Catalytic Alkyne Arylation Using Amines as Traceless ...

doi.org/10.26434/chemrxiv.6216116.v1

Catalytic Alkyne Arylation Using Amines as Traceless Directing GroupsJung-Woo Park, Bubwoong Kang, Vy M. Dong

Submitted date: 03/05/2018 • Posted date: 03/05/2018Licence: CC BY-NC-ND 4.0Citation information: Park, Jung-Woo; Kang, Bubwoong; Dong, Vy M. (2018): Catalytic Alkyne Arylation UsingAmines as Traceless Directing Groups. ChemRxiv. Preprint.

By developing a Pd(0)/Mandyphos catalyst, we have achieved a three-component aminoarylation of alkynesto generate enamines, which upon hydrolysis yield either α-arylphenones or α,α-diarylketones. ThisPd-catalyzed method overcomes well-established pathways to enable the use of amines as traceless directinggroups for C–C bond formation.

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Catalytic Alkyne Arylation Using Amines as Traceless Directing Groups

Jung-Woo Park,*[a,b] Bubwoong Kang[a] and Vy M. Dong*[a]

[a] Department of Chemistry, University of California, Irvine, 4403 Natural Sciences 1, Irvine, California 92697, United

States [b] Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of

Korea

Abstract: By developing a Pd(0)/Mandyphos catalyst, we

have achieved a three-component aminoarylation of

alkynes to generate enamines, which upon hydrolysis yield

either α-arylphenones or α,α-diarylketones. This Pd-

catalyzed method overcomes well-established pathways to

enable the use of amines as traceless directing groups for

C–C bond formation.

In nature, regiocontrol results from the precise

orientation of substrates in an enzymatic pocket, while

synthetic chemists devise strategies that include the tuning

of reagents, catalysts, and directing groups.1

Hydroamination is an attractive way to functionalize

alkynes, whereby both anti-Markovnikov and

Markovnikov selective variants have been demonstrated.2,3

In these studies, regioselectivity for the aminopalladation

step4 has been achieved by choice of amine, where bulky

amines add to the less hindered position of a terminal

alkyne (Scheme 1A).3a Inspired by these findings, we

hypothesized that amines could be used as directing groups

for C–C bond formation in the related, but less explored,

carboamination of alkynes.5-7 Herein, we report a three-

component carboamination of alkynes that upon

hydrolysis affords access to either α-arylphenone 4 or α,α-

diarylketone 5, depending on choice of the amine (Scheme

1B). This Pd-catalyzed strategy occurs by a distinct

mechanism and offers complementary scope to emerging

hydrative arylation of alkynes and α-arylation of

ketones.8,9 Moreover, we showcase the use of amines as

traceless directing groups for alkyne functionalization.1c,10

The aminoarylation of alkynes represents a promising

way to generate C–C bonds that warrants further

development. Pioneering examples include intramolecular

variants5a-c and annulative examples.5a,d,e To date, only one

example of an intermolecular, two-component

aminoarylation has been demonstrated. In this example,

enamines are generated from Michael acceptors, such as

alkyl- or aryl-propynoic esters.7 Encouraged by these

examples, we imagined developing a three-component

coupling between an amine, unactivated alkyne, and aryl-

electrophile by Pd-catalysis (Scheme 1B). As part of our

design, we proposed that aryl-electrophile 2 would

undergo oxidative addition to Pd(0) to generate a π-acidic

complex, which would bind to the alkyne. This π-complex

can then undergo addition with an amine to generate two

possible regioisomers.

We reasoned that choice of the amine could be used to

control regioselectivity in the nucleopalladation step,

whereby bulkier amines would favor addition to the less

hindered position. We recognized that it would be

challenging to overcome established transformations that

could compete with our proposed three-component

coupling,11 including Buchwald-Hartwig amination,12

hydroarylation,13 hydroamination,2 and aryl-alkyne

coupling (Figure 1C).14 If these challenges could be

overcome, our study would result in the first alkyne

aminoarylation to occur by three-component coupling.

Hydrolysis of the resulting enamines would furnish the α-

arylphenone 4 and α,α-diarylketone 5, two useful building

blocks for natural products and pharmaceuticals.15

Scheme 1. Three-component aminoarylation

To begin our studies, we chose 1-phenyl-1-propyne (1a),

3-methoxyphenyl triflate (2a), and morpholine (3a) as

model substrates for the three-component coupling (Table

1). First, we evaluated several commercially available

bidentate ligands for the desired aminoarylation.

Treatment of 1a, 2a and 3a with Pd and a variety of

bisphosphine ligands gave no desired aminoarylation

products.16 For example, with a Pd/DPPF catalyst, aryl

triflate 2a reacts with alkyne 1a to form polyenes, with no

amine incorporated. We observed a breakthrough by using

a P–N ligand; specifically, the Fc-PHOX ligand provided

aminoarylation in a 23% yield (4aa:5aa = 3:1), but starting

material 2a remained. On the basis of this lead, we

investigated other ligands that bear P–N and P–P moieties.

Among commercial ligands, Knochel’s Mandyphos (L1)17

gave an improved yield for ketone formation (41%, 4a:5a

= 3.1:1) after hydrolysis. A Mandyphos ligand with

electron-deficient aryl substituents (L2) gave no reactivity.

The Mandyphos derivative bearing two 3,5-xylyl groups

(L3) led to α-arylphenone 4a in 68% yield, with 5a in 17%

yield. The ligand bearing a 3,5-dimethyl-4-methoxyphenyl

(L4) was less effective (48%, 4a:5a = 3.8:1). Formation

coupling was prevented when the reaction was conducted

in high concentration (c > 0.8 M with amine 3a) with L3.

Weak bases appear to suppress the amination of aryl

triflates, while use of t-BuOLi base led to Buchwald-

Hartwig product, N-arylmorpholine.18,19 Thus, the choice

of base and ligand were both critical in achieving a three-

component coupling, in preference to well-established

pathways.

Table 1. Ligand effects on alkyne aminoarylation.[a]

[a] 1 (0.1 mmol), 2 (1.25 equiv), 3 (1.7 equiv), and MS 4A (25

mg / 0.1 mmol) were applied to the reactions. Yields and

regioisomeric ratio (rr) determined by 1H NMR using

triphenylmethane as an internal standard. [b] Determined by GC-

FID and GC-MS.

