4.7.1 Indole

Добавил:

Sekretar kiopkiopkiop18@yandex.ru t.me/Prokururor I Вовсе не секретарь, но почту проверяю Опубликованный материал нарушает ваши авторские права? Сообщите нам.

Вуз:

Ростовский Государственный Медицинский Университет

Предмет:

Медицина общая

Файл:

Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf

Скачиваний:

Добавлен:

10.10.2026

Размер:

8 Мб

Скачать

☆

<<< < Предыдущая 16 17 18 19 20 21 22 23 24 25 26 2728 / 4228 29 30 31 32 33 34 35 36 37 38 39 40 > Следующая >>>

4 Mechanism Problems from Reactions Give Expected Products248

N labeled reagent 4 is employed for preparation of amino pyrazole 5, then a

NNMR will address the mechanism uncertain.

4.7 Formation of Bicyclic and Polycyclic Aromatic

Heterocycles

4.7.1 Indole

Problem 98: Formation of 2,3-Disubstituted Indole

3-(2-Carboxyethyl)-1H-indole-2-carboxylic acid derivatives are antagonists of the

strychnine-insensitive glycine [286, 287] and GPR17 [288]. The synthesis of those

2,3-disubstituted indoles is based on Japp-Klingemann condensation followed by

Fischer indole synthesis [289]. Recently, a series of MCL-1 inhibitors were prepared

from 2,3-disubstituted indoles, such as compound 3. In a patent application [290],

compound 3 was prepared from aniline 1 and ethyl 2-oxocyclopentane-1-carboxyl-

ate 2 as shown below.

Please suggest a mechanism for the transformation from 1 to 3.

EtO

–

EtO

–

EtO

4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 249

Experimental Procedure (from WO2019/096922, A1)

Ethyl-7-bromo-3-(3-ethoxy-3-oxopropyl)-6-fluoro-1 H-indole-2-carboxylate

(3). To a stirred solution of 2-bromo-3-fluoroaniline 1 (CAS 111721-75-6, 9.50 g,

50.0 mmol, 1.00 eq.) in an aqueous hydrochloric acid solution (12.5 mL conc. HCI

in 80.0 mL of water, 150 mmol, 3.00 eq.) was added dropwise a 2.5 M solution of

sodium nitrite (20.0 mL, 50.0 mmol, 1.00 eq.) in water at a temperature of 0 °C.

After complete addition, a 4.5 M solution of sodium acetate in water (62.4 mL,

281 mmol, 5.62 eq.) was added via dropping funnel, followed by dropwise addition of

ethyl-2-oxocyclopentanecarboxylate 2 (CAS 611-10-9, 7.40 mL, 50.0 mmol, 1.00 eq.).

The resulting yellow suspension was maintained at 0 °C for 15 minutes and then

warmed to room temperature and stirred for 2 hours. The reaction mixture was

extracted thrice with DCM (100 mL each) and the combined organic extracts were

dried over magnesium sulfate, filtered and concentrated under reduced pressure

to give the crude hydrazone as a red oil (18.1 g). The residue was dissolved in eth-

anol (50.0 mL, 1.00 M), after which sulfuric acid (6.63 mL, 125 mmol, 2.50 eq.) was

added dropwise. The dark orange solution was heated at 95 °C for 6 days and then

cooled to room temperature. The dark brown solution was poured onto ice/water

(200 mL) and extracted thrice with DCM (200 mL each). The combined organic

extracts were washed with saturated aqueous bicarbonate solution (200 mL), dried

over magnesium sulfate, filtered and concentrated under reduced pressure to give

a brown solid. The residue was purified by flash column chromatography (0–30%

ethyl acetate/hexane gradient) and then recrystallized from hot ethyl acetate/

hexane (9 : 1) to give the title compound as a light yellow solid (8.35 g, 42%). R

0.22 (15% ethyl acetate/hexane, UV).

The Mechanism

The first stage is a Sandmeyer diazotization of the aniline 1 followed by the addition

of the deprotonated form of 2 to the N ≡ N triple bond of the diazonium salt A

to give intermediate B. Under the basic condition and the participation of sodium

acetate, B undergoes retro-Dieckmann reaction to generate the ester acid C. C is

isomerized to D and E, then a Fischer indole synthesis, and meanwhile esterifica-

tion of the terminal acid, leads to the product 3.

