A modified Curtius reaction: an efficient and simple method for direct isolation of free amine

Article abstract of DOI:10.1016/j.tetlet.2009.11.038

The Curtius rearrangement and related reactions are often used to convert carboxylic acids to the corresponding primary amines. However, this reaction often requires harsh conditions for hydrolysis of the isocyanate intermediates to amines, and can also be contaminated by the formation of corresponding ureas due to the reactive nature of the intermediates. We have discovered that by quenching the isocyanate intermediates with sodium trimethylsilanolate, the free amines can be isolated after aqueous workup. This mild and fast procedure provides free amines in one pot with good yields.

Full text of DOI:10.1016/j.tetlet.2009.11.038

Tetrahedron Letters 51 (2010) 385–386
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Tetrahedron Letters
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A modified Curtius reaction: an efficient and simple method for direct
isolation of free amine
*
*
Bin Ma , Wen-Cherng Lee
BiogenIdec Inc., 12 Cambridge Center, Cambridge, MA 02142, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The Curtius rearrangement and related reactions are often used to convert carboxylic acids to the corre-
sponding primary amines. However, this reaction often requires harsh conditions for hydrolysis of the
isocyanate intermediates to amines, and can also be contaminated by the formation of corresponding
ureas due to the reactive nature of the intermediates. We have discovered that by quenching the isocy-
anate intermediates with sodium trimethylsilanolate, the free amines can be isolated after aqueous
workup. This mild and fast procedure provides free amines in one pot with good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 29 October 2009
Accepted 9 November 2009
Available online 13 November 2009
Keywords:
Curtius reaction
NaOTMS
DPPA
Amine
Carboxylic acid
Amines are important functional groups in a variety of biologi-
cally interesting materials, including biopolymers, drugs, and
dyes.1 Among a number of methods developed to synthesize
amines, the Curtius rearrangement is particularly popular as it pro-
vides an efficient means to amines from readily available carbox-
ylic acids, especially for the synthesis of sterically hindered
amines.2 Discovered in 1890 by Theodor Curtius,3 this reaction in-
volves the formation of an unstable acyl azide (2) from a carboxylic
acid (1), followed by the rearrangement to an isocyanate (3) with
the loss of a N2. The isocyanate can be trapped by a variety of
nucleophiles. When the reaction is performed in the presence of
benzyl alcohol, the reaction generates Cbz-protected amines (4),4
while Boc-protected amines are formed with tert-butanol (5).5 Free
amines (6) can be obtained after deprotection of the Cbz- or Boc-
protected amines (Scheme 1).
reaction times, high temperatures, or the use of strong acids or
base, particularly for sterically hindered precursors.6 Often, the
hydrolyzed product may be contaminated with the corresponding
urea7 due to the reactive nature of the isocyanate intermediate. A
mercuration–demercuration method has been reported.8
In this Letter, we now report a very simple modification of Cur-
tius reaction by quenching the isocyanate intermediates (3) with
sodium trimethylsilanolate (NaOTMS), which provides an efficient
one-pot method for direct isolation of free amines. The experiment
was designed as a two-stage process. First, diphenylphosphoryl
azide (DPPA)9 was selected to convert the carboxylic acid into an
isocyanate with minimal accumulation of the unstable acyl azide,
and the isolation of isocyanate was avoided. Next, workup with
NaOTMS hydrolyzes the isocyanate to free amine.10 Based on this
strategy, toluene was found to be a suitable solvent for both steps,
and the free amine can be isolated after aqueous workup
(Scheme 2).
The hydrolysis of isocyanate (3) with water should give primary
amines (6) directly. However, this hydrolysis either requires long
H
N
R
R
Cbz
Boc
BnOH
tBuOH
4
O
O
H
O
N3-P
heat
C
N
R
N3
R
NH2
R
OH
R
N
1
2
3
5
6
hydrolysis
Scheme 1.
* Corresponding authors. Tel.: +1 617 914 4955; fax: +1 617 679 3635.
E-mail addresses: bin.ma@biogenidec.com (B. Ma), wen-cherng.lee@biogenidec.com (W.-C. Lee).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.038

