Journal of the American Chemical Society
Article
bond the 1,2,4,5-tetrazine, thereby activating it for reaction,
and yet not consume either the starting 1,2,4,5-tetrazine
because of the attenuated nucleophilic character of HFIP or
the conjugated enamine through protonation because of its
weakly acidic nature (pKa = 9.3).
Scheme 1. Screen of Secondary Amines
A more refined solvent survey for the reaction of 1a with
enamine 4b in a series of perfluoroalcohols was conducted.
Despite the variations in yields, the ratio of formal 1,4-
cycloaddition versus the conventional 3,6-cycloaddition that
provides 5b and pKa of the perfluoroalcohols, which is a
measure of their H-bonding capability,18 were found to
correlate exceptionally well (Figure 4). In fact, a clean switch
used or in the absence of an added secondary amine, and both
the 1,2,4,5-tetrazine 1a and aldehyde 2a were recovered
unchanged. Use of 0.5 equiv of pyrrolidine (with 1 equiv of
1a/3 equiv of 2a) as above provided similar results (79% yield)
indicating productive turnover, although use of ≤0.25 equiv
pyrrolidine resulted in lower yields even with extended
substoichiometric use of pyrrolidine with 2b improved with the
faster reaction of in situ generated 4b, where good conversion
was observed even with 0.25 equiv and dropped off only at 0.1
limited pyrrolidine turnover is possibly due to acid-promoted
self-condensation of the in situ generated enamine (Supporting
Substrate Scope. The carbonyl substrate scope for this
transformation was explored (Scheme 2). With the 1,2,4,5-
tetrazine 1a as the diene, 2-arylacetaldehyde substrates bearing
either electron-rich (3b, 3f, 3h, 3i, 3k, 3l) or electron-deficient
(3c−e, 3g, 3j, 3m−o) arenes are well tolerated, all
participating in the reaction effectively, although electron-
deficient arenes were found to display a lower reactivity. As a
result of the benign reaction conditions, a wide range of
functional groups are expected to be well tolerated, including
those illustrated herein, consisting of methoxy (3b), halides
(3c−e, 3j), phenyl (3f), trifluoromethyl (3g), ester (3m), and
nitrile (3o) substituents. Arenes with ortho-substitution (3i,
3k, 3n) that might suffer steric issues also provide the 1,2,4-
triazines in satisfactory yields. Heterocyclic as well the all-
carbon arenes are also compatible, including thiophene (3h),
indole (3k), and quinoline (3n). Nonconjugated enamines
(e.g., 1-pyrrolidinocyclopentene) did not react with 1a under
current reaction conditions likely due to their protonation by
Figure S6). Although the ketone 1-phenylacetone was
unreactive, conjugated cyclic ketones (see below) and two
related substrates containing five-membered heterocycles, 1-
(thiophen-2-yl)propan-2-one (2p) and 1-(furan-2-yl)propan-
2-one (2q), were found to be suitable substrates under the
current reaction conditions, providing the 1,2,4-triazines 3p
(79%) and 3q (26%), respectively. This differentiated behavior
can be attributed to a lower steric barrier (Me/O repulsion vs
Me/C−H repulsion) to achieving a conjugated coplanar
enamine conformation, increasing the enamine stability toward
nonproductive HFIP protonation and self-condensation
(Figure 5). This conclusion was further supported by
computation (AM1, Gaussian 09) of the C1−C2−C3−C4
Figure 4. Refined solvent survey. Yields were established by NMR.
from exclusive 3,6-cycloaddition to exclusive formal 1,4-
cycloaddition was observed as the pKa of the solvent decreased
from 15.5 (MeOH) to 9.3 (HFIP). As such, the results
highlight the unique behavior of HFIP and indicate that the
extent of the H-bonding interaction between the tetrazine and
solvent is the feature controlling the 1,4- versus 3,6-
cycloaddition selectivity. Experimentally, we observed that
the HFIP alcohol proton exhibits a pronounced downfield
chemical shift upon titration with 3,6-bis(thiomethyl)-1,2,4,5-
tetrazine (1a, Δ0.53 ppm, 0−2 equiv) consistent with this H-
S1). It is possible that the selectivity is altered due to change in
the LUMO molecular orbital distribution that is induced by
solvent H-bonding, leading to a conjugated nitrogen now more
susceptible to nucleophilic attack than carbon. Simple AM1
computation of the LUMO energy of free and protonated 1a
(−1.93 eV vs −6.17 eV) and sum of squared coefficients as
they relate to tetrazine carbons (C3, C6) and nitrogens (N1,
N2, N4, N5) (free 1a, 0.62 for C and 0.26 for N; protonated
Figure S2 for details) supports both the enhanced reactivity
(rel ELUMO) and a shift from C to N for attack of a nucleophile.
On the basis of the precedent that we first introduced4b and
with recognition that a preformed enamine may not always be
readily available, easily prepared and stored, or stable in open
air, we examined whether the enamine could be generated in
situ from the corresponding aldehyde and amine. To our
delight, replacement of enamine 4a (3 equiv) with phenyl-
acetaldehyde (2a, 3 equiv) and pyrrolidine (1 equiv) provided
3a in an improved yield (88%) under otherwise identical
conditions (0.1 M HFIP, 25 °C, 13 h, open flask) (Scheme 1).
A screen of alternative secondary amines revealed that the in
situ generated pyrrolidine enamine provided the highest
conversion to 3a of those examined (Scheme 1). No reaction
was observed either when a tertiary amine such as Et3N was
C
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX