Selective monoalkylation of ammonia: A high throughput synthesis of primary amines

Article abstract of DOI:10.1055/s-1999-2946

Primary amines are obtained in good to excellent yields by highly selective monoalkylation of ammonia with alkyl and aryl ketones using titanium(IV) isopropoxide and sodium borohydride.

Full text of DOI:10.1055/s-1999-2946

LETTER
1781
Selective Monoalkylation of Ammonia: A High Throughput Synthesis of
Primary Amines
Sukanta Bhattacharyya,a,1* Kurt A. Neidigh,b Mitchell A. Avery,b John S. Williamsonb
a Department of Chemistry, The University of Mississippi, University, MS 38677, USA
b Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS 38677, USA
Received 31 August 1999
Abstract: Primary amines are obtained in good to excellent yields
by highly selective monoalkylation of ammonia with alkyl and aryl
ketones using titanium(IV) isopropoxide and sodium borohydride.
Key words: primary amines, reductive amination, titanium (IV)
isopropoxide
The synthesis of amines and their derivatives has long
been of interest because of their versatile utility2 as medic-
inal agents and agrochemicals. The reductive amination of
carbonyl compounds that allows an expedient access to
diverse amines is one of the most widely applied reactions
in synthetic organic chemistry.3 The synthesis involves
Scheme
the formation of an imine or iminium intermediate upon
exposure of a carbonyl compound to an amine followed
by in situ reduction to an alkylated amine. Though many
converted to the desired primary amines in high yields; no
over-alkylation of the product primary amines was ob-
served. Titanium(IV) isopropoxide has been utilized7 as a
mild Lewis acid compatible with a variety of potentially
acid-sensitive functional groups including acetals, ace-
tonides, and silyl ethers. One of the traditional methods
for carrying out reductive amination has been catalytic
hydrogenation3 which is, however, incompatible with a
number of otherwise reducible functional groups such as
nitro, cyano, and ‘C-C’ multiple bonds.
of the reported protocols for reductive amination reactions
work well for the preparation of tertiary and secondary
amines, synthesis of primary amines by reductive alkyla-
tion of ammonia is mostly compromised by over-
alkylation4 reactions. The formation of variable amounts
of secondary and tertiary amines along with the desired
primary amines is common. The synthesis of primary
amines is, therefore, mostly addressed indirectly by using
ammonia equivalents5 such as tritylamine, diallylamine or
allylamine. These protocols routinely require a subse-
quent deprotection step to get primary amines.According-
ly, development of a straightforward route for the
synthesis of primary amines via selective monoalkylation
of ammonia is an important objective.
The relevance of this protocol has been demonstrated on
a structurally varied set of ketonic8 substrates. The ke-
tones were allowed to react with a mixture of ammonium
chloride, triethylamine and titanium(IV) isopropoxide,
followed by the treatment with sodium borohydride at
room temperature. The results obtained for this represen-
tative group of ketones are summarized in the Table. The
reaction may proceed through an intermediate ami-
nocarbinolatotitanium(IV) complex 1 (Scheme),6,7 which
is either reduced directly or via equilibration of 1 to form
a transient iminium species.9 Typically, the intermediate
complex 1 was first allowed to form by stirring a mixture
of the ketone, ammonium chloride-triethylamine and tita-
nium(IV) isopropoxide in absolute ethanol at ambient
temperature for 9 -11 h. Sodium borohydride was then
added and the resulting mixture was stirred for another 7-
8 h at ambient temperature. Finally, the reaction mixture
was quenched with aqueous ammonia (2 M) and then ex-
tracted with Et2O. The product amines were isolated in
their pure forms by simple extraction of the organic solu-
tion with hydrochloric acid (1 M), basification of the
aqueous layer and subsequent extraction with Et2O.
In connection with our ongoing investigations on reduc-
tive amination reactions, we have recently used a combi-
nation of titanium(IV) isopropoxide and sodium
borohydride in the reductive alkylations of primary and
secondary amines.6 Encouraged by our success, we envis-
aged that selective monoalkylation of ammonia with car-
bonyl compounds may be achieved with this one-pot
reagent system.
Indeed, this has been the case. We explored the applica-
tion of this one-pot reagent system in the selective
monoalkylation of ammonia with a variety of ketones to
provide primary amines in good to excellent yields and
the results are reported herein. A mixture of ammonium
chloride and triethylamine has been employed as the am-
monia equivalent; this requires no special handling tech-
niques and alleviates the use of excess gaseous ammonia.
In this reagent system, both alkyl and aryl ketones were
Synlett 1999, No. 11, 1781–1783 ISSN 0936-5214 © Thieme Stuttgart · New York

