N-Silylation of amines and amino acid esters under neutral conditions employing TMS-Cl in the presence of zinc dust

Article abstract of DOI:10.1016/j.tetlet.2005.04.007

An expedient synthetic approach to N-silylamines has been developed. The protocol, using TMS-Cl/zinc dust instead of BSA, is useful for the conversion of amines or amino acid esters to the corresponding silyl derivatives, followed by acylation with an acyl chloride or Fmoc-amino acid chloride to give the corresponding amide or peptide. This procedure, affording products in good to excellent yields, is also efficient for the coupling of sterically hindered amino acids like α,α-dialkylamino acids and NMe-amino acids. Further, the use of an equimolar quantity of organic base, such as Et ₃N/pyridine, is circumvented.

Full text of DOI:10.1016/j.tetlet.2005.04.007

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4099–4102
N-Silylation of amines and amino acid esters under neutral
conditions employing TMS-Cl in the presence of zinc dust
*
Vommina V. Suresh Babu, Ganga-Ramu Vasanthakumar and Subramanyam J. Tantry
Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi,
Bangalore 560001, India
Received 2 January 2005; revised 1 April 2005; accepted 4 April 2005
Available online 22 April 2005
Abstract—An expedient synthetic approach to N-silylamines has been developed. The protocol, using TMS-Cl/zinc dust instead of
BSA, is useful for the conversion of amines or amino acid esters to the corresponding silyl derivatives, followed by acylation with an
acyl chloride or Fmoc-amino acid chloride to give the corresponding amide or peptide. This procedure, affording products in good
to excellent yields, is also efficient for the coupling of sterically hindered amino acids like a,a-dialkylamino acids and NMe-amino
acids. Further, the use of an equimolar quantity of organic base, such as Et N/pyridine, is circumvented.
3
Ó 2005 Published by Elsevier Ltd.
1
. Introduction
the resulting N-trimethylsilyl amino acid esters for the
incorporation of sterically hindered amino acids into
1
2
The synthesis of N-silylamines is an important process in
–4
peptide sequences
by Carpino and BayermannÕs
1
organic and biological chemistry.
that the nucleophilicity of nitrogen can be increased by
It has been found
groups. However, the acetamide that resulted from
the reaction was difficult to remove from the reaction
medium and BSA is an expensive reagent. A prior
demonstration of the use of co-coupling agents such as
potassium salts of 1-hydroxybenzotriazole (KOBt) and
7-aza-1-hydroxybenzotriazole (KOAt), zinc dust, etc.,
with acid chlorides led us to explore N-silylation using
TMS-Cl and zinc dust under non-Schotten Baumann
5
silylation. Usually, the N-trimethylsilyl-amines or -lac-
tam derivatives have been synthesized by employing
trimethylchlorosilane (TMS-Cl) in the presence of an
equimolar quantity of an organic base such as Et N or
3
6
pyridine. The base abstracts the HCl liberated and
thereby the silylation goes to completion. Other reagents
used for N-silylation include trimethylsilylalkylamines,
hexamethyldisilazane, or a mixture of trimethylsilylam-
1
3–15
conditions.
7
ines and TMS-Cl. However, the methods available for
8
silylation of amines are not completely satisfactory.
The use of an equimolar quantity of a base results in side
2. Results and discussion
9
reactions including racemization in peptide synthesis.
Initially, N-silylation of aniline was carried out using
TMS-Cl and zinc dust to afford TMS-aniline as shown
in Scheme 1. This was then allowed to react with
benzoyl chloride at room temperature to furnish N-
phenyl- benzamide. The overall conversion took 10 min
b-Elimination of a Boc group was also observed in the
synthesis of microlin lipopeptides when silylation of a
lactam nitrogen was carried out in the presence of a
base. Whenever the situation requires the use of an
organic base to be avoided, N,O-bis(trimethylsilyl)acet-
amide (BSA) has been preferred. One such example re-
cently was illustrated by the use of BSA for silylation of
amino acid esters and the demonstration of the use of
1
0
1
1
H
N
TMS-Cl
1
R -COCl R1
R
NH2
TMS-HN
R
R
zinc dust
O
1
Keywords: N-Silylation; TMS-Cl/zinc dust; Acylation; Acid chlorides;
Peptides.
