4.5.4 Pyrrolidine

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4 Mechanism Problems from Reactions Give Expected Products138

added, the flask shaken, and the diethyl ether layer decanted off and discarded.

The process was repeated with two further portions of diethyl ether (500 mL), and

then the remaining volatiles were evaporated. Methanol (40 mL), H

O (40 mL),

and triethylamine (39.4 mL, 280 mmol) were successively added, and after 5 min

the yellow solid was filtered off, washed with a little MeOH, and dried to give 3

(5.05 g, 36%) of suitable purity for further use. An analytical portion was recrys-

tallized from boiling H

O: mp 226 °C (decomp). [α]

+135.6 (c 1.13, DMSO).

HNMR (DMSO-d

): δ 10.19 (bs, exchanged D

O, 1H), 7.29 (d, J = 5.0 Hz, slowly

exchanged D

O, 1H), 5.90 (s, exchanged D

O, 2H), 5.33 (d, J = 5.1 Hz, exchanged

O, 1H), 4.66 (dt, J = 5.0 and 1.3 Hz, 1H), 4.59 (t, J = 5.6 Hz, exchanged D

O, 1H),

4.39 (d, J = 10.3 Hz, exchanged D

O, 1H), 3.80 (bt, J = 1.8 Hz, exchanged D

O, 1H),

3.70 (m, 1H), 3.58 (dd, J = 10.3, 3.0 Hz, 1H), 3.53 (dt, J = 10.7 and 6.4 Hz, 1H), 3.43

(ddd, J = 11.2, 5.9, and 5.9 Hz, 1H), 3.35 (t, J = 6.3 Hz, 1H), 3.04 (bm, 1H).

CNMR

(DMSO-d

): δ 156.1 (C), 150.2 (C), 148.2 (C), 98.8 (C), 79.3 (CH), 76.3 (CH), 68.8 (CH),

68.4 (CH), 60.4 (CH

), 53.7 (CH). ESI-HRMS calcd for C

NaO

, (M + Na)

308.0965, found 308.0968. Anal. Calcd for C

O, 39.60 C, 5.65 H, 23.09

N, found 39.64 C, 5.71 H, 22.83 N. X-ray analysis of 3 confirmed the product as a

monohydrate (Supporting Information).

The Mechanism

The hydrazone 2 is isomerized to the ketone A via Amadori rearrangement. Then

regioselective Viscontini reaction occurs, the more basic 5-NH

group in 1 attacks

the carbonyl in A. After dehydration, cyclization and elimination of PhNHNH

, the

product 3 was produced.

4.5.4 Pyrrolidine

Problem 39: Formation of 2,5-Dibenzyltetrahydropyrrolo[3,4-c]pyrrole-1,

3-dione

RO5114436 is a CCR5 receptor antagonist which was developed by Roche [107].

2,5-Dibenzyltetrahydropyrrolo[3,4-c]pyrrole-1,3-dione (3) was a key building block

OHHO

OHO

PhNHNH

4.5 Formation of Nonaromatic Heterocycles 139

which was prepared from N-benzylmaleimide (1) and benzylglycine (2) in kilogram

scale as shown in the following reaction.

Please propose a mechanism for the formation of 3.

By using paraformaldehyde instead of formalin, lower yield (75%) [108] was

resulted and the process was problematic on kilogram scale [107].

Experimental Procedure (from Org. Process Res. Dev., 2010, 14, 592)

2,5-Dibenzyltetrahydropyrrolo[3,4-c]pyrrole-1,3-dione (3). Toluene (42 kg) was

added to a mixture of N-benzylglycine (2, 2.16kg, 13.11mol) and N-benzylmaleimide

