Angewandte
Chemie
reactive ketenimine 9.[17] Addition of the indole anion on the
ketenimine would then lead to the amidine 5a after proto-
nation and tautomerization. It can be hypothesized that the
stabilization of 8 facilitates the cleavage of the protecting
group under basic conditions in a similar fashion as for
pyrroles or indoles.[18] Alternatively, the ynamide could also
act as group donor, thus transferring the protecting group
onto the indole which could be deprotected thereafter.[19]
As the addition process of 6 to 1a to give 7 seems
counterintuitive in view of the polarization of the ynamide
triple bond, DFT calculations were carried out at the M05-
2X[20]/6-31 + G(d,p)[21] level to provide insights on its feasi-
bility. We first looked at the natural charges of ynamide 1a
and the deprotonated indole (Figure 1). As expected, Cb of 1a
bears a negative charge (À0.270) as does the nitrogen atom of
6 (À0.602). In spite of this unfavorable charge repulsion,
a transition state corresponding to the addition of 6 to Cb
could be located (TSA-7). The corresponding free energy of
activation is quite low (9.6 kcalmolÀ1) and the addition is
appreciably exothermic by 12.5 kcalmolÀ1. It should be noted
that in agreement with the experimental data, TSA-7 leads to
the Z-carbanion 7. The E diastereomer did not converge and
collapsed to the Z form. It is likely that electron–electron
repulsion strongly favors a trans relationship between the
sp2 orbital holding the electron pair at Ca of the carbanion and
the electron-rich indole moiety. In TSA-7, a charge of À0.231 is
transferred from the indolate to the ynamide. A significant
part of this excess negative charge is carried by Ca (À0.183)
and by the electron-withdrawing Ts group (À0.079).
Scheme 5. Reactivity switch. [a] Yields are those of isolated product.
[b] Yield determined by NMR spectroscopy using 1,3,5-trimethoxyben-
zene as internal standard: 5b 60%, 1m 15% and N-Boc-indole 15%.
Boc=tert-butoxycarbonyl.
conversion). Methanesulfonamide, acetamide, and tert-butox-
ycarbamate derivatives (1k–m) led to the same product, 5a,
the structure of which was further confirmed by crystallo-
graphic analysis.[14] Moreover, the benzylamine-derived
ynamide 1n also yielded an amidine derivative (5b), thus
indicating that this change in reactivity can be tuned not only
by changing the R group but also by changing the nature of
the EWG (compare 1a with 1n). Finally, the phenyl-
substituted ynamide 1o was submitted to the same reaction
conditions to give the amidine 5c with 69% yield.
This reactivity switch prompted us to devise a mechanistic
scenario for these unusual transformations (Scheme 6). First,
it can be assumed that the indole is deprotonated by the base
to give 6. For N,N-sulfonyl-alkyl ynamides such as 1a, direct
addition at the b-position would generate the anion 7 and 4aa
after protonation. For N-sulfonyl-N-aryl-, N-Ac-, and N-Boc-
ynamides (1j–n), either the indole anion or the base could
cleave the protecting group to give the amide 8,[16] which after
protonation and tautomerization would generate the highly
The approach of the indolate to the ynamide proceeds in
a very peculiar way, as revealed by the structure of TSA-7
(Figure 2). There is no alignment of Cb, the nitrogen atom of
À
the indolate, and the center of the C3 C4 bond marked in
purple (1488 instead of 1808). Thus, there is no overlap of the
in-plane nitrogen sp2 orbital of the indolate (corresponding to
its HOMOÀ2; see the Supporting Information) with the
p* orbitals of the alkyne moiety of the
ynamide (corresponding to its LUMO).[22]
Instead, the indolate presents its HOMO
p system, thus inducing the repulsion of the
Cb electrons towards Ca and forming a nascent
carbanion at Ca and reducing the negative
charge at Cb. Thus, the approach of the
nucleophile reduces the dipole moment of
the alkyne moiety.
This situation could be compared to the
addition of Br2 to an alkene giving rise to
a charge-transfer complex, yet in this case the
polarization of Br2 induces a positive charge
on the bridging bromine in the approach
transition state.[23] More relevant is the addi-
tion of singlet oxygen to an enecarbamate.[24]
In the computed transition state correspond-
ing to the first step of a [2+2] cycloaddition,
the approach of the enecarbamate induces
=
the polarization of the O O bond, the
rupture of its p component, and the forma-
tion of a s bond between the carbon atom and
the least negatively charged oxygen atom. In
Scheme 6. Mechanism proposal.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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