Tropylium ion mediated α-cyanation of amines

Article abstract of DOI:10.1021/ja109617y

Tropylium ion mediated α-cyanation of amines is described. Even in the presence of KCN, tropylium ion is capable of oxidizing various amine substrates, and the resulting iminium ions undergo salt metathesis with cyanide ion to produce aminonitriles. The byproducts of this transformation are simply cycloheptatriene, a volatile hydrocarbon, and water-soluble potassium tetrafluoroborate. Thirteen total substrates are shown for the α-cyanation procedure, including a gram scale synthesis of 17β-cyanosparteine. In addition, a tropylium ion mediated oxidative aza-Cope rearrangement is demonstrated.

Full text of DOI:10.1021/ja109617y

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Tropylium Ion Mediated r-Cyanation of Amines
Julia M. Allen and Tristan H. Lambert*
Department of Chemistry, Columbia University, New York, New York 10027, United States
S Supporting Information
b
ABSTRACT: Tropylium ion mediated R-cyanation of
amines is described. Even in the presence of KCN, tropy-
lium ion is capable of oxidizing various amine substrates,
and the resulting iminium ions undergo salt metathesis with
cyanide ion to produce aminonitriles. The byproducts of this
transformation are simply cycloheptatriene, a volatile hydro-
Figure 1. Tropylium ion.
in 195410 and is now commercially available as one of several
stable and easily handled salts. Our interest in this reagent was
piqued by a report that tropylium ion could effect the conversion
of amines to the corresponding R-tropylated iminium ions.11
Although of rather limited synthetic utility, this finding led us to
consider whether the hydride abstracting ability of tropylium ion
could be employed in synthetically useful ways.
carbon, and water-soluble potassium tetrafluoroborate. Thirteen
total substrates are shown for the R-cyanation procedure,
including a gram scale synthesis of 17β-cyanosparteine.
In addition, a tropylium ion mediated oxidative aza-Cope
rearrangement is demonstrated.
With this aim, we first examined the action of tropylium ion on
an amine substrate that would not be prone to enamine forma-
tion/R-alkylation, namely, triisobutylamine (eq 1). After stirring
i-Bu3N (1) and tropylium tetrafluoroborate for 30 min in
acetonitrile, we observed quantitative formation of iminium ion
2, along with cycloheptatriene. Notably, when potassium cyanide
was added to the reaction mixture prior to oxidation, we observed
the R-cyanated product 3 in 81% yield (eq 2). The compatibility
of tropylium and cyanide ions was surprising, since Doering had
reported the preparation of cycloheptatrienylnitrile by this very
combination.12 Nevertheless, we recognized that the fact that
tropylium did not undergo quenching by cyanide under these
conditions offered a practical new means to achieve the mild and
convenient R-cyanation of amines. Indeed, it is worth noting that
the only byproducts of this transformation were cyclohepta-
triene, a volatile hydrocarbon (bp 116 °C), and the water-soluble
salt potassium tetrafluoroborate.
minium ions are a functional group with broad utility for the
strategic formation of carbon-carbon bonds and amine stereo-
I
centers. Unfortunately, the traditional approach to iminium ion
formation by way of carbonyl-amine condensation presents
significant challenges in terms of scope, efficiency, and substrate
compatibility. In this regard, amine oxidation represents a highly
attractive conceptual alternative to the condensation approach
for iminium ion formation.1 When coupled with subsequent nucleo-
philic trapping, amine oxidation also offers a useful means to
achieve amine R-functionalization. In this communication, we
describe the use of tropylium ion as a powerful reagent for amine
oxidation and R-cyanation.
The value of amine oxidation has long been recognized, and
a variety of amine oxidation methods have been reported that
make use of transition metals,2 DDQ,3 PhI(OAc)2,4 or singlet
oxygen5 as oxidants. On the other hand, the substrate scope
reported with metal oxidants has been notably narrow, and is
often focused on N,N-dialkylaniline or tetrahydroisoquinoline
motifs. In addition, circumstances often exist in which the use of
metal reagents is undesirable, either for reasons of cost or toxicity.