MCL-1 inhibitor

1. NaNO

, HCl, H

0 °C

2. NaOAc

0 °C - rt, 2 h

3. EtOH, H

, 95 °C, 144 h

3, 42%

Steps

4 Mechanism Problems from Reactions Give Expected Products250

Problem 99: A Novel Synthesis of Indoles by Vinyl Grignard Reagent with

Nitroarenes

4-Bromo-7-chloro-1 H-pyrrolo[2,3-c]pyridine ( 3e) is used as a core structure of fos-

temsavir [ 291 ], a recently marketed anti-HIV medication. Compound 3e was pre-

pared from the pyridine 1 and vinyl magnesium bromide 2 [ 292 ].

Please provide mechanism for the transformation.

Experimental Procedure (from J. Med. Chem. , 2018 , 61, 6308, Supporting

Information)

4-Bromo-7-chloro-1 H-pyrrolo[2,3- c]pyridine (3e): At 78 °C, to a solution of

5-bromo-2-chloro-3-nitropyridine ( 5, 250 g, 0.97 mol) in THF (5 L), a solution of

freshly prepared vinyl magnesium bromide in THF (3.92 L, 3.92 mol) was added via

a cannula slowly, maintaining the temperature lower than 40 °C. The reaction was

carried out at 78 °C for 1.5 hours, followed by adding 1.5 L of saturated aqueous

Cl solution. The resulting mixture was stirred for 16 hours and the layers were

NaNO

, HCl

Br N

–

OAcNa

EtOH

–

OAc

Sandmeyer

reaction

Fischer indole synthesis

NaCl

retro-Dieckmann

condensation

–

EtO

AcONa

AcOH

AcO-

Hydrolysis

of anhydride

EtOH

HSO

EtO

–

EtO

MgBr

THF

–78–20 °C

35%

Fostemsavir

O O

4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 251

separated. The aqueous phase was extracted with EtOAc (3 × 1 L). The organic

extracts were combined, washed with brine, and concentrated under vacuum to give

a residue which was dried under vacuum. 1 L of EtOAc was added to the residue

to form a suspension, from which ~800 mL of EtOAc was removed under vacuum.

The residual suspension was left in a refrigerator for 1 hour. The solid was collected

via filtration, washed with EtOAc (2 × 50 mL) and EtOAc/hexanes (1:1, 50 mL

and 100 mL), dried under high vacuum to yield 3e (52.3 g, 23%) as a brown solid.

HNMR (500 MHz, DMSO-d

) δ ppm 12.5 (br, 1H), 8.05 (s, 1H), 7.79 (s, 1H), 6.58 (s,

1H).

CNMR (125 MHz, DMSO-d

) δ ppm 137.2, 134.4, 132.9, 131.6, 129.3, 110.9,

102.2. MS m/z: (M + H)

calcd. for C

BrClN

: 230.93; found 231.15.

(from J. Org. Chem., 2002, 67, 2345)

General Procedure for the Preparation of Azaindoles as Exemplified by

the Preparation of 7-chloro-6-azaindole (3c). 2-Chloro-3-nitropyridine 1c

(5.0 g, 31.5 mmol) was dissolved in dry THF (200 mL) under N

, and the solution

was cooled to 78 °C. Excess vinyl magnesium bromide (1.0 M in THF, 100 mL,

100 mmol) was added and the reaction mixture stirred at 20 °C for 8 h before the

reaction was quenched with 20% NH

Cl (150 mL). The aqueous phase was extracted

with EtOAc (3 × 150 mL) and the combined organic layer dried over MgSO

, fil-

tered, and concentrated. The crude product was purified by silica gel column chro-

matography to afford 7-chloro-6-azaindole 3c (1.5 g, 31%).

4-Bromo-7-chloro-6-azaindole 3e (35%).

HNMR (500 MHz, DMSO-d

) δ 8.05

(s, 1H), 7.79 (d, 1H, J = 3.00 Hz), 6.58 (d, 1H, J = 3.00 Hz), 3.40 (b, 1H);

CNMR

(125 MHz, DMSO-d

) δ 137.2, 134.3, 132.9, 131.6, 129.3, 110.9, 102.2; HRMS m/z:

(M-H)



calcd for C

BrClN

228.9168, found 228.9173.

The Mechanism

The reaction in question was originally developed by an Italian research group in

1989 [293]. The same group also investigated the mechanism of this reaction, which

can be outlined as follows [294]: In the initial step, the Grignard reagent targets

the oxygen atoms of the nitroarene, forming intermediate A. A second equivalent

of the Grignard reagent then reduces intermediate A to produce the N-aryl-O-

vinylhydroxylamino magnesium salt B. This intermediate undergoes a [3,3]-

sigmatropic rearrangement, resulting in the formation of compound C. Subsequently,

a rapid ring closure occurs, generating the bicyclic salt D. A third equivalent of

XMg

MgX

XMg

MgX

XMg

[3,3]-

sigmatropic

MgX

OMgX

XMg

OMgX

MgX

2Mg(OH)X

–

4 Mechanism Problems from Reactions Give Expected Products252

the Grignard reagent acts as a base on this bicyclic intermediate, facilitating the

re-aromatization of the six-membered ring. Finally, an acidic aqueous workup, fol-

lowed by the elimination of water, yields the indole product 3.

