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Beilstein J. Org. Chem. 2017, 13, 1542–1550.
robust conditions. Reported protocols have employed chloro- gish, at room temperature. Reaction of the crude indolium salt
form [3], acetonitrile [19], acetone [20], nitromethane [21], 1,2- 3a with 3-methoxy-5-nitrosalicylaldehyde (5) was also con-
dichlorobenzene [22], toluene [23], reaction in the absence of ducted at room temperature and generated the ethanoic acid
solvent [24] or use of microwave irradiation [25]. We found substituted spiropyran C2SP, albeit in modest yield (Table 1,
that refluxing acetonitrile was relatively effective, if slow entry 2).
(completion in ca. 60 h), and that a more rapid process occurred
if the solvent was allowed to evaporate during the course of the Our attempts to synthesise C4SP using our two-step protocol
reaction (completion in ca. 20 h). The reaction in the absence of were undermined by the ineffective alkylation of trimethylin-
solvent was less effective, perhaps due to inefficient stirring of dolenine (1) with 4-bromobutyric acid (2c). Under our alkyl-
the small reaction volume (ca. 0.3 mL) or the absence of polar ation conditions, intramolecular lactonisation of 4-bromobu-
aprotic solvent-mediated acceleration of this SN2 process tyric acid to γ-butyrolactone (8) was more rapid than N-alkyl-
(Table 1, compare entries 6, 7 and 8).
ation and no indolium product was observed (Scheme 4).
Consequently, to obtain C4SP, we employed an optimised
The relative instability of indolium salts is well-documented version of the three-step procedure of Natali et al. [3], wherein
[26] and our attempts to purify compounds 3 by silica gel chro- lactonisation is avoided through the use of ethyl 4-bromobu-
matography or recrystallisation were unsuccessful. In light of tyrate, and basic ester hydrolysis is required as a final step
this, and given that our alkylation reactions were relatively (Table 1, entry 5).
clean, crude indolium salts 3 were then condensed with 3-me-
thoxy-5-nitrosalicylaldehyde (5) to give the required spiropy-
rans CnSP (Table 1). Commonly, this has been achieved
through simple reflux in ethanol; however, this transformation
proved relatively ineffective for alkylcarboxyindolium salts 3
and consequently, we applied alternative conditions using MEK
and piperidine [27]. This two-step approach was used to synthe-
Scheme 4: Lactonisation of 4-bromobutyric acid 2c.
sise a range of N-alkylcarboxyspiropyrans derived from
bromoalkanoic acids of varying chain length in two-step yields
from 60–82% (Table 1, entries 3, 7, and 9–11).
Binding studies
Analysis of spiropyran–merocyanine equilibria with respect to
This protocol was ineffective for the synthesis of C2SP (n = 1) metal binding has frequently employed UV-visible spectrosco-
and C4SP (n = 3). In the former case, the intermediate py. Merocyanine–metal cation complexes absorb strongly in the
N-ethanoate indolium salt 3a underwent thermal decarboxyl- visible range (often 450–600 nm), giving rapid access to clear,
ation to give N-methylindolium salt 7, in a similar manner to quantitative data at low concentrations and without interference
that previously reported [28]. Presumably, this reaction from paramagnetic transition metal cations (a feature which
proceeds via azomethine ylid 6 (Scheme 3); analogous indolium causes significant problems with NMR analysis). Conversely,
ylids have been used synthetically in 1,3-dipolar cycloadditions use of bound merocyanine–metal cation absorbance intensity as
[29] and mechanistic studies have been published on the related the sole metric for quantification of metal binding of different
decarboxylation of pyridinium 2-carboxylates [30]. Fortunately, metal cations should be undertaken with caution. Direct com-
α-bromocarbonyls such as bromoacetic acid are excellent SN2 parison of absorbance intensity measurements (as a surrogate
electrophiles, and N-alkylation of 2,3,3-trimethylindolenine (1) for concentration) is only valid if the molar extinction coeffi-
with bromoacetic acid (2a) was successful, if somewhat slug- cient, ε, remains constant for all merocyanine complexes of dif-
Scheme 3: Decarboxylation of N-ethanoic acid indolium salt 3a.
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