Методы современного органического синтеза

Раздел 3. Методы окисления органических соединений и методы формирования С-С и C=C-связей

3.1. Методы окисления органических

O

соединений

14.

R

Ag2O / NH4OH

R

OH

CrO2 / H2SO4

H

1.

Me2CO, RT

O

R2

R3

OH >

OH

>

OH

>

CrO2

/ H2SO4

15.

R

Ar

R1

OH

2.

OH

Ag2CO3 / целит

R2

R1

Me2CO, RT

>

>

OH

Alk1

Alk2 Alk

3.

Ar-Me

CrO3

H2SO4

4.

Ar-OH

or

Ar-NH2

CrO3

H2SO4

5.

R1

CrO3

R2

H2SO4

R1, R2 = H or Alk or Ar or OAlk

6.

R

OH

PCC or PDC or CrO3 *2Py

DCM, RT

OH

KMnO4

7.

or Ar

Me

R

H2O or PhH (DCM) / 18-c-6 (TEBAC), T

OH

KMnO4

8.

or

Ar1

Ar2 H2O or PhH (DCM) / 18-c-6 (TEBAC), T

R1

R2

R1

R1

R2

KMnO4

9.

or

H2O

R2

or PhH (DCM) / 18-c-6 (TEBAC), RT

R1

R1

R2

KMnO4

10.

or

R2

H2O

R3

R4 or PhH (DCM) / 18-c-6 (TEBAC),

S

KMnO4

11.

R

H2O or PhH (DCM) / 18-c-6 (TEBAC)

R

1

2

R1, R2 =Alk or Ar

R2

R3

OH

12.

or

OH

MnO2

or

R1

Ar

ArHet

PhH,

OH

Rn

Rn

MnO

13.

Rn

or

or

NH

2

PhH,

N

N

H

H

16.R

17.R

18.

R1

HO

19.

R1

OH		RuO2 or RuCl3 (cat.)
			NaIO4 or NaClO
			or K2S2O8 (eq.)
			CCl4 / MecN / H2O
OH			RuO2 or RuCl3 (cat.)
			NaIO4 or NaClO
			or K2S2O8 (ex.)
			CCl4 / MecN / H2O
OH			RuO2 or RuCl3 (cat.)
			NaIO4 or NaClO
R2			or K2S2O8
			CCl4 / MecN / H2O
R			HO	R4		RuO2 or RuCl3 (cat.)
2
		or		R3
						NaIO4 or NaClO
			R
		2				or K2S2O8 (ex.)
OH			R1	OH
						CCl4			/ MecN / H2O

R	R	RuO2 or RuCl3 (cat.)
2	3
20.			NaIO4 or NaClO
			or K2S2O8 (eq.)
R1	R		CCl	/ MecN / H O
	4
R1-R4 = H or Alk or Ar			4	2

21.

R1

R3

22.

R1

R2			OsO4
	or
	R1	R2
R4	OsO4	(cat.) / NMO or K3FeCN6 or H2O2

H2O / t-BuOH

R2 Py or NEt3 or MsNH2 (cat.)

R1-R4 = H or Alk or Ar

RS	RM	AD-mix- or
23.			OsO4 / (DHQD)2PHAL (cat.) / NMO or K3FeCN6
			H2O / t-BuOH
RL
RS	RM		AD-mix- or
			OsO4 /(DHQ)2PHAL (cat.) / NMO or K3FeCN6
24.
			H2O / t-BuOH
RL

41

			OH			OH	DMSO /
25.	R			or			DCC or (COCl)2 or SOCl2 or TFAA
				R		R	NEt , -78OC -> RT
				1		2	3
	R2			R3		1. O3
26.
	R1			R4		2. NaHSO3 or PPh3 or Zn / AcOH
	R1-R4 = H or Alk or Ar
	R2			R3		1. O3
27.
	R1			R4		2. NaBH4

R1, R4 = H or Alk or Ar

28.R

29.

Rn

30.

