S1

Lithium Diisopropylamide-Mediated Ortholithiations:

Lithium Chloride Catalysis

Lekha Gupta, Alexander C. Hoepker, Kanwal Jit Singh and David B. Collum*

Contribution from the Department of Chemistry and Chemical Biology

Baker Laboratory, Cornell University

Ithaca, New York 14853-1301

Supporting Information

Page

Experimental

I Measurement of chloride concentration using potentiometry and ion- S6 chromatography

IR Rate Studies

I Representative in situ IR spectroscopic analysis of an ortholithiation S7

II Plot of IR absorbances versus time for the ortholithiation of S8 1,3-difluorobenzene

F

F

LDA/THF

-78 oC

F

F

Li

III Plot of IR absorbances versus time for the ortholithiation of S9 3-fluorophenyl-N,N-diisopropylcarbamate

F

O

O

N(i-Pr)2

F

O

O

N(i-Pr)2

LiLDA/THF

-78 oC

IV Plot of IR absorbances versus time for the ortholithiation of S10 1,3-bis(N,N-diisopropylcarbamoyl)benzene

O

O

O

N(i-Pr)2

O

O

O

N(i-Pr)2

LiLDA/THF

-78 oC

N(i-Pr)2

O

N(i-Pr)2

O

S2

V Plot of IR absorbances versus time for the ortholithiation of S11 3-fluoroanisole

OMe

F

LDA/THF-78 oC

OMe

F

Li

VI Plot of IR absorbances versus time for the ortholithiation of S12 1-chloro-3-fluorobenzene

Cl

F

LDA/THF-78 oC

Cl

F

Li

VII Plot of IR absorbances versus time for the ortholithiation of S12 2,6-difluoropyridine

N

F

F

N

F

F

Li

LDA/THF

-78 oC

VIII Plot of IR absorbances versus time for the ortholithiation of S13 2-(3-fluorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole

F F

LDA/THF

-78 oC

O

N

O

N

Li

Me

Me

Me

Me

IX Plot of IR absorbances versus time for the ortholithiation of S14 3-methoxymethoxyphenyl-N,N-diisopropylcarbamate

OCH2OCH3

O

O

N(i-Pr)2

OCH2OCH3

O

O

N(i-Pr)2

LiLDA/THF

-78 oC

X Plot of IR absorbances versus time for the ortholithiation of S15 2-fluoropyridine

N

F

LDA/THF

-78 oCN

FLi

S3

XI Plot of IR absorbances versus time for the ortholithiation of S16 1,4-difluorobenzene

F

LDA/THF

-78 oC

FLi

F F

XII Plot of IR absorbances versus time for the ortholithiation of S17 1,2-difluorobenzene

F

LDA/THF

-78 oC

FFF

Li

XIII Plot of IR absorbances versus time for the ortholithiation of S18 1,3-dichlorobenzene

Cl

LDA/THF

-78 oC

Cl

Cl Cl

Li

XIV Plot of IR absorbances versus time for the ortholithiation of S19 3-chlorobenzotrifluoride

CF3

LDA/THF

-78 oC

CF3

Cl Cl

Li

XV Plot of IR absorbances versus time for the ortholithiation of S20 3-methoxyphenyl-N,N-diethylcarbamate

OCH3

O

O

NEt2

OCH3

O

O

NEt2

LiLDA/THF

-78 oC

XVI Plot of IR absorbances versus time for the ortholithiation of S20 phenyl-N,N-dimethylcarbamate

O

O

NMe2

O

O

NMe2

LiLDA/THF

-78 oC

S4

XVII Plot of IR absorbances versus time for the ortholithiation of S21 2-phenyl-2-oxazoline

LDA/THF

-78 oC

O

N

O

N

Li

XVIII Plot of IR absorbances versus time for the ortholithiation of S22 1,3-bis(4’,4’-dimethyl-2’-oxazolinyl)benzene

LDA/THF

-78 oC

O

N

O

N

Li

Me

Me

Me

Me

N

O

N

OMe

Me

Me

Me

XIX Plot of IR absorbances versus time for the ortholithiation of S23 3-chloro-5-fluoroanisole

LDA/THF

-78 oCOMe

F

Cl

OMe

F

Cl

OMe

F

Cl

Li +

major minor

Li

XX Plot of 19F NMR peak integrations versus time for the ortholithiation S23 of 3-chloro-5-fluoroanisole