Next, we focused on achieving regiocontrol on the basis

of the amine structure (Table 2). We studied various cyclic

amines and found that morpholine (3a) was optimal for

promoting high yields and selectivity for the α-

arylphenone 4a (4a:5a = 4:1, 68% 4a, entry 1).20 We

examined a series of acyclic secondary amines and

discovered that the steric bulk of the amine could be used

to switch the regioselectivity to favor α,α-diarylacetone 5a.

For example, the use of N-methyl-α-methylbenzylamine

(3b) resulted in the preference of 5a over 4a in 2.1:1 ratio.

To improve regioselectivity, we designed and synthesized

N-methyl-α-isopropylbenzylamine (3e).21 Increasing the

size of the α-substituent from a methyl group to an

isopropyl group resulted in an increase of 2.1:1 to greater

than 20:1 rr, leading to 5a as the major regioisomer in 68%

yield (5a:4a > 20:1).22

Table 2. Amine effects on regioselectivity[a]

[a] 1 (0.08-0.1 mmol), 2 (1.25 equiv), 3 (1.7 equiv), and MS 4A

(25 mg / 0.1 mmol) were applied to the reactions. [b] Determined

by 1H NMR using triphenylmethane as an internal standard.

Next, we prepared α-arylphenones from various alkynes

and coupling partners (Table 3). Arylalkynes (1a–1h) with

substituted aryl triflates (2a–2h) and morpholine (3a)

underwent aminoarylation, to afford α-arylphenones 4 in

39–77% yields for the major isomer upon hydrolysis.

Arylalkynes containing oxygen (62% 4d, 8:1 rr; 77% 4e,

10:1 rr) and heteroaromatics (70% 4f, 8:1 rr; 63% 4g, 6.7:1

rr) were well tolerated under these conditions. The use of

aryl triflates with electron-deficient (2b) and electron-

neutral (2c) functional groups showed good conversion to

desired ketones (62% 4h, 9:1 rr; 62% 4i, 4.2:1 rr).

Electron-rich aryl triflate 2d shows moderate conversion

to ketone (53% 4j, 4:1 rr). The use of methyl 3-phenyl-2-

propyn-1-yl ether (1i) as the alkyne gave α-arylphenone

4m, where the methoxymethyl group was cleaved in situ

(48% 4m). This result indicates that the alkyne 1i can be

used as a synthetic equivalent of phenylacetylene.

Table 3. Preparation of α-arylphenone 4 using morpholine (3a)[a]


(25 mg / 0.1 mmol) were applied to the reactions. See SI for

detailed reaction conditions. Yields and regioisomeric ratio (rr)

determined by 1H NMR using triphenylmethane as an internal

standard. 1H NMR yield of the major isomer 4 are in parenthesis.

[b] 0.25 mmol 1a was used. [c] 0.5 mmol 1a was used. [d] Methyl

3-phenyl-2-propyn-1-yl ether (1i) was used. [e] Reaction

condition: BBr3 (10 equiv), DCM, rt, 12 h.

Using this method, we accessed a natural product, O-

desmethylangolensin (4o), an intestinal bacterial

metabolite of daidzein (soy phytoestrogen),15a,b and

precursors of natural neolignans 4q and 4r.15c Specifically,

the three-component reaction of alkyne 1h with aryl triflate

2g and morpholine (3a) gave ketone 4n after hydrolysis

(70% 4n, 10:1 rr). O-Desmethylangolensin (4o) was

obtained in 52% yield by demethylation of 4n using

BBr3.23 We prepared ketone 4p, which is a precursor for

natural neolignans. This ketone arises from the three-

component coupling of alkyne 1e with aryl triflate 2h and

morpholine (3a).

With amine 3e, we apply analogous conditions to

generate α,α-diarylacetones 5 (Table 4). Three-component

coupling of arylalkynes (1a, 1b, 1j–1p) with substituted

aryl triflates (2a–2f) yielded α,α-diarylacetones 5 in 48–79%

isolated yields for the major isomer after hydrolysis.

Additionally, from ketone 5a, which was prepared by

three-component aminoarylation with amine 3e, we

prepared a MeO-analogue of BRL-15572, an

antidepressant from GlaxoSmithKline (eq 1).24

Table 4. Preparation of α,α-diarylketone 5 using amine 3ea


(25 mg / 0.1 mmol) were applied to the reactions. See SI for

detailed reaction conditions. Regioisomeric ratio (rr) determined

by 1H NMR using an internal standard. Isolated yields of major

isomer 5a-l. [b] 0.25 mmol 1a was used.

On the basis of our observations and literature

precedence,4,5c we propose the mechanism shown in

Scheme 2. The Pd(0)-complex activates the aryl triflate 2

to form arylpalladium(II)-intermediate 6.

Nucleopalladation with amine 3 then occurs to afford

vinylpalladium(II)-intermediate 7. Regioselectivity for

this nucleopalladation depends on the sterics of the amine

3a versus 3e. Amines bearing small substituents (e.g., 3a)

favor the attack of the carbon adjacent to aryl group, while

amines bearing large substituents (e.g., 3e) favor attack on

the carbon distal to aryl group. Reductive elimination of

vinylpalladium 7 generates enamine 8 and regenerates

Pd(0).

Scheme 2. Proposed mechanism

To conclude, we have developed a three-component

coupling by using a Pd(0)/Mandyphos catalyst to access

enamines, which are classic and versatile intermediates for

organic synthesis. Mandyphos bears both P–N and P–P

moieties that are critical for regioselective aminoarylation.

Either α-arylphenones or α,α-diarylacetones can be

accessed through the novel application of amines, as

traceless directing groups for C–C bond formation.

Future studies will involve (1) designing chiral amines for

stereoselective applications25 and (2) elucidating the

mechanism of this three-component coupling to guide

alkyne functionalizations.

Corresponding Author

[email protected]

[email protected]

Notes

The authors declare no competing financial interests.

Acknowledgements

Funding was provided by the National Science Foundation

(CHE-1465263), and the Institute for Basic Science (IBS-

R10-Y1). B.K. acknowledges the Uehara Memorial

Foundation for a postdoctoral fellowship.

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[20] The use of pyrrolidine as the amine source showed better

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510.

