HIGHLIGHTS
Organic chemistry O
G. RICHARD STEPHENSON University of East Anglia, UK
Reverse polarity chemistry of amides Heteroatom-heteroatom bonds are often highly reactive, so installing such features in intermediates can open up new chemistry. However, if these reactions were easy to perform, nowadays it is probable that they will already be known. One of the challenges of inventing new synthetic transformations in organic chemistry is the ‘happy knack’ or ‘skilled science’ of getting reaction conditions that work well. An example published recently describes a useful way to add nucleo- philes to the α position of amides. Because amides feature in the repeat connections between amino acids in proteins (the ‘peptide bond’ is an amide) there has been a sustained interest in the synthesis of unnatural amino acids, and consequently, on the synthetic chemistry of amides (RCONR’R”). When the R group of RCONR’R” has a CH2
Scheme 1
bonyl group, this position is naturally nucleophilic, hence the interest in devising chemistry to add nu- cleophiles to position, reversing the natural pattern of reactivity (D. Kaiser, C. J. Teskey, P. Adler, .N. Maulide; J. Am. Chem. Soc., 2017, 139, 16040). The example shown in Scheme 1 has been made to work by careful optimisation, which identified 2-iodopyridine N-oxide as a suitable base and 2,6-lutidine as the source of the reactive N-O (heteroatom- heteroatom) bond.
next to the car- Scheme 1
(a) (a) (b) (b)
HAT and SAT working together to functionalise aldehydes Continuing with this simple, some would say classic, theme of reactivity α to carbonyl groups, another ‘December gem’ concerns the functionalisation of aldehydes, certainly a ‘classic organic functional group’. In this case, the unexpected feature of the chemistry is the ability to use non-electrophilic alkene as the coreactant (Scheme 2). To make this work, a combination of HAT and SET (photoredox) catalytic cycles has been developed (A. G. Capacci, J. T. Malinowski, N. J. McAlpine, J.
Scheme 2 Scheme 2 Nu
Bu O
O
Scheme 1 Scheme 1
Bu O
O N
Ts N Ts
(a) (a)
Bu O
Bu O
(b) (b)
O O
F3C N N
F3C Scheme 2
N H
O2Scheme 2 S2O8 , N,N-di- OH methylacetamide, O2
KI, K2
Scheme 3 A new reaction between allyl alcohols and anilines (a: methylenecyclopentane, Ag2 Scheme 2
N H
, , 120°C; b: KI, K2NH2 S2 O8
, N,N-diethylformamide, , 120°C)
NH2 Scheme 3 Scheme 3
(a, b) NH2 NH2
(a, b) OH OTMS
Ts Ts
F3C 1 OTMS CO3F3C 1 CF3 CF3
N H
N H
N O N O O(i)
N N
N O N O N Nu (iv) Nu O Nu (iv) N
Scheme 1 O
N (a)
Bu O
(b) O
Bu O
O N
Ts N CF3 CF3 Ts Ts
F3C F3C
O N
Nu Nu
(iv) (iv)
Bu O
O N
Nu Nu
O; (ii): 2-iodopyridine; (iii) lutidine N-oxide; (iv) an enolate (Nu–), functionalises the α position of amides
O O
N N
74% yield 90% ee
Bu O
85% yield 93% ee 10:1 dr
Bu O
O O
N N
74% yield 90% ee
85% yield 93% ee 10:1 dr
F3C
Scheme 2 An iridium catalyst (1 mol%) and an aryl thiol (10 mol%), not shown, and the chiral auxiliary 1 (20 mol%) are used in combination in DME at 10°C under irradiation using light from a blue LED to connect aldehydes and alkenes in either (a) intermolecular or (b) intramolecular C-C bond forming reactions
N H
OTMS OTMS
F3C 1 F3C 1 N
NH2 OHN OH
(a, b) (a, b)
70% CF3F3C 1 CF3
CF3 CF3
OH
(a, b) 70%
N N
70% 70%10 | 2017 45 N 70%
Ts Ts
N (iii)
O N O(iii)
Nu N
(iv)
N N
O N Nu
Scheme 1 A one-pot procedure using (i): Tf2
Kuhne, D. W. C. MacMillan; Nature Chem., 2017, 9, 1073).
Bu O
O
74% yield 90% ee
74% yield 90% ee
N
85% yield 93% ee 10:1 dr
OTMS group and the sp2
85% yield 93% ee 10:1 dr
Ts CF3 CF3
74% yield 90% ee
Double oxidative cyclisation to make quinolines There are many approaches available to make alkenes take part in new syn- thetic transformations. In an example which adds an additional aromatic ring to anilines, a sequential double oxidation process allows a very sim- ple alkene (allyl alcohol) to provide the necessary three carbon atoms to extend anilines into quinolines in a reaction that incorporates the aniline NH2
85% yield 93% ee 10:1 dr
nitrogen atom
of the quinoline ring (J. Wu., Z. Liao, D. Liu, C.-W. Chiang, Z. Li, Z. Zhou, H. Yi, X. Zhang, Z. Deng, A. Lei; Chem. Eur. J., 2017, 23, 15874).
N
(iii) (iii)
N O
N O
N O
N O
B (ii)
(i) (i)
B H (ii) (iii) N N
B B
(ii) (ii)
N N
N O
H (i)
O N
(i)
O Tf N
O Tf N
H H
H
O TfO Tf B
N N
(ii)
O
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