selective functionalization of complex heterocycles via an ... · selective functionalization of...

S. B. Boga,* S. W. Krska, S. Dreher, E. Streckfuss, P. Vachal Department of Discovery Chemistry MRL, Merck & Co., Inc., Rahway, NJ USA E-mail: [email protected] M. Christensen,* N. Perrotto, M. T. Tudge, E. R. Ashley, M. Poirier, M. Reibarkh, Y.Liu, L.-C. Campeau, R. T. Ruck, I. W. Davies Department of Process Research & Development MRL, Merck & Co., Inc., Rahway, NJ USA E-mail: [email protected] † We thank Daniel A. DiRocco (Merck) for helpful discussions, Donald V. Conway(Merck) for engineering support and Natalya Pissarnitski (Merck) for purification ofsamples.. Electronic Supplementary Information (ESI) available: [details of anysupplementary information available should be included here]. SeeDOI: 10.1039/x0xx00000x

Selective Functionalization of Complex Heterocycles via an Automated Strong Base Screening Platform† Sobhana Babu Boga,* Melodie Christensen,* Nicholas Perrotto, Shane W. Krska, Spencer

Dreher, Matthew T. Tudge, Eric R. Ashley, Marc Poirier, Mikhail Reibarkh, Yong Liu, Eric

Streckfuss, Louis-Charles Campeau, Rebecca T. Ruck, Ian W. Davies, Petr Vachal

Abstract: Knochel-Hauser bases, derived from 2,2,6,6-tetramethylpiperidinyl (TMP) metal amides, offer exceptional selectivity and functional group tolerance in the regioselective metalation of arenes and heteroarenes. The selectivity, stability and yield of these reactions are highly dependent on the nature of the base, additive and deprotonation temperature. We have developed and validated an automated micro-scale high throughput experimentation (HTE) approach to rapidly optimize base and temperature matrices. We describe the application of this approach to the regioselective functionalization of a variety of complex heterocycles and extension to the preparation of organometallic reagents for transition metal catalyzed cross-coupling screens.

Electronic Supplementary Material (ESI) for Reaction Chemistry & Engineering.This journal is © The Royal Society of Chemistry 2017

Supporting Information

Table of Contents

Materials and Methods

General Procedure for Automated Screening Platform

Strong Base and Temperature Screen Results

General Procedure for Scale-up Reactions

Reaction Conditions and Characterization of Compounds

Library Studio Design & Chemspeed Protocol Details

NMR Spectra

Materials and Methods:

All automated high throughput experimentation studies were carried out on a Chemspeed

SWING liquid handling robot equipped with a four needle head dispenser, V&P Scientific-

modified tumble stirrer and Huber Unistat 82T chiller. The robot deck was kept under a constant

sweep of 20 psi nitrogen. 96-well metal reaction blocks (Cat# 96960), 8 x 30 mm glass inserts

(Cat# 84001), core-resistant PFA films (Cat# 96967) and analysis plates (Cat# 17P687) were

purchased from Analytical Sales. The PFA film was held in place using a custom metal lid with

funneled needle-guiding holes (Figure 1). Agitation was achieved through the use of 1.98 x 4.80

mm tumble stir dowels (Cat# 711D-1), acquired from V&P Scientific. All glass vials and glass

inserts were dried in a vacuum oven. All solvents and were purchased from Sigma Aldrich as

anhydrous and used without further purification. TMPZnCl•LiCl (Cat# 797634), TMPMgCl•LiCl

(Cat# 703540), LDA (Cat# 774766), TMP2Zn (Cat# 697486), TMP2Zn•2MgCl2•2LiCl (Cat#

748188) and MeLi (Cat# 197343) solutions were purchased from Sigma Aldrich. BF3.Et2O (Cat#

216607) and I2 (Cat# 207772) were also purchased from Sigma-Aldrich. Glacial acetic acid was

purchased from Fisher Scientific.

