Page 458 - Advanced Organic Chemistry Part B - Reactions & Synthesis

reductive methylation of amines, in which heating a primary or secondary amine with 431
formaldehyde and formic acid results in complete methylation to the tertiary amine. 198
SECTION 5.5
RNH 2 + CH 2 O + HCO H RN(CH ) + CO 2 Reduction Reactions
2
3 2
Involving Hydrogen
Atom Donors
The hydride acceptor is the iminium ion that results from condensation of the amine
with formaldehyde.
+
R N CH 2
2
H
H
O C
O

5.5. Reduction Reactions Involving Hydrogen Atom Donors

Reduction by hydrogen atom donors involves free radical intermediates
and usually proceeds by chain mechanisms. Tri-n-butylstannane is the most
prominent example of this type of reducing agent. Other synthetically useful
hydrogen atom donors include hypophosphorous acid, dialkyl phosphites, and tris-
(trimethylsilyl)silane. The processes that have found most synthetic application are
reductive replacement of halogen and various types of thiono esters.
Tri-n-butylstannane is able to reductively replace halogen by hydrogen. Mecha-
nistic studies indicate a free radical chain mechanism. 199 The order of reactivity for
the halides is RI > RBr > RCl > RF, which reflects the relative ease of the halogen
atom abstraction. 200
In· + Bu 3 SnH In H + Bu Sn· (In· = initiator)
3
Bu Sn· + R X R· + Bu SnX
3
3
3
R· + Bu 3 SnH RH + Bu Sn·
Scheme 5.8 gives several examples of dehalogenation using tri-n-butylstannane.
Entries 1 and 2 are examples from the early studies of this method. Entries 3 and
4 illustrate selective dehalogenation of polyhalogenated compounds. The stabilizing
effect of the remaining halogen on the radical intermediate facilitates partial dehalo-
genation. These reactions also demonstrate stereoselectivity. In Entry 3, the stereo-
chemical preference is for hydrogen abstraction from the more accessible face of the
radical intermediate. Entry 4 shows retention of configuration at the fluorocyclopropyl
carbon. (The stereoisomeric compound also reacts with retention of configuration.)
This result indicates that hydrogen abstraction is faster than inversion for these cyclo-
propyl radicals (see Part A, Section 11.1.5).
A procedure that is catalytic in Bu SnH and uses NaBH as the stoichiometric
4
3
reagent has been developed. 201 This method has advantages in the isolation and purifi-
cation of product. Entry 5 is an example of this procedure. The reaction was carried
198
M. L. Moore, Org. React., 5, 301 (1949); S. H. Pine and B. L. Sanchez, J. Org. Chem., 36, 829 (1971).
199
L. W. Menapace and H. G. Kuivila, J. Am. Chem. Soc., 86, 3047 (1964).
200 H. G. Kuivila and L. W. Menapace, J. Org. Chem., 28, 2165 (1963).
201
E. J. Corey and J. W. Suggs, J. Org. Chem., 40, 2554 (1975).