Design, synthesis and biological evaluation of GPR55 agonists

Accepted Manuscript

Lara Fakhouri, Christopher D. Cook, Mohommed H. Al-Huniti, Linda M.

Console-Bram, Dow P. Hurst, Michael B.S. Spano, Daniel J. Nasrallah, Marc

G. Caron, Larry S. Barak, Patricia H. Reggio, Mary E. Abood, Mitchell P. Croatt

PII:

S0968-0896(17)30652-1

DOI:

http://dx.doi.org/10.1016/j.bmc.2017.06.016

BMC 13799

Reference:

Bioorganic & Medicinal Chemistry

To appear in:

Received Date:

Revised Date:

Accepted Date:

7 April 2017

5 June 2017

12 June 2017

Please cite this article as: Fakhouri, L., Cook, C.D., Al-Huniti, M.H., Console-Bram, L.M., Hurst, D.P., Spano,

M.B.S., Nasrallah, D.J., Caron, M.G., Barak, L.S., Reggio, P.H., Abood, M.E., Croatt, M.P., Design, synthesis and

biological evaluation of GPR55 agonists, Bioorganic & Medicinal Chemistry (2017), doi: http://dx.doi.org/10.1016/

j.bmc.2017.06.016

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Bioorganic & Medicinal Chemistry

jo u r n a l h o m e p a g e : w w w . e ls e v i e r . c o m

Design, synthesis and biological evaluation of GPR55 agonists

Lara Fakhouri,^aChristopher D. Cook,^aMohommed H. Al-Huniti,^aLinda M. Console-Bram,^bDow P. Hurst,^a

Michael B. S. Spano,^aDaniel J. Nasrallah,^aMarc G. Caron,^cLarry S. Barak,^cPatricia H. Reggio,^a,*Mary E.

Abood,^b,*and Mitchell P. Croatt.^a,*

^aDepartment of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, NC

27402, United States

^bTemple University School of Medicine, Anatomy and Cell Biology, Center for Substance Abuse Research, 3420 North Broad St., Philadelphia, Pennsylvania,

19140, United States

^cDuke Center of Excellence, 444 Sands Building, Department of Cell Biology, Durham, NC 27710, United States

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and

neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will

aid to further establish the specific physiological roles and pharmacology of the receptor.

Towards this goal, a targeted library of 22 compounds was synthesized in a modular fashion to

obtain structure-activity relationship information. The general route consisted of coupling a

variety of p-aminophenyl sulfonamides to isothiocyanates to form acylthioureas. For the

synthesis of a known naphthyl ethyl alcohol motif, route modification led to a shorter and more

efficient process. The 22 analogues were analyzed for their ability to serve as agonists at

GPR55 and valuable information for both ends of the molecule was ascertained.

Available online

Keywords:

GPR55

Homology model

Thiourea

β-Arrestin recruitment assay

Cancer

a CB₁antagonist, strongly activates GPR55.¹²Another example is the

CB₁and CB₂agonist CP55940¹³which acts as an antagonist when

1. Introduction

bound to GPR55. In addition, the results obtained for the same ligand

tested may vary depending on the assay employed and the cell

type.^14-16

GPR55 is a membrane-bound G protein-coupled receptor (GPCR)

that is highly expressed in the brain, particularly in the

hypothalamus, olfactory bulb, and striatum.^1-2It is also found in

other organs and tissues such as bone marrow,³neutrophils⁴and the

spleen.⁵It has been established so far that GPR55 is a potential target

for treating pain,⁶osteoporosis³and cancer.⁷In adjuvant-induced

inflammation and partial nerve ligation pain models, GPR55

knockout mice developed neither inflammatory nor neuropathic

mechanical hyperplasia.⁶The receptor-deprived mice also revealed a

role of GPR55 in regulating osteoclasts’ number and function based

on the finding that the number of inactive osteoclasts was higher

compared to wild type mice.³A recent study revealed high

expression of GPR55 in myenteric colonic neurons and the

involvement of the receptor in colonic motility.⁸The role of GPR55

in cancer proliferation has been recently well-established to be

proliferative rather than anti-proliferative.⁷It was not only detected

in various cancer cell lines such as breast, brain, skin⁷, and prostate⁹

but also discovered in a number of clinical isolates from cancer

patients.⁷Furthermore, it has been shown that GPR55 activation

stimulates angiogenesis¹⁰and metastasis,⁹which explains the

correlation of GPR55 expression with cancer aggressiveness.

L-α-lysophosphatidylinositol (LPI, 1; Figure 1) is the endogenous

agonist of GPR55, but not the best candidate to be labeled for

studying the receptor due to its lack of selectivity for GPR55. The

need for a selective and potent ligand prompted high-throughput

screening which was conducted by the Sanford-Burnham screening

center. Out of approximately 290,000 different compounds tested,

three chemically distinct compounds, namely CID1792197 (2),^17-18

CID1172084 (3), and CID2440433 (4), were identified as potent

agonists of GPR55 with EC₅₀’s of 0.11, 0.16 and 0.26 μM,

respectively.¹⁹In addition to the moderate potency of these ligands is

their selectivity for GPR55 over other cannabinoid receptors, > 30

μM activity of CB₁, CB₂and the closely related atypical cannabinoid

receptor GPR35, which renders them as appropriate leads to develop

probes for studying GPR55.¹⁷

For the study described herein, it was decided to explore analogues

of CID1792197 (2). There are a variety of reasons for this decision.

First, the synthetic approach, described hereafter, is modular in

nature to rapidly enable the independent modification of either end of

the molecule. Second, there was not many commercially available

derivatives of this molecule that explored modifications that we

desired. Third, it was envisioned that synthetic derivatives of

Initial in vitro screening identified GPR55 as a cannabinoid

receptor due to similarities with cannabinoid receptors CB₁and

CB₂.¹¹Yet the various cannabinoid ligands exert different

pharmacology when bound to GPR55. AM251 for instance, which is

———

^*Corresponding author. Tel.: +1 336 334 3785 (M.P.C.).

E-mail addresses: mpcroatt@uncg.edu (M.P. Croatt).

compound 2 could remove the α,β-unsaturated amide, which could

serve as an indiscriminate Michael acceptor with diverse off-target

activities. Finally, this compound was a selective GPR55 agonist

with no activity at CB1, CB2, or GPR35.¹⁷

Scheme 2. Synthetic scheme for synthesis of alkylphenyl amines 8a-

8e. Reagents and conditions: (a) aniline, ethanol, 80 °C (28-56%);

(b) i) NaBH₄, MeOH ii) HCl (52-72%); (c) i) ethanol, 80 °C ii)

NaBH₄, MeOH iii) HCl (34-96%).

Figure 1. Chemical structures of LPI (1), CID1792197 (2),

CID1172084 (3) and CID2440433 (4).

2.2. Synthesis of p-aminobenzene sulfonamides 7

2. Results and discussion

Upon the availability of the primary or secondary amines (8a-8k),

they were reacted with p-nitrophenyl sulfonyl chloride in basic

conditions to give corresponding p-nitrophenyl sulfonamides 11a-

11k (Scheme 3).²⁰Hydrogenation using Pd/C and an atmosphere of

hydrogen reduced the nitro group into an amine and yield anilines

7a-7k. In addition to these eleven sulfonamides, sulfisoxazole (7l)

was purchased and used in the subsequent synthetic route.

CID1792197 (2) was the scaffold chosen for further lead

development due to synthetic feasibility to obtain analogues.

Modifications of the lead (2) were targeted at the two termini in

order to increase activity as a selective GPR55 agonist, enhance

solubility, and eliminate the Michael acceptor functionality. In order

to synthesize analogues that explored the role that each end of the

molecule plays with respect to the overall activity of the analogue, a

retrosynthesis was designed to be modular in nature (Scheme 1). By

doing so, each end of the analogue could be independently modified

and the total number of steps to analogues would be fewer. It was

envisioned that the two parts of the molecule could be coupled by

reacting an acylisothiocyanate with an amine to generate the

acylthiourea moiety of the analogues (6). The acylisothiocyanates

could be synthesized from carboxylic acids 5. The anilines (7) could

be prepared by substituting the chloride in p-nitrophenyl sulfonyl

chloride with the proper amine (8),²⁰followed by catalytic

hydrogenation of the nitro group.²¹Many, but not all, of the

carboxylic acids (5) and amines (8) were commercially available and

the remainder were synthesized as described herein.

Scheme 3. Synthesis of p-nitro and p-amino benzene sulfonamides.

Reagents and conditions: (a) p-nitrophenyl sulfonyl chloride,

pyridine, CH₂Cl₂(5-91%); (b) Pd/C, H₂, MeOH (12-92%).

2.3. Preparation of aryl carboxylic acids 5

Three of the desired carboxylic acids (5v-5x) were commercially

available and the 6-hydroxymethyl and 6-hydroxyethyl 2-naphthoic

acids (5y and 5z) required synthetic routes (Scheme 4). The

naphthoic acid derivatives were prepared in lab starting with

commercially available methyl 6-bromo-2-naphthoate (12). Attempts

to reduce ester 12 to the corresponding aldehyde (14) using DIBAL-

H²³in a one pot reaction were not successful despite the efforts of

maintaining the temperature of the mixture at -78 °C throughout the

entire reaction time. The only product observed following quenching

the reaction at various times, even before the ester was fully

consumed, was alcohol 13. Thus, the number of equivalents of

DIBAL-H used was increased to ensure full conversion.

Alternatively, this reaction was also examined using flow chemistry.

It was previously determined that aryl esters were especially difficult

to reduce to the aldehyde,^24-25but using high flow rates (50 mL/min),

cold temperatures (-78 °C), and short reaction times (0.037 sec), we

were able to obtain a moderate yield of the aldehyde (14) directly,

although with some over-reduction to the alcohol (13). For

simplicity, it was decided to fully convert ester 12 to alcohol 13 and

then oxidize it to the aldehyde. For an alternate analogue, alcohol 13

was protected as a silyl ether to generate bromide 17.

Scheme 1. Retrosynthetic scheme of GPR55 Agonists

2.1. Preparation of amine precursors 8

Six of the amine precursors were commercially available (8f-8k),

and the remaining structures (8a-8e) were synthesized through

reductive amination (Scheme 2).²²As such, aniline was reacted

with the different aldehydes 9a-9e to give the corresponding imine

which was reduced into the target secondary amines (8a-8e) using

NaHB₄.²²In the case of isonicotinaldehyde (9a) and 5-

(hydroxymethyl)furan-2-carbaldehyde (9b), the resulting imines (9a

and 9b) were purified. For secondary amines 8c-8e, the imine

intermediates were reacted with the reducing agent without being

isolated.

In order to be systematic, all of the amines were combined with acid

5v since this was present in the parent system (2). These analogues

(6av-6lv) determined the role of the sulfonamide section of the

molecule. To explore the role of the carboxylate section, all of the

acids were coupled to amine 7f since the groups on this amine are

present in the parent molecule (2). Analogues 6fv-6fz therefore show

the role that the carboxylate plays for activity. Based on the

activities of these compounds (vide infra), the best two carboxylic

acids (5x and 5z) were coupled to the best sulfonamides (7a, 7b, 7e,

and 7g) to generate analogues 6ax, 6bx, 6ex, 6gx, 6bz, and 6gz.

Scheme 4. Synthesis of naphthoic acid derivatives. Reagents and

conditions: (a) DIBAL-H (3 equiv.), THF, - 40 °C - rt, 8 hr (90%

yield of 20); (b) DIBAL-H (3 equiv.), -78 °C, toluene, 0.03 sec (in

flow; 95% yield of a 1:1.6 mixture of 13 and 14); (c) MnO₂, CHCl₃

(47%); (d) 1) oxalyl chloride, DMSO; 2) Et₃N (60%); (e) Ph₃PCH₃I,

NaH, THF (65%); (f) 1) BH₃-THF, THF; 2) NaOH, H₂O₂(77%); (g)

TBSCl, DMAP, Et₃N (53% of 17); (h) TBSCl, DMAP, Et₃N (84% of

18); (i) 1) nBuLi, THF; 2) CO₂; 3) H₃O⁺(19% for 5y; 42% for 5z);

(j) Et₃NHCl, Zn, NiBr₂, bipy, NaI, DMPU, pyridine, ethylene oxide

(66%); (k) TBSCl, imidazole, DMAP (5 mol %), CH₂Cl₂; then

LiOH(aq)/THF, 50 °C (62% yield of 5z).

Alcohol 13 was oxidized using MnO₂in CHCl₃to give the

corresponding aldehyde 14.²⁶The low yields for this benzylic

oxidation reaction, in particular when scaling up the reaction,

benefitted from the use of the alternative Swern oxidation conditions.

The use of DMSO and oxalyl chloride followed by Et₃N significantly

enhanced the yields of oxidizing alcohol 13 to aldehyde 14. A Wittig

reaction, using methyltriphenylphosphonium iodide, was conducted

to prepare 2-bromo-6-vinylnaphthalene 15.²⁷Hydroboration and

oxidation of 15 gave the anti-Markovnikov alcohol 16.²⁸Protection

of the alcohol was done using TBSCl in basic conditions²⁹to

generate bromide 18. Conversion of the aryl bromide of silyl ether 18

into the corresponding carboxylic acid (5z) was achieved by lithium-

halogen exchange using n-butyl lithium followed by purging the

mixture with CO₂gas.³⁰Structurally similar precursor 17 was also

converted to the carboxylic acid (5y) to investigate the effect of the

side chain length on activity.

Scheme 5. Synthesis of analogues 6. Reagents and conditions: (a)

SOCl₂, 80 °C, 3 hrs; (b) i) KSCN, CH₃CN, -10 °C – r.t., 3 hrs; ii) 7a-

7l, 24 hrs (6-65%).

2.5. GPR55 agonist activities

The synthetic route described in Scheme 4 was successful in

obtaining compounds for examination, however, the inefficiency and

number of reactions led to a reexamination of the route, especially

for acid 5z. It was envisioned that the bromide could be converted

into an organometallic species, which could in turn open ethylene

oxide to access the same acid (5z) in a more straightforward fashion.

Initial attempts using metal-halogen exchange and opening of

ethylene oxide in the presence of Lewis acids were not successful.

