Sulfone-Mediated SNAr Reaction as a Powerful Tool for the Synthesis of 4-Quinolinyl Ethers and More-Application to the Synthesis of HCV NS3/4a Protease Inhibitor BI 201420

Article abstract of DOI:10.1021/acs.joc.0c00554

An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.

Full text of DOI:10.1021/acs.joc.0c00554

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Article
Sulfone Mediated SNAr Reaction as a Powerful Tool for the
Synthesis of 4-Quinolinyl Ethers and more – Application to
the Synthesis of HCV NS3/4a Protease Inhibitor BI 201420
Nitinchandra D Patel, Xudong Wei, Denis Byrne, Bikshandarkoil Narayanan, Scott Pennino, Max
Sarvestani, Anjan K. Saha, Nizar Haddad, Suresh Kapadia, Jon C. Lorenz, Philomen Decroos, Andrew
Ye, Heewon Lee, Nelu Grinberg, Azad Hossain, Carl A Busacca, Nathan K. Yee, and Chris H Senanayake
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00554 • Publication Date (Web): 28 May 2020
Downloaded from pubs.acs.org on May 28, 2020
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Sulfone Mediated SNAr Reaction as a Powerful Tool for the Synthesis
of 4-Quinolinyl Ethers and more – Application to the Synthesis of HCV
NS3/4a Protease Inhibitor BI 201420
Nitinchandra D. Patel,*,a, Xudong Wei,*,a Denis Byrne,a Bikshandarkoil A. Narayanan,a Scott
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†
b
a
a
a
a
Pennino, Max Sarvestani,a Anjan Saha, Nizar Haddad, Suresh Kapadia, Jon C. Lorenz,
Philomen DeCroos, a Andrew Ye, a Heewon Lee, a Nelu Grinberg, a Azad Hossain, a Carl A. Busacca,
a Nathan K. Yee, a and Chris H. Senanayake a
aChemical Development US; bMaterial and Analytical Sciences US, Boehringer-Ingelheim
Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box. 368, Ridgefield, CT 06877-0368, USA
Email:
nitinpatel43@gmail.com
xudongwei@yahoo.com
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Abstract:
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An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via highly
reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1o, 2o, 3o alcohols
with wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a
complex target of HCV NS3/4a Protease Inhibitor BI 201420 was accomplished.
Introduction
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Quinoline is an important class of heterocyclic compounds that has been extensively studied and
widely used in areas such as drug discovery, e.g. antiviral research programs1 for chronic hepatitis
C virus (HCV) infections (Figure 1).2 In the course of our process research efforts towards the
development of HCV protease inhibitors,3 however, we learned with surprise that synthesis of 4-
quinolinyl ethers is still a quite challenging task, particularly when elaborate structures and
quality product are quested. In marked contrast to the large number of readily available 4-
hydroxy and 4-chloroquinolines, there are few efficient methods for their conversion to the
requisite ethers.
Me
Me
Me
S
Br
S
NH
O
N
O
Me
Me
O
N
O
N
N
Me
Me
O
Me
Me
Me
O
O
S
N
OH
O
O
NH
NH
N
N
O
O
O
O
O
N
H
Me
H
O
BI 201335
Faldaprevir
(Boehringer Ingelheim)
Simeprevir
(Medivir/Janssen)
OMe
F
F
N
N
N
O
Cl
Me
O
O
O
O
O
O
O
O
NH
Me
N
S
N
H
HN
N
Me
Me
HN
S O
O
N
NH
H
O
O
O
O
Me
O
O
F
GS-9857
Voxilaprevir
(Gilead)
BMS-650032
Asunaprevir
(Briston-Myers Squibb)
F
Figure 1. Selective examples of HCV Protease Inhibitors.
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The SNAr reaction of a 4-chloroquinoline with alcohol is usually sluggish, especially when
reacting with a 2o or 3o alcohol,4 and byproducts accompany significantly under harsh conditions.
Transition metal catalyzed aryl ether formation has been a rapidly developing area in recent
years,5,6 but application to 4-quinoline ethers has been very rare, probably partly because
quinoline promoted ligand exchange can destroy some catalyst complexes. So far the most
frequently employed method in drug discovery is via alkylation of 4-hydroxyquinolines,7 (SN2
approach, Scheme 1), but it has the following limitation and drawbacks. (1) The regio-selectivity
of O-alkylation versus N-alkylation is poor and difficult to control,7a,b unless one position is totally
blocked. (2) Reactivity toward 2o alkylating agents decreases markedly than 1o ones, and reaction
with 3o alkylating agent is even less viable.7c It should be noted that in this regard the Mitsunobu
reaction3b, 7d-j, 8 (mostly 2o ones) is often employed to avoid harsh conditions. (3) Allylic or
propargylic alkylating agents could also go SN2’ pathway giving poor SN2/SN2’product distribution.
(4) SN2 reaction goes by a chiral center inversion mechanism, but it is known that complete
stereo-control can be a problem due to partial SN1 pathway, neighboring group effect or solvent
effect. Also, the alkylating agent with opposite configuration is not always readily available, e.g.
chiral compounds from a natural source. In summary, a facile, general and practical method for
the synthesis of quinolinyl ethers is much desired and will be very useful in medicinal chemistry.
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R2
O
X
N
O
N
R1
SNAr
R1
R2
R2
X
O
N
O
R1
SN2
R1
R2
N
Scheme 1. SNAr (top) vs SN2 (bottom).
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Result and Discussion
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Our research originated from an attempted synthesis of the macrocyclic HCV protease inhibitors
3a and 3b (BILN 2061) via a SNAr reaction of a macrocyclic 2o alcohol (2a) and chloroquinolines
1a and 1b as shown in Scheme 2. This is the most desirable approach, as it is highly convergent
and the macrocyclic intermediate can be made from the natural trans-4-hydroxy-(L)-proline
directly. However, this SNAr reaction proved to be very sluggish: conversion was slow even with
excess base (>5.0 eq) and significant decomposition of starting material and product were
observed during the long reaction time (12-24 h). Even after extensive optimization of solvent,
reagent and reaction condition, it failed to produce the desired product in reasonable yield and
quality. As a result, both of our exploratory synthesis and the 1st generation scale-up adopted the
SN2 approach, in which double inversion of a stereogenic center was executed.3b-d In a separate
work, chemists of Bristol-Myers Squibb obtained ~30% yield from a similar SNAr reaction even
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with the help of lanthanide catalyst LnCl3.9
HO
H
CO2H
N
t-BuOK,
N
R
MeO
N
H
+
O
N
O
O
DMF or DMSO, rt
<40% yield
O
Cl
1a, b
2a
MeO
N
N
R
a: R = Ph
b: R=
O
S
H
NH
N
CO2H
N
H
O
N
O
O
O
3a, 3b (BILN2061)
Scheme 2. SNAr approach to HCV protease inhibitors (BILN2061).
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In pursuit of a highly efficient SNAr reaction, we envisioned that an electron withdrawing group
which decreases the electron density of the aromatic ring would help, since SNAr reaction is a
two-step addition-elimination process and addition is usually the rate-determining step. After a
search, we found phenylsulfonyl quinoline, which can be easily prepared by reacting with sodium
benzenesulfinate,10 seemed to serve the purpose well. It should be noted that sulfone as a strong
activation group for SNAr reactions has been revealed in kinetic studies11, but surprisingly ignored
in application to the synthesis of quinolinyl ethers.12 As a qualitative analysis, we conducted a
competition reaction using 1-phenyl-1(S)-ethanol with a 1:1 mixture of 4-phenylsulfonylquinoline
and 4-chloroquinoline (0.5 equiv each). As shown in Table 1, when 1.0 equivalent of potassium t-
butoxide was added, sulfone 4c reacted rapidly forming the desired ether product completely in
just 15 minutes, while ~87% of the chloroquinoline 1c remained. After 1 hour, another 0.5
equivalent of base was added, but even though conversion of chloroquinoline reached only 48%
after 12 h and almost stopped thereafter. This clearly shows sulfone is a powerful activation
group.
