30−7.22 (m, 4H), 7.21−7.14 (m, 1H), 7.14−7.08
(m, 3H), 7.03 (d, J = 7.8 Hz, 1H), 7.01−6.94 (m, 2H), 5.38 (dd, J =
3.9, 8.3 Hz, 1H), 4.66 (t, J = 8.6 Hz, 1H), 4.55 (t, J = 7.8 Hz, 1H),
4.07 (dd, J = 3.7, 8.6 Hz, 1H), 3.99−3.86 (m, 2H), 3.83 (d, J = 14.7
Hz, 1H), 3.81−3.72 (m, 1H), 3.54−3.43 (m, 2H), 3.36 (dd, J = 6.8,
17.1 Hz, 1H), 2.83 (d, J = 12.2 Hz, 1H), 2.76 (dd, J = 8.8, 13.7 Hz,
1H), 2.19 (s, 3H), 2.15 (s, 3H), 1.59−1.43 (m, 1H), 1.40−1.26 (m,
1H), 1.03−0.92 (m, 3H). LC/MS (ESI) m/z: [M + H]+ calcd for
C37H39ClN3O4 624.3, found 624.4. Hydrolysis was carried out
according to general procedure 2 (0.268 g, 0.429 mmol) to afford
the desired product as a white amorphous solid (120 mg, 0.238 mmol,
1
yield). H NMR (400 MHz, DMSO-d6) δ = 12.14 (br s, 1H), 8.19
(dd, J = 1.2, 4.6 Hz, 1H), 7.47 (dd, J = 1.5, 7.8 Hz, 1H), 7.43−7.34
(m, 2H), 7.32−7.23 (m, 2H), 7.20 (dt, J = 1.5, 7.8 Hz, 1H), 7.09 (br
s, 1H), 7.08−7.00 (m, 2H), 4.79 (t, J = 7.8 Hz, 1H), 3.95 (d, J = 14.7
Hz, 1H), 3.86 (d, J = 14.2 Hz, 1H), 3.83−3.75 (m, 1H), 3.51 (s, 2H),
3.02 (dd, J = 8.3, 16.1 Hz, 1H), 2.96 (dd, J = 8.3, 16.1 Hz, 1H), 2.85
(d, J = 13.2 Hz, 1H), 2.77 (dd, J = 9.3, 13.7 Hz, 1H), 2.19 (s, 3H),
1.61−1.45 (m, 1H), 1.43−1.30 (m, 1H), 0.97 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (176 MHz, DMSO-d6) δ = 172.4, 154.4, 152.5, 143.1,
141.8, 139.2, 136.1, 134.7, 132.6, 129.9, 129.5, 129.3, 128.7, 128.1,
126.9, 125.9, 125.7, 123.4, 80.8, 60.7, 60.3, 56.5, 42.2, 40.4, 26.2, 18.2,
10.1. HRMS (ESI) m/z: [M + H]+ calcd for C27H30N2O3Cl 465.1945,
20
found 465.1947. [α]D −8 (c 0.20, MeOH).
(R)-3-(4-(Dimethylamino)phenyl)-3-(3-(((R)-2-ethyl-2,3-
dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)methyl)-4-
methylphenyl)propanoic Acid (6f). Michael addition was carried out
according to general procedure 1 with 5 (250 mg, 0.413 mmol) and
0.5 M (4- (dimethylamino)phenyl)magnesium bromide in THF to
afford the conjugate addition product as an off-white solid (193 mg,
0.296 mmol, 59.0% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.21
(dd, J = 1.5, 4.9 Hz, 1H), 7.40 (dd, J = 1.5, 8.3 Hz, 1H), 7.29−7.22
1
55.4% yield). H NMR (400 MHz, DMSO-d6) δ = 11.76 (s, 1H),
8.20 (dd, J = 1.5, 4.9 Hz, 1H), 7.39 (dd, J = 1.5, 8.3 Hz, 1H), 7.32 (d,
J = 8.3 Hz, 1H), 7.26 (dd, J = 4.6, 8.1 Hz, 1H), 7.21−7.13 (m, 2H),
7.08−6.97 (m, 3H), 4.49 (t, J = 7.8 Hz, 1H), 3.93 (d, J = 14.2 Hz,
1H), 3.82 (br d, J = 14.2 Hz, 1H), 3.80−3.73 (m, 1H), 3.49 (s, 2H),
2.96 (dd, J = 8.8, 16.1 Hz, 1H), 2.92−2.80 (m, 2H), 2.77 (dd, J = 8.8,
13.7 Hz, 1H), 2.24 (s, 3H), 2.19 (s, 3H), 1.59−1.43 (m, 1H), 1.40−
3129
https://dx.doi.org/10.1021/acs.joc.0c02639
J. Org. Chem. 2021, 86, 3120−3137

The Journal of Organic Chemistry
pubs.acs.org/joc
Featured Article
(m, 4H), 7.10−6.99 (m, 7H), 6.60 (d, J = 8.8 Hz, 2H), 5.38 (dd, J =
3.7, 8.6 Hz, 1H), 4.63 (t, J = 8.6 Hz, 1H), 4.31 (t, J = 7.6 Hz, 1H),
4.07 (dd, J = 3.4, 8.8 Hz, 1H), 3.97 (d, J = 14.2 Hz, 1H), 3.86 (d, J =
14.2 Hz, 1H), 3.84−3.75 (m, 1H), 3.80 (dd, J = 7.8, 16.6 Hz, 1H),
3.51 (s, 2H), 3.46 (dd, J = 7.8, 16.6 Hz, 1H), 2.89 (d, J = 13.7 Hz,
1H), 2.83 (s, 6H), 2.79 (dd, J = 9.3, 13.7 Hz, 1H), 2.20 (s, 3H),
1.61−1.47 (m, 1H), 1.39 (s, 1H), 0.99 (t, J = 7.3 Hz, 3H). LC/MS
(ESI) m/z: [M + H]+ calcd for C38H43N4O4 619.3, found 619.3.
Hydrolysis was carried out according to general procedure 2 (0.193 g,
0.312 mmol) to afford the desired product as a white amorphous solid
1.43−1.29 (m, 1H), 0.97 (t, J = 7.6 Hz, 3H). LC/MS (ESI) m/z: [M
+ H]+ calcd for C37H39FN3O5 624.3, found 624.3. Hydrolysis was
carried out according to general procedure 2 (0.272 g, 0.406 mmol, 93
wt %) to afford the desired product as a white amorphous solid (57
1
mg, 0.113 mmol, 27.9% yield). H NMR (400 MHz, DMSO-d6) δ =
11.95 (br s, 1H), 8.18 (dd, J = 1.5, 4.9 Hz, 1H), 7.39 (dd, J = 1.5, 7.8
Hz, 1H), 7.29−7.22 (m, 1H), 7.17−7.00 (m, 5H), 6.81 (ddd, J = 2.0,
4.4, 8.3 Hz, 1H), 4.33 (t, J = 8.1 Hz, 1H), 3.93 (d, J = 14.2 Hz, 1H),
3.86 (d, J = 14.2 Hz, 1H), 3.83−3.79 (m, 1H), 3.76 (s, 3H), 3.58−
3.47 (m, 2H), 3.04−2.93 (m, 2H), 2.88 (d, J = 13.2 Hz, 1H), 2.78
(dd, J = 9.3, 13.7 Hz, 1H), 2.19 (s, 3H), 1.61−1.45 (m, 1H), 1.45−
1.31 (m, 1H), 0.97 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ = 173.2, 155.0, 153.0, 150.5 (d, J = 242.1 Hz, 1C),
147.22 (d, J = 10.3 Hz, 1C), 143.6, 141.7 (d, J = 2.9 Hz, 1C), 141.5,
136.9, 135.4, 130.6, 129.2, 128.3, 126.5, 123.9, 119.7 (d, J = 6.6 Hz,
1C), 115.8 (d, J = 17.6 Hz, 1C), 113.7, 81.6, 61.8, 60.5, 57.1, 56.4,
46.5, 26.8, 18.7, 10.5. HRMS (ESI) m/z: [M + H]+ calcd for
C28H32N2O4F 479.2346, found 479.2346. [α]D20 −3 (c 0.50, MeOH).
(R)-3-(4-Acetylphenyl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-
f ][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic Acid
(6i). Michael addition was carried out according to general procedure
1 with 5 (250 mg, 0.413 mmol) and 0.5 M (4-(2-methyl-1,3-dioxolan-
2-yl)phenyl)magnesium bromide in 2-MeTHF to afford the conjugate
addition product as a white solid (195 mg, 0.265 mmol, 52.8% yield).
1H NMR (400 MHz, DMSO-d6) δ = 8.20 (dd, J = 1.5, 4.9 Hz, 1H),
1
(81 mg, 0.162 mmol, 52.1% yield). H NMR (400 MHz, DMSO-d6)
δ = 11.95 (br s, 1H), 8.19 (dd, J = 1.5, 4.9 Hz, 1H), 7.39 (dd, J = 1.5,
7.8 Hz, 1H), 7.30−7.22 (m, 1H), 7.11−6.98 (m, 5H), 6.63−6.55 (m,
2H), 4.22 (t, J = 8.1 Hz, 1H), 3.95 (d, J = 14.2 Hz, 1H), 3.91−3.79
(m, 1H), 3.87 (d, J = 14.7 Hz, 1H), 3.59−3.47 (m, 2H), 2.93−2.84
(m, 3H), 2.84−2.73 (m, 7H), 2.19 (s, 3H), 1.62−1.47 (m, 1H),
1.46−1.31 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101
MHz, DMSO-d6) δ = 173.3, 155.0, 153.1, 149.3, 143.6, 142.5, 136.7,
135.0, 132.5, 130.5, 129.1, 128.3, 128.3, 126.5, 123.9, 112.9, 81.5,
61.5, 60.6, 57.1, 45.9, 40.7, 26.8, 18.7, 10.6. HRMS (ESI) m/z: [M +
20
H]+ calcd for C29H36N3O3 474.2757, found 474.2758. [α]D −13 (c
1.0, MeOH).
