Selective C- tert -butoxycarbonylation using di- tert -butyl dicarbonate for the synthesis of multifunctional carbon compounds

Article abstract of DOI:10.1055/s-0029-1219826

The reaction of di-tert-butyl dicarbonate (Boc₂O) in the presence of the acylation catalyst 4-dimethylaminopyridine (DMAP) was examined with N-Boc or N-acyl cyanoglycinate. The couple Boc₂O/DMAP was found to act as an efficient agent for selective C-tert-butoxycarbonylation affording multifunctional carbon compounds.

Full text of DOI:10.1055/s-0029-1219826

LETTER
1331
Selective C-tert-Butoxycarbonylation Using Di-tert-butyl Dicarbonate for the
Synthesis of Multifunctional Carbon Compounds
Synthesis of
M
i
ultifun
é
c
tional Car
t
bon Co
r
mpound
i
s
ck Hudhomme*
Université d’Angers, CNRS UMR 6200, Institut des Sciences et Technologies Moléculaires d’Angers Moltech Anjou,
2 Boulevard Lavoisier, 49045 Angers, France
Fax +33(2)41735405; E-mail: pietrick.hudhomme@univ-angers.fr
Received 22 February 2010
Dedicated to Professor Guy Duguay on the occasion of his 77th birthday
H
C
H
C
H
Boc
Boc
Abstract: The reaction of di-tert-butyl dicarbonate (Boc2O) in the
presence of the acylation catalyst 4-dimethylaminopyridine
(DMAP) was examined with N-Boc or N-acyl cyanoglycinate. The
couple Boc2O/DMAP was found to act as an efficient agent for
selective C-tert-butoxycarbonylation affording multifunctional car-
bon compounds.
N
CN
N
N
CN
Boc
CO2R
CO2R
1a R = Me
1b R = t-Bu
2
Boc2O (1 equiv)
DMAP (0.1 equiv)
CH2Cl2, r.t.
CO2t-Bu
H
C
CN
Key words: acylation, carbanion, regioselectivity, protecting
groups, amino acids
Boc
CO2R
3a R = Me (79%)
3b R = t-Bu (76%)
Scheme 1
Di-tert-butyl dicarbonate (Boc2O) is a widely used
reagent1 for the efficient introduction of acid-labile Boc
protecting group for the amine functionality.2 This reagent
has also been investigated for the conversion of amines to
the corresponding isocyanates, carbamates, and urea de-
rivatives.3 In association with a catalytic amount of 4-
dimethylaminopyridine (DMAP),4 Boc2O is able to con-
vert N-acyl amino acid into the corresponding oxazole,5 to
react as an activating peptide-coupling reagent,6 or to al-
low the acylation of secondary amides in excellent
yields.7 The couple Boc2O/DMAP was also used for a
novel approach to prepare N,N-diacyl amino acid deriva-
tives.8 With the aim of realizing the N-tert-butoxycarbon-
ylation of N-Boc cyanoglycinates 1, we explored the
possibility of using the Boc2O/DMAP couple to reach cor-
responding N,N-diBoc derivatives 2.
We proceeded to extend this method by replacing the Boc
group with the acetyl group. Starting materials 4a11 and
4b were prepared by reaction of the corresponding 2-ami-
nocyanoglycinates using acetic anhydride in acetic acid.
Treatment of cyanoglycinates 4a and 4b with Boc2O and
a catalytic amount of DMAP afforded C-tert-butoxycar-
bonylated compounds 5a and 5b in 73% and 68% yield,
respectively (Scheme 2). The presence of the broad signal
for the NH group in the 1H NMR spectra and a quaternary
carbon at d = 59.9 and 60.7 ppm in 13C NMR spectra for
5a and 5b, respectively, are in agreement with structures
of compounds 5a and 5b.
Boc2O (1 equiv)
H
C
CO2t-Bu
CN
CO2R
H
H
DMAP (0.1 equiv)
Compounds 1 were prepared by treatment of 2-
aminocyanoglycinates9 with Boc2O in refluxing chloro-
form.10 Corresponding N-Boc cyanoglycinates 1a and 1b
were treated with Boc2O and a catalytic amount of DMAP
in CH2Cl2 at room temperature. Surprisingly, after work-
up and chromatographic purification, compounds 3a and
3b were isolated in 79% and 76% yield, respectively
(Scheme 1).
N
CN
N
C
CH2Cl2, r.t.
MeOC
MeOC
CO2R
4a R = Me
4b R = t-Bu
5a R = Me (73%)
5b R = t-Bu (68%)
Scheme 2
This reactivity could be explained by an initial reaction of
Boc2O with DMAP affording the highly reactive pyridin-
ium system which was accompanied with tert-butoxycar-
boxylate. The latter produced spontaneously carbon
dioxide and tert-butoxide which could act as a base.4 The
generation of the nucleophilic carbanion was followed by
the addition–elimination reaction on the pyridinium af-
fording C-tert-butoxycarbonylated product with regener-
ation of DMAP (Scheme 3). This catalytic effect of
DMAP has been proposed earlier by Knölker et al. in the
course of their isocyanate synthesis.3a
1
The H NMR spectra of 3a and 3b unambiguously con-
firmed the selective C-tert-butoxycarbonylation reaction
with the presence of a broad signal, characteristic of the
NH group. These structures of compounds 3a and 3b were
also in agreement with the presence in the 13C NMR spec-
tra of a quaternary carbon at d = 61.3 and 67.5 ppm, re-
spectively.
SYNLETT 2010, No. 9, pp 1331–1332
x
x.
x
x.
2
0
1
0
This constitutes an efficient procedure for C-tert-butoxy-
carbonylation using Boc2O reagent12 as an interesting
route to reach multifunctional carbon compounds.13 Final-
Advanced online publication: 15.04.2010
DOI: 10.1055/s-0029-1219826; Art ID: G06910ST
© Georg Thieme Verlag Stuttgart · New York