All scale-up reactions were carried out under nitrogen atmosphere in a glovebox or using

standard Schlenk techniques. 1H and 13C NMR spectra were recorded on Varian 500 MHz

and Bruker 600 MHz spectrometers at ambient temperature. 1H chemical shifts are

referenced to residual d5-DMSO resonance (2.50 ppm). 13C chemical shifts are

referenced to the d6-DMSO resonance (39.52 ppm). Data is reported as follows:

chemical shift in parts per million (δ, ppm), multiplicity (s = singlet, bs = broad singlet, d

= doublet, t = triplet, q = quartet, m = multiplet and om = overlapped multiplet), coupling

constants (Hz). HRMS data was obtained on Waters QTOF Premier (Waters, Milford, MA)

mass spectrometer. Reactions were monitored using a Waters Acquity UPLC-MS. Crude

reactions were purified using a Waters Auto Purification HPLC/MS system (2545 Binary

Gradient Flow System, 2767 Sample Manager, Waters SQD2 mass spectrometer detector,

2998 Photodiode Array UV Detector equipped with a Waters Sunfire Prep C18 OBD 5 μm

30x250mm column. The mobile phase was Water + .1% TFA / Acetonitrile + .1 %TFA.

Gradients from Water to Acetonitrile were developed to provide sufficient resolution of the

product peaks.

General Procedure for Automated Screening Platform:

A PFA sealed 96-well metal block with glass vial inserts was cooled to -45 °C under nitrogen

atmosphere with 300 rpm agitation. To the first row of each quadrant was dispensed a different

heterocycle in tetrahydrofuran (20 μmol, 0.20 M, 100 μl). If applicable, a solution of MeLi in

diethyl ether was dosed to these rows after 5 min equilibration (20 umol, 1.6 M, 13 ul). Upon 5

min hold, a solution of BF3.Et2O in toluene was dispensed to applicable wells (30 μmol, 1.5 M,

20 μl). Upon 20 min hold, six strong base solutions were dispensed across the first row of each

quadrant. The plate was aged for 3 h and a solution of iodine in tetrahydrofuran was dispensed

across the first row of each quadrant (30 μmol, 0.50 M, 60 μl). The plate was aged for 10

minutes and the first row of each quadrant was quenched with a solution of acetic acid in a

three to one mixture of acetonitrile to dimethyl sulfoxide (528 μmol, 0.88 M, 600 μl). These

dispense steps were then repeated sequentially at -20, 0 and 25 °C in the second, third and

fourth rows of each quadrant. Once the screen was completed, 28 μl from the reaction plate

was transferred to a collection plate containing 700 μl of acetonitrile. See Figure 2 for a picture

of the screen setup on the Chemspeed deck. See S5 through S8 for the Library Studio design,

S9 for the Chemspeed portocol and pages S10 through S11 for the Chemspeed log file of the

validation screen.

Figure 1. Design and specification of custom metal lid with needle-guiding holes

Figure 2. High throughput experimentation screen setup on Chemspeed robot deck

Six base solutions

Acetic acid quench

solutions Iodine

Analysis plate

Reaction block

Four heterocycle

solutions

BF3.Et2O solution

Tumble stirrer with chiller connection

Strong Base and Temperature Screen Results:

General Procedure for Scale-up Reactions:

To a dry and nitrogen flushed 1 dram (4 ml) vial equipped with a pressure release septa and

magnetic stir bar was charged with the aromatic substrate (0.34 mmol) and dry THF (2 mL).

The solution was then degassed by nitrogen sparging for 2-3 min. The reaction mixture was

cooled to the appropriate temperature before base (0.56 mmol) was added dropwise and stirred

for 3-16 h. Upon completion of the reaction (deprotonation), iodine (0.51 mmol) in THF (0.2 mL)

was added slowly and the mixture was allowed to slowly warm up to 25 °C. After stirring at

ambient temperature for 15 min, added aq. sat. NH4Cl solution (4 mL) and extracted with EtOAc

(3X10 mL). The organic solvents were dried with Na2SO4 and removed in vacuo. The crude

mixture was purified directly by Waters Auto Purification HPLC/MS system. Evaporation of the

fractions by genevac or lyophilization resulted in isolation of the desired products as TFA salts.