Fortunately, a milder procedure, recently reported by Weix and

coworkers, using nickel-catalysis produced the desired acid in 66%

yield which generates the protected silyl ether (5z) after facile

silylation and saponification. This modification of the route using

chemistry developed by Weix and coworkers shortened the synthesis

of acid 5z from 6 steps to 2 steps and increased the overall yield from

under 10% to more than 40%.

The synthesized final compounds (6) were tested for activation of

GPR55 using a β-arrestin assay. The parent compound was

previously tested in two other assays, MAPK and PKC translocation,

but the β-arrestin assay was chosen since it was most active in that

assay.¹⁷The β-arrestin assay was run using CHO-K1 cells stably

expressing GPR55, fused with a β-galactosidase enzyme fragment,

and β-arrestin fused to an N-terminal deletion mutant of β-

galactosidase (DiscoverX) in the PathHunter® β-arrestin assay as

previously published.³²Activation of GPR55 induces β-arrestin

recruitment, forcing complementation of the two β-galactosidase

enzyme fragments. Levels of this active enzyme are a direct result of

GPR55 activation and are quantitated using chemiluminescent

PathHunter® detection reagents containing the β-galactoside

substrate. The chemiluminesence signal was measured using a Perkin

Elmer Envision plate reader for 1 second. Ligand readings were

subtracted by their corresponding vehicle reading and analyzed in

GraphPad Prism. Agonist activity was evaluated along with LPI-

induced receptor activation. All data was analyzed using GraphPad

Prism version 5.0 (GraphPad, San Diego, CA) to obtain EC₅₀values

summarized in Figures 2 and 3.

2.4. Synthesis of completed analogues 6

The commercially available carboxylic acids (5v-5x) and

synthesized naphthoic acid derivatives (5y and 5z) were converted

into the more active acyl chlorides by refluxing with thionyl chloride

(Scheme 5). The resultant acyl chlorides were converted without

isolation into the isothiocyanate intermediates using potassium

thiocyanate.³¹The unpurified intermediates were further reacted with

the p-amino sulfonamides (7a-7l) to give the target analogues (6).²¹

The synthesized parent ligand activity was slightly lower (0.3 μM) in

comparison to the reported activity (0.11 μM), but in a similar range.

For analogues having the 2-methoxyphenyl acryloyl moiety (6av-

6lv), it is crucial to have an aromatic phenyl ring as one of the

substituents of the sulfonamide’s nitrogen; removing the phenyl ring

diminished the activity (6jv, 6kv, and 6lv). Even replacing the

phenyl group with another aromatic bioisostere; namely 3,4-

dimethylisoxazole of analogue 6lv led to the same result as when

removing the ring. Although, the aforementioned substituent leads

to solubility enhancement, the change of distribution and overall

electron density of the isoxazole π-system relative to the phenyl

counterpart may play a major contributing factor to disturbing pi-pi

stacking in the binding pocket of the receptor.

and 6gz) were both less active. Although the second generation

analogues did not receive a significant activity boost by modifying

both ends of the analogue, they still provide valuable information.

First, five different analogues containing the 7-quinoline moiety

were synthesized and all of them are relatively active. While this is

also true for the 2-methoxyphenyl acryloyl moiety of the parent

compound, the quinoline ring removes the Michael acceptor of the

parent system, making the compounds much more attractive as leads

and tools in biochemical systems. Another conclusion from the

second generation analogues is that the presence of hydroxyl groups

on both ends of the analogue was not beneficial.

3. Conclusion

Utilizing

a modular synthesis, 22 unique compounds were

synthesized. These included 12 different sulfonamide substitutions,

five different acyl groups attached to the thiourea, and six hybrid

analogues where both sections were modified. The activities of the

compounds indicated both beneficial and detrimental interactions.

For example, the potential and optimal positions of hydroxyl groups

for hydrogen bonding to the receptor (analogues 6bv, 6cv, 6dv, 6ev,

6gv, 6jv, 6kv, 6fy, 6fz, 6bx, 6ex, 6gx, 6bz, and 6gz) and the position

of aromatic nitrogen atoms (6av, 6iv, 6lv, 6fw, 6fx, 6ax, 6bx, 6ex,

and gx) on either end of the ligand were analyzed. These data serve

as a springboard for the design of even more potent and selective

ligands to serve as agonists at GPR55.

4. Experimental

4.1. General experimental procedures

Unless otherwise stated, all reactions were carried out under an

atmosphere of dry nitrogen in oven-dried glassware. Indicated

reaction temperatures refer to those of the reaction bath, while room

temperature (rt) is noted as 25 °C. All solvents and reagents were

obtained from commercial sources and were used as received.

Analytical thin layer chromatography (TLC) was performed on silica

gel 60 F254 precoated plates (0.25 mm) from Merck. Visualization

was accomplished by irradiation under a 254 nm UV lamp. Silicycle

silica gel 230−400 (particle size 40−63 μm) mesh was used for all

ﬂash column chromatography. If needed, products were puriﬁed by

reverse phase chromatography, which was performed using a Varian

puriﬁcation system employing a Phenomenex Gemini-NX, (5 µm,

C18, 110A, AX. 250 × 21.20 mm). The mobile phase was a mixture

of acetonitrile and H₂O containing 0.1% formic acid. ¹H NMR

spectra were recorded on a Jeol ECA 500 MHz spectrometer or a

Jeol ECS 400 MHz spectrometer in the solvent indicated. All ¹H

NMR experiments were run at 17 °C except for DMSO-d₆solvent

that was run at 25 °C. Chemical shifts are reported in δ units, parts

per million (ppm) downﬁeld of TMS, and were measured relative to

the signals for chloroform (7.26 ppm), methanol (3.31 ppm), acetone

(2.05 ppm) and dimethyl sulfoxide (2.50 ppm). All ¹³C NMR spectra

were reported in ppm relative to the signals for chloroform (77 ppm),

methanol (49 ppm), acetone (29.8 ppm) and dimethyl sulfoxide (39.5

Figure 2. EC₅₀Activities of First Generation GPR55 Agonists.

Confidence intervals included parenthetically for compounds with

EC₅₀values less than 1 micromolar.

Among the synthesized analogues possessing the 2-methoxyphenyl

acryloyl moiety, compounds 6av, 6bv, 6ev, and 6gv were selected

for further exploration since they were accessible and had good

activities (EC₅₀≤ 0.5 μM).

With respect to the different

carboxylates, it was decided to continue studying analogues 6fx and

6fz since they had the more potent activities.

1

ppm) with ¹H decoupled observation. Data for H NMR are reported

as follows: chemical shift (δ ppm), multiplicity (s = singlet, d =

doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, sept =

septet, oct = octet, m = multiplet), integration and coupling constant

(Hz), whereas ¹³C NMR analyses were reported in terms of chemical

1

shift and number of equivalent carbons if more than one. H and ¹³

C

NMR spectra for new all new compounds are included in the

Supporting Information. High resolution mass spectrometry data

(HRMS) were performed on a Thermo Fisher Scientific UPLC/LTQ

Orbitrap XL system.

Figure 3. EC₅₀Activities of Second Generation GPR55 Agonists.

Confidence intervals included parenthetically for compounds with

EC₅₀values less than 1 micromolar.

For the second generation analogues (Figure 3), it was determined

that the quinoline-based analogues (6ax, 6bx, 6ex, and 6gx) had

similar or slightly improved potency. Unfortunately, the second

generation analogues utilizing the hydroxyethylnaphthyl group (6bz

4.2. Synthesis of secondary amines (8a-8e)

4.2.1. Two-step synthesis of secondary amines (8a-8b)

Step 1: Synthesis of imines 10a-10b.³³Aniline (1 equiv.) and the

aldehyde 9a-9b (1 equiv.) were dissolved in dry ethanol (0.5 M) and

the resulting mixture heated under reflux for 3 hrs. The solution was

cooled to room temperature and the solvent removed under reduced

pressure. Purification of the product was done via recrystallization

using an appropriate mixture of solvents where enough volume of the

more polar solvent was added to dissolve the crude mixture and the

less polar solvent was added until reaching the saturation point.

concentrated under reduced pressure. Purification of the crude

product was accomplished via recrystallization using an appropriate

mixture of solvents where enough volume of the more polar solvent

was added to dissolve the crude mixture and the less polar solvent

was added until reaching the saturation point.

4.2.2.1. 2-((Phenylamino)methyl)phenol (8c)

The crude product was via recrystallization using a mixture of ethyl

1

acetate and hexane. Yield (0.359 g, 96%). H NMR matched that

Step 2: Reduction of Imines 10a-10b.²²To a solution of the imine

(10a-10b, 1 equiv.) in MeOH (0.5 M) was added NaBH₄(5 equiv.)

portion-wise and the mixture stirred for 24 hours at room

temperature. The solution was acidified to a pH of 3 using HCl (50

% v/v) followed by increasing the pH to 9 using NaOH (2 M). The

product was extracted using dichloromethane. The organic layer was

dried over MgSO₄, filtered and concentrated under reduced pressure.

Purification of the product was accomplished using flash column

chromatography or via recrystallization using an appropriate mixture

of solvents where enough volume of the more polar solvent was

added to dissolve the crude mixture and the less polar solvent was

added until reaching the saturation point.

previously reported.^{34 1}H NMR (400 MHz, CDCl₃): δ 8.44 (bs, 1H;

O-H), 7.26-7.20 (m, 3H; Ar-H), 7.16 (d. J = 6.9 Hz, 1H; Ar-H), 6.94-

6.84 (m, 5H; Ar-H), 4.41 (s, 2H, N-CH₂), 3.95 (bs, 1H; N-H).

4.2.2.2. 3-((Phenylamino)methyl)phenol (8d)

The crude product was purified via recrystallization using a mixture

1

of ethyl acetate and hexane. Yield (0.116 g, 36%). H NMR matched

that previously reported.^{35 1}H NMR (400 MHz, CD₃OD): δ 7.08 (t, J

= 7.8 Hz, 1H; Ar-H), 7.03 (t, J = 8.0 Hz, 2H; Ar-H), 8.24 (m, 2H;

Ar-H), 6.62-6.53 (m, 4H; Ar-H), 4.20 (s, 2H, N-CH₂).

4.2.2.3. 4-((Phenylamino)methyl)phenol (8e)

The crude product was purified via recrystallization using a mixture

1

4.2.1.1. (E)-N-Phenyl-1-(pyridin-4-yl)methanimine (10a)

of ethyl acetate and hexane. Yield (110 mg, 34%). H NMR matched

that previously reported.^{36 1}H NMR (500 MHz, CDCl₃): δ 7.24 (d, J

= 8.6 Hz, 2H; Ar-H), 7.17 (dd, J = 7.5, 8.6 Hz, 2H, Ar-H), 6.80 (d, J

= 8.6 Hz, 2H; Ar-H), 6.72 (t, J = 7.5 Hz, 1H; Ar-H), 6.63 (d, J = 8.6

Hz, 2H; Ar-H), 4.24 (s, 2H; N-CH₂).

The crude product was recrystallized using a mixture of ethyl

1

acetate and hexane. Yield (0.936 g, 28%). H NMR matched that

previously reported.^{22 1}H NMR (500 MHz, acetone-d₆): δ 8.73 (dd, J

= 1.7, 4.3 Hz, 2H; Ar-H), 8.64 (s, 1H; CH), 7.84 (dd, J = 1.7, 4.3 Hz,

2H; Ar-H), 7.42 (dd, J = 1.7, 6.6 Hz, 2 H; Ar-H), 7.26-7.30 (m, 3H;

Ar-H).

4.3. General procedure for the synthesis of p-nitro sulfonamides

(11a-11k).

4.2.1.2. (E)-(5-((Phenylimino)methyl)furan-2-yl)methanol (10b)

The crude product was recrystallized using

a mixture of

A suspension of p-nitrobenzenesulfonyl chloride (1.1 equiv.), in

CH₂Cl₂(0.6 M), was added to a solution of the amine (8a-8k, 1

equiv.) and pyridine (2 equiv.) in CH₂Cl₂(0.9 M) and the mixture

stirred for 24 hours. The solution was diluted with CH₂Cl₂and

quenched with 1M HCl and washed with 10% NaHCO₃. The organic

layer was dried and the solvent evaporated. Purification was done via

flash column chromatography or recrystallization using an

appropriate solvent or a mixture of solvents where enough volume of

the more polar solvent was added to dissolve the crude mixture and

the less polar solvent was added until reaching the saturation point.

1

dichloromethane and hexane. Yield (0.47 g, 56%). H NMR (500

MHz, acetone-d₆): δ 8.33 (s, 1H, N=CH), 7.37 (m, 2H; Ar-H), 7.20

(m, 3H; Ar-H), 7.00 (d, J = 3.3 Hz, Ar-H), 6.48 (d, J = 3.4 Hz, Ar-

H), 4.61 (s, 1H, O-CH₂), 4.60 (s, 1H, O-CH₂). ¹³C NMR (125 MHz,

acetone-d₆): δ 159.3, 152.0, 147.9, 129.2 (2C), 125.9 (2C), 120.9

(2C), 117.3, 109.3, 56.6. HRMS (ESI, m/z): Calculated for

C₁₂H₁₂NO₂[M + H]⁺202.0863; found 202.0855 (3.7 ppm).

4.2.1.3. N-(Pyridin-4-ylmethyl)aniline (8a)

The crude product was recrystallized using

a mixture of

dichloromethane and hexane. Yield (0.786 g, 52%). ¹H NMR

matched that previously reported.^{22 1}H NMR (500 MHz, acetone-d₆):

δ 8.46 (dd, J = 1.7, 4.6 Hz, 2H; Ar-H), 7.33 (dd, J = 1.7, 4.6 Hz, 2H;

Ar-H), 7.04 (dd, J = 1.7, 6.6 Hz, 2H; Ar-H), 6.54-6.59 (m, 3H; Ar-

H), 4.39 (d, J = 5.7 Hz, 2H, CH₂).

4.3.1.

4-Nitro-N-phenyl-N-(pyridin-4-

ylmethyl)benzenesulfonamide (11a)

The crude product was purified via recrystallization using ethyl

1

acetate. Yield (0.193 g, 38%). H NMR (500 MHz, acetone-d₆): δ

8.45 (d, J = 6.3 Hz, 2H; Ar-H), 8.43 (d, J = 9.2 Hz, 2H; Ar-H), 7.94

(d, J = 8.6 Hz, 2H; Ar-H), δ 7.31 (d, J = 6.3 Hz, 2H; Ar-H), 7.29-

7.25 (m, 3H, Ar-H), 7.17-7.15 (m, 2H, Ar-H), 4.96 (s, 2H, N-CH₂).