R

OH	OH		O2	/ Pt(cat.)
>
		R2
R1

OH

> Rn OH O2 / Pt(cat.)

OH	OH		TAPI (Dess-Martin periodinane)
or
			DCM, RT
R1
		R2

SeO2 / диоксан,

R1 R2

31.R1=Ar or HerAr or alkenyl or acyl R2 = Alk > H

R2	R3	H2O2	/ NaWO4	(cat.)

32.

R1

PTC (Aliqat 336)

R4

R1-R4 = H or Alk or Ar

OH

OH

H2O2 / RuCl3(cat.)

33.

R

or

R1

R2

OH

OH

H2O2

/ NaWO4

(cat.)

34.

R

or

R1

R2 PTC (Aliqat 336)

35.

H2O2 / NaOH, RT

R

N

O

36.

Oxone

Me

Me

H2O / NaHCO3, 5OC

R2

R3

Oxone

37.

R1

H2O / NaHCO3, 5OC

R4

R1-R4 = H or Alk or Ar

oxone

38.

R

NH2

NaHCO3

O

Oxone

39.

R1

R2

Al / DCM

R1, R2 = 3O > 2O > Bn > Ph >1O > Me

OH

OH

TBHP/ CrO3(cat.)

40.

or

R

R1

R2

R2

R3

TBHP

41.

PTC (Triton B)

R1

R4

R2

R3

DDO

42.

R1

R4

Me2CO

DDO

R

H

43.

Me2CO

R = 3O(axial > equat.) >> 2O

HO

R2

DDO

44.

R1

OH

DCM, OOC

DDO

45.

R

NH2

Me2CO, RT

S

DDO

46.

R

R

Me2CO, RT

1

2

R2

R3

O

47.

R

(MCPBA)

O

OH

R1

R4

R1-R4 = H or Alk or Ar

O

MCPBA

48.

R1

R2

R1, R2 = 3O > 2O > Bn > Ph >1O > Me

HO

R2

HO

R4

NaIO4

or

49.

R3

R2

MeOH / H2O

R1

OH

R1

OH

R2

R2

R3

NaIO4 / OsO4 (cat.)

or

50.

R1

R

R

t-BuOH / H2O

1

4

42

R Hal

R2

51.R1

R2

52.

R1

RL

53.

R3		R2		R3	TBHP
	or
					VO(AcAc)2 (cat.)
OH
		R1		OH	or Mo(CO)6(cat.)
R4				R4
R4= H or Alk or Ar
R3				TBHP
			(+)-DET / Ti(OPr)4(cat.) / MS
OH			or	(-)-DET / Ti(OPr)4(cat.) / MS
RS				NaClO

(S,S) or (R,R)-Jacobsen's cat. (Mn3+-salene complex)

3.2. Методы образования С-С-связей с помощью металлоорганических реагентов.

Mg

54.

R

Hal

Et2O or THF

R= Alk or All or Bn or Ar ; Hal = I > Br >Cl

55.

R1

H

R2-MgX

Et2O or THF

R

Hal

2Li

56.

hexane

R= Alk or Ar ; Hal = I, Br, Cl

Alk-Li

R Hal 57. Et2O or THF, -78OC

R= Ar or HetAr or alkenyl ; Hal = I > Br

Bu-Li

58. Et2O or THF or Trapp mix, -78OC R= Ar or HetAr ; Hal = I > Br

R

Hal

2 t-BuLi

Et2O or THF or Trapp mix, -78OC

59.

R= 1O Alk or All or Bn or Ar or HetAr or Vin;

Hal = I > Br

R3

Ar

H > R

R2

H

H >

>

60.

R2

S

R1

Bu-Li/TMEDA

Ar

or t-BuLi

>

H

>

NH >

H

Et2O or THF, -78OC

S

R1

61.

Me

Me

Me

Me Bu-Li

or

Me

N

Me

Me

N

Me Et2O, -78OC

H

H

X

Ar or

BuLi or t-BuLi or LDA

HetAr

H

Et2O or THF, -78OC

Me

62.