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Table 1. Reactivity of ArSO2Ph vs ArCl
t-BuOK,
Cl
N
SO2Ph
N
O
N
Ph
DMF,
22 o
C
HO
+
+
Ph
2b
4c
1c
5a
Time
0
ArCl (1c)a
100%
87%
ArSO2Ph (4c)a
Product (5a)a
0%
100%
0%
15 min
1 hb
4 h
56%
76%
0%
62%
55%
0%
73%
24 h
72 h
48%
0%
75%
47%
0%
76%
[a] Estimated by HPLC area% at 254 nm using toluene as an internal reference. [b] Additional
0.5 equiv t-BuOK was added.
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Encouraged by the results obtained above, we studied the scope and limitation of this SNAr
reaction next using a range of structurally diversified alcohols. As shown in Table 2, this proved
to be a very successful and general methodology. In most cases quinoline ether was prepared
very readily in excellent yield. For reaction with 2o alcohols, t-BuOK was found to be a suitable
base, while for reaction with 3o alcohols KHMDS was used due to the higher pKa of tertiary
alcohol group. Usually reaction goes to completion at ambient temperature very fast within 2
hours, and in a number of cases it took only a few minutes for a full clean conversion. p-
Methoxyphenol is a weaker nucleophile and reacts at ->70 oC. It should be noted that allylic and
propagylic alcohols work very well in this system, giving the desired product straight without any
complications associated the regio- / stereo-selectivity problems as it would have by SN2
approach. Even the very sterically hindered (-)-linalool reacts smoothly producing 5e in good yield.
For reactions of cis- and trans- cyclopentadiols, mono-ethers (5f, h) or di- ethers (5g, i) could be
obtained by using different ratio of the substrates. Despite the electron-donating effect of 2-
phenyl and 7-methoxy groups in phenylsulfonyl quinoline 4a, SNAr reaction is still very efficient
in producing the substituted quinoline ethers 5m-s successfully. It is noteworthy that several
functional groups are tolerated, such as aryl halogen, carboxylate, amide, carbamate and even
free amines NH or NH2, making this methodology very straightforward and practical. To the best
of our knowledge, this is the first report showcasing a wide scope towards the preparation of 4-
quinolinyl ethers from phenylsulfonyl quinolines.
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Table 2. Synthesis of Quinolinyl Ethera
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SO2Ph
OR
N
Base, DMF, rt
+
R'
ROH
R'
N
9
5
4a: R' = 2-Ph-7-MeO
4c: R' = H
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No
a
Product
Yield No
(%)
Product
Yield
(%)
92
k
81b
O
N
Ph
O
N
OMe
b
85
l
75d
O
N
O
N
Br
O
c
d
e
80
75
75c
m
n
91
O
N
N
O
MeO
Ph
78c
74e
O
N
N
MeO
Ph
O
N
o
O
CO2H
Ph
MeO
MeO
N
O
f
70b
76
p
q
85f
92f
O
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NH3
Ph
OH
N
N
Ph
g
O
N
O
N
O
N
Cl
NH3
Ph
MeO
MeO
Cl
NH3
h
73b
85
r
87f
84e
75g
O
O
N
OH
N
Ph
Boc
N
i
s
t
CO2H
O
O
N
O
N
MeO
N
Ph
Ph
iPr
j
80
O
O
N
N
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aGeneral conditions: 4-sulfonylquinoline (1 mmol), alcohol (1.2 mmol), DMF (3 mL) and t-BuOK
9
b
as base (1M in THF, 1.2 mmol) were stirred for 2 h (unless otherwise specified). Excess diol (4
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equiv.) was used. cSolid KHMDS was used as the base. dReaction was carried out at 80 oC using
Cs2CO3. e2.5 equiv of base was used. fStarting material is free amino alcohol. HCl salt was made
during workup for purification. g4-(phenylsulfonyl)pyridine sulfone was used.
We also explored the catalytic version of this SNAr reaction. Several sulfinate (RSO2Na, R = Ph, p-
Tol and Me) were tested for a reaction of 4-chloroquinoline and alcohol 2b with Cs2CO3 in DMF
at elevated temperature. It turned out that MeSO2Na was a suitable catalyst, possibly because of
its higher electron withdrawing ability. As shown in Scheme 3, with 0.4 equivalents of MeSO2Na,
quinolines 1c and 1a can react smoothly with 1-phenyl-1(S)-ethanol or exo-norborneol
respectively generating the desired ethers 5a and 5u in good yield, while reactions without this
sulfinate catalyst were much slower. LCMS confirmed the reaction pathway via methylsulfone,
and this provides a convenient method for the direct conversion of chloroquinolines to their
ethers using weaker base.
Cs2CO3 (1.5 equiv.)
0.4 equiv. MeSO2Na
DMF, 125 oC, 24 h
Cl
N
O
Ph
+
HO
Ph
N
1c
2b
5a, 75 % yield
Cs2CO3 (1.5 equiv.)
0.4 equiv. MeSO2Na
DMF, 125 oC, 24 h
Cl
N
O
+
OH
MeO
Ph
MeO
N
Ph
1a
5u, 70% yield
Scheme 3. MeSO2Na catalyzed SNAr reactions
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This new SNAr methodology has been successfully applied towards the practical and
chromatography free synthesis of our clinical candidates (BI 20133513a and BI 20130213b) for HCV
protease inhibitor program while avoiding less efficient SN2 or Mitsunobu approaches. Herein,
we report a further streamlined synthesis of a clinical candidate, BI 201420MU. As shown in
Scheme 4, dipeptide 2c was synthesized directly from trans-4-hydroxyproline ester 7 and (S)-tert-
Leucine carbamate 6 in two chemical steps in 80% yield.13c When the dipeptide 2c was reacted
with phenylsulfonyl quinoline13b 4b in the presence of 4.0 equivalents of potassium 3,7-
dimethyloctan-3-oxide (KDMO, 50wt% in heptane)14 in DMF at RT, unfortunately, the reaction
yielded only 60% isolated yield of the SNAr product 8c (with ~84% assay). We found that there
were several impurities formed in this reaction (scheme 5); mainly being decarboxylation (~10%
of 14) of the n-propyl carbamate group along with other minor impurities 15 (from the trans-
carbamoylation13a,b with DMO), 16 (from sulfone hydrolysis) and 17 (from displacement of
sulfonyl group from the alkoxide base and/or iPrOH resulting from decarboxylation of n-propyl
carbamate). From the exploration study of SNAr reaction with different sulfinates (Scheme 3), we
found that MeSO2Na was a better catalyst for this transformation. Thus, we turned our attention
to more streamlined and practical synthesis for the methylsulfonyl quinoline 4d to test this
reaction. Previously, for the synthesis of phenylsulfonyl quinoline13b, we used t-BuOK for the
cyclization of an amide 12 and an isolation of quinolone would be required before the tosylation
and sulfonyl formation steps could be performed. We envisioned a process where t-BuOK could
be formed in-situ from KOH/t-BuOH mixture for cyclization step followed by one-pot tosylation
with MeCN (without the use of DMAc)13b and methylsulfonyl quinoline 4d formation with
MeSO2Na in the presence of a catalytic amount of acid. Gratifyingly, an efficient and one-pot
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synthesis of methylsulfonyl quinoline 4d was developed from an amide 12 via quinolone and
tosylate 13 intermediates in 77% isolated yield over 3-steps. Delightfully, the subsequent SNAr
reaction with methylsulfonyl quinoline 4d with dipeptide 2c afforded much cleaner reaction
profile with 75% isolated yield (~90% assay yield) of 8c in high purity. The quinoline dipeptide
ether (SNAr product) 8c was then activated as the mixed anhydride using propyl chloroformate
and reacted with vinyl cyclopropane amino acid salt 9 to furnish the tripeptide heterocycle 10 in
93% yield with >98% purity. Propyl chloroformate was used as a mixed anhydride acylating agent
for step 3 in place of isopropyl chloroformate13b to avoid formation of any trans-carbamoylation
side product on the western part of the tripeptide. Furthermore, the hydrolysis of tripeptide 10
using LiOH in THF/water followed by pH adjustment with aq. HCl formed BI 201420ZW 11 in 90%
yield (step 4). Finally, the last transformation (step 5) proceeded smoothly to produce BI 201420
as a meglumine (MU), 3c salt in 90% yield with >99.3% purity, which met the requirement of
clinical trial supply. In addition, we were able to demonstrate this methodology to other HCV
protease inhibitors 3a and BILN2061 3b to provide 87% and 80% respective yields (see the
Supporting Information for details). Hence, this new SNAr approach for quinolinyl ethers enabled
the highly convergent, efficient and economical synthesis of the clinically valuable HCV protease
inhibitors.
