KBS48 - 49 (Mitsunobu reaction) - master page

[KlementineJBS]

This review has a single example of a Fukuyama-Mitsunobu on nosylated methylamine (p 52, compunds 390-392). Unsure if it will work with this substrate as alkyl chain is obviously longer, and the proposed alcohol (KBS28) is much more sterically bulky. There are more examples in this review, notably the alkylation of a dibutamine in the production of spermidine (222 -> 223) (find the original paper here), or this paperwhich includes benzylic alcohols (Table 1, entry 4).

reaction with benzylic alcohol = with a short chain amine (Me) reaction with longer chain amine is not shown to work with benzylic alcohol (they use another linear chain)

There is certainly precedent for Mitsunobu reactions on nosylated amines in SPPS,, e.g. in this review (see ref 962, where a fairly long linear chain is added) or this example with SPS (p 7308, adds a methyl).

Reaction scheme

[KlementineJBS]

Attempts

Identifier	Link	Solvent	Yield	Other
48-1	#180	THF	in progress	amine = KBS43
49-1	#183	THF	in progress	amine = KBS45
49-2	#184	THF/toluene	in progress	amine = KBS45

[KlementineJBS]

Notes

• Some people recommend adding the 'betaine' first (i.e. DIAD + PPh3) before substrate and nucleophile. This seems likely to cause off-target reactions so the original protocol is being followed to begin with.
• will try with half THF/half toluene next as this is said to improve yields
• seem to be getting the azide back - this also happened in previous alkylations (need to check where)

[KlementineJBS]

Mass spec table

Identifier	Link	Evidence of SM	Evidence of mono	Evidence of bis	Other/unknown
48-1 RM	#180	-	692.16-	-	313.23+, 975.19-
48-1 W1 triturated	#180
49-1 cr	#183	513.11-	-	951.31+	PPh3O adducts
49-1 F7	#183	-	-	951.33+	313.14+
49-1 F8-10	#183	-	-	963.37-, 951.29+	PPh3O adducts
49-2 RM	#184	513.12-	720.25-	963.27- , 951.27(3+) ?	313.18+, PPh3O adducts
49-2 RM (later)	#184	513.07-	720.27(-2) ?	963.35-	313.16+, PPh3O adducts
49-2 cr	#184	513.14-	720.26-	951.31+	PPh3O adducts

[KlementineJBS]

Alternative diazocarboxylates

DIAD is hard to remove. This paper suggests alternatives.

• DMEAD [CAS 940868-64-4] is most attractive (water soluble) but hard to get - $209 USD for 5 g from Arctom
• DCAD [CAS 916320-82-6] is an option - $43 for 1 g or $413 for 10 g from Merck catalogue
• DNAD [CAS 1191377-56-6] is a good option too but doesn't seem to be readily available

[KlementineJBS]

Characterisation

KBS49

NMR

1H NMR (500 MHz, Chloroform-d) δ 8.10 – 7.99 (m, 4H), 7.99 – 7.93 (m, 4H), 7.73 – 7.63 (m, 4H), 7.63 – 7.49 (m, 8H), 4.77 (s, 4H), 3.44 – 3.37 (m, 4H), 1.61 (q, J = 7.4, 7.0 Hz, 4H), 1.20 – 1.16 (m, 8H).

13C NMR (126 MHz, CDCl3) δ 148.05, 143.66, 134.17, 133.68, 133.59, 133.53, 131.84, 130.82, 130.54, 128.39, 128.34, 127.98, 127.14, 126.04, 124.97, 124.31, 123.55, 122.16, 48.00, 42.29, 28.84, 27.67, 26.24.

NEO500-20240314-6 KBS49-2 bis_1.zip NEO500-20240314-6 KBS49-2 bis_2.zip KBS49-2 bis.pdf