Problem 100: Deprotection of 2-Hydroxylethyl from Indole Derivative

PNU-142731A (3) is a potential lead compound as a treatment for asthma in

Pharmacia. In a process chemistry, the protection group 2-hydroxylethyl in

compound 1 was removed by the reactions as shown below [295].

Please suggest a mechanism for the deprotection.

Experimental Procedure (from Org. Process Res. Dev., 2001, 5, 144)

2,4-Di-1-pyrrolidinyl-5H-pyrimido[4,5-b]indole (2). A stirred, 10 °C solu-

tion of hydroxyethyl intermediate 1 (125 g, 0.36 mol) and triethylamine (36.4 g,

0.36 mol) in 2000 mL of CH

was treated with a solution of methanesulfonyl

chloride (40.8 g, 0.36 mol) in 200 mL of CH

, added over 30 min. After an addi-

tional 30 min, TLC analysis showed a small amount of 1 remaining, and therefore,

an additional 5 mL of Et

N and 1 mL of MsCl were added, and stirring at 10°

was continued for 15 min. The reaction mixture was then poured into 1 L of 10%

aqueous sodium bicarbonate and extracted thoroughly with CH

. The extracts

were washed with brine, dried over anhydrous sodium sulfate, and concentrated,

thereby affording the crude solid mesylate. This material (containing small amounts

of Et

N) was used directly in the cyanide displacement/elimination which follows.

(For other purposes, residual triethylamine and trace by-products could easily be

removed from the mesylate by trituration with 60/40 EtOAc/hexane.)

A solution of the above mesylate and sodium cyanide (186 g, 3.8 mol) in DMSO

(3.3 L) and water (300 mL) was heated at 115 °C for 12 h. Approximately two-thirds

of the DMSO was then removed in vacuo (bath temperature 100 °C), and the

residue was cooled to 25 °C and partitioned between CH

(2 L) and 10% aqueous

NaHCO

(800 mL). The aqueous layer was extracted with additional CH

(3 ×

300 mL), and the combined extracts were washed with brine (800 mL) and dried

with Na

. The residue resulting from removal of the solvents was triturated with

acetone (400 mL), filtered, washed with cold acetone, and dried (0.05 mm, 40 °C,

48 h) to afford 9 (101.5 g, 93%) as a white solid, completely clean by TLC and NMR:

mp 209–211 °C;

HNMR δ 9.70 (s, 1H), 7.87 (m, 1H), 7.22 (m, 1H), 7.15–7.06 (m,

1H), 3.95 (m, 4H), 3.67 (m, 4H), 2.02–1.95 (m, 8H);

CNMR δ 159.8, 158.2, 158.0,

135.9, 122.1, 121.8, 120.6, 119.8, 110.4, 90.4, 49.6, 46.8, 25.7; MS (FAB) 308 (M

+ H),

307. Anal. Calcd for C

: C, 70.33; H, 6.89; N, 22.78. Found: C, 70.28; H, 7.20;

N, 22.67.

1. MsCl, DCM

TEA

2. NaCN, DMSO

O, 115 °C

1. BuLi

3. HCl

83%

93%

3 (PNU-142731A)

4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 253

The Mechanism

The primary alcohol 1 is converted to mesylate A. Then the OMs is substituted by

CN to form B. Finally, acrylonitrile is eliminated via a retro-Michael reaction at

basic condition to give product 2.

Couty’s group reported a similar removal of hydroxyethyl group from tertiary

amines [296]. Due to the phenyl attached to the hydroxyethyl moiety, the

retro-Michael reaction was carried at room temperature. Without the phenyl attach-

ment, the reaction did not work at the conditions.

MsCl

TEA

NHCl

OMs

MsONa

NaCN

−

NaCN

–

HCN

H CN

NaCN

SOCl

THF, rt

KCN

DMSO-THF(1:1)

rt, 48–72 h

KCN

–

50–77%

NHPh

Stable conjugate

structure

1. SOCl

2. KCN

CNPh

No conjugation

with Ph

–

4 Mechanism Problems from Reactions Give Expected Products254

4.7.2 Indolizine

Problem 101: Access to 2-Iodoindolizines via Iodine-Mediated Cyclization of

2-pyridylallenes

Indolizines are key motifs in many biologically active compounds [297, 298].