(1, 1.76 kg, 9.38 mol) in a 120-L glass-lined reactor, and the resulting solution was

heated to just under reflux (~105 °C). Formaldehyde/water (1.06 kg, 37% w/w,

13.1 mol) was added at a rate of 300 mL/h while collecting toluene/water distil-

late. After the completion of the reaction, the reaction mixture was cooled, and the

solvent was distilled under reduced pressure (30–125 Torr) at 50 °C. MeOH (28 L)

was added and then distilled off, the mixture was cooled to ambient temperature,

and more MeOH (22.4 L) was added. Water (15 L) was slowly added to the solution

over 2 h, and the slurry was stirred at ambient temperature overnight and then

filtered. The solid was washed with MeOH/water (3 × 4 L, 60:40 v/v) and dried at

50 °C under reduced pressure (30–50 Torr) to give 3 (2.65 kg, 88% yield, 99% purity

by HPLC area) as a light gray solid.

HNMR (300 MHz, CDCl

) 2.13–2.58 (m, 2H),

3.07–3.25 (m, 2H), 3.30 (d, J = 10.2 Hz, 2H), 3.55 (s, 2H), 4.69 (s, 2H), 6.90–7.67

(m, 10H). MS m/z 321.1 [M + H]

The Mechanism

This is a [3 + 2] cycloaddition, which can also be regarded as a special Mannich

reaction. The reaction starts with the formation of an iminium ion A from ben-

zylglycine (2) and formaldehyde. Then a [3 + 2] cycloaddition occurs between

N-benzylmaleimide (1) and iminium ion A to give the adduct B. After decarboxyl-

ation, the product 3 is provided (next page).

Problem 40: Synthesis of trans-3-substituted Proline Derivatives

Schmalz’s group reported a synthesis of trans-3-substituted proline derivatives 3

[109]. The first step is a one-pot reaction of proline methyl ester 1 with NBS followed

by addition of Cbz-Cl to provide 2. The proline derivatives 3 was demonstrated in

the development of potent hepatitis C virus protease inhibitors [110] and farnesyl

transferase inhibitors [111].

Formalin

toluene

105 °C

88%

NHO

RO5114436

Steps

4 Mechanism Problems from Reactions Give Expected Products140

Please provide a mechanism for the reaction from 1 to 2.

Experimental Procedure (from Org. Lett., 2011, 13, 216, Supporting Information)

Synthesis of Methyl N-benzyloxycarbonyl-4,5-dihydropyrrole-2-carboxylate

(2). To a solution of 43.28 g (264.1 mmol) of hydrochloride 1 in 650 mL of CH

([1] = 0.4 mol/L) were added successively under vigorous stirring at 0 °C 80 mL

(2.2 eq., 575.1 mmol) of NEt

and 38.40 g (1.1 eq., 287.5 mmol) of NCS in small

portions.

[I]

After stirring for 2.5 h at room temperature, 49 mL of pyridine (2.3 eq.,

601.2 mmol) was added slowly within 1 h. The mixture was cooled to at 20 °C

and 82 mL of Cbz-Cl (2.2 eq., 575.1 mmol) was added.

[II]

The stirred mixture

(a suspension resulting from precipitated Et

NHCl and pyridine-HCl) was allowed

to slowly warm to room temperature (24 h) before it was washed twice with 150 mL

of 1 N HCl, once with 150 mL of saturated NaHCO

and brine. The organic phase

was dried over MgSO

and concentrated in vacuo. Finally, the crude product (98 g)

was subjected to column chromatography on silica gel (EtOAc/c-hex = 2:5) to give

53.193 g (203.6 mmol, 77%) of 2 as a pale yellow oil. The succinimide derivative

C was isolated as a side product. R

= 0.27 (SiO

, EtOAc/c-hex = 1:3);

𝟏

H NMR

(300 MHz, CDCl

): δ [ppm] = 7.33–7.27 (m, 5H, H-4´), 5.81 (t, 1H, H-3, 3J = 2.9(H-4)

Hz), 5.11(s, 2H, H-2´), 3.96 (t, 2H, H-5,

J = 9.1 (H-4) Hz), 3.62 (s, 3H, H-2´´), 2.63 (td,

2H, H-4,

J = 9.2 (H-5)/2.9(H-3) Hz);

