15 04 09 Heirtzler Research Summary Reactions

15 04 03 Heirtzler Research Summary Reactions.doc

Dr. Fenton Ransom Heirtzler 1034 Colorado Avenue, Apt. 1-D Palo Alto, California 94303

Phone (cell): 1 (301) 312-5145 E-mail: [email protected] Skype: fentonheirtzler www.linkedin.com/in/fentonhorgchem/

Reaction List and Schemes

Reaction list Condensation: Claisen, Wittig, Wittig-Horner-Emmons,

Coupling/alkylation: Suzuki, Stille, Glaser, DCC, EDCI, McMurry, Grignard, Wittig, phosphonium salt coupling

Cyclization/condensation synthesis: Formation of pyridines, pyrimidines and pyrazines from aldehydes, ketones and alpha-diketones

Elimination: CDI, TsOH, ClC(O)NCO, P(O)Cl3

Aromatic substitution reactions Friedel-Crafts acylation, Friedel-Crafts alkylation, Vilsmeijer, nucleophillic aromatic substitution, Sandmeyer, Smiles

Halogenation: PBr3, PCl3, POCl3, Br2, I2/NaNO3/HCl

Oxidation: Swern, I2, O2, H2O2, t-BuO2H, Br2/KOH, Chloramin-T, m-CPBA, MnO2, SeO2

Protection: t-Boc, CBZ, AcCl, ClCH2-C6H4-OCH3, dioxolane formation, ClSi(t-Bu)Me2,

Reduction: LiAlH4, BH3, Pd/C-H2, BaSO4/C-H2, Na, Zn, Hg(Al), Hg(Na), DIBAL-H, Red-Al, NaBH4

Esterification MeOH/H2SO4 or p-TsOH

15 04 03 Heirtzler Research Summary Reactions.doc of 12

Reaction schemes

NMeO2C CO2Me N CO2MeHO

a) MeOH, H2SO4, !b) NaBH4, MeOH/CH2Cl2

a) Me2SO, Et3N, CH2Cl2 , (ClC(O))2 , -70 °Cb) HOCH2CH2 , H2SO4 , PhH, !

N CO2MeO

O

N CO2MeO

ON CO2HO

O

NaOH,

H2O/MeOH

H2NOH

Cl OMe

Me

O

O N Me , CH2Cl2

NO

O

HN

OHO

a) Ph3P, CCl4 , CH2Cl2b) NaOH, !, H2O/p-dioxane NO

O N

O

N CO2MeHO

a) ClSi(t-Bu)Me2, pyridine, CH2Cl2b) NaOH, H2O/MeOH

N CO2HMe2(t-Bu)SiO

H2NOH

Cl OMe

Me

O

O N Me , CH2Cl2

NHN

OHO

a) Ph3P, CCl4 , CH2Cl2b) NaOH, !, H2O/p-dioxane

Me2(t-Bu)SiOin-situ deprotection!

NN

OHO


NMeN CO2R3R1 NR1

ON

6+

Base

R2

Yield

R2

R1 R2 R3

N

N N

4a

4bNMeO2C

4cH

H

H

H

6-Me

5-Me

6-Me

N

Me

Me

Me

Et

Me

Me

Me

(i)

(i)

(i)

(i)(ii)

(ii)

(ii)

5a (46%)

5b (78%)

5c (92%)

5d (40%)5e (oil, 39%)

5f (oil, 71%)

5g (28%)

4a-c-80 to 25° C

*

5a-g

4a

4a

4c

2 LDA/Et2O (i) or 1 n-BuLi + 1 LTMP/DME (ii)

a) 1 eq. m-CPBA, CH2Cl2/aq. NaHCO3b) 1 eq. I2, CH2Cl2

NR1

O

yield

N R2

R1

O

O

N R2

NN

O

2c (39%)

N

R1 R2

N5a

NMeO2C

H

H

H

H

6-Me

5-Me

6-Me

N

2a (57%)

2b (40%)

2d (36%)

2e (63%)

2f (32%)

2g (35%)

5b

5c

5d

5e

5f

5g

N

N

NN


R1

O

O

N R2N

N

N NN R1

R2

yield

1c (44%)

R1 R2

N2a

NMeO2C

H

H

H

H

6-Me

5-Me

6-Me

N

1a (71%)

1b (48%)

1d (30%)

1e (31%)

1f (21%)

1g (67%)

2b

2c

2d

2e

2f

2g

N

N

NN

NN

O

O

a. H2NCH2CH2NH2, EtOH, !b. Chloranil, xylenes, !