¹³C NMR (125 MHz, acetone-d₆): δ 150.6, 149.9 (2C), 145.3, 143.7,

138.5, 129.3 (2C), 129.2 (2C), 128.8 (2C), 128.4, 124.5 (2C), 123.0

(2C), 53.6. HRMS (ESI, m/z): Calculated for C₁₈H₁₆N₃O₄S [M + H]⁺

370.0856; found 370.0844 (3.3 ppm).

4.2.1.4. (5-((Phenylamino)methyl)furan-2-yl)methanol (8b)

The crude product was purified using flash column chromatography

over silica gel. It eluted with ethyl acetate and hexane (0.2:1, v/v).

Yield (0.514 g, 72%). ¹H NMR (500 MHz, acetone-d₆): δ 7.07 (dd, J

= 7.2, 8.6 Hz, 2H, Ar-H), 6.68 (dd, J = 1.2, 8.6 Hz, 2H, Ar-H), 6.58

(d, J = 7.2 Hz, Ar-H), 6.16 (d, J = 3.2 Hz, 1H, Fu-H), 6.15 (d, J =

3.2 Hz, 1H, Fu-H), 5.28 (bs, 1H; N-H), 4.44 (d, J = 5.7 Hz, 2H; O-

CH₂), 4.25 (d, J = 5.7 Hz, 2H; N-CH₂), 4.21 (t, J = 6.0 Hz, 1H; O-H).

¹³C NMR (125 MHz, acetone-d₆): δ 154.8, 153.0, 148.6, 128.9 (2C),

116.8, 112.7 (2C), 107.6, 107.4, 56.5, 40.7. HRMS (ESI, m/z):

Calculated for C₁₂H₁₄NO₂[M + H]⁺204.1019; found 204.1014 (2.5

ppm).

4.3.2.

N-((5-(Hydroxymethyl)furan-2-yl)methyl)-4-nitro-N-

phenylbenzenesulfonamide (11b)

The crude product was purified via recrystallization using a mixture

1

of ethyl acetate in hexane. Yield (9.3 mg, 5%). H NMR (500 MHz,

acetone-d₆): δ 8.38 (dd, J = 2.3, 8.6 Hz, 2H; Ar-H), 7.89 (dd, J = 2.3,

8.6 Hz, 2H, Ar-H), 7.31-7.26 (m, 3H; Ar-H), 7.05 (dd, J = 2.3, 8.0

Hz, 2H; Ar-H), 6.06 (d, J = 2.9 Hz, 1H; Fu-H), 6.03 (d, J = 2.9 Hz,

1H; Fu-H), 4.88 (s, 2H; N-CH₂), 4.36 (d, J = 5.7 Hz, 2H; N-CH₂),

4.21 (t, J = 5.7 Hz, 1H; O-H). ¹³C NMR (125 MHz, acetone-d₆): δ

156.1, 150.3, 148.6, 144.7, 138.7, 129.3 (2C), 129.2 (2C), 129.1

(4C), 128.5, 124.3 (2C), 110.7, 107.5, 56.3, 48.2. HRMS (ESI, m/z):

Calculated for C₁₈H₁₇N₂O₆S [M + H]⁺389.0802; found 389.0794

(2.0 ppm).

4.2.2. One-step synthesis of secondary amines (8c-8e)

Aniline 1.20 (1 equiv.) and the aldehyde 9c-9e (1 equiv.) were

dissolved in dry ethanol (0.8 M) and the resulting mixture heated

under reflux for 3 hrs. The solution was cooled to room temperature,

NaBH₄(5 equiv.) was added portion-wise and the mixture stirred for

an hour. The solution was diluted with H₂O and extracted with ethyl

acetate. The organic layer was dried over MgSO₄, filtered and

4.3.3.

N-(2-Hydroxybenzyl)-4-nitro-N-

eluted with ethyl acetate and hexane (0.75:1, v/v). Yield (0.366 g,

34%). H NMR (500 MHz, acetone-d₆): δ 8.49 (dd, J = 1.7, 4.6 Hz,

phenylbenzenesulfonamide (11c)

The crude product was purified via recrystallization using a mixture

of ethyl acetate and hexane. Yield (175 mg, 91%). H NMR (400

1

2H; Ar-H), 8.40 (dd, J = 2.3, 9.2 Hz, 2H; Ar-H), 7.90 (dd, J = 2.3,

9.2 Hz, 2H; Ar-H), 7.27 (dd, J = 1.7, 4.6 Hz, 2H; Ar-H), 3.34 (s, 3H;

N-CH₂). ¹³C NMR (125 MHz, acetone-d₆): δ 150.8 (2C), 148.3,

141.93, 141.92, 129.1 (2C), 124.6 (2C), 118.6 (2C), 36.5. HRMS

(ESI, m/z): Calculated for C₁₂H₁₂N₃O₄S [M + H]⁺294.0543; found

294.0539 (1.4 ppm).

MHz, CDCl₃): δ 8.35 (d, J = 8.7 Hz, 2H; Ar-H), 7.88 (d, J = 8.7 Hz,

2H; Ar-H), 7.32-7.24 (m, 3H; Ar-H), δ 7.15 (dt, J_d= 1.8 Hz, J_t= 7.3

Hz, 1H; Ar-H), 6.95 (dd, J = 1.8, 8.0 Hz, 2H; Ar-H), 6.72 (dt, J_t=

1.8 Hz, J_d= 7.8 Hz, 1H; Ar-H), 6.68 (t, J = 7.8 Hz, 1H; Ar-H), 4.76

(s, 2H; N-CH₂). ¹³C NMR (100 MHz, CDCl₃): δ 155.8, 151.1, 145.0,

139.7, 130.8, 129.9 (2C), 129.7 (2C), 129.6 (2C), 129.6, 128.8,

125.1, 122.7, 120.3, 115.9, 49.9. HRMS (ESI, m/z): Calculated for

C₁₉H₁₇N₂O₅S [M + H]⁺385.0853; found 385.0845 (2.0 ppm).

4.3.10. N-(2-Hydroxyethyl)-4-nitrobenzenesulfonamide (11j)

The crude product was purified via recrystallization using a mixture

1

of ethyl acetate and hexane. Yield (658 mg, 54%). H NMR (500

MHz, CD₃OD): δ 8.39 (d, J = 8.6 Hz, 2H; Ar-H), 8.08 (d, J = 8.6 Hz,

2H; Ar-H), 3.52 (t, J = 5.7 Hz, 2H; O-CH₂), 3.00 (t, J = 5.7 Hz, 2H;

N-CH₂). ¹³C NMR (125 MHz, CD₃OD) δ 150.0, 146.6, 128.1 (2C),

124.1 (2C), 60.5, 45.0. HRMS (ESI, m/z): Calculated for

C₈H₁₁N₂O₅S [M + H]⁺247.0383; found 247.0379 (1.7 ppm).

4.3.4.

N-(3-Hydroxybenzyl)-4-nitro-N-

phenylbenzenesulfonamide (11d)

The crude product was purified via recrystallization using a mixture

of ethyl acetate and hexane. Yield (260 mg, 67%). H NMR (500

1

MHz, DMSO-d₆) δ. 9.35 (bs, 1H; Ar-OH), 8.38 (d, J = 8.6 Hz, 2H;

Ar-H), 7.87 (d, J = 8.6 Hz, 2H; Ar-H), 7.27-7.21 (m, 3H; Ar-H), 7.05

(d, J = 7.5 Hz, 2H; Ar-H), 7.00 (dd, J = 7.5, 8.0 Hz, 1H; Ar-H), 6.68

(s, 1H; Ar-H), 6.60 (d, J = 7.5 Hz, 1H; Ar-H), 6.56 (d, J = 8.0 Hz,

1H; Ar-H), 4.73 (s, 2H; N-CH₂). ¹³C NMR (125 MHz, DMSO-d₆) δ.

157.9, 150.5, 143.8, 138.6, 137.7, 129.9, 129.6 (2C), 129.5 (2C),

129.1 (2C), 128.6, 125.2 (2C), 119.2, 115.4, 115.1, 54.4. HRMS

(ESI, m/z): calculated for C₁₉H₁₇N₂O₅S [M + H]⁺385.0853; found

385.0843 (2.5 ppm).

4.3.11.

(11k)

N-(2,3-Dihydroxypropyl)-4-nitrobenzenesulfonamide

The crude product was purified via flash column chromatography

over silica gel. It eluted using 70% ethyl acetate in hexane. Yield (69

1

mg, 45%). H NMR matched that previously reported.^{38 1}H NMR

(500 MHz, CD₃OD): δ 8.39 (d, J = 8.6 Hz, 2H; Ar-H), 8.08 (d, J =

8.6 Hz, 2H; Ar-H), 3.60 (p, J = 5.2 Hz, 1H; O-CH) 3.47-3.41 (m,

2H; O-CH₂), 3.07 (dd, J = 5.2, 13.2 Hz, 1H; N-CH₂), 2.86 (dd, J =

6.9, 13.2 Hz, 1H; N-CH₂).

4.3.5.

N-(4-Hydroxybenzyl)-4-nitro-N-

phenylbenzenesulfonamide (11e)

The crude product was purified via flash column chromatography

using ethyl acetate in hexane (0.2:1 % v/v). Yield (106 mg, 45%).

¹H NMR (500 MHz, CD₃OD): δ 8.38 (d, J = 9.2 Hz, 2H; Ar-H),

7.86 (d, J = 9.2 Hz, 2H; Ar-H), 7.22-7.21 (m, 3H; Ar-H), 6.99 (d, J =

8.6 Hz, 2H; Ar-H), 6.95-6.93 (m, 2H; Ar-H), 6.59 (d, J = 8.6 Hz, 2H;

Ar-H), 4.71 (s, 2H; N-CH₂). ¹³C NMR (125 MHz, CD₃OD) δ 156.9,

150.3, 144.3, 138.3, 129.9 (2C), 129.1 (2C), 128.8 (2C), 128.7 (2C),

128.0, 126.3, 124.0 (2C), 114.8 (2C), 54.3. HRMS (ESI, m/z):

Calculated for C₁₉H₁₇N₂O₅S [M + H]⁺385.0853; found 385.0845

(2.0 ppm).

4.4.

General procedure for the synthesis of p-amino

sulfonamides (7a-7k).

Nitro-substituted benzenesulfonamides 7a-7k were dissolved in

MeOH (0.1 M) and hydrogenated (1 bar-H₂) over 50% w/w

palladium on charcoal. The reaction mixture stirred at ambient

temperature for 1-5 hr, filtered through a pad of Celite®, and the

solvent was evaporated under reduced pressure. Purification was

done via flash column chromatography or recrystallized using an

appropriate solvent or mixture of solvents where enough volume of

the more polar solvent was added to dissolve the crude mixture and

the less polar solvent was added until reaching the saturation point.³⁹

4.3.6. N-Methyl-4-nitro-N-phenylbenzenesulfonamide (11f)

The crude product was purified via recrystallization using a mixture

1

of ethyl acetate and hexane. Yield (0.677 g, 26%). H NMR matched

4.4.1.

4-Amino-N-phenyl-N-(pyridin-4-

that previously reported.^{37 1}H NMR (500 MHz, acetone-d₆): δ 8.39

(d, J = 8.6 Hz, 2H; Ar-H), 7.80 (d, J = 8.6 Hz, 2H; Ar-H), 7.35-7.29

(m, 3H; Ar-H), 7.14 (d, J = 8.0 Hz, 2H; Ar-H), 3.25 (s, 3H; N-CH₃).

ylmethyl)benzenesulfonamide (7a)

The crude product was purified via recrystallization using ethyl

acetate. Yield (71 mg, 32%). H NMR (500 MHz, acetone-d₆): δ

1

8.42 (dd, J = 1.7, 4.6 Hz, 2H; Ar-H), 7.32-7.30 (m, 4H; Ar-H), 7.24-

7.20 (m, 2H; Ar-H), 7.19-7.16 (m, 1H; Ar-H), 7.16-7.12 (m, J = 2H;

Ar-H), 6.71 (dd, J = 2.3, 8.6 Hz, 2H; Ar-H), 5.62 (bs, 1H; N-H₂),

4.81 (s, 2H; N-CH₂). ¹³C NMR (125 MHz, acetone-d₆): δ 153.2,

149.8 (2C), 146.3, 139.9, 129.8 (2C), 128.7 (2C), 128.6 (2C), 127.5,

124.0, 123.1 (2C), 113.1, 52.8. HRMS (ESI, m/z): calculated for

C₁₈H₁₈N₃O₂S [M + H]⁺340.1114; found 340.1104 (3.0 ppm).

4.3.7. N-(2-Hydroxyethyl)-4-nitro-N-phenylbenzenesulfonamide

(11g)

The crude product was purified via recrystallization using ethyl

1

acetate. Yield (0.147 g, 10%). H NMR (500 MHz, acetone-d₆): δ

8.38 (dd, J = 2.3, 9.2 Hz, 2H; Ar-H), 7.88 (d, J = 9.2 Hz, 2H; Ar-H),

7.35-7.32 (m, 3H; Ar-H), 7.14 (dd, J = 2.3, 6.9 Hz, 2H; Ar-H), 3.91

(t, J = 5.7 Hz, 1H; O-H), 3.77 (t, J = 6.3 Hz, 2H; N-CH₂), 3.54 (q, J

= 5.7 Hz, 2H; O-CH₂). ¹³C NMR (125 MHz, acetone-d₆): δ 150.3,

144.4, 139.1, 129.3 (2C), 129.2 (2C), 129.1(2C), 128.4 (2C), 124.3,

59.4, 53.6. HRMS (ESI, m/z): Calculated for C₁₄H₁₅N₂O₅S [M + H]⁺

323.0696; found 323.0691 (1.6 ppm).

4.4.2.