While the use of DDQ or singlet oxygen for amine oxidation
has been shown in more diverse contexts, these reagents are not
highly amenable to broad structural modification. For these reasons,
the development of mild and selective new approaches to amine
oxidation stands as an important goal.6
As a highly intriguing conceptual alternative, the use of carbo-
cations, such as trityl7 and tropylium ions,8 to oxidize amines via
hydride abstraction has been demonstrated in a limited context,
although the synthetic utility of such processes has not been
broadly explored. Because of their wide steric and electronic
tunability, we have become interested in the development of
aromatic cations, such as tropylium ion, as versatile hydrocarbon-
based oxidizing agents.
Our rationale for the success of the reaction shown in eq 2
is centered on the fact that KCN is essentially insoluble in
acetonitrile, which therefore prevents the formation of cyclo-
heptatrienylnitrile (9) and allows tropylium ion to oxidize the
amine substrate (Figure 2, cf. 4 f 5). Indeed, the addition of
Tropylium ion,9 (Figure 1) the 6π-electron one-carbon homo-
logue of benzene, was first prepared by Doering and Knox
Received: October 26, 2010
Published: January 4, 2011
r
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Figure 3. Competitive but reversible N-alkylation of amines.
energies, but appears instead to reflect selective oxidation of
the most electron-rich methylene. (For comparison, DDQ in the
presence of KCN and 18-crown-6 effected R-cyanation of the
same substrate in 32% yield over the same time frame, with a 1.7
to 1 selectivity for the benzylic position, see Supporting Infor-
mation.) In support of this notion, a nitro substituent in the para
position of the benzyl group increased the selectivity for oxida-
tion at an aliphatic position to >20:1 (entry 2), while a methoxy
subsituent decreased the ratio somewhat and rendered the reac-
tion much less efficient (entry 3).
Figure 2. Mechanistic analysis of amine R-cyanation.
Table 1. Substrate Scope Studies for Amine R-Cyanation.a
The reaction also appears to be sensitive to steric factors. Thus, for
example, N,N-dimethylmesitylamine was found to undergo
methyl cyanation to furnish nitrile 13 (entry 4). Similar selec-
tivity was observed with a neopentyl substrate, which notably
reacted with high efficiency at room temperature (entry 5). In
contrast, however, the bicyclic amine giving rise to adduct 15 was
found to oxidize exclusively at a more sterically encumbered
methylene rather than the N-methyl group (entry 6).
In an effort to explore some of the functional group compat-
ibility of this method, we investigated substrates that gave rise to
nitrile products 16-18. Interestingly, N,N-diisobutylallylamine
underwent extremely facile reaction in only 15 min at room tem-
perature and with a complete regioselective preference for oxida-
tion at an aliphatic position (entry 7). An amino ester displayed
a similar selectivity (entry 8), although more forcing conditions
were required. We also found it possible to obtain R-cyanate
(-)sparteine (18) in high yield on a preparative scale (1 g) at
ambient temperature without complication from the second
amine functionality (entry 9).5
Interestingly, substrates that proved to be more problematic
included those that possessed only benzylic hydrogens (entry 10)
or for which the aliphatic positions were unreactive (entry 11).
Dimethylbenzylamine was a particularly poor substrate in part
for the reasons discussed below, although it should be noted that
the nitrile 21 was produced with a significant preference for
methyl oxidation (entry 12).
A number of the substrates in Table 1 required heating in part
because at ambient temperature they were prone to N-alkylation
by tropylium ion to form N-tropylammonium salts (cf. 8,Figure2).13
For example, when benzyldimethylamine 22 was combined with
a Reactions were performed by combining the substrate, 1 equiv tropylium
salt, and 2 equiv KCN in MeCN in a sealed vial. Yields determined on
isolated and purified products.
18-crown-6 to the reaction mixture or the use of TMSCN as the
cyanide source resulted in rapid formation of nitrile 9 and com-
plete suppression of amine oxidation. In the presence of the
insoluble cyanide source, however, iminium ion 5 can undergo
salt metathesis with KCN to produce an iminium cyanide inter-
mediate 6, which then collapses to the aminonitrile product 7.
It is not clear at present why iminium ion 5 is capable of solubiliz-
ing cyanide ion whereas tropylium ion is not.