CNMR (100 MHz, CDCl

): δ [ppm] = 162.4

(s, C-1´´), 153.5 (s, C-1´), 136.2 (s, C-2), 135.8 (s, C-3´), 128.5/128.4/128.3/128.2/128.0

(d, C-4´), 120.1 (d, C-3), 67.7 (t, C-2´), 52.1 (q, C-2´´), 48.4 (t, Cs-5), 28.6 (t, C-4); IR

(ATR): ν[cm

−1

] = 3090

(

)

, 3063 (w), 3031 (w), 2952 (m), 2895 (m), 2853 (w), 1734

(vs), 1698 (vs), 1628 (s), 1585 (w), 1497(m), 1438 (s), 1405 (vs), 1317 (vs), 1278 (s),

1243 (vs), 1194 (vs), 1161 (vs), 1026 (s), 915 (m), 871 (m), 747 (s), 694 (s); GC-MS

(EI, 70 eV): m/z (%) = 261 (1), 217 (5), 207 (5), 202 (5), 158 (1), 140 (5), 126 (5),

H.HCl

a, NCS, Et

N, DCM

b, Cbz-Cl, pyridine

Cbz

77%

Cbz

RMgX, CuBr-SMe

THF, –35 °C

[3+2]

Decarboxylation

–

4.5 Formation of Nonaromatic Heterocycles 141

94 (<5,), 92 (10), 91 (100), 77 (5), 67 (5), 65 (15), 59 (<5), 51 (5); Analytical data

of C: R

= 0.33 (SiO

, EtOAc/c-hex = 1:2);

𝟏

H NMR (300 MHz, CDCl

): δ [ppm] =

7.44–7.40 (m, 2H, H-4´), 7.39–7.29 (m, 2H, H-4´), 5.35 (s, 1H, H-2´), 2.74 (s, 4H, H-3);

CNMR (75 MHz, CDCl

): δ [ppm] = 172.4 (s, C-2), 148.1 (s, C-1´), 133.9 (s, C-3´),

128.8/128.6/128.3 (d, C-4´), 69.9 (t, C-2´), 28.5 (t, C-3); IR (ATR): ν [ cm

−1

]= 3062

(

)

3034 (m), 2943 (m), 2917 (w), 2892 (w), 2258 (w), 2078 (w), 1970 (w), 1893 (w), 1807

(vs), 1778 (vs), 1698 (vs), 1585 (w), 1497 (m), 1454 (s), 1425 (s), 1378 (s), 1325 (vs),

1269 (vs), 1204 (vs), 1160 (vs), 1082 (s), 1000 (vs), 945 (m), 903 (s), 857 (w), 814 (s)

m 746 (s), 694 (s), 662 (s).

[I]

: Because of its low solubility in CH

, NCS was added as a solid. Too fast

addition leads to decomposition of NCS (Cl

evolution).

[II]

: Cbz-Cl also decomposes if added too fast. This is indicated through gas evolu-

tion (CO

). To prevent decomposition, Cbz-Cl is added very slowly and the reaction

mixture is brought slowly to room temperature.

The Mechanism

The beginning of the reaction is the N-chlorination of proline methyl ester 1 with

NCS to give intermediate A and succinimide. Then elimination of HCl from A in

the presence of triethylamine provides dihydropyrrole B. Final acylation of the

dihydropyrrole by Cbz-Cl yields product 2. The by-product succinimide also reacts

with Cbz-Cl to generate the by-product C.