4-Amino-N-((5-(hydroxymethyl)furan-2-yl)methyl)-N-

phenylbenzenesulfonamide (7b)

The crude product was purified via flash column chromatography. It

eluted using ethyl acetate in hexane (0.4:1 % v/v). Yield (253 mg,

1

50%). H NMR (400 MHz, CDCl₃): δ 7.37 (d, J = 8.7 Hz, 2H; Ar-

4.3.8. 4-Nitro-N-phenylbenzenesulfonamide (11h)

H), 7.25-7.22 (m, 3H; Ar-H), 7.02-6.99 (m, 2H; Ar-H), δ 6.60 (d, J =

8.7 Hz, 2H; Ar-H), 6.07 (d, J = 3.2 Hz, 1H; Ar-H), 5.99 (d, J = 3.2

Hz, 1H; Ar-H), 4.69 (s, 2H; O-CH₂), 4.44 (s, 2H; N-CH₂). ¹³C NMR

(125 MHz, acetone-d₆): δ 155.5, 153.0, 149.4, 139.8, 129.8 (2C),

128.9 (2C), 128.6 (2C), 127.6, 124.6, 113.1 (2C), 110.0, 107.6, 56.4,

47.4. HRMS (ESI, m/z): Calculated for C₁₈H₁₉N₂O₄S [M + H]⁺

359.1060; found 359.1056 (1.1 ppm).

The crude product was purified via recrystallization was done using

1

ethyl acetate. Yield (68 mg, 5%). H NMR matched that previously

reported.^{37 1}H NMR (500 MHz, acetone-d₆): δ 9.29 (s, 1H; NH),

8.35 (dd, J = 2.3, 8.6 Hz, 2H; Ar-H), 8.02 (dd, J = 2.3, 8.6 Hz, 2H;

Ar-H), 7.28-7.24 (m, 2H; Ar-H), 7.21-7.19 (m, 2H; Ar-H), 7.12 (tt, J

= 1.2, 7.5 Hz, 1H; Ar-H).

4.3.9.

(11i)

N-Methyl-4-nitro-N-(pyridin-4-yl)benzenesulfonamide

4.4.3.

4-Amino-N-(2-hydroxybenzyl)-N-

phenylbenzenesulfonamide (7c)

The crude product was purified via flash column chromatography

The crude product was purified via flash column chromatography. It

1

using 30% ethyl acetate in hexane. Yield (70 mg, 76%). H NMR

MHz, acetone-d₆): δ 153.5, 150.2 (2C), 149.3, 129.5 (2C), 122.5,

117.4 (2C), 113.1, 113.0, 113.0 (2C), 35.7. HRMS (ESI, m/z):

Calculated for C₁₂H₁₄N₃O₂S [M + H]⁺264.0801; found 264.0794

(2.7 ppm).

(400 MHz, CD₃OD) δ 7.27 (d, J = 8.7 Hz, 2H; Ar-H), 7.19-7.13 (m,

4H; Ar-H), 7.02 (dd, J = 1.8, 7.8 Hz, 2H; Ar-H), 6.93 (dt, J_d=1.8 Hz,

J_t= 7.8 Hz, 2H; Ar-H), 6.66-6.59 (m, 4H; Ar-H), 4.72 (s, 2H; N-

CH₂). ¹³C NMR (100 MHz, Acetonitrile-d₃) δ: 155.0, 152.8, 139.6,

130.2, 129.8 (2C), 129.0, 128.7 (2C), 128.6 (2C), 127.7, 124.1,

122.2, 119.8, 115.4, 113.2 (2C), 49.0. HRMS (ESI, m/z): Calculated

for C₁₉H₁₉N₂O₃S [M + H]⁺355.1111; found 355.1102 (2.5 ppm).

4.4.10. 4-Amino-N-(2-hydroxyethyl)benzenesulfonamide (7j)

The crude product was purified via recrystallization using a mixture

of ethyl acetate in hexane. Yield (118 mg, 34%). ¹H NMR (500

MHz, CD₃OD) δ: δ 7.51 (d, J = 8.6 Hz, 2H; Ar-H), 6.68 (d, J = 8.6

Hz, 2H; Ar-H), 3.51 (t, J = 5.7 Hz, 2H; O-CH₂), 2.87 (t, J = 5.7 Hz,

2H; N-CH₂). ¹³C NMR (125 MHz, CD₃OD): δ 152.8, 128.6 (2C),

125.9, 113.1 (2C), 60.5, 44.8. HRMS (ESI, m/z): Calculated for

C₈H₁₃N₂O₃S [M + H]⁺217.0641; found 217.0637 (2.0 ppm).

4.4.4.

4-Amino-N-(3-hydroxybenzyl)-N-

phenylbenzenesulfonamide (7d)

The crude product was purified flash column chromatography using

30% ethyl acetate in hexane. Yield (63 mg, 68%). H NMR (400

1

MHz, CD₃OD): δ 7.27 (d, J = 8.7 Hz, 2H; Ar-H), 7.19-7.13 (m, 3H;

Ar-H), 7.00-6.94 (m, 3H; Ar-H), 6.69 (s, 1H; Ar-H), 6.63 (m, 3H;

4.4.11.

(7k)

4-Amino-N-(2,3-dihydroxypropyl)benzenesulfonamide

Ar-H), 6.55 (dd, J = 1.8, 7.8 Hz, 1H; Ar-H), 4.6 (s, 1H; N-CH₂). ¹³

C

NMR (125 MHz, CD₃OD): δ 157.1, 153.2, 139.5, 138.0, 129.5 (2C),

128.9 (2C), 128.9 (2C), 128.3, 127.3, 123.8, 119.4, 115.0, 114.0,

112.9, 53.9. HRMS (ESI, m/z): Calculated for C₁₉H₁₉N₂O₃S [M +

H]⁺355.1111; found 355.1096 (4.2 ppm).

The crude product was purified via flash column chromatography

1

using 100% ethyl acetate. Yield (47 mg, 92%). H NMR matched

that previously reported.^{38 1}H NMR (500 MHz, CD₃OD): δ 7.51 (d,

J = 8.6 Hz, 2H; Ar-H), 6.68 (d, J = 8.6 Hz, 2H; Ar-H), 3.62 (p, J =

5.2 Hz, 1H; CHO), 3.48 (dd, J = 4.6, 11.5 Hz, 1H; O-CH₂), 3.43 (dd,

J = 4.6, 11.5 Hz, 1H; O-CH₂), 2.91 (dd, J = 5.2, 13.2 Hz, 1H; N-

CH₂), 2.74 (dd, J = 5.2, 13.2 Hz, 1H; N-CH₂).

4.4.5.

4-Amino-N-(4-hydroxybenzyl)-N-

phenylbenzenesulfonamide (7e)

The crude product was purified via flash column chromatography

1

using 30% ethyl acetate in hexane. Yield (35.5 mg, 47%). H NMR

4.5.

Synthesis of 6-(((tert-Butyldimethylsilyl)oxy)methyl)-2-

(400 MHz, Acetonitrile-d₆): δ 7.29 (d, J = 8.7 Hz, 2H; Ar-H), 7.22-

7.15 (m, 3H; Ar-H), 7.02-6.97 (m, 4H; Ar-H), 6.83 (s, 1H; Ar-OH),

6.64 (d, J = 8.7 Hz, 2H; Ar-H), 6.60 (d, J = 8.2 Hz, 2H; Ar-H), 4.85

(bs, 2H; Ar-NH₂), 4.57 (s, 2H; N-CH₂). ¹³C NMR (100 MHz,

Acetonitrile-d₃): δ 156.3, 152.6, 139.6, 129.9 (2C), 129.7 (2C), 129.0

(2C), 128.6 (2C), 127.7, 127.5, 124.7, 115.0 (2C), 113.2 (2C), 53.3.

HRMS (ESI, m/z): Calculated for C₁₉H₁₉N₂O₃S [M + H]⁺355.1111;

found 355.1108 (0.8 ppm).

naphthoic acid (5y) and 6-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-

2-naphthoic acid (5z).

4.5.1. (6-Bromonaphthalen-2-yl)methanol (13)²³

Methyl 6-bromo-2-naphthoate (12) (1.5 g, 5.66 mmol) was dissolved

°

in anhydrous THF and cooled to -40 C in CH₃CN/dry ice bath.

DIBAL-H (17 mL, 17 mmol) was added drop wise and the mixture

left stirring at ambient temperature for 8 hours. The mixture was then

quenched using a saturated solution of NH₄Cl (15 mL) followed by

extraction with CH₃Cl (100 mL x 2). The organic layers were

combined, extracted with H₂O (100 mLx1), dried using anhydrous

4.4.6. 4-Amino-N-methyl-N-phenylbenzenesulfonamide (7f)

The crude product was purified via recrystallization using MeOH.

1

Yield (210 mg, 12%). H NMR matched that previously reported.³⁷

1

Na₂SO₄and the solvent evaporated. Yield (1.194 g, 90%). H NMR

¹H NMR (500 MHz, acetone-d₆) δ 7.29 (d, J = 7.5 Hz, 1H; Ar-H),

7.27 (d, J = 6.9 Hz, 1H; Ar-H), 7.23-7.20 (m, 1H, Ar-H), 7.16 (d, J

= 8.6 Hz, 2H; Ar-H), 7.12 (dd, J = 1.7, 7.5 Hz, 2H; Ar-H), 6.65 (d, J

= 8.6 Hz, 2H; Ar-H), 5.53 (bs, 1H; N-H₂), 3.08 (s, 3H, N-CH₃).

matched that previously reported.^{40 1}H NMR (500 MHz, acetone-d₆)

δ 8.07 (d, J = 1.7 Hz, 1H; Ar-H), 7.84-7.79 (m, 3H; Ar-H), 7.57-7.52

(m, 2H; Ar-H), 4.77 (s, 2H; O-CH₂), 4.85 (bs, 1H; O-H).

4.5.2. 6-Bromo-2-naphthaldehyde (14)⁴¹

4.4.7.

4-Amino-N-(2-hydroxyethyl)-N-

DMSO (2.9 mL, 41.2 mmol) was added drop-wise to a solution of

oxalyl chloride (1.77 mL, 20.58 mmol) in CH₂Cl₂(65 mL) at -78 ^°C.

A solution of (6-bromonaphthalen-2-yl)methanol (13) (1.22 g, 5.14

mmol) in CH₂Cl₂(12 mL) was then added drop-wise and the mixture

stirred for 15 minutes. Triethylamine (12.9 mL, 0.926 mmol) was

then added to mixture drop-wise followed by H₂O (5 mL) after 15

minutes. The mixture was diluted with EtOAc (100 mL) and

extracted with 20 KHSO₃(100 mLx2) and brine (100 mL). The

organic layer was dried and condensed under reduced pressure. Yield

(724 mg, 60%). ¹H NMR matched that previously reported.^{42 1}H

NMR (500 MHz, acetone-d₆): δ 10.16 (s, 1H; O=CH), 8.52 (s, 1H;

Ar-H), 8.24 (d, J = 2.3 Hz, 1H; Ar-H), 8.08 (d, J = 8.6 Hz, 1H; Ar-

H), 8.02 (d, J = 8.6 Hz, 1H; Ar-H), 7.96 (dd, J = 1.2, 8.6 Hz, 1H; Ar-

H), 7.74 (dd, J = 1.7, 8.6 Hz, 1H; Ar-H).

phenylbenzenesulfonamide (7g)

The crude product was purified via recrystallization using a mixture

1

of ethyl acetate and hexane. Yield (236 mg, 52%). H NMR (400

MHz, CDCl₃): δ 8.01 (d, J = 8.7 Hz, 2H; Ar-H), 7.79 (d, J = 8.7 Hz,

2H; Ar-H), 7.35-7.34 (m, 3H; Ar-H), 7.11-7.09 (m, 2H; Ar-H), 3.77

(t, J = 5.5 Hz, 2H; O-CH₂), 3.69 (t, J = 5.5 Hz, 2H; O-CH₂). ¹³C

NMR (100 MHz, CDCl₃): 154.3, 140.6, 139.0, 129.6 (2C), 129.02

(2C), 129.00 (2C), 128.7, 123.6 (2C), 60.5, 53.8. HRMS (ESI, m/z):

Calculated for C₁₄H₁₆N₂O₃S [M + H]⁺293.0954; found 293.0946

(2.9 ppm).

4.4.8. 4-Amino-N-phenylbenzenesulfonamide (7h)

The crude product was purified via recrystallization using methanol.

Yield (82 mg, 18%). ¹H NMR matched that previously reported.^{37 1}

H

NMR (500 MHz, acetone-d₆): δ 8.63 (bs, 1H; Ar-NH₂), 7.44 (dd, J =

2.3, 8.6 Hz, 2H; Ar-H), 7.21-7.16 (m, 4H; Ar-H), 6.99 (tt, J = 1.7,

6.9 Hz, 1H; Ar-H), 6.62 (dd, J = 2.3, 8.6, 2H; Ar-H), 5.45 (bs, 1H;

SO₂-NH).

4.5.3. Synthesis of 13 and 14 using flow chemistry

Following related reports,^24-25solutions of methyl 6-bromo-2-

naphthoate in toluene (12; 0.1 M) and DIBAL-H in toluene (0.3 M)

were added via in-house built syringe pumps⁴³into 0.04 inch internal

diameter tubing at a rate of 25 mL/min. Each solution was precooled

to -78 °C before mixing by submerging 1.6 feet of steel tubing into a

dry ice/acetone bath. The solutions were mixed by meeting at a T-

joint and the reactor length was 1.5 inches long (0.04 inch internal

diameter PFA tubing) before being mixed at a different T-joint with

saturated aqueous ammonium chloride. The retention time between

mixing of the reagents and quenching of the reaction for the

combined flow rate of 50 mL/min was 37 milliseconds. The

4.4.9.

(7i)

4-Amino-N-methyl-N-(pyridin-4-yl)benzenesulfonamide

The product was isolated without the need for further purification.

Yield (0.107 g, 73%). ¹H NMR (500 MHz, acetone-d₆): δ 8.42 (dd, J

= 1.7, 4.6 Hz, 2H; Ar-H), 7.29 (d, J = 2.3, 8.6 Hz, 2H; Ar-H), 7.25

(dd, J = 1.7, 4.6 Hz, 2H; Ar-H), 6.66 (d, J = 1.7, 8.6 Hz, 2H; Ar-H),

5.65 (d, J = 6.3 Hz, 1H; N-H₂), 3.20 (s, 3H; N-CH₃). ¹³C NMR (125

solutions were washed with diethyl ether to extract the organic

material and concentrated under reduced pressure. The conversion

of ester 12 and yields of alcohol 13 and aldehyde 14 were determined

by both NMR and GC/MS. A variety of flow rates, reactor lengths,

temperatures, and concentrations were screened, with the optimal

conditions described above giving 93% conversion of ester 12, 35%

yield of alcohol 12, and 57% yield of aldehyde 14 (average of six

experiments). The NMR data for the compounds matched those

described earlier in this experimental section.

was then diluted with CH₂Cl₂(10 mL, extracted with a saturated

solution of NH₄Cl (15 mLx2). The organic layer was dried using

anhydrous sodium sulfate and condensed under reduced pressure.