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S1

Supporting Information

Catalytic Alkyne Arylation Using Amines as Traceless

Directing Groups

Jung-Woo Park,*[a,b] Bubwoong Kang[a] and Vy M. Dong*[a]

[a] Department of Chemistry, University of California, Irvine, 4403 Natural Sciences 1,

Irvine, California 92697, United States

[b] Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS),

Daejeon 34141, Republic of Korea

<[email protected] / [email protected]>

Table of Contents: Page

1. General Considerations S2

2. Experimental S3

3. NMR Spectra S15

S2

1 General Considerations

All experiments were performed in oven-dried or flame-dried glassware under an atmosphere of N2. Tetrahydrofuran,

dichloromethane, toluene, and diethyl ether were purified using an Innovative Technologies Pure Solv system, degassed

by three freeze-pump-thaw cycles, and stored over 3A MS within a N2 filled glove box. Reactions were monitored either

via gas chromatography using an Agilent Technologies 7890A GC system equipped with an Agilent Technologies 5975C

inert XL EI/CI MSD or by analytical thin-layer chromatography on EMD Silica Gel 60 F254 plates. Visualization of the

developed plates was performed under UV light (254 nm) or using either KMnO4 or p-anisaldehyde stain. Column

chromatography was performed with Silicycle Silia-P Flash Silica Gel using glass columns. Automated column

chromatography was performed using a Teledyne Isco CombiFlash Rf 200 purification system. 1H and 13C spectra were

recorded on a Bruker DRX-400 (400 MHz 1H, 100 MHz 13C, 376.5 MHz 19F), GN-500 (500 MHz 1H, 125.7 MHz 13C) or

CRYO-500 (500 MHz 1H, 125.7 MHz 13C) spectrometer. 1H NMR spectra were internally referenced to the residual solvent

signal or TMS. 13C NMR spectra were internally referenced to the residual solvent signal. Data for 1H NMR are reported

as follows: chemical shift (δ ppm, δ 7.27 for CDCl3), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =

multiplet, br = broad), coupling constant (Hz), integration. Data for 13C NMR are reported in terms of chemical shift (δ

ppm, δ 77.16 for CDCl3). Infrared spectra were obtained on a Thermo Scientific Nicolet iS5 FT-IR spectrometer equipped

with an iD5 ATR accessory. High resolution mass spectrometry (HRMS) was performed by the University of California,

Irvine Mass Spectrometry Center.

All commercial chemicals were purchased and used without further purification unless otherwise noted. 1-Aryl-1-

propynes (1b–1p) were prepared by the procedure of decarboxylative alkynylation on the literature.1 All aryl triflates 2

were synthesized by the reactions of the corresponding phenols with triflic anhydride and triethylamine. N-methyl-α-n-

propylbenzylamine (3d) and N-methyl-α-isopropylbenzylamine (3e) were prepared by the procedure on the literature.2

1 T. Fujihara, Y. Tani, K. Semba, J. Terao, Y. Tsuji, Angew. Chem. 2012, 124, 11655; Angew. Chem. Int. Ed. 2012, 51,

11487. 2 H. J. Kumpaty, J. S. Williamson, S. Bhattacharyya, Synth. Commun. 2003, 33, 1411.

S3

2 Experimental

Representative procedure of Pd-catalyzed three-component aminoarylation (Table 1-4)

In a N2-filled glove box, a 1-dram vial was charged with the indicated amount of Pd2(dba)3, Mandyphos (L3), alkyne (1,

1.0 equiv. 0.08–0.1 mmol scale), aryl triflate (2, 1.25 equiv.), amine (3, 1.7 equiv.), DIPEA (1.1 equiv.) and 1,4-dioxane

(1.0–1.5 M). The vial was then sealed with a Teflon-lined screw cap, and the reaction mixture was gently stirred at 80–90

oC for the indicated reaction time. Reaction progress was monitored by analysis of the GC-FID / GC-MS chromatography

of the reaction mixture. Then the reaction mixture was diluted with THF (1.5 mL), and aqueous 2 N HCl (2.0 mL) was

added to the mixture. The mixture was stirred for the following time (2 hours for the reactions on table 1, 12 hours for the

reactions on table 2). Chemoselectivity was determined by 1H NMR analysis of the unpurified reaction mixture. The

products were isolated by preparative TLC.

2-(3-Methoxyphenyl)propiophenone (4a, CAS No. 197640-99-6)

0.08 mmol scale (c 1.0 M, 90 oC, 15 h), 68% isolated yield (13.1 mg obtained); 0.25 mmol scale

(c 1.2 M, 80 oC, 72 h), 56% isolated yield (33.7 mg obtained). The 1H NMR spectrum matched the

literature reported values.3

1H NMR (400 MHz, CDCl3) δ 7.97 – 7.94 (m, 2H), 7.48 – 7.46 (m, 1H), 7.39 – 7.35 (m, 2H),

7.23 – 7.19 (m, 1H), 6.89 – 6.87 (m, 1H), 6.84 – 6.83 (m, 1H), 6.75 – 6.73 (m, 1H), 4.66 (q, J = 6.9 Hz, 1H), 3.77 (s, 3H),

1.53 (d, J = 6.9 Hz, 3H).

2-(3-Methoxyphenyl)-1-(4-methylphenyl)propan-1-one (4b, CAS No. 1373764-95-4)

0.08 mmol scale, 62% isolated yield (12.6 mg obtained). The 1H NMR spectrum matched the


1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.22 – 7.07 (m, 3H), 6.87 (d, J = 7.6

Hz, 1H), 6.83 – 6.76 (m, 1H), 6.76 – 6.63 (m, 1H), 4.62 (q, J = 6.8 Hz, 1H), 3.76 (s, 3H), 2.34

(s, 3H), 1.51 (d, J = 6.9 Hz, 3H).

3 M. Kawatsura, J. F. Hartwig, J. Am. Chem. Soc. 1999, 121, 1473. 4 Z.-K. Xiao, L.-X. Shao, Synlett 2012, 44, 711.

S4

2-(3-Methoxyphenyl)propan-1-(naphthyl)-1-one (4c)

0.08 mmol scale, 61% isolated yield (14.2 mg obtained).

1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 1.2 Hz, 1H), 8.01 (dd, J = 8.7, 1.8 Hz, 1H), 7.89

(dd, J = 8.0, 1.2 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.55 (ddd, J = 8.2, 6.9, 1.4 Hz, 1H), 7.50

(ddd, J = 8.1, 6.9, 1.4 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.93 (ddd, J = 7.6, 1,4, 0.8 Hz, 1H),

6.88 (t, J = 2.1 Hz, 1H), 6.73 (ddd, J = 8.3, 2.6, 0.8 Hz, 1H), 4.81 (q, J = 6.8 Hz, 1H), 3.76 (s, 3H), 1.58 (d, J = 6.8 Hz,

3H).

13C NMR (101 MHz, CDCl3) δ 200.1, 160.0, 143.2, 135.4, 133.9, 132.5, 130.4, 130.0, 129.64, 128.4, 128.3, 127.7, 126.6,

124.6, 120.2, 113.6, 112.2, 55.2, 48.0, 19.5.