386
B. Ma, W.-C. Lee / Tetrahedron Letters 51 (2010) 385–386
These conditions worked very well for aliphatic amines, includ-
ing sterically hindered amines (Table 1).11 A variety of functional
groups were well tolerated (Table 1, entries 1–5). Aromatic amines
were also accessible, though the hydrolysis required a longer time
at room temperature (Table 1, entry 7). In addition to being a mild
and fast reaction, there was no epimerization for the conversion of
chiral carboxylic acids into the corresponding chiral amines (Ta-
ble 1, entries 8–10). For example, when the commercially available
acid 1h (99% ee) was treated under these conditions, 6h was ob-
tained with greater than 78:1 dr as determined by its Mosher ester
derivatives.
In conclusion, we have shown that the NaOTMS-modified Cur-
tius reaction can be used to convert a variety of carboxylic acids di-
rectly to the corresponding primary amines with good functional
group tolerance. This one-pot procedure is simple, mild, and effi-
cient, and is expected to be applied to the synthesis of structurally
more complicated molecules.
O
O
DPPA, toluene
reflux
NaOTMS,
R
NH2
C
R
N
R
OH
THF/toluene, 0° C
1
3
6
Scheme 2.
Table 1
NaOTMS-modified Curtius reaction of carboxylic acidsa
Entry
1
Carboxylic acid
Amine
Yieldb (%)
56
ButO2C
CO2H
CO2H
ButO2C
NH2
NH2
1a
1b
6a
6b
2
87
O2N
O2N
3
4
1c
6c
88
MeO
CO2H
MeO
NH2
Boc
CO2H
Boc
N
NH2
N
76c
1d
6d
Acknowledgement
63, 79c
1e
6e
We thank Professor John K. Snyder for reviewing this
manuscript.
5
CO2Me
CO2H
CO2Me
NH2
References and notes
1f
6f
6
7
8
70
1. (a) Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57, 7785–7811.
and references cited therein; (b) Miriyala, B.; Bhattacharyya, S.; Williamson, J.
Tetrahedron 2004, 60, 1463–1471. and references cited therein.
2. Selected reviews: (a) Smith, P. A. S. Org. React. 1946, 3, 337–349; (b) Scriven, E.
F.; Turnbull, K. Chem. Rev. 1988, 88, 297–368.
3. (a) Curtius, T. Ber. 1890, 23, 3023–3041; (b) Curtius, T. J. Prakt. Chem. 1894, 50,
275; (c) Curtius, T. J. Prakt. Chem. 1915, 91, 39–102.
4. Selected examples: (a) Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J.
Org. Chem. 1978, 43, 2164–2167; (b) Ende, D. J. A.; DeVries, K. M.; Clifford, P. J.;
Brenek, S. J. Org. Proc. Res. Dev. 1998, 2, 382–392.
5. Selected examples: (a) Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E.. In
Organic Syntheses; Wiley: New York, 1988; Vol. VI; (b) Nettekoven, M.; Jenny, C.
Org. Process Res. Dev. 2003, 7, 38–43; (c) Lebel, H.; Leogane, O. Org. Lett. 2005, 7,
4107–4110.
6. Selected examples: (a) Weinstock, J. J. Org. Chem. 1961, 26, 3511; (b) Boger, D.
L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc. 1993, 115, 10733–10741; (c)
Fairweather, K. A.; Mander, L. N. Org. Lett. 2006, 8, 3395–3398.
7. Selected examples: (a) Capson, T. L.; Poulter, C. D. Tetrahedron Lett. 1984, 25,
3515–3518; (b) Earley, W. G.; Jacobsen, J. E.; Madin, A.; Meier, G. P.; O’Donnell,