R = C H , C H CH , O NC H , H COC H ; R = C H
.
6
5
6
5
2
2
6
4
3
6
4
6
5
*
Corresponding author. Tel.: +91 80 2224 5566; fax: +91 80 2229
848; e-mail: hariccb@rediffmail.com
Scheme 1. Synthesis of amides employing N-silylated amines and acid
chlorides.
2
0
040-4039/$ - see front matter Ó 2005Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.04.007

4100
V. V. Suresh Babu et al. / Tetrahedron Letters 46(2005) 4099–4102
Table 1. Physical constants of amides
the characteristic stretching frequency for an acid
chloride at around 1780 cm
ꢀ1
.
Compound
Yield
%)
Melting point (°C)
(
17
Observed Reported
Since the addition of base is avoided, neither oxazol-5-
4H)-one formation nor the premature deblocking of
the Fmoc group was observed during coupling. The cou-
N-Phenylbenzamide
94
90
162–163
197–98
156–57
98
162
199
157
(
N-(4-Nitrophenyl)benzamide
N-(3-Nitrophenyl)benzamide
N-(2-Nitrophenyl)benzamide
N-Benzylbenzamide
88
1
pling, as monitored by H NMR, was free from racemiza-
8596–97
tion. Furthermore, the coupling of hindered amino acids,
such as a,a-dialkylamino acids and NMe-amino acids,
was also accomplished. The resulting peptide esters were
isolated and characterized as white solids in good yields
95104–106
104–105
N-(4-Methoxyphenyl)benzamide 92
N-(3-Methoxyphenyl)benzamide 87
N-(2-Methoxyphenyl)benzamide 89
152–53
103–104
60–61
153–154
—
60
(
Table 2). A comparison of the yields obtained using
different methods employing amino acid chlorides and
amino acid ester derivatives are given in Figure 1.
to complete. This encouraged us to extend the procedure
to other substituted anilines and benzylamine. In
these cases we observed that the silylation proceeded
smoothly and the resulting N-silylated derivatives were
acylated using benzoyl chloride to afford the corre-
In conclusion, an expedient approach for N-silylation of
both amines and amino acid esters by using TMS-Cl and
zinc dust instead of BSA has been demonstrated. The
resulting silylated derivatives were acylated using acid
chlorides under non-Schotten Baumann conditions.
sponding amides in good to excellent yields (Table 1).
All the amides prepared were characterized by
NMR and mass spectroscopy.
1
H
3. Experimental
Furthermore, the protocol for N-silylation of amino
acid esters was explored, which were to be used for pep-
tide coupling employing Fmoc-amino acid chlorides.
The amino acid methyl ester hydrochloride salt was ini-
3.1. Synthesis of amides employing N-silylated amines
and acid chlorides
tially deprotonated by stirring in dry CHCl for 10 min
3
in the presence of an equimolar quantity of zinc dust.
The resulting free amino acid ester was converted to its
To an amine (1 mmol) in dry CHCl (5mL), zinc dust
3
1
6
(0.070 g, 1 mmol) and TMS-Cl (0.1086 g, 1 mmol) were
added and mixture was stirred for 5min. The reaction
mixture was filtered under an N atmosphere, benzoyl
N-silylated derivative by treatment with TMS-Cl medi-
ated by zinc dust (Scheme 2). The silylation was found
2
chloride (1 mmol) added the filtrate and the stirring con-
tinued. After completion of the reaction (as monitored
by TLC), the mixture was diluted by adding CHCl3
1
to be complete within 5min as was confirmed by
H
NMR. The reaction mixture was filtered under an N2
atmosphere, to give the resulting N-silylated amino acid
esters. Fmoc-amino acid chloride in CHCl was added
(20 mL) and washed with 5% HCl, 5% NaHCO and
3
water and then dried over anhydrous Na SO . Evapora-
2
3
4
and stirring continued at room temperature. The acyl-
ation, as monitored by TLC and IR, was complete in
about 5–10 min. This was confirmed by the absence of
tion of the solvent in vacuo and recrystallization of the
resulting residue from CHCl /n-hexane (3:7) gave the
amide as a solid.