(S)-3-(3,4-Dimethoxyphenyl)-3-(3-(((R)-2-ethyl-2,3-
dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)methyl)-4-
methylphenyl)propanoic Acid (6g). Michael addition was carried out
according to general procedure 1 with 5 (250 mg, 0.413 mmol) and
0.5 M (3,4-dimethoxyphenyl)magnesium bromide in THF to afford
the conjugate addition product as an off-white solid (254 mg, 0.380
mmol, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.19 (dd, J =
1.5, 4.9 Hz, 1H), 7.39 (dd, J = 1.5, 8.3 Hz, 1H), 7.29−7.20 (m, 4H),
7.11 (s, 1H), 7.09−6.99 (m, 4H), 6.83 (d, J = 2.0 Hz, 1H), 6.80 (d, J
= 8.3 Hz, 1H), 6.72 (dd, J = 2.0, 8.3 Hz, 1H), 5.38 (dd, J = 3.4, 8.3
Hz, 1H), 4.64 (t, J = 8.8 Hz, 1H), 4.36 (t, J = 7.8 Hz, 1H), 4.07 (dd, J
= 3.7, 8.6 Hz, 1H), 3.94 (d, J = 14.7 Hz, 1H), 3.91−3.75 (m, 3H),
3.69 (s, 3H), 3.63 (s, 3H), 3.51 (s, 2H), 3.43 (dd, J = 7.6, 16.4 Hz,
1H), 2.90 (d, J = 13.2 Hz, 1H), 2.80 (dd, J = 9.3, 13.7 Hz, 1H), 2.19
(s, 3H), 1.61−1.46 (m, 1H), 1.45−1.31 (m, 1H), 0.97 (t, J = 7.3 Hz,
3H). LC/MS (ESI) m/z: [M + H]+ calcd for C38H42N3O6 636.3,
found 636.4. Hydrolysis was carried out according to general
procedure 2 (0.254 g, 0.400 mmol) to afford the desired product as
a white amorphous solid (67 mg, 0.130 mmol, 32.5% yield). 1H NMR
(400 MHz, DMSO-d6) δ = 11.63 (br s, 1H), 8.19 (dd, J = 1.5, 4.4 Hz,
1H), 7.39 (dd, J = 1.5, 7.8 Hz, 1H), 7.26 (dd, J = 4.6, 8.1 Hz, 1H),
7.13 (d, J = 1.5 Hz, 1H), 7.08 (dd, J = 1.5, 7.8 Hz, 1H), 7.02 (d, J =
7.8 Hz, 1H), 6.85 (d, J = 1.5 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.76
(dd, J = 2.0, 8.3 Hz, 1H), 4.28 (t, J = 7.8 Hz, 1H), 3.93 (d, J = 14.7
Hz, 1H), 3.86 (d, J = 14.2 Hz, 1H), 3.84−3.76 (m, 1H), 3.68 (s, 3H),
3.67 (s, 3H), 3.58−3.47 (m, 2H), 3.01−2.91 (m, 2H), 2.89 (d, J =
13.7 Hz, 1H), 2.79 (dd, J = 9.3, 13.7 Hz, 1H), 2.19 (s, 3H), 1.63−
1.46 (m, 1H), 1.46−1.31 (m, 1H), 0.97 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ = 173.3, 155.0, 153.1, 149.0, 147.6,
143.6, 142.0, 137.4, 136.8, 135.2, 130.5, 129.1, 128.3, 126.5, 123.9,
119.5, 112.2, 112.0, 81.7, 61.8, 60.4, 57.1, 55.9, 55.9, 46.4, 26.8, 18.7,
10.6. HRMS (ESI) m/z: [M + H]+ calcd for C29H35N2O5 491.2546,
7.40 (dd, J = 1.5, 7.8 Hz, 1H), 7.30−7.19 (m, 8H), 7.15−7.08 (m,
3H), 7.07−6.99 (m, 2H), 5.37 (dd, J = 3.7, 8.6 Hz, 1H), 4.63 (t, J =
8.8 Hz, 1H), 4.42 (t, J = 7.8 Hz, 1H), 4.08 (dd, J = 3.9, 8.8 Hz, 1H),
3.99−3.89 (m, 3H), 3.89−3.75 (m, 3H), 3.67−3.60 (m, 2H), 3.60−
3.53 (m, 1H), 3.53−3.45 (m, 2H), 2.88 (d, J = 13.2 Hz, 1H), 2.79
(dd, J = 9.3, 13.7 Hz, 1H), 2.19 (s, 3H), 1.49 (s, 3H), 1.60−1.45 (m,
1H), 1.45−1.32 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H). LC/MS (ESI) m/
z: [M + H]+ calcd for C40H43N3O6 662.3, found 662.4. Hydrolysis
was carried out according to a modified general procedure 2: To a
solution of (S)-3-((R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f ]-
[1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(4-(2-methyl-
1,3-dioxolan-2-yl)phenyl)propanoyl)-4-phenyloxazolidin-2-one
(0.195 g, 0.295 mmol) in tetrahydrofuran (8.84 mL) and water (2.95
mL) at 0 °C (water/ice bath) was added 30% H2O2 aqueous solution
(0.150 mL, 1.473 mmol) followed by 2 M LiOH aqueous solution
(0.442 mL, 0.884 mmol), and the resulting mixture was stirred over
15 min at 0 °C. Next, the reaction mixture was quenched with 10%
sodium metabisulfite solution and combined with additional water.
The resulting mixture was treated with 6 M HCl and stirred over 2 h.
Next, the mixture was basified to pH 5 with 5 M NaOH solution and
then extracted with EtOAc three times. The combined organic
extracts were dried over MgSO4, filtered, and concentrated to afford
the crude product mixture as a yellow oil. The crude product mixture
was purified via preparative HPLC to afford the desired product as a
1
white amorphous solid (80 mg, 0.161 mmol, 54.6% yield). H NMR
(400 MHz, DMSO-d6) δ = 11.70 (br s, 1H), 8.20 (dd, J = 1.5, 4.4 Hz,
1H), 7.83 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.39 (dd, J =
1.5, 7.8 Hz, 1H), 7.26 (dd, J = 4.6, 8.1 Hz, 1H), 7.16−7.08 (m, 2H),
7.04 (d, J = 7.8 Hz, 1H), 4.42 (t, J = 7.8 Hz, 1H), 3.94 (d, J = 14.2 Hz,
1H), 3.90−3.78 (m, 1H), 3.85 (d, J = 14.2 Hz, 1H), 3.57−3.47 (m,
2H), 2.98 (dd, J = 7.8, 16.1 Hz, 1H), 3.05 (dd, J = 7.8, 15.6 Hz, 1H),
2.84 (d, J = 13.2 Hz, 1H), 2.77 (dd, J = 8.8, 13.7 Hz, 1H), 2.52−2.51
(m, 3H), 2.19 (s, 3H), 1.60−1.44 (m, 1H), 1.42−1.27 (m, 1H), 0.96
(t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 197.8,
173.0, 155.0, 153.0, 150.3, 143.6, 141.0, 137.1, 135.7, 135.4, 130.7,
129.2, 128.8, 128.3, 128.2, 126.6, 123.9, 81.4, 61.5, 60.5, 56.9, 46.7,
39.9, 27.1, 26.8, 18.7, 10.6. HRMS (ESI) m/z: [M + H]+ calcd for
20
found 491.2543. [α]D −3 (c 1.0, MeOH).
(S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-(4-fluoro-3-methoxyphenyl)-
propanoic Acid (6h). Michael addition was carried out according to
general procedure 1 with 5 (250 mg, 0.413 mmol) and 0.5 M (4-
fluoro-3-methoxyphenyl)magnesium bromide in 2-MeTHF to afford
the conjugate addition product as an off-white solid (272 mg, 0.406
mmol, 81% yield, 93 wt %) containing unreacted 5 and residual DCM
1
20
(4 and 3% by weight by NMR, respectively). H NMR (400 MHz,
C29H33N2O4 473.2440, found 473.2439. [α]D −4 (c 1.0, MeOH).
DMSO-d6) δ = 8.19 (dd, J = 1.5, 4.4 Hz, 1H), 7.39 (dd, J = 1.5, 7.8
Hz, 1H), 7.28−7.21 (m, 4H), 7.14−7.00 (m, 7H), 6.76 (ddd, J = 2.0,
4.3, 8.4 Hz, 1H), 5.38 (dd, J = 3.7, 8.6 Hz, 1H), 4.65 (t, J = 8.8 Hz,
1H), 4.42 (t, J = 7.8 Hz, 1H), 4.08 (dd, J = 3.4, 8.8 Hz, 1H), 3.94 (d, J
= 14.2 Hz, 1H), 3.92−3.76 (m, 3H), 3.72 (s, 3H), 3.51 (s, 2H), 3.47
(dd, J = 7.3, 16.6 Hz, 1H), 2.88 (d, J = 12.7 Hz, 1H), 2.79 (dd, J =
9.3, 13.7 Hz, 1H), 2.19 (s, 3H), 1.53 (quind, J = 7.4, 14.8 Hz, 1H),
(R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-(4-(trifluoromethoxy)phenyl)-
propanoic Acid (6j). Michael addition was carried out according to
general procedure 1 with 5 (250 mg, 0.413 mmol) and 0.5 M (4-
(trifluoromethoxy)phenyl)magnesium bromide in THF to afford the
conjugate addition product as an off-white solid (216 mg, 0.304
mmol, 60.6% yield, 93 wt %) containing unreacted 5 and residual
3130
https://dx.doi.org/10.1021/acs.joc.0c02639
J. Org. Chem. 2021, 86, 3120−3137

The Journal of Organic Chemistry
pubs.acs.org/joc
Featured Article
DCM (6 and 1% by weight, by NMR). 1H NMR (400 MHz, DMSO-
d6) δ = 8.20 (br d, J = 3.9 Hz, 1H), 7.43−7.32 (m, 3H), 7.30−7.16
(m, 6H), 7.16−7.01 (m, 5H), 5.38 (dd, J = 3.7, 8.6 Hz, 1H), 4.65 (t, J
= 8.6 Hz, 1H), 4.48 (t, J = 7.8 Hz, 1H), 4.08 (dd, J = 3.9, 8.8 Hz, 1H),
3.95 (d, J = 14.2 Hz, 1H), 3.90−3.75 (m, 3H), 3.59−3.46 (m, 3H),
2.86 (d, J = 12.7 Hz, 1H), 2.77 (dd, J = 9.3, 13.7 Hz, 1H), 2.19 (s,
3H), 1.59−1.44 (m, 1H), 1.42−1.28 (m, 1H), 0.96 (t, J = 7.3 Hz,
3H). LC/MS (ESI) m/z: [M + H]+ calcd for C37H37F3N3O5 660.3,
found 660.4. Hydrolysis was carried out according to general
procedure 2 (0.216 g, 0.304 mmol) to afford the desired product as
mL) was added HBr (2.54 mL, 22.46 mmol, 48 wt %) and 2-bromo-
1,1-diethoxyethane (13.28 g, 67.4 mmol) in one charge. The mixture
was stirred at 60 °C over 48 h. After cooling, the mixture was treated
with 0.5 M Na2CO3 (100 mL) and extracted with DCM (100 × 2).
