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T. Baburaj, S. Thambidurai / Tetrahedron Letters 53 (2012) 2292–2294
able 50% aqueous NH2OH, by a two step high yielding chromatog-
raphy free synthesis.15
and deprotection (entries 6–10). Amino esters containing free NH
groups such as indole and imidazoles also reacted efficiently to
give the respective products (entries 11 and 12).
As an initial attempt the N-amination of L-phenyl alanine was
attempted using previously reported conditions for aliphatic
amines,15 and we could find that the reaction was not clean
and multiple impurities were observed. We felt that the solubility
of amino acid could be the reason for the failure and turned our
attention toward optimizing this. Carbamate esters of amino acids
were known to be produced using 1,4-dioxane and water solvent
combination with corresponding chloroformates or anhydrides, in
the presence of a base such as NaHCO3 or Na2CO3. When we used
this solvent combination (1,4-dioxane and water, 9:1) with
Na2CO3 as base and 1 equiv of 5, we could observe about 40%
of product formation. Increasing the quantity of 5 improved the
product formation to about 60%. In all these reactions we could
observe that reagent 5 was consumed within 30–45 min after
the addition. This clearly suggested that the reagent was decom-
posed when exposed to these reaction conditions for more than
30 min. Based on this observation, a reaction was carried out,
where reagent 5 was added lot-wise (0.25 eq/lot) with a time
gap of 30 min and interestingly the reaction showed about 70%
of conversion after the addition of one equivalent of reagent.
Complete conversion of the starting material was observed after
the addition of 1.5 equiv of reagent over a period of 3 h and the
isolated yield of the product was increased to 78%, after acid–base
work-up. Pure product 7a was collected by simple acid–base
work-up using glycolic acid followed by crystallization from
tert-butyl methyl ether, thus by avoiding stringent purification
by resin column chromatography.16 Since, the difficult task of
any conversion of amino acids and their derivatives is the reten-
tion of chiral purity, we decided to ensure the chiral purity of the
isolated product. For this study, we have converted DL-phenyl ala-
nine into the corresponding N-Boc-DL-phenyl hydrazino acid to
determine the enantiomeric purity of 7a by chiral HPLC, and we
could find that the reaction proceeded without any detectable
amount of racemization (no trace of the unwanted isomer was
in detectable limit).17
In conclusion, we have demonstrated a very efficient procedure
for the direct transformation of amino acids and its derivatives into
terminal Boc protected hydrazino acids and its derivatives by elec-
trophilic amination strategy. These protected hydrazino acid deriv-
atives could be used as very good intermediates to synthesize
biologically more active and metabolically more stable modified
peptides and other heterocyclic analogs. This methodology could
be employed to synthesize novel hydrazino analogs as well.
Acknowledgment
One of the authors, T.B. thanks the Anthem Biosciences Pvt. Ltd,
Bangalore, India, for infrastructure.
References and notes
1. Viret, J.; Gabard, J.; Collet, A. Tetrahedron 1987, 43, 891. and references cited
therein.
2.
a
-Azaamino acids as such are not known because of the instability of carbamic
acids, but the corresponding esters and amides are known.
3. (a) Karady, S.; Ly, M. G.; Pines, S. H.; Sletzinger, M. J. Org. Chem. 1971, 36, 1949;
(b) Gustafsson, H.; Ragnardsson, U. Acta Pharm. Suec. 1974, 11, 493; (c)
Gustafsson, H. Acta Chem. Scand. 1975, B29, 93.
4. Shestakov, P. Z. Angew. Chem. 1968, 46, 3013.
5. Sletzinger, M.; Firestone, R. A.; Reinhold, D. F.; Rooney, C. S.; Nicholson, W. H. J.
Med. Chem. 1968, 11, 261.
6. Achiwa, K.; Yamada, S. Tetrahedron Lett. 1975, 31, 2701.
7. (a) Gennari, C.; Colombo, L.; Bertolini, G. J. Am. Chem. Soc. 1986, 108, 6394; (b)
Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. J. Am. Chem. Soc. 1986, 108,
6395; (c) Trimble, L. A.; Vederas, J. C. J. Am. Chem. Soc. 1986, 108, 6397.