H.HCl

NCS

Cl O

Py.HCl

Cbz-Cl

Pyridine

Cbz

Cbz-Cl

Pyridine

Py.HCl

Cbz

N.HCI

Problem 41: Preparation of 5,5-Dimethyl-3-methylene-1-(prop-1-en-2-yl)

pyrrolidin-2-one

5,5-Dimethyl-3-methylenepyrrolidin-2-one (3) is used as a building block for the

synthesis of Elexacaftor [112]. The Vertex patent applications include an example

that described a 114-kg scale preparation of 3 [112]. In 1980, at almost the same

time, Lai’s group [113] and Lind’s group [114] reported a rearrangement of

2,2,6,6-tetramethylpiperidin-4-one (1) to 5,5-dimethyl-3-methylene-1-(prop-1-

en-2-yl)pyrrolidin-2-one (2) and 3. Both groups proposed the mechanism for the

products formation.

4 Mechanism Problems from Reactions Give Expected Products142

Without checking the references, could you please suggest the reaction

mechanism?

Experimental Procedure (from J. Org. Chem., 1980, 45, 1513)

N-Isopropenyl-5,5-dimethyl-3-methylene-2-pyrrolidinone (2). 2,2,6,6-

Tetramethyl-4-piperidone hydrate (5.20g, 30mmol), chloroform (11.94g, 100mmol),

and 18-crown-6 (0.40g, 1.5mmol) were placed in a 100-mL 3-neck flask immersed in a

refrigerated circulating bath. The temperature was kept below 5 °C while 50% aqueous

NaOH (24g, 300mmol) was added dropwise in 25min. The solution was stirred at 5 °C

for 7h after the addition and then water was added until all solids dissolved. The two

layers were separated and the aqueous layer was extracted with

two 25-mL portions of

CHCl

. The combined organic layers were washed with one 10-mL portion of H

dried, and concentrated under vacuum, 15mL of hexane was added, the mixture was

stirred, and the small amount of solid which formed was filtered off. The filtrate was

concentrated and distilled to give 3.5g (71%) of a clear oil at 63–7 °C (0.2 mm): IR

(neat) 1680,1655,1640 cm

1

;

HNMR δ 1.35 (s, 6H), 2.01 (d, 3H), 2.70 (t, 2H), 4.89

(s, 1H), 5.20 (q, 1H), 5.32 (dt, 1H), 6.00 (dt, 1H);

CNMR δ 22.04 (q), 28.15 (q), 29.48

(t), 42.12 (s), 114.60 (t), 115.51 (t), 139.47 (s), 140.18 (s), 166.35 (s); mass spectrum,

m/e 165 (M

). Anal. Calcd for C

NO: C, 72.69; H, 9.15; N, 8.48. Found: C,

71.35; H, 8.93; N, 8.42.

5,5-Dimethyl-3-methylene-2-pyrrolidone (3). The procedure was as above

except that 2.55 g (30 mmol) of piperidine was mixed with the reactants before

the addition of 50% NaOH. The obtained crude product was stirred with 15

mL of hexanes to yield 1.95 g (52%) of a slightly yellowish solid after filtration.

Recrystallization from heptane-toluene afforded colorless crystals: mp 139–142 °C;

IR (KBr) 3180,1680,1645cm

1

;

HNMR δ 1.32 (s, 6H), 2.61 (t, 2H), 5.33 (m, 1H),

5.97, (t, 1H);

CNMR δ 29.67 (q), 41.83 (t), 53.92 (s), 115.64 (t), 141.09 (s), 169.89

(s); mass spectrum, m/e 125 (M

). Anal. Calcd for C

NO: C, 67.17; H, 8.86; N,

11.19.

Found: C, 66.89; H, 8.75; N, 11.12.

(from WO/2019/028228 A1)

i. Under a nitrogen atmosphere, 2,2,6,6-tetramethylpiperidin-4-one (257.4 kg,

1658.0 mol, 1.00 eq), tri-butyl methyl ammonium chloride (14.86 kg, 63.0 mol,

0.038 eq), chloroform (346.5kg, 2901.5mol, 1.75 eq), and DCM (683.3kg) were

added to a 5000L enamel reactor. The reaction was stirred at 85rpm and cooled

to 15~17 °C. The solution of 50 wt% sodium hydroxide (1061.4kg, 13264.0mol,

8.00 eq) was added dropwise over 40 h while maintaining the temperature

Elexacaftor

BnN

–

, CHCl

50% NaOH (aq.)

