Synthesis and biological evaluation of biphenyl amides that modulate the US28 receptor

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DOI: 10.1002/cmdc.201300369

Synthesis and Biological Evaluation of Biphenyl Amides

That Modulate the US28 Receptor

Ana Kralj, Elif Kurt, Nuska Tschammer,* and Markus R. Heinrich*^[a]

To prepare and biologically evaluate 38 new potential US28 al-

losteric modulators, we employed a straightforward synthetic

route involving radical arylation. The study was based on

a former lead structure but with the dihydroisoquinolinone

moiety replaced by substituted biphenyls. The investigation of

structure–activity relationships among the new biphenyl-de-

rived ligands led to a preliminary pharmacophore model and

the discovery of four promising candidates with full inverse ag-

onist properties.

Introduction

Infection with human cytomegalovirus (HCMV) is the major

cause of morbidity and mortality in immunocompromised

newborns, transplant patients, AIDS patients, and some oncol-

ogy patients.^[1]There are five systemic drugs approved for

HCMV treatment: ganciclovir, valganciclovir, foscarnet, and ci-

dofovir target the viral DNA polymerase,^[2]and fomivirsen acts

as an antisense antiviral by blocking the translation of viral

mRNA.^[3]Because the routine use of these drugs is associated

with intolerable toxicities, selection for resistant HCMV strains,

and high treatment costs, the development of new anti-HCMV

therapeutics is highly desirable. Among the potential drug tar-

gets are the viral G-protein-coupled receptors (GPCRs). GPCRs

are an excellent drug target; more than 30% of current drugs

on the market target this receptor class.^[4]HCMV encodes four

viral GPCRs, including the US28 receptor.

has also been investigated as a co-receptor for HIV entry.^[9]

Similarly, the expression of the US28 receptor on the surface of

vascular smooth muscle cells (VSMC) induces their migration

toward a gradient of CC-type chemokines,^[10]which are highly

expressed in atherosclerotic lesions.^[11]Moreover, constitutive

signaling by the US28 receptor may affect transcription of viral

and host genes and can activate transcription factors that are

necessary for virus reactivation from latency.^[12]Therefore, the

US28 receptor is an interesting target, and the search for

a potent inverse agonist of its constitutive activity is an ongo-

ing challenge.

Several studies have recently been reported on the synthesis

and biological evaluation of novel ligands for the US28 recep-

tor. Inhibitors of chemokine binding to the US28 receptor, such

as methiothepin (1), have been studied by Schall et al. in com-

petitive binding assays that use radiolabeled [¹²⁵I]Fractalkine/

CX₃CL1 (Figure 1).^[13]

The US28 receptor possesses significant homology to

human chemokine receptors,^[5]and participates in many ac-

tions that enable viral survival and dissemination in infected

hosts as well as causing aggravation of diseases associated

with HCMV infection. For example, the US28 receptor scaveng-

es chemokines,^[6]which might be a viral strategy for prevent-

ing leukocyte recruitment in the infected area, thereby allow-

ing the virus to evade host immune attack on infected cells.

The US28 receptor also appears to have high affinity for sever-

al CC-type chemokines, as well as for Fractalkine/CX₃CL1,^[7]

which acts as an adhesion molecule on most cell types. Be-

cause of its affinity for Fractalkine/CX₃CL1, US28 receptors ex-

pressed on HCMV-infected cells might enhance cell adhesion

and cell–cell interactions, thus contributing to the spread and

transmission of the virus.^[8]In this context the US28 receptor

The characterization of a broad variety of VUF ligands (e.g.,

VUF2274 (2)) in functional assays, measuring the accumulation

of inositol triphosphate in the PLCb pathway, and the inhibi-

[a] Dr. A. Kralj, E. Kurt, Dr. N. Tschammer, Prof. Dr. M. R. Heinrich

Department Chemie und Pharmazie, Pharmazeutische Chemie

Friedrich-Alexander-Universitꢀt Erlangen-Nꢁrnberg

Schuhstraße 19, 91052 Erlangen (Germany)

E-mail: nuska.tschammer@fau.de

Figure 1. Ligands that bind the US28 receptor: methiothepin (1),^[13]VUF2274

(2),^[14c]dihydroisoquinolinone 3, tetrahydroisoquinoline 4, and flavonoid-

based derivative 5.^[15]

markus.heinrich@fau.de

Supporting information for this article is available on the WWW under

http://dx.doi.org/10.1002/cmdc.201300369.

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tion of [¹²⁵I]Rantes/CCL5 binding has been reported by Leurs

and co-workers.^[14]Dihydroisoquinolinones, tetrahydroisoquino-

lines, and the chalcone- and flavonoid-based derivatives (c.f. li-

gands 3, 4, and 5) have been described as allosteric modula-

tors of the US28 receptor by our research group and Phan-

stiel’s group.^[15]The luciferase-based PathDetect Elk1 gene re-

porter assay was used to characterize the inverse agonist prop-

erties of the compounds.^[15]Dihydroisoquinolinone 3 has

inverse agonist properties with slightly improved potency and

similar activity to VUF2274 (2; see Table 1 below for data). To

ensure the broad and straightforward accessibility of new com-

pounds for biological testing, it is our general goal to exploit

recently developed and efficient synthetic strategies with

a broad substrate scope for the preparation of potential li-

gands.

In our first study on the US28 receptor,^[15]we used radical

carboamination reactions as a key step to synthesize dihydroi-

soquinolinones such as amide 3.^[16,17]Given the promising re-

sults obtained with ligands of this type, we then considered re-

placement of the isoquinolinone moiety 6a with a biphenyla-

mine 6b for three main reasons: 1) our synthetic access to

substructure 6b allows a broad variation of the substituents

R¹, 2) the possibility to vary the dihedral angle of the biphenyl

unit in 6b through introduction of suitable substituents, and

3) the straightforward accessibility of biphenylamines 6b from

simple starting materials through only one synthetic step.^[18,19]

Moreover, biphenyl units are commonly found as structural el-

ements in many pharmaceuticals.^[20]

Figure 2. General approach to biphenylamine ligands 7.

started with a reductive titanium(III)-mediated radical aryl–aryl

coupling (Scheme 1). By reacting the two aryl diazonium chlor-

ides 8a and 8b with 4-anisidine (9a), and salt 8c with 4-ami-

nophenol (9b) or 1,4-phenylenediamine (9c), a set of four bi-

phenyls 10a–d were available through a simple synthetic step

and without any further protecting group strategy.^[19a]Regard-

ing the dihedral angle of these biphenyls, 10a can be expect-

ed to be slightly twisted because of the occupancy of just one

out of four ortho positions (relative to the aryl–aryl bond) by

Herein we report the synthesis of a novel class of biphenyla-

mine derivatives and their biological evaluation with regard to

inhibition of constitutive signaling of the US28 receptor. The

general biphenylamine structure 7 depicted in Figure 2 was

varied in eight different ways to gain insight into structure–ac-

tivity relationships. For better understanding, the groups of

structural variations 1–8 correspond to Schemes 1–8 in the fol-

lowing section.

Results and Discussion

Chemistry

One reason for choosing biphen-

yls as a structural core motif for

the potential US28 receptor li-

gands was the associated option

to vary the torsion or dihedral

angle of the aryl–aryl bond

through the substitution pattern.

In this way, we focused on the

preparation of

a

structurally

more diverse library of test com-

pounds than would have been

possible through the simple re-

placement of substituents on

a given central unit, such as

a benzene core. The synthesis of

Scheme 1. Variation of torsion angle and conformationally fixed derivatives. Reagents and conditions: a) TiCl₃, HCl/

H₂O/CH₃CN, RT, 8a–c added over 15 min (10a: 57%, 10b: 31%, 10c: 34%, 10d: 18%); b) 2-chloro-N,N-dimethyle-

thylamine·HCl, H₂O, microwave irradiation at 1508C, 20 min (11 a: 38%, 11 b: 31%, 11 c: 23%, 11 d: 9%);

the first group of compounds c) H₁₉C₉COCl, NEt₃, 1,2-C₂H₄Cl₂, 508C, 12 h (12a: 38%, 12b: 75%, 12c: 35%).

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the methoxy group. Higher degrees of substitution at the

ortho positions, such as in the dichloro derivative 10b, can be

expected to lead to increased dihedral angles of ~508–808.^[21]

Because the ester group of the diazonium salt 8c readily

reacts with proximal hydroxy or amino functionalities as pres-

ent in 9b and 9c, aryl–aryl coupling furnished the nearly

planar dibenzopyranone 10c and phenanthridinone 10d

through a subsequent instantaneous cyclization step.

above. Because the benzylamines 13b and 13c could not be

alkylated with 2-chloro-N,N-dimethylethylamine hydrochloride

under the aforementioned microwave conditions, the synthetic

sequence was modified in the way that 13a–c were first acy-

lated to give the corresponding amides 14a–c. Deprotonation

of 14a–c with sodium hydride then allowed attachment of the

alkylamino side chain through reaction with 2-chloro-N,N-di-

methylethylamine hydrochloride. Saponification of the ester

groups and formation of carboxylates 15a–c occurred during

the aqueous workup after the alkylation step.

Titanium(III)-mediated radical arylations of 4-anisidine (9a)

and 4-aminophenol (9b) commonly give yields in the range of

40–70%.^[19a]The comparatively lower yield obtained for 10b is

most probably because more acetonitrile had to be added to

the reaction mixture to solubilize the less polar diazonium salt

8b.^[22]Reactions of acceptor-substituted electron-poor diazoni-

um salts, such as 8c with 9b and 9c, can be complicated if

these substrates can be oxidized to the corresponding quinone

imines by the diazonium salt. The reagents for the following

steps to give 11 a–d and 12a–c were chosen in a way to main-

tain structural similarity and thus comparability with dihydro-

isoquinolinone 3 from our previous study (Figure 2). The alky-

lation of 10a–d with 2-chloro-N,N-dimethylethylamine hydro-

chloride under microwave irradiation produced moderate to

low yields.^[23]Amides 12a–c were finally obtained under stan-

dard conditions with decanoyl chloride as the acylating agent.

To evaluate the influence of polar substituents on the bi-

phenyl core, the radical aryl–aryl coupling was also conducted

with the meta- and para-methoxycarbonyl-substituted diazoni-

um salts 8d and 8e (Scheme 2). Because neither of the two

substrates 4-anisidine (9a) and 4-methoxybenzylamine (9d) is

easily oxidized and no acetonitrile had to be added for solubili-

ty reasons, the desired biphenyls 13a–c were obtained in fair

yields of 54–63%, which are in the usual range mentioned

After the alkylation procedure, we were surprised to find the

by-product 15d, which appears to arise from an attack of the

carboxylate salt 15c by the alkylating agent. This side reaction

is likely to occur during workup, when the ester has been con-

verted into a more nucleophilic carboxylate.^[24,25]

Besides attaching the alkylamino and the decanoyl side

chains at the nitrogen atom of the biphenylamine core unit

(c.f. structure 7, Figure 2), we also wanted to explore the bio-

logical effects of linking those structural elements via the phe-

nolic oxygen atom, which has so far been protected as

a methyl ether. To avoid the presence of an additional polar

substituent in the final racemic products 17 and 18, the typical

amino group on the biphenyl core was replaced by less polar

fluoro or bromo substituents (Scheme 3). To help clarify the

Scheme 3. Introduction of the alkylamine side chain at the phenolic oxygen

atom. Reagents and conditions: a) TiCl₃, HCl/H₂O/CH₃CN, RT, over 15 min

(16a: 35%, 16b: 21%); b) epichlorohydrine, pyridine, RT, 24 h (a: 71% b-

chloro alcohol, b: 31% b-chloro alcohol + 13% epoxide, epoxide used for

step d); c) 0.71n NaOH, EtOH, RT, 1 h (a: 55% epoxide); d) NEt₂H, H₂O, RT,

24 h, (17a: 53%, 167: 65%); e) H₁₉C₉COCl, NEt₃, 1,2-C₂H₄Cl₂, 508C, 12 h (18a:

18%).

close structural relationship between the biphenyl ether 18a

and previously described compounds such as 12a, the struc-

ture of 18a has been rotated in Scheme 3. Starting from the

biphenyl alcohols 16a and 16b, which were again prepared

by titanium(III)-mediated aryl–aryl coupling, alkylation was ach-

ieved with epichlorohydrin.^[26]The reaction with 16a exclusive-

ly gave a b-chloro alcohol, which was converted into the corre-

sponding epoxide by treatment with dilute sodium hydroxide

in step c). Under similar conditions, 16b led directly to the ep-

oxide along with major amounts the b-chloro alcohol. Subse-

Scheme 2. Introduction of polar residues. Reagents and conditions: a) TiCl₃,

HCl/H₂O, over 15 min, RT, (13a: 63%, 13b: 54%, 13c: 58%); b) H₁₉C₉COCl,

NEt₃, 1,2-C₂H₄Cl₂, 508C, 12 h, (14a: 58%, 14b: 33%, 14c:18%); c) NaH, DMA,

1 h at 08C, then 2-chloro-N,N-dimethylethylamine·HCl, RT, 16 h (15a: 13%,

15b: 18%, 15c: 5%, 15d: 20%).

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quent amination through ring opening of both intermediate

epoxides^[27]with diethylamine furnished amino alcohols 17a

and 17b, the former of which was further converted into 18a

under standard acylation conditions.

Related to the compounds 11 c,d and 12c (Scheme 1), which

incorporate a more or less planar biphenyl unit, we also inves-

tigated replacement of the biphenyl substructure by a benzo-

phenone or xanthone unit (Scheme 4). In case of high affinity

Scheme 5. Variation of chain length. Reagents and conditions: a) TiCl₃, HCl/

H₂O, over 15 min (22a: 65%, 22b: 48%), b) H₁₉C₉COCl, NEt₃, 1,2-C₂H₄Cl₂,

508C, 12 h (23a: 32%, 23b: 14%); c) NaH, DMA, 1 h at 08C, then 2-chloro-

N,N-dimethylethylamine·HCl, RT, 16 h (24a: 77%, 24b: 30%).

Scheme 4. Replacement of biphenyl by photoexcitable benzophenones. Re-

agents and conditions: a) H₁₉C₉COCl, NEt₃, 1,2-C₂H₄Cl₂, 508C, 12 h (20a: 80%,

20b: quant); b) NaH, DMA, 08C, 1 h, then 2-chloro-N,N-dimethylethylami-

ne·HCl, RT, 16 h (21a: 38%, 21b: 8%).

for the US28 receptor, such ligands could be valuable tools in

photolabeling experiments^[28]to determine the proximal amino

acids in the binding pocket. Starting from 2-aminoxanthone

(19a)^[29]or 3-aminobenzophenone (19b), acylation with dec-

anoyl chloride proceeded without difficulty to give amides

20a and 20b. Deprotonation with excess sodium hydride and

alkylation with 2-chloro-N,N-dimethylethylamine then provided

the desired target compounds 21a and 21b.^[30]

Titanium(III)-mediated radical arylations of phenols and

phenyl ethers proceed best when water can be used as the

only solvent because this mostly limits undesired hydrogen ab-

straction by the aryl radicals. With regard to the required solu-

bility in acidic aqueous solutions, aminophenols such as 9a

and 9b and hydroxy- or methoxybenzylamines such as 9d rep-

resent ideal substrates for this reaction type.^[19b]Not surprising-

ly, fair yields were obtained from the arylation reactions of 4-

methoxybenzylamine (9d) with the diazonium salts 8a and 8b

(Scheme 5). The lower yield of 22b can again be explained by

the necessity to add acetonitrile to solubilize the diazonium

salt 8b. In the next steps, the biphenylmethylamines 22a and

22b were first acylated with decanoyl chloride to give 23a

and 23b, and then alkylated under the previously established

conditions to obtain the desired target compounds 24a and

24b.

Variations of the carbonyl part of the amide were carried out

with biphenyl 11 a as the starting material (Scheme 6). Acyla-

tion with five acid chlorides under standard conditions gave

amides 25a–e in good-to-high yields with the exception of the

furoyl derivative 25b. For the purification of amides 25b, 25d,

and 25e, it was particularly useful to remove the carboxylic

acid derivatives, which arise from hydrolysis of the acid chlor-

ides during workup, through filtration over aluminum oxide.

4-Aryl-4-hydroxypiperidine and 2,2-diphenylpentanenitrile

occur as common structural motifs in a number of known

Scheme 6. Variation of the acyl moiety of the amide. Reagents and condi-

tions: a) PhCOCl or furan-2-carboxylic acid chloride or PhCH₂COCl or cyclo-

propanecarboxylic acid chloride or cyclohexanecarboxylic acid chloride, NEt₃,

1,2-C₂H₄Cl₂, 508C, 12 h (25a: 73%, 25b: 22%, 25c: 68%, 25d: 49%, 25e:

88%).

US28 ligands such as VUF2274, VUF5743, and VUF6984.^[14c]To

investigate the influence of these established building blocks

in combination with the biphenylamine unit, two sets of

hybrid ligands were prepared (Scheme 7). Depending on

whether the final product should be a benzylamide or a benzyl-

amine, the starting materials 22a and 22b were either acylat-

ed with decanoyl chloride (a) or protected with an acid-sensi-

tive tert-butyloxycarbonyl (Boc) group (b) to give the four key

intermediates 23a,b and 26a,b. The attachment of the 4-aryl-

4-hydroxypiperidine unit to yield compounds 27a–d was car-

ried out in two steps: amides 23a,b and carbamates 26a,b

were first N-alkylated with 1-bromo-3-chloropropane (c) to

give alkyl chlorides,^[31]which were then reacted with 4-(4-

chlorophenyl)-4-hydroxypiperidine under iodide catalysis at

elevated temperatures (d).^[32,33]To obtain the diphenylpentane-

nitrile-substituted biphenylmethylamines 28a–d, the above-

mentioned key intermediates 23a,b and 26a,b were deproton-

ated with sodium hydride and then treated with 5-bromo-2,2-

diphenylpentanenitrile (e).^[30,34]After the final Boc deprotection

with trifluoroacetic acid (f), benzylamines 28c and 28d

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sient expression of the US28 receptor in human em-

bryonic kidney (HEK) 293T cells leads to a significant

increase in basal accumulation of the reporter gene

luciferase. This US28-receptor-mediated accumulation

can be efficiently inhibited by various ligands.^[15]

Initially the cytotoxicity of all compounds in the

HEK293T cell line was investigated with the CellTiter

96 AQueous One Solution Cell Proliferation Assay

(Promega). This is a colorimetric method for deter-

mining the number of viable cells in cytotoxicity

assays. Several compounds demonstrated a negative

effect on cell viability at a concentration of 10 mm

(Supporting Information, table S1). The VUF hybrids

with a 4-(4-chlorophenyl)-4-hydroxypiperidine moiety

(27a–d) were characterized as the highest cytotoxic

derivatives. Interestingly, the hydroxy group in this

structural element was previously suggested to be

a site of potential metabolic toxicity.^[36]All com-

pounds showing cytotoxicity (entries: 12c, 23a, 25e,

and 27a–d) were omitted from further biological

evaluation.

Investigations concerning the influence of the tor-

sion angle of the biphenyls (Scheme 1, Table 1, en-

tries 11 a–d and 12a–c) on the potency and inverse

agonist activity revealed that there is no significant

effect on potency; only some differences in inverse

agonist properties were observed (ꢀ31% for para-

chloro (12a) and ꢀ62% for the ortho,ortho-dichloro

derivative 12b; Table 1).^[37]The conformationally fixed

derivatives 11 c,d showed negligible activity. The cy-

totoxicity observed for dibenzopyranone 12c could

be related to ring opening and unselective acylation

of various targets.