Martinez et al. reported a straightforward preparation of 2-iodoindolizines via

iodine-mediated cyclization of 2-pyridylallenes [299]. An example is shown below.

Please propose a mechanism for this reaction.

Experimental Procedure (from Org. Process Res. Dev., 2020, 24, 817, Supporting

Information)

2-Iodo-1,3-diphenylindolizine (2). In anhydrous glassware, a solution of allene 1

(1.0 g, 3.07 mmol, 1 equiv), iodine (1.56 g, 6.15 mmol, 2 equiv.), and potassium car-

bonate (850 mg, 6.15 mmol, 2 equiv) in acetonitrile (61 mL) was heated at 70 °C over

20 h. The mixture was quenched with a 5 w% aqueous NaHSO

solution (50 mL). The

solid was filtered, washed with a 5 w% aqueous NaHSO

solution (2 × 25 mL), and

dried under high vacuum to afford compound 2 as a green solid (1.11 g, 92% yield).

m.p. = 128–129 °C. IR (neat): (cm

1

) = 3063, 3018, 1949, 1597, 1530, 1520, 1441,

1339, 1303, 1243, 1176, 1140, 1071, 1028, 753, 736, 72, 698, 671.

HNMR (400 MHz,

CDCl

) δ 7.92 (dt, J = 7.2, 0.8 Hz, 1H, H

), 7.64 – 7.51 (m, 6H, H

), 7.53 – 7.43 (m,

4H, H

and

), 7.38 (tt, J = 6.9, 1.2 Hz, 1H, H

), 6.68 (ddd, J = 9.1, 6.5, 1.0 Hz, 1H,

), 6.47 – 6.35 (m, 1H, H

CNMR (101 MHz, CDCl

) δ 135.4 (C, C

), 131.6

(C, C

), 131.2 (2CH, C

), 130.9 (C, C

), 130.5 (2CH, C

), 129.2 (2CH, C

), 128.8

(CH, C

), 128.5 (2CH, C

), 126.9 (CH, C

), 126.6 (C, C

), 122.8 (CH, C

), 118.5

(CH, C

), 118.4 (C, C

), 117.9 (CH, C

), 111.4 (CH, C

), 77.0 (C, C

). HRMS (ESI)

calcd. for C

IN ([M + H]

) 396.0199 found 396.0230.

The Mechanism

Addition of iodine to 1,2-diene in 1 gives iodonium transition state A. Then cycli-

zation of A provides indolizinium intermediate B. Under basic condition, here is

, elimination of 2-methylprop-1-ene leads to the product 2 (next page).

4.7.3 Quinolone

Problem 102: Oxidative Rearrangement of Carboline to Quinolone

R301249 (RWJ387273) and R290629 (RWJ444772) are two PDE-V inhibitors active in

the treatment of erectile dysfunction. In a synthesis of those compounds, oxidation

of β-carboline 1 with dimethyldioxirane, generated in situ from Oxone and acetone,

followed by further oxidation with mCPBA gave the desired keto-lactam 2 and an

impurity hydroxy ketone 3 [300]. Intramolecular condensation of 2 provided qui-

nolone 4.

t-Bu

, K

MeCN, 70 °C, 19 h

92%

4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 255

Please propose mechanisms for the formation of 2 and 3.

Experimental procedure (from Org. Process Res. Dev. 2006, 10, 1275)

Benzyl (3R)-3-(2,3-Dihydro-1-benzofuran-6-yl)-2,7-dioxo-1,2,3,5,6,7-

hexahydro-4H-1,4-benzodiazonine-4-carboxylate (2). A 250 mL vessel was

charged successively with 1-(R)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-

1H-β-carboline (5.22 g, 0.018 mol), ethyl acetate (150 mL), and triethylamine (2.1 g,

0.0208 mol). The mixture was heated to 40–45 °C. Then the heating was stopped,

and benzylchloroformate (3.55 g, 0.0208 mol) was added dropwise. The addition

was slightly exothermic, and the temperature rose from 42 to 51 °C. The mixture

t-Bu

KI, KHCO

2-methylprop-1-ene

–

δ–

δ+

R301249 (RWJ387273)

R290629 (RWJ444772)

N CBZ

1. Oxone, acetone

2. mCPBA

N CBZ

CBZ

NaOH

EtOH

N CBZ

R301249 (RWJ387273)

R290629 (RWJ444772)