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S
Br
KDMO
NH
HO
MeO
N
O
N
OK
HO
H
OH
OH
O
DMF, rt
Br
N
Step 2
NH
2 steps
nPrO
O
8c
O
+
80% yield
CO2Me
O
60% yield (with 4b)
75% yield (with 4d)
NH
S
N
Cl
nPrO
NH
OH
H
N
Step 1
MeO
N
N
O
O
6
7
O
2c
4b
4d
R1 = Ph,
R2 = Me,
nPrO
NH
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SO2R
S
O
Product: 4d
MeCN, MeSO2Na
0.3% equiv MeSO3H
NH
O
N
S
Br
1) KOH
t-BuOH/THF
Br
1) nPrOCOCl, -10 oC, NMM
2)
NH
NH
MeO
N
MeO
N
CO2Me
H2N
77% yield, 3-steps
2) TsCl, MeCN
Step 3
TsOH
9
O
OTs
Amide 12
Tosylate 13
S
S
Br
Br
N
NH
N
NH
N
MeO
MeO
N
10
93% yield
O
O
Meglumine,
MeOAc-water
LiOH (THF/water)
90% yield
3c, BI 201420MU,
H
90% yield
H
CO2Me
N
CO2H
90% isolated yield
Step 5
N
N
N
Step 4
O
O
O
O
nPrO
NH
nPrO
NH
O
O
11
BI 201420ZW
Scheme 4. Convergent synthesis of HCV protease inhibitor, BI 201420MU using SNAr strategy.
Br
S
Br
S
NH
NH
O
N
O
O
N
O
N
Me
N
Me
Me
Me
Me
Me
Me
Me
N
N
OH
O
OH
H2N
NH
O
O
O
O
O
15
14
Br
S
Br
S
NH
O
N
NH
O
N
N
Me
N
Me
OR
OH
Ether "impurity"
"Quinolone"
16
17
Scheme 5. trans-Carbamoylation and other impurities from SNAr.
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This methodology was further extended to other nucleophiles to promote the C-X bond
formation (where X = N, S or C), highlighting the generality of this approach (Scheme 6). Sodium
azide formed azido-quinoline (18) in DMF under heat to give 80% yield.15 Benzyl mercaptan
(BnSH) gave smooth conversion to C-S bond formation to afford quinoline thio ether (19) in good
77% yield. Finally, C-C bond formations are also feasible in high yields using this methodology.15
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4a
BnSH, t-BuOK
NaN3,
DMF, r.t.
DMF, 90 o
C
O
N
O
N
Me
Me
18
80% yield
19
SBn
N3
77% yield
Scheme 6. SNAr products (18 and 19) with other nucleophiles.
CONCLUSIONS
In summary, we demonstrated a very efficient general approach to 4-quinolinyl ethers via the
highly reactive sulfone mediated SNAr reaction. It has the advantages that quinoline ethers can
be made in high quality from any type of available alcohols such as secondary, tertiary, allylic or
propargylic without regio- or stereo-selectivity problems, it also tolerates many functional groups
(e.g. aryl halides and free amines) that other methods would not, and no heavy metal removal is
needed which is particularly suitable for the late stage synthesis of active pharmaceutical
ingredients. It has been successfully applied for the synthesis of therapeutically known HCV
protease inhibitors (including BI 201420MU), and we believe that this novel approach will enable
many structurally diversified quinoline compounds easily accessible in pharmaceutical research.
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General. Commercially available reagents and solvents were used without further
purification unless otherwise mentioned. KDMO in heptane (50% w/w) was purchased
from BASF and used as is. 1H NMR spectra were recorded on Bruker 400, 500 or 600 MHz
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instrument using CDCl3, MeOD or DMSO-d6 as solvent unless otherwise stated. The H
and 13C chemical shifts are reported in δ ppm relative to TMS as an internal standard. For
thin-layer chromatography, analytical TLC plates (SIL G/UV254 and 230-400 mesh silica
gel) were used. Melting points were measured using a Mel-Temp 3.0 melting point
apparatus and are uncorrected. High resolution mass spectral data was acquired using
6230 Agilent LC/MS TOF and Thermo FT/MS (Agilent Eclipse Plus C18, 3.0 x 100mm, 3.5
µm). Sample solution was delivered to mass spectrometer with an HPLC system, and
analyzed in an electrospray ionization mode (ESI) and direct analysis in real time (DART).
7-Methoxy-2-phenyl-4-(phenylsulfonyl) quinoline (4a). To a solution of 1-(2-amino-4-
methoxyphenyl)ethan-1-one (10.0 g, 60.4 mmol) in acetonitrile (70 mL) was charged
trimethylamine (6.5 g, 6.4 mmol, 1.05 equiv). The resulting mixture was cooled to 0-5 oC
and treated with benzoyl chloride (8.94 g, 6.4 mmol, 1.05 equiv) while keeping internal
o
temperature below 10 C. The resulting mixture was stirred for 2h until reaction
completion and quenched with water (125 mL) and stirred for additional 1h at r.t. The
solids were collected by filtration, rinsed with water and dried under vacuum at 60 oC for
12h to afford 16.0 g of N-(2-acetyl-5-methoxyphenyl)benzamide as light tan solid (Yield:
98.1%). To a solution of t-BuOK (13.3 g, 118.8 mmol (4.0 equiv) in dimethoxyethane (110
mL) at 87-89 oC (reflux conditions using a heating mantle) was added a premixed solution
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of (N-(2-acetyl-5-methoxyphenyl)benzamide (8.0 g, 29.7 mmol, 1.0 equiv) in
dimethoxyethane (50 mL) over 1h. The resulting mixture was held at this temperature
for additional 20 min until reaction completion before it was cooled down to r.t. The
reaction mixture was treated with 1N HCl (92 mL, 92 mmol) over 1h while keeping the
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internal temperature below 25 C until the neutral pH (~7) was obtained. The resulting
slurry was stirred for additional 3h, treated with water (125 mL) slowly over 1h and
stirred for additional 5h before the solids were collected by filtration and dried under
vacuum at 65 oC for 12h to afford 7.4 g of 7-methoxy-2-phenylquinolin-4-ol as tan solid
(Yield: 99.1%). Sulfone formation: To a solution of 7-methoxy-2-phenylquinolin-4-ol (6.0
g, 23.88 mmol, 1 equiv) in acetonitrile (55.0 mL) was charged N-methylmorpholine (3.14
g, 31.04 mmol, 1.3 equiv) slowly over 5 min. The resulting mixture was cooled to 5-8 oC
and charged benzenesulfonyl chloride (5.9 g, 33.43 mmol, 1.4 equiv) over 1h while
o
keeping the internal temperature below 10 C. After reaction completion by HPLC,
benzenesulfinic acid sodium salt was charged (6.67 g, 40.5 mmol, 1.7 equiv) followed by
2M HCl (4.3 g, 7.1 mmol, 0.3 equiv) with vigorous stirring. Heated the resulting contents
and stirred for 1-2h. Upon reaction completion, the mixture cooled to r.t. and added
water (50 mL) and saturated sodium bicarbonate (15 mL) to adjust the pH to 8-9. The
resulting mixture was stirred for 1h after which the solids were collected by filtration,
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rinsed with 1:3 mixture of ACN/water (30 mL) and dried under vacuum at 65 C with a
bleed of N2 until the KF is <0.18% of water to afford 7.5 g of 7-methoxy-2-phenyl-4-
(phenylsulfonyl)quinoline (4a) as greenish yellow solid. Yield: 83.7 %. White solid. MP
195-198 oC. 1H NMR (CD3OD, 500 MHz) δ 3.96 (s, 3H), 7.40 (dd, J = 2.5, 9.5 Hz, 1H), 7.56-
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7.67 (m, 6H), 7.73 (t, J = 7.0 Hz), 8.17 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 7.0 Hz), 8.46 (d, J =
9.5 Hz, 1H), 8.58 (s, 1H); 13C {1H} NMR (CD3OD, 125 MHz) δ 55.7, 108.8, 115.0, 116.4,
121.4, 124.6, 127.4, 127.7, 128.9, 129.8, 130.3, 137.4, 139.7, 144.9, 150.9, 156.4, 160.9.