Scheme 7. Variation of the alkylamine side chain. Reagents and conditions: a) H₁₉C₉COCl,

NEt₃, 1,2-C₂H₄Cl₂, 508C, 12 h (23a: 32%, 23b:14%); b) Boc₂O, NEt₃, 1,2-C₂H₄Cl₂, 508C,

12 h (26a: 43%, 26b: 44%); c) NaH, DMF, 1 h at 08C, then 1-bromo-3-chloropropane, RT,

16 h (a: 14%, b: 12%, c: 47%, d: 57%); d) 4-(4-chlorophenyl)-4-hydroxypiperidine, NaI,

Na₂CO₃, n-butanol, 1008C, 20 h (27a: 14%, 27b: 25%, c: 60%, d: 56%); e) NaH, DMF, 1 h

at 08C, then 5-bromo-2,2-diphenylpentanenitrile, RT, 16 h (28a: 66%, 28b: 22%, c: 74%,

d: 86%); f) TFA, CH₂Cl₂, 08C, 3 h (27c: 100%, 27d: 100%, 28c: 38%, 28d: 16%).

showed unexpectedly high hydrophilicity, which in turn com-

plicated the extraction of these compounds from the aqueous

phase and led to relatively low yields in this otherwise simple

step. To avoid this difficulty for the related hydroxypiperidines

27c and 27d, these compounds were isolated as bis-trifluoroa-

cetate salts.

Although the known ligand VUF2274 had been converted

into a quaternary ammonium salt that led to a complete loss

of binding affinity and activity at the US28 receptor,^[14b,35]we

wanted to determine whether a comparable structural modifi-

cation of our ligands would lead to a similar effect. We turned

to the synthesis of a set of quaternary ammonium salts

(Scheme 8). Starting from anilides 12a and 12b, benzylamides

24a and 24b, and xanthone and benzophenone derivatives

21a and 21b, six ammonium iodides—29a,b, 30a,b, and

31a,b—could be cleanly prepared through alkylation with

methyl iodide.^[35]

Biological evaluation

The ability of compounds to inhibit the constitutive activity of

the US28 receptor was tested with a reporter gene assay using

the PathDetect trans-Elk11 system (Stratagene/Agilent).^[15]Tran-

Scheme 8. Permanent charges—ammonium salts. Reagents and conditions:

a) CH₃I, CH₂Cl₂, RT, 24 h (100% for all).

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Table 1. Biological evaluation of compounds in transiently transfected

human embryonic kidney (HEK) 293T cells containing the US28 receptor

and the components of the PathDetect trans-Elk1 reporter gene assay.^[a]

Table 1. (Continued)

Compd

Scheme/Figure

EC₅₀[mm]^[b]

pEC₅₀ꢁSEM^[b]

Efficacy [%]

29a

29b

30a

30b

31a

31b

4.60

4.90

4.96

4.65

NE

5.33ꢁ0.15

5.31ꢁ0.01

5.30ꢁ0.01

5.33ꢁ0.03

NE

ꢀ61ꢁ8

ꢀ47ꢁ4

ꢀ100ꢁ2

ꢀ95ꢁ2

NE

Compd

Scheme/Figure

Figure 1

EC₅₀[mm]^[b]

pEC₅₀ꢁSEM^[b]

6.46ꢁ0.46

5.34ꢁ0.45

4.82ꢁ0.10

Efficacy [%]

1

2

3

0.35

4.50

15.0

10ꢁ3

ꢀ22ꢁ8

ꢀ37ꢁ9

Scheme 8

NE

[a] Functional data were obtained on HEK293T cells that transiently ex-

press US28 and components of the PathDetect trans-Elk11 reporter gene

system.^[24]Dose–response curves of 3–5 experiments (performed in tripli-

cate) were normalized and pooled to generate a mean curve from which

the EC₅₀value and maximum intrinsic activity of each compound was ob-

tained. The resulting reporter gene assay data were analyzed by nonlin-

ear regression using the algorithms in Prism 5.0 (GraphPad Software, San

Diego, CA, USA). [b] Curves were fitted to the sigmoid curve by nonlinear

regression analysis in which the ꢀlogEC₅₀values (pEC₅₀ꢁSEM) were de-

termined. NE=no effect when tested at 10 mm compound; NA=EC₅₀

value not available because of incomplete curves, only the efficacy at

10 mm reported; TOX=toxic compound. [c] Efficacy estimated at 10 mm

compound.

11 a

11 c

11 d

12a

12b

12c

NE

NA

NE

3.01

4.11

TOX

NE

NA

NE

ꢀ36ꢁ2^[c]

NE

ꢀ31ꢁ2

ꢀ62ꢁ2

TOX

Scheme 1

5.52ꢁ0.10

5.39ꢁ0.05

TOX

15a

15b

15c

15d

NA

1.74

NA

NE

NA

5.76ꢁ0.09

NA

ꢀ48^[c]

ꢀ80ꢁ5

ꢀ31ꢁ5^[c]

NE

Scheme 2

NE

17a

17b

18a

NA

NE

3.39

NA

NE

5.47ꢁ0.15

ꢀ18ꢁ5^[c]

NE

ꢀ71ꢁ8

Scheme 3

Scheme 4

21a

21b

NE

23a

23b

24a

24b

TOX

NA

2.41

10.8

TOX

NA

5.62ꢁ0.03

4.96ꢁ0.04

TOX

ꢀ49

Scheme 5

Scheme 6

ꢀ100ꢁ2

ꢀ47ꢁ2

25a

25b

25c

25d

25e

NA

3.43

NA

5.47ꢁ0.10

NA

ꢀ53ꢁ4^[c]

ꢀ53ꢁ10^[c]

ꢀ47ꢁ7

ꢀ50ꢁ8^[c]

TOX

Figure 3. Biological characterization of the most potent novel compounds

15b, 24a, and 30a. HEK293T cells were transiently transfected with the

US28 receptor and components of the PathDetect trans-Elk1 reporter gene

assay. Normalized curves from 3–5 experiments, each performed in triplicate,

are shown; error bars represent SEM.

TOX

27a

27b

27c

27d

28a

28b

28c

28d

TOX

NA

9.73

6.61

TOX

NA

TOX

Scheme 7

ꢀ23ꢁ10^[c]

ꢀ27ꢁ10^[c]

ꢀ91ꢁ4

ꢀ59ꢁ4

best potency and efficacy in this series (15b, EC₅₀: 1.74 mm, ef-

ficacy: ꢀ80%, Figure 3) contains the carboxylate group at the

meta position of the biphenyl group attached to the methoxy-

benzylamine. Moving the carboxylate group to the para posi-

tion led to a significant loss of potency and efficacy (15c, effi-

cacy at 10 mm: ꢀ31%). Beside this substitution pattern, we dis-

covered that the distance between the biphenyl core and the

nitrogen atom significantly influences the biological properties

of the compounds. Elimination of the methylene group be-

tween the aryl moiety and the nitrogen atom again resulted in

a significant loss of activity (from n=1 (15b) to n=0 (15a); ef-

ficacy ꢀ80 and ꢀ48%, respectively) and potency (15b:

1.74 mm and 15a: >10 mm).

NA

5.01ꢁ0.02

5.18ꢁ0.02

Importantly, and almost independent of the substitution pat-

tern of the biphenyl unit, only the derivatives containing a dec-

anoyl side chain acted as inverse agonists. At this early stage

the presence of the decanoyl side chain thus appeared to be

necessary for the inverse agonist properties of our biphenyl

derivatives.

Exchange of the halogen substituents on the biphenyl core

for a polar carboxylate group yielded a very active compound

(Scheme 2, Table 1, entries 15a–d). The compound with the

Besides attachment to the alkylamino and the decanoyl side

chains, as in compounds 12a and 15a, and to the nitrogen

atom on the biphenylamine unit, we also explored the biologi-

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cal effects of linking the biphenyl and those structural ele-

tho,ortho-dichloro derivative 28d displayed less efficacy but

greater potency (ꢀ59%, EC₅₀: 6.61 mm) than its para-mono-

chlorinated counterpart 28c (ꢀ91%, EC₅₀: 9.73 mm). In general,

two lipophilic side chains in 28c,d appear not to be tolerated,

whereas replacement of the decanoyl part by the lipophilic

pentanenitrile results only in a partial loss of activity. This ob-

servation could be at least partially explained by the fact that

28c,d contains a basic nitrogen atom, which is not present in

28a,b. A similar structure–activity relationship has been ob-

served before for the biphenylmethylamines 23a,b (without

basic nitrogen) and 24a,b (with basic nitrogen).

Although the conversion of VUF2274 into a quaternary am-

monium salt led to a complete loss of binding affinity and ac-

tivity at the US28 receptor,^[14b,35]we investigated a similar struc-

tural modification of our ligands (Scheme 8, Table 1, Figure 3,

entries 29a,b, 30a,b, and 31a,b). Compounds 29a,b and

30a,b had only slightly reduced potency at the US28 receptor

while retaining good efficacy (up to ꢀ100%). Again, the dis-

tance between the biphenyl core and the nitrogen atom dic-

tated the inverse agonist properties of the compounds as al-

ready observed for 15a–c. Interestingly, the differences in po-

tency and efficacy between the para-chloro- and ortho,ortho-

dichloro-substituted ligands (29a vs. 29b, 30a vs. 30b) were

negligible for the ammonium salts (Table 1). In the case of ben-

zophenone derivatives the introduction of the permanent

charge did not help to improve the biological properties. Ben-

zophenones 21a,b and their charged derivatives 31a,b

showed no measurable inverse agonism.

ments via

a

central isopropanolamine core structure

(Scheme 3, Table 1, entries 17a,b and 18a). In this series only

18a acted as an inverse agonist, with an EC₅₀value of 3.39 mm

and an efficacy of ꢀ71%. This again underscores the impor-

tance of the decanoyl side chain for the potency and inverse

agonist activity of the compounds, as this structural element is

absent in 17a,b.

Replacement of the biphenyl core with benzophenone or

xanthone units, which are commonly used as reactive sub-

structures of photoexcitable ligands, resulted in a complete

loss of inverse agonist properties for 21a,b (Scheme 4, Table 1,

entries 21a,b). This indicates that the US28 receptor does not

tolerate even a minor enlargement of the biphenyl moiety.

This effect might be further negatively enhanced by the rigidi-

ty of the benzophenone-derived ligands 21a,b, which do not

possess a methylene spacer between the aromatic part and

the amide.

A comparison of the biological properties of 23a,b and

24a,b unambiguously shows that the presence of the dime-

thylethylamine side chain is essential for both potency and in-

verse agonist activity (Scheme 5, Table 1, entries 23a,b and

24a,b). Compounds 23a,b, in which this side chain is absent,

were either cytotoxic or had no measurable effects. The deriva-

tives containing the dimethylethylamine side chain (24a–b),

on the other hand, demonstrated good potency and remark-

able efficacy, with the para-chloro-substituted biphenyl moiety

(24a, EC₅₀: 2.41 mm, efficacy: ꢀ100%, Figure 3) being superior

to the ortho,ortho-dichloro derivative (24b, EC₅₀: 2.03 mm, effi-

cacy: ꢀ54%).

To determine whether the US28 receptor would tolerate

a variation of the acyl moiety of the amide, we replaced the

original decanoyl chain with various aromatic and cyclic ali-

phatic appendages (Scheme 6, Table 1, entries 25a–e). The cy-

clohexyl derivative proved to be cytotoxic. Other appendages

yielded partial inverse agonists (up to ꢀ53%), but only for 25c

was the determination of the EC₅₀value possible (3.43 mm).

This indicates the importance of the flexibility of the side

chain, which is provided only in 25c through the presence of

a methylene group between the amide bond and the phenyl

ring.

Figure 4. Biphenylamine-scaffold-based pharmacophore model depicting

crucial structural elements that dictate inverse agonist properties of US28 al-

losteric modulators.

4-Aryl-4-hydroxypiperidine and 2,2-diphenylpentanenitrile

are known as common structural motifs in a number of US28

ligands such as VUF2274, VUF5743, and VUF6984.^[14c]To evalu-

ate these building blocks in combination with the best scaffold

we have found thus far, which is a biphenylmethylamine, two

sets of hybrid ligands were prepared (Scheme 7, Table 1, en-

tries 27a–d and 28a–d). All compounds that contained the 4-

hydroxypiperidine moiety (27a–d) were highly cytotoxic (Sup-

porting Information, table S1). The second set of compounds

incorporating the 2,2-diphenylpentanenitrile scaffold differed

significantly in their biological properties. The nitriles 28a,b

that contained the nonpolar decanoyl side chain as well as the

comparably lipophilic pentanenitrile unit showed only weak

partial inverse agonist activity (ꢀ23 and ꢀ27%, respectively).

The nitriles 28c,d lacking the decanoyl side chain regained

some potency and efficacy with the unique feature that the or-

Conclusions

We have shown that the biphenyl derivatives, which are readily

available through radical arylation reactions of 4-anisidine and

4-methoxybenzylamine, are valuable building blocks for the

design and synthesis of novel US28 allosteric modulators with

intrinsic negative efficacy (inverse agonism). When we started

with the radical reaction, most of the ligands were easily acces-

sible in only three or four simple synthetic steps. Biological

evaluation in the reporter gene assay of 38 potential ligands

led to the discovery of three promising candidates with poten-

cies of <5 mm and efficacies in the range between ꢀ80 and

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pressure. The residue was dissolved in EtOAc (50 mL) and washed

with saturated Na₂CO₃solution (50 mL) and brine (50 mL). The or-

ganic phase was dried over anhydrous Na₂SO₄, and the solvent

was evaporated under reduced pressure.

ꢀ100% (entries 15b, 24a, and 30a,b); these data are superior

to those of any published small-molecule US28 ligand.

Through multiple variations of side chains and functional

groups, crucial structural elements that dictate inverse agonist

properties of ligands have been unambiguously determined.

The preliminary structure–activity relationship summary

(Figure 4) can now serve as a solid foundation for further opti-

mizations.

Alkylation of amides (procedure 4): The amide (250 mmol,

1.0 equiv) and NaH (7.50 mmol, 30 equiv) were dissolved in N,N-di-

methylformamide or N,N-dimethylacetamide (4 mL) under argon

atmosphere. The reaction mixture was stirred for 1 h at 08C. After

addition of the alkyl halide (2.50 mmol, 10 equiv) the solution was

stirred for another 4 h at room temperature. The reaction mixture

was diluted with H₂O, extracted with EtOAc (2ꢁ50 mL), and

washed with brine. The combined organic phases were dried over

anhydrous Na₂SO₄, and the solvent was removed under reduced

pressure.

Experimental Section

Chemistry

1

Solvents and reagents were used as received. H NMR spectra were

Alkylation with epichlorohydrin (procedure 5):^[26]The hydroxy-

biaryl (500 mmol, 1.0 equiv), epichlorohydrin (2.50 mmol, 5.0 equiv),

and pyridine (0.1 mL) were stirred at room temperature for 24 h.

The unreacted epichlorohydrin and pyridine were removed in

vacuo. The residue was dissolved in EtOH (1 mL), and NaOH

(30 mg) was added. This reaction mixture was stirred for 1 h, then

concentrated under reduced pressure, diluted with H₂O (50 mL),

and extracted with EtOAc (3ꢁ75 mL). The combined organic

phases were washed with brine and dried over anhydrous Na₂SO₄,

and the solvent was removed under reduced pressure.

recorded on 360 and 600 MHz spectrometers with CDCl₃and

CD₃OD used as solvents referenced to TMS (d=0 ppm) and CHCl₃

(d=7.26 ppm). Chemical shifts are reported in parts per million.

Coupling constants (J) are in Hz. The following abbreviations are

used for the description of signals: s (singlet), d (doublet), dd

(double doublet), t (triplet), q (quadruplet), m (multiplet), and br

(broad). ¹³C NMR spectra were recorded at 90.6 and 151 MHz in

CDCl₃and CD₃OD referenced to CDCl₃(d=77.0 ppm) and CD₃OD

(d=49.5 ppm). Chemical shifts are given in parts per million. Mass

spectra were recorded as electron impact (EI) or electrospray ioni-

zation (ESI). Analytical thin-layer chromatography (TLC) was carried

out on Merck silica gel plates with short wavelength (254 nm) UV

light used to visualize components. Silica gel (Kieselgel 60, 40–

63 mm) was used for flash column chromatography.

Amination of epoxide (procedure 6):^[27]The epoxide (60.0 mmol)

was dissolved in H₂O (1 mL) at 08C, and NEt₂H (2 mL) was added.

The mixture was stirred at room temperature for 24 h. The reaction

mixture was diluted with H₂O (30 mL) and extracted with Et₂O (3ꢁ

30 mL). The combined organic phases were washed with brine and

dried over anhydrous Na₂SO₄, and the solvent was removed under

reduced pressure.

General procedures

Radical biaryl synthesis (procedure 1):^[18b]To a solution of the ani-

line (10.0 mmol, 2.5 equiv) in H₂O (10 mL) and HCl (3m, 10 mL),

which was degassed with nitrogen and cooled to 08C, NaNO₂

(10.0 mmol, 2.5 equiv) dissolved in H₂O (5 mL) was added dropwise

over a period of 10 min. The reaction mixture was stirred for

20 min. The arenediazonium salt solution (10.0 mL, 0.4m,

4.00 mmol, 1.0 equiv) was added dropwise to a previously de-

gassed solution of p-anisidine/p-methoxybenzylamine/para-substi-

tuted phenol (20.0 mmol, 5.0 equiv) in H₂O (32 mL) and TiCl₃

(8.00 mmol, 1m in 3n HCl, 8 mL) over a period of 15 min. After

5 min of additional stirring, the base was added when indicated in

the individual procedure, and the resulting mixture was extracted

with Et₂O (3ꢁ100 mL). The combined organic phases were washed

with brine and dried over anhydrous Na₂SO₄, and the solvent was

evaporated under reduced pressure. Purification by distillation

and/or column chromatography gave pure biaryl compounds.

Alkylation of amines via Finkelstein reaction (procedure 7):^[32]To

a solution of the alkyl halide (100 mmol, 1.0 equiv) and 4-(4-chloro-

phenyl)-4-hydroxypiperidine (200 mmol, 2.0 equiv) in n-butanol

(4 mL), Na₂CO₃(100 mmol, 1.0 equiv) and NaI (100 mmol, 1.0 equiv)

were added under argon atmosphere. The reaction mixture was

stirred at 1008C for 20 h. After cooling to room temperature the

product was filtered, and the filtrate was concentrated under re-

duced pressure and purified by column chromatography.

Removal of Boc protecting group (procedure 8): The Boc-protect-

ed amine was dissolved in trifluoroacetic acid (1 mL) and CH₂Cl₂

(3 mL) under an argon atmosphere. The reaction mixture was

stirred for 3 h at 08C. The solution was made basic (pH~12) with

aqueous NaOH (2m) before being extracted with Et₂O (2ꢁ50 mL).

The combined organic phases were washed with brine and dried

over anhydrous Na₂SO₄, and the solvent was removed under re-

duced pressure.

Microwave-assisted N-alkylation of arylamines (procedure 2):^[23]

A mixture of arylamine (3.00 mmol, 1.0 equiv) and 2-chloro-N,N-di-

methylethylamine·HCl (6.00 mmol, 2.0 equiv) in H₂O (2 mL) was ir-

radiated at 1508C for 20 min. The solution was adjusted to pH 12

with aqueous NaOH (2m) and then extracted with Et₂O (3ꢁ20 mL).

The combined organic phases were washed with brine and dried

over anhydrous Na₂SO₄, and the solvent was evaporated under re-

duced pressure.