8. Brosse, N.; Pinto, M. F.; Bodiguel, J.; Jamart-Gregoire, B. J. Org. Chem. 2001, 66,
2869.
9. Vidal, J.; Drouin, J.; Collet, A. J. Chem. Soc., Chem. Commun. 1991, 435.
10. Niederer, D. A.; Kapron, J. T.; Vederas, J. C. Tetrahedron Lett. 1993, 34, 6859.
11. Vidal, J.; Hannachi, J. C.; Hourdin, G.; Mulatier, J. C.; Collet, A. Tetrahedron Lett.
1998, 39, 8845.
12. Vidal, J.; Guy, L.; Sterins, S.; Collet, A. J. Org. Chem. 1993, 58, 4791.
13. Carpino, L. A.; Giza, C. A.; Carpino, B. A. J. Am. Chem. Soc. 1959, 81, 955.
14. Genet, J. P.; Mallart, S.; Greck, C.; Piveteau, E. Tetrahedron Lett. 1991, 32, 2359.
15. Baburaj, T.; Thambidurai, S. Synlett 2011, 1993.
Having a very good method in hand, we screened a series of
amino acids and we could obtain good yields for all the amino
acids attempted by simple acid–base work-up (Table 1), except
in the cases of histidine and tryptophan (not shown in table). Since,
the starting materials’ consumption were observed in both the
cases, we suspect that sufficient quantity of the product was lost
during the work-up and this needs to be optimized further.
To study the reactivity of 5 with other amino acid derivatives, a
series of amino esters and amino alcohols were screened under
these reaction conditions (except the work-up procedure),18 and
we could isolate the required hydrazino derivatives with excellent
yields after purification by column chromatography over silica gel
(Table 2).
16. Typical procedure for amino acids: To a stirred suspension of L-phenyl alanine
(1 g, 6.1 mmol) in 1,4-dioxane and water (9:1, 50 ml) was added Na2CO3
(1.28 g, 12.1 mmol) and then Boc-NHOTs (2.61 g, 9.1 mmol) as six lots with a
time interval of 30 min. Reaction mixture was stirred at RT for 30 min, diluted
with water (25 mL), and extracted with tert-butyl methyl ether (2 Â 25 mL).
The combined organic layer was discarded and the aqueous layer collected was
acidified to pH ca. 5, using glycolic acid and extracted with EtOAc (25 mL Â 3).
The combined organic layer was dried over Na2SO4, filtered, and concentrated.
The solid obtained was crystallized from tert-butyl methyl ether to get the pure
product as white solid. 1H NMR (300 MHz, DMSO-d6): d = 1.06 (s, 9H), 3.02–
3.12 (m, 2H), 4.33–4.42 (m, 1H), 6.33 (d, J = 8.4 Hz, 1H), 7.15–7.32 (m, 5H), 8.74
(s, 1H), 11.45 (bs, 1H). 13C NMR (75 MHz, DMSO-d6): d = 26.6, 37.3, 53.7, 79.7,
127.0, 128.7, 129.7, 137.9, 160.4, 173.75. LC–MS (-ESI): 279.6 (MÀH)+.
17. Chiral HPLC: Chiralpack AD-H column, 250 Â 0.46 mm, 5
lM; mobile phase
A = n-hexane, B = 0.1% trifluoroacetic acid in ethanol; isocratic, A:B = 90:10;
wave length = 250 nm; flow rate = 1.0 mL/min; RT = 16.96 for R isomer and
27.04 for S isomer.
18. After the reaction was completed, 1,4-dioxane was removed under reduced
pressure and the residue diluted with water was extracted with EtOAc
(25 mL Â 3). The combined organic layer was dried over Na2SO4, filtered, and
concentrated. The crude obtained was purified by column chromatography over
silicagel using gradient of petroleum ether and EtOAc as solvent to get the pure
products.
The yields obtained for amino esters are slightly better than the
corresponding free amino acids (entries 2–4). It is noteworthy that
the amino esters and amino alcohols containing free hydroxy
groups need not be protected for this conversion under these reac-
tion conditions, thus avoiding the additional burden of protection