3
R5 R6
R5 R6
R5 R6
zinc dust
TMS-Cl
OMe
OMe
OMe
HCl.HN
R4
HN
R4
TMS-N
zinc dust
O
O
R4
O
1
+
R2 R3
R
N
4
O
R2 R3
Cl
Fmoc-N
R1
OMe
Fmoc-N
R5 R6
O
R1
O
3
2
1
2
3
4
5
6
Entry
R
R
H
R
R
R
R
a
b
c
d
e
f
H
H
H
H
H
H
CH
CH
CH
CH
H
2
2
2
2
C
6
H
5
H
H
H
H
H
CH
CH
CH
CH
H
CH
2
C
6
H
5
H
CH(CH
3
)
2
H
C
C
6
H
H
5
H
C
C
6
H
H
5
H
6
5
H
6
5
CH
H
CH
H
3
3
CH(CH
3
)
2
H
CH
H
3
3
CH
CH
CH
3
3
3
2
CH
CH
H
3
CH
CH
CH
3
3
3
2
3
3
3
2
g
h
i
3
H
CH
H
H
H
CH
CH
3
CH
2
CH
3
CH
CH
3
CH
3
2
3
5
6
j
R -R = (CH
2
)
5
H
R -R = (CH
2
)
5
entry : c, L-isomer ; entry : d, D-isomer
Scheme 2. Synthesis of peptides employing N-silylated amino acid esters and Fmoc-amino acid chlorides.

V. V. Suresh Babu et al. / Tetrahedron Letters 46(2005) 4099–4102
Table 2. Physical constants of N -Fmoc-protected dipeptide esters
4101
a
2
D
5
1
Peptide
Yield (%) Mp (°C) ½aꢁ (lit.)
H NMR (400 MHz, CDCl
3
)
18a
Fmoc-Gly-Phe-OMe
84
136
3
+16.12 (+16.0) (c = 1, CHCl )
d 2.11 (2H, s), 2.72 (2H, J = 6.4, d),
4
.25(1H, J = 6.8, t), 4.50 (2H, J = 6.8, d), 5.00 (1H, s),
.51 (1H, br), 7.32–7.80 (13H, m)
5
18b
Fmoc-Phe-Leu-OMe
90
156–57
ꢀ21.6 (ꢀ21.6) (c = 1, CHCl
3
)
d 0.85(6H, J = 7.32, d), 1.50–1.62 (3H, m), 3.04 (1H, q),
3
4
.20 (1H, q), 3.68 (3H, s), 4.22 (2H, J = 6.8, d),
.33 (1H, J = 6.8, d), 4.40 (2H, J = 6.6, d), 4.68 (1H,
J = 6.6, d), 6.41 (1H, br s), 6.90 (1H, br s),
and 7.12–7.70 (13H, m)
1
8c
Fmoc-L-Phg-Phe-OMe
93
92
191–92
192–93
+22.6 (+22.6) (c = 0.5, DMF) d 2.92 (2H, J = 6.6, t), 3.16 (1H, J = 6.6, t), 3.64 (3H, s),
.25(1H, J = 6.8, t), 4.52 (2H, J = 6.8, d), 5.22 (1H,
4
J = 6.6, d), 6.20 (1H, br s), 6.95(1H, br s),
and 7.30–7.90 (18H, m)
18c
Fmoc-D-Phg-Phe-OMe
+22.6 (+22.6) (c = 0.5, DMF) d 2.92 (2H, J = 6.6, t), 3.18 (1H, J = 6.6, t), 3.73 (3H, s),
4
.25(1H, J = 6.8, t), 4.52 (2H, J = 6.8, d), 5.23 (1H,
J = 6.6, d), 6.20 (1H, br s), 6.95(1H, br s), and
.3–7.9 (18H, m)
d 0.80 (6H, J = 7.4, d), 1.32 (3H, J = 7.4, d), 1.50
2H, J = 6.6, t), 2.42 (4H, m), 3.61 (3H, s), 4.12 (1H,
7
13b
Fmoc-NMeVal-Sar-OMe
83
88
88
88
82
86
80–82
70–71
70–71
70–71
122–24
164–66
3
+168.08 (c = 1, CHCl )
(
J = 6.8, d), 4.30 (2H, J = 6.8, t), 7.30–7.80 (8H, m)