Methylation of tertiary amines (procedure 9): The tertiary amine

(50.0 mmol, 1.0 equiv) was dissolved in CH₂Cl₂(2 mL). CH₃I

(1.50 mmol, 30 equiv) was added dropwise, and the reaction mix-

ture was stirred for 24 h. The solvent and excess CH₃I were evapo-

rated under reduced pressure.

Compounds

Acylation of amines or alcohols (procedure 3): The amine/alcohol

(2.00 mmol, 1.0 equiv) was dissolved in a mixture of 1,2-dichloro-

ethane (10 mL) and NEt₃(4.00 mmol, 2.0 equiv) under argon at-

mosphere. The acid chloride (4.00 mmol, 2.0 equiv) or anhydride

(2.00 mmol, 1.0 equiv) was added dropwise, and the reaction mix-

ture was stirred for 12 h. The solvent was removed under reduced

4’-Chloro-6-methoxybiphenyl-3-amine (10a): Preparations from 4-

chloroaniline (1.28 g, 10.0 mmol) and p-anisidine (9a) (2.46 g,

20.0 mmol) were made according to general procedure 1 described

above. The final reaction mixture was made basic with NaOH

(4.00 g) and Na₂SO₃(4.00 g) in H₂O (40 mL) prior to extraction. Pu-

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rification by Kugelrohr distillation and column chromatography

(CH₂Cl₂/EtOAc=30:1) gave the title compound 10a as a dark solid

(533 mg, 2.28 mmol, 57%). R_f=0.6 (CH₂Cl₂/EtOAc=20:1) [UV];

¹H NMR (360 MHz, CDCl₃): d=3.70 (s, 3H), 6.64–6.68 (m, 2H), 6.80–

6.84 (m, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.44 ppm (d, J=8.8 Hz, 2H);

¹³C NMR (90.6 MHz, CDCl₃): d=56.1 (CH₃), 113.0 (CH), 115.0 (CH),

117.6 (CH), 127.8 (2ꢁCH), 130.1 (C_q), 130.4 (2ꢁCH), 132.5 (C_q), 136.7

(C_q), 139.9 (C_q) 149.4 ppm (C_q); MS (EI): m/z (%)=233 (43) [M]⁺, 219

(21), 218 (22), 217 (13), 203 (13), 187 (12), 184 (14), 183 (100), 85

(57), 83 (83), 47 (11); HRMS (EI): C₁₃H₁₂ClNO [M]⁺calcd: 233.0607,

found: 233.0607.

(CH), 124.5 (C_q), 126.6 (CH), 126.7 (CH), 127.8 (C_q), 131.7 (CH), 134.0

(C_q), 142.4 (C_q), 161.1 ppm (CO); MS (EI): m/z (%)=210 (100) [M]⁺,

211 (16), 209 (6), 182 (9), 181 (16), 154 (9), 128 (4), 127 (7), 105 (5),

91 (8), 77 (6); HRMS (EI): C₁₃H₁₀N₂O [M]⁺calcd: 210.0793, found:

210.0793.

N’-(4’-Chloro-6-methoxybiphen-3-yl)-N,N-dimethylethane-1,2-dia-

mine (11a): Preparations from compound 10a (630 mg,

2.70 mmol) were made according to general procedure 2 described

above. Purification by column chromatography (CHCl₃/MeOH=

20:1) gave the title compound (4a) as a violet oil (313 mg,

1.03 mmol, 38%). R_f=0.5 (CHCl₃/MeOH=3:1) [UV]; ¹H NMR

(360 MHz, CDCl₃): d=2.27 (s, 6H), 2.55–2.60 (m, 2H), 3.12–3.17 (m,

2H), 3.70 (s, 3H), 6.60–6.65 (m, 2H), 6.85–6.89 (m, 1H), 7.35 (d, J=

8.7 Hz, 2H), 7.46 ppm (d, J=8.7 Hz, 2H); ¹³C NMR (90.6 MHz,

CDCl₃): d=41.9 (CH₂), 45.1 (2ꢁCH₃), 56.6 (CH₂), 58.1 (CH₃), 113.0

(CH), 113.6 (CH), 115.8 (CH), 128.1 (2ꢁCH), 130.4 (C_q), 130.8 (2ꢁCH),

132.7 (C_q), 137.3 (C_q), 134.0 (C_q), 149.0 ppm (C_q); MS (EI): m/z (%)=

304 (35) [M]⁺, 248 (8), 247 (10), 246 (25), 245 (20), 230 (11), 202 (9),

139 (8), 59 (22), 58 (100); HRMS (EI): C₁₇H₂₁ClN₂O [M]⁺calcd:

304.1342, found: 304.1342.

2’,6’-Dichloro-6-methoxybiphenyl-3-amine (10b): Preparations

from 2,6-dichloroaniline (1.62 g, 10.0 mmol) and p-anisidine (9a)

(2.46 g, 20.0 mmol) were made according to general procedure 1

described above. For better solubility of 2,6-dichloroaniline, the di-

azonium salt was prepared in an CH₃CN/3n HCl/H₂O mixture at

2:2:1. The final reaction mixture was basified with NaOH (4.00 g)

and Na₂SO₃(4.00 g) in H₂O (40 mL) prior to extraction. Purification

by Kugelrohr distillation and column chromatography (CH₂Cl₂/

EtOAc=100:1) gave the title compound (10b) as a brown oil

(332 mg, 1.24 mmol, 31%). R_f=0.6 (CH₂Cl₂/EtOAc=100:1) [UV];

¹H NMR (360 MHz, CDCl₃): d=3.70 (s, 3H), 6.53 (d, J=2.8 Hz, 1H),

6.78 (dd, J=2.8 Hz, J=8.7 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 7.19 (dd,

J=7.6 Hz, J=8.5 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.37 ppm (d, J=

8.5 Hz, 1H); ¹³C NMR (90.6 MHz, CDCl₃): d=56.6 (CH₃), 113.0 (CH),

116.7 (CH), 118.2 (CH), 127.0 (C_q), 127.7 (2ꢁCH), 128.9 (CH), 135.4

(2ꢁC_q), 136.7 (C_q), 139.3 (C_q) 150.2 ppm (C_q); MS (EI): m/z (%)=267

(50) [M]⁺, 269 (33), 268 (8), 254 (10), 252 (17), 219 (33), 218 (14),

217 (100), 108 (9), 98 (9); HRMS (EI): C₁₃H₁₁Cl₂NO [M]⁺calcd:

267.0218, found: 267.0218.

N’-(2’,6’-Dichloro-6-methoxybiphen-3-yl)-N,N-dimethylethane-

1,2-diamine (11b): Preparations from compound 10b (174 mg,

649 mmol) were made according to general procedure 2 described

above. Purification by column chromatography (CHCl₃/MeOH=

20:1) gave the title compound 11 b as a brown oil (68.1 mg,

201 mmol, 31%). R_f=0.5 (CHCl₃/MeOH=10:1) [UV]; ¹H NMR

(360 MHz, CDCl₃): d=2.28 (s, 6H), 2.56–2.61 (m, 2H), 3.12–3.17 (m,

2H), 3.69 (s, 3H), 6.45 (d, J=2.9 Hz, 1H), 6.71 (dd, J=2.9 Hz, J=

8.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.19 (dd, J=7.6 Hz, J=8.5 Hz,

1H),7.37 (d, J=7.6 Hz, 1H), 7.37 ppm (d, J=8.5 Hz, 1H); ¹³C NMR

(90.6 MHz, CDCl₃): d=41.8 (CH₂), 45.2 (2ꢁCH₃), 56.8 (CH₂), 58.1

(CH₃), 113.2 (CH), 114.0 (CH), 115.7 (CH), 127.1 (C_q), 127.7 (2ꢁCH),

128.8 (2ꢁC_q), 135.5 (CH), 137.1 (C_q), 142.5 (C_q), 149.2 ppm (C_q); MS

(EI): m/z (%)=338 (45) [M]⁺, 340 (29), 283 (13), 282 (45), 281 (44),

280 (71), 279 (54), 230 (24), 229 (11), 202 (13), 173 (15), 59 (89), 58

(100), 57 (13); HRMS (EI): C₁₇H₂₀Cl₂N₂O [M]⁺calcd: 338.0953, found:

338.0953.

2-Amino-6H-benzo[c]chromen-6-one (10c): Preparations from

methyl anthranilate (1.51 g, 10.0 mmol) and p-aminophenol (9b)

(2.18 g, 20.0 mmol) were made according to general procedure 1

described above. After completion of the reaction, the resulting

mixture was basified to pH 10 using Na₂CO₃and 25% aqueous NH₃

prior to extraction. Purification by column chromatography

(hexane/EtOAc/AcOH=10:20:1) gave the title compound (10c) as

a yellow solid (288 mg, 1.36 mmol, 34%). R_f=0.6 (hexane/EtOAc/

AcOH=10:20:1) [UV]; ¹H NMR (360 MHz, CDCl₃/CD₃OD): d=6.88

(dd, J=2.6 Hz, J=8.7 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.38 (d, J=

2.7 Hz, 1H), 7.59 (m, 1H), 7.83 (ddd, J=1.4 Hz, J=7.3 Hz, J=8.1 Hz,

1H), 8.08 (d, J=8.1 Hz, 1H), 8.37 ppm (ddd, J=0.6 Hz, J=1.4 Hz,

J=8.0 Hz, 1H); ¹³C NMR (90.6 MHz, CDCl₃/CD₃OD): d=107.7 (CH),

118.5 (CH), 118.6 (CH), 118.6 (C_q), 121.3 (C_q), 121.8 (CH), 128.9 (CH),

130.6 (CH), 134.9 (CH), 135.0 (C_q), 143.5 (C_q), 144.6 (C_q), 162.2 ppm

(CO); MS (EI): m/z (%)=211 (100) [M]⁺, 212 (16), 207 (10), 183 (31),

155 (18), 154 (29), 128 (11), 127 (15), 91 (12), 77 (15); HRMS (EI):

C₁₃H₉NO₂[M]⁺calcd: 211.0633, found: 211.0633.

2-(2-Dimethylaminoethylamino)benzo[c]chromen-6-one

(11c):

Preparations from compound 10c (245 mg, 1.16 mmol) were made

according to general procedure 2 described above. Purification by

column chromatography (CHCl₃/MeOH=20:1!3:1) gave the title

compound (11 c) as a yellow solid (76.3 mg, 270 mmol, 23%). R_f=

1

0.3 (CHCl₃/MeOH=3:1) [UV]; H NMR (360 MHz, CDCl₃): d=2.31 (s,

6H), 2.64 (m, 2H), 3.24 (m, 2H), 6.79 (dd, J=2.6 Hz, J=8.8 Hz, 1H),

7.19 (d, J=2.6 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.55 (ddd, J=1.1 Hz,

J=7.3 Hz, J=8.0 Hz, 1H), 7.79 (ddd, J=1.4 Hz, J=7.3 Hz, J=8.0 Hz,

1H), 8.06 (d, J=8.0 Hz, 1H), 8.40 ppm (ddd, J=0.6 Hz, J=1.4 Hz,

J=8.0 Hz, 1H); ¹³C NMR (90.6 MHz, CDCl₃): d=41.2 (CH₂), 44.8 (2ꢁ

CH₃), 57.5 (CH₂), 103.9 (CH), 116.2 (CH), 118.1 (CH), 118.1 (C_q), 121.2

(C_q), 121.3 (CH), 128.2 (CH), 130.3 (CH), 134.2 (CH), 134.8 (C_q), 143.6

(C_q), 145.2 (C_q), 161.3 ppm (CO); MS (EI): m/z (%)=282 (27) [M]⁺,

235 (15), 233 (44), 224 (14), 223 (12), 139 (22), 83 (26), 72 (96), 71

(41), 59 (32), 58 (100), 57 (13), 55 (28); HRMS (EI): C₁₇H₁₈N₂O₂[M]⁺

calcd: 282.1368, found: 282.1368.

2-Aminophenanthridin-6(5H)-one (10d): Preparation from methyl-

anthranilate (1.51 g, 10.0 mmol) and 1,4-phenylenediamine (9c)

(2.16 g, 20.0 mmol) according to general procedure 1 described

above. After completion of the reaction, the resulting mixture was

basified to pH 10 with Na₂CO₃and 25% aqueous NH₃prior to ex-

traction. Purification by column chromatography (hexane/EtOAc/

AcOH=10:20:1) gave the title compound (10d) as a yellow solid

(151 mg, 720 mmol, 18%). R_f=0.4 (hexane/EtOAc/AcOH=10:20:1)

2-(2-Dimethylaminoethylamino)-5H-phenanthridin-6-one (11d):

Preparations from compound 10d (70 mg, 333 mmol) were made

according to general procedure 2 described above. Purification by

column chromatography (CHCl₃/MeOH=20:1!3:1) gave the title

compound (11 d) as a yellow solid (8.43 mg, 30.0 mmol, 9%). R_f=

1

[UV]; H NMR (360 MHz, CDCl₃/CD₃OD): d=6.98 (dd, J=2.4 Hz, J=

8.6 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.60 (ddd, J=1.1 Hz, J=7.2 Hz,

J=8.1 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.82 (ddd, J=1.5 Hz, J=

7.2 Hz, J=8.2 Hz, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.41 ppm (ddd, J=

0.6 Hz, J=1.5 Hz, J=8.0 Hz, 1H); ¹³C NMR (90.6 MHz, CDCl₃/

CD₃OD): d=106.9 (CH), 116.2 (CH), 117.9 (CH), 118.6 (C_q), 121.3

1

0.2 (CHCl₃/MeOH=3:1) [UV]; H NMR (360 MHz, CDCl₃): d=2.32 (s,

6H), 2.66 (m, 2H), 3.27 (m, 2H), 6.88 (dd, J=2.4 Hz, J=8.6 Hz, 1H),

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7.24 (d, J=8.6 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.59 (ddd, J=1.1 Hz,

J=7.2 Hz, J=8.1 Hz, 1H), 7.76 (ddd, J=1.3 Hz, J=7.2 Hz, J=8.0 Hz,

1H), 8.22 (d, J=8.1 Hz, 1H), 8.58 ppm (ddd, J=0.4 Hz, J=1.3 Hz,

J=8.0 Hz, 1H); ¹³C NMR (90.6 MHz, CDCl₃): d=41.6 (CH₂), 45.1 (2ꢁ

CH₃), 57.9 (CH₂), 104.5 (CH), 117.0 (CH), 117.7 (CH), 119.4 (C_q), 122.0

(CH), 126.0 (C_q), 127.5 (CH), 128.3 (CH), 128.3 (C_q), 132.3 (CH), 143.8

(C_q), 144.5 (C_q), 162.1 ppm (CO); MS (EI): m/z (%)=281 (13) [M]⁺,

223 (7), 222 (9), 221 (2), 195 (2), 194 (2), 167 (2), 166 (3), 139 (4), 59

(5), 58 (100), 57 (2); HRMS (EI): C₁₇H₁₉N₃O [M]⁺calcd: 281.1528,

found: 281.1528.

29.4 (CH₂), 30.9 (CH₂), 31.8 (CH₂), 34.6 (CH₂), 45.5 (2ꢁCH₃), 46.9

(CH₂), 56.8 (CH₂), 119.0 (CH), 119.1 (C_q), 121.3 (C_q), 121.8 (CH), 123.1

(CH), 129.6 (CH), 130.6 (CH), 130.8 (CH), 134.1 (C_q), 135.1 (CH), 139.1

(C_q), 150.4 (C_q), 160.7 (CO), 173.1 ppm (CO); MS (EI): m/z (%)=436

(1) [M]⁺, 390 (7), 253 (7), 224 (16), 223 (17), 211 (32), 72 (65), 71

(100), 59 (15), 58 (100), 57 (12); HRMS (EI): C₂₇H₃₆N₂O₃[M]⁺calcd:

436.2726, found: 436.2725.

5’-(N-(2-(Dimethylamino)ethyl)decanamido)-2’-methoxybiphenyl-

3-carboxylate (15a): The intermediate 11 a was prepared from

methyl 3-aminobenzoate (1.51 g, 10.0 mmol) and p-anisidine (9a)

(2.46 g, 20.0 mmol) according to general procedure 1 described

above. The reaction mixture was basified with NaOH (4.00 g) and

Na₂SO₃(4.00 g) in H₂O (40 mL) prior to extraction. Purification by

Kugelrohr distillation gave compound 13a as a black oil (648 mg,

2.52 mmol, 63%). R_f=0.3 (CH₂Cl₂/EtOAc=40:1) [UV]; ¹H NMR

(600 MHz, CDCl₃): d=3.74 (s, 3H), 3.92 (s, 3H), 6.85–6.90 (m, 3H),

7.45 (t, J=7.7 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.99 (d, J=7.8 Hz,

1H), 8.17 ppm (t, J=1.7 Hz, 1H). 13a (751 mg, 2.92 mmol) was

treated with decanoyl chloride (608 mL, 2.92 mmol; 1:1 equiv due

to possible double acylation) according to general procedure 3 de-

scribed above. Purification by column chromatography (hexane/

EtOAc=4:1) gave compound 14a as an orange solid (697 mg,

1.69 mmol, 58%). R_f=0.7 (hexane/EtOAc=2:1) [UV]; ¹H NMR

(CDCl₃, 360 MHz): d=0.87 (t, J=6.9 Hz, 3H), 1.20–1.42 (m, 12H),

1.72 (m, 2H), 2.34 (t, J=7.6 Hz, 2H), 3.78 (s, 3H), 3.92 (s, 3H), 6.94

(d, J=8.8 Hz, 1H), 7.13 (s, 1H), 7.37 (d, J=2.7, 1H), 7.45 (t, J=

7.8 Hz, 1H), 7.57 (dd, J=2.7 Hz, J=8.8 Hz, 1H), 7.72 (d, J=7.8 Hz,

1H), 7.99 (d, J=7.8 Hz, 1H), 8.17 ppm (t, J=1.8 Hz, 1H). 14a

(697 mg, 1.69 mmol) was treated with 2-chloro-N,N-dimethyletha-

namine·HCl (1.83 g, 16.9 mmol) in N,N-dimethylacetamide accord-

ing to general procedure 4 described above. Purification by

column chromatography (CHCl₃/MeOH=5:1) gave the title com-

pound 15a as an orange oil (102.9 mg, 220 mmol, 13%). R_f=0.2

Decanoic acid (4’-chloro-6-methoxybiphen-3-yl)-(2-dimethylami-

noethyl)amide (12a): Preparations from compound 11 a (47.0 mg,

166 mmol) and decanoyl chloride (100 mL, 482 mmol) were made ac-

cording to general procedure 3 described above. Purification by

column chromatography (CHCl₃/MeOH=20:1) and filtration

through Al₂O₃gave the title compound (12a) as a yellow oil

(29.2 mg, 63.6 mmol, 38%). R_f=0.6 (CHCl₃/MeOH=10:1) [UV];

¹H NMR (600 MHz, CDCl₃): d=0.86 (t, J=7.1 Hz, 3H), 1.16–1.22 (m,

10H), 1.23–1.29 (m, 2H), 1.52–1.59 (m, 2H), 2.06 (m, 2H), 2.24 (s,

6H), 2.44 (m, 2H), 3.81 (t, J=7.1 Hz, 2H), 3.85 (s, 3H), 6.98 (d, J=

8.4 Hz, 1H), 7.12–7.16 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.45 ppm (d,

J=8.4 Hz, 2H); ¹³C NMR: (90.6 MHz, CDCl₃): d=14.1 (CH₃), 22.6

(CH₂), 25.5 (CH₂), 29.2 (CH₂), 29.3 (CH₂), 29.4 (2ꢁCH₂), 31.8 (CH₂),

34.3 (CH₂), 45.5 (2ꢁCH₃), 47.0 (CH₂), 55.8 (CH₃), 56.7 (CH₂), 111.8

(CH), 128.3 (2ꢁCH), 128.6 (CH), 130.4 (CH), 130.4 (C_q), 130.7 (2ꢁ

CH), 133.4 (C_q), 135.7 (C_q), 135.8 (C_q), 155.6 (C_q), 173.3 ppm (CO);

MS (EI): m/z (%)=459 (1) [M]⁺, 389 (11), 387 (30), 275 (13), 246

(10), 235 (16), 233 (43), 72 (83), 71 (46), 58 (100), 57 (10).