1332
P. Hudhomme
LETTER
O
O
( – CO2)
DMAP
O
O
–O
N+
+
N
–O
Ot-Bu
Ot-Bu
t-BuO
O
Ot-Bu
O
H
C
+
N
H
N
N
CN
R2
C
Ot-Bu
CO2R1
O
O
+
–
..
N
N
H
CO2t-Bu
CN
CO2R1
H
Ot-Bu
N
C
CN
R2
C
+
+
DMAP
N
C
HO
R2
CO2R1
C
O
O
Scheme 3
CH3CO), 3.94 (s, 3 H, CO2CH3), 6.92 (br s, 1 H, NH). 13C NMR
(62.5 MHz, CDCl3): d = 22.2, 27.5, 55.0, 59.9, 88.0, 113.1, 159.6,
162.4, 169.5. Anal. Calcd for C11H16N2O5 (256.26): C, 51.56; H,
6.29; N, 10.93. Found: C, 51.50; H, 6.31; N, 10.66.
ly, the N-tert-butoxycarbonylation could be achieved by
treatment of compound 3a with Boc2O in the presence of
DMAP and triethylamine to afford N,N-diBoc compound
6a in 65% yield (Scheme 4).
1
Compound 5b: white crystals; mp 129–130 °C (EtOAc–PE). H
NMR (250 MHz, CDCl3): d = 1.54 (s, 18 H, 2 CO2t-Bu), 2.11 (s, 3
H, CH3CO), 6.85 (br s, 1 H, NH). 13C NMR (62.5 MHz, CDCl3):
d = 22.3, 27.6, 60.7, 87.0, 113.5, 160.2, 169.5. Anal. Calcd for
C14H22N2O5 (298.33): C, 56.36; H, 7.43; N, 9.39. Found: C, 56.45;
H, 7.48; N, 9.31.
Boc2O (1 equiv)
Et3N (1 equiv)
DMAP (1 equiv)
CO2t-Bu
C CN
CO2t-Bu
CN
H
Boc
Boc
N
N
C
CH2Cl2, r.t.
Boc
CO2Me
CO2Me
Compound 6a: colorless oil. 1H NMR (250 MHz, CDCl3): d = 1.48
(s, 9 H, CO2t-Bu), 1.53 (s, 18 H, 2 Boc), 3.89 (s, 3 H, CO2CH3).
Anal. Calcd for C19H30N2O8 (414.45): C, 55.06; H, 7.30; N, 6.76.
Found: C, 55.18; H, 7.34; N, 6.85.
6a
3a
Scheme 4
In conclusion, the Boc2O/DMAP couple was shown to act
as an efficient C-tert-butoxycarbonylation agent for the
conversion of N-Boc and N-acyl cyanoglycinates into
multifunctional carbon compounds. This convenient
method opens up interesting possibilities for functionaliz-
ing quaternary carbon atoms in the field of non-natural
amino acid derivatives.
References and Notes
(1) (a) Wakselman, M. In Encyclopedia of Reagents for Organic
Synthesis, Vol. 3; Paquette, L. A., Ed.; John Wiley and Sons:
New York, 1995, 1602. (b) Mohapatra, D. K. Synlett 2001,
1995.
(2) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Chemistry, 3rd ed.; John Wiley and Sons: New York, 1999,
518.
(3) (a) Knölker, H. J.; Braxmeier, T.; Schlechtingen, G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2497. (b) Knölker, H. J.;
Braxmeier, T.; Schlechtingen, G. Synlett 1996, 502.
(c) Knölker, H. J.; Braxmeier, T. Tetrahedron Lett. 1996, 37,
5861.
