PAPER
Hexafluoroisopropanol as Catalyst for N-Boc Protection of Amines
3129
Table 2 Comparison of the Effect of Catalysts in N-Boc Protection
The physical data (mp, IR, NMR) of known compounds were found
to be identical with those reported in the literature. Spectroscopic
data for selected examples are given below.
of Aniline with (Boc) O
2
Entry Catalyst
Catalyst Time
load (%)
Solvent Isolated
yield (%)
tert-Butyl Azetidine-1-carboxylate (3j)
1
H NMR (500 MHz, CDCl ): d = 1.54 (s, 9 H), 2.18 (quint, J = 6.5
3
1
2
3
4
5
6
7
8
9
0
InCl3
10
10
10
10
10
20
5
30 min neat
1 h neat
90
Hz, 2 H), 3.94 (t, J = 5.0 Hz, 4 H).
1
3
FeCl3
89
74
89
95
C NMR (125 MHz, CDCl ): d = 15.7 (CH ), 28.7 (CH ), 44.1
3 2 3
(
CH ), 79.4 (C), 156.6 (C=O).
2
CAN
30 min neat
30 min neat
30 min neat
tert-Butyl (2-Hydroxyphenyl)carbamate (3k)
Yb(OTf)3
I2
1
H NMR (500 MHz, CDCl ): d = 1.57 (s, 9 H), 6.69 (br s, 1 H, OH),
.89 (t, J = 7.5 Hz, 1 H), 7.01 (d, J = 9.5 Hz, 1 H), 7.06–7.11 (m, 2
3
6
H), 8.17 (br s, 1 H, NH).
13
Yttria-zirconia
Zn(ClO ) ·6H O
14 h
MeCN 90
C NMR (125 MHz, CDCl ): d = 28.69 (CH ), 82.43 (C), 119.06
3
3
(
(
CH), 121.18 (CH), 121.71 (C), 125.87 (CH), 126.1 (CH), 147.75
C), 155.4 (C=O).
12 h
CH Cl
92
75
90
98
4
2
2
2
2
b-cyclodextrin
10
0.5
–
2.5 h
8 min
H O
2
tert-Butyl Benzyl-(2-hydroxyethyl)carbamate (3n)
1
H PW O
CH Cl
H NMR (500 MHz, CDCl ): d = 1.51 (s, 9 H), 2.18 (br s, 1 H, OH),
.44 (m, 2 H), 3.74 (m, 2 H), 4.50 (s, 2 H), 7.27–7.32 (m, 3 H), 7.37
3
3
12 40
2
2
3
1
(CF ) CHOH
10 min HFIP
3
2
(m, 2 H).
1
3
C NMR (125 MHz, CDCl ): d = 28.8 (CH ), 50.12 (CH ), 52.40
2 2
3
3
2
(
CH ), 62.2 (CH ), 80.94 (C), 128.0 (CH), 128.9 (CH), 138.68
reaction, the HFIP can be easily separated from the prod-
uct and reused (after fractional distillation from the co-
product tert-butyl alcohol) without any decrease in its ac-
tivity. For example, the reaction of (S)-a-methylbenzyl-
(
CH), 147.19 (C), 157.64 (C=O).
tert-Butyl [2-(2-Hydroxyethoxy)ethyl]carbamate (3q)
1
H -NMR (500 MHz, CDCl ): d = 1.37 (s, 9 H), 3.24 (m, 2 H), 3.47
3
amine (1e) and (Boc) O afforded the corresponding N- (t, J = 5.5 Hz, 2 H), 3.49 (t, J = 4 Hz, 2 H), 3.65 (t, J = 5 Hz, 2 H),
2
5
1
.25 (br s, 1 H, OH), 5.44 (br s, 1 H, NH).
Boc in 98, 95, and 95% isolated yield over three cycles.