HRMS (ESI) m/z : [M + H]+ Calcd for (C22H18NO3S+) 376.1001; found 376.0992.
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4-(Phenylsulfonyl)quinoline (4c). To a solution of 4-chloroquinoline 1c (3.3 g, 20.0 mmol,
1.0 equiv) in THF (30 mL) at 30 oC was charged benzenesulfinic acid sodium salt (4.43 g,
27.0 mmol, 1.35 equiv). Charged methanesulfonic acid (384 mg, 4 mmol, 20 mol%)
dropwise with vigorous stirring and then heated to 50 oC (using heating mantle) for 1-2h
until reaction completion. Distilled THF under reduced pressure and solvent was switch
to DMF (15 mL) and distilled again to remove residual THF. The resulting mixture was
cooled to r.t., charged water (30 mL) and 1M NaOH (4 mL) over 20 min to adjust the pH
to 12 with additional stirring for 1h. The solids were collected by filtration, rinsed with
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water (15 mL) and dried under vacuum at 65 C (12h) to afford 4.94 g of 4-
(phenylsulfonyl)quinoline as off-white to white solids (HPLC purity: 99.2 A%). Yield: 91.7%.
MP 162 oC (from DSC). 1H NMR (CDCl3, 500 MHz) δ 7.52 (t, J = 7.5 Hz, 2H), 7.59 (t, J = 7.5
Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 8.01 (d, J = 7.5 Hz, 2H), 8.17 (d, J =
4.5 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 8.65 (d, J = 9.0 Hz, 1H), 9.13 (d, J = 4.5 Hz, 1H); 13C
{1H} NMR (CDCl3, 125 MHz) δ 121.3, 122.1, 124.2, 127.9, 128.9, 129.5, 130.4, 130.7, 133.9,
140.3, 144.9, 149.5, 149.7. HRMS (ESI) m/z: [M + H]+ calcd for (C15H12NO2S +) 270.0589;
found 270.0582.
N-isopropyl-4-(7-methoxy-4-(phenylsulfonyl)quinolin-2-yl)thiazol-2-amine (4e). To a
solution of t-BuOK (11.2 g, 110.0 mmol (4.0 equiv) in dimethoxyethane (110 mL) at 87-
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89 C (reflux) was added a premixed solution of N-(2-acetyl-5-methoxyphenyl)-2-
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6
7
(isopropylamino)thiazole-4-carboxamide (8.4 25.0 mmol, 1.0 equiv) in
g
,
8
9
dimethoxyethane (50 mL) over 1h. The resulting mixture was held at this temperature
for additional 20 min until reaction completion before it was cooled down to r.t. The
reaction mixture was treated with 1N HCl (92 mL, 92 mmol) over 1h while keeping the
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internal temperature below 25 C until the neutral pH (~7) was obtained. The resulting
slurry was stirred for additional 3h, treated with water (125 mL) slowly over 1h and
stirred for additional 5h before the solids were collected by filtration and dried under
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vacuum at 65 C for 12h to afford 6.16 g of 2-(2-(isopropylamino)thiazol-4-yl)-7-
methoxyquinolin-4(1H)-one as tan solid (Yield: 78.1%). Sulfone formation: To a solution
of 2-(2-(isopropylamino)thiazol-4-yl)-7-methoxyquinolin-4(1H)-one (6.0 g, 19.02 mmol, 1
equiv) in acetonitrile (55.0 mL) was charged N-methylmorpholine (2.5 g, 24.73 mmol, 1.3
o
equiv) slowly over 5 min. The resulting mixture was cooled to 5-8 C and charged
benzenesulfonyl chloride (4.7 g, 26.63 mmol, 1.4 equiv) over 1h while keeping the
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internal temperature below 10 C. After reaction completion by HPLC, benzenesulfinic
acid sodium salt was charged (5.30 g, 32.3 mmol, 1.7 equiv) followed by 2M HCl (3.4 g,
5.71 mmol, 0.3 equiv) with vigorous stirring. Heated the resulting contents and stirred
for 1-2h. Upon reaction completion, the mixture cooled to r.t. and added water (50 mL)
and saturated sodium bicarbonate (15 mL) to adjust the pH to 8-9. The resulting mixture
was stirred for 1h after which the solids were collected by filtration, rinsed with 1:3
mixture of ACN/water (30 mL) and dried under vacuum at 65 oC with a bleed of N2 until
the KF is <0.18% of water to afford 7.5 g of N-isopropyl-4-(7-methoxy-4-
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(phenylsulfonyl)quinolin-2-yl)thiazol-2-amine (4e) as greenish yellow solid. Yield: 89.7 %.
MP 215-218 oC. 1H NMR (CD3OD, 500 MHz) δ 1.26 (d, J = 6.0 Hz, 6H), 3.79-3.86 (m, 1H),
3.94 (s, 3H), 7.36 (dd, J = 2.0, 9.5 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.60 (s, 1H) 7.64-7.69
(m, 2H), 7.74-7.79 (m, 1H), 7.86 (d, J = 7.5 Hz, 1H), 8.06 (d, J = 8.0 Hz, 2H), 8.41 (d, J = 9.5
Hz, 1H), 8.59 (s, 1H);
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13C {1H} NMR (CD3OD, 125 MHz) δ 22.3, 46.6, 55.6, 107.2, 108.3, 115.05, 116.9, 120.9,
124.7, 127.6, 129.9, 134.4, 139.4, 144.7, 149.0, 150.8, 152.6, 160.82, 168.1. HRMS (ESI)
+
m/z: [M + H]+ Calcd for (C22H21BrN3O3S2 ) 518.0202; found 518.0207.
4-(phenylsulfonyl)pyridine. To a solution of 4-chloropyridine hydrochloride (1.0
g, 7 mmol) and benzenesulfinic acid sodium salt (2.2 g, 13.33 mmol, 2.0 equiv) in
DMF (5 mL) was added trimethylamine (0.93 mL, 6.67 mmol, 1.0 equiv) and
heated to 110 oC (using heating mantle) for 4h. The mixture was cooled to r.t. and
concentrated to one third of the original volume and then partitioned between
EtOAc (20 mL), water (10 mL) and saturated sodium bicarbonate solution (10 mL).
The aqueous layer was extracted with EtOAc (20 mL) and the combined organics
were washed with water (20 mL), dried over sodium sulfate and concentrated
under reduced pressure to afford 1.35 g of 4-(phenylsulfonyl)pyridine as off-white
solid. Yield: 92.4 %. HRMS (ESI) m/z: [M + H]+ Calcd for (C11H10NO2S+) 220.0426;
found 220.0425. Characterization data is in accordance with that reported in
literature.17 General procedure for synthesis of quinolinyl ethers (5a-5t): To a round
bottom flask with cooling bath 4-sulfonylquinoline (1 mmol), alcohol (1.2 mmol) and DMF
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(3 mL) are added and stirred to mix well. Potassium t-butoxide (for reaction with 2o
alcohols) or potassium hexamethyldisilylamide (for reaction with 3o alcohols) (1.2 mmol,
solid or 1 M solution in THF) is added at 15 - 20 oC, and the reaction mixture is stirred for
0.5 to 2 h monitored by LCMS (unless otherwise specified). Water (0.5 ml) is added to
quench the reaction, and product is isolated either by precipitation directly with
additional amount of water or by extraction with ethyl acetate (10 ml) and purification
by silica gel column chromatography.