Decanoic acid (2’,6’-dichloro-6-methoxybiphen-3-yl)-(2-dimethy-

laminoethyl)amide (12b): Preparations from compound 11 b

(60.0 mg, 177 mmol) and decanoyl chloride (100 mL, 482 mmol) were

made according to general procedure 3 described above. Purifica-

tion by column chromatography (CHCl₃/MeOH=10:1) and filtration

through Al₂O₃gave the title compound (12b) as a colorless oil

(65.5 mg, 133 mmol, 75%). R_f=0.6 (CHCl₃/MeOH=10:1) [UV];

¹H NMR (600 MHz, CDCl₃): d=0.86 (t, J=6.9 Hz, 3H), 1.14–1.28 (m,

12H), 1.50–1.59 (m, 2H), 2.09 (m, 2H), 2.27 (s, 6H), 2.49 (t, J=

7.1 Hz, 2H), 3.81 (s, 3H), 3.82–3.89 (m, 2H), 6.97 (d, J=2.6 Hz, 1H),

7.01 (d, J=8.6 Hz, 1H), 7.24 (dd, J=2.6 Hz, J=8.6 Hz, 1H), 7.25 (dd,

J=7.5 Hz, J=8.6 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.40 ppm (d, J=

8.6 Hz, 1H); ¹³C NMR (90.6 MHz, CDCl₃): d=14.1 (CH₃), 22.6 (CH₂),

25.4 (CH₂), 29.2 (CH₂), 29.3 (2ꢁCH₂), 29.4 (CH₂), 31.8 (CH₂), 34.5

(CH₂), 45.3 (2ꢁCH₃), 46.4 (CH₂), 56.0 (CH₃), 56.5 (CH₂), 111.9 (CH),

127.0 (C_q), 127.8 (2ꢁCH), 129.3 (CH), 129.4 (CH), 131.3 (CH), 135.1

(C_q), 135.3 (2ꢁC_q), 135.6 (C_q), 156.1 (C_q), 173.7 ppm (CO); MS (EI):

m/z (%)=492 (2) [M]⁺, 423 (16), 421 (24), 309 (14), 280 (12), 269

(30), 267 (49), 72 (83), 71 (34), 58 (100); HRMS (EI): C₂₇H₃₈Cl₂N₂O₂

[M]⁺calcd: 492.2310, found: 492.2311.

1

(CHCl₃/MeOH=3:1) [UV]; H NMR (CDCl₃, 600 MHz): d=0.84 (t, J=

7.1 Hz, 3H), 1.09–1.29 (m, 12H), 1.46–1.54 (m, 2H), 1.97–2.05 (m,

2H), 2.54 (s, 6H), 2.82–2.92 (m, 2H), 3.71 (s, 3H), 3.88–3.98 (m, 2H),

6.83–6.90 (m, 1H), 6.98–7.03 (m, 1H), 7.07–7.18 (m, 1H), 7.22–7.32

(m, 1H), 7.44–7.55 (m, 1H), 7.83–7.93 (m, 1H), 8.00–8.12 ppm (m,

1H); ¹³C NMR (CDCl₃, 151 MHz): d=14.1 (CH₃), 22.6 (CH₂), 25.3

(CH₂), 29.3 (2ꢁCH₂), 29.4 (2ꢁCH₂), 31.8 (CH₂), 34.2 (CH₂), 43.9 (2ꢁ

CH₃), 45.9 (CH₂), 55.1 (CH₂), 55.7 (CH₃), 111.8 (CH), 127.3 (CH), 127.8

(CH), 128.6 (C_q), 130.3 (CH), 130.5 (CH), 131.9 (CH), 132.0 (CH), 134.9

(C_q), 135.2 (C_q), 136.7 (C_q), 155.9 (C_q), 173.8 ppm (CO); MS (EI): m/z

(%)=467 (2) [M]⁺, 398 (16), 397 (56), 285 (17), 256 (11), 252 (15),

243 (41), 72 (44), 71 (24), 58 (100).

5’-((N-(2-(Dimethylamino)ethyl)decanamido)methyl)-2’-methoxy-

biphenyl-3-carboxylate (15b): The intermediate 13b was pre-

pared from methyl 3-aminobenzoate (1.51 g, 10.0 mmol) and p-me-

thoxybenzylamine (9d) (2.74 g, 20.0 mmol) according to general

procedure 1 described above. The reaction mixture was basified

with NaOH (4.00 g) and Na₂SO₃(4.00 g) in H₂O (40 mL) prior to ex-

traction. Purification by Kugelrohr distillation gave compound 13b

as a dark-red oil (586 mg, 2.16 mmol, 54%). ¹H NMR (600 MHz,

CDCl₃): d=3.80 (s, 3H), 3.85 (s, 2H), 3.92 (s, 3H), 6.95 (d, J=8.1 Hz,

1H), 7.26–7.30 (m, 2H), 7.46 (t, J=7.7 Hz, 1H), 7.74 (ddd, J=1.2 Hz,

J=1.8 Hz, J=7.7 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 8.19 ppm (t, J=

1.7 Hz, 1H). 13b (586 mg, 2.16 mmol) was treated with decanoyl

chloride (450 mL, 2.16 mmol; 1:1 equiv due to possible double acy-

lation) according to general procedure 3 described above. Purifica-

tion by column chromatography (hexane/EtOAc=2:1) gave com-

pound 14b as an orange oil (303 mg, 713 mmol, 33%). R_f=0.3

Decanoic acid (6-oxo-6H-benzo[c]chromen-2-yl)-(2-dimethylami-

noethyl)amide (12c): Preparations from compound 11 c (50.0 mg,

177 mmol) and decanoyl chloride (100 mL, 482 mmol) were made ac-

cording to general procedure 3 described above. Purification by

column chromatography (CHCl₃/MeOH=20:1) and filtration

through Al₂O₃gave the title compound (12c) as a yellow oil

(26.8 mg, 61.4 mmol, 35%). R_f=0.5 (CHCl₃/MeOH=10:1) [UV];

¹H NMR (600 MHz, CDCl₃): d=0.84 (t, J=7.2 Hz, 3H), 1.15–1.25 (m,

12H), 1.55–1.62 (m, 2H), 2.07 (t, J=7.5 Hz, 2H), 2.26 (s, 6H), 2.45 (t,

J=6.7 Hz, 2H), 3.88 (t, J=6.7 Hz, 2H), 7.35 (dd, J=2.3 Hz, J=

8.6 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.89 (dt,

J=1.1 Hz, J=7.6 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 8.11 (d, J=8.0 Hz,

1H), 8.45 ppm (dd, J=1.0 Hz, J=8.0 Hz, 1H); ¹³C NMR (90.6 MHz,

CDCl₃): d=14.1 (CH₃), 22.6 (CH₂), 25.5 (CH₂), 29.2 (CH₂), 29.3 (CH₂),

1

(hexane/EtOAc=2:1) [UV]; H NMR (CDCl₃, 600 MHz): d=0.85–0.90

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(m, 3H), 1.20–1.35 (m, 12H), 1.62–1.68 (m, 2H), 2.19–2.23 (m, 2H),

3.81 (s, 3H), 3.93 (s, 3H), 4.43 (d, J=5.1 Hz, 2H), 6.95 (d, J=8.4 Hz,

1H), 7.23 (d, J=2.1 Hz, 1H), 7.25–7.29 (m, 1H), 7.47 (t, J=7.7 Hz,

1H), 7.70 (d, J=7.7 Hz, 1H), 8.00 (td, J=1.3 Hz, J=7.8 Hz, 1H),

8.16 ppm (t, J=1.7 Hz, 1H). 14b (303 mg, 713 mmol) was treated

with 2-chloro-N,N-dimethylethanamine·HCl (772 mg, 7.13 mmol) in

N,N-dimethylformamide according to general procedure 4 de-

scribed above. Purification by column chromatography (CHCl₃/

2-(Dimethylamino)ethyl 5’-((N-(2-(dimethylamino)ethyl)decana-

mido)methyl)-2’-methoxybiphenyl-4-carboxylate (15d): Com-

pound 15d was obtained as a side product in the last synthetic

step (general procedure 4) of compound 15c. Purification by

column chromatography (CHCl₃/MeOH=10:1) gave the title com-

pound (15d) as a colorless oil (46.3 mg, 83.6 mmol, 20%). R_f=0.7

(CHCl₃/MeOH=3:1) [UV]; ¹H NMR (CDCl₃, 600 MHz): d=0.85–0.89

(m, 3H_maj+min), 1.20–1.36 (m, 12H_maj+min), 1.61–1.72 (m, 2H_maj+min),

2.23 (s, 12H_min), 2.34–2.39 (m, 2H_maj+min), 2.34–2.39 (m, 12H_maj),

2.40–2.45 (m, 2H_min), 2.57–2.63 (m, 2H_maj), 2.76 (t, J=5.1 Hz,

2H_maj+min), 3.34 (t, J=7.1 Hz, 2H_min), 3.55 (t, J=6.4 Hz, 2H_maj), 3.80

(s, 3H_min), 3.81 (s, 3H_maj), 4.44–4.49 (m, 2H_maj+min), 4.60 (d,

J=4.3 Hz, 2H_maj+min), 6.93 (d, J=8.5 Hz, 1H_min), 6.98 (d, J=8.5 Hz,

1H_maj), 7.12 (d, J=2.1 Hz, 1H_maj), 7.16 (dd, J=2.3 Hz, J=8.4 Hz,

1H_maj), 7.20 (d, J=1.9 Hz, 1H_min), 7.25 (dd, J=2.0 Hz, J=8.3 Hz,

1H_min), 7.55–7.59 (m, 2H_maj+min), 8.05–8.09 ppm (m, 2H_maj+min).

MeOH=5:1) gave the title compound 15b as

a yellow oil

(61.8 mg, 128 mmol, 18%). R_f=0.6 (CHCl₃/MeOH=3:1) [UV];

¹H NMR (CDCl₃, 600 MHz): d=0.85–0.89 (m, 3H_maj+min), 1.20–1.34

(m, 12H_maj+min), 1.58–1.69 (m, 2H_maj+min), 2.28 (s, 6H_min), 2.34–2.41

(m, 2H_maj+min), 2.45–2.52 (m, 2H_min), 2.55 (s, 6H_maj), 2.81–2.92 (m,

2H_maj), 3.35–3.40 (m, 2H_min), 3.55–3.62 (m, 2H_maj), 3.72 (s, 3H_maj),

3.77 (s, 3H_min), 4.50–4.58 (m, 2H_maj+min), 6.85–6.91 (m, 1H_maj+min),

7.00–7.08 (m, 2H_maj), 7.13–7.19 (m, 2H_min), 7.27–7.34 (m, 1H_maj+min),

7.49–7.57 (m, 1H_maj+min), 7.91–7.98 (m, 1H_maj+min), 7.07–8.18 ppm

(m, 1H_maj+min); ¹³C NMR (CDCl₃, 91 MHz): d=14.5 (CH₃), 23.7 (CH₂),

26.3 (CH₂), 30.4 (2ꢁCH₂), 30.5 (CH₂), 30.6 (CH₂), 33.0 (CH₂), 34.2

(CH₂), 40.5 (2ꢁCH₃), 44.7 (CH₂), 52.3 (CH₂), 56.3 (CH₃), 57.2 (CH₂),

113.2 (CH), 128.3 (CH), 128.6 (CH), 129.2 (C_q), 130.1 (CH), 130.4 (CH),

131.2 (C_q), 131.6 (C_q), 132.4 (CH), 133.1 (CH), 139.3 (C_q), 157.7 (C_q),

177.0 ppm (CO); HRMS (ESI): C₂₉H₄₃N₂O₄[M+H] calcd: 483.3217,

found: 483.3217.

4’-Chloro-5-fluorobiphenyl-2-ol (16a): Preparations from 4-chlor-

oaniline (1.28 g, 10.0 mmol) and 4-fluorophenol (9e) (2.24 g,

20.0 mmol) were made according to general procedure 1 described

above. For better solubility 4-fluorophenol (9e) was dissolved in

a H₂O/TiCl₃(1m in 3n HCl)/CH₃CN=2:2:1 mixture. Purification by

column chromatography (CH₂Cl₂/hexane=10:3) gave the title com-

pound 16a as a brown solid (312 mg, 1.40 mmol, 35%). R_f=0.6

(CH₂Cl₂/hexane=10:3) [UV]; ¹H NMR (600 MHz, CDCl₃): d=4.85

(brs, 1H), 6.90 (ddd, J=0.7 Hz, J=4.7 Hz, J=8.6 Hz, 1H), 6.93–6.98

(m, 2H), 7.41 (d, J=8.7 Hz, 2H), 7.46 ppm (d, J=8.7 Hz, 2H);

¹³C NMR (90.6 MHz, CDCl₃): d=115.7 (d, J=23.0 Hz, CH), 116.4 (d,

J=23.5 Hz, CH), 117.0 (d, J=8.2 Hz, CH), 128.0 (d, J=7.6 Hz, C_q),

129.4 (2ꢁCH), 130.3 (2ꢁCH), 134.4 (C_q), 134.7 (d, J=1.6 Hz, C_q),

148.4 (d, J=2.2 Hz, C_q) 157.1 ppm (d, J=239.1 Hz, C_q); MS (EI): m/z

(%)=222 (100) [M]⁺, 221 (6), 188 (11), 187 (79), 186 (27), 159 (42),

157 (15), 133 (17), 93 (11), 79 (6), 69 (11); HRMS (EI): C₁₂H₈ClFO [M]⁺

calcd: 222.0248, found: 222.0250.

5’-((N-(2-(Dimethylamino)ethyl)decanamido)methyl)-2’-methoxy-

biphenyl-4-carboxylate (15c): The intermediate 13c was prepared

from 4-aminobenzoate (1.51 g, 10.0 mmol) and p-methoxybenzyla-

mine (2d) (2.74 g, 20.0 mmol) according to general procedure 1

described above. The reaction mixture was basified with NaOH

(4.00 g) and Na₂SO₃(4.00 g) in H₂O (40 mL) prior to extraction. Pu-

rification by Kugelrohr distillation gave compound 13c as a dark-

red oil (630 mg, 2.32 mmol, 58%). ¹H NMR (600 MHz, CDCl₃): d=

3.79 (s, 3H), 3.82 (s, 2H), 3.93 (s, 3H), 6.96 (d, J=8.3 Hz, 1H), 7.29

(d, J=2.3 Hz, 1H), 7.31 (dd, J=2.3 Hz, J=8.3 Hz, 1H), 7.60 (d, J=

8.6 Hz, 2H), 8.06 ppm (d, J=8.6 Hz, 2H). 13c (630 mg, 2.32 mmol)

was treated with decanoyl chloride (483 mL, 2.16 mmol; 1:1 equiv

due to possible double acylation) according to general procedure 3

described above. Purification by column chromatography (hexane/

EtOAc=2:1) gave compound 14c as an orange oil (178 mg,

5-Bromo-4’-chlorobiphenyl-2-ol (16b): Preparations from 4-chlor-

oaniline (1.28 g, 10.0 mmol) and 4-bromophenol (9 f) (3.46 g,

20.0 mmol) were made according to general procedure 1 described

above. For better solubility 4-bromophenol (9 f) was dissolved in

a H₂O/TiCl₃(1m in 3n HCl)/CH₃CN=2:2:1 mixture. Purification by

column chromatography (CH₂Cl₂/hexane=10:3) gave the title com-

pound (16b) as an orange oil (238 mg, 840 mmol, 21%). R_f=0.5

(CH₂Cl₂/hexane=10:3) [UV]; ¹H NMR (360 MHz, CDCl₃): d=5.17

(brs, 1H), 6.85 (d, J=9.0 Hz, 1H), 7.32–7.37 (m, 2H), 7.40 (d, J=

8.8 Hz, 2H), 7.46 ppm (d, J=8.8 Hz, 2H); ¹³C NMR (90.6 MHz,

CDCl₃): d=112.9 (C_q), 117.9 (CH), 128.4 (C_q), 129.0 (C_q), 129.4 (2ꢁ

CH), 130.4 (2ꢁCH), 132.0 (CH), 132.7 (CH), 134.4 (C_q), 151.6 ppm

(C_q); MS (EI): m/z (%)=282 (70) [M]⁺, 249 (7), 247 (9), 202 (8), 175

(7), 169 (12), 168 (100), 140 (10), 139 (35), 69 (9); HRMS (EI):

C₁₂H₈BrClO [M]⁺calcd: 281.9447, found: 281.9445.

1

418 mmol, 18%). R_f=0.6 (hexane/EtOAc=1:2) [UV]; H NMR (CDCl₃,

600 MHz): d=0.87 (t, J=7.1 Hz, 3H), 1.20–1.35 (m, 12H), 1.65 (m,

2H), 2.20 (m, 2H), 3.81 (s, 3H), 3.94 (s, 3H), 4.45 (d, J=5.5 Hz, 2H),

6.96 (d, J=8.3 Hz, 1H), 7.23 (d, J=2.3 Hz, 1H), 7.27 (dd, J=2.3 Hz,

J=8.3 Hz, 1H), 7.58 (d, J=8.6 Hz, 2H), 8.06 ppm (d, J=8.6 Hz, 2H).

14c (178 mg, 418 mmol) was further treated with 2-chloro-N,N-di-

methylethanamine·HCl (453 mg, 4.18 mmol) in N,N-dimethylforma-

mide according to general procedure 4 described above. Purifica-

tion by column chromatography (CHCl₃/MeOH=10:1) gave the

title compound 15c as a yellow oil (10.1 mg, 20.9 mmol, 5%). R_f=

0.7 (CHCl₃/MeOH=3:1) [UV]; ¹H NMR (CDCl₃, 360 MHz): d=0.84–

0.92 (m, 3H_maj+min), 1.20–1.38 (m, 12H_maj+min), 1.60–1.71 (m,

2H_maj+min), 2.32 (s, 6H_min), 2.37–2.43 (m, 2H_min), 2.42–2.48 (m,

2H_maj+min), 2.63 (s, 6H_maj), 2.92–3.00 (m, 2H_maj), 3.40–3.47 (m, 2H_min),

3.62–3.69 (m, 2H_maj), 3.80 (s, 3H_min), 3.81 (s, 3H_maj), 4.60 (s, 2H_min),

4.63 (s, 2H_maj), 6.95–7.03 (m, 1H_maj+min), 7.13–7.17 (m, 2H_maj), 7.20–

7.25 (m, 2H_min), 7.49–7.57 (m, 2H_maj+min), 8.01–8.07 ppm (m,

2H_maj+min); ¹³C NMR (CDCl₃, 151 MHz): d=14.1 (CH₃), 22.8 (CH₂),

25.4 (CH₂), 29.5 (CH₂), 29.6 (2ꢁCH₂), 29.7 (CH₂), 32.0 (CH₂), 33.5

(CH₂), 44.1 (2ꢁCH₃), 45.3 (CH₂), 51.4 (CH₂), 55.5 (CH₂), 55.9 (CH₃),

112.1 (CH), 127.2 (CH), 128.5 (CH), 129.4 (2ꢁC_q), 129.4 (2ꢁCH),

129.5 (2ꢁCH), 130.8 (C_q), 141.7 (C_q), 156.4 (C_q), 175.3 ppm (CO); MS

(EI): m/z (%)=482 (20) [M]⁺, 270 (9), 242 (8), 241 (26), 85 (12), 83

(10), 71 (49), 58 (100), 57 (8), 55 (9), 44 (23), 43 (9).