IR (ATR): 3016, 2972, 2931, 2835, 1669, 1583, 1485, 1262, 1238, 1226, 1178, 1149, 1043, 904, 860, 783, 760. 728, 697

cm−1.

HRMS (CI-TOF) m / z calcd for C20H18O2Na [M + Na]+: 313.1205, found: 313.1199.

2-(3-Methoxyphenyl)-1-(4-methoxyphenyl)-1-propanone (4d, CAS No. 921929-36-4)



1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.1 Hz, 2H), 7.20 (t, J = 7.9 Hz, 1H), 6.88 – 6.83

(m, 4H), 6.73 (ddd, J = 8.2, 2.5, 0.9 Hz, 1H), 4.60 (q, J = 6.8 Hz, 1H), 3.81 (s, 3H), 3.76 (s,

3H), 1.51 (d, J = 6.9 Hz, 3H).

2-(3-Methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-propan-1-one (4e)


1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 8.2, 1.8 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.21

(t, J = 8.0 Hz, 1H), 6.85 (dt, J = 8.0, 1.0 Hz, 1H), 6.80 (dd, J = 2.5, 1.0 Hz, 1H), 6.76 (d, J =

8.2 Hz, 1H), 6.74 (ddd, J = 8.0, 2.5, 1.0, 1H), 5.99 (s, 2H), 4.55 (q, J = 6.8 Hz, 1H) 3.77 (s,

3H), 1.50 (d, J = 6.8 Hz, 3H).

13C NMR (101 MHz, CDCl3) δ 198.2, 160.0, 151.5, 148.1, 143.4, 131.3, 130.0, 125.0, 120.1, 113.4, 112.2, 108.6, 107.8,

101.8, 55.2, 47.7, 19.5.

IR (ATR): 3078, 2972, 2930, 2836, 1675, 1605, 1597, 1372, 1261, 1174, 1125, 728, 703, 678, 665, 584 cm−1.

HRMS (ESI-TOF) m / z calcd for C17H17O4 [M + H]+: 285.1127, found: 285.1121.

5 L. Ackermann, J. H. Spatz, C. J. Gschrei, R. Born, A. Althammer, Angew. Chem. 2006, 118, 7789; Angew. Chem. Int.

Ed. 2006, 45, 7627.

S5

2-(3-methoxyphenyl)-1-(thiophen-3-yl)propan-1-one (4f)


1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 2.9, 1.3 Hz, 1H), 7.51 (dd, J = 5.1, 1.3 Hz, 1H), 7.24

– 7.17 (m, 2H), 6.88 (dt, J = 8.0, 1.1, 1H), 6.82 (t, J = 2.1 Hz, 1H), 6.76 (ddd, J = 8.2, 2.6, 0.9 Hz,

1H), 4.43 (q, J = 6.9 Hz, 1H), 3.77 (s, 3H), 1.51 (d, J = 6.9 Hz, 3H).

13C NMR (101 MHz, CDCl3) δ 194.4, 160.0, 143.1, 141.6, 132.6, 130.0, 127.6, 126.0, 120.2, 113.5, 112.3, 55.2 , 49.8,

19.1.

IR (ATR): 3016, 2972, 2930, 2835, 1669, 1597, 1583, 1508, 1485, 1452, 1436, 1409, 1262, 1238, 1226, 1178, 1148, 1043,

904, 860, 783, 760, 728, 697 cm−1.

HRMS (CI-TOF) m / z calcd for C14H15O2 [M + H]+: 247.0793, found: 247.0787.

2-(3-Methoxyphenyl)-1-(1-tosyl-1H-indol-5-yl)propan-1-one (4g)


1H NMR (400 MHz, CDCl3) δ 8.16 (t, J = 1.2 Hz, 1H), 7.94 (d, J = 1.2 Hz, 2H), 7.78 – 7.69

(m, 2H), 7.58 (d, J = 3.7 Hz, 1H), 7.20 (ddd, J = 15.9, 6.5, 4.3 Hz, 3H), 6.92 – 6.85 (m, 1H),

6.85 – 6.79 (m, 1H), 6.72 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H), 6.67 (d, J = 3.7 Hz, 1H), 4.68 (q, J =

6.8 Hz, 1H), 3.74 (s, 3H), 2.32 (s, 3H), 1.52 (d, J = 6.8 Hz, 3H).

13C NMR (101 MHz, CDCl3) δ 199.6, 160.0, 145.4, 143.2, 137.1, 135.1, 132.1, 130.5, 130.0, 130.0, 127.5, 126.9, 125.2,

123.0, 120.1, 113.5, 113.3, 112.1, 109.5, 55.2, 47.9, 21.6, 19.6.

IR (ATR): 3142, 3114, 2973, 2931, 2870, 2836, 1675, 1597, 1372, 1261, 1174, 1125. 728, 703, 678, 665 cm−1.

HRMS (ESI-TOF) m / z calcd for C25H23NO4SNa [M + Na]+: 456.1245, found: 456.1260.

2-(3-Chlorophenyl)propiophenone (4h, CAS No. 14161-85-4)



1H NMR (400 MHz, CDCl3) δ 8.03 – 7.88 (m, 2H), 7.55 – 7.47 (m, 1H), 7.44 – 7.37 (m, 2H), 7.30

(t, J = 1.9 Hz, 1H), 7.25 – 7.12 (m, 3H), 4.67 (q, J = 6.9 Hz, 1H), 1.53 (d, J = 6.8 Hz, 3H).

6 J. A. Landgrebe, A. G. Kirk, J. Org. Chem. 1967, 32, 3499.

S6

2-(4-Methylphenyl)propiophenone (4j, CAS No. 107271-15-8)

0.10 mmol scale, 52% isolated yield (11.6 mg obtained). The 1H NMR spectrum matched the literature

reported values.3


(d, J = 8.1 Hz, 2H), 7.13 – 7.06 (m, 2H), 4.65 (q, J = 6.8 Hz, 1H), 2.28 (s, 3H), 1.52 (d, J = 6.9 Hz,

3H).

2-(2-Naphthyl)propiophenone (4k, CAS No. 889445-31-2)

0.5 mmol scale (c 1.2 M, 80 oC, 72 h), 68% isolated yield (88.3 mg obtained). The 1H NMR spectrum

matched the literature reported values.7

1H NMR (400 MHz, CDCl3) δ 8.03 – 7.98 (m, 2H), 7.83 – 7.76 (m, 3H), 7.74 (d, J = 1.8 Hz, 1H),

7.49 – 7.41 (m, 4H), 7.40 – 7.34 (m, 2H), 4.86 (q, J = 6.8 Hz, 1H), 1.63 (d, J = 6.8 Hz, 3H).