XXI Plot of IR absorbances versus time for the ortholithiation of S24 4-fluorophenyl-N,N-diisopropylcarbamate

O O

LiLDA/THF

-78 oC

N(i-Pr)2

O

N(i-Pr)2

O

F F

ON(i-Pr)2

O

F Li

+

major minor

XXII Plot of 19F NMR peak integrations versus time for the ortholithiation of S24 N,N-diisopropyl-4-fluorocarbamate

XXIII Plot of IR absorbances versus time for the ortholithiation of S25 1,4-difluorobenzene in the presence of different lithium salts

XXIV Plot of IR absorbances versus time for the ortholithiation of S26 1,4-difluorobenzene using different sources of LDA

S5

Note:

1) All reported LiCl mol percentages are with respect to [LDA]. 2) Rates corresponding to the plots from XV to XVIII were determined at

temperatures other than -78 ºC. 3) Be aware of frequent changes in the scale on x-axis.

S6

Experimental I. Measurement of chloride concentration: Potentiometry: The chloride concentration was determined potentiometrically by measuring the potential against a saturated potassium chloride solution. After calibrating with known concentrations of chloride, the concentration was calculated with the Nernst equation (E=E°-(RT/zF)log10Q, where Q=[Cl-]; RT/zF is determined via calibration and is ideally 59.1 mV). The potential was measured with a potentiostat of low impedence. Both reference and indicating electrodes are made of silver plated with silver chloride (Ag/AgCl). Samples were prepared by quenching 25 mg of LDA or 100 µl of 1.6 M n-BuLi with high-purity water (from Abruña group), evacuating to dryness and redissolving in water. Because the electrodes require a near neutral pH, the quenched base solutions needed to be neutralized with HNO3. The LiCl standards were accordingly enriched with NaNO3 to ensure comparable activity. Both HNO3 and NaNO3 contained <0.5 ppm and <0.0003% Cl-, respectively. The lower detection limit for Cl- is approximately 0.5 ppm.

Ion Chromatography: Ion chromatography was performed on a Dionex ICS-2000 system (Sunnyvale, CA) with a Dionex Ionpac AG18 guard column and a Dionex Ionpac AS18 separation column. Samples and standards were run in the isocratic mode (1.0 ml/min) using 38 mM KOH as eluent. Elution time of chloride varied from 3.94 to 4.23 min. The suppression was achieved by a Dionex ASRS ULTRA II 4 mm self-regenerating suppressor. The column temperature was 30 °C and the working electric current was 100 mA. The eluent flow rate is 1.0 ml/min. The injection volume is 25 µl. Samples were prepared by quenching 25 mg of LDA or 100 µl of 1.6 M n-BuLi with high-purity water (from Abruña group), evacuating to dryness and redissolving in water. Aqueous samples of pH 12-13 were injected in duplicate into the chromatograph. The lower detection limit is approximately 10 ppb.

S7

IR Rate Studies

F

LDA/THF

-78 oC

FLi

F F

I. Representative in situ IR spectroscopic analysis of the ortholithiation of 1,4-difluorobenzene (0.1 M) with LDA (0.12 M) in neat THF at -78 ºC: (A) no added LiCl; (B) 0.5 mol % LiCl. The IR absorbance at 1507 cm-1 corresponds to 1,4-difluorobenzene, whereas the absorbance at 1418 cm-1 corresponds to its lithiated form.

A.

B.

S8

F

F

LDA/THF

-78 oC

F

F

Li

II. Plot of IR absorbances (black – 1606 cm-1, red – 1406 cm-1) versus time for the ortholithiation of 1,3-difluorobenzene (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl; (C) 0.5 and 10 mol% LiCl.

C.

10 mol%

LiCl

A.

t1/2 ! 80 s

B.

t1/2 ! 40 s

S9

F

O

O

N(i-Pr)2

F

O

O

N(i-Pr)2

LiLDA/THF

-78 oC

III. Plot of IR absorbances (black – 1715 cm-1, red – 1657 cm-1) versus time for the ortholithiation of 3-fluorophenyl-N,N-diisopropylcarbamate (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl.

A.

t1/2 ! 170 s

B.

t1/2 ! 80 s

S10

O

O

O

N(i-Pr)2

O

O

O

N(i-Pr)2

LiLDA/THF

-78 oC

N(i-Pr)2

O

N(i-Pr)2

O

IV. Plot of IR absorbances (black – 1721 cm-1, red – 1661 cm-1) versus time for the ortholithiation of 1,3-bis(N,N-diisopropylcarbamoyl)benzene (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl; (C) 0.5 and 10 mol% LiCl.