(ꢁ)-1-(4’-Chloro-5-fluorobiphen-2-yloxy)-3-diethylaminopropan-

2-ol (17a): Compound 16a (150 mg, 674 mmol), epichlorohydrin

(258 mL, 3.37 mmol) and 1 drop of pyridine were stirred at room

temperature for 24 h. The unreacted epichlorohydrin and pyridine

were removed in vacuo (first part of general procedure 5 described

above). Purification by column chromatography (CH₂Cl₂/hexane=

10:3) gave the b-chloro alcohol as a yellow oil (151 mg, 479 mmol,

71%). R_f=0.3 (CH₂Cl₂/hexane=10:3) [UV]; ¹H NMR (360 MHz,

CDCl₃): d=2.24 (brs, 1H), 3.56 (dd, J=5.2 Hz, J=11.3 Hz, 1H), 3.60

(dd, J=5.2 Hz, J=11.3 Hz, 1H), 3.98–4.10 (m, 3H), 6.91–6.97 (m,

1H), 6.98–7.04 (m, 2H), 7.37–7.44 ppm (m, 4H); ¹³C NMR (90.6 MHz,

CDCl₃): d=45.7 (CH₂), 69.7 (CH), 70.1 (CH₂), 114.7 (d, J=8.5 Hz, CH),

115.0 (d, J=22.8 Hz, CH), 117.3 (d, J=23.5 Hz, CH), 128.4 (2ꢁCH),

130.5 (2ꢁCH), 131.7 (d, J=7.6 Hz, C_q), 133.7 (C_q), 135.6 (d, J=

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1.6 Hz, C_q), 151.2 (d, J=2.3 Hz, C_q) 157.7 ppm (d, J=240.8 Hz, C_q);

MS (EI): m/z (%)=314 (38) [M]⁺, 224 (35), 223 (16), 222 (100), 221

(10), 200 (10), 199 (13), 187 (42), 186 (33), 170 (13), 159 (10), 157

(17), 85 (30), 83 (43); HRMS (EI): C₁₅H₁₃Cl₂FO₂[M]⁺calcd: 314.0277,

found: 314.0278. The product was reacted according to second

part of general procedure 5 to obtain the respective epoxide

(73.4 mg, 263 mmol, 55%). The epoxide (126 mg, 452 mmol) was

further submitted to the general procedure 6 described above. Pu-

rification by column chromatography (CHCl₃/MeOH=20:1) gave

the title compound 17a as a yellow oil (84.3 mg, 240 mmol, 53%).

R_f=0.6 (CHCl₃/MeOH=3:1) [UV]; ¹H NMR (360 MHz, CDCl₃): d=

0.99 (t, J=7.1, Hz, 6H), 2.40–2.44 (m, 2H), 2.45–2.54 (m, 2H), 2.54–

2.65 (m, 2H), 3.82–3.91 (m, 1H), 3.92–3.95 (m, 2H), 6.93 (dd, J=

4.7 Hz, J=8.7 Hz, 1H), 6.96–7.04 (m, 2H), 7.36 (d, J=8.8 Hz, 2H),

7.47 ppm (d, J=8.8 Hz, 2H); ¹³C NMR (90.6 MHz, CDCl₃): d=11.8

(2ꢁCH₃), 47.3 (2ꢁCH₂), 55.8 (CH₂), 65.8 (CH₂), 71.7 (CH), 114.3 (d,

J=8.3 Hz, CH), 114.8 (d, J=22.6 Hz, CH), 117.1 (d, J=23.5 Hz, CH),

128.2 (2ꢁCH), 130.8 (2ꢁCH), 131.3 (d, J=7.6 Hz, C_q), 133.4 (C_q),

135.8 (d, J=1.7 Hz, C_q), 151.9 (d, J=2.3 Hz, C_q) 157.4 ppm (d, J=

238.7 Hz, C_q); MS (EI): m/z (%)=351 (27) [M]⁺, 336 (11), 334 (19),

264 (16), 222 (24), 200 (21), 199 (20), 187 (24), 186 (48), 170 (22),

159 (10), 157 (23), 116 (40), 114 (14), 87 (92), 86 (100), 84 (10), 72

(29), 58 (73), 57 (13), 56 (23); HRMS (EI): C₁₉H₂₃ClFNO₂[M]⁺calcd:

351.1401, found: 351.1402.

made according to general procedure 3 described above. Purifica-

tion by column chromatography (hexane/EtOAc=4:1) gave the

title compound 18a as a colorless oil (21.2 mg, 41.9 mmol, 18%).

R_f=0.8 (hexane/EtOAc=2:1) [UV]; ¹H NMR (600 MHz, CDCl₃): d=

0.88 (t, J=7.1, Hz, 3H), 0.95 (t, J=7.1 Hz, 6H), 1.22–1.31 (m, 12H),

1.51–1.57 (m, 2H), 2.15–2.25 (m, 2H), 2.47–2.55 (m, 4H), 2.54–2.61

(m, 2H), 4.03 (dd, J=5.3 Hz, J=10.1 Hz, 1H), 4.11 (dd, J=3.6 Hz,

J=10.1 Hz, 1H), 5.13–5.18 (m, 1H), 6.91 (dd, J=4.6 Hz, J=9.0 Hz,

1H), 6.98 (ddd, J=3.1 Hz, J=7.8 Hz, J=8.9 Hz, 1H), 7.02 (dd, J=

3.1 Hz, J=9.0 Hz, 1H), 7.36 (d, J=8.7 Hz, 2H), 7.45 ppm (d, J=

8.7 Hz, 2H); ¹³C NMR (90.6 MHz, CDCl₃): d=11.6 (2ꢁCH₃), 14.1

(CH₃), 22.6 (CH₂), 24.8 (CH₂), 29.1 (CH₂), 29.2 (CH₂), 29.3 (CH₂), 29.4

(CH₂), 31.8 (CH₂), 34.4 (CH₂), 47.8 (2ꢁCH₂), 52.7 (CH₂), 68.9 (CH₂),

70.2 (CH), 114.0 (d, J=8.4 Hz, CH), 114.7 (d, J=22.7 Hz, CH), 117.1

(d, J=23.6 Hz, CH), 128.1 (2ꢁCH), 130.8 (2ꢁCH), 131.2 (d, J=

7.5 Hz, C_q), 133.3 (C_q), 135.6 (d, J=1.6 Hz, C_q), 151.6 (d, J=2.3 Hz,

C_q), 157.3 (d, J=239.8 Hz, C_q), 173.1 ppm (CO); HRMS (ESI):

C₂₉H₄₂ClFNO₃[M+H] calcd: 506.2832, found: 506.2834.

N-(2-(Dimethylamino)ethyl)-N-(9-oxo-9H-xanthen-2-yl)decana-

mide (21a): The starting material 19a was synthesized according

to procedure described by Szajnman et al.^[29]A solution of xan-

thone (1.00 g, 5.10 mmol, 1.0 equiv) in concentrated H₂SO₄(3 mL)

was cooled to 08C before fuming HNO₃(180 mL, 2.56 mmol,

0.5 equiv) in concentrated H₂SO₄(0.6 mL) was added dropwise. The

reaction mixture was stirred at 08C for 40 min and then poured

onto crushed ice. The solid was filtered off, washed with cold H₂O

until pH 7 was attained, and dried with a high-vacuum pump. The

crude product contained unsubstituted xanthone, 1-nitroxanthone,

(ꢁ)-1-(5-Bromo-4’-chlorobiphen-2-yloxy)-3-diethylaminopropan-

2-ol (17b): Compound 16b (110 mg, 388 mmol) was treated with

epichlorohydrin (150 mL, 1.94 mmol) and pyridine (0.1 mL) accord-

ing to general procedure 5 described above. Purification by

column chromatography (CH₂Cl₂/hexane=10:1) gave, apart from

the b-chloro alcohol (31%), the desired epoxide as an orange oil

(17.1 mg, 50.4 mmol, 13%). R_f=0.7 (CH₂Cl₂/hexane=10:1) [UV];

¹H NMR (600 MHz, CDCl₃): d=2.65 (dd, J=2.7 Hz, J=5.0 Hz, 1H),

2.82 (dd, J=4.1 Hz, J=5.0 Hz, 1H), 3.22–3.26 (m, 1H), 3.92 (dd, J=

5.3 Hz, J=11.2 Hz, 1H), 4.23 (dd, J=2.7 Hz, J=11.2 Hz, 1H), 6.86 (d,

J=8.6 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.40 (dd, J=2.3 Hz, J=

8.6 Hz, 1H), 7.42 (d, J=2.3 Hz, 1H), 7.44 ppm (d, J=8.7 Hz, 2H);

¹³C NMR (90.6 MHz, CDCl₃): d=44.4 (CH₂), 50.0 (CH), 69.3 (CH₂),

113.9 (C_q), 114.8 (CH), 128.3 (2ꢁCH), 130.7 (2ꢁCH), 131.5 (CH),

132.0 (C_q), 133.3 (CH), 133.5 (C_q), 135.3 (C_q) 154.4 ppm (C_q); MS (EI):

m/z (%)=338 (80) [M]⁺, 286 (15), 284 (56), 282 (44), 216 (20), 204

(26), 203 (13), 202 (81), 173 (11), 168 (49), 151 (10), 140 (11), 139

(66), 138 (12), 57 (84); HRMS (EI): C₁₅H₁₂BrClO₂[M]⁺calcd:

337.9709, found: 337.9709. The epoxide (14.0 mg, 41.2 mmol) was

further treated with NEt₂H (2 mL) according to general procedure 6

described above. Purification by column chromatography (CHCl₃/

MeOH=20:1) gave the title compound 17b as a brown oil

(11.1 mg, 26.8 mmol, 65%). R_f=0.5 (CHCl₃/MeOH=3:1) [UV];

¹H NMR (600 MHz, CDCl₃): d=1.01 (t, J=7.2, Hz, 6H), 2.45–2.48 (m,

2H), 2.52 (qd, J=7.1 Hz, J=14.0 Hz, 2H), 2.64 (qd, J=7.2 Hz, J=

14.5 Hz, 2H), 3.91–3.99 (m, 3H), 6.87 (d, J=9.3 Hz, 1H), 7.36 (d, J=

8.8 Hz, 2H), 7.39–7.42 (m, 2H), 7.44 ppm (d, J=8.8 Hz, 2H);

¹³C NMR (90.6 MHz, CDCl₃): d=11.5 (2ꢁCH₃), 47.4 (2ꢁCH₂), 56.0

(CH₂), 65.6 (CH₂), 71.0 (CH), 113.6 (C_q), 114.5 (CH), 128.2 (2ꢁCH),

130.8 (2ꢁCH), 131.5 (CH), 131.8 (C_q), 133.1 (CH), 133.4 (C_q), 135.5

(C_q), 154.8 ppm (C_q); MS (EI): m/z (%)=411 (10) [M]⁺, 396 (14), 284

(26), 282 (22), 204 (15), 202 (42), 168 (44), 151 (12), 139 (40), 116

(36), 114 (15), 87 (92), 86 (100), 84 (11), 72 (29), 58 (78), 57 (15), 56

(24); HRMS (EI): C₁₉H₂₃BrClNO₂[M]⁺calcd: 411.0601, found:

411.0601.

2-nitroxanthone,

and

2,7-dinitroxanthone.

2-Nitroxanthone

(114 mg, 473 mmol) was isolated by column chromatography

(hexane/EtOAc=5:1; R_f=0.3) and was further dissolved in EtOAc

(20 mL) in the presence of Pd/C as catalyst (40.0 mg). After being

stirred under 40 atm H₂overnight in the autoclave, the reaction

mixture was filtered, and the filtrate was concentrated under re-

duced pressure. Purification by column chromatography (hexane/

EtOAc=2:1) gave compound 19a as a yellow solid (75.4 mg,

357 mmol, 7% over two steps). R_f=0.4 (hexane/EtOAc=1:1) [UV];

¹H NMR: (600 MHz, CDCl₃): d=7.30 (dd, J=2.9 Hz, J=8.9 Hz, 1H),

7.39 (ddd, J=1.1 Hz, J=7.1 Hz, J=8.0 Hz, 1H), 7.43 (d, J=8.9 Hz,

1H), 7.51 (d, J=8.6 Hz, 1H), 7.61 (d, J=2.9 Hz, 1H), 7.75 (ddd, J=

1.7 Hz, J=7.1 Hz, J=8.6 Hz, 1H), 8.30 ppm (dd, J=1.7 Hz, J=

8.0 Hz, 1H). 19a (70.0 mg, 331 mmol) was further treated with dec-

anoyl chloride (68.7 mL, 331 mmol; 1:1 equiv due to possible double

acylation) according to general procedure 3 described above. Pu-

rification by column chromatography (hexane/EtOAc=4:1) and fil-

tration through Al₂O₃gave compound 20a as a yellow solid

(96.8 mg, 265 mmol, 80%). R_f=0.6 (hexane/EtOAc=2:1) [UV];

¹H NMR (360 MHz, CDCl₃): d=0.88 (t, J=6.8 Hz, 3H), 1.20–1.48 (m,

12H), 1.70–1.82 (m, 2H), 2.39–2.49 (m, 2H), 7.39 (t, J=7.5 Hz, 1H),

7.51 (d, J=8.5 Hz, 2H), 7.71–7.77 (m, 1H), 8.09 (s, 1H), 8.33 (dd, J=

1.6 Hz, J=8.0 Hz, 1H), 8.45 ppm (d, J=8.5 Hz, 1H). 20a (90.0 mg,

245 mmol) was further treated with 2-chloro-N,N-dimethylethanami-

ne·HCl (352 mg, 2.45 mmol) in N,N-dimethylformamide according

to general procedure 4 described above. Purification by column

chromatography (CHCl₃/MeOH=20:1) gave the title compound

21a as a colorless solid (41.0 mg, 93.9 mmol, 38%). R_f=0.4 (CHCl₃/

1

MeOH=10:1) [UV]; H NMR (600 MHz, CDCl₃): d=0.84 (t, J=7.1 Hz,

3H), 1.14–1.27 (m, 12H), 1.53–1.60 (m, 2H), 2.04 (t, J=7.5 Hz, 2H),

2.27 (s, 6H), 2.49 (t, J=6.9 Hz, 2H), 3.90 (t, J=6.9 Hz, 2H), 7.44 (t,

J=7.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.64

(dd, J=2.5 Hz, J=8.8 Hz, 1H), 7.78 (ddd, J=1.6 Hz, J=7.2 Hz, J=

8.6 Hz, 1H), 8.19 (d, J=2.5 Hz, 1H), 8.37 ppm (dd, J=1.6 Hz, J=

8.0 Hz, 1H); ¹³C NMR (151 MHz, CDCl₃): d=14.0 (CH₃), 22.6 (CH₂),

(ꢁ)-1-((4’-Chloro-5-fluorobiphen-2-yl)oxy)-3-(diethylamino)pro-

pan-2-yl decanoate (18a): Preparations from compound 17a

(75.0 mg, 233 mmol) and decanoyl chloride (100 mL, 482 mmol) were

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25.3 (CH₂), 29.2 (2ꢁCH₂), 29.3 (2ꢁCH₂), 31.8 (CH₂), 34.6 (CH₂), 45.4

(2ꢁCH₃), 46.8 (CH₂), 56.5 (CH₂), 118.0 (CH), 119.6 (CH), 121.5 (CH),

122.4 (C_q), 124.4 (CH), 126.1 (CH), 126.8 (CH), 135.2 (CH), 135.3 (C_q),

138.7 (C_q), 155.0 (C_q), 156.1 (C_q), 173.0 (CO), 176.6 ppm (CO); HRMS

(ESI): C₂₇H₃₇N₂O₃[M+H] calcd: 437.2799, found: 437.2808.

better solubility of 2,6-dichloroaniline, the diazonium salt was pre-

pared in an CH₃CN/3n HCl/H₂O=2:2:1 mixture. After completion

of the reaction, the resulting mixture was basified with NaOH

(4.00 g) and Na₂SO₃(4.00 g) in H₂O (40 mL) prior to extraction. Pu-

rification by Kugelrohr distillation gave compound 7b as a dark oil

(542 g, 1.92 mmol, 48%). ¹H NMR: (360 MHz, CDCl₃): d=3.77 (s,

3H), 3.86 (s, 2H), 6.98 (d, J=8.4 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H),

7.21 (dd, J=7.5 Hz, J=8.6 Hz, 1H), 7.30–7.40 ppm (m, 3H). Com-

pound 22b (560 mg, 1.98 mmol) was further treated with decanoyl

chloride (412 mL, 1.98 mmol; 1:1 equiv due to possible double acy-

lation) according to general procedure 3 described above. Purifica-

tion by column chromatography (hexane/EtOAc=4:1!2:1) gave

the title compound 23b as a yellow solid (119 mg, 272 mmol,

N-(3-Benzoylphenyl)-N-(2-(dimethylamino)ethyl)decanamide

(21b): The intermediate 20b was prepared from 3-aminobenzo-

phenone (700 mg, 3.55 mmol) and decanoyl chloride (737 mL,

3.55 mmol; 1:1 equiv caused by to possible double acylation) ac-

cording to general procedure 3 described above. The reaction

gave 20b (1.42 g) in quantitative yield as a yellow solid, which was

used further without purification. R_f=0.8 (hexane/EtOAc=2:1)

[UV]; ¹H NMR (360 MHz, CDCl₃): d=0.87 (t, J=6.9 Hz, 3H), 1.20–

1.40 (m, 12H), 1.67–1.77 (m, 2H), 2.37 (m, 2H), 7.40–7.52 (m, 4H),

7.56–7.62 (m, 1H), 7.77–7.83 (m, 3H), 7.98 ppm (d, J=8.0 Hz, 1H).

In a second step, 20b (1.25 g, 3.55 mmol) was treated with 2-

chloro-N,N-dimethylethanamine·HCl (1.45 g, 10.1 mmol) in N,N-di-

methylformamide according to general procedure 4 described

above. Purification by column chromatography (CHCl₃/MeOH=

10:1) gave the title compound 21b as a colorless solid (125 mg,

1

14%). R_f=0.4 (hexane/EtOAc=2:1) [UV]; H NMR (360 MHz, CDCl₃):

d=0.88 (t, J=6.9 Hz, 3H), 1.21–1.35 (m, 12H), 1.57–1.68 (m, 2H),

2.21 (m, 2H), 3.77 (s, 3H), 4.39 (s, 2H), 6.98 (d, J=8.5 Hz, 1H), 7.03

(d, J=2.3 Hz, 1H), 7.24 (dd, J=7.5 Hz, J=8.6 Hz, 1H), 7.32 (dd, J=

2.3 Hz, J=8.5 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.39 ppm (d, J=

8.6 Hz, 1H); ¹³C NMR (90.6 MHz, CDCl₃): d=14.1 (CH₃), 22.8 (CH₂),

26.0 (CH₂), 29.4 (2ꢁCH₂), 29.5 (CH₂), 29.6 (CH₂), 32.0 (CH₂), 36.7

(CH₂), 42.9 (CH₂), 56.1 (CH₃), 111.6 (CH), 126.5 (C_q), 128.0 (2ꢁCH),

129.3 (CH), 129.6 (CH), 130.5 (CH), 130.6 (C_q), 135.6 (2ꢁC_q), 136.5

(C_q), 156.3 (C_q), 174.4 ppm (CO); MS (EI): m/z (%)=435 (30) [M]⁺,

325 (17), 323 (24), 282 (7), 280 (11), 269 (10), 268 (11), 267 (64), 266

(17), 265 (100), 215 (9); HRMS (EI): C₂₄H₃₁Cl₂NO₂[M]⁺calcd:

435.1732, found: 435.1732.