The organic layers were combined, dried over anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure to afford
crude product mixture. The crude product was diluted with DCM (30
mL) and combined in a slurry with 100−200 silica gel mesh (10 g).
The sample was purified by column chromatography (column size 5
× 25 cm, column volume: 200 mL, silica gel size (100−200 mesh)
quantity: 80 g) and eluted with MeOH/DCM with a gradient from 3
to 5%. The desired fractions were combined and concentrated under
reduced pressure to afford the product which was additionally treated
with n-hexane to provide the desired product as a beige solid (3.684 g,
1
a white amorphous solid (106 mg, 0.200 mmol, 65.6% yield). H
NMR (400 MHz, DMSO-d6) δ = 12.15 (br s, 1H), 8.19 (dd, J = 1.5,
4.9 Hz, 1H), 7.45−7.36 (m, 3H), 7.30−7.24 (m, 1H), 7.22 (d, J = 7.8
Hz, 2H), 7.16−7.08 (m, 2H), 7.05 (d, J = 7.8 Hz, 1H), 4.39 (t, J = 8.1
Hz, 1H), 3.94 (d, J = 14.2 Hz, 1H), 3.90−3.78 (m, 1H), 3.85 (d, J =
14.2 Hz, 1H), 3.59−3.47 (m, 2H), 3.08−2.93 (m, 2H), 2.85 (d, J =
13.2 Hz, 1H), 2.77 (dd, J = 9.3, 13.7 Hz, 1H), 2.19 (s, 3H), 1.60−
1.45 (m, 1H), 1.43−1.29 (m, 1H), 0.97 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ = 173.1, 155.0, 153.1, 147.1, 147.1,
144.3, 143.6, 141.2, 137.1, 135.6, 130.7, 129.7, 129.2, 128.3, 126.5,
123.9, 121.3, 120.5 (q, J = 256.0 Hz, 1C), 81.4, 61.5, 60.6, 56.9, 46.1,
26.8, 18.7, 10.5. HRMS (ESI) m/z: [M + H]+ calcd for
C28H30N2O4F3 515.2158, found 515.2158. [α]D20 −5 (c 1.0, MeOH).
2-(4-Bromo-3-methylphenoxy)tetrahydro-2H-pyran (7). To a
solution of 4-bromo-3-methylphenol (1.669 g, 8.92 mmol) in
anhydrous dichloromethane (29.7 mL) was added 3,4-dihydro-2H-
pyran (1.224 mL, 13.39 mmol) followed by pyridinium p-
toluenesulfonate (0.112 g, 0.446 mmol). The resulting mixture was
stirred at room temperature for 16 h. Next, the mixture was washed
with saturated NaHCO3 solution three times and once with brine.
The organic layer was then dried over MgSO4, filtered, and
concentrated to afford the crude product mixture as a light yellow
oil. The crude product mixture was purified via chromatography on
silica gel (0−10% EtOAc/petroleum ether, 40 g RediSep Rf Gold
column) to afford the desired product (2.36 g, 8.27 mmol, 93% yield)
as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.45 (d, J = 8.8
Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 2.9, 8.8 Hz, 1H), 5.46
(t, J = 3.4 Hz, 1H), 3.77−3.67 (m, 1H), 3.59−3.49 (m, 1H), 2.29 (s,
3H), 1.94−1.66 (m, 3H), 1.66−1.46 (m, 3H). 13C{1H} NMR (101
MHz, DMSO-d6) δ = 156.3, 138.7, 133.0, 119.7, 116.4, 116.0, 96.2,
61.9, 30.2, 25.1, 23.0, 18.9. HRMS (ESI) m/z: [M + H]+ calcd for
C12H16BrO2 271.0328, found 271.0331.
1
17.28 mmol, 77% yield). H NMR (400 MHz, DMSO-d6) δ = 8.35
(d, J = 7.3 Hz, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.54 (d, J = 1.0 Hz, 1H),
7.03 (d, J = 6.8 Hz, 1H), 2.56−2.52 (m, 3H). 13C{1H} NMR (101
MHz, DMSO-d6) δ = 145.4, 133.7, 126.3, 125.6, 118.1, 116.3, 114.7,
17.1. HRMS (ESI) m/z: [M + H]+ calcd for C8H8N2Br 210.9871,
found 210.9876.
7-Bromo-3,8-dimethylimidazo[1,2-a]pyridine (10). To a solution
of 4-bromo-3-methylpyridin-2-amine (5 g, 26.7 mmol) in ethanol (50
mL) were added HBr (4.54 mL, 40.1 mmol, 48 wt %) and 2-bromo-
1,1-dimethoxypropane (14.68 g, 80 mmol) in one charge. The
mixture was stirred at 80 °C over 48 h. After cooling, the mixture was
treated with 0.5 M Na2CO3 solution (100 mL) and extracted with
DCM (100 × 2). The organic layers were combined, dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure to afford crude product mixture. The crude product was
diluted with DCM (30 mL) and combined in a slurry with 100−200
silica gel mesh (10 g). The sample was purified by column
chromatography (column size 5 × 25 cm, column volume: 200 mL,
silica gel size (100−200 mesh) quantity: 80 g) and eluted with
MeOH/DCM with a 3−5% gradient. The desired fractions were
combined and concentrated under reduced pressure to afford the
product that was additionally treated with n-hexane to afford the
desired product as a beige solid (3.063 g, 13.54 mmol, 50.7% yield).
1H NMR (400 MHz, DMSO-d6) δ = 8.06 (d, J = 7.3 Hz, 1H), 7.33
(d, J = 1.0 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H), 2.53 (s, 3H), 2.42 (d, J =
1.0 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 145.0, 131.6,
126.2, 123.1, 121.9, 117.2, 116.0, 17.0, 9.2. HRMS (ESI) m/z: [M +
H]+ calcd for C9H10N2Br 225.0027, found 225.0027.
2-(3-Bromo-2-methylphenyl)-2-methyl-1,3-dioxolane (8). To a
solution of 1-(3-bromo-2-methylphenyl)ethan-1-one (3.045 g, 14.29
mmol) in anhydrous toluene (23.82 mL) was added ethylene glycol
(4.78 mL, 86 mmol) followed by p-toluenesulfonic acid monohydrate
(0.544 g, 2.86 mmol). A Dean−Stark apparatus was attached along
with a condenser and the solution was heated (heating block) under
reflux for 16 h. At 16 h, TLC (10% EtOAc/heptane) still indicated the
presence of starting material. It was noted that a large amount of
ethylene glycol was collected in the Dean−Stark apparatus and so
additional fresh ethylene glycol (3.19 mL, 57.2 mmol) was added and
the mixture was refluxed over another 40 h. The reaction mixture was
then cooled to room temperature and quenched with saturated
NaHCO3 solution. The biphasic mixture was transferred to a
separatory funnel and the aqueous layer was drained. The organic
layer was then washed with saturated NaHCO3 solution three times
and once with brine, dried over MgSO4, filtered and concentrated to
afford the crude product mixture. The crude product mixture was
purified via chromatography on silica gel (0−15% EtOAc/heptanes,
80g RediSep Rf Gold column) to afford the desired product as a
5-Bromo-1,4-dimethyl-1H-indazole (11) and 5-Bromo-2,4-di-
methyl-2H-indazole (12). To a solution of 4-bromo-2,3-dimethylani-
line (10 g, 50.0 mmol) in chloroform (100 mL) were added acetic
anhydride (10.20 g, 100 mmol), potassium acetate (5.40 g, 55.0
mmol), and 18-crown-6 (2.64 g, 10.00 mmol), and then tert-butyl
nitrite (10.31 g, 100 mmol) was added in one charge. The reaction
mixture was stirred at 75 °C for 16 h. Next, the resulting solution was
washed with saturated sodium bicarbonate (2 × 50 mL), and the
combined organic layers were extracted with dichloromethane (2 ×
50 mL) and then concentrated under reduced pressure. To the
resulting residue were added methanol and hydrochloric acid. The
reaction mixture was stirred at 50 °C for 2 h and concentrated under
reduced pressure to afford the crude product which was carried on to
the next step without further purification. To a solution of the
intermediate 5-bromo-4-methyl-1H-indazole (13.6 g, 64.4 mmol) in
N,N-dimethylformamide (100 mL) stirred at 0 °C was added NaH
(5.15 g, 129 mmol) and MeI (4.83 mL, 77 mmol). The reaction
mixture was stirred at room temperature for 16 h. The reaction
mixture was quenched with water (50 mL). The resulting solution
was extracted with ethyl acetate (3 × 30 mL), and the organic layers
were combined, washed with brine (2 × 30 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure to afford crude product mixture. The crude product was
diluted with dichloromethane (50 mL), made into a slurry with 100−
200 silica gel mesh, and purified by column chromatography (column
size 5 × 25 cm, column volume: 200 mL, silica gel size (100−200
mesh) quantity: 80 g) eluted with ethyl acetate/petroleum ether. The
desired fractions were combined and concentrated under reduced
1
yellow oil (2.918 g, 10.78 mmol, 75% yield). H NMR (400 MHz,
DMSO-d6) δ = 7.56 (dd, J = 1.2, 8.1 Hz, 1H), 7.50 (dd, J = 1.5, 7.8
Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 4.05−3.93 (m, 2H), 3.71−3.60 (m,
2H), 2.50 (s, 3H), 1.59 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-
d6) δ = 143.7, 135.0, 132.6, 127.7, 127.5, 125.6, 108.8, 64.3, 26.9,
20.7. HRMS (ESI) m/z: [M + H]+ calcd for C11H14BrO2 257.0172,
found 257.0172.