Reaction Conditions and Characterization of Compounds:

2-iodo-4H-chromen-4-one (2a)[7]

According to General procedure with Conditions: TMP2Zn•2MgCl2•2LiCl, – 45 °C, 3 h

1H NMR (500 MHz, DMSO-d6) δ 8.01 (d, J = 7.9 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.65 (d, J =

8.4 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 6.95 (s, 1H).

HRMS (M+H) calc’d for C9H5IO2 272.9407, found 272.9419

3-iodo-4H-chromen-4-one (3a)[7]

According to General procedure with Conditions: TMPZnCl•LiCl, 0 °C, 3 h or TMP2Zn 25 °C, 3 h

1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H),

7.65 (d, J = 8.5 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H).

HRMS (M+H) calc’d for C9H5IO2 272.9407, found 272.9411

3-iodo-2H-chromen-2-one (2b)

According to General procedure with Conditions: TMP2Zn•2MgCl2•2LiCl, 25 °C, 3 h

1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.71 – 7.58 (om, 2H), 7.42 – 7.31 (om, 2H). 13C NMR (126 MHz, DMSO-d6) δ 157.71, 153.79, 152.86, 132.74, 127.92, 125.17, 120.54,

116.66, 87.63. HRMS (M+H) calc’d for C9H5IO2 272.9407, found 272.9411

5-iodo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (2c)

According to General procedure with Conditions: TMP2Zn•2MgCl2•2LiCl, 25 °C, 3 h

1H NMR (500 MHz, DMSO-d6) δ 8.26 (s, 1H), 3.30 (s, 3H), 3.21 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 160.89, 151.65, 149.49, 66.68, 36.97, 29.29.

HRMS (M+H) calc’d for C6H7IN2O2 266.9625, found 266.9624

6-iodo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (3c)

According to General procedure with Conditions: TMP2Zn•2MgCl2•2LiCl, – 45 °C, 3 h

1H NMR (500 MHz, DMSO-d6) δ 6.43 (s, 1H), 3.54 (s, 3H), 3.12 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 161.38, 150.00, 117.06, 112.96, 41.73, 28.30.


6-iodo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2d)

According to General procedure with Conditions: TMPMgCl•LiCl, – 45 °C, 3 h

1H NMR (500 MHz, DMSO-d6) δ 8.53 (d, J = 2.5 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 7.94 (d, J =

8.1 Hz, 3H), 7.47 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 2.35 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 146.72, 143.38, 142.40, 142.21, 138.66, 134.99, 130.79,

127.82, 120.89, 88.95, 21.59.

HRMS (M+H) calc’d for C13H10IN3O2S 399.9594, found 399.9599

(5-iodoimidazo[1,2-a]pyrazin-3-yl)(phenyl)methanone (2e)

According to General procedure with Conditions: TMPMgCl•LiCl, – 45 °C, 16 h

1H NMR (500 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.03 (d, J = 7.6 Hz, 2H),

7.79 (t, J = 7.4 Hz, 1H), 7.65 (t, J = 7.6 Hz, 2H).

13C NMR (126 MHz, DMSO-d6) δ 182.68, 144.34, 142.83, 142.70, 142.68, 137.71, 134.64,

130.44, 129.61, 128.34, 87.84.

HRMS (M+H) calc’d for C13H8IN3O 349.9785, found 349.9796

(8-iodoimidazo[1,2-a]pyrazin-3-yl)(phenyl)methanone (3e)

According to General procedure with Conditions: TMPZnCl•LiCl, – 45 °C, 16 h

1H NMR (500 MHz, DMSO-d6) δ 9.41 (d, J = 4.5 Hz, 1H), 8.44 (s, 1H), 8.10 (d, J = 4.5 Hz, 1H),

7.93 (d, J = 7.5 Hz, 2H), 7.74 (t, J = 7.5 Hz, 1H), 7.63 (t, J = 7.6 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 185.39, 144.29, 142.90, 138.08, 133.51, 133.30, 129.50,

129.40, 125.55, 121.24, 115.40.