N

Me

NMe2

X=

O

>

CF3 >

F >

>

>

O

O

OR

>

NMe

>

NMe2 > Br

>

2

R

O

63.

R2

OH

2LDA

R1

Et2O, -78OC

O

64.

R2

OR3

LTMP

Et2O, -78OC

R1

CO2

...

H

65.

R

M

M = Li or MgX

O

66.

R2

X

O

R1

M

M = Li or MgHal; X= Cl or OR2

B(OR )

H2O/H

R1

M

2 3

...

67.

M = Li or MgHal

R2= Me or Et or i-Pr

Me

O

Me

O

68.

MeO

B

or MeO

B

O

Me

O

R1

M

Me

M = Li or MgHal

R2

C

N

H O/H

69.

...

2

R1

M

M = Li or MgHal

O

70.

X

R

H2O/H

R1

M

2

...

M = Li or MgHal

X= Cl or OR3 or NMe2 or N(Me)OMe

43

HC(OMe)3

71.

...

H2O/H

R

MgHal

R2

C

N

...

NaBH4

72.

O

R1

M

Et2O or THF, -78 C

M = Li or MgHal

or

O*BF3

73. R1

M

O

H2O/H

Et2O or THF, -78OC ...

M = Li or MgHal

O

74.

R2

R3

H O/H

...

2

R1

M

M = Li or MgHal; R , R

= H or Alk or Ar or HetAr

2

3

O

1/2

75.

R2O

R3

H O/H

...

2

R1

M

M = Li or MgHal; R2 = Me or Et or Ar

O

76.

R2

R3

HBr/AcOH

MgBr

Et O or THF ...

2

R4

N

77.

R2

R3

H O/H

...

2

R1

M

M = Li or MgHal

O

Me

1.

R1

78.

H

1. R2

Li/Et2O

Me

OH

MgSO4/DCM

2. TMS-Cl/Py

... 2. H2O/H

NH2

Me

Me

R1

79.

NaIO4

N

H2O

R

2

H

OH

R2 X

R1 M

80.R1= Alkynyl or Bn or All or 1,3-dithianyl-2 M = Li or MgHal

R2 = 1OAlk or 2OAlk or Bn or All

X= I or Br or OTs

R2

O

R1

M

81.

...

H2O/H

R3

H

M = Li or MgHal

R4

R2

O

R1

Li

82.

...

H2O/H

R3

R5

R4

R5 = Alk or Ar or HetAr

R2

O

R1

MgHal

H O/H

R5 CeCl3 (anh.) ...

2

83.

R3

R4

R5 = Alk or Ar or HetAr

R2

O

R1

MgHal

H O/H

...

2

84.

R3

R5

O

CuI/THF, -78 C

R4

R5 = Alk or Ar or HetAr

Ar I Cu

85.or

ArHet I DMF, 150OC

CuI

86.2 R Li

THF

R

Li

CuCN

87.

THF

88.

CuCN

R Li

Li

...

S

THF

MeO

1. BuLi

R Li

89.

Me

H

...

2. CuI

Me

CuI

90.2 R MgHal

THF

R

Cu

R

Li

R2

X

1

1

91.

MeO

or

X=OTf > OTs, I >> Br or OTs

Сu

R1 Li

Me

Me R1, R2 = Alk or Ar or HetAr or Alkenyl

44

	O
92.							Tf2O
				R2
R1					Py or 2,6-di(t-Bu)-4-Me-pyridine
R1		M			R2		X
				CuI or Li2CuCl4 / THF

93.M = Li or MgHal

R2 = 1OAlk or 2OAlk or Bn or All X= I or Br

R2

Li

R1

Cu

R1

O

94.

MeO

or

R3

Me

Сu

R1

Li

Me R1 = Alk or Ar or HetAr or Alkenyl

R2

O

95.

R1

M

R3

CuI or Li2CuCl4 / THF

M = Li or MgHal

n

O

R

Cu

R

Li

96.