A.

t1/2 ! 190 s

B.

t1/2 ! 90 s

C.

10 mol%

LiCl

S11

OMe

F

LDA/THF

-78 oC

OMe

F

Li

V. Plot of IR absorbances (black – 1617 cm-1, red – 1412 cm-1) versus time for the ortholithiation of 3-fluoroanisole (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl (C) 0.5 and 10 mol% LiCl.

C.

10 mol%

LiCl

t1/2 ! 240 s

A.

t1/2 ! 50 s

B.

S12

Cl

F

LDA/THF

-78 oC

Cl

F

Li

VI. Plot of IR absorbances (black – 1595 cm-1, red – 1397 cm-1) versus time for the ortholithiation of 1-chloro-3-fluorobenzene (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl.

N

F

F

N

F

F

Li

LDA/THF

-78 oC

VII. Plot of IR absorbances (black – 1610 cm-1, red – 1514 cm-1) versus time for the ortholithiation of 2,6-difluoropyridine (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl.

B. A.

t1/2 ! 450 s t1/2 ! 50 s

A.

t1/2 ! 1950 s

B.

t1/2 ! 170 s

S13

F F

LDA/THF

-78 oC

O

N

O

N

Li

Me

Me

Me

Me

VIII. Plot of IR absorbances (black – 1653 cm-1, red – 1622 cm-1) versus time for the ortholithiation of 2-(3-fluorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole

(0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl.

A.

t1/2 ! 2850 s s

B.

t1/2 ! 285 s

S14

OCH2OCH3

O

O

N(i-Pr)2

OCH2OCH3

O

O

N(i-Pr)2

LiLDA/THF

-78 oC

IX. Plot of IR absorbances (black – 1719 cm-1, red – 1659 cm-1) versus time for the ortholithiation of 3-methoxymethoxyphenyl-N,N-diisopropylcarbamate (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl; (C) 0.5 and 10 mol% LiCl.

C.

10 mol%

LiCl

A.

t1/2 ! 2900 s

B.

t1/2 ! 1450 s

S15

N

F

LDA/THF

-78 oCN

FLi

X. Plot of IR absorbances (black – 1597 cm-1) versus time for the ortholithiation of 2-fluoropyridine (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl.

t1/2 ! 80 s

B.

t1/2 ! 3600 s

A.

S16

F

LDA/THF

-78 oC

FLi

F F

XI. Plot of IR absorbances (black – 1507 cm-1, red – 1418 cm-1) versus time for the ortholithiation of 1,4-difluorobenzene (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl; (C) 0.5 and 10 mol% LiCl.

A.

C.

10 mol%

LiCl

t1/2 ! 4300 s s ss s

B.

t1/2 ! 70 s

S17

F

LDA/THF

-78 oC

FFF

Li

XII. Plot of IR absorbances (black – 1509 cm-1, red – 1391 cm-1) versus time for the ortholithiation of 1,2-difluorobenzene (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl; (C) 0.5 and 10 mol% LiCl.

C.

10 mol%

LiCl

A.

t1/2 ! 5600 s

B.

t1/2 ! 100 s

S18

Cl

LDA/THF

-78 oC

Cl

Cl Cl

Li

XIII. Plot of IR absorbances (black – 1576 cm-1, red – 1534 cm-1) versus time for the ortholithiation of 1,3-dichlorobenzene (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl.

A.

t1/2 ! 7900 s

B.

t1/2 ! 145 s

S19

CF3

LDA/THF

-78 oC

CF3

Cl Cl

Li

XIV. Plot of IR absorbances (black – 1326 cm-1, red – 1306 cm-1) versus time for the ortholithiation of 3-chlorobenzotrifluoride (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no added LiCl; (B) 0.5 mol% LiCl; (C) 0.5 and 50 mol% LiCl.

C.

50 mol%

LiCl

A.

t1/2 ! 104 s

B.

t1/2 ! 103 s

S20

OCH3

O

O

NEt2

OCH3

O

O

NEt2

LiLDA/THF

-65 oC

XV. Plot of IR absorbances (black – 1725 cm-1, red – 1675 cm-1) versus time for the ortholithiation of 3-methoxyphenyl-N,N-diethylcarbamate (0.10 M) with LDA (0.12 M) in neat THF at -65 °C: (A) no added LiCl; (B) 0.5 mol% LiCl.