7-Bromo-8-methylimidazo[1,2-a]pyridine (9). To a solution of 4-
bromo-3-methylpyridin-2-amine (4.2 g, 22.46 mmol) in ethanol (30
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Featured Article
pressure to afford 11 (5.509 g, 24.38 mmol, 37.8% yield) and 12
crude product mixture as a yellow oil. The crude product mixture was
purified via flash chromatography on silica gel (0−30% EtOAc/
heptane, 4 g of RediSep Rf Gold column) to afford 14a (61 mg, 0.39
mmol, 66.9% yield) and 14c (23 mg, 0.107 mmol, 18.27% yield) as
light yellow oils. Analytical data for 14a: 1H NMR (400 MHz,
DMSO-d6) δ = 7.64 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 7.1, 8.4 Hz,
1H), 7.18 (d, J = 6.7 Hz, 1H), 4.29 (s, 3H), 2.69 (s, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ = 145.5, 133.7, 129.8, 127.5, 123.9,
108.2, 34.6, 16.8. HRMS (ESI) m/z: [M + H]+ calcd for C8H10N3
(3.178 g, 13.70 mmol, 21.3% yield) as beige solids. Analytical data for
1
11: H NMR (400 MHz, DMSO-d6) δ = 8.14 (d, J = 1.0 Hz, 1H),
7.51−7.45 (m, 1H), 7.44−7.38 (m, 1H), 4.02 (s, 3H), 2.55 (s, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ = 138.9, 132.1, 130.3, 130.0,
125.7, 115.0, 109.6, 36.1, 19.1. HRMS (ESI) m/z: [M + H]+ calcd for
C9H10N2Br 225.0027, found 225.0033. Analytical data for 12: 1H
NMR (400 MHz, DMSO-d6) δ = 8.47 (s, 1H), 7.42−7.36 (m, 1H),
7.34−7.29 (m, 1H), 4.16 (s, 3H), 2.51 (s, 3H). 13C{1H} NMR (101
MHz, DMSO-d6) δ = 147.2, 129.9, 129.6, 125.0, 124.4, 116.8, 115.1,
40.6, 19.7. HRMS (ESI) m/z: [M + H]+ calcd for C9H10N2Br
225.0027, found 225.0031.
1
148.0875, found 148.0876. Analytical data for 14c: H NMR (400
MHz, DMSO-d6) δ = 7.66 (td, J = 0.8, 8.4 Hz, 1H), 7.42 (dd, J = 7.1,
8.4 Hz, 1H), 7.17 (td, J = 0.9, 7.0 Hz, 1H), 4.67 (t, J = 7.0 Hz, 2H),
2.68 (s, 3H), 1.95−1.83 (m, 2H), 1.36−1.13 (m, 4H), 0.82 (t, J = 7.2
Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 145.6, 133.2,
129.9, 127.5, 123.9, 108.2, 47.9, 29.4, 28.7, 22.0, 16.8, 14.2. HRMS
(ESI) m/z: [M + H]+ calcd for C12H18N3 204.1501, found 204.1502.
General Procedure 3 (In Situ formation of (n-Bu)3MgLi). To 2.5
M solution of n-butyllithium in hexanes (2.05 equiv) in anhydrous
toluene or THF (1.75 mL/mmol) at −10 °C (acetonitrile/dry ice)
was added 2.0 M solution of n-BuMgCl in THF (1.03 equiv), and the
resulting white suspension was stirred over 10 min at −10 °C. Next, a
solution of aryl bromide (2.0 equiv) in anhydrous tetrahydrofuran
(3.52 mL/mmol) was added dropwise. The reaction mixture was
stirred over 5 min at −10 °C. A solution of copper(I) bromide−
dimethyl sulfide complex (1.55 equiv) with DMS (10 equiv) in
anhydrous tetrahydrofuran (0.44 mL/mmol) was added dropwise.
The resulting solution was stirred at −10 °C over 15 min. Next, the
reaction mixture was cooled to −40 °C (acetonitrile/dry ice), and
then solid 5 was added under dry nitrogen protection. The resulting
mixture was stirred at −40 °C over 1 h. Next, the reaction mixture was
quenched with saturated NH4Cl solution and then warmed to room
temperature. The biphasic mixture was combined with extra water
and EtOAc. The layers of the filtrate were then separated, and then
the blue aqueous layer was extracted with EtOAc three times. The
combined organic portions were dried over MgSO4, filtered, and
concentrated to afford the crude product mixture. The crude product
mixture was purified via chromatography on silica gel to afford the
desired product.
General Procedure 4 (Using Commercial (n-Bu)3MgLi Solution).
To a commercially available 0.7 M solution of tri-n-butyllithium
magnesate in diethyl ether/hexanes (1.05 equiv) at −10 °C
(acetonitrile/dry ice) was added a solution of aryl bromide (2.0
equiv) in anhydrous tetrahydrofuran (3.55 mL/mmol of 23), and the
resulting white suspension was stirred over 5 min at −10 °C. Next, a
solution of copper(I) bromide−dimethyl sulfide complex (1.55 equiv)
with DMS (10 equiv) in anhydrous tetrahydrofuran (0.44 mL/mmol)
was added dropwise. The resulting suspension was stirred at −10 °C
over 15 min. Next, the reaction mixture was cooled to −40 °C
(acetonitrile/dry ice), and then solid 5 was added under dry nitrogen
protection. The resulting mixture was stirred at −40 °C over 1 h.
Next, the reaction mixture was quenched with saturated NH4Cl
solution and then warmed to room temperature. The biphasic mixture
was combined with extra water and EtOAc. The biphasic mixture was
extracted with EtOAc three times. The combined organic portions
were dried over MgSO4, filtered, and concentrated to afford the crude
product mixture. The crude product mixture was purified via
chromatography on silica gel to afford the desired product.
5-Bromo-1,4-dimethyl-1H-benzo[d]imidazole (13). A mixture of
4-bromo-N-1,3-dimethylbenzene-1,2-diamine (2.15 g, 10.00 mmol) in
HCl (16.6 mL, 546 mmol) and formic acid (10 mL) was stirred for 16
h at 65 °C. Next, the reaction mixture was cooled in an ice−water
bath, and the pH was slowly adjusted to 8−9 with 28% concentrated
NH4OH solution. The resulting mixture was then extracted with
EtOAc (3 × 100 mL), and the organic layers were combined, washed
with brine (2 × 100 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure to afford crude
product mixture. The crude product was purified by reverse phase
column chromatography (column: C18 spherical 20−35 um 100A
300 g; mobile phase A: water (0.05% TFA), mobile phase B: MeCN;
flow rate: 65 mL/min; gradient: 12% B to 15% B in 30 min; 254 nm;
tR 5 min) to afford the desired product a dark brown solid (2.761 g,
11.78 mmol, quantitative) as a beige solid. 1H NMR (400 MHz,
DMSO-d6) δ = 8.19 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 8.6
Hz, 1H), 3.83 (s, 3H), 2.58 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ = 145.4, 144.2, 133.7, 129.0, 126.0, 116.5, 109.8, 31.4,
17.0. HRMS (ESI) m/z: [M + H]+ calcd for C9H10N2Br 225.0027,
found 225.0029.
1,4-Dimethyl-1H-benzo[d][1,2,3]triazole (14a) and 1,4-Dimeth-
yl-1H-benzo[d][1,2,3]triazole-5-d (14b). In an oven-dried microwave
vial with a magnetic stirrer were placed magnesium metal turnings
(0.016 g, 0.652 mmol) and iodine (6.62 mg, 0.026 mmol). The vial
was capped under dry nitrogen gas, and the solids were heated at 79
°C (heating block) briefly to vaporize the iodine. Next, a solution of
D (0.118 g, 0.522 mmol) in anhydrous tetrahydrofuran-d8 (0.580
mL) was added slowly to the reaction vessel at 79 °C. The reaction
was stirred under refluxing conditions for 16 h. At 16 h, the reaction
mixture was allowed to cool to room temperature and was then
quenched with saturated NH4Cl solution. It was then combined with
additional water and EtOAc, and the layers separated. The water layer
was removed, and the organic layer was washed two additional times
with water, once with 10% aq sodium thiosulfate solution, and once
with brine. It was subsequently dried over MgSO4, filtered, and
concentrated to afford the crude product mixture as a dark amber oil.
The crude product mixture was purified via chromatography con silica
gel (15% EtOAc/heptane, isocratic, 12 g RediSep Rf Gold column) to
afford a mixture of 14b (38 mg, 0.159 mmol, 30.5% yield) containing
14a (38% by weight by NMR) as a light yellow oil. Analytical data for
the isotopic mixture of 14a and 14b: 1H NMR (400 MHz, DMSO-d6)
δ = 7.67−7.59 (m, 1H), 7.47−7.39 (m, 1H), 7.21−7.14 (m, 1H), 4.28
(s, 3H), 2.68 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ =
145.5, 133.7, 129.7, 127.5, 127.4, 127.4, 123.9, 123.6 (t, J = 24.5 Hz,
1C), 108.2, 34.6, 16.8, 16.7. HRMS (ESI) m/z: [M + H]+ calcd for
C8H9N3D 149.0937, found 149.0934.