HRMS (M+H) calc’d for C13H8IN3O 349.9785, found 349.9783

methyl 4-(2-iodo-1H-imidazol-1-yl)benzoate (2f)

According to General procedure with Conditions: TMPZnCl•LiCl, – 20 °C, 16 h

1H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J = 8.0 Hz, 2H), 7.77 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H),

7.36 (s, 1H), 3.91 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 165.92, 141.52, 130.92, 130.84, 129.96, 127.55, 126.04,

94.32, 53.05.


(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(5-iodo-1H-1,2,4-triazol-1-

yl)butan-2-ol (2g)

To a dry and nitrogen flushed 1 dram (4 ml) vial equipped with a pressure release septa and

magnetic stir bar was charged (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-

1,2,4-triazol-1-yl)butan-2-ol; VoriconazoleR (50 mg, 0.143 mmol) and dry THF (2 mL). The

solution was then degassed by nitrogen sparging for 2-3 min. The reaction mixture was cooled

to 0 °C, MeLi (0.089 mL of 1.6 M in Diethyl ether, 0.143 mmol) was added dropwise and stirred

for 30 min. Bis(2,2,6,6-tetramethylpiperidin-1-yl)zinc (0.429 mL of 0.5 M in THF, 0.215 mmol)

was added dropwise and stirred for 16 h at 0 °C. Iodine (55mg, 0.215 mmol in 0.2 mL THF) was

added slowly and the mixture was allowed to slowly warm up to 25 °C. After stirring at ambient

temperature for 15 min, aq. sat. NH4Cl solution (4 mL) was added and extracted with EtOAc

(3X10 mL). The organic solvents were dried with Na2SO4 and removed in vacuo. The crude

mixture was purified directly by mass directed HPLC. Evaporation of the fractions by genevac

resulted in isolation of the desired products as TFA salts.

1H NMR (600 MHz, DMSO-d6) δ 9.06 (d, J = 2.5 Hz, 1H), 8.90 (d, J = 1.7 Hz, 1H), 7.69 (s, 1H),

7.38 (m, 1H), 7.18 (m, 1H), 6.99 (td, J = 8.6, 2.5 Hz, 1H), 6.38 (bs, 1H), 4.63 (d, J = 14.5 Hz,

1H), 4.25 (d, J = 14.5 Hz, 1H), 3.99 (q, J = 7.1 Hz, 1H), 1.05 (d, J = 7.1 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 162.45 (dd, J = 246.6, 12.7 Hz), 159.04 (dd, J = 246.7, 12.2

Hz), 158.26 (d, J = 12.3 Hz), 156.41 (d, J = 263.8 Hz), 154.00 (d, J = 7.7 Hz), 153.89, 146.03 (d,

J = 22.1 Hz), 130.91 (dd, J = 9.3, 5.9 Hz), 125.13 (dd, J = 12.1, 3.5 Hz), 111.59 (d, J = 20.2 Hz),

106.55, 104.50 (dd, J = 28.1, 26.0 Hz), 77.89 (d, J = 5.2 Hz), 56.34 (d, J = 4.7 Hz), 38.25 (d, J =

5.3 Hz), 14.89.

HRMS (M+H) calc’d for C16H13F3IN5O 476.0190, found 476.0201

2,6-dichloro-4-(2,4-difluorophenyl)pyridine (4h)

To a 0 °C solution of 2,6-dichloropyridine (1.00 g, 6.76 mmol) in 2-methyl-THF (10.00 ml) was

added lithium magnesium 2,2,6,6-tetramethylpiperidin-1-ide dichloride (1.0 M in THF/Toluene,

10.14 ml, 10.14 mmol) dropwise over 5 min. The mixture was aged at 0 °C for 4 h, then cooled

to −40 °C. A solution of zinc chloride (1.9 M in 2-methyl-THF, 5.33 ml, 10.14 mmol) was added

dropwise over 2 min. The solution was aged at −40 °C for 10 min, then allowed to warm to

ambient temperature. Separately, 2,4-difluoro-1-iodobenzene (1.946 g, 8.11 mmol) and tri-tButyl

phosphine G2 precatalyst (0.173 g, 0.338 mmol) were dissolved in 2-Methyl-THF (10.00 ml).