1

296 mmol, 8%). R_f=0.7 (CHCl₃/MeOH=5:1) [UV]; H NMR (600 MHz,

CDCl₃): d=0.85 (t, J=7.1 Hz, 3H), 1.15–1.23 (m, 10H), 1.23–1.28 (m,

2H), 1.53–1.59 (m, 2H), 2.05 (t, J=7.4 Hz, 2H), 2.29 (s, 6H), 2.48–

2.55 (m, 2H), 3.88 (t, J=6.5 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.51 (t,

J=7.8 Hz, 2H), 7.55 (t, J=7.8 Hz, 1H), 7.61–7.65 (m, 2H), 7.78–

7.81 ppm (m, 3H); ¹³C NMR (151 MHz, CDCl₃): d=14.1 (CH₃), 22.7

(CH₂), 25.4 (CH₂), 29.3 (2ꢁCH₂), 29.4 (2ꢁCH₂), 31.9 (CH₂), 34.6 (CH₂),

45.3 (2ꢁCH₃), 46.8 (CH₂), 56.5 (CH₂), 128.5 (2ꢁCH), 129.4 (CH),

129.7 (CH), 129.8 (CH), 130.0 (2ꢁCH), 132.4 (CH), 132.9 (CH), 137.1

(C_q), 139.2 (C_q), 142.9 (C_q), 173.0 (CO), 195.5 ppm (CO); HRMS (ESI):

C₂₇H₃₉N₂O₂[M+H] calcd: 423.3006, found: 423.3008.

Decanoic acid (4’-chloro-6-methoxybiphen-3-ylmethyl)-(2-dime-

thylaminoethyl)amide (24a): Preparations from compound 23a

(100 mg, 249 mmol) and 2-chloro-N,N-dimethylethanamine·HCl

(270 mg, 2.49 mmol) in N,N-dimethylacetamide were made accord-

ing to general procedure 4 described above. Purification by

column chromatography (CHCl₃/MeOH=10:1) and filtration

through Al₂O₃gave the title compound 24a as an orange oil

(90.7 mg, 192 mmol, 77%). By the addition of trifluoroacetic acid

only one stereoisomer was obtained. R_f=0.5 (CHCl₃/MeOH=10:1)

[UV]; ¹H NMR (600 MHz, CDCl₃): d=0.87 (t, J=7.1 Hz, 3H), 1.21–

1.36 (m, 12H), 1.59–1.67 (m, 2H), 2.48 (m, 2H), 2.95 (s, 3H), 2.96 (s,

3H), 3.32–3.37 (m, 2H), 3.71 (t, J=6.4 Hz, 2H), 3.82 (s, 3H), 4.58 (s,

2H), 6.97 (d, J=8.5 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 7.10 (dd, J=

2.3 Hz, J=8.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.41 ppm (d, J=

8.5 Hz, 2H); ¹³C NMR (90.6 MHz, CDCl₃): d=14.1 (CH₃), 22.7 (CH₂),

25.0 (CH₂), 29.3 (CH₂), 29.4 (3ꢁCH₂), 31.9 (CH₂), 33.1 (CH₂), 40.9

(CH₂), 43.5 (2ꢁCH₃), 50.9 (CH₂), 54.9 (CH₂), 55.8 (CH₃), 111.9 (CH),

127.3 (CH), 127.8 (C_q), 128.3 (2ꢁCH), 128.9 (CH), 130.3 (C_q), 130.7

(2ꢁCH), 133.3 (C_q), 136.2 (C_q), 156.3 (C_q), 175.2 ppm (CO); MS (EI):

m/z (%)=472 (8) [M]⁺, 233 (11), 232 (5), 231 (31), 181 (9), 85 (5), 72

(13), 71 (99), 59 (8), 58 (100), 57 (5); HRMS (EI): C₂₈H₄₁ClN₂O₂[M]⁺

calcd: 472.2857, found: 472.2858.

Decanoic acid (4’-chloro-6-methoxybiphen-3-ylmethyl)amide

(23a): Biphenyl 22a was prepared from 4-chloroaniline (1.28 g,

10.0 mmol) and p-methoxybenzylamine (9d) (2.74 g, 20.0 mmol)

according to general procedure 1 described above. The final reac-

tion mixture was basified with NaOH (4.00 g) and Na₂SO₃(4.00 g)

in H₂O (40 mL) prior to extraction. Purification by Kugelrohr distilla-

tion gave compound 22a as a dark oil (644 mg, 2.60 mmol, 65%).

¹H NMR (360 MHz, CDCl₃): d=3.79 (s, 3H), 3.85 (s, 2H), 6.94 (d, J=

8.4 Hz, 1H), 7.23–7.31 (m, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.46 ppm (d,

J=8.8 Hz, 2H). Compound 22a (551 mg, 2.22 mmol) was further

treated with decanoyl chloride (462 mL, 2.22 mmol; 1:1 equiv possi-

bly caused by possible double acylation) according to general pro-

cedure 3 described above. Purification by column chromatography

(hexane/EtOAc=4:1!2:1) gave the title compound 23a as

a yellow oil (286 mg, 710 mmol, 32%). R_f=0.4 (hexane/EtOAc=2:1)

[UV]; ¹H NMR: (360 MHz, CDCl₃): d=0.87 (t, J=6.9 Hz, 3H), 1.21–

1.35 (m, 12H), 1.59–1.69 (m, 2H), 2.19 (m, 2H), 3.79 (s, 3H), 4.41 (d,

J=5.6 Hz, 2H), 5.74 (brs, 1H), 6.93 (d, J=8.4 Hz, 1H), 7.19 (d, J=

2.3 Hz, 1H), 7.24 (dd, J=2.3 Hz, J=8.4 Hz, 1H), 7.36 (d, J=8.8 Hz,

2H), 7.43 ppm (d, J=8.8 Hz, 2H); ¹³C NMR (90.6 MHz, CDCl₃): d=

14.1 (CH₃), 22.6 (CH₂), 25.8 (CH₂), 29.2 (CH₂), 29.3 (2ꢁCH₂), 29.4

(CH₂), 31.8 (CH₂), 36.8 (CH₂), 43.0 (CH₂), 55.7 (CH₃), 111.5 (CH), 128.2

(2ꢁCH), 128.4 (CH), 129.7 (C_q), 130.2 (CH), 130.7 (2ꢁCH), 130.9 (C_q),

133.0 (C_q), 136.5 (C_q), 155.8 (C_q), 172.9 ppm (CO); MS (EI): m/z (%)=

401 (77) [M]⁺, 291 (16), 290 (9), 289 (45), 246 (18), 234 (9), 233 (52),

232 (27), 231 (100), 216 (9), 195 (8), 181 (16), 152 (9); HRMS (EI):

C₂₄H₃₂ClNO₂[M]⁺calcd: 401.2122, found: 401.2121.

Decanoic acid (2’,6’-dichloro-6-methoxybiphen-3-ylmethyl)-(2-di-

methylaminoethyl)amide (24b): Preparations from compound

23b (68.0 mg, 156 mmol) and 2-chloro-N,N-dimethylethanami-

ne·HCl (169 mg, 1.56 mmol) in N,N-dimethylacetamide were made

according to general procedure 4 described above. Purification by

column chromatography (CHCl₃/MeOH=20:1) and filtration

through Al₂O₃gave the title compound 24b as a yellow oil

(23.8 mg, 46.8 mmol, 30%). By addition of trifluoroacetic acid only

one stereoisomer was obtained. R_f=0.5 (CHCl₃/MeOH=10:1) [UV];

¹H NMR (600 MHz, CDCl₃): d=0.87 (t, J=7.1 Hz, 3H), 1.20–1.31 (m,

12H), 1.59–1.65 (m, 2H), 2.43 (m, 2H), 2.85 (s, 6H), 3.12 (t, J=

6.6 Hz, 2H), 3.74 (t, J=6.6 Hz, 2H), 3.78 (s, 3H), 4.58 (brs, 2H), 6.86

(d, J=2.2 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 7.24 (dd, J=7.8 Hz, J=

8.4 Hz, 1H), 7.26 (dd, J=2.2 Hz, J=8.4 Hz, 1H), 7.39 ppm (d, J=

Decanoic acid (2’,6’-dichloro-6-methoxybiphen-3-ylmethyl)amide

(8b): Biphenyl 22b was synthesized from 2,6-dichloroaniline

(1.62 g, 10.0 mmol) and p-methoxybenzylamine (9d) (2.74 g,

20.0 mmol) according to general procedure 1 described above. For

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8.1 Hz, 2H); ¹³C NMR (90.6 MHz, CDCl₃): d=14.1 (CH₃), 22.7 (CH₂),

25.0 (CH₂), 29.3 (CH₂), 29.4 (3ꢁCH₂), 31.8 (CH₂), 33.2 (CH₂), 41.1

(CH₂), 43.4 (2ꢁCH₃), 51.3 (CH₂), 55.0 (CH₂), 55.9 (CH₃), 111.9 (CH),

126.8 (C_q), 127.5 (C_q), 127.9 (2ꢁCH), 129.0 (2ꢁCH), 129.3 (CH),

135.3 (2ꢁC_q), 136.0 (C_q), 156.7 (C_q), 175.0 ppm (CO); MS (EI): m/z

(%)=506 (52) [M]⁺, 438 (18), 436 (28), 280 (10), 269 (27), 268 (22),

267 (100), 266 (34), 265 (100), 231 (14), 229 (16), 217 (13), 215 (34),

195 (18), 166 (11), 165 (15), 152 (10), 85 (13), 73 (11), 72 (100), 71

(100), 59 (37), 58 (100), 57 (25), 55 (11); HRMS (EI): C₂₈H₄₀Cl₂N₂O₂

[M]⁺calcd: 506.2467, found: 506.2467.

(20), 202 (14), 91 (50), 72 (100), 71 (52), 59 (15), 58 (100); HRMS (EI):

C₂₅H₂₇ClN₂O₂[M]⁺calcd: 422.1761, found: 422.1761.

Cyclopropanecarboxylic acid (4’-chloro-6-methoxybiphen-3-yl)-

(2-dimethylaminoethyl)-amide (25d): Preparation from com-

pound 11 a (47.0 mg, 166 mmol) and cyclopropanecarboxylic acid

chloride (100 mL, 1.10 mmol) according to general procedure 3 de-

scribed above. Purification by column chromatography (CHCl₃/

MeOH=20:1) and filtration through Al₂O₃gave the title compound

25d as a colorless solid (30.5 mg, 81.8 mmol, 49%). R_f=0.4 (CHCl₃/

MeOH=10:1) [UV]; ¹H NMR (360 MHz, CDCl₃): d=0.58–0.65 (m,

2H), 0.97–1.03 (m, 2H), 1.33–1.42 (m, 1H), 2.24 (s, 6H), 2.45 (m,

2H), 3.84 (m, 2H), 3.84 (s, 3H), 6.99 (d, J=9.1 Hz, 1H), 7.22–7.27

(m, 2H), 7.39 (d, J=8.7 Hz, 2H), 7.46 ppm (d, J=8.7 Hz, 2H);

¹³C NMR (151 MHz, CDCl₃): d=8.4 (2ꢁCH₂), 12.7 (CH), 45.6 (2ꢁCH₃),

47.3 (CH₂), 55.8 (CH₃), 56.6 (CH₂), 111.8 (CH), 128.3 (2ꢁCH), 128.7

(CH), 130.4 (C_q), 130.5 (CH) 130.7 (2ꢁCH), 133.4 (C_q), 135.7 (C_q),

135.8 (C_q), 155.5 (C_q), 173.6 ppm (CO); MS (EI): m/z (%)=372 (1)

[M]⁺, 303 (15), 302 (10), 301 (48), 233 (22), 72 (90), 71 (48), 69 (34),

59 (15), 58 (100), 57 (15); HRMS (EI): C₂₁H₂₅ClN₂O₂[M]⁺calcd:

372.1605, found: 372.1605.

N-(4’-Chloro-6-methoxybiphen-3-yl)-N-(2-dimethylaminoethyl)-

benzamide (25a): Preparations from compound 11 a (47.0 mg,

166 mmol) and benzoyl chloride (100 mL, 868 mmol) were made ac-

cording to general procedure 3 described above. Purification by

column chromatography (CHCl₃/MeOH=20:1) gave the title com-

pound 25a as a yellow oil (49.7 mg, 122 mmol, 73%). R_f=0.3

(CHCl₃/MeOH=10:1) [UV]; ¹H NMR: (600 MHz, CDCl₃): d=2.32 (s,

6H), 2.59–2.66 (m, 2H), 3.76 (s, 3H), 4.02–4.10 (m, 2H), 6.80 (d, J=

8.6 Hz, 1H), 6.91–6.95 (m, 1H), 7.06 (d, J=7.1 Hz, 1H), 7.15–7.26

(m, 5H), 7.29–7.33 ppm (m, 4H); ¹³C NMR (90.6 MHz, CDCl₃): d=

45.5 (2ꢁCH₃), 48.1 (CH₂), 55.7 (CH₃), 56.3 (CH₂), 111.5 (CH), 127.7

(CH), 127.8 (2ꢁCH), 128.2 (2ꢁCH), 128.6 (2ꢁCH), 129.4 (CH), 129.8

(C_q), 130.3 (CH), 130.3 (C_q), 130.6 (2ꢁCH), 133.3 (C_q), 135.7 (C_q),

136.4 (C_q), 154.7 (C_q), 170.5 ppm (CO); MS (EI): m/z (%)=408 (1)

[M]⁺, 339 (30), 338 (20), 337 (89), 202 (16), 105 (94), 77 (48), 72

(96), 71 (46), 59 (18), 58 (100); HRMS (EI): C₂₄H₂₅ClN₂O₂[M]⁺calcd:

408.1605, found: 408.1606.

Cyclohexanecarboxylic acid (4’-chloro-6-methoxybiphen-3-yl)-(2-

dimethylaminoethyl)amide (25e): Preparations from compound

11 a (47.0 mg, 166 mmol) and cyclohexanecarboxylic acid chloride

(100 mL, 748 mmol) were made according to general procedure 3

described above. Purification by column chromatography (CHCl₃/

MeOH=20:1) and filtration through Al₂O₃gave the title compound

25e as a colorless oil (60.6 mg, 146 mmol, 88%). R_f=0.4 (CHCl₃/

MeOH=10:1) [UV]; ¹H NMR: (360 MHz, CDCl₃): d=0.92–1.06 (m,

2H), 1.12–1.27 (m, 1H), 1.46–1.60 (m, 3H), 1.61–1.72 (m, 4H), 2.13–

2.20 (m, 1H), 2.22 (s, 6H), 2.43 (m, 2H), 3.78 (m, 2H), 3.86 (s, 3H),

6.98 (d, J=8.1 Hz, 1H), 7.11–7.16 (m, 2H), 7.39 (d, J=8.8 Hz, 2H),

7.44 ppm (d, J=8.8 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃): d=25.5

(2ꢁCH₂), 25.6 (CH₂), 29.4 (2ꢁCH₂), 41.5 (CH), 45.5 (2ꢁCH₃), 47.1

(CH₂), 55.7 (CH₃), 56.5 (CH₂), 111.7 (CH), 128.3 (2ꢁCH), 128.4 (CH),

130.2 (CH), 130.2 (C_q) 130.6 (2ꢁCH), 133.3 (C_q), 135.6 (C_q), 135.7

(C_q), 155.5 (C_q), 176.3 ppm (CO); MS (EI): m/z (%)=414 (1) [M]⁺,

345 (23), 344 (16), 343 (66), 246 (10), 235 (14), 233 (45), 202 (12), 83

(27), 72 (88), 71 (36), 59 (11), 58 (100), 55 (28); HRMS (EI):

C₂₄H₃₁ClN₂O₂[M]⁺calcd: 414.2074, found: 414.2075.

Furan-2-carboxylic acid (4’-chloro-6-methoxybiphen-3-yl)-(2-di-

methylaminoethyl)amide (25b): Preparations from compound

11 a (47.0 mg, 166 mmol) and furan-2-carboxylic acid chloride

(100 mL, 1.01 mmol) were made according to general procedure 3

described above. Purification by column chromatography (CHCl₃/

MeOH=20:1) and filtration through Al₂O₃gave the title compound

25b as a yellow oil (14.8 mg, 37.1 mmol, 22%). R_f=0.5 (CHCl₃/

1

MeOH=10:1) [UV]; H NMR (600 MHz, CDCl₃): d=2.33 (s, 6H), 2.62

(t, J=3.1 Hz, 2H), 3.86 (s, 3H), 4.00 (t, J=7.1 Hz, 2H), 5.81 (s, 1H),

6.21–6.24 (m, 1H), 6.98 (d, J=8.6 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H),

7.21 (dd, J=2.7 Hz, J=8.6 Hz, 1H), 7.35–7.38 (m, 3H), 7.40 ppm (d,

J=8.8 Hz, 2H); ¹³C NMR (90.6 MHz, CDCl₃): d=45.4 (2ꢁCH₃), 48.0

(CH₂), 55.9 (CH₃), 56.3 (CH₂), 111.0 (CH), 111.9 (CH), 116.4 (CH), 128.3

(2ꢁCH), 128.6 (CH), 130.5 (C_q), 130.6 (CH), 130.7 (2ꢁCH), 133.5 (C_q),

135.3 (C_q), 135.6 (C_q), 144.4 (CH), 147.1 (C_q), 156.0 (C_q), 159.2 ppm

(CO); MS (EI): m/z (%)=399 (1) [M]⁺, 329 (51), 328 (30), 327 (100),

202 (23), 139 (11), 95 (100), 72 (100), 71 (71), 59 (32), 58 (100), 57

(13).

Decanoic acid (4’-chloro-6-methoxybiphen-3-ylmethyl)-{3-[4-(4-

chlorophenyl)-4-hydroxypiperidin-1-yl]propyl}amide (27a): Com-

pound 23a (240 mg, 597 mmol) and 1-bromo-3-chloropropane

(500 mL, 5.05 mmol) were reacted in N,N-dimethylformamide ac-

cording to general procedure 4 described above. The intermediate

was purified by column chromatography (hexane/EtOAc=4:1; R_f=

0.4) and reacted further with 4-(4-chlorophenyl)-4-hydroxypiperi-

dine (40.0 mg, 189 mmol) according to general procedure 7 de-

scribed above. Purification by column chromatography (CHCl₃/

MeOH=20:1!3:1) gave the title compound 27a as a yellow oil

(7.81 mg, 11.9 mmol, 2% over two steps). By addition of trifluoro-

acetic acid, only one stereoisomer was obtained. R_f=0.5 (CHCl₃/

MeOH=10:1) [UV]; ¹H NMR: (600 MHz, CDCl₃): d=0.87 (t, J=

7.1 Hz, 3H), 1.21–1.33 (m, 12H), 1.60–1.65 (m, 2H), 1.98 (d, J=

14.4 Hz, 2H), 2.09 (brs, 2H), 2.46–2.54 (m, 4H), 3.10 (brs, 2H), 3.29–

3.38 (m, 2H), 3.46–3.53 (m, 4H), 3.82 (s, 3H), 4.57 (s, 2H), 6.98 (d,

J=8.4 Hz, 1H), 7.05 (d, J=1.9 Hz, 1H), 7.11 (dd, J=1.9 Hz, J=

8.4 Hz, 1H), 7.36 (d, J=8.7 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.40 (d,

J=8.7 Hz, 2H), 7.42 ppm (d, J=8.6 Hz, 2H); ¹³C NMR: (151 MHz,

CDCl₃): d=14.1 (CH₃), 22.5 (CH₂), 22.6 (CH₂), 25.5 (CH₂), 29.2 (CH₂),

29.3 (CH₂), 29.4 (2ꢁCH₂), 31.8 (CH₂), 33.3 (CH₂), 35.5 (2ꢁCH₂), 42.8

(CH₂), 49.2 (2ꢁCH₂), 50.8 (CH₂), 55.1 (CH₂), 55.8 (CH₃), 69.1 (C_q),

111.9 (CH), 125.8 (2ꢁCH), 127.1 (CH), 127.4 (C_q), 128.3 (2ꢁCH),

N-(4’-Chloro-6-methoxybiphen-3-yl)-N-(2-dimethylaminoethyl)-2-

phenylacetamide (25c): Preparations from compound 11 a

(47.0 mg, 166 mmol) and phenylacetyl chloride (100 mL, 756 mmol)

were made according to general procedure 3 described above. Pu-

rification by column chromatography (CHCl₃/MeOH=20:1) gave

the title compound 25c as a yellow oil (47.6 mg, 113 mmol, 68%).

