G. Blaser et al. / Tetrahedron Letters 49 (2008) 2795–2798
2797
of lower reactivity and gave moderate yields. More electron
rich indoles were found to be highly reactive towards elec-
trophilic attack, leading to double-substitution at positions
C-2 and C-3. Reaction yields were therefore maximised by
adjusting the stoichiometry accordingly, either by increas-
ing or decreasing the amount of indole for electron defi-
cient and electron rich compounds, respectively. The
highest yields were observed for substituents with interme-
diate electron releasing ability (Table 1, entries a, b, g and
h; R = Cl, F). The total conversion of indole to product
could be further improved by recycling unreacted indole
recovered from the reaction.
A drawback of the substitution reaction is the racemisa-
tion of the amino acid stereocentre. As the reaction
between indole and L-serine is conducted under acidic con-
ditions, it is probable that the observed racemisation pro-
ceeds neither via oxazolone formation, nor via a classical
direct enolisation, both of which require the presence of a
base. On the other hand, azlactone formation is promoted
under the conditions used in this synthesis, which will
undoubtedly contribute to the formation of racemates.11
It also seems likely that racemisation can occur during
the formation of reactive intermediates from serine. Inter-
estingly, N-acetyl dehydroalanine (9, Scheme 2) was iso-
lated as a by-product in reactions with less reactive indoles.
The above observation is consistent with the known
reaction between indole and 9 to produce tryptophan,
which occurs under acidic conditions.12,13 Formation of 9
from either L-serine or D,L-serine by heating with acetic
anhydride in acetic acid has been described.13 However,
on repeating this reaction we found the major component
of the mixture to be N,O-diacetyl D,L-serine (7b).
A plausible mechanism for the formation of 9 is through
acid-promoted loss of acetic acid from the acylated L-serine
intermediate 7a (Scheme 1). This will be assisted by neigh-
bouring group participation from the N-acetyl group, lead-
ing to the formation of the cationic species 8a as a transient
intermediate, before the loss of a proton to form 9. These
kinds of neighbouring group effects have been observed
for serine in the gas phase14 and are likely to persist to a
lesser extent in solution. Under the conditions used, N-
acetyl dehydroalanine would be susceptible to the addition
of acetic acid across the olefinic double bond to form 7b
(the racemic counterpart of 7a). Protonation of the olefinic
bond of 9 as a precursor to addition of acetic acid will form
8b (the racemic counterpart of 8a), with neighbouring
group participation again helping to stabilise the cationic
species. We anticipate that the reaction of indoles with elec-
trophile 8b is the product forming step in the conversion to
tryptophan analogues. Under the experimental conditions
used, the steady-state concentration of electrophile 8b is
expected to be extremely low, but nevertheless sufficient
for product formation. Direct reaction of N-acetyl dehy-
droalanine (9) with indoles in the presence of acetic anhy-
dride and acetic acid tends to give significantly lower
yields than the corresponding reaction with serine,13 which
suggests that the equilibrium between 9 and 8b lies in
Figure 1. Molecular structure of the methyl ester of 3eÁCDCl3. Thermal
ellipsoids are drawn at the 50% probability level (CCDC Ref. 670184).
extremely long intermolecular N–HÁ Á ÁO bond (NÁ Á ÁO dis-
˚
tance of 3.522(2) A), which can be explained by competi-
tion from the intramolecular interaction N2–HÁ Á ÁO2. The
N1–H group, which has no such hindrance, forms only a
weak N–HÁ Á Áp bond with the indole C-8 atom of an adja-
cent molecule. The planar C14–O1–O2–C1–C11 ester
group (i) and the N2–C12–O3–O4 moiety (ii) form an
interplanar angle of 15.8° between them and are inclined
by 52.4° and 45.8° to the indole plane, which forms a
70.3° angle with the fluorene plane.
Compounds 1b (Fig. 2) and 6b both crystallise in centro-
symmetric space groups (i.e., as racemates). Bond distances
are unexceptional (see Supplementary data, Table S3),
˚
although the C–Cl distances (1.754(2) and 1.757(4) A,
respectively) fall within the longest decile of C(sp2)–Cl
bonds present in the Cambridge Structural Database (cf.
˚
˚
the mean of 1.742(7) A and the median value of 1.741 A
for low-temperature structures).8 In either structure all
the NH and OH groups donate intermolecular hydrogen
bonds to terminal (carbonyl) O atoms, giving rise to a 3-
dimensional network, in which the chlorine atom plays
no role. In other respects, the tryptophan conformations
are similar to those of the parent compounds.9,10
The relative success of the electrophilic substitution
depends on the electron density distribution on the indole
ring. The less electron rich nitro-substituted indoles were
Figure 2. Molecular structure of 1b (L molecule in the racemic crystal;
CCDC Ref. 670183). Thermal ellipsoids are drawn at the 50% probability
level.