Synthesis of secondary amines by titanium-mediated transfer of alkenyl groups from alcohols

Article abstract of DOI:10.1021/ja0628811

Reaction of Ti(NMe₂)₄ with allyl alcohols and primary amines leads to the selective formation of secondary allylic amines. The allyl transfer from the alcohol to the amine occurs with selective allylic transposition. Due to substituent effects in the reactions, we postulate that the reaction occurs through a [2 + 2]/retro-[2 + 2]-cycloaddition mechanism. It was also found that a similar reaction could be accomplished with homoallylic alcohol. In this case, the more complex mechanism leads to the formation of 1-aza-spiro[5.5]undecane. Possible pathways for the homoallylic transfer and cyclization are discussed. Copyright

Full text of DOI:10.1021/ja0628811

Published on Web 07/01/2006
Synthesis of Secondary Amines by Titanium-Mediated Transfer of Alkenyl
Groups from Alcohols
Balasubramanian Ramanathan and Aaron L. Odom*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received May 3, 2006; E-mail: odom@cem.msu.edu
Table 1. Examples of Titanium-Mediated Amine Allylation
Allylic amines are found in some natural products and are of
great synthetic utility.1 Methods for the selective synthesis of various
allylic amines are generally marked with several challenges, among
which are preventing overalkylation if a secondary amine is
desirable and control of the regioselectivity of the allylic substitu-
ent.2 A method for the direct use of allylic alcohols, perhaps the
most abundant source of commercially available allylic groups, as
the allylating agent is preferable. Here, we describe an initial study
on the use of commercially available Ti(NMe2)4 as the mediator
for selective conversion of primary amines to secondary allylic
amines, potential mechanisms, and a remarkable increase in scope
for the reaction.
The design for the synthesis is shown in Scheme 1.3 Ti(NMe2)4
has been used for in situ generation of titanium imido complexes
for the hydroamination of alkynes and alkenes.4 In this work,
primary amine is added to in situ generated Ti(NMe2)3(OR) to
access an imido alkoxide. Three diverse amines were chosen to
explore the reaction scope: aniline, cyclohexylamine, and benzhy-
drylamine.5 These amines were reacted with methyl- and phenyl-
substituted allylic alcohols in addition to parent allyl alcohol (Table
1).6 The reactions are selective for allylic transposition.7 To further
probe the regioselectivity, we prepared 1,1-dideuteroallyl alcohol
1
2
(Scheme 2).8,9 A single product is observed by H and H NMR.
Lack of reactivity was noted with some allylic alcohols under
theseconditions(Chart1).NoreactivitywasseenwithMe2CdCHCH2-
OH and any of the amines employed, which is readily explained
by steric considerations. More puzzling was the lack of reactivity
with 2-methylallyl alcohol. Adding a methyl group to this position
should not inhibit a [3,3]-sigmatropic rearrangement (Scheme 1).
Scheme 1. Conceptual Scheme for the Use of Allylic Alcohols in
the Allylation of Primary Amines. Other Ligands on Titanium Not
Shown
a Cy ) C6H11 (cyclohexyl). b Ratio of cis:trans 1:2. c Ratio of cis:trans
2:1. d Estimated GC/FID yield. Chromatography did not completely separate
product from starting amine. e Ratio of cis:trans 1:5. f Yields for protio.
Scheme 2. Reaction with Deuterated Allyl Alcohol
Rearrangement of imido allylic alkoxides has been studied as a
possible step of the SOHIO process for acrylonitrile synthesis.9,10
The mechanism proposed for these processes is a [3,3]-sigmatropic
rearrangement to generate the allylic amido and a terminal oxo. In
academic11 and industrial12 allylic alcohol rearrangements, a similar
mechanism is postulated.13 Inhibition by methylation of the
2-position of allyl alcohol brought this mechanism into question
for this titanium system. An alternative is a [2 + 2]/retro-[2 + 2]
pathway (Scheme 1), which appears to have received little attention
in the literature. There is ample precedent for the inhibition of [2
+ 2]-cycloadditions on olefin substitution,14 and this pathway offers
an explanation for 2-methylallyl alcohol inactivity.
Unlike a methyl group in the 2-position, 2-phenylallyl alcohol
did show activity with some amines (entries 13 and 14, Table 1).
This increased activity with phenyl suggests that the inhibition by
a 2-methyl group has an electronic component. On formation of
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10.1021/ja0628811 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Chart 1. Olefin-Substituted Allylic Alcohols with Olefin Substitution
Supporting Information Available: Synthetic details and char-
acterization data for products. This material is available free of charge
via the Internet at http://pubs.acs.org.
Patterns that Inhibited Reactions
References
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Scheme 3. Possible Mechanism for the Homoallylic Group
Transfer and Cyclization. Likely Oligomerization of Terminal Oxo
Complexes and Other Ligands Are Not Shown for Simplicity
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The chemistry illustrated provides a simple, effective route to
selectively produce secondary allylic amines in a regioselective
manner. The starting materials are readily available alkenyl alcohols,
allylic or homoallylic. Currently, we favor the [2 + 2]-pathway
(Scheme 1) for this titanium system due to 2-methyl inhibition in
allyl transfer.21 While other methodologies exist for amine allyla-
tion,2 the flexibility of these mechanisms potentially opens new
avenues useful for organic synthesis.
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Acknowledgment. The research in our group is supported
financially by the National Science Foundation, U.S. Department
of Energy-Defense Programs, and Michigan State University.
A.L.O. is an Alfred P. Sloan Fellow. A.L.O. would like to thank
Jim Mayer and Laurel Schafer for helpful discussions.
(21) Interestingly, current evidence regarding the rearrangement of coordinated
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