(S)-3-((S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-
(((R)-2-ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)-
methyl)-4-methylphenyl)propanoyl)-4-phenyloxazolidin-2-one
(15) and (S)-3-((S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f][1,4]-
oxazepin-4(5H)-yl)methyl)-4-methylphenyl)heptanoyl)-4-phenyl-
oxazolidin-2-one (16). Prepared according to general procedure 3
with 5 (1.00 g, 1.65 mmol) and the magnesiate complex formed in
toluene to afford 15 (611 mg, 0.862 mmol, 42.9% yield) as a light
yellow solid and 16 (409 mg, 0.736 mmol, 36.6% yield, 90:10 dr by
NMR) as a yellow amorphous glass. Analytical data for 15: 1H NMR
(400 MHz, DMSO-d6) δ = 8.20 (br d, J = 2.3 Hz, 1H), 7.56 (d, J =
8.9 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.39 (dd, J = 1.1, 8.0 Hz, 1H),
7.27 (dd, J = 4.7, 8.0 Hz, 1H), 7.20−7.13 (m, 1H), 7.13−7.01 (m,
1,4-Dimethyl-1H-benzo[d][1,2,3]triazole (14a) and 4-Methyl-1-
pentyl-1H-benzo[d][1,2,3]triazole (14c) (Scheme 7). In an oven-
dried microwave vial with a magnetic stirrer and an internal
temperature probe was prepared a solution of D (0.133 g, 0.588
mmol) in anhydrous tetrahydrofuran (1.961 mL). This solution was
cooled to −78 °C, and then 2.5 M solution of n-butyllithium in
hexane (0.235 mL, 0.588 mmol) was added dropwise so that the
temperature never increased above −70 °C. The resulting solution
was stirred at −78 °C over 5 min. The reaction mixture was quenched
with saturated NH4Cl solution. Water and EtOAc were added and the
layers separated. The aqueous layer was extracted with EtOAc three
times, dried over MgSO4, filtered, and concentrated to afford the
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5H), 7.00−6.92 (m, 2H), 5.38 (dd, J = 3.7, 8.5 Hz, 1H), 4.84 (t, J =
7.7 Hz, 1H), 4.66 (t, J = 8.6 Hz, 1H), 4.25 (s, 3H), 4.12−3.99 (m,
2H), 3.94 (d, J = 14.2 Hz, 1H), 3.85 (d, J = 14.4 Hz, 1H), 3.82−3.74
(m, 1H), 3.57−3.46 (m, 3H), 2.86 (d, J = 12.4 Hz, 1H), 2.77 (dd, J =
9.4, 13.7 Hz, 1H), 2.60 (s, 3H), 2.20 (s, 3H), 1.57−1.40 (m, 1H),
1.37−1.22 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101
MHz, DMSO-d6) δ = 170.2, 153.7, 152.5, 145.8, 143.1, 140.4, 139.3,
136.4, 136.3, 134.9, 131.6, 130.2, 128.7, 128.4, 127.8, 127.6, 126.4,
126.2, 125.2, 123.4, 107.4, 80.9, 70.0, 61.2, 59.8, 56.8, 56.3, 40.7, 40.3,
34.0, 26.2, 18.2, 12.7, 10.0. HRMS (ESI) m/z: [M + H]+ calcd for
1H), 4.59 (t, J = 7.7 Hz, 1H), 4.07 (dd, J = 3.8, 8.6 Hz, 1H), 3.98−
3.81 (m, 3H), 3.81−3.72 (m, 1H), 3.55−3.44 (m, 2H), 3.39 (dd, J =
7.2, 17.1 Hz, 1H), 2.85 (d, J = 13.2 Hz, 1H), 2.77 (dd, J = 9.1, 13.7
Hz, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 1.59−1.44 (m, 1H), 1.42−1.28
(m, 1H), 0.98 (t, J = 7.4 Hz, 3H). LC/MS (ESI) m/z: [M + H]+
calcd for C37H40N3O4 590.3, found 590.6. Hydrolysis was carried out
according to general procedure 2 (0.168 g, 0.248 mmol, 87 wt %) to
afford the desired product a white amorphous solid (81 mg, 0.173
mmol, 69.8% yield).
(S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-(4-hydroxy-2-methylphenyl)-
propanoic Acid (6k). Prepared according to general procedure 4 with
5 (550 mg, 0.908 mmol) and 8 (0.559 g, 2.211 mmol) to afford the
conjugate addition product as a white solid (307 mg, 0.423 mmol,
20
C38H41N6O4 645.3189, found 645.3187. [α]D −27 (c 0.50, DCM).
1
mp 107 °C. Analytical data for the mixture of diastereomers 16: H
NMR (400 MHz, DMSO-d6) δ = 8.20−8.11 (m, 1H), 7.42−7.18 (m,
7H), 7.06−6.90 (m, 3H), 5.43−5.30 (m, 1H), 4.74−4.55 (m, 1H),
4.14−4.04 (m, 1H), 4.00−3.92 (m, 1H), 3.91−3.79 (m, 2H), 3.57−
3.47 (m, 2H), 3.27−3.17 (m, 1H), 3.17−3.07 (m, 1H), 3.03−2.86
(m, 2H), 2.84−2.73 (m, 1H), 2.26−2.16 (m, 3H), 1.64−1.35 (m,
4H), 1.26−0.88 (m, 7H), 0.80−0.70 (m, 3H). 13C{1H} NMR (101
MHz, DMSO-d6) δ = 171.3, 171.2, 155.0, 154.9, 154.2, 153.1, 143.6,
141.6, 140.3, 140.1, 136.7, 136.6, 135.3, 135.2, 130.5, 129.3, 129.2,
129.0, 128.3, 128.3, 126.8, 126.1, 125.9, 123.8, 81.5, 70.5, 61.6, 60.6,
57.4, 57.1, 55.4, 42.3, 40.9, 36.1, 29.5, 26.8, 22.5, 18.8, 14.3, 10.6.
HRMS (ESI) m/z: [M + H]+ calcd for C34H42N3O4 556.3175, found
1
38.2% yield, 95 wt %). H NMR (400 MHz, DMSO-d6) δ = 8.23−
8.17 (m, 1H), 7.42−7.37 (m, 1H), 7.29−7.17 (m, 5H), 7.14−7.05
(m, 2H), 7.01 (d, J = 8.3 Hz, 2H), 6.99−6.92 (m, 1H), 6.84−6.77 (m,
1H), 6.72 (dd, J = 2.7, 6.1 Hz, 1H), 5.44−5.32 (m, 2H), 4.65 (t, J =
8.8 Hz, 1H), 4.52 (t, J = 7.6 Hz, 1H), 4.11−4.04 (m, 1H), 3.98−3.69
(m, 5H), 3.62−3.43 (m, 3H), 3.39−3.33 (m, 1H), 2.92−2.83 (m,
1H), 2.83−2.73 (m, 1H), 2.18 (s, 3H), 2.12 (d, J = 1.5 Hz, 3H),
1.92−1.44 (m, 7H), 1.44−1.29 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H).
LC/MS (ESI) m/z: [M + H]+ calcd for C42H48N3O6 690.4, found
690.5. Hydrolysis was carried out according to a modified general
procedure 2: To a solution of (4S)-3-((3S)-3-(3-(((R)-2-ethyl-2,3-
dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphen-
yl)-3-(2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-
propanoyl)-4-phenyloxazolidin-2-one (0.307 g, 0.423 mmol) in
tetrahydrofuran (6.34 mL) and water (2.114 mL) at 0 °C (water/
ice) was added 30% H2O2 aqueous solution (0.216 mL, 2.114 mmol)
followed by 2 M LiOH aqueous solution (0.507 mL, 1.015 mmol),
and the resulting mixture was stirred over 15 min at 0 °C. Next, the
reaction mixture was quenched with 10% sodium metabisulfite
solution and combined with additional water to produce a cloudy
solution. To this mixture was added 6 M HCl until pH level of about
2 was reached; at that point the solution became transparent. This
mixture was stirred over 20 min. Next, the pH of the reaction mixture
was adjusted to 5 using 5 M NaOH solution. The resulting suspension
was extracted with DCM three times. The combined organic extracts
were dried over MgSO4, filtered, and concentrated to afford the crude
product mixture as a yellow oil. The crude product mixture was
purified via MDAP to afford the desired product as a white
amorphous solid (109 mg, 0.225 mmol, 53.2% yield). 1H NMR
(400 MHz, DMSO-d6) δ = 11.39 (br s, 1H), 9.09 (br s, 1H), 8.19
(dd, J = 1.5, 4.4 Hz, 1H), 7.39 (dd, J = 1.5, 7.8 Hz, 1H), 7.26 (dd, J =
4.6, 8.1 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 7.03−6.94 (m, 3H), 6.55−
6.46 (m, 2H), 4.41 (t, J = 7.8 Hz, 1H), 3.93 (d, J = 14.2 Hz, 1H), 3.84
(d, J = 14.2 Hz, 1H), 3.82−3.75 (m, 1H), 3.49 (s, 2H), 2.93−2.71
(m, 4H), 2.18 (s, 3H), 2.14 (s, 3H), 1.60−1.45 (m, 1H), 1.44−1.30
(m, 1H), 0.98 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-
d6) δ = 173.4, 155.7, 155.0, 153.1, 143.6, 141.8, 137.1, 136.7, 135.0,
132.8, 130.4, 129.5, 128.3, 127.5, 126.8, 123.9, 117.5, 113.0, 81.5,
61.6, 60.4, 57.0, 42.0, 41.6, 26.8, 20.0, 18.7, 10.6. HRMS (ESI) m/z:
20
556.3181. [α]D +72 (c 1.0, DCM).
(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-
ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)methyl)-4-
methylphenyl)propanoic Acid (419). Hydrolysis was carried out
according to general procedure 2 with 15 (0.115 g, 0.178 mmol) to
afford the desired product as a white solid (36 mg, 0.068 mmol, 38.4%
1
yield, 98:2 dr). H NMR (400 MHz, DMSO-d6) δ = 8.17 (d, J = 3.9
Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.41−
7.35 (m, 1H), 7.25 (dd, J = 4.6, 8.1 Hz, 1H), 7.09 (br d, J = 4.9 Hz,
2H), 7.06−7.01 (m, 1H), 4.77 (br t, J = 7.6 Hz, 1H), 4.22 (s, 3H),
3.91 (d, J = 14.2 Hz, 1H), 3.86−3.75 (m, 1H), 3.83 (d, J = 14.7 Hz,
1H), 3.50 (s, 2H), 3.00 (br d, J = 7.8 Hz, 2H), 2.85 (d, J = 13.2 Hz,
1H), 2.76 (dd, J = 9.3, 13.7 Hz, 1H), 2.71 (s, 3H), 2.18 (s, 3H),
1.56−1.42 (m, 1H), 1.38−1.22 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ = 173.3, 155.0, 152.9, 146.4,
143.6, 141.2, 137.3, 136.9, 135.4, 132.1, 130.6, 129.3, 128.3, 126.9,
126.8, 126.6, 123.8, 107.9, 81.4, 61.7, 60.3, 57.0, 41.7, 40.9, 34.5, 26.7,
18.7, 13.3, 10.5. HRMS (ESI) m/z: [M + H]+ calcd for C29H34N5O3
20
500.2662, found 500.2663. [α]D −60 (c 0.20, MeOH).