2-(3,4-Methylenedioxyphenyl)propiophenone (4l, CAS No. 917906-01-5)


reported values.7

1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 8.4, 1.4 Hz, 2H), 7.54 – 7.45 (m, 1H), 7.42 – 7.35 (m,

2H), 6.79 – 6.69 (m, 3H), 5.94 – 5.83 (m, 2H), 4.60 (q, J = 6.9 Hz, 1H), 1.49 (d, J = 6.9 Hz, 3H).

2-(3-Methoxyphenyl)acetophenone (4m, CAS No. 29955-26-8)




– 7.22 (m, 1H), 6.87 (ddq, J = 7.5, 1.6, 0.7 Hz, 1H), 6.84 – 6.77 (m, 2H), 4.27 (s, 2H), 3.80 (s, 3H).

7 Y.-T. Hong, A. Barchuk, M. J. Krische, Angew. Chem. 2006, 118, 7039; Angew. Chem. Int. Ed. 2006, 45, 6885. 8 J. Saevmarker, J. Lindh, P. Nilsson, Tetrahedron Lett. 2010, 51, 6886.

S7

1-(2,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)propan-1-one (4n, CAS No. 95334-79-5)

0.10 mmol scale, 90 oC, 24 h. 70% isolated yield (18.9 mg obtained). The 1H NMR spectrum

matched the literature reported values.9

1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.82 – 6.74

(m, 2H), 6.45 (dd, J = 8.7, 2.3 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 4.72 (q, J = 6.9 Hz, 1H), 3.83

(s, 3H), 3.80 (s, 3H), 3.75 (s, 3H), 1.45 (d, J = 6.9 Hz, 3H).

13C NMR (101 MHz, CDCl3) δ 202.1, 164.1, 160.0, 158.3, 134.4, 133.1, 129.2, 121.6, 114.0, 105.2, 98.6, 55.6, 55.5, 55.4,

50.5, 19.4.

Preparation of O-desmethylangolensin (4o, CAS No. 21255-69-6)

BBr3 (1.0 M solution in DCM) was added to the DCM (2 mL) solution of 4n (18.9 mg, 0.07 mmol),

and the resulting solution was stirred at room temperature for 12 hours. The resulting organic

solution was washed with water for 3 times. The resulting organic layer was dried over MgSO4,

filtered and concentrated. The title compound was obtained by preparatory TLC (52% isolated

yield, 9.4 mg obtained). The 1H NMR spectrum matched the literature reported values.9

1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.60 (s, 1H), 9.30 (s, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.18 – 7.04 (m,

2H), 6.76 – 6.62 (m, 2H), 6.30 (dd, J = 8.9, 2.4 Hz, 1H), 6.21 (d, J = 2.4 Hz, 1H), 4.76 (q, J = 6.7 Hz, 1H), 1.34 (d, J =

6.7 Hz, 3H).

Preparation of a precursor for a natural neolignan analog 4p

– Procedure for synthesis of 3-methoxy-4-((triisopropylsilyl)oxy)phenyl trifluoromethanesulfonate (2h)

Step 1: A mixture of vanillin (2.03 g, 13.3 mmol), imidazole (2.72 g, 40.0 mmol, 3 equiv) and TIPSCl (3.85 g, 20.0

mmol (1.5 equiv) in DMF (10 ml) was stirred at rt for 3 hours. The reaction mixture was diluted with hexanes (50 ml),

washed with water (50 mL) for 3 times and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under

reduced pressure. The residue was used for the next step without purification.

Step 2: To the solution of the above unpurified aldehyde in DCM (40 mL) was added mCPBA (4.8 g, 27.9 mmol, 2.1

equiv). After 3 hours, the solution was diluted with hexane (100 ml), washed with saturated aqueous NaHCO3 (50 mL ×

2), saturated aqueous sodium thiosulfate (50 mL × two times), and brine (50 mL), dried over anhydrous sodium sulfate,

and concentrated in vacuo. The resulting residue was dissolved in MeOH (30 mL), and Na2CO3 (0.28 g, 0.20 equiv) was

added to the solution. After 30 min, the solution was evaporated, and the residue was diluted with the mixed solvent of

9 H. J. Hong, J. I. Lee, J. Korean Chem. Soc. 2014, 58, 569.

S8

hexane and diethyl ether (60 mL, 1:1). The organic solution was washed with 0.5 N aqueous HCl (75 mL) and brine (60

mL), and dried over anhydrous sodium sulfate. Removing solvents under reduced pressure gave the crude oil. The pure 3-

methoxy-4-(triisopropylsiloxy)phenol (2.80 g, 9.45 mmol, 71% in 2 steps) was obtained by flash column chromatography

(hexanes/EA = 7:1). The 1H NMR spectrum matched the literature reported values.10

Step 3: To DCM solution (15 mL) of 3-methoxy-4-(triisopropylsiloxy)phenol (2.80 g, 9.45 mmol) and pyridine (3.8 mL,

47 mmol, 5.0 equiv) was slowly added triflic anhydride (3.92 mL, 23.3 mmol, 2.5 equiv) at 0 oC. After 1 hour, the solution

was diluted with hexanes (50 ml), washed with water (50 mL × 3 times) and brine (50 mL), dried over sodium sulfate, and

concentrated in vacuo. The pure aryl triflate 2h (3.64 g, 8.49 mmol, 90%) was obtained by flash column chromatography

(hexanes only) as a pale-yellow oil.

Characterization data for 3-methoxy-4-((triisopropylsilyl)oxy)phenyl trifluoromethane-sulfonate (2h)

1H NMR (400 MHz, CDCl3) δ 6.87 (dd, J = 7.8, 1.3 Hz, 1H), 6.76 – 6.67 (m, 2H), 3.81 (s, 3H),

1.28 – 1.19 (m, 3H), 1.08 (d, J = 7.2 Hz, 18H).

13C NMR (101 MHz, CDCl3) δ 151.6, 145.5, 143.2, 120.2, 118.8 (q, J = 322 Hz), 112.9, 105.7,

55.7, 17.8, 12.8.

IR (ATR): 2945, 2894, 2868, 1604, 1506, 1423, 1228, 1207, 1141, 1118, 945, 904, 883, 848, 680, 626, 601 cm−1.