d 0.92–2.10 (12H, m), 3.80 (3H, s), 4.1 (1H, J = 6.8, d),
15
Fmoc-Aib-Aib-OMe
—
—
—
—
—
4
7
.21 (2H, J = 6.8, t), 6.82 (1H, br s), and
.22–7.80 (9H, m)
12
Fmoc-NMeAib-Aib-OMe
d 0.92–2.11 (12H, m), 3.62 (3H, s), 3.80 (3H, s),
.10 (1H, J = 6.8, d), 4.21 (2H, J = 6.8, t), 6.82
1H, br s), and 7.22–7.80 (9H, m)
d 0.92–2.10 (9H, m), 3.65(3H, s), 3.82 (3H, s),
.10 (1H, J = 6.8, d), 4.21 (2H, J = 6.8, t), 6.80
1H, br s), and 7.20–7.80 (9H, m)
d 0.82–2.00 (20H, m), 3.70 (3H, s), 4.21
1H, J = 6.8, d), 4.32 (2H, J = 6.8, t), 6.60 (1H, br s),
.02 (1H, br s), and 7.20–7.80 (8H, m)
d 0.80–2.10 (20H, m), 3.72 (3H, s), 4.20 (2H, J = 6.8, t),
.51 (1H, J = 6.8, d), 5.93 (1H, s), 6.80 (1H, s),
and 7.30–7.80 (8H, m)
4
(
12
Fmoc-Ala-NMeAib-OMe
4
(
18d
Fmoc-Deg-Deg-OMe
(
7
18d
6 6
Fmoc-Ac c-Ac c-OMe
4
Comparison of yields obtained in different methods
employing Fmoc-Phg-Cl and H-Phe-OMe
acid chloride (1 mmol) in CHCl was added to the fil-
3
trate and the stirring was continued. After completion
of the reaction (as monitored by TLC), the mixture
was diluted by adding CHCl (20 mL) and washed with
1
00
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
3
5% HCl, 5% NaHCO and water and then dried over
3
anhydrous Na SO . Evaporation of the solvent in vacuo
2
4
and recrystallization of the resulting residue from
CHCl /n-hexane (3:7) gave the peptide as a solid.
3
TMS-HN-Phe-OMe
H-Phe-OMe, zinc dust
H-Phe-OMe, KOAt
H-Phe-OMe, KOBt
Acknowledgements
0
5
10
15
20
25
30
35
Time (min.)
These studies were supported by the Department of Bio-
technology, Government of India. We thank the faculty
members of the Sophisticated Instruments Facility, I. I.
Sc., for NMR data.
Figure 1. Comparison of yields obtained using different methods
employing Fmoc-Phg-Cl and H-Phe-OMe.
3.2. Synthesis of peptides employing N-silylated amino
acid esters and Fmoc-amino acid chlorides
References and notes
1
2
. Bircofer, L.; Ritter, A. Chem. Ber. 1960, 93, 424–427.
. Bircofer, L.; Ritter, A.; Neuhausen, P. Liebigs Ann. Chem.
The amino acid methyl ester hydrochloride salt
(
(
1 mmol) was deprotonated by stirring in dry CHCl3
5mL) with zinc dust (0.140 g, 2 mmol) for 10 min.