(R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-phenylpropanoic Acid (6a)
(Table 4). Prepared according to general procedure 3 with 5 (250
mg, 0.413 mmol) and the magnesiate complex formed in toluene to
the conjugate addition product a white solid (188 mg, 0.310 mmol,
61.7% yield); 96:4 dr by chiral HPLC (CHIRALPAK IA column, 95/
1
05 ethanol/heptane + 0.1% isopropylamine, 20 min run). H NMR
(400 MHz, DMSO-d6) δ = 8.20 (dd, J = 1.5, 4.6 Hz, 1H), 7.39 (dd, J
= 1.5, 8.1 Hz, 1H), 7.32−7.19 (m, 8H), 7.19−6.99 (m, 6H), 5.37 (dd,
J = 3.7, 8.5 Hz, 1H), 4.63 (t, J = 8.6 Hz, 1H), 4.43 (t, J = 7.7 Hz, 1H),
4.07 (dd, J = 3.7, 8.7 Hz, 1H), 3.96 (d, J = 14.2 Hz, 1H), 3.90−3.75
(m, 3H), 3.61−3.45 (m, 3H), 2.88 (d, J = 13.4 Hz, 1H), 2.79 (dd, J =
9.4, 13.7 Hz, 1H), 2.19 (s, 3H), 1.61−1.45 (m, 1H), 1.44−1.30 (m,
1H), 0.98 (t, J = 7.4 Hz, 3H). LC/MS (ESI) m/z: [M + H]+ calcd for
C36H38N3O4 576.3, found 576.5. Hydrolysis was carried out according
to general procedure 2 (0.264 g, 0.408 mmol, 89 wt %) to afford the
desired product a white amorphous solid (115 mg, 0.254 mmol,
62.2% yield).
(S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-(o-tolyl)propanoic Acid (6b)
(Table 4). Prepared according to general procedure 3 with 5 (250
mg, 0.413 mmol) and the magnesiate complex formed in toluene to
the conjugate addition product as a white solid (180 mg, 0.290 mmol,
57.7% yield); >99:1 dr by chiral HPLC (CHIRALPAK IA column,
15/85 ethanol/heptane +0.1% isopropylamine, 15 min run). 1H NMR
(400 MHz, DMSO-d6) δ = 8.20 (dd, J = 1.4, 4.7 Hz, 1H), 7.39 (dd, J
= 1.4, 8.0 Hz, 1H), 7.35−7.21 (m, 5H), 7.19−6.99 (m, 7H), 6.97 (dd,
J = 2.0, 7.9 Hz, 1H), 5.38 (dd, J = 3.7, 8.5 Hz, 1H), 4.65 (t, J = 8.7 Hz,
20
[M + H]+ calcd for C28H33N2O4 461.2440, found 461.2441. [α]D
+32 (c 1.0, MeOH).
(S)-3-(3-Acetyl-2-methylphenyl)-3-(3-(((R)-2-ethyl-2,3-
dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)methyl)-4-
methylphenyl)propanoic Acid (6l). Prepared according to a modified
general procedure 4: To 0.7 M solution of tri-n-butyllithium
magnesate in diethyl ether/hexanes (1.809 mL, 1.266 mmol) at
−10 °C (acetonitrile/dry ice) was added a solution of 9 (0.620 g,
2.412 mmol) in anhydrous tetrahydrofuran (4.29 mL), and the
resulting white suspension was stirred over 5 min at −10 °C; however,
the reaction did not reach completion at that time. Additional 0.7 M
solution of tri-n-butyllithium magnesate in diethyl ether/hexanes
(0.568 mL, 0.398 mmol) was added, the reaction mixture was stirred
over another 5 min at −10 °C, and the reaction reached completion.
Next, a solution of copper(I) bromide−dimethyl sulfide complex
(0.384 g, 1.869 mmol) with DMS (0.892 mL, 12.06 mmol) in
anhydrous tetrahydrofuran (0.54 mL) was added dropwise. The
3133
https://dx.doi.org/10.1021/acs.joc.0c02639
J. Org. Chem. 2021, 86, 3120−3137

The Journal of Organic Chemistry
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resulting suspension was stirred at −10 °C over 15 min. Next, the
reaction mixture was cooled to −40 °C (acetonitrile/dry ice) and
then solid 5 (0.600 g, 1.206 mmol) were added under dry nitrogen
protection. The resulting mixture was stirred at −40 °C over 1 h.
Next, the reaction mixture was quenched with saturated NH4Cl
solution and then warmed to room temperature. The biphasic mixture
was combined with extra water and EtOAc. The layers of the filtrate
were then separated, and then the blue aqueous layer was extracted
with EtOAc three times. The combined organic portions were dried
over MgSO4, filtered, and concentrated to afford the crude product
mixture as a yellow oil. The crude product mixture was purified via
chromatography on silica gel (35−65% EtOAc/heptane, 24 g RediSep
Rf Gold column) to afford the conjugate addition product as an off-
white solid (302 mg, 0.357 mmol, 29.6% yield, 80 wt %) containing
unreacted 5 and residual DCM (15 and 5% by weight by NMR,
respectively) and was advanced to the next step without further
13.2 Hz, 1H), 2.77 (dd, J = 9.3, 13.7 Hz, 1H), 2.19 (s, 3H), 2.06 (s,
3H), 1.57−1.45 (m, 1H), 1.40−1.27 (m, 1H), 0.96 (t, J = 7.3 Hz,
3H). LC/MS (ESI) m/z: [M + H]+ calcd for C38H41FN3O5 638.3,
found 638.4. Hydrolysis was carried out according to general
procedure 2 (0.351 g, 0.501 mmol, 91 wt %) to afford the desired
product a white amorphous solid (153 mg, 0.295 mmol, 58.9% yield);
1H NMR (400 MHz, DMSO-d6) δ = 11.22 (br s, 1H), 8.18 (dd, J =
1.5, 4.9 Hz, 1H), 7.38 (dd, J = 1.2, 8.1 Hz, 1H), 7.25 (dd, J = 4.6, 8.1
Hz, 1H), 7.12−7.01 (m, 4H), 6.94 (d, J = 12.7 Hz, 1H), 4.46 (t, J =
7.8 Hz, 1H), 3.90 (d, J = 14.2 Hz, 1H), 3.83 (d, J = 14.2 Hz, 1H),
3.80−3.73 (m, 1H), 3.72 (s, 3H), 3.56−3.47 (m, 2H), 3.01 (dd, J =
8.3, 15.6 Hz, 1H), 2.86 (d, J = 12.7 Hz, 1H), 2.90 (dd, J = 7.3, 15.6
Hz, 1H), 2.77 (dd, J = 9.3, 13.7 Hz, 1H), 2.19 (s, 3H), 2.15 (s, 3H),
1.60−1.43 (m, 1H), 1.43−1.26 (m, 1H), 0.96 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ = 173.3, 155.0, 153.1, 145.0
(d, J = 242.1 Hz, 1C), 145.2 (d, J = 10.3 Hz, 1C), 143.6, 140.7, 138.7
(d, J = 3.7 Hz, 1C), 136.9, 135.3, 130.5, 129.3, 128.9 (d, J = 5.9 Hz,
1C), 128.3, 126.9, 123.9, 117.8 (d, J = 17.6 Hz, 1C), 112.9, 81.8, 61.9,
60.5, 57.2, 56.5, 42.6, 41.1, 26.8, 18.8, 18.7, 10.5. HRMS (ESI) m/z:
1
purification. H NMR (400 MHz, DMSO-d6) δ = 8.20 (br s, 1H),
7.42−7.36 (m, 1H), 7.36−7.31 (m, 1H), 7.31−7.23 (m, 5H), 7.18−
7.08 (m, 3H), 7.08−6.90 (m, 3H), 5.38 (dd, J = 3.7, 8.6 Hz, 1H),
4.74−4.59 (m, 2H), 4.07 (dd, J = 3.7, 8.6 Hz, 1H), 3.99−3.73 (m,
6H), 3.62−3.37 (m, 5H), 2.89−2.81 (m, 1H), 2.81−2.71 (m, 1H),
2.33 (s, 3H), 2.18 (s, 3H), 1.66−1.50 (m, 1H), 1.49 (s, 3H), 1.40−
1.26 (m, 1H), 0.97 (br t, J = 7.3 Hz, 3H). LC/MS (ESI) m/z: [M +
H]+ calcd for C41H46N3O6 676.3, found 676.5. Hydrolysis was carried
out according to a modified general procedure 2: To a solution of (S)-
3-((S)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-(2-methyl-3-(2-methyl-1,3-di-
oxolan-2-yl)phenyl)propanoyl)-4-phenyloxazolidin-2-one (0.302 g,
0.357 mmol) in tetrahydrofuran (10.72 mL) and water (3.57 mL)
at 0 °C (water/ice) was added 30% H2O2 aqueous solution (0.183
mL, 1.787 mmol) followed by 2 M LiOH aqueous solution (0.536
mL, 1.072 mmol) and the resulting mixture was stirred over 15 min at
0 °C. Next, the reaction mixture was quenched with 10% sodium
metabisulfite solution. To hydrolyze the ketal protecting group, 6 M
HCl solution was added until the solution turned transparent and the
pH was about 1. This solution was stirred at room temperature over 4
h. Next, the mixture was basified with 2 M LiOH solution until pH of
5 was reached. The mixture was then extracted with EtOAc three
times. The combined organic extracts were dried over MgSO4,
filtered, and concentrated to afford the crude product mixture as a
yellow oil. The crude product mixture was purified via preparative
HPLC to afford a light blue solid. This light blue solid was further
purified via chromatography on silica gel (0−80% 3:1 EtOAc:EtOH/
Heptane, 12 g RediSep Rf Gold column) to afford desired product as
a white amorphous solid (96 mg, 0.187 mmol, 52.4% yield). 1H NMR
(400 MHz, DMSO-d6) δ = 12.15 (br s, 1H), 8.20 (dd, J = 1.2, 4.6 Hz,
1H), 7.52−7.42 (m, 2H), 7.39 (dd, J = 1.2, 8.1 Hz, 1H), 7.31−7.19
(m, 2H), 7.10−6.99 (m, 3H), 4.63 (t, J = 7.8 Hz, 1H), 3.92 (d, J =
14.2 Hz, 1H), 3.87−3.73 (m, 1H), 3.83 (d, J = 14.2 Hz, 1H), 3.55−
3.45 (m, 2H), 3.00 (dd, J = 8.3, 16.1 Hz, 1H), 2.91 (dd, J = 7.3, 16.1
Hz, 1H), 2.88−2.83 (m, 1H), 2.79 (dd, J = 9.3, 13.7 Hz, 1H), 2.48 (s,
3H), 2.26 (s, 3H), 2.19 (s, 3H), 1.61−1.44 (m, 1H), 1.44−1.28 (m,
1H), 0.97 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ = 204.3, 173.1, 155.0, 153.1, 143.8, 143.6, 141.3, 140.6, 136.9,
135.5, 133.8, 130.6, 129.5, 129.2, 128.3, 126.9, 126.1, 125.9, 123.9,
81.5, 61.8, 60.4, 56.9, 42.4, 41.2, 31.1, 26.8, 18.7, 16.1, 10.6. HRMS
(ESI) m/z: [M + H]+ calcd for C30H35N2O4 487.2597, found
20
[M + H]+ calcd for C29H34FN2O4 493.2503, found 493.2505. [α]D
+84 (c 1.0, MeOH).