1782
S. Bhattacharyya et al.
LETTER
Table Reductive Amination of ketonesa,b
of over-alkylation of the product amines was not ob-
served. The compatibility6,7 of titanium(IV) isopropoxide
with a variety of acid- or base-sensitive groups provides
an additional advantage for targeting the syntheses of
amines with reagent-sensitive motifs.
In conclusion, an efficient one-pot reagent system has
been developed for the synthesis of primary amines by se-
lective monoalkylation of ammonia with alkyl and aryl
ketones using titanium(IV) isopropoxide and sodium
borohydride. Because this method allows easy, direct ac-
cess to diverse primary amines, it should find widespread
application.
General Experimental Procedure. A mixture of the ke-
tone (10 mmol), titanium(IV) isopropoxide (5.9 mL, 20
mmol), ammonium chloride (1.07 g, 20 mmol) and trieth-
ylamine (2.79 mL, 20 mmol) in absolute ethanol (20 mL)
was stirred in a capped flask at ambient temperature for 9-
11 h. Sodium borohydride (0.57 g, 15 mmol) and was then
added and the resulting mixture was stirred for an addi-
tional 7-8 h at ambient temperature. The reaction was then
quenched by pouring into aqueous ammonia (30 mL, 2
M), and the inorganic precipitate was filtered and washed
with diethyl ether (50 mL). The organic layer was separat-
ed and the aqueous layer was extracted once with diethyl
ether (50 mL). The combined organic extracts were next
extracted with hydrochloric acid (20 mL x 2.1 M) to sep-
arate the non-basic materials. The acidic aqueous solution
was washed once with diethyl ether (20 mL), then treated
with aqueous sodium hydroxide (2 M) to pH 10-12, and
extracted with diethyl ether (25 mL x 3). The combined
organic extracts were washed with brine (30 mL), dried
(MgSO4) and the solvent was removed to afford the pri-
mary amine in good to excellent yield. The products were
typically more than 90% pure after work-up. Preparative
TLC or column chromatography (CH2Cl2/MeOH, 9:1)
was performed to obtain analytical samples. All products
were identified by their spectral and analytical data.
Acknowledgement
We are grateful to Agnes Rimando of the USDA-ARS-NPURU
(Oxford, Mississippi) for the GC-MS analyses. We thank Sharon A.
Dunn for assistance in the preparation of this manuscript.
References and Notes
As shown in the Table, the ketones were converted to the
corresponding primary amines in good yields. A compar-
ison of the data in the Table shows little difference in the
reactivity of the ketones towards reductive amination un-
der the reaction conditions employed. Steric hindrance ap-
peared to play only a limited role in dictating the outcome
of the reactions in this series, with the only notable excep-
tions being entries 5 and 9. The reaction conditions were
found to be tolerant to the substrates containing acid-sen-
sitive carbamate (entry 11) and nucleophile/base-sensitive
amide (entry 12) groups. Under these reaction conditions,
only primary amines are formed – the traditional problem
(1) To whom correspondence should be addressed. Current
Address: Argonaut Technologies, 887 Industrial Road, Suite
G, San Carlos, CA 94070. Email:
sbhattacharyya@argotech.com.
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Synlett 1999, No. 11, 1781–1783 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Selective Monoalkylation of Ammonia: A High Throughput Synthesis of Primary Amines
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Article Identifier:
1437-2096,E;1999,0,11,1781,1783,ftx,en;S05299ST.pdf
Synlett 1999, No. 11, 1781–1783 ISSN 0936-5214 © Thieme Stuttgart · New York