5 °C

4.5 Formation of Nonaromatic Heterocycles 143

ii. The suspension was diluted with DCM (683.3 kg) and water (1544.4 kg). The

organic phase was separated. The aqueous phase was extracted with DCM

(683.3 kg). The organic phases were combined, cooled to 10 °C and then 3 M

hydrochloric acid (867.8 kg, 2559.0 mol, 1.5 eq) was added. The mixture was

stirred at 10~15 °C for 2 h. The organic phase was separated. The aqueous phase

was extracted with DCM (683.3 kg × 2). The organic phases were combined,

dried over Na

(145.0 kg) for 6 h. The solid was filtered off and washed with

DCM (120.0 kg). The filtrate was stirred with active charcoal (55 kg) for 6 h. The

resulting mixture was filtered and the filtrate was concentrated under reduced

pressure (30–40 °C), 0.1 MPa). Then isopropyl acetate (338 kg) was added

and the mixture was heated to 87~91 °C, stirring for 1 h. Then the solution was

cooled to 15 °C in 18 h and stirred for 1 h at 15 °C. The solid collected by fil-

tration was washed with 50% isopropyl acetate/hexane (80.0 kg × 2) and dried

overnight in the vacuum oven at 50 °C to afford 5,5-dimethyl-3-methylene-

2-one as an off-white solid, 55% yield (114.2 kg).

The Mechanism

Lind postulated [114] that the formation of epoxide 4 involved the addition of

dichlorocarbene to the carbonyl group, whereas Lai later demonstrated that the

reactive species was actually the trichloromethide ion [113]. This conclusion was

supported by the absence of N-formylpiperidine upon the addition of piperidine.

Under acidic condition, 2 was hydrolyzed to 3 [115].

HCl

Acetone

HCl

–

CCl

–

4 Mechanism Problems from Reactions Give Expected Products144

Problem 42: Synthesis of Heteroaromatic-Fused Pyrrolidines via

Cyclopropane Ring-Opening Reaction

A one-step synthesis of heteroaromatic-fused pyrrolidines via cyclopropane

ring-opening reaction was developed by Japanese chemists [116] and the method

was applied to the synthesis of the protein kinase C-beta inhibitor JTT-010 [117].

The process is presented by the following reaction.

HCl (aq.)

OTs

DMF

85 °C, 15 h

OEtO

76%

1. aq. NaOH

2. HCl, heating

quantitative

Steps

JTT-010

.CH

MeO

Please suggest mechanisms for the transformations from 1, 2 to 3 and 3 to 4.

Experimental Procedure (from Org. Lett., 2007, 9, 3331, Supporting Information)

(3aR,10aS)-3a-Ethyl 4-methyl 3-oxo-3a,10a-dihydro-1H,10H-furo[3,4-c]pyrrolo

[1,2-a]indole-3a,4-dicarboxylate (3). To a solution of unpurified 2 (obtained from

609 mmol (R)-epichlorohydrin in 57% yield) in DMF (300 mL), 1 (100 g, 290 mmol)

and K

(48.0 g, 347 mmol) were added, and the mixture was stirred for 18 h at

75–85 °C. After cooling to 40 °C, toluene (150 mL) and heptane (150 mL) were suc-

cessively added. To the resulting slurry, water (300 mL) was added dropwise, and

the mixture was stirred for 1 h at 0–5 °C. The precipitated solid was collected by

filtration and rinsed with water (500 mL). The obtained wet cake was suspended in

MeOH (500 mL) and stirred for 1 h at 15–25 °C. The precipitates were collected by

4.5 Formation of Nonaromatic Heterocycles 145

filtration, rinsed with MeOH (300 mL), and dried in vacuo to provide 3 (68.2 g; yield

68%, purity 94%) as an off-white solid. The product was purified by preparative TLC