HRMS (CI-TOF) m / z calcd for C17H27F3O5SSi [M + NH4]+: 446.1644, found: 446.1649.

1-(Benzo[d][1,3]dioxol-5-yl)-2-(3-methoxy-4-((triisopropylsilyl)oxy)phenyl)propan-1-one (4p)

Reaction condition: 0.08 mmol scale, 90 oC, 24 hr. 52% combined 1H NMR yield (4.7:1 rr),

39% isolated yield of 4p (14.2 mg obtained).

1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.2 Hz, 1H), 7.40 (s, 1H), 6.76 (dd, J = 14.3, 8.4

Hz, 2H), 6.68 (d, J = 6.1 Hz, 2H), 5.98 (s, 2H), 4.47 (q, J = 6.7 Hz, 1H), 3.75 (s, 3H), 1.47

(d, J = 6.8 Hz, 3H), 1.20 (dd, J = 14.8, 7.3 Hz, 3H), 1.05 (d, J = 7.3 Hz, 18H).

13C NMR (101 MHz, CDCl3) δ 198.8, 151.3, 151.2, 148.0, 144.4, 134.9, 131.5, 125.0, 120.7, 120.0, 111.3, 108.7, 107.7,

101.7, 55.5, 47.6, 19.6, 17.9, 12.84.

IR (ATR): 2943, 2893, 2866, 1674, 1513, 1488, 1463, 1438, 1287, 1245, 1037, 1245, 1037, 931, 882, 816, 776, 676 cm−1.

HRMS (ESI-TOF) m / z calcd for C26H36O5SiNa [M + Na]+: 479.2230, found: 479.2231.

10 M. G. Banwell, B. L. Flynn, S. G. Stewart, J. Org. Chem. 1998, 63, 9139.

S9

– Characterization Data for Compounds in Table 4

1-(3-Methoxyphenyl)-1-phenylpropan-2-one (5a)

0.10 mmol scale (c 1.5 M, 80 oC, 72 h), 68% 1H NMR yield, >20:1 rr; 0.25 mmol scale (c 2.0 M, 80

oC, 72 h), 55% isolated yield (33.4 mg obtained, 68% 1H NMR yield, >20:1 rr)


– 6.73 (m, 1H), 5.08 (s, 1H), 3.77 (s, 3H), 2.24 (s, 3H).

13C NMR (101 MHz, CDCl3) δ 206.3, 159.9, 139.8, 138.2, 129.7, 129.0, 128.7, 127.3, 121.4, 115.0, 112.5, 65.0, 55.2,

30.1.

IR (ATR): 3085, 3062, 3027, 2956, 2935, 2918, 2836, 1717, 1597, 1584, 1488, 1261, 1154, 1049, 908, 728, 701.

HRMS (CI-TOF) m / z calcd for C16H16O2 [M + H]+: 241.1228, found: 241.1233.

1-(3-Fluorophenyl)-1-(3-methoxyphenyl)propan-2-one (5b)



6.77 (t, J = 2.1, 1H), 5.06 (s, 1H), 3.78 (s, 3H), 2.25 (s, 3H).

13C NMR (101 MHz, CDCl3) δ 205.7, 247.3 (d, J = 247.3 Hz), 160.0, 140.7 (d, J = 7.3 Hz),

139.0, 130.01 (d, J = 8.4), 129.95, 124.6 (d, J = 2.9), 121.3, 116.1 (d, J = 22.2), 115.0. 114.2,

112.8, 64.5, 55.2, 30.1.

19F NMR (376 MHz, CDCl3) δ –112.7.

IR (ATR): 3063, 3003, 2918, 2849, 2838, 1717, 1585, 1485, 1437, 1355, 1260, 1159, 1049, 946, 876, 768, 701, 690.

HRMS (ESI-TOF) m / z calcd for C16H15FO2Na [M + Na]+: 281.0954, found:281.0952.

1-(4-Chlorophenyl)-1-(3-methoxyphenyl)propan-2-one (5c)


1H NMR (400 MHz, CDCl3) δ 7.30 – 7.24 (m, 3H), 7.14 (dt, J = 8.3, 2.5, 2H), 6.84 – 6.79 (m,

2H), 6.75 (t, J = 2.1 Hz, 1H), 5.04 (s, 1H), 3.78 (s, 3H), 2.23 (s, 3H).

13C NMR (101 MHz, CDCl3) δ 205.9, 160.0, 139.3, 136.7, 133.2, 130.3, 130.0, 128.8, 121.2,

114.9, 112.7, 64.2, 55.2, 30.0.

IR (ATR): 3003, 2957, 2934, 2837, 1715, 1599, 1584, 1489, 1261, 1155, 1091, 1050, 1015, 907, 780, 728, 692, 648 cm−1.

HRMS (ESI-TOF) m / z calcd for C16H15ClO2Na [M + Na]+: 297.0658, found: 297.0651.

S10

1-(3,5-Dimethoxyphenyl)-1-(3-methoxyphenyl)propan-2-one (5d)


1H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 8.0 Hz, 1H), 6.85 – 6.78 (m, 2H), 6.78 – 6.73 (m,

1H), 6.41 – 6.33 (m, 3H), 5.00 (s, 1H), 3.77 (s, 3H), 3.75 (s, 6H), 2.24 (s, 3H).

13C NMR (126 MHz, CDCl3) δ 206.3, 161.2, 160.0, 140.4, 139.7, 129.8, 121.5, 115.2, 112.7,

107.5, 99.3, 65.2, 55.8, 55.5, 30.2.

IR (ATR): 3001, 2954, 2924, 2851, 2839, 1717, 1661, 1593, 1456, 1427, 1350, 1321, 1302, 1289, 1266, 1204, 1156, 1065,

995, 837, 756, 698 cm−1.

HRMS (ESI-TOF) m / z calcd for C18H20O4Na [M + Na]+: 323.1259, found: 323.1250.

1-(3-Methoxyphenyl)-1-(p-tolyl)propan-2-one (5e)



2H), 6.77 (t, J = 2.0 Hz, 1H) 5.05 (s, 1H), 3.78 (s, 3H), 2.33 (s, 3H), 2.34 (s, 3H).

13C NMR (101 MHz, CDCl3) δ 206.6, 159.8, 140.0, 137.0, 135.2, 129.7, 129.4, 128.8, 121.4,

115.0, 112.4, 64.7, 55.2, 30.0, 21.0.