O

O

NMe2

O

O

NMe2

LiLDA/THF

-30 oC

XVI. Plot of IR absorbances (black – 1725 cm-1, red – 1675 cm-1) versus time for the ortholithiation of phenyl-N,N-dimethylcarbamate (0.10 M) with LDA (0.12 M) in neat THF at -30 °C: (A) no added LiCl; (B) 0.5 mol% LiCl.

B. A.

B. A.

S21

LDA/THF

0oC

O

N

O

N

Li

XVII. Plot of IR absorbances (black – 1652 cm-1, red – 1526 cm-1) versus time for the ortholithiation of 2-phenyl-2-oxazoline (0.10 M) with LDA (0.12 M) in neat THF at 0 °C: (A) no added LiCl; (B) 0.5 mol% LiCl.

B. A.

S22

LDA/THF

21 oC

O

N

O

N

Li

Me

Me

Me

Me

N

O

N

OMe

Me

Me

Me

XVIII. Plot of IR absorbances (black – 1654 cm-1, red – 1520 cm-1) versus time for the ortholithiation of 1,3-bis(4’,4’-dimethyl-2’-oxazolinyl)benzene (0.10 M) with LDA (0.12 M) in neat THF at 21 °C: (A) no added LiCl; (B) 0.5 mol% LiCl.

A. B.

S23

LDA/THF

-78 oCOMe

F

Cl

OMe

F

Cl

OMe

F

Cl

Li +

major minor

Li

XIX. Plot of IR absorbances (black – 1611 cm-1, red – 1553 cm-1) versus time for the ortholithiation of 3-chloro-5-fluoroanisole (0.10 M) with LDA (0.12 M) in neat THF at -78 ºC: (A) no added LiCl; (B) 0.5 mol% LiCl.

XX. Plot of 19F NMR peak integrations (black: ! -110.1, red: ! -77.8, green: ! -76.6) versus time for the ortholithiation of 3-chloro-5-fluoroanisole (0.05 M) with LDA (0.20 M) in neat THF at -78 ºC: (A) no added LiCl; (B) 10 mol% LiCl.

B. A.

t1/2 ! 1000 s s

t1/2 ! 150 s

B. A.

S24

O O

LiLDA/THF

-78 oC

N(i-Pr)2

O

N(i-Pr)2

O

F F

ON(i-Pr)2

O

F Li

+

major minor

XXI. Plot of IR absorbances (black – 1717 cm-1, red – 1657 cm-1) versus time for the ortholithiation of 4-fluorophenyl-N,N-diisopropylcarbamate (0.025 M) with LDA (0.12 M) in neat THF at -78 ºC: (A) no added LiCl; (B) 0.5 mol% LiCl.

XXII. Plot of 19F NMR peak integrations (black: ! -118.8, red: ! -123.7, green: ! 85.5, yellow: ! -124.1) versus time for the ortholithiation of 4-fluorophenyl-N,N-diisopropylcarbamate (0.05 M) with LDA (0.20 M) in neat THF at -78 ºC: (A) no added LiCl; (B) 10 mol% LiCl.

B. A.

B. A.

t1/2 ! 840 s t1/2 ! 70 s

S25

XXIII. Plot of IR absorbances (black – 1507 cm-1, red – 1418 cm-1) versus time for the ortholithiation of 1,4-difluorobenzene (0.10 M) with LDA (0.12 M) in neat THF at -78 °C: (A) no additive; (B) 10 mol% LiCl; (C) 10 mol% LiBr; (D) 10 mol% PhCCLi; (E) 10 mol% PhCOOLi; (F) 10 mol% PhOLi.

t1/2 ! 4300 s s

A. B.

D.

E. F.

C.

t1/2 < 15 s

t1/2 ! 50 s t1/2 ! 50 s

t1/2 ! 135 s t1/2 ! 2000 s s

S26

XXIV. Plot of IR absorbances (black/red – duplicated rates) versus time for the ortholithiation of 1,4-difluorobenzene (0.10 M) with LDA (0.12 M) in 10.0 M THF/hexane at -78 °C using: (A) Acros n-BuLi – batch1; (B) Acros n-BuLi – batch2; (C) Aldrich n-BuLi – batch1; (D) Aldrich n-BuLi – batch2; (E) Acros LDA; (F) Aldrich LDA

A. B.

D.

E. F.

C.