The solid residue was purified via flash column chromatography (0-

5% EtOAc/Hexane) to afford the desired product. Yield (62 mg,

1

53%). H NMR matched that previously reported.^{46 1}H NMR (500

MHz, CDCl₃): δ 7.96 (d, J =1.7 Hz, 1H; Ar-H), 7.67 (d, J = 8.6 Hz,

1H; Ar-H), 7.64 (d, J = 8.6 Hz, 1H; Ar-H), 7.62 (s, 1H; Ar-H), 7.51

(dd, J = 2.3, 8.6 Hz, 1H; Ar-H), 7.37 (dd, J = 1.7, 8.6 Hz, 1H; Ar-H),

3.87 (t, J = 6.9 Hz, 2H; O-CH₂), 2.96 (t, J = 6.9 Hz, 2H; Ar-CH₂),

0.85 (s, 9H, Si-C(CH₃)₃), -0.05 (s, 6H; Si(CH₃)₂).

4.5.4. 2-Bromo-6-vinylnaphthalene (15)²⁷

Sodium hydride (0.299 g, 12.46 mmol) was added to a suspension of

6-bromo-2-naphthaldehyde (14) (0.586 g, 2.49 mmol) and

triphenylphosphonium iodide (1.61 g, 3.99 mmol) in anhydrous THF

(30 mL) and the mixture stirred for 25 hours. The mixture was

diluted with CHCl₃(30 mL) and extracted with brine (100 mL x 3).

The organic layer was dried using anhydrous Na₂SO₄and condensed

under reduced pressure. The solid residue was purified via flash

column chromatography (5% Ethyl acetate/Hexane) to afford the

desired product. Yield (377 mg, 65%). ¹H NMR matched that

previously reported.^{44 1}H NMR (400 MHz, CDCl₃): δ 7.95 (d, J =

1.8 Hz, 1H; Ar-H), 7.70-7.63 (m, 4H; Ar-H), 7.52 (dd, J = 2.3, 8.7

Hz, 1H; Ar-H), 6.84 (dd, J = 11.0, 17.9 Hz, 1H; Ar-CH=C), 5.86 (d,

J = 17.9 Hz, 1H; C=CH₂), 5.36 (d, J = 11.0 Hz, 1H; C=CH₂).

4.5.8. 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-naphthoic acid

(5y)³⁰

A

solution

of

(2-(6-Bromonaphthalen-2-yl)methoxy)(tert-

butyl)dimethylsilane (17) (100 mg, 0.29 mmol) in anhydrous THF

°

(10 mL) was cooled to -78 C was added drop-wise to a previously

cooled n-butyllithium (0.12 mL, 0.30 mmol) and the mixture stirred

for 3 hours. The mixture was purged with CO₂gas at -78 ^°C for half

an hour then allowed to warm to room temperature. The mixture was

then acidified with 1 M HCl, extracted with ethyl acetate (20 mL x 2)

and the organic layer dried over anhydrous Na₂SO₄and condensed

under reduced pressure. Purification was done via flash column

chromatography using 20% ethyl acetate in hexane. Yield (17.0 mg,

1

19%). H NMR matched that previously reported.^{47 1}H NMR (500

4.5.5. 2-(6-Bromonaphthalen-2-yl)ethan-1-ol (16)²⁸

MHz, CDCl₃): δ 8.67 (bs, 1H; Ar-H), 8.10 (dd, J = 1.7, 8.6 Hz, 1H;

Ar-H), 7.94 (d, J = 8.6 Hz, 1H; Ar-H), 7.89 (d, J = 8.6 Hz, 1H; Ar-

H), 7.84 (s, 1H; Ar-H), 7.50 (dd, J = 1.2, 8.6 Hz, 1H; Ar-H), 4.93 (s,

2H; O-CH₂), 0.98 (s, 9H, Si-C(CH₃)₃), 0.14 (s, 6H; Si(CH₃)₂).

2-Bromo-6-vinylnaphthalene (15) (200 mg, 0.858 mmol) was added

to a cooled solution of BH₃.THF (0.64 mL, 0.64 mmol) in anhydrous

THF (4 mL) and the mixture stirred for 2 hours at ambient

temperature. NaOH (3M, 0.52 mL) followed by 30% H₂O₂(0.17

mL) were added and the mixture stirred for additional 2 hours. The

mixture was then diluted with EtOAc (20 mL), extracted with H₂O

and brine (20 mL x 2), dried over anhydrous Na₂SO₄) and condensed

under reduced pressure. The solid residue was purified via flash

column chromatography (0-60% EtOAc/Hexane) to afford the

desired product. Yield (98 mg, 46%). ¹H NMR matched that

previously reported.^{40 1}H NMR (500 MHz, CDCl₃): δ 7.97 (d, J =1.8

Hz, 1H; Ar-H), 7.70 (d, J = 8.6 Hz, 1H; Ar-H), 7.65 (d, J = 8.7 Hz,

1H; Ar-H), 7.64 (s, 1H; Ar-H), 7.52 (dd, J = 2.3, 8.6 Hz, 1H; Ar-H),

7.38 (dd, J = 1.7, 8.6 Hz, 1H; Ar-H), 3.94 (t, J = 6.3 Hz, 2H; O-

CH₂), 3.00 (t, J = 6.3 Hz, 2H; Ar-CH₂).

4.5.9. 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-naphthoic acid

(5z)³⁰

A

solution

of

(2-(6-Bromonaphthalen-2-yl)ethoxy)(tert-

butyl)dimethylsilane (18) (61.9 mg, 0.17 mmol) in anhydrous THF

°

(4 mL) was cooled to -40 C was added drop-wise to a previously

cooled n-butyllithium (0.25 mL, 0.25 mmol) and the mixture stirred

for 3 hours. The mixture was purged with CO₂gas at -40 ^°C for half

an hour then allowed to warm to room temperature. The mixture was

then acidified with 1 M HCl, extracted with brine (20 mL x 2) and

the organic layer dried over anhydrous Na₂SO₄and condensed under

reduced pressure. Purification was done via flash column

chromatography using 50% v/v ethyl acetate in hexane. Yield (29.7

mg, 53%). ¹H NMR (500 MHz, CDCl₃): δ 8.67 (bs, 1H; Ar-H), 8.09

(dd, J = 1.7, 8.6 Hz, 1H; Ar-H), 7.90 (d, J = 8.6 Hz, 1H; Ar-H), 7.84

(d, J = 8.6 Hz, 1H; Ar-H), 7.72 (s, 1H; Ar-H), 7.45 (dd, J = 1.7, 8.6

Hz, 1H; Ar-H), 3.91 (t, J = 6.9 Hz, 2H; O-CH₂), 3.01 (t, J = 6.9 Hz,

2H; Ar-CH₂), 1.25 (s, 9H, Si-C(CH₃)₃), 0.86 (s, 6H; Si(CH₃)₂). ¹³C

NMR (100 MHz, CD₃OD): δ 169.3, 139.9, 135.7, 131.4, 130.4,

128.7, 128.5, 127.9, 127.3, 127.2, 125.2, 63.9, 39.3, 25.0, -6.7.

HRMS (ESI, m/z): Calculated for C₁₉H₂₇O₃Si [M + H]⁺331.1724;

found 331.1720 (1.2 ppm).

4.5.6.

((6-bromonaphthalen-2-yl)methoxy)(tert-

butyl)dimethylsilane (17)²⁹

tert-Butyldimethylsilyl chloride (100 mg, 0.42 mmol), 4-

dimethylaminopyridine (12.9 mg, 0.11 mmol), and trimethylamine

(0.22 mL, 0.55 mmol) were added to a solution of 2-(6-

bromonaphthalen-2-yl)methanol (13, 100 mg, 0.42 mmol) in CH₂Cl₂

(5 mL) and stirred at room temperature for 25 hours. The mixture

was then diluted with CH₂Cl₂(10 mL), extracted with a saturated

solution of NH₄Cl (15 mLx2). The organic layer was dried using

anhydrous sodium sulfate and condensed under reduced pressure.

The solid residue was purified via flash column chromatography (0-

5% EtOAc/Hexane) to afford the desired product. Yield (125 mg,

4.5.10. 6-Bromo-2-naphthoic acid (S1)⁴⁸

Potassium hydroxide (127 mg, 2.26 mmol) was added to a

suspension of methyl 6-bromo-2-naphthoate (200 mg, 0.75 mmol) in

methanol (50 mL) and the mixture heated at 50 °C for 48 hours. The

solvent was evaporated and the residue diluted with water (30 mL),

acidified with HCl (1M) and the extracted with ethyl acetate (30 mL

x 2). The combined organic layers were dried with anhydrous

magnesium sulfate and the solvent evaporated under reduced

pressure. The crude product was purified via recrystallization using

ethyl acetate to give the product as white crystals (105 mg, yield

1

84%). H NMR matched that previously reported.^{45 1}H NMR (500

MHz, CDCl₃): δ 7.97 (s, 1H; Ar-H), 7.74 (s, 1H; Ar-H), 7.70 (t, J =

8.2 Hz, 2H; Ar-H), 7.52 (dd, J = 1.8, 8.7 Hz, 1H; Ar-H), 7.44 (d, J =

8.2 Hz, 1H; Ar-H), 4.87 (s, 2H; O-CH₂), 0.97 (s, 9H, Si-C(CH₃)₃),

0.13 (s, 6H; Si(CH₃)₂). ¹³C NMR (100 MHz, CDCl₃) δ 139.6, 133.8,

129.8, 129.6, 129.4, 127.1, 126.0, 125.7, 124.3, 119.43, 65.0, 26.1,

18.6, -5.1.

1

56%). H NMR matched that previously reported.^{48 1}H NMR (400

4.5.7.

(2-(6-Bromonaphthalen-2-yl)ethoxy)(tert-

butyl)dimethylsilane (18)²⁹

MHz, CD₃OD): δ 8.58 (s, 1H; Ar-H), 8.14 (s, 1H; Ar-H), 8.06 (dd, J

= 1.8, 8.7 Hz, 1H; Ar-H), 7.92 (d, J = 8.7 Hz, 1H; Ar-H), 7.87 (d, J =

8.7 Hz, 1H; Ar-H), 7.64 (dd, J = 1.8, 8.7 Hz, 1H; Ar-H).

tert-butyldimethylsilyl chloride (57.6 mg, 0.38 mmol), 4-

dimethylaminopyridine (9.7 mg, 0.08 mmol), and trimethylamine

(58 µL, 0.414 mmol) were added to

bromonaphthalen-2-yl)ethanol 16 (80.0 mg, 0.32 mmol) in CH₂Cl₂

(4 mL) and stirred at room temperature for 25 hours. The mixture

a solution of 2-(6-

4.5.11. Methyl 6-(2-Hydroxyethyl)-2-naphthoate (S2)

Methyl 6-bromo-2-naphthoate (1.0 g, 3.8 mmol), triethylamine

hydrochloride (523 mg, 3.80 mmol), zinc dust (497 mg, 7.60 mmol),

nickel(II) bromide (83 mg, 0.38 mmol), 2,2’-bipyridyl (59 mg, 0.38

mmol), and sodium iodide (140 mg, 0.95 mmol) were added to flask

Hz, 2H; Ar-H), 7.28-7.26 (m, 3H; Ar-H), 7.04-7.00 (m, 3H; Ar-H),

6.97 (d, J = 8.0 Hz, 1H; Ar-H), 6.66 (d, J = 15.5 Hz, 1H; CH=CO),

4.80 (s, 2H; N-CH₂), 3.95 (s, 3H; O-CH₃). ¹³C NMR (125 MHz,

CDCl₃): δ 178.4, 166.7, 159.3, 149.5, 146.1, 143.6, 142.1, 138.6,

134.9, 132.9, 130.9, 129.4 (2C), 128.7 (2C), 128.5, 123.4, 123.1

(2C), 122.4, 121.0, 118.6, 11.5, 55.7, 53.9. HRMS (ESI, m/z):

Calculated for C₂₉H₂₇N₄O₄S₂[M + H]⁺559.1396; found 559.1446.

inside

a

glove box. 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-

pyrimidinone (20 mL), pyridine (0.06 mL, 0.8 mmol), and ethylene

oxide (2.0 mL, 5.1 mmol) were all added to the flask inside a hood.

The mixture stirred for 24 hours at room temperature. The mixture

was poured into 300 mL of 0.1 M pH 8 phosphate buffer, and then

extracted with diethyl ether. The organic layers were combined,

washed with brine, and dried over MgSO₄. Purification was done via

flash column chromatography using 20% ethyl acetate in hexane to

give the product as a white solid (575.8 mg, yield 66%). ¹H NMR

(500 MHz, CDCl₃): δ 8.48 (s, 1H), 7.96 (dd, J = 8.6, 1.15 Hz, 1H),

7.80 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.34

(dd, J = 8.6, 1.72 Hz, 1H), 3.91 (s, 3H), 3.88 (t, J = 6.6 Hz, 2H), 2.96

(t, J = 6.6 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 167.5, 139.3,

135.7, 131.2, 130.9, 129.6, 128.4, 127.8, 127.4, 126.8, 125.4, 63.3,

52.3, 39.5. HRMS (ESI, m/z): Calculated for C₁₄H₁₅O₃[M + H]⁺

231.1021; found 231.1019 (0.87 ppm).

4.6.2.