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(S)-4-(1-Phenylethoxy)quinoline (5a). Performed using 1 mmol sulfone substrate. Rf = 0.2
1
(30:70 EtOAc:hexanes). Pale yellow oil (230 mg, 92%). H NMR (CDCl3, 500 MHz) δ 1.79
(d, J = 6.5 Hz, 3H), 5.57 (q, J = 6.5 Hz, 1H), 6.56 (d, J = 5.0 Hz, 1H), 7.25-7.29 (m, 1H), 7.32-
7.35 (m, 2H), 7.40 (d, J = 7.5 Hz, 2H), 7.52-7.55 (m, 1H), 7.68-7.70 (m, 1H), 8.01 (d, J = 8.0
Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.58 (d, J = 5.0 Hz, 1H); 13C {1H} NMR (CDCl3, 100 MHz) δ
24.3, 76.7, 102.6, 121.9, 122.0, 125.3, 125.6, 127.9, 128.9, 128.9, 129.7, 141.9, 149.4,
151.2, 160.4. HRMS (ESI) m/z: [M + H]+ calcd for (C17H16NO +) 250.1226; found 250.1224.
4-(But-3-en-2-yloxy)quinoline (5b). Performed using 1 mmol sulfone substrate. Clear oil
(169 mg, 85%). 1H NMR (CDCl3, 500 MHz) δ 1.59 (d, J = 6.5 Hz, 3H), 5.06 – 5.11 (m, 1H),
5.25 (d, J = 10.5 Hz, 1H), 5.36 (d, J = 17.5 Hz, 1H), 5.95 – 6.01 (m, 1H), 6.73 (d, J = 5.0 Hz,
1H), 7.48-7.51 (m, 1H), 7.67-7.70 (m, 1H), 8.02 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H),
8.70 (d, J = 5.0 Hz, 1H);
13C {1H} NMR (CDCl3, 100 MHz) δ 21.1, 75.2, 102.2, 116.4, 121.9, 122.0, 125.4, 128.9,
+
129.6, 137.8, 149.4, 151.2, 160.5. HRMS (ESI) m/z: [M + H]+ calcd for (C13H14NO )
200.1069; found 200.1063.
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(S)-4-(but-3-yn-2-yloxy)quinoline (5c). Performed using 1 mmol sulfone substrate
(reaction temperature: 0-5 oC). Isolated using 0-15% EtOAc in hexanes. White solid (208
mg, 80%). MP: 82-83 oC. 1H NMR (CDCl3, 500 MHz) δ 1.84 (d, J = 6.5 Hz, 3H), 2.56 (d, J =
1.0 Hz, 1H), 5.11 (dq, J = 1.0, 6.5 Hz, 1H), 6.95 (d, J = 5.5 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H),
7.70 (t, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.78 (d, J = 5.5 Hz,
1H); 13C {1H} NMR (CDCl3, 125 MHz) δ 21.9, 63.9, 75.1, 81.5, 102.2, 121.5, 121.9, 125.7,
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+
128.9, 129.8, 149.4, 151.2, 159.8. HRMS (ESI) m/z: [M + H]+ calcd for (C13H12NO )
198.0913; found 198.0913.
4-Tert-butoxyquinoline (5d). Performed using 1 mmol sulfone substrate. Clear oil (151
mg, 75%).1H NMR (CDCl3, 500 MHz) δ 1.64 (s, 3H), 6.92 (d, J = 5.5 Hz, 1H), 7.48 (t, J = 8.0
Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.70 (d, J =
5.5 Hz, 1H); 13C {1H} NMR (CDCl3, 125 MHz) δ 28.7, 80.8, 106.4, 122.7, 123.9, 125.5, 128.8,
+
129.6, 149.5, 150.6, 159.7. HRMS (ESI) m/z: [M + H]+ calcd for (C13H16NO ) 202.1226;
found 202.1225.
(R)-4-(3,7-Dimethylocta-1,6-dien-3-yloxy)quinoline (5e). Performed using 1 mmol
sulfone substrate, solid KHMDS (2.0 equiv.) and ROH (1.0 equiv.). Rf = 0.35 (0-30% EtOAc
in hexanes). Clear oil (210 mg, 75%). 1H NMR (CDCl3, 400 MHz) δ 1.58 (s, 3H), 1.67 (s, 3H),
1.68 (s, 3H), 1.87-1.95 (m, 1H), 1.96-2.05 (m, 1H), 2.10-2.30 (m, 2H), 5.13-5.18 (m, 1H),
5.30 (d, J = 17.6 Hz, 1H), 5.33 (d, J = 11.2 Hz, 1H), 6.16 (dd, J = 11.2, 17.6 Hz, 1H), 6.92 (d,
J = 5.0 Hz, 1H), 7.45-7.50 (m, 1H), 7.65-7.70 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 8.23 (dd, J =
1.0, 8.0 Hz, 1H), 8.62 (d, J = 5.0 Hz, 1H); 13C {1H} NMR (CDCl3, 125 MHz) δ 17.6, 22.3, 22.5,
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25.7, 42.2, 83.3, 105.7, 115.1, 122.3, 123.1, 123.7, 125.4, 128.9, 129.4, 132.2, 142.5,
149.6, 150.7, 159.1.
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(1S,2S)-2-(Quinolin-4-yloxy)cyclopentanol (5f). Performed using 1 mmol sulfone
substrate. White solid (160.4 mg, 70%). MP: 154-156 oC.MP 154-156 oC. 1H NMR (DMSO-
d6, 400 MHz) δ 1.60–1.66 (m, 1H), 1.72-1.87 (m, 3H), 1.90-2.00 (m, 1H), 2.20–2.30 (m,
1H), 4.20-4.30 (m, 1H), 4.71-4.80 (m, 1H), 5.17 (d, J = 4.0 Hz, 1H), 7.09 (d, J = 5.0 Hz, 1H),
7.55 (t, J = 8.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz,
1H), 8.73 (d, J = 5.0 Hz, 1H); 13C {1H} NMR (DMSO-d6, 100 MHz) δ 21.4, 29.5, 32.6, 75.2,
85.2, 102.4, 121.1, 121.6, 125.5, 128.6, 129.6, 148.8, 151.2, 159.8. HRMS (ESI) m/z: [M +
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H]+ calcd for (C14H16NO2 ) 230.1175; found: 230.1175.
(1S,2S)-1,2-Bis(quinolin-4-yloxy)cyclopentane (5g). Quinolinesulfone 4c (539 mg, 2
mmol), tBuOK (3 equiv.) and ROH (0.5 equiv.). Rf = 0.21 (100% EtOAc). White solid (542
mg, 76%). MP: 90-91 oC. 1H NMR (CDCl3, 500 MHz) δ 2.00-2.16 (m, 4H), 2.41-2.49 (m, 2H),
5.21-5.23 (m, 2H), 6.78 (d, J = 5.0 Hz, 2H), 7.51-7.56 (m, 2H), 7.70-7.76 (m, 2H), 8.06 (d, J
= 8.0 Hz, 2H), 8.23 (d, J = 8.0 Hz, 2H), 8.70 (d, J = 5.0 Hz, 2H); 13 C {1H} NMR (CDCl3, 100
MHz) δ 22.7, 30.9, 83.1, 101.8, 121.6, 121.7, 125.9, 129.1, 129.9, 149.4, 151.2, 159.9.
+
HRMS (ESI) m/z: [M + H]+ calcd for (C23H21N2O2 ) 357.1597; found: 357.1590.
(1R,2S)-2-(Quinolin-4-yloxy)cyclopentanol (5h). Performed using 1 mmol sulfone
substrate. White solid (167.3 mg, 73%). MP: 94-96 oC. 1H NMR (CDCl3, 500 MHz) δ 1.62-
1.76 (m, 1H), 1.90-2.10 (m, 4H), 2.11- 2.19 (m, 1H), 2.67 (br, 1H), 4.35-4.43 (m, 1H), 4.75-
4.83 (m, 1H), 6.73 (d, J = 5.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 8.03
(d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.69 (d, J = 5.0 Hz, 1H); 13C {1H} NMR (CDCl3,
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100 MHz) δ 19.6, 28.1, 31.2, 73.5, 80.3, 101.9, 121.60, 121.7, 125.7, 129.0, 129.9, 149.4,
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+
151.2, 160.3. HRMS (ESI) m/z: [M + H]+ calcd for (C14H16NO2 ) 230.1176, found 230.1175.