The solution was sparged with nitrogen for 10 min, then added to the ambient temperature

pyridyl zinc chloride solution. The mixture was aged for 18 h, then partitioned between ethyl

acetate (20 mL) and 1.0 M aqueous tartaric acid (40 mL). The aqueous was cut away, and the

organics were washed with 0.5 M aqueous citric acid (20 mL) followed by water (20 mL). The

organics were then dried over magnesium sulfate, filtered, concentrated, and purified by silica

gel chromatography (1:99 to 15:85 A:B, A=3:1 EtOAc:EtOH, B=hexanes followed by a second

column of 0:100 to 50:50 dichloromethane:Hexanes) to provide the title compound 4h (1.48 g,

5.68 mmol, 84% yield) as a white amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ 7.82 (m, 1H), 7.79 (s, 2H), 7.50 (m, 1H), 7.29 (td, J = 8.5, 2.5

Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 163.27 (dd, J = 251.2, 12.4 Hz), 159.41 (dd, J = 252.2, 12.4

Hz), 149.54, 148.00, 132.38 (d, J = 10.2, 3.7 Hz), 122.92 (d, J = 3.4 Hz), 119.82 (dd, J = 12.5,

3.9 Hz), 112.54 (dd, J = 21.4, 3.6 Hz), 104.94 (t, J = 26.3 Hz).

HRMS (M+H) calc’d for C11H5Cl2F2N 259.9840, found 259..9848

2,5-dichloro-4-(2,4-difluorophenyl)pyridine (4i)

A solution of 2,5-dichloropyridine (10.0 g, 67.6 mmol) in dry THF (50 ml) was added to lithium

diisopropylamide (freshly prepared, 140ml, 74.3mmole) at -60°C over 20 minutes. The resulting

suspension was stirred at -60°C for 20min. A solution of zinc chloride (1.9 M in 2-methyl-THF,

35.6 ml, 67.6 mmol) was slowly added. The solution was aged at −60 °C for 10 min, then

allowed to warm to ambient temperature. Seperately, 2,4-difluoro-1-iodobenzene (8.08 ml, 67.6

mmol) and XPhos Pd G2 (1.861 g, 2.365 mmol) were dissolved in THF (100 ml). The solution

was sparged with nitrogen for 10 min and the zincate solution was added at ambient

temperature. The mixture was aged for 24 h, then partitioned between ethyl acetate (150 mL)

and 10% aqueous citric acid (150 mL). The aqueous solution was extracted with ethyl acetate

and the combined solution was dried over magnesium sulfate. The product was purified by silica

gel chromatography (elution 5% MTBE/hexanes) to give the title compound 4i (13.6 g, 52.3

mmol, 77% yield) as a amorphous solid.

1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.76 (s, 1H), 7.60 (td, J = 8.5, 6.4 Hz, 1H), 7.50

(td, J = 9.9, 2.5 Hz, 1H), 7.30 (td, J = 8.5, 2.5 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 163.11 (dd, J = 249.1, 12.3 Hz), 158.75 (dd, J = 250.1, 12.7

Hz), 149.05, 148.69, 144.38, 132.47 (dd, J = 10.1, 3.8 Hz), 129.97, 126.49, 119.18 (dd, J =

15.4, 3.9 Hz), 112.12 (dd, J = 21.8, 3.6 Hz), 104.46 (t, J = 26.1 Hz).

HRMS (M+H) calc’d for C11H5Cl2F2N 259.9840, found 259.9849