To characterize this phenomenon in additional detail,
electronic structure calculations were undertaken to predict
the structures and reactivities of the N-methyl-4,5-, 5,6-, and
6,7-indolynes with furan and 2-alkylfurans. Similar calcula-
tions were also undertaken for the benzofuran and ben-
zothiophene analogues of the indolynes as these heterocycles
may prove useful for the construction of other interesting
natural (or unnatural) products. With respect to methodology,
all structures were optimized using the M06-2X density
functional10 and 6-311+G(2df,p) basis set11 as implemented
in MN-GFM,12 a locally modified version of the Gaussian03
software package.13 Analytical frequency calculations were
employed to characterize the nature of all gas-phase struc-
tures as minima or transition states. In select instances, the
effects of diethyl ether solvation were taken into account
using the SMD14 implicit solvation model.
Table 2. ∆Gq Values in kcal/mol for the Reaction of Indolynes
with Substituted Furans
entry
aryne
furan, R
∆Gq (a)
∆Gq (b)
Table 2 lists the activation free energies computed for the
reaction of the N-methylindolynes with the furans. With
unsubstituted furan, ∆Gq is similar for the 4,5- and 5,6-
indolyne isomers, and slightly smaller for the 6,7-isomer.
Considering 2-t-butylfuran, the predicted free energies of
activation are reduced by 3-4 kcal/mol compared to reaction
with furan itself in the 4,5- and 5,6-indolyne cases. Regi-
oselection becomes possible upon 2-substitution of the furan,
and the differential free energies of activation in these two
instances are predicted to be 1 kcal/mol or less. In the 6,7-
indolyne case, by contrast, a free energy of activation similar
to those for 4,5 and 5,6 is predicted for the formation of
26a (which is equivalent to 19 but lacks the 3-phenyl
substituent), but no transition-state (TS) structure for the
formation of 26b (corresponding to desphenyl 20) could be
locatedsthe approach of the furan to the indolyne led
smoothly and without barrier to the final tetracyclic product
in every instance.
1
2
3
4
5
6
7
8
9
21
22
23
21
22
23
23
23
23
H
H
H
t-Bu
t-Bu
t-Bu
Me
Et
10.5
10.0
8.7 (8.4)a
6.3
7.3
6.9
6.1
b
7.0 (8.0)
9.2 (9.4)
9.0 (9.4)
9.7 (10.3)
7.5 (7.8)
7.8 (8.2)
7.6 (8.2)
i-Pr
a Values in parentheses include continuum ethereal solvation effects.
b No barrier to reaction is predicted in the gas phase or continuum solution.
of the latter in each case, with the margin being largest (2.1
kcal/mol) for R ) i-Pr. Ethereal solvation effects on the free
energies of activation are predicted from the SMD continuum
model to be 1 kcal/mol or smaller in every instance and to
have no influence on regioselection.
Inspection of the TS structures for the formation of 26b
with the smaller alkyl groups provides insight into the failure
to find such a TS structure for t-Bu. There are significant
steric interactions between the N-Me group of the indolyne
and the 2-alkyl group on the furan so that the bond forming
to the 6 position is substantially shorter than that to the 7
position. The difference in the two formation bond lengths
becomes increasingly long as the substituent is varied from
Me to Et to i-Pr. This increase, however, is probably not
associated with larger steric bulk since each of these furan
2-alkyl substituents orients a C-H bond toward the N-methyl
group to minimize steric clash. Instead, it becomes clear from
consideration of the preference for 26b over 26a and
inspection of partial atomic charges that the 6,7-“cycload-
dition” has substantial electrophilic substitution character.
Thus, the electron-poor indolyne attacks the 2-substituted
furan to generate the more stable 2-alkyldihydrofurylcarbe-
nium ion. As the 2-substituent is varied from Me to Et to
i-Pr, the increased stabilization provided by the larger alkyl
groups increases this character and leads to increased
regioselection and increased electrophilic substitution char-
acter so that bond formation becomes decreasingly synchro-
nous. Thus, it appears that in the case of R ) t-Bu the
combination of unavoidably increased sterics (there is no
longer a C-H bond that can be disposed toward the N-Me
group) and enhanced carbenium ion stabilization switches
To better understand this point, the reactions of other
2-alkylfurans with 23 were modeled. With R ) Me, Et, or
i-Pr, TS structures for formation of 26b could be found in
every instance. Interestingly, the differential free energies
of activation for formation of 26a vs 26b favored formation
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Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
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Org. Lett., Vol. 12, No. 1, 2010