New protocol for converting alcohols into amines

Article abstract of DOI:10.1081/SCC-100103987

The reactions between diethyl N-(t-butoxycarbonyl)phosphoramidate 1, diisopropyl azodicarboxylate (DIAD), triphenylphosphine (TPP) and primary or secondary alcohols lead to the corresponding diethyl N-alkyl-N-(t-butoxycarbonyl)phosphoramidates 2a-o. Deprotection of crude 2 by refluxing with p-toluenesulfonic acid monohydrate in ethanol affords ammonium tosylates 3a-o in moderate to good overall yields. The N-alkylation of 1 proceeds stereoselectively with complete inversion of the configuration of the alkyl group.

Full text of DOI:10.1081/SCC-100103987

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NEW PROTOCOL FOR
CONVERTING ALCOHOLS INTO
AMINES
Anna Klepacz a & Andrzej Zwierzak b
a Institute of Organic Chemistry, Technical
University, (Politechnika), Żeromskiego 116, Lódź,
PL-90924, Poland
b Institute of Organic Chemistry, Technical
University, (Politechnika), Żeromskiego 116, Lódź,
PL-90924, Poland
Published online: 09 Nov 2006.
To cite this article: Anna Klepacz & Andrzej Zwierzak (2001): NEW PROTOCOL FOR
CONVERTING ALCOHOLS INTO AMINES, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:11, 1683-1689
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SYNTHETIC COMMUNICATIONS, 31(11), 1683–1689 (2001)
NEW PROTOCOL FOR CONVERTING
ALCOHOLS INTO AMINES
Anna Klepacz and Andrzej Zwierzak*
Institute of Organic Chemistry, Technical University
_
(Politechnika), Zeromskiego 116,
PL-90924 Lodz, Poland
ABSTRACT
The reactions between diethyl N-(t-butoxycarbonyl)pho-
sphoramidate 1, diisopropyl azodicarboxylate (DIAD), tri-
phenylphosphine (TPP) and primary or secondary alcohols
lead to the corresponding diethyl N-alkyl-N-(t-butoxy-
carbonyl)phosphoramidates 2a–o. Deprotection of crude 2
by refluxing with p-toluenesulfonic acid monohydrate in etha-
nol affords ammonium tosylates 3a–o in moderate to good
overall yields. The N-alkylation of 1 proceeds stereoselectively
with complete inversion of the configuration of the alkyl group.
Phthalimide was first subjected to N-alkylation with alcohols in
Mitsunobu reaction.1 This synthesis of primary amines directly from
alcohols suffers from undesirably vigorous conditions necessary for cleavage
of phthaloyl protection. A number of alternatives2 to phthalimide such as
iminodicarbonates,3 acylcarbamates4 and sulfonylcarbamates5 have been
* Corresponding author.
1683
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1684
KLEPACZ AND ZWIERZAK
also used for converting alcohols into amines but the procedures required
reagents which are not conveniently accessible or needed rather drastic
conditions of deprotection.
Judicious combination of the Staudinger and the Mitsunobu reactions
was proposed by Golding et al6 for transforming alcohols into amines. Some
years ago we reported on possible application of diethyl N-(t-butoxy-
carbonyl)-phosphoramidate 1 for the synthesis of amines from alcohols
under Mitsunobu conditions.7 Despite its simplicity and satisfactory yields
of amine hydrochlorides obtained this procedure suffered from some
significant drawbacks: (a) – poor reproducibility of the reactions leading
to sec-alkyl amine hydrochlorides; (b) – the use of toxic benzene as solvent
and relatively expensive diethyl azodicarboxylate (DEAD) as hydroxyl
group activating reagent; (c) – inconvenient deprotection procedure using
gaseous hydrogen chloride in benzene. All these disadvantages, obviously
diminishing the preparative value of the reported methodology, can be cir-
cumvented or at least partially avoided. It is the aim of this paper to present
our attempts in this matter.
It has been well established now that the present version of the
previously reported procedure offers the most effective way of transforming
alcohols into corresponding ammonium tosylates 3a–o. (Scheme) Diethyl
N-(t-butoxycarbonyl)-phosphoramidate 1 is relatively strong NH-acid
(pKa ¼ 9.32)8 and can be easily subjected to N-alkylation under
Mitsunobu conditions. The Mitsunobu reaction between 1 and primary or
secondary alcohols can be most effectively carried out in tetrahydrofuran in
the presence of 10% excess of triphenylphosphine (TTP) and diisopropyl
azodicarboxylate (DIAD). It was found that twice less expensive DIAD
can be used as a substitute of more often recommended diethyl azodicar-
boxylate (DEAD) without affecting the yields of amines.
N-Alkylation of 1 is completed after 2 hours at room temperature.
Crude diethyl N-alkyl-N-(t-butoxycarbonyl)phosphoramidates 2 can be
easily separated from triphenylphosphine oxide and other by-products by
evaporation of solvent followed by extraction of solidified residue with
hexane. Cumbersome chromatographic purification can be thus avoided.
Crude 2 are easily and conveniently deprotected to the corresponding
ammonium tosylates 3a–o by refluxing with p-toluenesulfonic acid mono-
hydrate in ethanol. Compounds 2k–o with secondary alkyl groups linked to
nitrogen atom are completely deprotected after 12 hours in concentrated
ethanolic solutions of p-toluenesulfonic acid monohydrate. For N-alkyl
derivatives 2a–j, derived from primary alcohols, refluxing for 6 hours in
less concentrated solution is sufficient to achieve full deprotection.
Ammonium tosylates 3a–o can be easily isolated in spectroscopically pure
state by evaporation of solvent followed by precipitation with diethyl ether.