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(1R,2S)-1,2-Bis(quinolin-4-yloxy)cyclopentane (5i). Quinolinesulfone 4c (1 mmol),
tBuOK (2.5 equiv.) and ROH (0.5 equiv.). Rf = 0.2 (100% EtOAc). White solid (303 mg, 85%).
MP: 147-148 oC. 1H NMR (CDCl3, 500 MHz) δ 1.84-1.92 (m, 1H), 2.15-2.29 (m, 3H), 2.32-
2.38 (m, 2H), 5.15-5.17 (m, 2H), 6.76 (d, J = 5.0 Hz, 2H), 7.35 (t, J = 8.0 Hz, 2H), 7.64 (t, J =
8.0 Hz, 2H), 7.95-8.00 (m, 2H), 8.68 (d, J = 5.0 Hz, 2H); 13C {1H} NMR (CDCl3, 100 MHz) δ
19.8, 28.6, 78.6, 101.6, 121.7, 121.9, 125.6, 128.9, 129.8, 149.4, 151.0, 160.7. HRMS (ESI)
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m/z: [M + H]+ calcd for (C23H21N2O2 ) 357.1597; found 357.1592.
4-((1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl oxy)quinoline (5j). Performed using 1
mmol sulfone substrate. Rf = 0.35 (0-30% EtOAc in hexanes). White solid (227 mg, 80%).
o
1
MP = 85-87 C. H NMR (CDCl3, 400 MHz) δ 0.76 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 7.2 Hz,
6H), 0.98-1.05 (m, 1H), 1.10-1.23 (m, 2H), 1.51-1.61 (m, 1H), 1.70-1.85 (m, 3H), 2.15-2.23
(m, 1H), 2.25-2.30 (m, 1H), 4.30-4.42 (m, 1H), 6.74 (d, J = 5.5 Hz, 1H), 7.48 (t, J = 8.0 Hz,
1H), 7.68 (t, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.72 (d, J = 5.5
Hz, 1H); 13C {1H} NMR (CDCl3, 100 MHz) δ 16.9, 20.6, 22.1, 23.9, 26.6, 31.4, 34.4, 39.5,
47.9, 77.9, 100.3, 122.0, 122.4, 125.1, 128.2, 129.1, 149.6, 151.4, 160.9. HRMS (ESI) m/z:
[M + H]+ calcd for (C19H26NO +) 284.2009; found 284.2005.
4-(1-Methylcyclohexyloxy)quinoline (5k). Solid KHMDS (678 mg, 3.4 mmol, 1.7 equiv.)
was added to a mixture quinolinesulfone 4a (539 mg, 2 mmol), 1-methylcyclohexan-1-ol
(343 mg, 3 mmol, 1.5 equiv.) and DMF (~5 mL) and stirred at r.t. for 4 h after which the
reaction mixture was quenched with water and extracted with EtOAc. The organics were
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dried over sodium sulfate, concentrated to afford crude oil which was purified by column
chromatography (0-30% EtOAc in hexanes) to afford title compound 5k. Clear oil (391
mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 1.30-1.42 (m, 1H), 1.50-1.70 (m, 7H), 1.58 (s, 3H),
2.30-2.35 (m, 2H), 6.90 (d, J = 5.0 Hz, 1H), 7.45-7.50 (m, 1H), 7.64-7.69 (m, 1H), 8.01 (d, J
= 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.67 (d, J = 5.0 Hz, 1H); 13C {1H} NMR (CDCl3, 100
MHz) δ 22.2, 25.3, 25.7, 37.5, 81.7, 105.8, 122.6, 123.8, 125.4, 129.0, 129.4, 149.8, 150.8,
159.1. HRMS (ESI) m/z: [M + H]+ calcd for (C16H20NO +) 242.1539; found 242.1538.
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4-(4-methoxyphenoxy)quinoline (5l). Performed using 1 mmol sulfone substrate, Cs2CO3
(1.20 equiv.) and ROH (1.20 equiv.) at temperature 80 oC (using an oil bath) for 12h. Pale
1
orange foam (188.5 mg, 75.0%). H NMR (CDCl3, 400 MHz) δ 3.85 (s, 3H), 6.50 (d, J = 5.0
Hz, 1H), 6.97–7.00 (m, 2H), 7.10- 7.14 (m, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.76 (dd, J = 1.0,
8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.65 (d, J = 5.0 Hz, 1H); 13C
{1H} NMR (CDCl3, 125 MHz) δ 55.7, 103.7, 115.3, 121.4, 121.8, 122.3, 126.0, 129.1, 130.1,
+
147.5, 149.7, 151.2, 157.3, 162.5. HRMS (ESI) m/z: [M + H]+ calcd for (C16H14NO2
)
252.1019, found 252.1012.
(R)-4-(1-(2-Bromophenyl)ethoxy)-7-methoxy-2-
phenylquinoline (5m). Performed using 0.5 mmol sulfone substrate. Crude solids after
the work up were recrystallized from diethyl ether. White solid (198 mg, 91%). MP: 151-
152 oC. 1H NMR (CDCl3, 400 MHz) δ 1.79 (d, J = 6.4 Hz, 3H), 3.96 (s, 3H), 6.01 (q, J = 6.4
Hz, 1H), 6.87 (s, 1H), 7.10-7.18 (m, 2H), 7.22-7.26 (m, 1H), 7.38-7.51 (m, 5H), 7.60 (dd, J
= 0.8, 7.6 Hz, 1H), 7.94-7.96 (m, 2H), 8.24 (d, J = 8.8 Hz, 1H); 13C {1H} NMR (CDCl3, 100
MHz) δ 22.7, 55.5, 75.2, 99.2, 107.6, 115.3, 118.1, 121.5, 122.9, 126.7, 127.4, 128.4, 128.7,
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129.1, 129.5, 132.8, 140.2, 141.1, 151.3, 159.0, 160.6, 161.2. HRMS (ESI) m/z: [M + H]+
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7
+
calcd for (C24H21BrNO2 ) 434.0750; found 434.0743.
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7-Methoxy-2-phenyl-4-(tricyclo[3.3.1.1 ]decan-1-yloxy)-quinoline (5n). Performed
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using 0.5 mmol sulfone substrate, Solid KHMDS (1.5 equiv.) and ROH (1.2 equiv.). Crude
product was recrystallized from EtOH. White solid (152 mg, 78%). MP 145-146 oC.
1H NMR (CDCl3, 500 MHz) δ 1.57 (s, 6H), 2.06 (d, J = 3.0 Hz, 6H), 2.14 (s, 3H), 3.84 (s, 3H),
7.01 (dd, J = 2.5, 9.0 Hz, 1H), 7.21 (s, 1H), 7.31-7.34 (m, 1H), 7.38-7.41 (m, 3H), 7.94-7.98
(m, 3H); 13C {1H} NMR (CDCl3, 100 MHz) δ 28.6, 33.7, 40.3, 53.1, 78.6, 104.7, 104.9, 115.8,
116.6, 121.8, 125.1, 126.4, 126.7, 138.0, 149.3, 156.2, 157.5, 158.7. HRMS (ESI) m/z: [M
+
+ H]+ calcd for (C26H28NO2 ) 386.2115; found 386.2113.
(1R,2S)-2-(7-Methoxy-2-phenylquinolin-4-yloxy)cyclopentanecarboxylic acid (5o).