R_f=0.5 (CHCl₃/MeOH=10:1) [UV]; ¹H NMR: (360 MHz, CDCl₃): d=

2.27 (s, 6H), 2.50 (t, J=7.0 Hz, 2H), 3.49 (s, 2H), 3.83 (t, J=7.0 Hz,

2H), 3.85 (s, 3H), 6.96 (d, J=12.1 Hz, 1H), 6.97 (d, J=0.6 Hz, 1H),

7.04–7.08 (m, 2H), 7.12 (dd, J=2.7 Hz, J=8.6 Hz, 1H), 7.18–7.24 (m,

3H), 7.32 (d, J=8.8 Hz, 2H), 7.36 ppm (d, J=8.8 Hz, 2H); ¹³C NMR:

(151 MHz, CDCl₃): d=32.9 (CH₂), 36.7 (2ꢁCH₃), 38.4 (CH₂), 47.3

(CH₃), 47.6 (CH₂), 103.3 (CH), 118.0 (CH), 119.7 (2ꢁCH), 119.8 (2ꢁ

CH), 120.2 (CH), 120.4 (2ꢁCH), 121.8 (C_q), 122.1 (3ꢁCH), 124.8 (C_q),

126.6 (C_q), 126.9 (C_q), 127.0 (C_q), 147.3 (C_q), 162.7 ppm (CO); MS (EI):

m/z (%)=422 (1) [M]⁺, 353 (26), 352 (18), 351 (74), 246 (11), 233

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128.7 (CH), 129.0 (2ꢁCH), 130.3 (C_q), 130.7 (2ꢁCH), 133.4 (C_q),

134.1 (C_q), 136.1 (C_q), 143.7 (C_q), 156.3 (C_q), 176.2 ppm (CO); MS (EI):

m/z (%)=652 (21) [M]⁺, 238 (14), 233 (27), 232 (14), 231 (74), 226

(33), 225 (15), 224 (100), 210 (18), 206 (17), 192 (14), 191 (14), 189

(40), 181 (10), 154 (13), 127 (12), 99 (22), 97 (13), 84 (13), 71 (12), 57

(19), 56 (22), 55 (12); HRMS (EI): C₃₈H₅₀Cl₂N₂O₃[M]⁺calcd: 652.3199,

found: 652.3199.

CDCl₃): d=21.2 (CH₂), 35.7 (2ꢁCH₂), 45.1 (CH₂), 48.8 (2ꢁCH₂), 51.0

(CH₂), 54.8 (CH₂), 55.6 (CH₃), 69.0 (C_q), 111.7 (CH), 123.4 (C_q), 126.0

(2ꢁCH), 128.3 (2ꢁCH), 128.6 (2ꢁCH), 129.9 (C_q), 130.6 (CH), 130.7

(2ꢁCH), 132.2 (CH), 133.4 (2ꢁC_q), 135.7 (C_q), 145.1 (C_q), 157.2 ppm

(C_q); HPLC–MS: m/z (%)=499.4 [M+H].

4-(4-Chlorophenyl)-1-{3-[(2’,6’-dichloro-6-methoxybiphen-3-ylme-

thyl)amino]propyl}piperidin-4-ol (27d): Compound 22b (560 mg,

1.98 mmol) and di-tert-butyl dicarbonate (500 mL, 2.18 mmol) were

reacted according to general procedure 3 described above. Purifi-

cation by column chromatography (hexane/EtOAc=4:1) gave com-

pound 26b as a pink solid (330 mg, 863 mmol, 44%). R_f=0.5

(hexane/EtOAc=4:1) [UV]; ¹H NMR: (360 MHz, CDCl₃): d=1.46 (s,

9H), 3.76 (s, 3H), 4.28 (d, J=4.7 Hz, 2H), 6.96 (d, J=8.4 Hz, 1H),

7.05 (d, J=2.2 Hz, 1H), 7.21 (dd, J=7.5 Hz, J=8.4 Hz, 1H), 7.32 (dd,

J=2.2 Hz, J=8.5 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.37 ppm (d, J=

8.5 Hz, 1H). Compound 19b (190 mg, 497 mmol) was treated with

1-bromo-3-chloropropane (500 mL, 5.05 mmol) in N,N-dimethylfor-

mamide according to general procedure 4 described above. The in-

termediate was purified by column chromatography (hexane/

EtOAc=4:1; R_f=0.4) and reacted further with 4-(4-chlorophenyl)-4-

hydroxypiperidine (120 mg, 567 mmol) according to general proce-

dure 7 described above. Purification by column chromatography

(CHCl₃/MeOH=20:1; R_f=0.4) gave the pure Boc-protected product.

The removal of Boc protection via general procedure 8 described

above gave the title compound 27d as a yellow oil (84.9 mg,

159 mmol, 32% over three steps). R_f=0.3 (CHCl₃/MeOH/NEt₃=

Decanoic acid {3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-

propyl}-(2’,6’-dichloro-6-methoxybiphen-3-ylmethyl)amide (27b):

Compound 23b (218 mg, 500 mmol) and 1-bromo-3-chloropropane

(500 mL, 5.05 mmol) were reacted in N,N-dimethylformamide ac-

cording to general procedure 4 described above. The intermediate

was purified by column chromatography (hexane/EtOAc=4:1; R_f=

0.4) and reacted further with 4-(4-chlorophenyl)-4-hydroxypiperi-

dine (40.0 mg, 189 mmol) according to general procedure 7 de-

scribed above. Purification by column chromatography (CHCl₃/

MeOH=20:1!3:1) gave the title compound (27b) as a colorless

oil (10.3 mg, 15.0 mmol, 3% over two steps). By addition of tri-

fluoroacetic acid only one stereoisomer was obtained. R_f=0.5

(CHCl₃/MeOH=10:1) [UV]; ¹H NMR: (600 MHz, CDCl₃): d=0.87 (t,

J=7.1 Hz, 3H), 1.20–1.31 (m, 12H), 1.58–1.65 (m, 2H), 1.92 (d, J=

14.2 Hz, 2H), 2.00–2.07 (m, 2H), 2.53–2.65 (m, 4H), 2.98–3.05 (m,

2H), 3.20–3.29 (m, 2H), 3.44–3.49 (m, 4H), 3.78 (s, 3H), 4.55 (s, 2H),

6.87 (d, J=2.2 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 7.23 (dd, J=2.2 Hz,

J=8.4 Hz, 1H), 7.24 (t, J=8.1 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.39

(d, J=8.1 Hz, 2H), 7.42 ppm (d, J=8.6 Hz, 2H); ¹³C NMR: (90.6 MHz,

CDCl₃): d=14.1 (CH₃), 22.7 (2ꢁCH₂), 25.3 (CH₂), 29.3 (CH₂), 29.4 (2ꢁ

CH₂), 29.5 (CH₂), 31.9 (CH₂), 33.4 (CH₂), 35.5 (2ꢁCH₂), 42.7 (CH₂),

48.9 (2ꢁCH₂), 50.6 (CH₂), 55.1 (CH₂), 56.0 (CH₃), 69.3 (C_q), 111.8 (CH),

125.9 (2ꢁCH), 126.7 (C_q), 127.8 (C_q), 127.9 (2ꢁCH), 128.4 (CH),

128.8 (CH), 128.9 (2ꢁCH), 129.2 (CH), 133.9 (C_q), 135.4 (2ꢁC_q),

136.1 (C_q), 144.1 (C_q), 156.5 (C_q), 175.0 ppm (CO); MS (EI): m/z (%)=

686 (22) [M]⁺, 267 (45), 266 (14), 265 (66), 252 (12), 238 (17), 226

(35), 225 (16), 224 (100), 210 (17), 206 (18), 192 (18), 191 (21), 190

(13), 189 (62), 154 (21), 127 (13), 112 (11), 99 (32), 97 (13), 57 (15),

56 (20); HRMS (EI): C₃₈H₄₉Cl₃N₂O₃[M]⁺calcd: 686.2827, found:

686.2808.

1

100:5:1) [UV]; H NMR: (600 MHz, CD₃OD): d=1.86 (d, J=14.2 Hz,

2H), 2.10–2.17 (m, 2H), 2.24 (dt, J=4.0 Hz, J=14.2 Hz, 2H), 3.07

(m, 2H), 3.18 (m, 2H), 3.33 (t, J=11.8 Hz, 2H), 3.43 (d, J=11.8 Hz,

2H), 3.69 (s, 3H), 4.14 (s, 2H), 7.09 (d, J=8.6 Hz, 1H), 7.17 (d, J=

2.3 Hz, 1H), 7.23 (dd, J=7.7 Hz, J=8.5 Hz, 1H), 7.27 (d, J=8.6 Hz,

2H), 7.35 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 7.48 ppm (dd,

J=2.3 Hz, J=8.6 Hz, 1H); ¹³C NMR: (151 MHz, CD₃OD): d=22.3

(CH₂), 36.6 (2ꢁCH₂), 45.3 (CH₂), 50.5 (2ꢁCH₂), 51.9 (CH₂), 55.0 (CH₂),

56.4 (CH₃), 69.2 (C_q), 113.0 (CH), 124.2 (C_q), 127.4 (2ꢁCH), 128.2 (C_q),

129.1 (2ꢁCH), 129.6 (2ꢁCH), 130.9 (CH), 133.2 (CH), 133.5 (CH),

134.4 (C_q), 136.6 (2ꢁC_q), 137.2 (C_q), 146.9 (C_q), 159.4 ppm (C_q);

HPLC–MS: m/z (%)=535.1 [M+H].

1-{3-[(4’-Chloro-6-methoxybiphen-3-ylmethyl)amino]propyl}-4-

(4-chlorophenyl)piperidin-4-ol (27c): Compound 22a (500 mg,

2.02 mmol) and di-tert-butyl dicarbonate (500 mL, 2.18 mmol) were

reacted according to general procedure 3 described above. Purifi-

cation by column chromatography (hexane/EtOAc=4:1) gave com-

pound 26a as a yellow oil (301 mg, 865 mmol, 43%). R_f=0.4

(hexane/EtOAc=4:1) [UV]; ¹H NMR: (360 MHz, CDCl₃): d=1.46 (s,

9H), 3.79 (s, 3H), 4.28 (d, J=4.8 Hz, 2H), 6.92 (d, J=8.3 Hz, 1H),

7.19 (d, J=2.1 Hz, 1H), 7.22–7.26 (m, 1H), 7.36 (d, J=8.8 Hz, 2H),

7.44 ppm (d, J=8.8 Hz, 2H). Compound 26a (226 mg, 650 mmol)

was further treated with 1-bromo-3-chloropropane (500 mL,

5.05 mmol) in N,N-dimethylformamide according to general proce-

dure 4 described above. The intermediate was purified by column

chromatography (hexane/EtOAc=4:1; R_f=0.5) and reacted further

with 4-(4-chlorophenyl)-4-hydroxypiperidine (120 mg, 567 mmol)

according to general procedure 7 described above. Purification by

column chromatography (CHCl₃/MeOH=20:1; R_f=0.5) gave pure

Boc-protected product. The removal of Boc protection via general

procedure 8 described above gave the title compound 27c as an

orange oil (90.9 mg, 182 mmol, 28% over three steps). R_f=0.3

(CHCl₃/MeOH/NEt₃=100:5:1) [UV]; ¹H NMR: (600 MHz, CDCl₃): d=

1.78 (d, J=13.3 Hz, 2H), 2.11–2.24 (m, 4H), 2.95–3.10 (m, 6H), 3.14–

3.22 (m, 2H), 3.75 (s, 3H), 3.97 (s, 2H), 6.90 (d, J=8.4 Hz, 1H), 7.23

(d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H),

7.34–7.37 (m, 2H), 7.41 ppm (d, J=8.4 Hz, 2H); ¹³C NMR: (151 MHz,

Decanoic acid (4’-chloro-6-methoxybiphen-3-ylmethyl)-(4-cyano-

4,4-diphenylbutyl)amide (28a): Preparations from compound 23a

(100 mg, 249 mmol) and 5-bromo-2,2-diphenylpentanenitrile

(314 mg, 1.00 mmol) in N,N-dimethylformamide were made accord-

ing to general procedure 4 described above. Purification by

column chromatography (hexane/EtOAc=4:1) gave the title com-

pound 28a as a yellow oil (105 mg, 165 mmol, 66%). R_f=0.4

1

(hexane/EtOAc=1:4) [UV]; H NMR: (360 MHz, CDCl₃): d=0.83–0.92

(m, 3H_maj+min), 1.20–1.32 (m, 12H_maj+min), 1.58–1.72 (m, 5H_maj+min),

2.24–2.39 (m, 3H_maj+min), 3.26 (t, J=7.4 Hz, 2H_min), 3.44 (t, J=7.0 Hz,

2H_maj), 3.79 (s, 3H_min), 3.80 (s, 3H_maj), 4.43 (s, 2H_maj), 4.49 (s, 2H_min),

6.88 (d, J=8.4 Hz, 1H_min), 6.93 (d, J=8.4 Hz, 1H_maj), 7.00 (d, J=

2.2 Hz, 1H_maj), 7.06 (d, J=2.3 Hz, 1H_min), 7.06 (dd, J=2.2 Hz, J=

8.4 Hz, 1H_maj), 7.13 (dd, J=2.3 Hz, J=8.4 Hz, 1H_min), 7.26–7.35 (m,

10H_maj+min), 7.35–7.38 (m, 2H_maj+min), 7.38–7.43 ppm (m, 2H_maj+min);

¹³C NMR: (151 MHz, CDCl₃): d=13.9 (CH_3maj+min), 22.5 (CH_2maj+min),

23.8 (CH_2maj), 24.6 (CH_2min), 25.4 (CH_2maj+min), 29.1 (CH_2maj), 29.2

(CH_2min), 29.3 (3ꢁCH_2maj+min), 31.7 (CH_2maj+min), 33.1 (CH_2min), 33.3

(CH_2maj), 36.5 (CH_2min), 36.6 (CH_2maj), 44.2 (C_{q maj}), 46.1 (C_{q min}), 47.2

(CH_2min), 49.7 (CH_2maj), 51.2 (CH_2min), 51.5 (CH_2maj), 55.5 (CH_3min), 55.6

(CH_3maj), 111.3 (CH_min), 111.5 (CH_maj), 121.8 (CN_min), 122.1 (CN_maj),

126.5 (4ꢁCH_min), 126.6 (4ꢁCH_maj), 127.7 (2ꢁCH_maj), 128.0 (2ꢁCH_min),

128.0 (2ꢁCH_min), 128.1 (2ꢁCH_maj), 128.5 (C_{q maj}), 128.6 (C_{q min}), 128.7

(C_{q maj}), 128.8 (C_{q min}), 128.8 (4ꢁCH_maj), 128.9 (4ꢁCH_min), 129.4 (C_q

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_min), 129.8 (C_{q maj}), 129.9 (C_{q min}), 130.2 (C_{q maj}), 130.6 (2ꢁCH_maj), 130.7

(2ꢁCH_min), 132.8 (C_{q min}), 133.0 (C_{q maj}), 136.2 (C_{q maj}), 136.4 (C_{q min}),

139.5 (CH_min), 139.8 (CH_maj), 155.5 (C_{q min}), 155.7 (C_{q maj}), 173.0

(CO_min), 173.5 ppm (CO_maj), one CH is missing due to overlap of sig-

nals; MS (EI): m/z (%)=634 (53) [M]⁺, 522 (11), 442 (23), 400 (13),

330 (15), 249 (12), 248 (17), 246 (51), 233 (54), 232 (28), 231 (100),

181 (16), 70 (14), 57 (13); HRMS (EI): C₄₁H₄₇ClN₂O₂[M]⁺calcd:

634.3326, found: 634.3325.

and 8 described above. Purification by column chromatography

(CHCl₃/MeOH=20:1) gave the title compound 28d as a yellow oil

(10.8 mg, 20.9 mmol, 14% over two steps). R_f=0.6 (CHCl₃/MeOH=

1

10:1) [UV]; H NMR: (600 MHz, CDCl₃): d=1.61–1.68 (m, 2H), 2.45–

2.49 (m, 2H), 2.69 (t, J=6.9 Hz, 2H), 3.75 (s, 2H), 3.77 (s, 3H), 6.96

(d, J=8.5 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 7.22 (dd, J=7.8 Hz, J=

8.4 Hz, 1H), 7.24–7.28 (m, 3H), 7.30–7.34 (m, 4H), 7.36–7.40 ppm

(m, 6H); ¹³C NMR: (90.6 MHz, CDCl₃): d=25.5 (CH₂), 37.3 (CH₂), 47.7

(C_q), 51.6 (CH₂), 52.3 (CH₂), 55.9 (CH₃), 111.4 (CH), 122.3 (CN), 126.0

(C_q), 126.9 (5ꢁCH), 127.8 (2ꢁCH), 127.9 (2ꢁCH), 128.9 (4ꢁCH),

129.0 (CH), 129.9 (CH), 130.9 (CH), 135.5 (2ꢁC_q), 136.5 (C_q), 140.1

(2ꢁC_q), 156.0 ppm (C_q); MS (EI): m/z (%)=514 (20) [M]⁺, 294 (13),

269 (12), 268 (11), 267 (66), 266 (18), 265 (100), 235 (45), 234 (20),

233 (21), 215 (12), 207 (12), 206 (10), 195 (10), 193 (27), 192 (41),

190 (11), 180 (12), 166 (13), 165 (50), 156 (16), 129 (15), 105 (18),

104 (36), 91 (15); HRMS (EI): C₃₁H₂₈Cl₂N₂O [M]⁺calcd: 514.1579,

found: 514.1579.