N

N

N

NCHO

N O

O

Br

N N

O

O

N N

OH

OHNN

N

NBpy Bpy

BpyBpy

NN

N NN

N

N

N Bpy

Bpy

2 31

4 8

5 67

i ii

iii

iv

vvi

vii

Reagents and conditions: (i) SeO2, H2O, dioxane, reflux, 30 h, 46%; (ii) nBuLi, ethyl 2-pyridyl sulfoxide, THF/Et2O/hexanes, -70°C, 28%; (iii) NaCN, EtOH/H2O, reflux, 2 h, 91%; (iv) I2, CH2Cl2, 25°C, 3 h, 53%; (v) 1,2-diaminoethane, EtOH, reflux, 90 min, then chloranil, xylene, reflux, 16 h, 64%; (vi) ortho-phenylenediamine, EtOH, reflux, 1 h, 67%; (vii) NH4OAc, 180°C, 2 h, 30%.


N BrO ON Br

O

p-TsOH,HO OH

PhH, !, 81%

4 5

N S(O)EtN SH

a. EtI, NaOH/H2O, ambient temp.b. 0.5 MMPP*/MeOH, 0 °C

67% over 2 steps

6

1.2 eq. n-BuLi, -70 °C

hexanes/Et2ON Li

O O

67%

NNO

2

a. 6b. 2 M HCl, 60 °C

NO

8a: R1 = Me; R2 = H (37%)8b: R1 = Et; R2 = H (76%)8c: R1 = H; R2 = Me (8c:7c = 2:3, not isolated)N Br

R1

R2 R2

R1a. 1 eq. n-BuLi, -70 to -78°Cb. 1.0 eq.DMA*

hexanes/Et2O

7a-c 8a-c

N CN

t-Bu

NO

t-Bu2.6 eq. MeMgI,-15 ° C, Et2O

(45%)

8d9


NO

R2

R1

8a, c

2 KO-t-Bu, 1 CS2, 2 EtITHF, 0 °C to ambient N

OR2

R1

9a, c

SEt

SEt

N NO

2(69%)

9a: R1 = Me; R2 = H (81%)9c: R1 = H; R2 = Me (11% from 7c)

-"--"- N NO

SEt

SEt9j

NO

NMe2

10a

2 - 3 eq. HC(OMe)2NMe2neat, !

NO

R2

R1

8a

R1

R2(61%)

2(85%)

-"--"-N N

O

NMe2

10j

10a: R1 = Me; R2 = H


N NO

2

1a: R1 = Me; R2 = H; R3 = SEt (31%)1c: R1 = H; R2 = Me; R3 = SEt (46%)1e: R1 = H; R2 = H; R3 = SMe (39%)

a. 2 KO-t-Bu, THF, 0 °C to ambientb. 5 eq. NH4Cl, AcOH, !

NO

R2

R1

9a, c, e

R3

R3

NNNN

R3

R1

R2

NNNN

R3

R1

R2

1b: R1 = Et; R2 = H; R3 = SEt (60%)1d: R1 = t-Bu; R2 = H; R3 = SEt (33%)

N NO

SEt

SEt9j

+-"--"-

NO

R2

R1

8b, d

N NO

NMe2

10j

NO

Me

8f

NO

NMe2

10a

t-Bu

N NO

2

NNNN

Me

+

+

a. 2 KO-t-Bu, THF, 0 °C to ambientb. 5 eq. NH4Cl, AcOH, !

