Unfortunately, reliable pKa data could not be obtained for
the 5- and 6-isomers since both appeared to undergo
decomposition under the conditions of the determination.10
In contrast to the results of these two coupling reactions,
it was of interest to compare reactivities for a system in which
neighboring group effects cannot be involved. Such a reaction
is that outlined in eq 2, namely the SN2 demethylation of
the methyl ethers of the HOAt derivatives by thiophenoxide
ion.11 Here the order should be determined only by the
leaving group ability of 21, which should follow the order
of acidity of the HOAt derivatives.
mp 140-141 °C, that we assign as the O-methyl ether
structure, based on the X-ray crystallographic determination,
1
which confirms the H NMR assignment. It is not certain
whether these two compounds are the same. The various
methylation products are listed in Table 5, Supporting
Information.
Rough demethylation reactivities were easily determined
by an NMR method using the thiophenoxide ion11b as
nucleophile. The results are collected in Table 2. As expected
Table 2. Approximate Halftimes for the Demethylation of the
O-Methyl Ethers of Various 1-Hydroxybenzotriazoles by Means
of Sodium Thiophenoxide
pKa of the
appropriate
t1/2 (min) for
t1/2 (min) for
ether
n-HOAt or HOBt DMSO-d6/CDCl3 DMF-d7/CDCl3
The ethers were easily synthesized by reaction with various
methylating agents.12 Previously methylation products de-
rived from the 7- and 4-isomers have been described, with
the 7-compound being assigned the normal O-ether structure
23 and the 4-compound the N-structure 24.13
Me-7-OAt
Me-6-OAt
Me-5-OAt
Me-4-OAt
Me-OBt
3.47
19
4
6
11
50
26
4
8
3.14
4.70
12
for the systems for which pKa data have been reported,5 the
speed of SN2 demethylation is correlated to the acidity of
the HOXt system, with the most acidic derivative providing
for the highest reactivity. For the 4- and 7-HOAt isomers,
these reactivities are the reverse of those seen during peptide
coupling reactions.
The high reactivity shown by the 5- and 6-isomers,
especially the latter, is suggestive of a higher acidity for these
isomers relative to the 4-isomer. Validation of this prediction
must await a determination of the appropriate pKa values.
In addition to enhancing the reactivity of active esters
derived from 7-HOAt, the neighboring group effect has also
been suggested as an explanation for the lowered loss of
configuration observed generally for segment coupling
processes involving 7-HOAt as an additive relative to cases
involving either 4-HOAt or HOBt.1 These tests have now
been extended to include the 5- and 6-isomers.
In earlier work, methylation of HOBt was shown to give
a mixture of O- and N-forms 25 and 26.12b Of the two
1
N-hydroxy benzotriazole dervivatives, 25 shows in its H
NMR spectrum a singlet for the O-methyl ether at δ 4.39
whereas the N-methyl peak of 26 is found at δ 4.11. All
four ethers derived from the four HOAt isomers show
singlets at δ 4.43-4.49 indicative of the O-methyl structure.
Two systems were examined. One involved the [2 + 1]
coupling of Z-Phe-Val-OH and H-Pro-NH2 by a method
The compound described by Azev and co-workers13 as
24 had a mp 136-138 °C. Carrying out the methylation
under comparable conditions gave in our hands a compound,
Table 3. Effect of Various Additives on Loss of Configuration
at Valine during Formation by Segment Coupling in DMF of
the Tripeptide Z-Phe-Val-Pro-NH2 and the Hexapeptide
Z-Gly-Gly-Val-Ala-Gly-Gly-OMea
(10) For the method used, see: Isaacs, N. S. Experiments in Physical
Organic Chemistry; Macmillan: London, 1996; pp 8-14.
(11) The demethylation of aryl methyl ethers is a well-known model for
this reaction. For examples of useful nucleophiles and selectivities seen
based on the position of substitution by electron-withdrawing groups, see:
(a) Cahn, R. J. Chem. Soc. 1931, 1121. (b) Hansson, C.; Wickberg, B.
Synthesis 1976, 191. (c) Feutrill, G. I.; Mirrignton, R. N. Tetrahedron Lett.
1970, 12, 1327. (d) Sheehan, J. C.; Daves, G. D., Jr. J. Org. Chem. 1964,
29, 2006.
(12) (a) Yutilov, Yu. M.; Ignatenko, A. G. Khim. Prom-st. Ser. Reakt.
Osobo Chist. VeshchestVa 1981, 3, 27 [Chem. Abstr. 1982, 96, 68773s].
(b) Brady, O.; Reynolds, C. V. J. Chem. Soc. 1928, 193. (c) Aoyama, T.;
Terasawa, S.; Sudo, K.; Shiori, T. Chem. Pharm. Bull. 1984, 32, 3759. (d)
Aoyama, T.; Shiori, T. Tetrahedron Lett. 1990, 31, 5507.
Z-Phe-Val-Pro-NH2, Z-Gly-Gly-Val-Ala-Gly-Gly-OMe,
additive
% LDL (yield, %)
% DL (yield, %)
7-HOAt
6-HOAt
5-HOAt
4-HOAt
HOBt
6.2 (95)
11.0 (95)
12.0 (95)
13.2 (95)
19.8
1.9 (89)
4.7 (85)
4.7 (84)
3.6 (91)
5.3 (98)
a Conditions: EDC‚HCl/TMP (1)/n-HOAt (1). The results given are the
averages for three separate runs.
(13) Azev, Yu. A.; Mokrushina, G. A.; Postovskii, I. Ya.; Sheinker, Yu.
N.; Anisimova, O. S. Chem. Heterocycl. Compds. 1976, 1172.
Org. Lett., Vol. 2, No. 15, 2000
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