CONVERTING ALCOHOLS INTO AMINES
1685
Scheme.
One recrystallization from the suitable solvent (see Table 1) affords analy-
tically pure samples of 3a–o. Overall yields, melting points, and reported
melting points of ammonium tosylates 3a–o are presented in Table 1. All
new compounds prepared could be satisfactorily analyzed and gave IR,
1HN MR and MS spectra fully compatible with the expected structures.
For unknown reasons hydroxyacetone (acetol) and 2-hydroxyacetophenone
did not react with 1 under Mitsunobu conditions. Stereochemical course of
N-alkylation, proceeding with complete inversion of the configuration, was
confirmed using both enantiomers of 2-octanol as model compounds. From
20
S-(þ)-2-octanol, ½aꢀD þ 10.0 (c 1, EtOH) R-(ꢁ)-1-methylheptylamine,
20
20
½aꢀD ꢁ5.2 (c 2, C6H6) was obtained and R-(ꢁ)-2-octanol, ½aꢀD ꢁ10.0
(c 1, EtOH) afforded S-(þ)-1-methylheptylamine, [a]2D0 þ 5.2 (c 2, C6H6)
respectively.

1686
KLEPACZ AND ZWIERZAK
Table 1. Preparation of Ammonium Tosylates (3)
M.p. (ꢂC) (Solvent)
Compound
Overall Yield (%)a
Found
Reported
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
76
65
30
76
73
52
49
76
71
66
77
62
70
71
70
69
65
0
120–121 (EtOH/Et2O)
115–116 (EtOH/Et2O)
163–165 (EtOH/Et2O)
123–124 (EtOH/Et2O)
94–95 (AcOEt)
150–151 (EtOH/Et2O)
269–271 dec. (MeOH)
175–176 (EtOH)
173–174 (EtOH)
209–210 (EtOH)
122–124 (EtOH/Et2O)
76–78 (EtOH/Et2O)
129–131 (EtOH)
119–119.510
b
b
124–12510
96–9710
152–15310
b
186–18811
172–17411
203–20410
b
b
b
b
b
b
b
—
—
112–114 (EtOH/Et2O)
127–129 (EtOH/Et2O)
99–101 (EtOH/Et2O)
99–101 (EtOH/Et2O)
—
3o (dl)
3o (+)
3o (ꢁ)
3p
3q
0
—
a Overall yields of spectroscopically pure compounds.
b Satisfactory microanalysis obtained C Æ 0.20, H Æ 0.25, N Æ 0.15.
This optimized procedure for converting alcohols into amines exem-
plifies a useful, attractive, and relatively inexpensive alternative to the pre-
viously reported methods.
EXPERIMENTAL
All solvents and reagents were of reagent grade and were purchased
from Fluka. Melting points (determined in open capillary tubes) are uncor-
rected. IR spectra (KBr discs) were measured using a Specord M 80
(C. Zeiss) instrument. 1H NMR spectra were recorded on a Bruker AVANCE
DPX-250 spectrometer operating at 250 MHz, using D2O solutions. FAB/
MS were measured on an APO Electron (Ukraine) Model M1 12001 E mass
spectrometer equipped with a FAB ion source (thioglycerol matrix).
Diethyl N-(t-butoxycarbonyl)phosphoramidate 1 was obtained as
described previously.9

