Organic Letters
Letter
enamines could be used in the IEDDA/PIRO reaction; 1-(6-
methoxy-3H-inden-1-yl)pyrrolidine (2c) and 1-(6-methly-3H-
inden-1-yl)pyrrolidine (2d), respectively, were converted to
the corresponding photo products 4h and 4i in good yields.
For the 5-bromo-substituted enamine 2e, the reaction
temperature was increased to 130 °C and the irradiation was
done at 425 and 470 nm. Again, the elimination reaction was
preferred in this case due to the harsher conditions, and the
corresponding photo product 4j was only isolated in a yield of
acid with the phthalazine reactant (1a). Nevertheless, the
desired photo product 4a was isolated in a 61% yield.
Based on previous studies of the IEDDA reaction, the
following mechanistic proposal is put forward for the IEDDA/
PIRO reaction. In the first step of the catalytic cycle, the
bidentate Lewis acid 3 coordinates to the phthalazine (1a) to
37
form complex 6. The activated phthalazine can now react
with an electron-rich dienophile, in this case enamine 7, to
form the intermediate 8 via an IEDDA reaction. The
elimination of nitrogen regenerates the BDLA and leads to
7
%.
Enamines with an increased ring size would give access to
37,40
the quinodimethane intermediate 9.
For the ring-opening,
even larger carbocycles. For example, the IEDDA/PIRO
reaction of phthalazine (1a) and 1-(1-cyclohepten-1-yl)-
pyrrolidine (2f) provided the 11-membered carbocycle 4k,
although in lower yields and as both double-bond isomers. To
obtain a better understanding of why the synthesis of 4k
yielded both isomers and that of 4g yielded a single isomer, a
computational analysis was conducted. Therefore, conformer
ensembles of compounds 4k_cis, 4k_trans, 4g_cis, and the
theoretical 4g_trans were computed with the Conformer−
a visible-light-promoted opening of the quinodimethane
42
intermediate 9 to enamine 10 is hypothesized. With 10π
electrons involved, this photo electrocyclization reaction has to
proceed conrotatory according to the Woodward−Hoffmann
43,54
rules.
The cyclic enamine 10 is transformed to the
corresponding cyclic ketone 11 during aqueous workup
(Scheme 2).
Scheme 2. Catalytic Cycle of the Domino Bidentate Lewis
Acid-Catalyzed IEDDA Reaction of Phthalazine (1a) and an
45,46
Rotamer Ensemble Sampling Tool (CREST)
developed by
a
Grimme and co-workers. The structures of the conformer with
Electron-Rich Dienophile 7
47
the lowest energy were further optimized on the PBE0 level
49,50
48
of theory with a def2-TZVP basis set and the D3-BJ
dispersion correction. High-level single-point corrections were
51
computed at the DLPNO−CCSD(T) level, also using the
def2-TZVP basis set. This computational analysis showed that
the difference in ΔG° between 4k_cis and 4k_trans was
merely 0.37 kcal/mol. For 4g and its theoretical trans-isomer,
this difference increased to 4.20 kcal/mol due to the higher
ring strain, clearly favoring the formation of a bowl-shaped
(
yield can be rationalized by the decomposition of the BDLA
over time, as the IEDDA reaction proceeded much slower.
42
Furthermore, both 1-(1-cyclohexen-1-yl)pyrrolidine and 1-(1-
cycloocten-1-yl)pyrrolidine were tested in the IEDDA/PIRO
reaction. However, these substrates did not react in the
IEDDA, probably due to the increased steric demand of these
enamines. In previous publications, we also showed that these
enamines need higher temperatures to undergo the IEDDA
38,52
reaction and form the corresponding eliminated products.
Therefore, we also tested the IEDDA/PIRO reaction with the
two isomeric six-membered enamines 1-(3,4-dihydronaphth-1-
yl)pyrrolidine and 1-(3,4-dihydronaphth-2-yl)pyrrolidine.
These reaction partners should have more planar ring systems
than 1-(1-cyclohexen-1-yl)pyrrolidine, reducing the steric
hindrance. However, the IEDDA reaction also did not proceed
in these cases.
a
The catalytic cycle was followed by the photoinduced ring-opening
(PIRO) reaction.
The method can easily be carried out on a gram scale. The
reaction of phthalazine (1a) and enamine 2b was set up in a
Schlenk tube, and the reaction mixture was irradiated with two
LEDs (470 and 500 nm). However, the larger diameter of the
reaction vessel reduced the penetration depth of the light,
favoring side reactions. Hence, the photo product 4a was
obtained in a lower yield of 57% compared to that of the small
scale.
In summary, we established the IEDDA/PIRO reaction of
phthalazines and cyclic enamines as a powerful tool for the
synthesis of medium-sized carbocycles. The scope of this
reaction was shown by screening differently substituted
phthalazines 1a−f and cyclic enamines 2a−f. We demonstrated
that the electron-rich enamines 2c and 2d and especially the
electron-deficient phthalazines 1b−e provided the correspond-
ing medium-sized carbocycles in good to very good yields.
However, the electron-rich phthalazine 1f and electron-
deficient enamine 2e only reacted sluggishly in the domino
IEDDA/PIRO reaction. By using enamines with different ring-
sizes, it was shown that sterics also influence the IEDDA/
PIRO reaction. Over all, the IEDDA/PIRO reaction offers a
Additionally, the IEDDA/PIRO reaction of phthalazine (1a)
and enamine 2a was performed with the air-stable variant of
53
temperature was slightly increased to 90 °C to speed up the
exchange of the coordinated pyridazine on the bidentate Lewis
2
091
Org. Lett. 2021, 23, 2089−2093