C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127,
18046–18053; (c) Yue, T.-Y.; McLeod, D. D.; Albertson, K. B.; Beck, S. R.;
Deerberg, J.; Fortunak, J. M.; Nugent, W. A.; Radesca, L. A.; Tang, L.; Xiang, C. D.
Org. Process Res. Dev. 2006, 10, 262–271.
8. Malanga, C.; Urso, A.; Lardicci, L. Tetrahedron Lett. 1995, 36, 8859–8860.
9. (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203–6205;
(b) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151–2157; (c)
Wolff, O.; Waldvogel, S. R. Synthesis 2004, 1303–1305.
CO2H
NH2
45d
76
1g
6g
CO2H
OH
NH2
1h
6h
6i
NH2
O
O
O
OBut
OBut
O
O
67 ,76c
1i
1j
9
OH
NH2
OBut
OBut
O
6j
O
10
58
OH
NH2
a
Conditions: DPPA (1.0 equiv), Et3N (1.2 equiv), toluene, reflux, 2–3 h; NaOTMS
(2.0 equiv, 1 M in THF), 0 °C or rt.
b
Yield after column chromatography purification.
Crude yield, after the acidic/basic extraction.
Hydrolysis complete within 6 h at room temperature.
c
d
10. Using NaOH the produced amine contaminated with urea, and a much higher
temperature and long reaction time were required for hydrolysis.
11. All starting carboxylic acids were purchased from commercial sources, except
1i and 1j. 1i and 1j were synthesized from the corresponding Evan’s auxiliaries
as shown in the following scheme.
The following is a typical procedure. To a solution of acid (1i,
44 mg, 0.20 mmol) in toluene (3 mL) were added Et3N (34
0.24 mmol) and diphenylphosphoryl azide (45 L, 0.20 mmol),
O
O
O
lL,
O
O
OBut
OBut
OBut
allylic bromide
30%H2O2,LiOH
THF/H2O 4 :1
O
HO
N
l
O
N
O
O
O
NaN(TMS)2,THF
and then the reaction mixture was heated to reflux for 2–3 h. After
cooling to 0 °C, a 1 M solution of sodium trimethylsilanolate in THF
(0.4 mL) was added and the mixture was stirred for 20 min at room
temperature. After quenching with 5% citric acid (5 mL), the mix-
ture was concentrated to half-volume, and then was washed with
Et2O (2 times). The remained aqueous solution was made basic
with 1 N NaOH, and then extracted with CH2Cl2. The combined
CH2Cl2 extracts were washed with brine, dried, and concentrated.
The crude product was very clean, and could be further purified
by chromatography to give the pure product 6i (26 mg, 67% yield).
Bn
Bn
7
8
1j
Compound 8: 1H NMR (300 MHz, CDCl3): 7.33–7.18 (m, 5H), 5.85–5.71 (m, 1H),
5.11–5.05 (m, 2H), 4.72–4.64 (m, 1H), 4.23–4.06 (m, 3 H), 3.25 (dd, J = 13.3,
3.3 Hz, 1H), 2.79 (dd, J = 17.0, 11.0 Hz, 1H), 2.67 (dd, J = 13.3, 9.9 Hz, 1H), 2.45
(dt, J = 13.7, 6.8 Hz, 1H), 2.40 (dd, J = 17.0, 3.9 Hz, 1H), 2.22 (dt, J = 13.7, 7.6 Hz,
1H), 1.39 (s, 9H).Compound 1j: 1H NMR (300 MHz, CDCl3): 5.79–5.66 (m, 1H),
5.11–5.05 (m, 2H), 2.88 (m, 1H), 2.58 (dd, J = 16.7, 9.1 Hz, 1H), 2.23–2.48 (m,
3H), 1.41 (s, 9H).Compound 6j: 1H NMR (300 MHz, CDCl3): 5.81–5.67 (m, 1H),
5.11–5.05 (m, 2H), 3.20 (m, 1H), 2.37 (dd, J = 15.9, 4.2 Hz, 1H), 2.00–2.21 (m,
3H), 1.64 (s, 2H), 1.42 (s, 9H). The dr of the Mosher’s ester derivatives was
greater than 60:1.