IR (ATR): 3050, 3023, 3002, 2922, 2850, 2836, 1717, 1599, 1512, 1583, 1512, 1488, 1464, 1452, 1436, 1354, 1261, 1155,

1049, 771, 696 cm−1.


1-(4-Ethyl)-1-(3-Methoxyphenyl)propan-2-one (5f)



3H), 5.04 (s, 1H), 3.77 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 2.23 (s, 3H), 1.22 (d, J = 7.6 Hz, 3H).

13C NMR (101 MHz, CDCl3) δ 206.7, 160.0, 143.4, 140.2, 135.5, 129.8, 129.1, 128.4, 121.6,

115.2, 112.6, 64.9, 55.4, 30.2, 28.6, 15.6.

IR (ATR): 3053, 3025, 3002, 2964, 2930, 2873, 2857, 2837, 1717, 1655, 1599, 1583, 1512, 1488, 1454, 1435, 1354, 1311,

1280, 1262, 1155, 1049, 761, 697 cm−1.


S11

1-(3-Chlorophenyl)-1-(3-methoxyphenyl)propan-2-one (5g)



6.76 – 6.64 (m, 1H), 5.04 (s, 1H), 3.78 (s, 3H), 2.24 (s, 3H).

13C NMR (101 MHz, CDCl3) δ 205.9, 160.0, 139.3, 136.8, 133.2, 130.3, 130.0, 128.8, 121.2,

114.9, 112.7, 64.2, 55.3, 30.0.

IR (ATR): 3053, 3004, 2957, 2934, 2836, 1715, 1599, 1584, 1489, 1261, 1155, 1091, 1050, 1015, 907, 728, 692, 648 cm−1.

HRMS (ESI-TOF) m / z calcd for C16H15ClO2Na [M + Na]+: 297.0658, found: 297.0656.

1-(4-Methoxycarbonylphenyl)-1-(3-methoxyphenyl)propan-2-one (5h)


1H NMR (400 MHz, CDCl3) δ 8.00 – 7.97 (m, 2H), 7.31 – 7.25 (m, 3H), 6.85 – 6.81 (m,

2H), 6.77 (t, J = 2.1), 5.12 (s, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 2.25 (s, 3H).

13C NMR (101 MHz, CDCl3) δ 205.6, 166.8, 160.0, 143.4, 139.0, 130.0, 129.9, 129.1, 129.0,

121.3, 115.0, 112.8, 64.8, 55.3, 52.1, 30.1.

IR (ATR): 3055, 3001, 2951, 2918, 2838, 1716, 1599, 1583, 1488, 1435, 1276, 1183, 1156, 1107, 1048, 1020, 773, 751,

707 cm−1.


1-(4-Ethoxycarbonylphenyl)-1-(3-methoxyphenyl)propan-2-one (5i)


1H NMR (400 MHz, CDCl3) δ 8.01 – 7.98 (m, 2H), 7.31 – 7.25 (m, 3H), 6.84 – 6.80 (m,

2H), 6.76 (t, J = 2.1 Hz, 1H), 5.12 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 2.25 (s,

3H), 1.37 (t, J = 7.1 Hz, 3H)

13C NMR (101 MHz, CDCl3) δ 205.6, 166.3, 160.0, 143.2, 139.0, 130.0, 129.9, 129.0, 121.3,

115.0, 112.8, 64.8, 61.0, 55.3, 30.1, 14.3.

IR (ATR): 3060, 2980, 2961, 2937, 2837, 1714, 1600, 1584, 1488, 1465, 1436, 1417, 1367, 1275, 1181, 1157, 1105, 1049,

1022, 775, 752, 707 cm−1.


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1-(3-Chlorophenyl)-1-phenylacetone (5j)


1H NMR (400 MHz, CDCl3) δ 7.42 – 7.35 (m, 2H), 7.35 – 7.29 (m, 1H), 7.26 (m, 2H), 7.23 (m, 2H),

7.12 (dt, J = 6.6, 2.1 Hz, 1H), 5.10 (s, 1H), 2.27 (s, 3H).

13C NMR (151 MHz, CDCl3) δ 205.8, 140.5, 137.7, 134.6, 130.0, 129.3, 129.1, 129.06, 127.8, 127.6,

127.3, 64.7, 30.3.

IR (ATR): 3062, 3027, 2923, 1714, 1534, 1152, 1080, 778, 732, 698, 587 cm−1.

HRMS (ESI-TOF) m / z calcd for C15H13OClNa [M + Na]+: 267.0547, found: 267.0544

1,1-Diphenylacetone (5k, CAS No. 781-35-1)


reported values.11

1H NMR (400 MHz, CDCl3) δ 7.35 – 7.30 (m, 6H), 7.28 – 7.22 (m, 4H), 5.11 (s, 1H), 2.24 (s, 3H).

1-(4-Methylphenyl)-1-phenylacetone (5m, CAS No. 35730-02-0)


reported values.12

1H NMR (400 MHz, CDCl3) δ 7.33 (m, 3H), 7.22 (dd, J = 6.9, 1.6 Hz, 2H), 7.14 (m, 4H), 5.09 (s, 1H),

2.33 (s, 3H), 2.25 (s, 3H).

1-Phenyl-1-(2-naphthyl)acetone (5m, CAS No. 116672-41-4)


reported values.13

1H NMR (400 MHz, CDCl3) δ 7.81 (m, 3H), 7.68 (s, 1H), 7.51 – 7.45 (m, 2H), 7.36 (m, 3H), 7.32 –

7.27 (m, 3H), 5.30 (s, 1H), 2.31 (s, 3H).

11 S. Nagasawa, Y. Sasano, Y. Iwabuchi, Angew. Chem. 2016, 128, 13383; Angew. Chem. Int. Ed. 2016, 55, 13189. 12 A. R. Katritzky, D. Toader, L. Xie, J. Org. Chem. 1996, 61, 7571. 13 Z. Hou, K. Takamine, O. Aoki, H. Shiraishi, Y. Fujiwara, H. Taniguchi, J. Org. Chem. 1988, 53, 6077.

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Preparation of BRL-15572 analog (Eq 1)

Steps 1 and 2: To a stirred solution of ketone 5a (9.3 mg, 38 µmol) and Et3N (55 µL, 0.39 mmol) in DCM (1.0 mL),

was added TMSOTf (35 µL, 0.20 mmol) at 0 °C. The mixture was allowed to warm at room temperature. After 30 minutes,

water (5 mL) was added to the mixture, and the mixture was extracted with hexane (5 mL) for two times. The combined

organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The resulting colorless oil was

dissolved in a 1:1 mixture of THF and water (0.7 mL) and cooled in an ice–water bath. To the solution was added NBS

(6.4 mg, 36 µmol), and the reaction mixture was stirred for 30 min. Water (5 mL) was added to the reaction mixture, and

the resulting mixture was extracted with EtOAc (5 mL × 2). The combined organic layers were washed with brine (5 mL),

dried over Na2SO4 and evaporated. The resulting colorless oil, containing the title compound, was used in the next reaction.