MeO

or

O

n=1-4

Сu

R

Li

Me

Me

R = Alk or Ar or HetAr or Alkenyl

	Rs	O
	RM		R			M
	100.
		H	M = Li or MgHal
	RL
	Rs	H
	RL		R3			M
	101.		M = Li or MgHal
	X	O

X= OR1 or NR1R2

3.3. Методы образования С-С-связей с помощью реакций кросс-сочетания, катализируемых комплексами палладия

			R2 MgHal
R1		X
			Pd(PPh3)4 or PdCl2(dppf)(cat.)
102.

R1= Ar or HetAr or Alkenyl; X= OTf, I > Br >> Cl

R2 B(OH)2 / Na2CO3 or Cs2CO3 or K3PO4

1X

103.Pd(PPh3)4 or PdCl2(dppf)(cat.), PrOH / H2O,R

R1,R2 = Ar or HetAr or Alkenyl; X= OTf, I > Br >> Cl

R2

B(OH)2 / Cs2CO3 or K3PO4

R1

Cl

Pd2(dba)3 / P(t-Bu)3 or P(c-Hex)3(cat.),

104.

dioxane / H2O,

R1,R2 = Ar or HetAr or Alkenyl;

Catecholborane or DBBS

105. R

H2O/H

...

HO

OH

MeO

97.

Me Me

O

R1

Cu

R1

Li

or

X

R2

Сu R1 Li

R1, R2 = Alk or Ar or HetAr or Alkenyl X= Cl > H >> Alk or Ar or OR3

98.

99.

R2

O

Li

R3

R5

R1

Cu

R1

MeO

or

R4

Сu

R1

Li

R5 = Alk or Ar or HetAr

Me

Me

R2

O

R3

R5

R

Cu

R

Li

R4

1

or

1

R5 = Alk or Ar or HetAr

MeO

Сu

R1 Li

Me

Me

H2O/H

...

...R6 X

R6= Alk or Bn; X= OTs or I or Br or Cl

or

106.

OH Me

Me HO

OH

Me Me

R

B

Ph-H, (-H2O, azeotropic remooval)

OH

Me

Me

Me

O

O

Me

107.

Me

B

B

Me

O

O

R

X

Me

Me

AcOK / Pd(PPh3)4(cat.), DMSO, 90OC

R= Ar or HetAr or Alkenyl; X= OTf,

I > Br

Me

O

Me

O

R2

B

or

R2

B

108.

O

Me

O

R1

X

Me

K3PO4 / PdCl2(dppf)(cat.), PrOH/H2O,

R1,R2 = Ar or HetAr or Alkenyl; X= OTf,

I > Br >> Cl

45

R2 / B / Pd(0)cat. / T

R1 X

109. R1= Ar or HetAr or Alkenyl; X= OTf, I > Br >> Cl; R2= Acyl > CO2R3 > CO2H > Ar or HetAr > H > OR3;

B = Na2CO3 or NEt3 or Cs2CO3 or Ag2CO3 Pd(0) = Pd(PPh3)4 or Pd(OAc)2 / PPh3

R2 / B / Pd(0)cat. / T

R1 Cl

110.R1= Ar or HetAr

R2= Acyl > CO2R3 > CO2H > Ar or HetAr > H > OR3; B = Cs2CO3 or Ag2CO3

Pd(0) = Pd2(dba)3 / P(t-Bu)3 or P(c-Hex)3

111.

R1

X

H

R2

NEt3 / CuI(cat.) / PdCl2(PPh3)2(cat.), THF,

R1= Ar or HetAr or Alkenyl;

X= OTf,

I > Br >> Cl

R2

R3

HetAr

or

N

N

112.

H

H

R1

X

t-BuOK / Pd(0)cat.,

Ph-Me,

R1= Ar or HetAr ; X= OTf, I > Br >> Cl;

Pd(0)= PdCl2(dppf) or Pd2(dba)3 / BINAP

3.4. Методы образования С=С связей

Grubbs or Schrock cat.

113.