(S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-(2-methyl-4-(trifluoromethyl)-
phenyl)propanoic Acid (6n). Prepared according to general
procedure 3 with 5 (650 mg, 1.073 mmol) and the magnesiate
complex formed in THF to afford the conjugate addition product as a
dark yellow solid (394 mg, 0.569 mmol, 43.6% yield, 95 wt %)
containing unreacted 5 and DCM (4 and 1% by weight by NMR,
respectively). 1H NMR (400 MHz, DMSO-d6) δ = 8.20 (br d, J = 4.4
Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.43−
7.35 (m, 2H), 7.31−7.19 (m, 4H), 7.16−7.09 (m, 2H), 7.08−6.97
(m, 3H), 5.38 (dd, J = 3.9, 8.3 Hz, 1H), 4.67 (t, J = 8.8 Hz, 1H),
4.73−4.60 (m, 1H), 4.08 (dd, J = 3.9, 8.3 Hz, 1H), 3.98 (dd, J = 8.8,
17.1 Hz, 1H), 3.94 (d, J = 14.2 Hz, 1H), 3.83 (d, J = 14.2 Hz, 1H),
3.80−3.72 (m, 1H), 3.55−3.47 (m, 2H), 3.41 (dd, J = 6.6, 17.4 Hz,
1H), 2.83 (d, J = 12.2 Hz, 1H), 2.76 (dd, J = 8.8, 13.7 Hz, 1H), 2.25
(s, 3H), 2.20 (s, 3H), 1.58−1.43 (m, 1H), 1.39−1.25 (m, 1H), 0.95
(t, J = 7.3 Hz, 3H). LC/MS (ESI) m/z: [M + H]+ calcd for
C38H39F3N3O4 658.3, found 658.2. Hydrolysis was carried out
according to general procedure 2 (0.394 g, 0.599 mmol) to afford
the desired product a white amorphous solid (124 mg, 0.230 mmol,
1
38.4% yield). H NMR (400 MHz, DMSO-d6) δ = 12.32 (br s, 1H),
8.20 (dd, J = 1.5, 4.4 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.50−7.43
(m, 2H), 7.39 (dd, J = 1.5, 7.8 Hz, 1H), 7.26 (dd, J = 4.6, 8.1 Hz,
1H), 7.06 (s, 3H), 4.60 (t, J = 7.8 Hz, 1H), 3.93 (d, J = 14.2 Hz, 1H),
3.83 (d, J = 14.2 Hz, 1H), 3.80−3.74 (m, 1H), 3.50 (s, 2H), 3.05 (dd,
J = 8.3, 16.1 Hz, 1H), 2.94 (dd, J = 7.3, 15.6 Hz, 1H), 2.84 (d, J =
12.7 Hz, 1H), 2.77 (dd, J = 8.8, 13.7 Hz, 1H), 2.35 (s, 3H), 2.20 (s,
3H), 1.59−1.43 (m, 1H), 1.41−1.26 (m, 1H), 0.96 (t, J = 7.3 Hz,
3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 173.0, 155.0, 153.0,
147.3, 143.6, 139.9, 137.7, 137.0, 135.7, 130.7, 129.5, 128.3, 127.5,
127.1 (q, J = 2.9 Hz, 1C), 127.1 (q, J = 31.5 Hz, 1C), 126.9, 123.9,
124.8 (q, J = 271.4 Hz, 1C), 123.0 (q, J = 4.4 Hz, 1C), 81.4, 61.6,
60.4, 56.8, 42.5, 40.7, 26.7, 19.8, 18.7, 10.5. HRMS (ESI) m/z: [M +
20
H]+ calcd for C29H32F3N2O3 513.2365, found 513.2365. [α]D +28
(c 1.0, MeOH).
(S)-3-(4-Chloro-2,6-dimethylphenyl)-3-(3-(((R)-2-ethyl-2,3-
dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)methyl)-4-
methylphenyl)propanoic Acid (6o). Prepared according to general
procedure 4 with 5 (550 mg, 0.908 mmol) to afford to afford the
conjugate addition product as an off-white solid (332 mg, 0.364
mmol, 32.9% yield, 70 wt %) containing unreacted 5, 16, and residual
DCM (13, 15, and 2% by weight by NMR, respectively); advanced to
the next step without further purification. LC/MS (ESI) m/z: [M +
H]+ calcd for C38H41ClN3O4 638.3, found 638.4. Hydrolysis was
carried out according to general procedure 2 (0.332 g, 0.364 mmol, 70
wt %) to afford the desired product a white amorphous solid (118 mg,
0.227 mmol, 62.4% yield). 1H NMR (400 MHz, DMSO-d6) δ = 12.19
(br s, 1H), 8.13 (dd, J = 1.5, 4.9 Hz, 1H), 7.37 (dd, J = 1.5, 7.8 Hz,
1H), 7.23 (dd, J = 4.9, 7.8 Hz, 1H), 7.16−6.92 (m, 3H), 6.91−6.81
20
487.2594. [α]D −28 (c 1.0, MeOH).
(S)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f ][1,4]oxazepin-
4(5H)-yl)methyl)-4-methylphenyl)-3-(4-fluoro-5-methoxy-2-
methylphenyl)propanoic acid (6m). Prepared according to general
procedure 4 with 5 (600 mg, 0.991 mmol) to afford the conjugate
addition product as an off-white solid (351 mg, 0.501 mmol, 41.5%
yield, 91 wt %) containing unreacted 5 (7% by weight by NMR). 1H
NMR (400 MHz, DMSO-d6) δ = 8.18 (dd, J = 1.2, 4.6 Hz, 1H), 7.39
(dd, J = 1.2, 8.1 Hz, 1H), 7.29−7.20 (m, 4H), 7.10−7.00 (m, 6H),
6.91 (d, J = 12.7 Hz, 1H), 5.40 (dd, J = 3.7, 8.6 Hz, 1H), 4.68 (t, J =
8.3 Hz, 1H), 4.52 (dd, J = 6.4, 9.3 Hz, 1H), 4.12−3.99 (m, 2H), 3.92
(d, J = 14.2 Hz, 1H), 3.83 (d, J = 14.2 Hz, 1H), 3.79−3.73 (m, 1H),
3.72 (s, 3H), 3.51 (s, 2H), 3.32 (dd, J = 6.4, 16.6 Hz, 1H), 2.85 (d, J =
3134
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(m, 2H), 4.90 (t, J = 7.6 Hz, 1H), 3.90 (d, J = 14.7 Hz, 1H), 3.87−
3.78 (m, 2H), 3.57−3.46 (m, 2H), 3.23 (dd, J = 7.8, 15.7 Hz, 1H),
2.87 (d, J = 12.7 Hz, 1H), 2.82−2.70 (m, 2H), 2.24−2.19 (m, 6H),
2.21 (s, 3H), 1.61−1.48 (m, 1H), 1.46−1.33 (m, 1H), 0.98 (t, J = 7.3
Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 173.9, 154.8,
152.6, 143.5, 140.1, 139.6, 139.6, 136.8, 135.1, 130.8, 130.6, 128.2,
125.6, 123.7, 81.6, 61.5, 60.5, 57.4, 37.0, 26.7, 21.0, 18.7, 10.6. HRMS
(ESI) m/z: [M + H]+ calcd for C29H34N2O3Cl 493.2258, found
41.8, 41.0, 26.7, 19.0, 12.9, 10.5, 9.1. HRMS (ESI) m/z: [M + H]+
calcd for C30H35N4O3 499.2704, found 499.2700.
