Efficient conversion of primary and secondary alcohols to primary amines

Article abstract of DOI:10.1016/j.tetlet.2007.09.034

A convenient single-vessel conversion of primary and secondary alcohols to primary amines is reported. Use of this method results in substantially cleaner crude products than similar procedures reported in the literature. A simple work-up also makes this procedure ideal for parallel synthesis.

Full text of DOI:10.1016/j.tetlet.2007.09.034

Tetrahedron Letters 48 (2007) 7745–7746
Efficient conversion of primary and secondary alcohols to
primary amines
Weilin Sun and Jeffrey C. Pelletier*
Department of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
Received 8 August 2007; accepted 5 September 2007
Available online 11 September 2007
Abstract—A convenient single-vessel conversion of primary and secondary alcohols to primary amines is reported. Use of this
method results in substantially cleaner crude products than similar procedures reported in the literature. A simple work-up also
makes this procedure ideal for parallel synthesis.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The conversion of alcohols to amines is one of the most
common transformations in organic chemistry. Typical
procedures involve 2–3 steps encompassing alcohol acti-
vation, nucleophilic displacement, and manipulation of
the post-nucleophile product to an amine.1 Each step
generally requires isolation and purification making it
cumbersome, particularly for parallel synthesis proce-
dures. In spite of the frequency of this conversion and
the accompanying inconvenience of intermediate char-
acterization and purification there are only a few meth-
ods describing this functional group manipulation in a
single operation.2–4 Each of these methods has limita-
tions due to harsh conditions required to drive the reac-
tion to completion, narrow scope and/or purification of
desired products contaminated with triphenylphosphine
oxide and other significant byproducts of the Staudinger
and Mitsunobu reactions.
the reaction scheme allows for the isolation of the pri-
mary amines with few byproducts. Further purification
by normal or reversed phase chromatography occurs
without an incident.
An example of the conversion is shown in Scheme 1.
Hence, a mixture of 2-(1-naphthyl)ethanol (1.0 equiv),
OH
i. tBuO2CN=NCO2t-Bu,
(Boc)2NH,
TPP
then addition of TFA
Several years ago we reported a variant of the Mitsun-
obu reaction in which all byproducts and excess reagents
were removed using standard workup procedures
including aqueous wash, filtration, and evaporation.5
Products were usually isolated in high yield and better
than 90% purity before chromatography. Judicious
choice of reagents, allowing for easy removal of excess
reagent as well as reagent by-products, was key to this
convenient procedure. We now report an extension of
this technique to generate primary amines from primary
and secondary alcohols. Addition of the key acidic
nitrogen component, bis-t-butyliminodicarbonate, into
ii. Workup - filter, evaporate,
aqueous wash
NH2
88%
Abbreviations: (Boc)2NH = bis-tert-butyliminodicarbonate, TFA =
trifluoroacetic acid, -TPP = polystyrene resin bound
triphenylphosphine.
*
Scheme 1. Conversion of 2-(1-naphthyl)ethanol to 2-(1-naphthyl)eth-
Corresponding author. Tel.: +1 484 865 2912; fax: +1 484 865
ylamine in a single operation.
9399; e-mail: pelletj@wyeth.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.034

7746
W. Sun, J. C. Pelletier / Tetrahedron Letters 48 (2007) 7745–7746
Table 1. Single-vessel conversion of primary and secondary alcohols
to aminesa
the case of the secondary alcohol (Table 1, entry 9) a
reasonable yield of 55% is obtained.
TPP, DBAD,
In summary, primary and secondary alcohols are readily
converted to primary amines via a modified Mitsunobu
reaction protocol. The method requires reagents and/or
converted reagents that are readily removed from the
reaction mixtures via typical workup conditions. In
addition, all reagents used in the process are commer-
cially available from several vendors.
ROH
RNH2
Boc2NH, DCM, TFA
Entry
1
Structure (R)b
Yield (%)
91
2
3
88
86
Acknowledgments
The authors thank Magid Abou-Gharbia, Ron Magol-
da and Jay Wrobel of Wyeth research for support.
W.S. thanks Peter Doukas and Dan Canney of Temple
University.
4
5
79
74
O
References and notes
O
1. Larock, R. C. In Comprehensive Organic Transformations;
VCH: New York, NY, 1989; pp 419–420.
2. White, E. H.; Elliger, C. A. J. Am. Chem. Soc. 1965, 87,
5261–5262.
3. Fabiano, E.; Golding, B. T.; Sadeghi, M. M. Synthesis
1987, 190–192.
4. Vidya Sagar Reddy, G.; Venkat Rao, G.; Subramanyam,
R. V. K. Synth. Commun. 2000, 30, 2233–2237.
O
O
6
7
87
83
5. Pelletier, J. C.; Kincaid, S. Tetrahedron Lett. 2000, 41, 797–
800.
8
9
90
55
6. Typical experimental details: 2-(1-naphthyl)ethanol
(0.050 g, 0.29 mMol), triphenylphosphine resin (3 mMol/g,
0.4 g, 1.2 mMol) and di-t-butyl iminodicarboxylate (0.252 g,
1.2 mMol) were mixed in anhydrous dichloromethane
(4 mL) in an oven-dried, N2-purged 8 mL vial. The mixture
was magnetically stirred and cooled in an ice bath for
10 min. Di-t-butylazodicarbolylate (DBAD, 0.2 g, 0.87
mMol) was added all at once and the reaction mixture
stirred for 30 min. The ice bath was removed and trifluro-
acetic acid (TFA, 1 mL) was added. After an hour the
reaction mixture was filtered through Celiteꢁ, the residue
was washed with a mixture of methanol and dichlorometh-
ane (1:1, 15 mL) and the combined filtrate was treated with
saturated aqueous Na2CO3 solution (30 mL). The mixture
was extracted with ethyl acetate (2 · 20 mL) and the
combined organic layers were washed with brine (20 mL),
dried over MgSO4, and evaporated in vacuo. The residue
was purified by reversed phase PREP-HPLC (5–95%
acetonitrile in water with 0.05% TFA buffer), to afford a
yellow solid 2 (43 mg, 88%). 1H NMR (MeOH-d4): d 8.04 (d,
J = 8.5 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.80 (d, J =
7.5 Hz, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.51 (t, J = 8.1 Hz,
1H), 7.38–7.44 (m, 2H), 3.41 (t, J = 7.3 Hz, 2H), 3.24 (t,
J = 7.3 Hz, 2H); MS (ES): 171.9; HRMS [M+H]: 172.1114
(calculated, 172.1121); HPLC: retention time: 5.6 min;
purity: 100%.
O
a Abbreviations: DCM = dichloromethane, DBAD = Di-tert-butyldi-
carbonate, see scheme for others.
b Products characterized by 1H NMR and MS.
bis-tert-butyliminodicarboxylate (4.0 equiv) and poly-
styrene resin bound triphenylphosphine (4.0 equiv) in
dichloromethane was treated with di-tert-butylazodicar-
bonate (3.0 equiv) and stirred for 30 min. The mixture
was treated with trifluoroacetic acid (TFA) and stirred
an additional hour. Following filtration and evapora-
tion of solvents the crude product was subjected to
typical aqueous workup. The product, 2-(1-
naphthyl)ethylamine was obtained in 88% yield and
>90% purity (HPLC). It is important to note that no
unreacted reagents or reagent byproducts were detected
in the product. Further purification to obtain the prod-
uct in >99% purity (HPLC, NMR) was easily accom-
plished with reversed phase, semi-preparative HPLC.6
Table 1 shows several other alcohols converted to
amines using this method. Yields are generally high. In