(CHCl3/EtOAc, 5:1) and further recrystallized from hexane/EtOAc to give analyti-

cally pure 3 as an off-white solid. Mp 205.0–206.0 °C; [ɑ ]

150.3° (c 0.48, CHCl3);

IR 1778, 1733, 1697, 1559, 1299, 1283, 1173, 1158, 1035, 981, 750, 743 cm

1

;

HNMR

(400 MHz, CDCl3) δ 8.23–8.19 (1H, m), 7.32–7.27 (3H, m), 4.66 (1H, dd, J = 9.8 and

6.6 Hz), 4.64 (1H, dd, J = 10.2 and 8.2 Hz), 4.42–4.25 (3H, m), 4.20–4.13 (1H, m),

4.10 (1H, dd, J = 10.3 and 5.9 Hz), 3.90 (3H, s), 1.30 (3H, t, J = 7.1 Hz);

CNMR

(100 MHz, CDCl3) δ 168.02, 167.12, 164.08, 142.43, 132.42, 130.84, 123.41, 122.64,

122.55, 109.98, 102.63, 68.63, 62.97, 60.49, 50.93, 50.91, 48.61, 14.09; Anal. Calcd for

C18H17NO6: C, 62.97; H, 4.99; N, 4.08. Found: C, 62.84; H, 4.94; N, 3.92.

(S)-2,3-Dihydro-1H-pyrrolo[1,2-a]indol-2-ylmethanol (4). A 6 M aqueous

NaOH solution (420 mL) was added to a suspension of 3 (106 g, purity 98%,

301 mmol) in EtOH (433 mL), and the mixture was heated to reflux for 3.5 h. The

mixture was acidified by dropwise addition of concentrated HCl (220 mL) and then

stirred for 1 h under reflux. A similar basifying–acidifying procedure was repeated

twice (refluxing the mixture with successive addition of NaOH (55 mL), HCl

(25 mL), NaOH (30 mL), and HCl (20 mL) every 30 min). The reaction mixture

was cooled to room temperature, neutralized with a 6 M aqueous NaOH solution

(10 mL), and concentrated to a weight of 930 g in vacuo. The organic layer of the

obtained residue was separated with EtOAc (415 mL), and the aqueous layer was

extracted with EtOAc (105 mL). The combined organic layers were dried over anhy-

drous Na

and then concentrated in vacuo to a weight of 63 g. The obtained

residue was azeotroped with toluene (150 mL × 2) to afford ethanol-free 4 (60.0 g,

containing toluene) as a pale brown solid. No further purification was attempted

on this compound, which was used directly in the next step. Purification by prepar-

ative TLC (hexane/EtOAc, 1:1) followed by recrystallization from hexane/EtOAc

gave analytically pure 4 as an off-white solid. Mp 80.3–81.5 °C; [ɑ]

+4.51° (c 0.40,

CHCl

); IR 3260, 1457, 1044, 1013, 764, 740 cm

1

;

HNMR (400 MHz, CDCl

) δ7.54

(1H, d, J = 7.7 Hz), 7.23 (1H, dd, J = 8.1, 0.9 Hz), 7.11 (1H, td, J = 7.6 and 1.6 Hz),

7.05 (1H, td, J = 7.4 and 1.2 Hz), 6.15 (1H, d, J = 0.9 Hz), 4.21 (1H, dd, J = 10.2 and

7.4 Hz), 3.95 (1H, dd, J = 10.2 and 5.1 Hz), 3.82 (1H, dd, J = 10.2 and 6.3 Hz), 3.74

(1H, dd, J = 10.1 and 7.5 Hz), 3.28–3.12 (2H, m), 2.82 (1H, ddd, J = 15.4, 9.0, and

1.0 Hz);

CNMR (100 MHz, CDCl

) δ 143.26, 133.11, 132.77, 120.34, 120.29, 119.22,

109.35, 92.83, 65.11, 46.34, 44.33, 27.37; Anal. Calcd for C

NO: C, 76.98; H, 7.00;

N, 7.48. Found: C, 76.85; H, 7.04; N, 7.33. The enantiomeric excess was determined

to be >99% by HPLC (Daicel CHIRALCEL OD-H 250 mm × 4.6 mm i.d.; Hexane/

EtOH = 99/1–97/3 (10 min), then 97/3 (35 min); flow rate = 1.0 mL/min; temp =

25 °C; t

= 36.5 min (R) or 41.3 min (S)).