4 Mechanism Problems from Reactions Give Expected Products256

was stirred for another 2 h at 51 to 42 °C. Water (18 mL) was added, and the layers

were separated while keeping the temperature at 35–40 °C. To the organic layer, ace-

tone (107 mL) was added, and the mixture was cooled to 20–25 °C. Subsequently,

water (36 mL) and NaHCO

(4.82 g, 0.057 mol) were added, and the mixture was

further cooled to 0–5 °C. A solution of oxone (15.5 g, 0.025 mol) in water (60 mL)

was added by means of a dosing pump over a 2 h period at 0–5 °C. After the addition

was complete, the mixture was stirred for another 2 h at 0–5 °C. Subsequently, a

solution of m-chloroperbenzoic acid 71% (5.34 g, 0.217 mol) in DCM (62 mL) was

added in 15 min at 0–5 °C. The mixture was stirred for another 1.5 h at 0–5 °C and

then washed successively with water (76 mL) and with a solution of NaHCO

(6 g)

in water (76 mL). After checking for peroxides, the organic layer was evaporated

to nearly dryness, and the resulting oily residue was crystallized from ethyl acetate

(40 mL). After stirring for 18 h at 10–25 °C the precipitate was filtered, washed with

ethyl acetate (2 mL), and dried in vacuo at 50 °C for 20 h yielding 3 g (36.5%) of

the title compound.

HNMR (400 MHz, DMSO-d

) showed a mixture of rotamers:

δ ppm [2.75–2.90] (m, 2H); [3.08–0.019] (m, 3H); [4.45–4.53] (o, 3H); [5.01–5.24]

(4 × d (o), 2H); 5.93, 5.96 (2 × s, 1H); [6.67–6.72] (2 × d (o), 1H); [6.84–6.90] (2 × d

(o)n 1H); 7.01, 7.03 (2 × s, 1H); [7.19–7.67] (o.m. 9H); 10.84, 10.86 (2 × s, 1H).

Probably other rotamers visible: [3.38–4.28] (m); [4.60–4.77] (2 × d); 5.54, 5.61

(2 × s); 9.68, 9.73 (2 × s). o: overlapping.

The Mechanism

The first step is an epoxidation of the 2,3-double bond of indole in 1 by dimethyldiox-

irane, generated in situ from acetone and Oxone. The epoxide A in turn rearranges

to hydroxy-imine B. Further oxidation of the imine with mCPBA gives the peracid

ester C. Subsequently, cleavage of the 2,3-C─C bond provides the keto-lactam 2.

Once the epoxide A is formed, the elimination of a proton could also take place

from the piperidine side to generate the enamine D. Then the double bond is further

N Cbz

DMD

Acetone

N Cbz

mCPBA

N Cbz

mCBA

Cbz

4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 257

oxidized by mCPBA to give epoxide E. The epoxide E is opened in the assistance

of the ɑ-amino group to afford the iminodiol F. Finally, F is rearranged to hydroxy

ketone 3.

4.7.4 Indazole

Problem 103: A Special Cadogan Reductive Cyclization-Preparation of

Indazole

2H-indazoles as pharmacophores in drug discovery has been exemplified in sev-

eral cases such as MK-4827 and pazopanib. Genung’s group reported a conve-

nient Cadogan reductive cyclization by using tri-n-butylphosphine as the reducing

reagent [301]. For example, (E)-1-(2-nitrophenyl)-N-phenylmethanimine 1 is trans-

formed into 2-phenyl-2H-indazole 2 in 87% yield.

Please propose a mechanism for this reaction.

N Cbz

mCPBA

N Cbz

CBZ

N N

Pazopanib

MK-4827

(PARP inhibitor)

(n-Bu)

P (3 eq.)

i-PrOH, 80 °C, 16 h

87%

<<< < Предыдущая 16 17 18 19 20 21 22 23 24 25 26 2728 / 4228 29 30 31 32 33 34 35 36 37 38 39 40 > Следующая >>>

Соседние файлы в папке Библиотека им академика М.И. Перельмана

#
10.10.202610 Мб0Книга_5257_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.202610 Мб0Книга_5258_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20269 Мб0Книга_5259_Библиотеки_им_академика_М_И_Перельмана.pdf
#
29.08.202689 Мб0Книга_526_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20269 Мб0Книга_5261_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20268 Мб0Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20268 Мб0Книга_5263_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20268 Мб0Книга_5264_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20268 Мб0Книга_5265_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20267 Мб1Книга_5266_Библиотеки_им_академика_М_И_Перельмана.pdf
#
10.10.20267 Мб0Книга_5267_Библиотеки_им_академика_М_И_Перельмана.pdf