(9.3%)

-"--"-NNNN

t-Bu

1f

1g

(22%)

NN

NN

X

Me

c

bF2, X = SEt

F6, X = SO2Et

F7, X = CN


Reagents and conditions - a: AICl3, AcCI, CH2Cl2, -70 to 25°C; b: Br2, KOH, dioxane; c: LiAIH4, THF/!T ; d: MnO2, CH2CI2; e: TiCl4, Zn, pyridine, THF/!T.

CH3

O

RCO2H RCH2OH RCHO

a b

c d eR R

R = 4-[2.2.2]paracyclophanyl

Step "a" performed on100 g scale (the starting material was a gift fromindustry)

a bCH2OH

5

Reagents and conditions - a: PBr3, CH2Cl2/-15 °C; b: PPh3, PhMe/!T; c: (EtO)2P(O)CH2CN, NaH, THF/!T; d: DIBAH, hexane/THF; e: PCl3, PCl5, PhH; f: LDA, THF; g: n-BuLi, (CH2O)3, THF/!T; h: Pd, CaCO3/3%, PbII acetate, quinoline, H2, EtOH/EtOAc; i: MnO2,CH2Cl2; j: I2, PhH/!T; k: LiOEt, EtOH-CH2Cl2.

CH2Br

7

RCH2Ph3+Br-

CHO

6

R CN

8

cR CHO

10a9

d

CH3

O

3

R CH2

ClR CH

e f

11 12

R

13

CH2OHg h

R CH2OH R CHO 10a

10b14b

i j

8 + 10ak

R R

2b



CH3

O

3

TiCl4, Zn(0), Pyridine

THF/!TR R R R


+

20a 20b

a

13

CH2OH

R14a

bCH2OH R15

CH2Br c

16R CH2PPh3

+ Br-

Reagents and conditions - a: Na+ H2AI(OCH2CH2OCH3)2- , Et2O/!T; b: PBr3 -, CH2Cl2/ -15 °C; c: PPh3,

PhMe/!T; d: LiOEt,EtOH/CH2CI2.

CHO

6

16 + R R

2b

d


Reagents and conditions - a: i. n-BuLi, THF/-70 to -40 °C; ii. LiAlH4, EtOH, THF/0 °C; iii. H3O+; b: 8, LiOEt, EtOH/CH2CI2; c: TiCI4, Zn, pyridine,THF/!T

aCHO

6

R CHO

RCH2Ph3+Br-

8

R CHO

10a

17

17 +b

cR R

2c

OCH3HC

+


CH

CuCl2, O2

Py

NH

O

OO2N

Zn(0), 2 M NaOH

70-80° C, 3 d

O

O

H2N

7 8

1.1 NaNO2, HCl, 10 KI

H2O, 3 h

7 2: 60%

O

I

O2

1.1 to 2.0 eq. DIBAH

PhMe-Et2O, -44 °C

I CHO

19

OH

OI OH

H

I

CHO

OH

19

I

18c: X = H

X

CH2OH

+ Ph Ph3P Br(a) or (b)

2 Eq'n. 3

(a) 2 H3CS(O)CH2 Na , DMSO/THF; (b) 2 iPr2N Li , THF

PhI

cis/trans-18b

I2, hydroquinone

(trace)

PhH/!, 3 d

I

PhH

OSitBuMe2

H

trans-18b

I

PhH

OH

H

trans-18c

OSitBuMe2 H3O


IX

CH2OCH3

31 + 1.1

1.3 iPr2N Li , THF

THF, 0 to 25 °CPh Ph3P Br

30I CH2OCH3

CHO31

Et3N, Me2S(O), [C(O)Cl]2

CH2Cl2, -70 °C

PhI

18c

CH2OH

a. DIMSYL,b. Me2SO4

DMSYL/THF/!18d

18d

BH3•THF I CH2OCH3

CH2OH29

30

THF

O2N CO2H

Cl32

O2N CO2CH3

Cl33

O2N CH2OH

Cl34

HCl

MeOH

BH3•THF

THF

(a)

(a) or (b)

(b)O2N CO2CH3

N(CH3)235

O2N CO2CH3

Ph

X

36a

O2N CH2OH

Ph36b

+ 34

15 04 09 Heirtzler Research Summary Reactions

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