Science - USA (2022-04-29)

530 29 APRIL 2022¥VOL 376 ISSUE 6592 science.orgSCIENCE

2af, 47%

[Hg Lamp: 0%]

N Me

Br

O

O

Minisci

alkylation

then

N

H

O

O

MeO

Cl

O

+ N

O

Cl

Me

MeO

O

MeO

2ag, 56%*

Indometacin Derivative

(anti-inflammatory)

then

Pfitzinger

Me

Quinoline

Synthesis

synthetic synergy

N

Me

O

O O

Br

4p

nucleophilic

radical

nucleophilic

heterocycle

electrophilic

heterocycle

N

Cl

O O

MeO 2 C

N

Me

O

N

Me

O

2u, 64 %

2n, R = CO 2 Me, 91%

2o, R = P(O)(OEt) 2 , 84%

2p, R = Br, 82%

2q, R = BMIDA, 62%

2r, R = OMe, 72%

N

Me

O

F

R

N

Me

O

N

Me

O

NH

Boc

NH

Boc

2y, 83%

[Hg Lamp: 0%]

2z, 69%

N

O

then TFA,

25 oC, 2 – 5 h

N

O

N

NC

O

2j, 72% 2k, 57%

2b, 46%* 2d, 71%† 2h, 49%

N

O

N

O

N

O

Me

Ph

N

O

2e, 62%

N

O

N

O

N

O

O

OMe

O

N

Me O

Me

F 3 CO

N

Me

O

HN

Boc

2f, 36%

N

2c, 52%

[Hg Lamp: 10%]

2g, 61%

2m, 81%*

N

nPr O

Br

NH

2aa, 62%† 2ad, 57%†

Cl

Boc

N

Me

O

Me

N

Me

O

R

2ab, 67% 2ac, 63%*

[Hg Lamp: 0%]

N

Me

O

F 3 C

Cl

N

Me

O

F

F

N

Me

O

Me

Cl

Cl

N

2s, R = SO 2 Me, 53%*

[Hg Lamp: 0%]

2t, R = Cl, 64%

[Hg Lamp: 13%]

N

Me

O

F

Cl

2x, 51%*

[Hg Lamp: 0%]

2ae, 38%†

[Hg Lamp: 7%]

2v, 78% 2w, 65%†

[Hg Lamp: 0%]

2l, 50%

N

O

N

N

Me F

2i, 78%†

[Hg Lamp: 9%]

2ah, 71%† 2ak, 29%‡

N

N

Ph

O

Ph

Ph N N

Me

O

N N

N

Me

Me

Me

O

CO 2 Me

2ai, 48%†

O

Toluene

25 oC, 0.5 – 5 h

N

O

ring

1m rearrangement

N

Me

N Me O

4 a 2 a

one-pot

protocol

H 2 O 2 (2 equiv), MTO,

CH 2 Cl 2 , then dilute with

Toluene, 390 nm LED

then TFA

69% (c.f. 78% from 1b)

excised substituent

N

O

S

skeletal diversity

O N

N

Me

O

Me CO 2 Me

2aj, 27%

[Hg Lamp: 3%]

O

S

2al, 44%

from Montelukast

(leukotriene receptor antagonist)

N

O

O O

MeMe

CO 2 tBu

F

2am, 52%

[Hg Lamp: 0%]

from Pitavastatin

(HMG-CoA reductase inhibitor)

late-stage scaffold hopping

c.f. Fluvastatin

(Fig. 1B)

HO Me

Me

1 2

indole substitution

, TFA

, TsOH

(BzO) 2 , TFA

Fig. 3. Scope of the photochemical conversion of azaareneN-oxides into
acylazoles.Conditions: 1 (0.3 mmol), toluene (0.06 M), 390-nm LED, 0.5
to 5 hours at 25°C, then TFA (0.3 mmol) for 2 to 5 hours at 25°C. Isolated yields
are given. The asterisk symbol indicates where acidolysis was conducted with
TsOH¥H 2 O instead of TFA. The single-dagger symbol indicates where acidolysis
was conducted at 60°C. The double-dagger symbol indicates where, instead of

acidolysis, photolysate was concentrated and refluxed in H 2 O/MeOH (1:1).

Hg lamp yields measured by proton nuclear magnetic resonance versus

an internal standard. Ph, phenyl group; OMe, methoxy group; MTO, methyl-

trioxorhenium; BMIDA,N-methyliminodiacetyl boronate; Boc, butoxycarbonyl;

nPr,n-propyl; TsOH,para-toluenesulfonic acid; (BzO)

2 , benzoyl peroxide;

tBu,tert-butyl.

RESEARCH | REPORTS