3
C NMR (125 MHz, CDCl ): d = 28.73 (CH ), 40.70 (CH ), 61.71
2 2 2
3
3
2
In summary, we have described here an efficient method-
ology for N-tert-butoxycarbonylation of various electron-
ically and structurally divergent amines in good to
(
CH ), 70.58 (CH ), 72.67 (CH ), 79.56 (C), 156.64 (C=O).
excellent isolated yields. In contrast to the existing meth- Acknowledgment
ods using potentially hazardous catalysts/additives, this
Research supported by the National research Council of I. R. Iran as
a National Research project under the number 984.
new method offers the following competitive advantages:
i) avoiding the use of any base, metal, or Lewis acid cat-
(
alysts and reaction at room temperature (~25–30 °C), (ii)
short reaction times, (iii) ease of product isolation/non-
aqueous workup, (iv) high chemoselectivity, (v) no side
reaction, and (vi) simplicity in process and handling. The
recovered HFIP is ready for reuse.
References
(
1) (a) Wuensch, E. In Houben-Weyl, Methods of Organic
Chemistry, 4th ed.; Vol. 15/1; Mueller, E.; Bayer, O.;
Meerwein, H.; Ziegler, K., Eds.; Thieme: Stuttgart, 1974,
46. (b) Xiuo, X.; Ngu, K.; Choa, C.; Patel, D. V. J. Org.
Chem. 1997, 62, 6968. (c) Kociensky, P. J. Protecting
Groups; Thieme: Stuttgart, 2000. (d) Greene, T. W.; Wuts,
P. G. M. Protective Group in Organic Synthesis, 3rd ed.;
Wiley: New York, 1999.
All NMR spectra were recorded on a Bruker Avance 500 spectrom-
eter operating at 500 MHz ( H NMR) or 125.7 MHz ( C NMR) in
1
13
CDCl . Chemical shifts (d) are given in ppm relative to TMS. Cou-
3
pling constants are given in Hz. All starting materials and HFIP are
commercially available.
(2) Merrifield, R. B. J. Am. Chem. Soc. 1964, 86, 304.
(3) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368.
(
4) (a) Aqueous NaOH: Lutz, C.; Lutz, V.; Knochel, P.
N-tert-Butoxycarbonylation of Amines or Amine Derivatives;
General Procedure
Tetrahedron 1998, 54, 6385. (b) K CO -Bu NI in DMF:
2
3
4
Handy, S. T.; Sabatini, J. J.; Zhang, Y.; Vulfora, I.
To a solution containing di-tert-butyl dicarbonate (218 mg, 1 mmol)
in HFIP (1 mL) was added the amine or amine derivative (1 mmol)
and the mixture was vigorously stirred at r.t. Effervescence oc-
curred immediately after the addition of the amine. The products
were isolated by filtration (for solid products) or after selective
evaporation of the HFIP (for liquid products) to yield the highly
pure N-Boc derivatives.
Tetrahedron Lett. 2004, 45, 5057. (c) Me NOH·5H O in
MeCN: Khalil, E. M.; Subasinghe, N. L.; Johnson, R. L.
4
2
Tetrahedron Lett. 1996, 37, 3441. (d) NaHCO in MeOH
3
under sonication: Eunhorn, J.; Einhorn, C.; Luche, J.-L.
Synlett 1991, 37. (e) NaHMDS in THF: Kelly, T. A.;
McNeil, D. W. Tetrahedron Lett. 1994, 35, 9003.
(
(
(
5) Knoelker, H.-J.; Braxmeier, T. Tetrahedron Lett. 1996, 37,
5861.
The recovery of HFIP from the product mixture was done by frac-
tional distillation below 60 °C. Upon evaporation of the solvent,
pure HFIP was obtained (by NMR analysis). The recovered HFIP
was reused for subsequent runs.
6) Darnbrough, S.; Mervic, M.; Condon, S. M.; Burns, C. J.
Synth. Commun. 2001, 31, 3273.
7) Heydari, A.; Kazem Shiroodi, R.; Hamadi, H.; Esfandyari,
M.; Pourayoubi, M. Tetrahedron Lett. 2007, 48, 5865.
Synthesis 2008, No. 19, 3126–3130 © Thieme Stuttgart · New York