Synthetic Organic Chemistry (6KM33)
Friday, 28th March, 2014, 08:45–09:30 (45 min)
Attempt all questions. Explain your answers clearly. GOOD LUCK!
Question 1. The chemical versatility of 1,3-dithianes.
Over the last two months you have hopefully learnt that 1,3-dioxanes (2) are
incredibly useful as protecting groups for aldehydes and ketones (1), and that
they are formed and later removed under acid-catalyzed conditions. The sulfur
analogs, 1,3-dithianes (3) are lesser-known carbonyl protecting groups, which
are also formed under acid-catalyzed conditions, but which typically require
stronger conditions to remove (e.g. HgO, BF3.OEt2).
a) Propose a curly arrow mechanism for the formation of 1,3-dithiane 3
from 1,3-propanedithiol and 1, in the case where R = Ph and R’ = Et.
Interestingly, 1,3-propanedithiol reacts with propargylic ketones (e.g. 4)
under basic conditions to form keto-1,3-dithianes (e.g. 5), so called “masked”
or “latent” 1,3-dicarbonyls. Deprotection then gives 1,3-diketone 6 in this
case.
b) Propose a curly arrow mechanism for the formation of 5 from 4 and 1,3propanedithiol under the basic conditions described above.
c) Propose and different synthesis of 6 starting from simple starting
materials. Compare and contrast your route with the keto-1,3-dithiane
strategy above. Which do you prefer and why?
Under the same basic conditions, propargylic ketone 7 does not form 8, but
instead undergoes a tandem addition-intramolecular aldol reaction to form 9.
d) Propose a structure for 9 and a curly arrow mechanism for its
formation.
e) Propose a synthesis of 7 starting from building blocks 10-12.
f) Therefore, propose a synthesis of 8 starting from the same building
blocks.
Perhaps the most intriguing property of 1,3-dithianes, however, is their
umpolung (polarity inversion) chemistry. As you should know, carbonyls such as
13 are by nature electrophilic, and are subject to 1,2-addition reactions by
various oxygen-, nitrogen-, sulfur- and carbon-centered nucleophiles (i.e.
14). Mono-substituted 1,3-dithianes, represented by 15, can be basedeprotonated (16) and then reacted with electrophiles to form 17, which on
deprotection yields the ketone, 18.
g) The pKa of proton highlighted red is approximately 31. Suggest a
suitable base for the generation of carbanion 16.
h) Making using of the 1,3-dithiane chemistry described above, propose a synthesis of 20
starting from benzyl alcohol (19), giving reagents at each synthetic step.