(4) Basel, Y.; Hassener, A. J. Org. Chem. 2000, 65, 6368.
(5) Mohapatra, D. K.; Datta, A. Synlett 1996, 1129.
(6) Mohapatra, D. K.; Datta, A. J. Org. Chem. 1999, 64, 6879.
(7) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. J. Chem. Soc.,
Chem. Commun. 1985, 1317.
Typical Procedure
To a solution of N-Boc or N-acetyl cyanoglycinate 1 or 4, respec-
tively (10 mmol) in anhyd CH2Cl2 (or MeCN; 50 mL) were added
successively Boc2O (11 mmol) and DMAP (1 mmol). After stirring
for 3 h at r.t. under nitrogen atmosphere, the solution was washed
with a 10% aq solution of NaHCO3 (50 mL), then two times with
H2O (50 mL). The organic layer was dried (MgSO4), and the solvent
was removed in vacuo. The residue was purified by silica gel chro-
matography using CH2Cl2 as the eluent.
Compound 3a: colorless oil. 1H NMR (250 MHz, CDCl3): d = 1.47
(s, 9 H, Boc), 1.53 (s, 9 H, CO2t-Bu), 3.93 (s, 3 H, CO2CH3), 6.04
(br s, 1 H, NH). 13C NMR (62.5 MHz, CDCl3): d = 27.6, 28.2, 55.0,
61.3, 82.6, 87.6, 113.8, 153.1, 159.8, 162.8. Anal. Calcd for
C14H22N2O6 (314.33): C, 53.49; H, 7.05; N, 8.91. Found: C, 53.59;
H, 7.08; N, 9.02.
(8) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl.
1985, 24, 510.
(9) Duguay, G.; Guémas, J. P.; Meslin, J. C.; Pradère, J. P.;
Reliquet, F.; Reliquet, A.; Tea-Gokou, C.; Quiniou, H.;
Rabiller, C. J. Heterocycl. Chem. 1980, 17, 767.
(10) Hudhomme, P.; Duguay, G. Tetrahedron 1990, 46, 5263.
(11) Chehna, M.; Hudhomme, P.; Blanchard, P.; Duguay, G.
Sulfur Lett. 1994, 17, 317.
(12) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. Acta Chem.
Scand. Ser. B 1986, 40, 745.
(13) (a) Takeuchi, Y. Rev. Heteroat. Chem. 1991, 4, 64.
(b) Fujiwara, T.; Takeuchi, Y. J. Fluorine Chem. 2005, 126,
941.
1
Compound 3b: white crystals; mp 109-111 °C (Et2O–PE, 1:3). H
NMR (250 MHz, CDCl3): d = 1.48 (s, 9 H, Boc), 1.53 (s, 18 H, 2
CO2t-Bu), 5.96 (br s, 1 H, NH). 13C NMR (62.5 MHz, CDCl3):
d = 27.5, 27.8, 67.5, 85.2, 85.9, 114.2, 150.8, 159.0. Anal. Calcd for
C17H28N2O6 (356.41): C, 57.29; H, 7.92; N, 7.86. Found: C, 57.32;
H, 7.92; N, 8.25.
Compound 5a: white crystals; mp 108–110 °C (EtOAc–PE, 1:4). 1H
NMR (250 MHz, CDCl3): d = 1.54 (s, 9 H, CO2t-Bu), 2.12 (s, 3 H,
Synlett 2010, No. 9, 1331–1332 © Thieme Stuttgart · New York

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