R2	R3
R1	R	4	H, T

114.

H = H2SO4 or H3PO4 or HBr or HCl

HO

H

3

O

O

O

or (CO2H)2 or Burgess regent

> 2

> 1

R1

R2

H, T

R3

115.

R4

H = H2SO4 or H3PO4 or HBr or HCl

HO

R1-R4 = Alk or Ar

R2

R3

R1

R4

1. S=C=S / t-BuOK

T

116.

2. MeI

...

HO

H

3O > 2O > 1O

R2

R3

Ts-Cl or SOCl2

R1

R4

B, T

117.

Py / DCM

...

HO

H

3O > 2O > 1O B = t-BuOK or qinoline or DBU or KOH/EtOH

R2	R3		B, T
R1	R	4

118.

X

H

3O > 2O > 1O; X = I > OTs, Br > Cl ;

B = KOH/EtOH or t-BuOK or qinoline or DBU or DABCO

R1

R2

R1

R2

DBU, 70-100OC

119. Br

or

Ph-Me or DMF or DMSO

Br

Br

Br

B = KOH/EtOH or t-BuOK or qinoline or DBU or DABCO

R2

X

PPh3

B

H

...

120.

R1

R1, R2 = Alk or Ar or HetAr or Alkenyl

X = I > OTs, Br > Cl ;

B = BuLi or LDA or t-BuOK or NaH

PPh3

O

121.

R4S

R3L

R2S

R1L

R1 - R4 = H or Alk or Ar or HetAr

H

O

O

122.

X

R2S

R1L

Ph3P

X = OAlk or Alk or Ar;

R1,

R2 = H or Alk or Ar or HetAr

123. RR

, RX

P(OMe)3 or P(OEt)3

= Alk or Ar or HetAr or Alkenyl

1

2

X = I > OTs, Br > Cl ;

O

O

B

R2L

R3S

124.

R1

P

OAlk

DMF

...

OAlk

R1

= CO2Alk or Ar or HetAr or Alkenyl

B = KOH or t-BuOK or NaH

O

O

O

125.

R2L

P

R3S

MeO

OCH2CF3

OCH2CF3

KHMDS / 18-c-6, THF

O

O

R3L

R4S

1. LDA

126. R1

P

OAlk

O ...

B, DMF

OAlk

2. R2

B = NaH or t-BuOK

R1-R4 = Alk or Ar or HetAr

OMe

46

Контрольная работа № 3,

Вариант1

I. Приведите структуру и укажите стереохимию продуктов реакций (3, 8*) (10 балов):

1.

2.

3*.

4.

5.

6.

7*.

8.

9.

10

	O
	O		O
				RuCl3-NaIO4
			O	CCl4-MeCN-H2O
		OH	O
		OH	O	NaIO4
EtO
			OEt
	O OH
		Me		OsO4-NMO
EtO			Et
				(DHQ)2PHAL
	O
			O	Br	Br
EtO
				2 LTMP
			OEt
	O			Et2O -78oC
		O
				MgBr	HBr
MeO			OMe
			Li	Am	O
Me	O
				OTBDPS
Me			Cu		OTBDPS
Me				THF
	O		O	Me-Li
Me		O
			H	Et2O
Me

MeO

Br HN

NMe

Pd(OAc)2, PPh3

KO-t-Bu,Ph-Me 1100C

OTf

CN

Pd(OAc)2, PPh3

NEt , DMF, 1000C

3

O O

OCH2-CF3

O

MeO

P

OCH2-CF3

O

H

o

KHMDS, 18-c-6

0-5 C

II.Заполните схему превращений (10 балов):

O			O	O OMe
				P
			MeO					полупродукт
OH	BH *THF	(COCl)		OMe		H2	LiAlH
	3	2					4	для синтеза
		... DMSO ...					... Et O
BocN			NaH, DMF		...	Pd/C		... тирофибана
							2
		NEt3

47

ЗАЧЕТНАЯ РАБОТА Вариант 1

I. Приведите структуру продуктов реакций и их стереохимию (в реакциях 6,7*) (10 балов):

	O
1.	1.HS	BF3-Et2O SH	Br	ТMS
	H
		2. BuLi
	F

2.