(E)-N-((4-(N-((5-(Hydroxymethyl)furan-2-yl)methyl)-N-

phenylsulfamoyl)phenyl)carbamothioyl)-3-(2-

methoxyphenyl)acrylamide (6bv)

1

The product precipitated as a yellow solid. Yield (98 mg, 61%). H

NMR (500 MHz, acetone-d₆): δ 8.14 (d, J = 15.8 Hz, 1 H; Ar-

CH=C), 8.08 (d, J = 8.9 Hz, 2H; Ar-H), 7.66 (d, J = 8.6 Hz, 2H; Ar-

H), 7.62 (dd, J = 1.7, 7.7 Hz, 2H; Ar-H), 7.45 (dt, J_t= 1.7, J_d= 7.7

Hz, 1H; Ar-H), 7.28-7.25 (m, 3H; Ar-H), 7.19 (d, J = 15.5 Hz, 1H;

C=CHCO), 7.11 (d, J = 8.6 Hz, 1H; Ar-H), 7.07-7.05 (m, 2H; Ar-H),

7.01 (t, J = 7.5 Hz, 1H; Ar-H), 6.05 (d, J = 3.2 Hz, 1H; Fu-H), 6.02

(d, J = 3.2 Hz, 1H; Fu-H), 4.84 (s, 2H; O-CH₂), 4.39 (s, 2H; N-CH₂),

3.94 (s, 3H; O-CH₃). ¹³C NMR (125 MHz, acetone-d₆): δ 179.2,

167.3, 159.0, 155.9, 149.0, 142.3, 141.4 (2C), 139.2, 135.7, 132.6,

129.5, 129.1 (2C), 128.9 (2C), 128.5 (2C), 128.0, 122.8 (2C), 120.9,

119.5, 111.7, 110.3, 107.4, 56.4, 55.3, 47.8. HRMS (ESI, m/z):

Calculated for C₂₉H₂₈N₃O₆S₂[M + H]⁺578.1414; found 578.1395

(3.3 ppm).

4.5.12. 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-naphthoic acid

(5z)

tert-Butyldimethylsilyl chloride (79 mg, 0.52 mmol) was added to a

CH₂Cl₂solution (5.0 mL) of imidazole (59.2 mg, 0.87 mmol) and 4-

dimethylaminopyridine (5 mg, 0.04 mmol). The reaction mixture

was stirred at room temperature for 10 min and methyl 6-(2-

hydroxyethyl)-2-naphthoate (100 mg, 0.43 mmol) in CH₂Cl₂(1.0

mL) was slowly added. The reaction was allowed to stir at ambient

temperature for 24 hours. Upon completion, the reaction mixture was

washed with water (5.0 mL x 3) and the organic layer was dried and

concentrated under reduced pressure. The residue was purified by

column chromatography using 10% ethyl acetate in hexane to obtain

the desired product (115 mg, 71% yield). ¹H NMR (500 MHz,

acetone-d₆): δ 8.56 (s, 1H; Ar-H), 8.01 – 7.96 (m, 2H; Ar-H), 7.90

(d, J = 8.6 Hz, 1H; Ar-H), 7.80 (s, 1H; Ar-H), 7.52 (dd, J = 8.4, 1.7

Hz, 1H; Ar-H), 3.92 (t, J = 6.6 Hz, 2H; OCH₂) 3.91 (s, 3H; O-CH₃),

2.98 (t, J = 6.6 Hz, 2H; Ar-CH₂), 0.82 (s, 9H; Si-C(CH₃)₃), -0.07 (s,

6H; Si(CH₃)₂). This TBS-protected derivative (100 mg, 0.29 mmol)

was then dissolved in THF (6.0 mL) and water (3.0 mL). LiOH (52

mg, 2.14 mmol) was added and the mixture was stirred at 50 °C for

24 hr. After that time, THF was removed under reduced pressure and

the resultant aqueous solution was washed with CH₂Cl₂(3.0 mL x 3),

acidified with HCl (2N), and extracted with ethyl acetate (10 ml x 2).

The desired product was isolated after removal of solvent under

reduced pressure (88% yield). NMR data for this compound matched

that for 5z prepared by the previous method.

4.6.3.

(E)-N-((4-(N-(2-Hydroxybenzyl)-N-

phenylsulfamoyl)phenyl)carbamothioyl)-3-(2-

methoxyphenyl)acrylamide (6cv)

1

The product precipitated as a yellow solid. Yield (39 mg, 48%). H

NMR (400 MHz, CDCl₃): δ 8.62 (s, 1H, N-H), 8.07 (d, J = 15.6 Hz,

1H; Ar-CH=C), 8.03 (d, J = 8.7 Hz, 2H; Ar-H), 7.73 (d, J = 8.7 Hz,

2H; Ar-H), 7.50 (d, J = 8.0 Hz, 1H; Ar-H), 7.43 (t, J = 8.0 Hz, 1H;

Ar-H), 7.27 (d, J = 2.3 Hz, 2H; Ar-H), 7.17-7.12 (m, 1H; Ar-H), 7.02

(d, J = 7.8 Hz, 1H; Ar-H), 6.99-6.96 (m, 3H; Ar-H), 6.90 (d, J = 7.3

Hz, 2H; Ar-H), 6.65 (d, J = 15.6 Hz, 1H; CH=CO), 6.63 (d, J = 4.6

Hz, 2H; Ar-H), 4.71 (s, 2H; N-CH₂), 3.95 (s, 3H; O-CH₃). ¹³C NMR

(100 MHz, acetone-d₆): δ 179.2, 167.3, 159.0, 155.0, 142.4, 141.4,

139.5, 135.3, 132.6, 129.9, 129.5, 128.8 (2C), 128.7 (2C), 128.6,

128.5 (2C), 127.6, 122.9 (2C), 122.9, 122.4, 119.5, 119.5, 115.2,

111.7, 55.3, 48.7. HRMS (ESI, m/z): Calculated for C₃₀H₂₈N₃O₅S₂

[M + H]⁺574.1465; found 574.1449 (2.8 ppm).

4.6.4.

(E)-N-((4-(N-(3-Hydroxybenzyl)-N-

phenylsulfamoyl)phenyl)carbamothioyl)-3-(2-

methoxyphenyl)acrylamide (6dv)

1

4.6. General procedure for the synthesis of thiourea compounds

(6)

The product precipitated as a yellow solid. Yield (32 mg, 44%). H

NMR (400 MHz, CDCl₃): δ 8.62 (s, 1H, N-H), 8.06 (d, J = 15.6 Hz,

1H; Ar-CH=C), 7.97 (d, J = 8.7 Hz, 2H; Ar-H), 7.67 (d, J = 8.7 Hz,

2H; Ar-H), 7.50 (dd, J = 1.8, 8.0 Hz, 1H; Ar-H), 7.43 (t, J = 8.0 Hz,

1H; Ar-H), 7.22 (dd, J = 1.8, 5.0 Hz, 2H; Ar-H), 7.07 (t, J = 7.8 Hz,

1H; Ar-H), 7.03-6.96 (m, 4H; Ar-H), 6.75-6.72 (m, 2H; Ar-H), 6.67-

6.65 (m, 1H; Ar-H), 6.64 (d, J = 15.6 Hz, 1H; CH=CO), 4.70 (s, 1H;

O-H), 4.68 (s, 2H; N-CH₂), 3.94 (s, 3H; O-CH₃). ¹³C NMR (100

MHz, acetone-d₆): δ 179.2, 167.3, 159.0, 157.5, 142.4, 141.4, 139.3,

138.2, 135.4, 132.6, 129.5, 129.4, 128.9 (2C), 128.8 (2C), 128.4

(2C), 127.7, 122.9 (2C), 122.8, 120.9, 119.5, 119.4, 115.2, 114.5,

111.7, 55.3, 54.1. HRMS (ESI, m/z): Calculated for C₃₀H₂₈N₃O₅S₂

[M + H]⁺574.1465; found 574.1438 (4.7 ppm).

The carboxylic acid (5, 1 equiv.) was refluxed with thionyl chloride

(120 equiv.) and the mixture heated under reflux for 3 hours. The

solution was cooled to room temperature and concentrated under

reduced pressure. The residue was further dried via high vacuum and

used in the proceeding reaction without further purification. KSCN

(1-2 equiv.) was added to the solution of crude acyl chloride in

anhydrous acetonitrile (0.5 M) and the reaction was allowed to stir

for 4 hours at room temperature. The solid KCl was removed through

ﬁltration and the aniline (7, 1 equiv.), dissolved in acetonitrile (0.1

M), was added drop wise to the ﬁltrate and the mixture stirred for 24

hours.³¹The product either precipitated and needed no further

purification, recrystallized using the appropriate mixture of solvents

or purified via flash column chromatography or preparative HPLC.

4.6.5.

(E)-N-((4-(N-(4-Hydroxybenzyl)-N-

phenylsulfamoyl)phenyl)carbamothioyl)-3-(2-

methoxyphenyl)acrylamide (6ev)

The product precipitated as a yellow solid. Yield (104 mg, 54%). ¹H

NMR (400 MHz, DMSO-d₆): δ 11.76 (s, 1H; N-H), 9.31 (s, 1H; N-

H), 7.99 (d, J = 8.70 Hz, 2H; Ar-H), 7.94 (d, J = 16.0 Hz, 1H; Ar-

CH=C), 7.63 (d, J = 8.7 Hz, 2H; Ar-H), 7.54 (dd, J = 1.4, 7.8 Hz,

1H; Ar-H), 7.44 (dd, J = 7.3, 7.8 Hz, 1Hz; Ar-H), 7.23-7.09 (m, 6H;

Ar-H), 7.03 (d, J = 7.3 Hz, 1H; Ar-H), 6.99-6.95 (m, 5H; Ar-H), 6.56

(d, J = 8.2 Hz, 2H; Ar-H), 4.64 (s, 2H; N-CH₂), 3.87 (s, 3H; O-CH₃).

4.6.1.

(E)-3-(2-Methoxyphenyl)-N-((4-(N-phenyl-N-(pyridin-4

ylmethyl)sulfamoyl)phenyl)carbamothioyl)acrylamide (6av)

The product precipitated as a yellow solid. Yield (16.5 mg, 28%). ¹H

NMR (500 MHz, CDCl₃): δ 8.69 (s, 1H, N-H), 8.53 (d, J = 6.0 Hz,

2H; Ar-H), 8.07 (d, J = 15.5 Hz, 1H; Ar-CH=C), 8.00 (d, J = 8.6 Hz,

2H; Ar-H), 7.64 (d, J = 8.6 Hz, 2H; Ar-H), 7.59 (dd, J = 1.7, 8.0 Hz,

2H; Ar-H), 7.43 (dt, J_t= 1.7, J_d= 8.0 Hz, 1H; Ar-H), 7.38 (d, J = 4.0

¹³C NMR (125 MHz, CDCl₃): δ 178.1, 167.3, 142.3, 141.6, 141.4,

135.9, 133.7, 131.8, 129.8, 129.5, 129.1 (2C), 129.0, 128.8 (2C),

128.2, 127.6, 126.8 (2C), 125.1, 123.3, 122.9 (2C), 65.0, 38.3.

HRMS (ESI, m/z): Calculated for C₃₀H₂₈N₃O₅S₂[M + H]⁺

574.1465; found 574.1452 (2.2 ppm).

The product was isolated after column chromatography using 5%

methanol in CH₂Cl₂. Yield (20.0 mg, 19% yield). H NMR (500

1

MHz, DMSO-d₆): δ 12.95 (s, 1H; N-H), 11.70 (s, 1H; N-H), 7.95-

7.92 (m, 3H; Ar-H), 7.79 (d, J = 9.2 Hz, 2H; Ar-H), 7.59 (t, J = 6.1

Hz, 1H; Ar-H), 7.54 (dd, J = 1.5, 7.6 Hz, 1H; Ar-H), 7.43 (dt, J_d=

1.5 , J_t= 7.6 Hz, 1H; Ar-H), 7.13 (d, J = 16.1 Hz, 1H; Ar-CH=C),

7.10 (d, J = 7.6 Hz, 1H; Ar-H), 7.02 (t, J = 7.6 Hz, 1H; Ar-H), 4.66

(t, J = 6.1 Hz, 1H; O-H), 3.87 (s, 3H; O-CH₃), 3.35 (q, J = 6.1 Hz,

2H; O-CH₂), 2.78 (q, J = 6.1 Hz, 2H; N-CH₂). ¹³C NMR (125 MHz,

DMSO-d₆): δ 179.7, 167.4, 158.9, 141.7, 140.7, 138.0, 133.0, 129.8,

127.7 (2C), 124.6 (2C), 122.8, 121.5, 120.6, 112.4, 60.5, 56.2, 45.6.

HRMS (ESI, m/z): Calculated for C₁₉H₂₂N₃O₅S₂[M + H]⁺

436.0995; found 574.1452 (1.7 ppm).

4.6.6.

(E)-3-(2-Methoxyphenyl)-N-((4-(N-methyl-N-

phenylsulfamoyl)phenyl)carbamothioyl)acrylamide (6fv)

1

The product precipitated as a yellow solid. Yield (25 mg, 46%). H

NMR (500 MHz, acetone-d₆): δ 8.05 (d, J = 15.5 Hz, 1 H, Ar-CH=),

7.95 (d, J = 8.6, 2H, Ar-H), 7.56 (d, J = 8.6, 2H, Ar-H), 7.49 (dd, J =

1.7, 8.0 Hz, 1H, Ar-H), 7.42 (dd, J = 1.7, 8.0 Hz, 1H, Ar-H ), 7.30

(m, 3H, Ar-H), 7.12 (s, 1 H, Ar-H), 7.10 (d, J = 7.5 Hz, 1 H, Ar-H),

7.00 (t, J = 7.5 Hz, 1 H, Ar-H), 6.96 (d, J = 8.6 Hz, 1 H, Ar-H), 6.66

(d, J = 15.5 Hz, 1 H, C=CHCO), 3.19 (s, 3H; N-CH₃), 3.94 (s, 3H;

O-CH₃). ¹³C NMR (125 MHz, DMSO-d₆): δ 179.4, 167.4, 158.9,

142.6, 141.6, 140.8, 133.3, 133.1, 129.8, 129.5 (2C), 128.8 (2C),

127.8, 126.8 (2C), 123.9 (2C), 122.9, 121.4, 120.5, 112.5, 56.2, 38.5.

HRMS (ESI, m/z): Calculated for C₂₄H₂₄N₃O₄S₂[M + H]⁺

482.1203; found 482.1184 (3.9 ppm).

4.6.11.