1
. Lukkainen, T.; VandenHeuvel, W. J.; Horning, E. C.
962, 659, 190–199.
3
TMS-Cl (0.1086 g, 1 mmol) was added and stirring
was continued for another 5min. The reaction mixture
was filtered under an N atmosphere, the Fmoc-amino
Biochem. Biophys. Acta 1962, 62, 153–159.
4. Horii, Z.; Makita, M.; Tamura, Y. Chem. Ind. 1965,
1494.
2

4102
V. V. Suresh Babu et al. / Tetrahedron Letters 46(2005) 4099–4102
5
. (a) Rajeswari, S.; Jones, R. J.; Cava, M. P. Tetrahedron 11. Klebe, J. F.; Finkbeiner, H.; White, D. M. J. Am. Chem.
Lett. 1987, 28, 5099–5102; (b) Podlech, J. In Methods of
Organic Chemistry (Houben–Weyl): Synthesis of Peptides
and Peptidomimetics; Goodman, M., Felix, A., Moroder,
L., Toniolo, C., Eds.; George Thieme Verlag Stuttgart:
New York, 2002; Vol. E22a, p 141.
Soc. 1966, 88, 3390–3395.
12. Wenschuh, H.; Bayermann, M.; Winter, R.; Bienert, M.;
Ionescu, D.; Carpino, L. A. Tetrahedron Lett. 1996, 37,
5483–5486.
13. (a) Sivanandaiah, K. M.; Suresh Babu, V. V.; Renukesh-
war, H. C. Int. J. Peptide Protein Res. 1992, 39, 201–206;
(b) Sivanandaiah, K. M.; Suresh Babu, V. V.; Shan-
karamma, S. C. Int. J. Peptide Protein Res. 1994, 44, 24–30.
14. Gopi, H. N.; Suresh Babu, V. V. Ind. Chem. Soc. 1998, 75,
511–513.
6
. (a) Hils, J.; Ruehlmann, K. Chem. Ber. 1967, 100, 1638–
1645; (b) Kricheldorf, H. R. Justus Liebigs Ann. Chem.
1972, 763, 17–38.
7
. Heberle, J.; Simchen, G. Silylating Agents, 2nd ed.;
Buchs, 1995.
8
. The silylating agents used are hexamethyldisilazane,
trimethylsilyalkylamines, or a mixture of trimethylsilyl-
amine and TMS-Cl. Silylations with hexamethyldisi-
lazane or silyl amines require prolonged heating and
continuous removal of ammonia or amine. The chlorosi-
lane-silazane mixture, while more reactive, has the
disadvantage of producing amine hydrochlorides
which are often difficult to separate from the desired
product.
15. Gopi, H. N.; Suresh Babu, V. V. Tetrahedron Lett. 1998,
39, 9769–9772.
16. Ananda, K.; Suresh Babu, V. V. J. Peptide Res. 2001, 57,
223–226.
17. Rodriguez, J.-G.; Rosa, M.-V.; Ramos, S. New J. Chem.
1998, 865–868, and references cited therein.
18. (a) Sivanandaiah, K. M.; Suresh Babu, V. V.; Shan-
karamma, S. C. Ind. J. Chem. 1992, 31B, 379–380; (b)
Suresh Babu, V. V.; Ananda, K.; Vasanthakumar, G.-R.
J. Chem. Soc., Perkin Trans 1 2000, 4328–4331; (c)
Carpino, L. A. J. Org. Chem. 1988, 53, 875–878; (d)
Ananda, K.; Gopi, H. N.; Suresh Babu, V. V. Lett.
Peptide Sci. 1998, 5, 277–283.
9
. Carpino, L. A.; Chao, H.-G.; Beyermann, M.; Bienert, M.
J. Org. Chem. 1991, 56, 2635–2642.
0. Mattern, R.-H.; Gunasekera, S. P.; McConnell, O. J.
1
Tetrahedron Lett. 1997, 38, 2197–2200.