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M. Kurosu et al. / Tetrahedron Letters 47 (2006) 4871–4875
As a result of reaction screenings it was found that
methylation of secondary amines with methyl iodide
on the polymer-support using triphenylphosphine
(TPP) and diisopropylazocarboxylate (DIAD) in THF
provided the corresponding tertiary amines in good
yields (>95%) after cleavage; no quaternizations were
observed even with a large excess of methyl iodide.
ucts in less than 5% conversion. Thus, direct N-alkyla-
tions of secondary amines were achieved in excellent
yields with alkyl iodides, and allyl and benzyl bromides.
Because acid-cleavable p-methoxybenzylamine deriva-
tives such as 1f in Table 1 are excellent substrates for
the N-alkylation reactions, we next demonstrated utility
of this protocol for the syntheses of low-molecular-
weight secondary amine building blocks which are
applied to diversifying combinatorial library molecules
through path b in Scheme 1.
Efficient direct N-methylations can likely be attributed to
the following reasons. The reagent generated under dialk-
ylazocarboxylate and triphenylphosphine deprotonates
secondary amine through a transition state iii to afford
the intermediate iv that react with methyl iodide. The
generated tertiary amines would form the complexes with
an ionic species such as Ph3PI2.7 Complexation of ter-
tiary amines with generated by-product(s) prevents quat-
ernization with an excess of methyl iodide (Scheme 2).
As summarized in Table 2, secondary amine salts were
synthesized by HCl cleavage of the p-methoxybenzyl
group of 4 and 7. The tertiary amine resins 7 were syn-
thesized in reliable two steps, reductive amination
(NaBH4, Ti(OiPr)4)9 and N-alkylation (DIAD, TPP,
alkyl halides). N-Alkylation on the polymer-support
followed by acid cleavage is very useful protocol for
the synthesis of low-molecular-weight secondary amine
building blocks; secondary amines can be synthesized
without no purification throughout this sequence.
Although a combination of trialkyl or triphenylphos-
phine and dialkylazocarboxylate (Mitsunobu condi-
tions) have been utilized in the syntheses of esters,
phenol ethers, aminations of alcohols, and iodinations
of alcohols, Mitsunobu conditions had never been
applied to the syntheses of tertiary amines from second-
ary amines.8
In summary, direct N-alkylation of secondary amines
that is amenable to the reactions on the polymer-sup-
port are demonstrated. Although the syntheses of ter-
tiary amines described here is not using a new reagent,
these protocols, however, are exceedingly useful for the
generation of tertiary amine containing library mole-
cules. We are currently applying the described N-alkyl-
ation method to deliver small optimized libraries for
the development of MenA inhibitors.
To explore the scope and limitations of the tertiary
amine synthesis using TPP (or polymer-bound TPP
(PS-TPP))/DIAD/alkyl halide, a variety of secondary
amines were tested against representative alkyl halides.
In order to facilitate the purification of generated
tertiary amines, PS-TPP was utilized in the solution
reactions. As summarized in Table 1, dialkylamines,
dibenzylamines, and phenylmethylamines, 1a–1i, re-
acted with methyl, ethyl, and butyl iodides to afford
the corresponding tertiary amines, 2a–2t, in greater than
90% yields. Although ally bromide and benzyl bromide
were applicable to the PS-TPP/DIAD mediated N-alkyl-
ation reactions, the corresponding chlorides did not ex-
hibit good enough electrophilicity; the reactions with
ally chloride and benzyl chloride gave the desired prod-
General procedure for the synthesis of tertiary amine in
solution phase. To a stirred suspension of the secondary
amine (1.0 mmol), PS-TPP (ꢀ3.0 mmol/g, 1.5 equiv),
and DIAD (1.5 mmol) in THF (5 mL) was added alkyl
iodide (3 mmol). The reaction was stirred gently at rt
for 12 h and the reaction mixture was filtered, and all
volatiles are evaporated in vaccuo. The crude product
was purified through a silica gel pad to provide tertiary
amine.
OiPr
OiPr
N
O
OiPr
O
HN
O
N
iPrO
O
O
N
N
PPh3
R2
R1
O
iPrO
N
ii
N
H
i
H
iPrO
R1
Ph3P
N
R1
Ph3P
N
R2
R2
iii
iv
R1 linked to the polymer
R3I
OiPr
O
R3
R3I
HN
O
R2
R1
R2
R1
N
N
N
+
I-
Ph3PI2
iPrO
R3
R3
R3
v
vi
vii
Scheme 2. Plausible mechanism of N-alkylation of secondary amine with TPP, DIAD, and alkyl iodides.