We have found that the substrate scope of tropylium-mediated
amine R-cyanation is usefully broad, and displays some intriguing
regioselective preferences (Table 1). For example, benzyl diiso-
butylamine 10 underwent R-cyanation in good yield at elevated
temperature with a 5.9:1 selectivity for aliphatic oxidation (entry 1),
presumably reflecting an inherent ∼3:1 selectivity of aliphatic
versus benzylic positions. This selectivity is opposite that which
would be expected from a comparison of C-H bond dissociation
an equivalent of tropylium BF4 at room temperature, ammo-
3
nium salt 23 was observed by 1H NMR (Figure 3). Heating 23,
which presumably allowed for reversion to amine and tropylium
ion, in the presence of KCN then slowly produced the nitrile
product 21. That this competitive N-alkylation is subtly affected
by steric and electronic factors can be seen by the variable tem-
peratures required by the substrates in Table 1.
With an eye toward expanding the potential synthetic application
of this amine oxidation, we decided to explore whether tropylium
ion mediated oxidation could be employed for carbon-carbon
bond formation in alternative contexts. Toward this goal, we prepared
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’ AUTHOR INFORMATION
Corresponding Author
TL2240@Columbia.edu
’ ACKNOWLEDGMENT
T.H.L. is grateful for an Alfred P. Sloan Research Fellowship
and Young Investigator Awards from Abbott and Amgen. J.M.A.
is an NSF Graduate STEM Fellow.
Figure 4. Mechanistic alternatives for tropylium ion mediated amine
oxidation.
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methyl benzophenone imine. In the presence of 1.5 equiv of
tropylium BF4- at 120 °C in acetonitrile (sealed vial), 24 under-
went facile oxidation/aza-Cope rearrangement to provide imine
25 in 73% yield. It is notable that this oxidative procedure was
successful even in the presence of a secondary amine. We presume
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Finally, in regard to the mechanism of tropylium-mediated
amine oxidation, we recognize two likely possibilities, the first
being direct hydride abstraction from amine 26 and the second
involving initial electron transfer to produce an amine radical
cation intermediate 28 and tropyl radical (Figure 4).14 Although
at present we cannot say which of these two possibilities might be
operative, we reemphasize that oxidation of substrate leading to
product 10 (Table 1) with DDQ, typically a single electron
oxidant,3 resulted in a significantly different ratio of regioisomers
for benzylic versus aliphatic oxidation.
(6) For a review of other organic amine oxidants, see: Kaitmazova,
G. S.; Gambaryan, N. P.; Rokhlin, E. M. Russ. Chem. Rev. 1989, 58, 1145.
(7) For the oxidation with trityl ion, see: Damico, R.; Broaddus,
C. D. J. Org. Chem. 1966, 31, 1607. As an issue of practicality, we note
that, in contrast to tropylium ion, the byproduct of hydride abstraction
by trityl ion is triphenylmethane, which is a nonvolatile, non water-
soluble compound.
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Another important consideration is the possibility of electron
donor-acceptor (EDA) complexes (cf. 29) with substrates posses-
sing aryl rings. Such EDA complexes with tropylium ion are known15
and their formation might be expected to drastically alter the
reactivity and selectivity of aromatic substrates. Positing intermedi-
ates of the type 29 would also help explain the relatively poor
efficiency of the benzylic oxidations in Table 1 relative to the purely
aliphatic substrates. In this regard, it is noteworthy that the efficiency
of formation of the p-methoxybenzyl product 12 (Table 1) was
especially poor, since a more stable EDA complex would be expected
to form in this case. Further experiments to determine the presence
and potential impact of these putative structures are underway.
As demonstrated here, aromatic cations such as tropylium ion have
the capacity to serve as useful reagents for amine oxidation. The broad
structural and electronic tunability of these reagents should offer
unique opportunities for reaction design and the pursuit of novel
selectivities. Mechanistic investigations and further development of
aromatic cation oxidations will be the focus of our future efforts.
(10) Doering, W. v. E.; Knox, L. H. J. Am. Chem. Soc. 1954, 76, 3203.
(11) McGeachin, S. G. Can. J. Chem. 1969, 47, 151.
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(13) McGeachin reported the quaternary ammonium salt resulting
from addition of trimethylamine to tropylium ion. See ref 11.
(14) Single electron reduction of tropylium ion is more difficult than
trityl cation by about 440 mV. Wasielewski, M. R.; Breslow, R. J. Am.
Chem. Soc. 1976, 98, 4222.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
(15) Takahashi, Y.; Sankararaman, S.; Kochi, J. K. J. Am. Chem. Soc.
1989, 111, 2954.
product characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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