Performed using 0.5 mmol sulfone substrate. The reaction was neutralized with aqueous
HCl solution and the crude product after work up was recrystallized from EtOH. White
solid (135 mg, 74.3 %). MP: 190-195 oC. 1H NMR (CD3OD, 400 MHz) δ 1.79-1.86 (m, 1H),
1.99-2.06 (m, 3H), 2.33-2.39 (m, 2H), 3.22 (s, 1H), 3.95 (s, 3H), 5.46 (s, 1H), 7.12-7.14 (m,
1H), 7.17-7.21 (m, 1H), 7.38 (s, 1H), 7.53-7.54 (m, 3H), 7.99-8.10 (m, 3H); 13C {1H} NMR
(CD3OD, 100 MHz) δ 21.7, 25.2, 31.0, 49.0, 55.1, 80.4, 97.6, 107.1, 114.6, 117.4, 122.5,
126.9, 128.3, 129.1, 139.0, 150.3, 157.5, 160.1, 160.5, 172.3. HRMS (ESI) m/z: [M + H]+
+
calcd for (C22H22NO4 ) 364.1543; found 364.1542.
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(S)-2-(7-Methoxy-2-phenylquinolin-4-yloxy)propan-1-aminium
chloride
(5p).
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Performed using 0.5 mmol sulfone substrate. HCl salt was prepared from the crude
product after the work up using HCl in IPA. White solid (147 mg, 85.0%). MP: 170-185 oC.
1H NMR (CD3OD, 400 MHz) δ 1.63 (d, J = 6.4 Hz, 3H), 3.55–3.57 (m, 2H), 4.07 (s, 3H), 5.64–
5.69 (m, 1H), 7.49 (dd, J = 2.4, 9.5 Hz, 1H), 7.68–7.76 (m, 5H), 8.15 (dd, J = 1.5, 8.0 Hz,
2H), 8.53 (d, J = 9.5 Hz, 1H); 13C {1H} NMR (CD3OD, 100 MHz) δ 17.1, 44.7, 57.1, 75.9,
100.6, 102.3, 116.2, 121.9, 126.9, 130.1, 130.8, 133.2, 133.9, 143.7, 158.2, 166.7, 168.1.
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+
HRMS (DART) m/z: [M]+ calcd for (C19H21N2O2 ) 309.1598; found 309.1598.
(S)-2-(7-Methoxy-2-phenylquinolin-4-yloxy)-2-phenylethanaminium chloride (5q).
Performed using 0.5 mmol sulfone substrate. HCl salt was prepared from the crude
product after the work up using HCl in IPA. Off-white solid (188 mg, 92.4%). MP: 136-145
oC (decomposition). 1H NMR (CD3OD, 400 MHz) δ 3.85 (dd, J = 5.0, 14.0 Hz, 1H), 3.92 (dd,
J = 7.0, 14.0 Hz, 1H), 3.99 (s, 3H), 5.07 (dd, J = 5.0, 7.0 Hz, 1H), 6.83 (s, 1H), 7.21-7.33 (m,
4H), 7.38 (d, J = 2.8 Hz, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.61–7.68 (m, 3H), 7.84–7.87 (m, 2H),
8.26 (d, J = 9.5 Hz, 1H); 13C {1H} NMR (CD3OD, 100 MHz) δ 51.8, 56.7, 73.5, 98.3, 101.2,
111.7, 119.1, 125.3, 127.4, 129.0, 129.1, 129.6, 130.5, 132.9, 134.3, 142.4, 143.5, 154.1,
+
157.6, 165.4. HRMS (DART) m/z: [M]+ calcd for (C24H23N2O2 ) 371.1754; found: 371.1757.
Trans-4-(7-methoxy-2-phenylquinolin-4-yloxy)cyclohexanaminium
chloride
(5r).
Performed using 0.5 mmol sulfone substrate. HCl salt was prepared from the crude
product after the work up using HCl in IPA. Beige color solid (168 mg, 87 %). MP: 220-250
oC. 1H NMR (CD3OD, 500 MHz) δ 1.80- 1.91 (m, 4H), 2.19-2.25 (m, 2H), 2.42-2.49 (m, 2H),
3.29-3.35 (m, 1H), 4.05 (s, 3H), 5.24-5.26 (m, 1H), 7.41 (dd, J = 2.0, 9.5 Hz, 1H), 7.59 (d, J
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= 2.0 Hz, 1H), 7.64 (s, 1H), 7.69- 7.74 (m, 3H), 8.09–8.13 (m, 2H), 8.30 (d, J = 9.5 Hz, 1H);
13C {1H} NMR (CD3OD, 125 MHz) δ 29.1, 30.1, 50.1, 56.9, 78.8, 100.9, 101.9, 116.1, 121.6,
126.1, 129.9, 130.7, 133.6, 133.8, 144.1, 158.4, 166.3, 168.3. HRMS (DART) m/z: [M]+
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calcd for (C22H25N2O2 ) 349.1911; found 349.1910.
(2S,4R)-1-(Tert-butoxycarbonyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-
carboxylic acid (5s). Performed using 0.5 mmol sulfone substrate, tBuOK (2.3 equiv.) and
ROH (1.05 equiv.). Base was slowly added at 10oC. The reaction was quenched to pH ~5
using aqueous HCl solution and worked up as described in the general procedure. Crude
product was crystallized from EtOAc. White solid (195 mg, 84%). MP: 193-200 oC. 1H NMR
(DMSO-d6, 400 MHz) δ 1.37 (s, 9H), 2.33-2.43 (m, 1H), 2.64-2.73 (m, 1H), 3.74-3.79 (m,
2H), 3.93 (s, 3H), 4.38 (dd, J = 8.0, 16.0 Hz, 1H), 5.54-5.69 (m, 1H), 7.17 (dd, J = 2.5, 9.0
Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.43 (s, 1H), 7.48-7.57 (m, 3H), 8.0 (d, J = 9.0 Hz, 1H), 8.28
(d, J = 7.0 Hz, 2H), 12.73 (br s, 1H); 13C {1H} NMR (DMSO-d6, 125 MHz) Two rotamers
found. Number in bracket is for minor rotamer. δ 27.8 (27.9), 36.1 (35.2), 51.8 (52.1),
55.4, 57.8 (57.5), 75.7 (76.4), 79.4 (79.3), 98.2, 107.4, 114.7, 117.9, 122.8, 127.4, 128.6,
129.5, 139.1, 150.6, 153.3, 153.7, 157.8, 160.9 (160.0), 173.8 (173.3). HRMS (ESI) m/z: [M
+ H]+ calcd for (C26H29N2O6 ) 465.2020; found: 465.2017.
+
(S)-4-(1-Phenylethoxy)pyridine (5t). Performed using 0.5 mmol sulfone substrate.
Isolated with 0-15% EtOAc in hexanes. Clear oil (75 mg, 75.3%). 1H NMR (CDCl3, 400 MHz)
δ 1.68 (d, J = 6.4 Hz, 3H), 5.41 (q, J = 6.4 Hz, 1H), 6.82 (d, J = 5.2 Hz, 2H), 7.29-7.38 (m,
5H), 8.35 (d, J = 5.2 Hz, 2H); 13C {1H} NMR (CDCl3, 100 MHz) δ 24.1, 76.7, 111.8, 125.4,
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128.0, 128.9, 141.4, 149.4, 165.1. HRMS (ESI) m/z: [M + H]+ calcd for (C13H14NO )
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200.1069; found 200.1067.
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4-((1R,2R,4S)-Bicyclo[2.2.1]heptan-2-yloxy)-7-methoxy-2-phenylquinoline
(5u).
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Chloro-quinoline 1a (1 mmol), exo-norborneol (1.2 equiv.), Cs2CO3 (1.5 equiv.), MeSO2Na
1
(0.4 equiv.) and DMF. Cream solid (242 mg, 70%). MP: 125-128oC. H NMR (CDCl3, 500
MHz) δ 1.20-1.34 (m, 3H), 1.53-1.60 (m, 1H), 1.62-1.74 (m, 2H), 1.79 (d, J = 10.0 Hz,1H),
1.92 (ddd, J = 2.0, 6.5, 13.5 Hz, 1H), 2.40 (s, 1H), 2.65 (d, J = 4.5 Hz, 1H), 3.95 (s, 3H), 4.50
(d, J = 6.5 Hz, 1H), 7.00 (s, 1H), 7.1 (dd, J = 2.5, 9.0 Hz, 1H), 7.42-7.46 (m, 2H), 7.51 (t, J =
7.5 Hz, 2H), 8.05–8.07 (m, 3H); 13C {1H} NMR (CDCl3, 125 MHz) δ 24.20, 28.4, 35.5 (2x),
40.1, 41.3, 55.5, 80.8, 98.6, 107.5, 115.6, 117.8, 123.1, 127.6, 128.7, 129.0, 140.8, 151.3,
159.3, 160.9, 161.1; HRMS (ESI) m/z: [M + H]+ calcd for (C23H24NO2 +) 346.1801; found
346.1793.