(E)-N-((4-(N-(2,3-

Dihydroxypropyl)sulfamoyl)phenyl)carbamothioyl)-3-(2-

methoxyphenyl)acrylamide (6kv)

The product precipitated as a yellow solid. Yield (77 mg, 59%). ¹H

NMR (400 MHz, DMSO-d₆): δ 12.95 (s, 1H; N-H), 11.73 (s, 1H; N-

H), 7.95-7.91 (m, 3H; Ar-CH=C and Ar-H), 7.78 (d, J = 8.7 Hz, 2H;

Ar-H), 7.58-7.52 (m, 2H; Ar-H), 7.43 (t, J = 7.3 Hz, 2H; Ar-H), 7.13

(d, J = 15.6 Hz, 1H; C=CH), 7.10 (d, J = 8.7 Hz, 1H; Ar-H), 7.01 (t,

J = 7.3 Hz, 1H; Ar-H), 4.77 (d, J = 5.0 Hz, 1H; O-H), 4.53 (t, J = 6.0

Hz, 1H; O-H), 3.86 (s, 3H; O-CH₃), 3.43 (dq, J_d= 6.9, J_q= 5.5 Hz,

1H; O-CH), 3.23 (m, 2H; O-CH_2-), 2.85 (m, 1H; N-CH₂), 2.57 (m,

1H; N-CH₂). ¹³C NMR (125 MHz, DMSO-d₆): δ 179.6, 167.4, 158.9,

141.7, 140.8, 138.0, 133.1, 129.9, 127.8 (2C), 124.5 (2C), 122.8,

121.4, 120.5, 112.5, 70.9, 64.0, 56.2, 46.6. HRMS (ESI, m/z):

Calculated for C₂₀H₂₄N₃O₆S₂[M + H]⁺466.1101; found 466.1088

(2.8 ppm).

4.6.7.

(E)-N-((4-(N-(2-Hydroxyethyl)-N-

phenylsulfamoyl)phenyl)carbamothioyl)-3-(2-

methoxyphenyl)acrylamide (6gv)

1

The product precipitated as a yellow solid. Yield (58%). H NMR

(500 MHz, acetone-d₆): δ 10.54 (s, 1H; N-H), 8.13 (d, J = 15.8 Hz,

1H; Ar-CH=C), 8.08 (d, J = 8.6 Hz, 2H; Ar-H), 7.64-7.61 (m, 3H;

Ar-H), 7.44 (d, J = 7.7 Hz, 1H; Ar-H), 7.35-7.29 (m, 3H; Ar-H), 7.19

(d, J = 15.8 Hz, 1H; CH=CO), 7.14-7.10 (m, 3H; Ar-H), 7.01 (t, J =

7.5 Hz, 1H; Ar-H), 3.94 (s, 3H; O-CH₃), 3.83 (t, J = 5.7 Hz, 1H; O-

H), 3.73 (t, J = 6.3 Hz, 2H, N-CH₂), 3.54 (q, J = 6.0 Hz, 2H; O-CH₂).

¹³C NMR (125 MHz, acetone-d₆) δ 179.2, 167.3, 159.0, 142.3,

141.3, 139.9, 135.5, 132.6, 129.5, 129.1 (2C), 129.0 (2C), 128.4

(2C), 127.9, 122.8 (2C), 120.9 (2C), 119.5, 111.7 (2C), 59.6, 55.3,

53.2. HRMS (ESI, m/z): Calculated for C₂₅H₂₆N₃O₅S₂[M + H]⁺

512.1308; found 512.1287 (4.2 ppm).

4.6.12.

(E)-N-((4-(N-(3,4-Dimethylisoxazol-5-

yl)sulfamoyl)phenyl)carbamothioyl)-3-(2-

methoxyphenyl)acrylamide (6lv)

1

The product precipitated as a pure yellow solid. Yield (63%). H

NMR (400 MHz, CDCl₃): δ 8.69 (s, 1H; N-H), 8.05 (d, J = 15.6 Hz,

1H; Ar-CH=C), 8.02 (d, J = 8.7 Hz, 2H; Ar-H), 7.83 (d, J = 8.7 Hz,

2H; Ar-H), 7.49 (d, J = 7.6 Hz, 1H; Ar-H), 7.42 (dt, J_d= 1.4, J_t= 8.0

Hz, 1H; Ar-H), 7.00 (t, J = 7.3 Hz, 1H; Ar-H), 6.96 (d, J = 8.4 Hz,

1H; Ar-H), 6.65 (d, J = 15.6 Hz, 1H; C=CHCO), 6.63 (bs, 1H;

SO₂N-H), 3.93 (s, 3H; O-CH₃), 2.19 (s, 3H; Ar-CH₃), 1.92 (s, 3H;

Ar-CH₃). ¹³C NMR (125 MHz, CDCl₃): δ 179.4, 167.2, 161.6,

159.0, 155.4, 142.8, 141.4, 137.0, 132.6, 129.5, 127.9, 123.3, 123.2,

122.8, 120.9, 119.5, 11.7, 106.5, 55.3, 9.9, 5.7. HRMS (ESI, m/z):

Calculated for C₂₂H₂₃N₄O₅S₂[M + H]⁺487.1104; found 487.1088

(3.4 ppm).

4.6.8.

(E)-3-(2-Methoxyphenyl)-N-((4-(N-

phenylsulfamoyl)phenyl)carbamothioyl)acrylamide (6hv)

1

The product precipitated as a yellow solid. Yield (21 mg, 38%). H

NMR (500 MHz, acetone-d₆): δ 8.10 (d, J = 15.8 Hz, 1H; Ar-

CH=C), 8.02 (d, J = 8.6 Hz, 2H;Ar-H), 7.80 (d, J = 8.6 Hz, 2H; Ar-

H), 7.59 (dd, J = 1.7, 7.7 Hz, 2H; Ar-H), 7.42 (d, J = 8.1 Hz, 1H; Ar-

H), 7.25-7.20 (m, 3H; Ar-H), 7.15 (d, J = 15.8 Hz, 1H; CH=CO),

7.08 (d, J = 8.1 Hz, 1H; Ar-H), 7.07-7.03 (m, 2H; Ar-H), 7.01 (t, J =

7.5 Hz, 1H; Ar-H), 3.91 (s, 3H; O-CH₃). ¹³C NMR (125 MHz,

acetone-d₆): δ 179.2, 167.2, 159.0, 142.3, 141.3, 137.9, 136.7, 132.6,

129.5, 129.2 (2C), 127.9 (2C), 124.6, 122.9 (2C), 122.8, 120.9 (2C),

119.5, 111.7 (2C), 55.3. HRMS (ESI, m/z): Calculated for

C₂₃H₂₂N₃O₄S₂[M + H]⁺468.1046; found 468.1028 (3.9 ppm).

4.6.13.

N-((4-(N-methyl-N-

phenylsulfamoyl)phenyl)carbamothioyl)quinoline-3-

carboxamide (6fw)

The product precipitated as a pure yellow solid. Yield (59 mg, 65%).

¹H NMR (500 MHz, acetone-d₆): δ 9.40 (d, J = 2.3 Hz, 1H; Ar-H),

9.23 (s, 1H; Ar-H), 8.26 (d, J = 8.6Hz, 1H; Ar-H), 8.22 (d, J = 8.0

Hz, 1H; Ar-H), 8.10 (dd, J = 6.3, 8.6 Hz, 2H; Ar-H), 8.01 (d, J = 7.7

Hz, 1H; Ar-H), 7.80 (d, J = 7.5 Hz, 1H; Ar-H), 7.59 (d, J = 8.9 Hz,

2H; Ar-H), 7.35-7.27 (m, 3H; Ar-H), 7.15 (dd, J = 1.7, 8.3 Hz, 2H;

Ar-H), 3.22 (s, 3H; N-CH₃). ¹³C NMR (100 MHz, DMSO-d₆): δ

179.6, 167.4, 149.6, 149.5, 142.7, 141.6, 138.6, 133.5, 132.8, 130.2,

129.5 (2C), 129.3, 128.8 (2c), 128.3, 127.8, 126.8 (2C), 126.5, 125.6,

124.3 (2C), 38.5. HRMS (ESI, m/z): calculated for C₂₄H₂₁N₄O₃S₂

[M + H]⁺477.1050; found 477.1030 (4.1 ppm).

4.6.9.

(E)-3-(2-Methoxyphenyl)-N-((4-(N-methyl-N-(pyridin-4-

yl)sulfamoyl)phenyl)carbamothioyl)acrylamide (6iv)

Purification was done via recrystallization using methanol. Yield (12

mg, 15%). H NMR (500 MHz, CDCl₃): δ 8.78 (s, 1H; N-H), 8.53

1

(dd, J = 1.7, 4.6 Hz, 2H; Ar-H), 8.06 (d, J = 15.8 Hz, 1H; Ar-CH=C),

7.97 (d, J = 8.9 Hz, 2H; Ar-H), 7.60 (d, J = 8.6 Hz, 2H; Ar-H), 7.49

(dd, J = 1.7, 7.5 Hz, 1H; Ar-H), 7.43 (dd, J = 1.7, 7.7 Hz, 1H; Ar-

H), 7.18 (dd, J = 1.7, 4.7 Hz, 2H; Ar-H), 7.00 (t, J = 7.5 Hz, 1H; Ar-

H), 6.96 (d, 8.6 Hz, 1H; Ar-H), 6.65 (d, J = 15.8 Hz, 1H; C=CH-

CO), 3.93 (s, 3H; N-CH₃). ¹³C NMR (125 MHz, CDCl₃): δ 178.5,

166.8, 159.2, 150.7 (2C), 148.8, 143.5, 142.4, 133.2, 132.9, 130.9,

128.4 (2C), 123.1 (2C), 122.4, 121.0, 118.6, 118.3 (2C), 111.4, 55.7,

36.7. HRMS (ESI, m/z): Calculated for C₂₃H₂₃N₄O₄S₂[M + H]⁺

483.1155; found 483.1134 (4.4 ppm).

4.6.14.

N-((4-(N-Methyl-N-

phenylsulfamoyl)phenyl)carbamothioyl)quinoline-7-

carboxamide (6fx)

Purification was done via recrystallization using a mixture of

1

chloroform and hexane. Yield (8.0 mg, 11%). H NMR (500 MHz,

4.6.10.

(E)-N-((4-(N-(2-

acetone-d₆): δ 9.02 (dd, J = 1.7, 4.0 Hz, 1H; Ar-H), 8.76 (s, 1H; Ar-

H), 8.44 (dd, J = 1.2, 8.6 Hz, 1H; Ar-H), 8.14 (s, 2H), 8.11 (d, J =

8.6 Hz, 2H; Ar-H), 7.66 (dd, J = 4.0, 8.6 Hz, 1H; Ar-H), 7.59 (d, J =

Hydroxyethyl)sulfamoyl)phenyl)carbamothioyl)-3-(2-

methoxyphenyl)acrylamide (6jv)

8.9 Hz, 2H; Ar-H), 7.35-7.27 (m, 3H; Ar-H), 7.15 (d, J = 8.0 Hz, 2H;

Ar-H), 3.22 (s, 3H; N-CH₃). ¹³C NMR (125 MHz, acetone-d₆): δ.

179.0, 168.2, 152.1, 147.4, 142.4, 141.8, 135.9, 133.7, 132.8, 130.9,

130.7, 129.0, 128.9 (2C), 128.6 (2C), 127.3, 126.6 (2C), 124.8,

123.6, 123.2, 37.7. HRMS (ESI, m/z): Calculated for C₂₄H₂₁N₄O₃S₂

[M + H]⁺477.1050; found 477.1030 (4.1 ppm).

48.0. HRMS (ESI, m/z): Calculated for C₂₉H₂₅N₄O₅S₂[M + H]⁺

573.1261; found 573.1243 (3.1 ppm).

4.6.19.

N-((4-(N-(4-Hydroxybenzyl)-N-

phenylsulfamoyl)phenyl)carbamothioyl)quinoline-7-

carboxamide (6ex)

The product precipitated as a yellow solid. Yield (42.5 mg, 29%). ¹H

NMR (400 MHz, DMSO-d₆): δ 12.73 (s, 1H; N-H), 12.04 (s, 1H; N-

H), 9.13 (bs, 1H; O-H), 9.03 (dd, J = 1.8, 4.1 Hz, 1H; Ar-H), 8.65 (s,

1H; Ar-H), 8.48 (d, J = 7.8 Hz, 1H; Ar-H), 8.12 (d, J = 8.2 Hz, 1H;

Ar-H), 8.07-8.01 (m, 3H; Ar-H), 7.69-7.64 (m, 3H; Ar-H), 7.24-7.16

(m, 3H; Ar-H), 6.99-6.96 (m, 4H; Ar-H), 6.56 (d, J = 8.2 Hz, 2H;

Ar-H), 4.65 (s, 2H, N-CH₂). ¹³C NMR (125 MHz, DMSO-d₆): δ

179.5, 157.4, 152.2, 147.1, 142.6, 139.1, 136.7, 135.5, 133.4, 131.1,

130.8, 130.1 (2C), 129.3 (2C), 129.1 (2C), 128.6 (2C), 128.2, 126.6,

125.7, 124.4 (2C), 124.0, 115.6, 53.8. HRMS (ESI, m/z): Calculated

for C₃₀H₂₅N₄O₄S₂[M + H]⁺569.1312; found 569.1295 (2.9 ppm).

4.6.15.

6-(Hydroxymethyl)-N-((4-(N-methyl-N-

phenylsulfamoyl)phenyl)carbamothioyl)-2-naphthamide (6fy)

The product precipitated as a yellow solid. Yield (13.25 mg, 48%).

¹H NMR (500 MHz, CDCl₃): δ 9.26 (s, 1H; N-H), 8.40 (s, 1H; Ar-

H), 7.98-7.92 (m, 4H; Ar-H), 7.87 (dd, J = 1.4, 8.7 Hz, 1H; Ar-H),

7.57 (d, J = 8.7 Hz, 2H; Ar-H), 7.51 (dd, J = 1.8, 8.2 Hz, 1H; Ar-H),

7.33-7.27 (m, 3H; Ar-H), 7.10 (dd, J = 1.8, 6.9 Hz, 2H; Ar-H), 3.99

(t, J = 6.4 Hz, 2H; O-CH₂), 3.19 (s, 3H; N-CH₃), 3.08 (t, J = 6.4 Hz,

2H; Ar-CH₂). ¹³C NMR (100 MHz, CDCl₃): δ 178.1, 167.3, 141.7,

141.4, 140.5, 136.0, 133.8, 131.3, 129.7, 129.4, 129.2, 129.1 (2C),

129.0, 128.9 (2C), 127.7, 127.6, 126.8 (2C), 123.2, 123.0 (2C), 63.3,

39.5, 38.3. HRMS (ESI, m/z): Calculated for C₂₆H₂₄N₃O₄S₂[M +

H]⁺506.1203; found 506.1186 (3.3 ppm).