3.

4.

5.

6*.

7*.

8.

	OH	O	OMe
			OH
			OMe
HO		OH	TsOH, T
	OH

						O	1. DPPA/NEt3, T
N						OH	2. HCl/H2O
Me
Cbz						1. H-Phe-OBn, PyBop, DIEA
Boc-Lys-OH
						2. TFA
O				O			O
2										NaOH	H+
							H H
EtO
						OEt Pip*AcOH, T				H O	T
										2

			O
						2-(Me)-CBS-
						-оксаборолидин
F						BH3*THF

O	t-BuOOH
OH	VO(AcAc) 2
O

		Br LDA				H+
				O
N		Et2O	BF3
		-78OC

			TBDPSO			Me
						OTf
	O
9.			Me	Me		N	O
		O
			Me
		B			O	BnO
	HO	O Me			Pd2(dba)3
			Me	Cs2CO3/DCM/DMF
10	Br	1. PPh				O	NMe
		3
		2. BuLi

48

II. Заполните схему превращений (10 балов):

O

O	OMe

	NH				Ac2O		OsO4-NMO		K2CO3
		LiAlH4	H+	(1 экв)		CrO		CrO
		... (избыток) ...					3	3		...
	Ph-H, T			...	Py	... ацетон... (DHQD)2PHAL...		ацетон ...	MeOH
O
	(-H2O)									кортизон

III. Заполните схему превращений (10 балов):

I

Me

Me

O

Br

Br

Me

O

Me

B

B

2 t-Bu-Li

1. B(OMe)3

Me

O

O

Me

N

Me

Me

Et2O ... 2. H+

N

... Pd(OAc)

2 , PPh3

...

PdCl (dppf)

2

...

N

O

2

-78 C

Na2CO3, T

KOAc

PdCl2(dppf)2

диоксан, 100OC

...

F

Na2CO3

F

O

диоксан, 100OC GSK2126458

S

Cl

(ACS Med Chem Lett 2010)

H2N

Br

O

...

MeO

N

NEt3

49

Приложение. Строение и сокращенные обозначения белковых аминокислот.
		Заменимые							Незаменимые
№	Название		Структура				№	Название		Структура
1	Глицин		O				11	Валин		СH3 O
	(Gly,G)	H2N						(Val, V)
				OH						СH3	OH
										NH2
2	Аланин		O				12	Лейцин			O
	(Ala, A)	СН3						(Leu, L)		СН3
				OH							OH
			NH2							СН3	NH2
3	Пролин			O			13	Изолейцин		CH3 O
	(Pro, P)							(Ile, I)		H3C
		N		OH							OH
		H									NH2
4	Cерин			O			14	Треонин		OH	O
	(Ser, S)							(Thr, T)
		HO		OH						H3C	OH
			NH2							NH2
5	Цистеин			O			15	Метионин			O
	(Cys, C)							(Met, M)		H3C S
		HS		OH							OH
			NH2								NH2
6	Тирозин						16	Фенилаланин
	(Tyr, Y)	HO				O		(Phe, F)			O
				H2N		OH				H2N	OH
7	Аспарагиновая				O		17	Триптофан			O
	кислота	HO						(Trp, W)
	(Asp, D)				OH						OH
			O	NH2						N	NH2
										H
8	Аспарагин			O			18	Гистидин		N
	(Asn, N)	H2N						(Hys, H)		N	O
					OH
										H
											OH
			O	NH	2					H2N
9	Глутаминовая		O		O		19	Лизин			O
	кислота	HO				OH		(Lys, K)	H2N		OH
	(Glu, E)
				NH2							NH2
10	Глутамин		O		O		20	Аргинин		NH2	O
	(Gln, Q)							(Arg, R)
		H2N				OH			HN	N	OH
				NH2						H	NH2
											50