Synthesis of BI 201420 MU.
(2S,4R)-1-((S)-3,3-Dimethyl-2-((propoxycarbonyl)amino)butanoyl)-4-
hydroxypyrrolidine-2-carboxylic acid (2c): A 2L, 4-neck RBF equipped with a
thermocouple and a 1L addition funnel was charged with tert-Leucine (80 g, 610 mmol)
and THF (320 mL). The reaction contents were cooled to 5 oC using i-PrOH/CO2 bath. The
addition funnel was then charged with 2.0N NaOH (1.015L, 2030.0 mmol, 3.33 equiv) in
under N2 and then slowly added to the RBF in a dropwise manner while keeping the
internal temperature below 10 oC. Note: A nearly clear solution was obtained after 700
mL aq. NaOH had been added. A new addition funnel was then installed and the addition
funnel was charged with the n-propyl chloroformate (82.3 mL, 732 mmol, 1.09 equiv),
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followed by dropwise addition while keeping the internal temperature below 10 oC. The
cooling bath was then removed, and the reaction was allowed to warm to r.t. and aged
for additional 3h. To the reaction mixture was charged MTBE (400 mL) and stirred
vigorously for 5 minutes, then agitation was stopped and the phases were separated and
the upper organic phase was discarded as waste. The lower aqueous phase was returned
to the flask, and cooled using an ice bath. Conc. HCl (115 mL, 1380 mmol, 1.20 equiv) was
slowly charged at 9 oC to adjust the pH to 2.50. The resulting solution was then extracted
with EtOAc (1 X 400 mL, then 1 X 200 mL). The combined organic phases were then
washed with H2O (1 X 200 mL). The organic volatiles were then removed by short path
distillation (60oC/~ 50 mm, house vacuum) into a chilled receiver, until thick oil was
obtained. Heptane (200 mL) was then added to the oil and distillation again performed
until thick oil was obtained, then the azetropic distillation repeated with a second portion
of heptane (200 mL). This final oil was then dissolved in heptane (100 mL) and seeded
with 1g of pure seeds, causing rapid crystallization. The resulting slurry was stirred for 2h
at ~23oC, then filtered, and air-dried on the frit for 4h to give tert-Leu-carbamate (6, 112g,
85%) as colorless needles. Amide coupling: A 2L, 4-neck RBF equipped with a
thermocouple and a 500 mL addition funnel was charged with tert-Leu-carbamate 6 (55.8
g, 257 mmol, 1.0 equiv) and MeCN (125 mL). The resultant slurry was cooled to an
internal temperature of -2 °C in an ice/salt mixture. N-methylmorpholine (NMM), (141
mL, 1280 mmol, 5.0 equiv) was then added dropwise via addition funnel over 15 minutes
keeping the internal temp. < 2 °C. MeCN (10 mL) was then used to wash the walls of the
addition funnel into the flask. In a separate flask, a solution of p-toluenesulfonyl chloride
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(50.4 g, 264 mmol, 1.03 equiv) in MeCN (175 mL) was prepared by stirring the two
components together for 10 minutes, giving a clear solution. This solution was then
poured into the addition funnel. The solution was then added dropwise to the reaction
mixture over 30 minutes, keeping the internal temp. < 2 °C. The mixture was stirred 1.5h
at about 0 oC, then an aliquot was removed by syringe and quenched into a vial containing
few drops of benzylamine. HPLC analysis indicated formation of benzylamide. The
reaction mixture was cooled to -5 °C, then the H-Hyp-OMe HCl 7 (51.3 g, 282 mmol, 1.1
equiv) was added at once, causing an exotherm to 10 °C over ~ 5 minutes, which then fell
back to 5 °C over a further ~ 5 minutes. After reaction completion indicated by HPLC
analysis, LiOH solution (3.2 M, 370 mL, 1180 mmol, 4.6 equiv) was then charged to the
addition funnel and added dropwise to the reaction mixture over 30 minutes, keeping
the internal temperature < 10 °C. The cold bath was then removed and replaced by a
warm H2O bath, bringing the internal temperature to 23 oC in 10 minutes. After reaction
completion indicated by HPLC analysis, the mixture was then cooled to -10 °C and 220
mL 6N HCl (220 mL, 1320 mmol, 5.1 equiv) was added dropwise over 20 minutes, using
an in situ pH meter to bring the pH to 8.0. MeCN was then removed by short-path
distilation at 45 °C/~100 mm (house vacuum) into a chilled (-78 °C) receiver, collecting
270 mL. The residual aqueous solution was then heated to 50 °C, then the pH was
adjusted to 2.5 by the dropwise addition of 6N HCl (50 mL). The mixture was aged one
hour at 50 °C, then the pH was further adjusted to 1.25 by 6N HCl (~ 10 mL). This mixture
was aged one hour at 50 °C (using heating mantle), then allowed to cool. When the
internal temperature reached 37 °C, 0.5g of pure seeds were added, causing rapid
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crystallization. The resultant slurry was stirred two hours at 23 °C, then filtered. The filter
cake was washed with 0.1N HCl (1 X 200 mL), then dried under a vigorous stream of N2
on the frit for one hour. The resultant solid was then dried at 50 °C/100 mm for 16h to
give 67.9g of 2c as a colorless solid. Yield: 80.0%. MP 145 oC (from DSC). The identity of
2c was confirmed by NMR analysis (1H, 13C, COSY, ROESY, HMQC and HMBC) in DMSO-d6
at 26 oC. 1H NMR (DMSO-d6, 500 MHz, 299 K) δ 6.94 (d, J = 9.3 Hz, 1H), 5.16 (s(br), 1H),
4.32 (br, 1H), 4.25 (t, J = 8.1 Hz, 1H), 4.18 (d, J = 9.2 Hz, 1H), 3.90 (m, 2H), 3.64 (m, 2H),
2.09 (m, 1H), 1.88 (m, 1H), 1.55 (m, 2H), 0.95 (s, 9H), 0.87 (t, , J = 7.3 Hz 3H); 13C {1H} NMR
(DMSO-d6, 125 MHz) δ 173.3, 169.9, 156.4, 68.8, 65.5, 58.8, 57.7, 56.0, 37.3, 35.1, 26.2,
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22.0, 10.2. HRMS (ESI) m/z: [M + H]+ calcd for [C15H27N2O6 ] 331.1864; found 331.1864.
N-(6-Acetyl-2-bromo-3-methoxyphenyl)-2-(isopropylamino)thiazole-4-carboxamide
(12): This material was synthesized using the literature reference.13b Characterization
data is in accordance with that reported in literature.13b
4-(8-Bromo-7-methoxy-4-(phenylsulfonyl)quinolin-2-yl)-N-isopropylthiazol-2-amine
(4b): This material was synthesized using the literature reference.13b Characterization
data is in accordance with that reported in literature.13b
4-(8-Bromo-7-methoxy-4-(methylsulfonyl)quinolin-2-yl)-N-isopropylthiazol-2-amine
(4d): A 0.5 L jacketed reactor fitted with a mechanical stirrer, thermocouple, N2 inlet,
and addition funnel was charged with N-(6-acetyl-2-bromo-3-methoxyphenyl)-2-
(isopropylamino)thiazole-4-carboxamide 12 (41.2 g, 100 mmol, 1.0 equiv, KF = 0.05% H2O)
and KOH pellets (5.05 g, 90 mmol, 0.9 equiv). To the reactor was charged THF (280 mL)
and t-BuOH (160 mL) and heated to 70 oC (using heating mantle) and stirred for additional
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