4.6.20.

N-((4-(N-(2-Hydroxyethyl)-N-

phenylsulfamoyl)phenyl)carbamothioyl)quinoline-7-

carboxamide (6gx)

The product precipitated as a yellow solid. Yield (24.3 mg, 55%). ¹H

NMR (500 MHz, CDCl₃): δ 9.42 (s, 1H; N-H), 9.07 (dd, J = 1.7, 4.0

Hz, 1H; Ar-H), 8.68 (s, 1H; Ar-H), 8.27 (dd, J = 1.2, 8.6 Hz, 1H; Ar-

H), 8.05-8.02 (m, 2H; Ar-H), 8.00 (d, J = 9.2 Hz, 2H; Ar-H), 7.66 (d,

J = 9.2 Hz, 2H; Ar-H), 7.59 (dd, J = 4.0, 8.0 Hz, 1H; Ar-H), 7.37-

7.32 (m, 3H; Ar-H), 7.11-7.09 (m, 2H; Ar-H), 3.75 (m, 2H; O-CH₂),

3.68 (m, 2H; N-CH₂). ¹³C NMR (125 MHz, CDCl₃): δ 177.9, 166.7,

152.4, 147.4, 141.7, 139.3, 136.1, 135.4, 132.0, 131.2, 120.0, 129.6,

129.5 (2C), 129.0 (2C), 128.7 (2C), 128.6, 124.1, 123.8, 123.2 (2C),

60.5, 53.7. HRMS (ESI, m/z): Calculated for C₂₅H₂₃N₄O₄S₂[M +

H]⁺507.1155; found 507.1145 (2.0 ppm).

4.6.16.

6-(2-Hydroxyethyl)-N-((4-(N-methyl-N-

phenylsulfamoyl)phenyl)carbamothioyl)-2-naphthamide (6fz)

The residue was puriﬁed by preparative HPLC using a Phenomenex

Gemini-NX column C18 (250 x 21.20 mm, 110 A, 5 μm spherical

particle size). The column was perfused at a ﬂow rate of 21.24

mL/min with a linear gradient from 60% (CH₃CN-H₂O) to 80% over

1

15 min. The compound eluted at 12.5 min. Yield (7.4 mg, 6%). H

NMR (500 MHz, CDCl₃): δ 9.26 (s, 1H; N-H), 8.40 (s, 1H; Ar-H),

7.98-7.92 (m, 4H; Ar-H), 7.87 (dd, J = 1.4, 8.7 Hz, 1H; Ar-H), 7.57

(d, J = 8.7 Hz, 2H; Ar-H), 7.51 (dd, J = 1.8, 8.2 Hz, 1H; Ar-H), 7.33-

7.27 (m, 3H; Ar-H), 7.10 (dd, J = 1.8, 6.9 Hz, 2H; Ar-H), 3.99 (t, J =

6.4 Hz, 2H; O-CH₂), 3.19 (s, 3H; N-CH₃), 3.08 (t, J = 6.4 Hz, 2H;

Ar-CH₂). ¹³C NMR (100 MHz, CDCl₃): δ 178.1, 167.3, 141.7, 141.4,

140.5, 136.0, 133.8, 131.3, 129.7, 129.4, 129.2, 129.1 (2C), 129.0,

128.9 (2C), 127.7, 127.6, 126.8 (2C), 123.2, 123.0 (2C), 63.3, 39.5,

38.3. HRMS (ESI, m/z): Calculated for C₂₇H₂₆N₃O₄S₂[M + H]⁺

520.1359; found 520.1339 (3.9 ppm).

4.6.21. 6-(2-hydroxyethyl)-N-((4-(N-((5-(hydroxymethyl)furan-2-

yl)

methyl)-N-phenylsulfamoyl)phenyl)carbamothioyl)-2-

naphthamide (6bz)

The product was purified by column chromatography (40% EtOAC:

hexane) and then recrystallized using acetone and hexane. Yield (5.4

1

mg, 3%). H NMR (500 MHz DMSO-d6): δ 12.86 (s, 1H; N-H),

11.86 (s, 1H, N-H), 8.7 (s, 1H, Ar-H), 8.13 – 7.94 (m, 5H; Ar-H),

7.92 (s, 1H; Ar-H), 7.67 (d, J = 8.7 Hz, 2H; Ar-H), 7.61 (dd, J = 8.6,

1.6 Hz, 1H; Ar-H), 7.34 – 7.24 (m, 3H, Ar-H), 7.04 (dd, J = 7.9, 2.0

Hz, 2H), 6.08 (d, J = 3.0 Hz, 1H; Ar-H), 6.04 (d, J = 3.0 Hz, 1H; Ar-

H), 5.17 (t, J = 5.8 Hz, 1H; OH), 4.82 (s, 2H), 4.28 (d, J = 5.8 Hz,

2H; CH₂OH), 4.00 (t, J = 6.9 Hz, 2H), 3.26 (t, J = 6.9 Hz, 2H). ¹³C

NMR (100 DMSO-d6): δ 179.7, 168.7, 156.1, 148.8, 142.7, 141.3,

138.9, 135.7, 135.2, 130.8, 130.5, 129.7, 129.6, 129.4 (2C), 129.1

(2C), 128.8, 128.7 (2C), 128.5, 128.2, 127.4, 125.0, 124.3 (2C),

110.8, 108.0, 65.5, 62.3, 56.1, 47.9. HRMS (ESI, m/z): Calculated

for C₃₂H₂₉N₃O₆S₂[M + H]+ 616.1576; found 616.1559 (2.8 ppm).

4.6.17.

N-((4-(N-phenyl-N-(Pyridin-4-

ylmethyl)sulfamoyl)phenyl)carbamothioyl)quinoline-7-

carboxamide (6ax)

1

The product precipitated as a yellow solid. Yield (80 mg, 63%). H

NMR (500 MHz, DMSO-d₆): δ 12.74 (s, 1H; N-H), 12.02 (s, 1H; N-

H), 9.02 (dd, 1.5, 4.6 Hz, 1H; Ar-H), 8.65 (s, 1H; Ar-H), 8.46 (d, J =

8.4 Hz, 1H; Ar-H), 8.43 (d, J = 6.1 Hz, 2H; Ar-H), 8.12 (d, J = 8.4

Hz, 1H; Ar-H), 8.05 (d, J = 8.4 Hz, 3H; Ar-H), 7.69-7.65 (m, 3H;

Ar-H), 7.29 (d, J = 5.4 Hz, 2H; Ar-H), 7.26 (d, J = 7.6 Hz, 2H; Ar-

H), 7.23-7.20 (m, 1H; Ar-H), 7.11 (d, J = 6.9 Hz, 2H; Ar-H), 4.87 (s,

2H; N-CH₂). ¹³C NMR (125 MHz, DMSO-d₆): δ 179.6, 168.3, 152.5

(2C), 150.1 (2C), 147.1, 146.2, 142.9, 139.1, 136.5, 134.7, 133.4,

131.1, 130.8, 129.6 (2C), 129.1, 128.8 (2C), 128.7 (2C), 128.5,

125.7, 124.4, 124.1, 123.4 (2C), 53.2. HRMS (ESI, m/z): Calculated

for C₂₉H₂₄N₅O₃S₂[M + H]⁺554.1315; found 554.1298 (3.1 ppm).

4.6.22.

6-(2-hydroxyethyl)-N-((4-(N-(2-hydroxyethyl)-N-

phenylsulfamoyl) phenyl)carbamothioyl)-2-naphthamide (6gz)

The residue was puriﬁed by preparative HPLC using a Phenomenex

Gemini-NX column C18 (250 x 21.20 mm, 110 A, 5 μm spherical

particle size). The column was perfused at a ﬂow rate of 21.24

mL/min with a linear gradient from 60% (CH₃CN-H₂O) to 80% over

4.6.18.

N-((4-(N-((5-(Hydroxymethyl)furan-2-yl)methyl)-N-

phenylsulfamoyl)phenyl)carbamothioyl)quinoline-7-

carboxamide (6bx)

1

15 min. The compound eluted at 14.96 min. Yield (6.1 mg, 9%). H

1

NMR (500 MHz, Chloroform-d) δ 9.27 (s, 1H), 8.41 (d, J = 1.4 Hz,

1H; Ar-H), 8.01 (d, J = 8.8 Hz, 2H; Ar-H), 7.96 (dd, J = 8.4, 6.3 Hz,

2H; Ar-H), 7.90 (dd, J = 8.7, 1.9 Hz, 1H; Ar-H), 7.79 (br. s, 1H, Ar-

H), 7.66 (d, J = 8.8 Hz, 2H; Ar-H), 7.54 (dd, J = 8.4, 1.7 Hz, 1H; Ar-

H), 7.38 – 7.32 (m, 4H; Ar-H), 7.12 – 7.08 (m, 2H; Ar-H), 4.01 (t, J

= 6.5 Hz, 2H), 3.74 (t, J = 5.3 Hz, 2H), 3.70 – 3.64 (m, 4H), 3.25 –

3.18 (m, 3H), 3.10 (t, J = 6.4 Hz, 5H), 1.44 (dt, J = 14.8, 7.4 Hz,

4H), 1.01 (t, J = 7.3 Hz, 5H). ¹³C NMR (100 MHz, DMSO-d₆): δ

179.7, 168.7, 142.6, 139.6 (2C), 135.5, 135.3, 131.1, 130.5, 130.02,

129.6 (2C), 129.2, 129.2 (2C), 129.0, 128.5, 128.4 (2C), 128.3,

127.8, 125.3, 124.3 (2C), 59.2, 53.3, 45.7, 38.8. HRMS (ESI, m/z):

The product precipitated as yellow solid. Yield (45 mg, 34%). H

NMR (500 MHz, DMSO-d₆): δ 12.04 (s, 1H; N-H), 9.02 (dd, J =

1.4, 4.1 Hz, 1H; Ar-H), 8.64 (s, 1H; Ar-H), 8.46 (d, J = 8.2 Hz, 1H;

Ar-H), 8.11 (d, J = 8.7 Hz, 1H; Ar-H), 8.04 (dd, J = 1.7, 8.7 Hz, 1H;

Ar-H), 7.99 (d, J = 8.7 Hz, 2H; Ar-H) 7.66 (dd, J = 4.1, 8.2 Hz, 1H;

Ar-H), 7.62 (d, J = 8.7 Hz, 2H; Ar-H), 7.27-7.25 (m, 3H; Ar-H), 7.00

(dd, J = 2.3, 7.8 Hz, 2H; Ar-H), 6.04 (d, J = 3.2 Hz, 1H; Fur-H), 6.00

(d, J = 3.2 Hz, 1H; Fur-H), 5.17 (t, J = 6.0 Hz, 1H; O-H), 4.78 (s,

2H; N-CH₂), 4.24 (d, J = 6.0, 2H; O-CH₂). ¹³C NMR (125 MHz,

DMSO-d₆): δ 179.6, 168.2, 156.1, 152.1, 148.8, 142.7, 139.0, 137.4,

135.4, 133.7, 130.8, 130.4, 129.4 (2C), 129.2, 129.1 (2C), 128.7

(2C), 128.7 (2C), 128.5, 126.0, 124.3, 124.1, 110.8, 108.0, 56.1,

Calculated for C₂₈H₂₇N₃O₅S₂[M

572.12733 (2.9 ppm).

+

Na]⁺572.12898; found

7.

Andradas, C.; Caffarel, M. M.; Perez-Gomez, E.; Salazar,

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Li, K.; Fichna, J.; Schicho, R.; Saur, D.; Bashashati, M.;

4.7. Analysis of GPR55 agonist activity. Agonist activity was

evaluated using DiscoveRx PathHunter® Complementation

technology. CHO-K1 cells stably expressing GPR55 (fused to a β-

galactosidase enzyme fragment), and β-arrestin (fused to an N-

terminal deletion β-galactosidase mutant), were grown in selection

media and were passaged up to 10 times according to manufacturer

protocols. In the presence of agonist and PathHunter® detection

reagents containing β-galactosidase substrate, a chemiluminescent

signal is generated due to the forced complementation of the GPR55

fused β-galactosidase fragment and the β-arrestin fused N-terminal

deletion mutant fragment of β-galactosidase. In this

complementation assay, a chemiluminescent signal arises due to a

1:1 interaction between the GPR55- β-galactosidase enzyme

fragment and the mutant β-galactosidase-β-arrestin fragment in the

presence of substrate at room temperature. The cells were licensed

from DiscoverX (Fremont, CA), catalog # 93-0245C2. The beta

arrestin reporter sequence is proprietary. Assays were conducted

according to the manufacturer’s instructions using concentrations of

ligands ranging from 0.5 nM to 30 µM. The chemiluminescence

signal was measured using a Perkin Elmer Envision plate reader for

1 second. Experiments were run in triplicate and repeated at a

minimum of 3 times. Ligand readings, expressed as relative

luminescence units, were subtracted from corresponding vehicle

readings and analyzed in GraphPad Prism version 5.0 (GraphPad,

San Diego, CA) to obtain EC₅₀values (Figures 2 and 3). LPI was

used as the positive control and vehicle served as the negative

control.

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Acknowledgments

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Heynen-Genel, S.; Dahl, R.; Shi, S.; Milan, L.; Hariharan,

This research was supported in part by the National Institutes of

Health grants R01DA023204, P32DA013429, and P30DA029925.

The authors thank Dr. Franklin J. Moy (UNCG) for assisting with the

analysis of NMR data and Dr. Daniel A. Todd (UNCG) for

acquisition of the high resolution mass spectrometry data at the Triad

Mass Spectrometry Laboratory at the University of North Carolina at

Greensboro.

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Article Doi

Design, synthesis and biological evaluation of GPR55 agonists

DOI: 10.1016/j.bmc.2017.06.016

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Full text of DOI:10.1016/j.bmc.2017.06.016

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