CONVERTING ALCOHOLS INTO AMINES
1687
Table 2. Spectroscopic Data for New Ammonium Tosylates (3)
IR (KBr)
(cmꢁ1
1H NMR (D2O/TMS)
MS-FAB
m/z MHþ (%)
Compound
3b
)
d, J (Hz)
3424, 3064, 1632,
1524, 1180, 1124,
1032, 1008, 816,
684, 568
0.96 (d, 6H, J ¼ 6.75),
1.87–1.98 (m, 1H), 2.38
(s, 3H) 2.82 (d, 2H,
J ¼ 7.0), 7.34–7.70
—
(AAØ, XXØ system, 4H)
3c
2968, 1624, 1536,
1480, 1172, 1140,
1124, 1036, 1024,
1008, 816, 680,
568
2992, 1236, 1180,
1152, 1120, 1024,
1004, 688, 568
1.00 (s, 9H), 2.39 (s, 3H),
2.81 (s, 2H), 7.35–7.70
(AAØ, XXØ system, 4H)
—
—
3g
3k
2.38(s, 6H), 3.88 (s, 4H),
7.34–7.70 (AA
system, 8H)
Ø, XXØ
3424, 3040, 2752,
1528, 1464, 1188,
1128, 1032, 1008,
816, 684, 568
1.28 (d, 6H, J ¼ 6.5), 2.38
232 (25)
60 (100; MþK)
(s, 3H), 3.46 (7 lines, 1H,
Ø,
J ¼ 6.5), 7.34–7.70 (AA
XXØ system, 4H)
3l
3064, 1512, 1456,
1184, 1136, 1120,
1040, 1008, 820,
684, 568
0.95 (t, 3H, J ¼ 7.5), 1.26
(d, 3H, J ¼ 6.5), 1.51–1.72
(m, 2H), 2.39 (s, 3H), 3.26
(sextet, 1H, J ¼ 6.5),
246 (16)
74 (100; MþK)
7.34–7.70 (AA
system, 4H)
Ø, XXØ
3m
3n
3016, 1188, 1120,
1032, 1008, 680,
568
1.55–2.13 (m, 8H), 2.38
(s, 3H), 3.54–3.68 (m, 1H),
258 (15)
86 (100; MþK)
7.34–7.70 (AA
system, 4H)
Ø, XXØ
3088, 1636, 1532,
1496, 1460, 1224,
1216, 1192, 1136,
1128, 1040, 1012,
816, 688, 576
0.86 (dist.t., 3H, J ¼ 6.9),
1.22–1.63 (m, 9H),
2.38 (s, 3H), 3.30
274 (11.5)
102 (100; MþK)
(sextet, 1H, J ¼ 6.7),
7.33–7.68 (AA
system, 4H)
Ø, XXØ
3o
3072, 1460, 1192,
1128, 1040, 1008,
816, 688, 568
0.84 (dist.t, 3H, J ¼ 6.5),
1.24–1.63 (m, 13H),
2.38 (s, 3H), 3.31
302 (6) 130
(100; MþK)
(sextet, 1H, J ¼ 6.7)
7.34–7.69 (AA
system, 4H)
Ø, XXØ

1688
KLEPACZ AND ZWIERZAK
Conversion of Alcohols into Ammonium Tosylates 3a–o;
General Procedure
A solution of diisopropylazodicarboxylate (DIAD, 2.22 g, 11 mmol) in
THF (5 mL) was added dropwise with stirring and external cooling (ice-salt
bath) to a mixture of 1 (2.53 g, 10 mmol), triphenylphosphine (2.88 g,
11 mmol), the respective alcohol (10 mmol), and THF (20 mL) at 0ꢂ–þ5ꢂC
within ca. 15 min. After the addition was complete, the temperature of the
mixture was raised to 20–25ꢂC, and stirring was continued at this tempera-
ture for 2 h. In the case of isobutyl alcohol the mixture was refluxed for 2 h
and in the case of neopentyl alcohol – for 12 h. Solvent was then evaporated
and the residue was extracted with hexane (3 ꢃ 25 mL). On evaporation the
combined extracts in vacuo, crude diethyl N-alkyl-N-(t-butoxycarbonyl)-
phosphoramidate 2a–o was obtained as pale yellow oil. This was dissolved
in ethanol (20 mLfor R ¼ 1ꢂ alkyl or 10 mLfor R ¼ 2ꢂ alkyl) and refluxed
with TsOHꢄH2O (1.91 g, 10 mmol) for 6 h (R ¼ 1ꢂ alkyl) or 12 h (R ¼ 2ꢂ
alkyl). The resultant solution was concentrated, diluted with Et2O
(40 mL), and refrigerated overnight. Crystalline ammonium tosylate 3a–o
was filtered off, washed thoroughly with dry Et2O, dried over P2O5, and
recrystallized from the suitable solvent. (Table 1) Yields, melting points, and
spectroscopic data of ammonium tosylates 3a–o are compiled in Tables 1
and 2. Optically active 1-methylheptylamines were liberated from the tosy-
lates (prepared as described above) by the following procedure: the solution
of crude tosylate 3o in ethanol (5 mL) was made strongly alkaline with 20%
NaOHaq and the free amine was extracted with CH2Cl2 (3 ꢃ 15 mL). The
extracts were dried over anhydrous Na2SO4, filtered, and evaporated in
vacuo. Crude 1-methylheptylamines 3o thus obtained were used for specific
rotation determinations.
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CONVERTING ALCOHOLS INTO AMINES
1689
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Accepted in the Netherlands August 3, 2000