Pure 3-bromo-1-(3-methoxyphenyl)-1-phenylpropan-2-one (52%, 2 steps) was obtained by preparative TLC (eluting with

5% EtOAc in hexanes) as a colorless oil.

3-Bromo-1-(3-methoxyphenyl)-1-phenylpropan-2-one

1H NMR (400 MHz, CDCl3) δ 7.37 – 7.21 (m, 5H), 6.85 – 6.81 (m, 2H), 5.51 (s, 1H), 6.78 (t, J =

2.0 Hz, 1H), 4.00 (d, J = 12.2 Hz, 1H), 3.96 (d, J = 12.2 Hz, 1H), 3.78 (s, 3H).

13C NMR (101 MHz, CDCl3) δ 199.5, 160.0, 138.7, 137.2, 129.9, 128.94, 128.86, 128.8, 128.5,

127.7, 121.30, 115.0, 122.9, 60.8. 55.2, 34.0.

IR (ATR): 3061, 3027, 3003, 2924, 2850, 2836, 1719, 1597, 1583, 1488, 1261, 1145, 1043 cm−1.

HRMS (CI-TOF) m / z calcd for C16H15BrO2Na [M]+: 318.0255, found: 318.0269.

Step 3: To a stirred solution of the 3-bromo-1-(3-methoxyphenyl)-1-phenylpropan-2-one in DCM (0.7 mL), was added

Et3N (40 µL, 0.30 mmol) and 1-(3-chlorophenyl)piperazine (7.2 mg, 37 µmol) at 0 °C. The mixture was allowed to warm

at rt. After 2 hours, water (5 mL) was added to the solution, and the mixture was extracted with DCM (5 mL × 2 times).

The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated

in vacuo. The residue was purified by preparative TLC (eluting with 25% EtOAc in hexanes) to give the compound (3-(4-

(3-chlorophenyl)piperazin-1-yl)-1-(3-methoxyphenyl)-1-phenylpropan-2-one, 78% isolated yield) as a colorless oil.

3-(4-(3-Chlorophenyl)piperazin-1-yl)-1-(3-methoxyphenyl)-1-phenylpropan-2-one

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1H NMR (400 MHz, CDCl3) δ 7.34 – 7.22 (m, 6H), 7.15 (t, J = 8.1, 1H), 7.87 – 7.79

(m, 5H), 6.76 (ddd, J = 8.4, 2.3, 0.5 Hz, 1H), 5.37 (s, 1H), 3.20 (t, J =5.0 Hz, 4H), 2.59

(t, J =5.0 Hz, 4H).

13C NMR (101 MHz, CDCl3) δ 206.0, 159.8, 152.2, 139.6, 138.0, 135.0, 130.0, 129.7,

128.9, 128.7, 127.3, 121.3, 119.4, 115.8, 114.9, 113.9, 112.5, 67.3, 60.8, 55.2, 53.1, 48.6.

IR (ATR): 2925, 2833, 1720, 1593, 1486, 1451, 1260, 1235, 1142, 1050, 945 cm−1.

HRMS (ESI-TOF) m / z calcd for C26H27ClN2O2Na [M + Na]+: 457.1659, found: 457.1667.

Step 4: To a stirred solution of 3-(4-(3-chlorophenyl)piperazin-1-yl)-1-(3-methoxyphenyl)-1-phenylpropan-2-one

(4.6 mg, 11 µmol) in THF (0.3 mL) was added a BH3･THF solution (0.1 M in THF, 120 µL, 120 µmol) at 0 oC. After 1

hour, water (2 mL) was added, and volatile materials were removed by evaporation. The residue was extracted with EtOAc

(2 mL × 3), and the combined organic layer was washed with brine (2 mL), dried over Na2SO4 and concentrated. The

residue was purified by preparative TLC (eluting with 25% EtOAc in hexanes) to give the BRL-15572 analog (3-(4-(3-

chlorophenyl)piperazin-1-yl)-1-(3-methoxyphenyl)-1-phenylpropan-2-ol, 25% isolated yield) as a colorless oil and 1:1

diastereomeric mixture.

3-(4-(3-chlorophenyl)piperazin-1-yl)-1-(3-methoxyphenyl)-1-phenylpropan-2-ol

1H NMR (400 MHz, CDCl3) δ 7.46 – 7.45 (m, 2H), 7.38 – 7.34 (m, 6H), 7.29 – 7.24

(m, 4H), 7.20 (t, J = 16.0, 2H), 7.05 (d, J = 7.4 Hz, 1H), 7.02 (t, 1.8 Hz, 1H), 6.95 (d, J

= 7.7), 6.91 – 6.90 (m, 3H), 6.86 – 6.84 (m, 2H), 6.82 – 6.79 (m, J = 2 Hz, 4H), 4.55 –

4.50 (m, 2H), 3.89 – 3.83 (m, 2H), 3.83 (s, 6H), 3.41– 3.18 (m, 8H), 2.86 – 2.81 (m,

4H), 2.57 – 2.53 (m, 4H), 2.46 – 2.34 (m, 4H).

13C NMR (101 MHz, CDCl3) δ 159.7, 159.6, 152.2, 143.5, 143.4, 141.7, 141.6, 134.9, 130.0, 129.6, 129.4, 128.7, 128.5,

128.3, 126.7, 126.6, 121.1, 120.7, 119.4, 115.8, 115.1, 114.7, 113.9, 111.49, 111.3, 68.4, 68.3, 62.60, 62.58, 56.72, 56.71,

55.17, 55.15, 52.9, 48.8.

IR (ATR): 3358, 2922, 2853, 1705, 1660, 1596, 1488, 1455, 1259 cm−1.

HRMS (ESI-TOF) m / z calcd for C26H29ClN2O2Na [M + Na]+: 459.1815, found: 459.1810.

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3 NMR spectra for new compounds

(4c)

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(4e)

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(4f)

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(4g)

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(2h)

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(4p)

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(5a)

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(5b)

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(5c)

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(5d)

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(5e)

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(5f)

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(5g)

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(5h)

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(5i)

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(5j)

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(5k)

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