Decanoic acid (4-cyano-4,4-diphenylbutyl)-(2’,6’-dichloro-6-me-

thoxybiphen-3-ylmethyl)amide (28b): Preparations from com-

pound 23b (50 mg, 115 mmol) and 5-bromo-2,2-diphenylpentane-

nitrile (90 mg, 287 mmol) in N,N-dimethylformamide were made ac-

cording to general procedure 4 described above. Purification by

column chromatography (hexane/EtOAc=4:1) gave the title com-

pound 28b as a yellow oil (16.9 mg, 25.3 mmol, 22%). R_f=0.2

1

(hexane/EtOAc=4:1) [UV]; H NMR: (360 MHz, CDCl₃): d=0.83–0.91

(m, 3H_maj+min), 1.19–1.33 (m, 12H_maj+min), 1.57–1.73 (m, 5H_maj+min),

2.23–2.40 (m, 3H_maj+min), 3.22 (t, J=7.6 Hz, 2H_min), 3.44 (t, J=6.9 Hz,

2H_maj), 3.76 (s, 3H_min), 3.77 (s, 3H_maj), 4.43 (s, 2H_maj), 4.49 (s, 2H_min),

6.83 (d, J=2.1 Hz, 1H_maj), 6.87 (d, J=2.1 Hz, 1H_min), 6.91 (d, J=

8.5 Hz, 1H_min), 6.96 (d, J=8.5 Hz, 1H_maj), 7.13–7.40 ppm (m, 14H_maj+

_min); ¹³C NMR: (90.6 MHz, CDCl₃): d=14.1 (CH_3maj+min), 22.7 (CH_2maj+

_min), 23.8 (CH_2maj), 24.5 (CH_2min), 25.5 (CH_2maj), 25.6 (CH_2min), 29.3

(CH_2maj+min), 29.5 (3ꢁCH_2maj+min), 31.9 (CH_2maj+min), 33.3 (CH_2min),

33.5 (CH_2maj), 36.6 (CH_2min), 36.8 (CH_2maj), 44.1 (C_{q maj}), 45.6 (C_{q min}),

46.9 (CH_2min), 49.7 (CH_2maj), 51.4 (CH_2min), 51.6 (CH_2maj), 55.9 (CH_3min),

56.0 (CH_3maj), 111.3 (CH_min), 111.7 (CH_maj), 122.0 (CN_min), 122.3 (CN_maj),

126.1 (C_qmin), 126.5 (C_qmaj), 126.7 (4ꢁCH_min), 126.8 (4ꢁCH_maj), 127.8

(2ꢁCH_maj+min), 127.9 (2ꢁCH_maj), 128.0 (2ꢁCH_min), 128.1 (CH_maj),

128.4 (CH_min), 128.9 (4ꢁCH_maj), 128.9 (CH_min), 129.0 (CH_maj), 129.0

(4ꢁCH_min), 129.2 (CH_maj), 129.5 (CH_min), 130.0 (C_{q maj}), 131.0 (C_{q min}),

135.4 (2ꢁC_{q maj}), 135.5 (2ꢁC_{q min}), 136.2 (C_{q maj}), 136.4 (C_{q min}), 139.7

(2ꢁC_{q min}), 140.1 (2ꢁC_{q maj}), 156.1 (C_{q min}), 156.2 (C_{q maj}), 173.1 (CO_min),

173.8 ppm (CO_maj); MS (EI): m/z (%)=668 (44) [M]⁺, 556 (11), 478

(16), 476 (23), 434 (11), 364 (13), 282 (30), 280 (48), 269 (17), 268

(16), 267 (97), 266 (26), 265 (100), 249 (11), 215 (14), 165 (10), 112

(11), 70 (18); HRMS (EI): C₄₁H₄₆Cl₂N₂O₂[M]⁺calcd: 668.2936, found:

668.2936.

2-(N-(4’-Chloro-6-methoxybiphen-3-yl)decanamido)-N,N,N-trime-

thylethanaminium iodide (29a): Preparations from compound

12a (25.3 mg, 55.1 mmol) were made according to general proce-

dure 9 described above. The title compound 29a was obtained as

a brown oil (26.1 mg, 55.1 mmol, 100%). R_f=0.3 (CHCl₃/MeOH=

10:1) [UV]; ¹H NMR: (600 MHz, CDCl₃): d=0.86 (t, J=7.2 Hz, 3H),

1.15–1.22 (m, 10H), 1.23–1.28 (m, 2H), 1.49–1.54 (m, 2H), 2.08 (m,

2H), 3.48 (s, 9H), 3.83 (m, 2H), 3.85 (s, 3H), 4.02–4.28 (m, 2H), 7.08

(d, J=8.8 Hz, 1H), 7.09 (d, J=2.7 Hz, 1H), 7.36 (dd, J=2.7 Hz, J=

8.8 Hz, 1H), 7.39 (d, J=8.7 Hz, 2H), 7.52 ppm (d, J=8.7 Hz, 2H);

¹³C NMR: (90.6 MHz, CDCl₃): d=14.0 (CH₃), 22.6 (CH₂), 25.1 (CH₂),

29.1 (CH₂), 29.2 (2ꢁCH₂), 29.3 (CH₂), 31.7 (CH₂), 34.1 (CH₂), 44.2

(CH₂), 54.0 (3ꢁCH₃), 56.0 (CH₃), 63.5 (CH₂), 112.8 (CH), 128.3 (2ꢁ

CH), 128.9 (CH), 129.4 (CH), 130.9 (2ꢁCH), 131.1 (C_q), 133.5 (C_q),

134.0 (C_q), 135.2 (C_q), 156.3 (C_q), 174.7 ppm (CO); HRMS (ESI):

+

C₂₈H₄₂ClN₂O₂[M+H] calcd: 473.2935, found: 473.2936.

2-(N-(2’,6’-Dichloro-6-methoxybiphen-3-yl)decanamido)-N,N,N-tri-

methylethanaminium iodide (29b): Preparations from compound

12b (25.2 mg, 51.1 mmol) were made according to general proce-

dure 9 described above. The title compound 29b was obtained as

a brown oil (26.0 mg, 51.1 mmol, 100%). R_f=0.4 (CHCl₃/MeOH=

10:1) [UV]; ¹H NMR: (600 MHz, CDCl₃): d=0.86 (t, J=7.1 Hz, 3H),

1.14–1.23 (m, 10H), 1.24–1.30 (m, 2H), 1.48–1.54 (m, 2H), 2.12 (m,

2H), 3.53 (s, 9H), 3.82 (s, 3H), 3.86 (m, 2H), 4.09–4.29 (m, 2H), 6.90

(d, J=2.7 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.26 (dd, J=7.7 Hz, J=

8.5 Hz, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.55 ppm (dd, J=2.8 Hz, J=

8.8 Hz, 1H); ¹³C NMR: (151 MHz, CDCl₃): d=14.0 (CH₃), 22.6 (CH₂),

25.1 (CH₂), 29.2 (3ꢁCH₂), 29.3 (CH₂), 31.8 (CH₂), 34.3 (CH₂), 44.1

(CH₂), 54.1 (3ꢁCH₃), 56.2 (CH₃), 63.8 (CH₂), 113.0 (CH), 127.4 (C_q),

127.9 (2ꢁCH), 129.5 (CH), 129.9 (CH), 130.1 (CH), 133.4 (C_q), 135.0

(C_q), 135.2 (2ꢁC_q), 156.8 (C_q), 174.9 ppm (CO); HRMS (ESI):

C₂₈H₄₁Cl₂N₂O₂[M+H] calcd: 507.2540, found: 507.2549.

5-[(4’-Chloro-6-methoxybiphen-3-ylmethyl)amino]-2,2-diphenyl-

pentanenitrile (28c): Preparations from compound 26a (52.0 mg,

149 mmol; for synthesis see compound 27c) and 5-bromo-2,2-di-

phenylpentanenitrile (175 mg, 557 mmol) in N,N-dimethylforma-

mide were made according to the general procedures 4 and 8 de-

scribed above. Purification by column chromatography (CHCl₃/

MeOH=20:1) gave the title compound 28c as a yellow oil

(20.1 mg, 41.7 mmol, 28% over two steps). R_f=0.5 (CHCl₃/MeOH=

1

10:1) [UV]; H NMR: (360 MHz, CDCl₃): d=1.67–1.77 (m, 2H), 2.42–

2.49 (m, 2H), 2.74 (t, J=6.7 Hz, 2H), 3.73–3.78 (m, 2H), 3.75 (s, 3H),

6.89 (d, J=8.3 Hz, 1H), 7.22–7.38 (m, 14H), 7.44 ppm (d, J=8.7 Hz,

2H); ¹³C NMR: (90.6 MHz, CDCl₃): d=23.9 (CH₂), 36.9 (CH₂), 46.7

(C_q), 51.2 (CH₂), 51.5 (CH₂), 55.6 (CH₃), 111.5 (CH), 122.1 (CN), 126.7

(C_q), 126.8 (4ꢁCH), 128.0 (2ꢁCH), 128.2 (2ꢁCH), 128.9 (4ꢁCH),

129.6 (CH), 129.8 (CH), 130.8 (2ꢁCH), 131.5 (CH), 133.1 (C_q), 136.2

(C_q), 139.8 (2ꢁC_q), 156.3 ppm (C_q); MS (EI): m/z (%)=480 (26) [M]⁺,

479 (11), 478 (16), 321 (9), 260 (17), 234 (9), 233 (47), 232 (25), 231

(100), 192 (9), 181 (19), 165 (19); HRMS (EI): C₃₁H₂₉ClN₂O [M]⁺calcd:

480.1968, found: 480.1968.

2-(N-((4’-Chloro-6-methoxybiphen-3-yl)methyl)decanamido)-

N,N,N-trimethylethanaminium iodide (30a): Preparations from

compound 24a (15.0 mg, 31.7 mmol) were made according to gen-

eral procedure 9 described above. The title compound 30a was

obtained as a brown oil (15.5 mg, 31.7 mmol, 100%). R_f=0.4

(CHCl₃/MeOH=10:1) [UV]; ¹H NMR: (600 MHz, CDCl₃): d=0.87 (t,

J=7.1 Hz, 3H), 1.21–1.32 (m, 12H), 1.60–1.66 (m, 2H), 2.43 (m, 2H),

3.37 (s, 9H), 3.75 (t, J=6.8 Hz, 2H), 3.81 (s, 3H), 3.95 (t, J=6.8 Hz,

2H), 4.81–4.82 (brs, 2H), 6.98 (d, J=8.4 Hz, 1H), 7.15 (d, J=2.4 Hz,

1H), 7.27 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 7.36 (d, J=8.6 Hz, 2H),

7.45 ppm (d, J=8.6 Hz, 2H); ¹³C NMR: (90.6 MHz, CDCl₃): d=14.1

(CH₃), 22.6 (CH₂), 25.1 (CH₂), 29.2 (CH₂), 29.4 (3ꢁCH₂), 31.8 (CH₂),

33.1 (CH₂), 39.4 (CH₂), 50.7 (CH₂), 54.0 (3ꢁCH₃), 55.8 (CH₃), 62.6

5-[(2’,6’-Dichloro-6-methoxybiphen-3-ylmethyl)amino]-2,2-diphe-

nylpentanenitrile (28d): Preparations from compound 26b

(57.0 mg, 149 mmol; for synthesis see compound 27d) and 5-

bromo-2,2-diphenylpentanenitrile (175 mg, 557 mmol) in N,N-dime-

thylformamide were made according to the general procedures 4

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(CH₂), 111.9 (CH), 127.3 (CH), 127.8 (C_q), 128.3 (2ꢁCH), 129.0 (CH),

130.0 (C_q), 130.8 (2ꢁCH), 133.2 (C_q), 136.2 (C_q), 156.2 (C_q),

174.7 ppm (CO); HRMS (ESI): C₂₉H₄₄ClN₂O₂[M+H] calcd: 487.3086,

with 0.1 mg Elk1, 5 mg Luc, and 5 mg US28 vector or an empty

pcDNA3 vector (mock cells). The US28 receptor that we used was

cloned from the clinically relevant and highly endotheliotropic

HCMV strain TB40/E (Genbank Accession No. ABV71518.1).^[39]Five

hours after transfection, the cells were washed with DMEM/F-12

containing 1% FBS, harvested, seeded in a white half-area 96-well

plate (20000 cells per well) and incubated with the indicated con-

centrations of test compounds. The incubation buffer consisted of

DMEM/F-12, 1% FBS, 2 mm l-glutamine, 1% penicillin–streptomy-

cin, and 1% DMSO. The cells were incubated at 378C under a hu-

midified atmosphere with 5% CO₂for an additional 20–24 h. The

luciferase substrate BrightGlo (Promega)^[40]was used according to

the manufacturers’ instructions. The luminescence intensity was ac-

quired with a microplate reader Victor³V (PerkinElmer). The basal

luminescence of mock transfected cells was ~500 RLU, and the

basal luminescence of US28 transfected cells up to 8–10-fold

higher (4000–5000 RLU). Data were analyzed by nonlinear regres-

sion with the algorithms in Prism 5.0 (GraphPad Software, San

Diego, CA, USA). The dose–response curves of 3–8 experiments

performed in triplicate were normalized and pooled to generate

a mean sigmoidal curve from which the EC₅₀value and the maxi-

mum intrinsic activity of each compound was obtained.

+

found: 487.30861.

2-(N-((2’,6’-Dichloro-6-methoxybiphen-3-yl)methyl)decanamido)-

N,N,N-trimethylethanaminium iodide (30b): Preparations from

compound 24b (5.00 mg, 9.85 mmol) were made according to gen-

eral procedure 9 described above. The title compound 30b was

obtained as a brown oil (5.15 mg, 9.85 mmol, 100%). R_f=0.4

(CHCl₃/MeOH=10:1) [UV]; ¹H NMR: (600 MHz, CDCl₃): d=0.87 (t,

J=7.1 Hz, 3H), 1.20–1.32 (m, 12H), 1.59–1.65 (m, 2H), 2.44 (m, 2H),

3.31 (s, 9H), 3.68 (t, J=6.9 Hz, 2H), 3.79 (s, 3H), 3.81 (m, 2H), 4.77

(brs, 2H), 6.90 (d, J=2.3 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 7.25 (dd,

J=7.7 Hz, J=8.4 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.44 ppm (dd, J=

2.3 Hz, J=8.5 Hz, 1H); ¹³C NMR: (151 MHz, CDCl₃): d=14.1 (CH₃),

22.6 (CH₂), 25.0 (CH₂), 29.2 (CH₂), 29.3 (CH₂), 29.4 (2ꢁCH₂), 31.8

(CH₂), 33.3 (CH₂), 40.0 (CH₂), 51.2 (CH₂), 54.0 (3ꢁCH₃), 56.0 (CH₃),

63.1 (CH₂), 112.0 (CH), 126.6 (C_q), 127.4 (C_q), 127.9 (2ꢁCH), 128.9

(CH), 129.3 (CH), 129.6 (CH), 135.2 (2ꢁC_q), 135.9 (C_q), 156.6 (C_q),

+

174.7 ppm (CO); HRMS (ESI): C₂₉H₄₃Cl₂N₂O₂

521.2696, found: 521.2698.

[M+H] calcd:

N,N,N-Trimethyl-2-(N-(9-oxo-9H-xanthen-2-yl)decanamido)etha-

naminium iodide (31a): Preparations from compound 21a

(25.0 mg, 57.3 mmol) were made according to general procedure 9

described above. The title compound 31a was obtained as

a yellow solid (25.9 mg, 57.3 mmol, 100%). R_f=0.4 (CHCl₃/MeOH=

10:1) [UV]; ¹H NMR: (600 MHz, CDCl₃): d=0.82 (t, J=7.1 Hz, 3H),

1.10–1.19 (m, 10H), 1.19–1.24 (m, 2H), 1.48–1.55 (m, 2H), 2.06 (t,

J=7.6 Hz, 2H), 3.52 (s, 9H), 3.94 (t, J=6.8 Hz, 2H), 4.23–4.29 (m,

2H), 7.43 (t, J=7.5 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.68 (d, J=

8.8 Hz, 1H), 7.77 (ddd, J=1.7 Hz, J=7.2 Hz, J=8.6 Hz, 1H), 7.94

(dd, J=2.7 Hz, J=8.8 Hz, 1H), 8.08 (d, J=2.7 Hz, 1H), 8.28 ppm

(dd, J=1.5 Hz, J=7.9 Hz, 1H); ¹³C NMR: (90.6 MHz, CDCl₃): d=14.1

(CH₃), 22.6 (CH₂), 25.1 (CH₂), 29.1 (CH₂), 29.2 (CH₂), 29.3 (2ꢁCH₂),

31.8 (CH₂), 34.4 (CH₂), 44.4 (CH₂), 54.2 (3ꢁCH₃), 63.4 (CH₂), 118.2

(CH), 121.2 (CH), 121.3 (C_q), 122.5 (C_q), 124.6 (CH), 125.4 (CH), 126.6

(CH), 135.5 (CH), 135.6 (CH), 137.2 (C_q), 155.5 (C_q), 156.1 (C_q), 174.3

(CO), 176.4 ppm (CO); HRMS (ESI): C₂₈H₃₉N₂O₃[M+H] calcd:

451.2955, found: 451.2967.

Cytotoxicity assay: To estimate the general toxicity of each novel

compound the CellTiter 96 AQueous One Solution Cell Proliferation

Assay (Promega) was performed. Briefly, HEK293T cells were

seeded in half-area 96-well plates at 10000 cells per well, and the

compounds were added at a concentration of 10 mm. After addi-

tion of the compounds and DMSO (0.1%) as the negative control,

the cells were incubated at 378C in 5% CO₂for 24 h. Then the

MTS reagent (Promega Cell Titer 96 AQueous One Solution Cell

Proliferation Reagent) was added (10 mL), and incubated for an ad-

ditional 2 h. The absorbance at 490 nm was measured on a Victor³V

(PerkinElmer) plate reader. The control run using solely 0.1%

DMSO in the media drug showed no toxicity over the 24 h period.

The data are shown in Supporting Information table S1. The one-

way ANOVA test for repeated measures followed by Tukey’s multi-

ple comparison test was used to determine the significance of the

observed cytotoxicity on the HEK293T cells.

Acknowledgements

2-(N-(3-Benzoylphenyl)decanamido)-N,N,N-trimethylethanamini-

um iodide (31b): Preparations from compound 21b (25.0 mg,

59.2 mmol) were made according to general procedure 9 described

above. The title compound 31b was obtained as a brown oil

(25.9 mg, 59.2 mmol, 100%). R_f=0.4 (CHCl₃/MeOH=10:1) [UV];

¹H NMR: (600 MHz, CDCl₃): d=0.86 (t, J=7.1 Hz, 3H), 1.15–1.22 (m,

10H), 1.23–1.29 (m, 2H), 1.50–1.56 (m, 2H), 2.08 (t, J=7.6 Hz, 2H),

3.50 (s, 9H), 3.90 (t, J=6.8 Hz, 2H), 4.18–4.22 (m, 2H), 7.50–7.54 (m,

2H), 7.60–7.64 (m, 2H), 7.66 (t, J=7.8 Hz, 1H), 7.74 (d, J=7.8 Hz,

1H), 7.78 (d, J=7.8 Hz, 1H), 7.82 ppm (d, J=7.8 Hz, 2H); ¹³C NMR:

(90.6 MHz, CDCl₃): d=14.1 (CH₃), 22.6 (CH₂), 25.1 (CH₂), 29.2 (2ꢁ

CH₂), 29.3 (CH₂), 29.4 (CH₂), 31.8 (CH₂), 34.4 (CH₂), 44.2 (CH₂), 54.2

(3ꢁCH₃), 63.4 (CH₂), 128.6 (2ꢁCH), 128.9 (CH), 130.1 (2ꢁCH), 130.4

(CH), 130.8 (CH), 132.7 (CH), 133.0 (CH), 136.8 (C_q), 139.6 (C_q), 141.6

(C_q), 174.1 (CO), 195.3 ppm (CO); HRMS (ESI): C₂₈H₄₁N₂O₂[M+H]

calcd: 437.3162, found: 437.3166.

The authors are grateful to Josefa Hofmann for the experiments

conducted during her internship. N.T. and E.K. were financially

supported by the Collaborative Research Center 796 (SFB796) of

the German Research Foundation (DFG). M.R.H. acknowledges

the DFG for financial support within the related project HE5413/

2-2.

Keywords: amides · biphenyls · human cytomegalovirus ·

inverse agonism · US28 receptor

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Received: September 12, 2013

Revised: October 23, 2013

Published online on November 21, 2013

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Synthesis and biological evaluation of biphenyl amides that modulate the US28 receptor

DOI: 10.1002/cmdc.201300369

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