(S)-3-(1,4-Dimethyl-1H-indazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-
dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)methyl)-4-
methylphenyl)propanoic Acid (6r). Prepared according to general
procedure 3 with 5 (500 mg, 0.825 mmol) and the magnesiate
complex formed in THF to afford the conjugate addition product as
an off-white solid (352 mg, 0.514 mmol, 51.1% yield, 94 wt %)
containing residual EtOAc (6% by weight, by NMR); 1H NMR (400
MHz, DMSO-d6) δ = 8.19 (br d, J = 3.9 Hz, 1H), 8.01 (s, 1H), 7.42−
7.29 (m, 3H), 7.29−7.11 (m, 2H), 7.11−6.97 (m, 5H), 6.96−6.88
(m, 2H), 5.37 (dd, J = 3.7, 8.6 Hz, 1H), 4.78 (t, J = 7.6 Hz, 1H), 4.64
(t, J = 8.6 Hz, 1H), 4.09−3.96 (m, 5H), 3.93 (d, J = 14.7 Hz, 1H),
3.84 (d, J = 14.2 Hz, 1H), 3.82−3.73 (m, 1H), 3.54−3.40 (m, 3H),
2.86 (d, J = 12.7 Hz, 1H), 2.77 (dd, J = 9.3, 13.7 Hz, 1H), 2.42 (s,
3H), 2.19 (s, 3H), 1.57−1.41 (m, 1H), 1.38−1.23 (m, 1H), 0.93 (t, J
= 7.3 Hz, 3H). LC/MS (ESI) m/z: [M + H]+ calcd for C39H42N5O4
644.3, found 644.3. Hydrolysis was carried out according to general
procedure 2 (0.502 g, 0.733 mmol, 94 wt %) to afford the desired
product as a white amorphous solid (165 mg, 0.314 mmol, 42.9%
20
493.2262. [α]D −107 (c 1.0, MeOH).
(S)-3-(3,4-Difluoro-2-methylphenyl)-3-(3-(((R)-2-ethyl-2,3-
dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)methyl)-4-
methylphenyl)propanoic Acid (6p). Prepared according to general
procedure 3 with 5 (535 mg, 0.883 mmol) and the magnesiate
complex formed in THF to afford the conjugate addition product as
an off-white solid (288 mg, 0.276 mmol, 24.0% yield, 56 wt %)
containing unreacted 5 (37% by weight by NMR); advanced to the
1
next step without further purification. H NMR (400 MHz, DMSO-
d6) δ = 8.22−8.18 (m, 1H), 7.43−7.22 (m, 6H), 7.22−6.98 (m, 6H),
5.39 (dd, J = 3.9, 8.8 Hz, 1H), 4.68 (t, J = 8.8 Hz, 1H), 4.57 (dd, J =
6.8, 8.8 Hz, 1H), 4.09 (dd, J = 3.9, 8.8 Hz, 1H), 3.99−3.80 (m, 3H),
3.80−3.73 (m, 1H), 3.50 (s, 2H), 3.37 (dd, J = 6.4, 17.1 Hz, 1H),
2.85 (br d, J = 12.2 Hz, 1H), 2.78 (dd, J = 8.8, 13.7 Hz, 1H), 2.21 (s,
3H), 2.09 (d, J = 2.4 Hz, 3H), 1.68−1.42 (m, 1H), 1.38−1.26 (m,
1H), 0.97 (t, J = 7.3 Hz, 3H). LC/MS (ESI) m/z: [M + H]+ calcd for
C37H38F2N3O4 626.3, found 626.4. Hydrolysis was carried out
according to general procedure 2 (0.288 g, 0.276 mmol, 60 wt %)
to afford the desired product a white amorphous solid (82 mg, 0.162
mmol, 58.7% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.19 (dd, J
= 1.5, 4.4 Hz, 1H), 7.38 (dd, J = 1.5, 7.8 Hz, 1H), 7.26 (dd, J = 4.6,
8.1 Hz, 1H), 7.22−7.11 (m, 2H), 7.08−7.02 (m, 2H), 7.00 (s, 1H),
4.51 (t, J = 7.8 Hz, 1H), 3.92 (d, J = 14.2 Hz, 1H), 3.86−3.73 (m,
1H), 3.82 (d, J = 14.7 Hz, 1H), 3.50 (s, 2H), 2.96 (dd, J = 8.3, 16.1
Hz, 1H), 2.92−2.81 (m, 2H), 2.77 (dd, J = 8.8, 13.7 Hz, 1H), 2.20 (s,
3H), 2.18 (d, J = 2.4 Hz, 3H), 1.61−1.44 (m, 1H), 1.42−1.26 (m,
1H), 0.96 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ = 173.0, 155.0, 153.0, 150.5−146.6 (m, 1C), 148.6 (dd, J = 18.0,
250.2 Hz, 1C), 143.6, 140.3, 140.2−140.1 (m, 1C), 137.0, 135.7,
130.7, 129.4, 128.3, 126.8, 125.7 (d, J = 11.7 Hz, 1C), 123.9, 123.0−
122.4 (m, 1C), 114.2 (d, J = 16.1 Hz, 1C), 81.4, 61.7, 60.4, 56.8, 42.2,
40.9, 26.7, 18.7, 11.1−10.8 (m, 1C), 10.5. HRMS (ESI) m/z: [M +
1
yield). H NMR (400 MHz, DMSO-d6) δ = 11.75 (br s, 1H), 8.18
(dd, J = 1.5, 4.4 Hz, 1H), 8.04 (s, 1H), 7.38 (dd, J = 1.5, 7.8 Hz, 1H),
7.36−7.29 (m, 2H), 7.26 (dd, J = 4.9, 7.8 Hz, 1H), 7.12−7.04 (m,
2H), 7.02 (d, J = 7.8 Hz, 1H), 4.71 (t, J = 8.1 Hz, 1H), 3.96 (s, 3H),
3.92 (d, J = 14.2 Hz, 1H), 3.84 (d, J = 14.2 Hz, 1H), 3.81−3.76 (m,
1H), 3.50 (s, 2H), 3.04−2.98 (m, 1H), 2.98−2.92 (m, 1H), 2.85 (d, J
= 13.2 Hz, 1H), 2.76 (dd, J = 9.3, 13.7 Hz, 1H), 2.53 (s, 3H), 2.18 (s,
3H), 1.57−1.41 (m, 1H), 1.37−1.24 (m, 1H), 0.93 (t, J = 7.3 Hz,
3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 173.4, 155.0, 153.0,
143.6, 141.8, 138.6, 136.8, 135.1, 133.6, 132.0, 130.5, 129.3, 128.3,
127.9, 126.6, 125.9, 125.4, 123.8, 107.4, 81.5, 61.6, 60.4, 57.0, 41.6,
41.2, 35.7, 26.7, 18.7, 15.6, 10.5. HRMS (ESI) m/z: [M + H]+ calcd
20
for C30H35N4O3 499.2709, found 499.2710. [α]D −52 (c 1.0,
MeOH).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02639.
1H and 13C NMR spectra, chiral HPLC chromatograms,
20
H]+ calcd for C28H31F2N2O3 481.2303, found 481.2306. [α]D +42
CHN and water content (compound D only) (PDF)
(c 1.0, MeOH).
(S)-3-(3,8-Dimethylimidazo[1,2-a]pyridin-7-yl)-3-(3-(((R)-2-ethyl-
2,3-dihydropyrido[2,3-f ][1,4]oxazepin-4(5H)-yl)methyl)-4-
methylphenyl)propanoic Acid (6q). Prepared according to general
procedure 4 with 5 (775 mg, 1.279 g) to afford the conjugate addition
product as a light brown solid (238 mg, 0.325 mmol, 20.75% yield, 88
wt %) containing residual DCM, EtOAc, and heptane (12% by weight
by NMR). 1H NMR (400 MHz, DMSO-d6) δ = 8.52−7.43 (m, 3H),
7.37 (d, J = 7.8 Hz, 1H), 7.30−6.94 (m, 11H), 5.39 (dd, J = 3.7, 8.6
Hz, 1H), 4.78 (br t, J = 7.3 Hz, 1H), 4.67 (t, J = 8.8 Hz, 1H), 4.08
(dd, J = 3.4, 8.8 Hz, 1H), 4.05−3.95 (m, 1H), 3.91 (d, J = 14.2 Hz,
1H), 3.86−3.75 (m, 2H), 3.56−3.44 (m, 3H), 2.88 (d, J = 13.2 Hz,
1H), 2.83−2.74 (m, 2H), 2.78 (br dd, J = 9.3, 13.7 Hz, 1H), 2.44 (s,
3H), 2.20 (s, 3H), 1.56−1.42 (m, 1H), 1.39−1.28 (m, 1H), 0.91 (t, J
= 7.3 Hz, 3H). LC/MS (ESI) m/z: [M + H]+ calcd for C39H42N5O4
644.3, found 644.3. Hydrolysis was carried out according to general
procedure 2 (0.225 g, 0.308 mmol, 88 wt %) to afford the desired
product as a white amorphous solid (32 mg, 0.061 mmol, 19.82%
yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.15 (dd, J = 1.5, 4.9 Hz,
1H), 7.94 (d, J = 7.3 Hz, 1H), 7.37 (dd, J = 1.2, 8.1 Hz, 1H), 7.28−
7.21 (m, 2H), 7.13−7.07 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 6.82 (d, J
= 7.3 Hz, 1H), 4.69 (t, J = 7.8 Hz, 1H), 3.91 (d, J = 14.2 Hz, 1H),
3.88−3.76 (m, 1H), 3.83 (d, J = 14.7 Hz, 1H), 3.51 (s, 2H), 2.96−
2.82 (m, 3H), 2.77 (dd, J = 9.3, 13.7 Hz, 1H), 2.53 (s, 3H), 2.38 (s,
3H), 2.19 (s, 3H), 1.57−1.42 (m, 1H), 1.40−1.27 (m, 1H), 0.92 (t, J
= 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 173.6,
154.9, 152.9, 143.6, 141.1, 136.9, 136.4, 135.4, 130.8, 130.6, 129.4,
128.3, 126.5, 123.8, 123.1, 121.5, 120.2, 111.7, 81.5, 61.7, 60.4, 57.0,
AUTHOR INFORMATION
Corresponding Author
■
Michal P. Glogowski − GlaxoSmithKline, Collegeville,
Pennsylvania 19426, United States; orcid.org/0000-
0003-2508-811X; Email: michal.x.glogowski@gsk.com
Authors
Jay M. Matthews − GlaxoSmithKline, Collegeville,
Pennsylvania 19426, United States
Brian G. Lawhorn − GlaxoSmithKline, Collegeville,
Pennsylvania 19426, United States; orcid.org/0000-
0003-4618-5314
Kevin P. C. Minbiole − Department of Chemistry, Villanova
University, Villanova, Pennsylvania 19085, United States;
orcid.org/0000-0003-4263-9833
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02639
Notes
The authors declare no competing financial interest.
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