The Mechanism

Under basic conditions (K

), the NH group in compound 1 is deprotonated,

forming a nucleophile that attacks the electron-deficient cyclopropane compound 2

to generate carbanion 3a. This carbanion is stabilized by the electron-withdrawing

diester groups and subsequently attacks the carbon bearing the leaving group Ots,

completing the insertion of the heteroaromatic N(1)-C(2) unit to form compound 3.

4 Mechanism Problems from Reactions Give Expected Products146

After the tri-ester hydrolysis by aqueous NaOH, the salt is acidified by HCl to

release the tri-acid. Upon heating, decarboxylation occurs to give the product 4. The

triple decarboxylation may be stepwise and the last decarboxylation of indole-3-

carboxylic acid should be catalyzed by acid [118].

Problem 43: Synthesis of Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one

BI-0252 (1), a novel spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compound, was

identified as an orally active inhibitor of the MDM2-p53 interaction [119]. The

construction of the core spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one (2) was based

on a three-component [3 + 2] cycloaddition [120]. The representative reaction is

shown as below [119]. Treatment of 1-(2-fluoro-3-chlorophenyl)-2-nitroethene (3),

6-chloroisatin (4), and L-homoserine (5) in refluxing methanol provided rac-2 in

46% yield [119].

Please suggest a mechanism for this transformation.

Experimental Procedure (from J. Med. Chem., 2016, 59, 10147)

rac-(3S,3′S,4′S,5′S)-6-Chloro-3′-(3-chloro-2-fluorophenyl)-5′-(2-hydroxyethyl)-

4′-nitro-1,2-dihydrospiro[indole-3,2′-pyrrolidine]-2-one (rac-2). 6-Chloroisatin

(4, 8.0 g, 44.05 mmol), 1-(2-fluoro-3-chlorophenyl)-2-nitroethene (3, 8.9 g,

44.05 mmol), and L-homoserine (5, 5.24 g, 44.05 mmol) were stirred under reflux

OTs

OEtO

KOTs

1. NaOH

(ester

hydrolysis)

2. HCl

OTs

–

KHCO

MeO

–

OO H

HO O

HCl

O O

HCl, CO

–

4.5 Formation of Nonaromatic Heterocycles 147

in MeOH (10 mL) for 18 h. The reaction mixture was concentrated in vacuo, and the

residue titurated in acetonitrile. The solid was filtered and dried to give rac-2, which

was used in the next step without further purification. rac-2, 8.9 g, 20.2 mmol, 46%.

HNMR (500 MHz, DMSO-d

) δ ppm 1.491.63 (m, 2H) 3.443.52 (m, 1H) 3.523.61

(m, 1H) 4.09 (d, J = 7.25 Hz, 1H) 4.524.63 (m, 2H) 4.74 (d, J = 8.51 Hz, 1H) 6.06

(t, J = 8.51 Hz, 1H) 6.66 (s, 1H) 7.11 (dd, J = 7.88 and 0.95 Hz, 1H) 7.17 (t, J = 7.88 Hz,

1H) 7.44 (br t, J = 6.94 Hz, 2H) 7.56 (d, J = 7.88 Hz, 1H) 10.32 (s, 1H). LC/MS:

[M + H]

= 440; t

= 1.21 min.

rac-2

Steps

1 (BI-0252)

MeOH

reflux

18 h

46%

rac-2

[3+2]

1,3-dipolar

cycloaddition

rac-2

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