Synthesis of some 3-furylamine derivatives

Article abstract of DOI:10.1071/CH02178

The method for the synthesis of 3-furylamines was discussed. The method used was Michael addition of amines to acyclic keto alkynol precursors. Further the products of Michael addition were analyzed by gas chromatography and nuclear magnetic resonance. It

Full text of DOI:10.1071/CH02178

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Aust. J. Chem. 2002, 55, 795–798
Synthesis of Some 3-Furylamine Derivatives
Anthony R. Lingham,A Trevor J. RookA and Helmut M. HügelA,B
A RMIT University, Department of Applied Chemistry, G.P.O. Box 2476V, Melbourne 3001, Victoria, Australia.
B Author to whom correspondence should be addressed (e-mail: helmut.hugel@rmit.edu.au).
A general and efficient method for the synthesis of 3-furylamines via Michael addition of amines to acyclic keto
alkynol precursors has been achieved.The preparation of various 3-furylamines has been carried out using a flexible
methodology which also allows modification of the substituent at the 5-position.
Manuscript received: 30 August 2002.
Final version: 15 October 2002.
Introduction
3-acetamidofuran may be complicated due to the presence of
the amide functional group.
Furans serve as versatile building blocks in synthetic
chemistry,[1,2] and many biologically-active molecules[3] and
natural products[4] incorporate the furan moiety. This has
resulted in the continued development of many routes to furan
derivatives.[5] These compounds can be synthesized by func-
tional group interconversions on the furan ring or by cycliza-
tion of acyclic precursors. Although the chemistry of furans
permits ready functionalization at the 2- and 5-positions,
similar operations at the 3- or 4-positions are difficult to
achieve.
Electron-rich furan derivatives are exceptionally useful
dienes for use in Diels–Alder reactions. Recently, in an
attempt to significantly increase the electron density and
hence the reactivity of furans, Padwa et al.[6] prepared
2-aminofuran derivatives to be used in Diels–Alder reac-
tions.These were subsequently used for preparing substituted
anilines.
Research projects currently undertaken by our group have
required the synthesis of a series of 5-alkyl-3-aminofurans as
asymmetric precursors for the synthesis of bridged oxabicy-
clo compounds. Literature searches revealed numerous syn-
theses of 3-amino substituted furans from acyclic precursors.
Theseincludethebasecatalyzed[3,2]-sigmatropicrearrange-
ment of a phenyl-(prop-2-ynyl) ammonium salt to give an
allene intermediate, which spontaneously cyclizes to give
the 2-methyl-5-phenyl-3-N-substituted furan.[7] Reaction of
diacetylenic glycols with amines under aqueous conditions
has also proven to give 2,5-dialkyl-3-dialkylaminofurans in
good yields.[8] However, these approaches provide furans
containing additional substitution at the 2- and 5-positions
and removal or modification of these substituents while
following the same synthetic methodology may be quite
difficult. Syntheses by functional group interconversions
on the 3-substituted furan ring included the preparation of
the stable 3-acetamidofuran from commercially available
3-furoic acid,[9] but methods of further substitution onto the
None of these well known or recently published prepara-
tions of 3-aminofuran derivatives[7–10] provides a means of
incorporating both a 5-alkyl group and a variety of 3-amino
substituents.
Results and Discussion
Reports of 3-aminofuran derivatives are scarce in published
literature and the chemical properties of these compounds
remain largely unexplored. Numerous references[11,12] imply
that 3-aminofuran itself would be relatively unstable. Its
enthalpy of tautomerization is remarkably low (0.061 eV)[11]
(Fig. 1), which suggests that the imine tautomer may be
abundant and provide a facile pathway for unwanted side
reactions.
In addition, ab initio molecular-orbital studies[12] suggest
that the presence of an amino group on the furan ring, espe-
cially in the 3- and 4-positions, has a considerably larger
destabilizing effect than it does on a benzene ring.
Given the inherent instability of the unsubstituted 3-
aminofuran, approaches to the preparation of mono and bis
N-substituted 3-aminofurans were investigated. An exhaus-
tive search of the literature revealed one reference for the
preparation of 3-piperidino-2,5-dipropyl furan.[13]
Wehavefoundthatmodificationofthisolderandgenerally
unutilized methodology provides a general and efficient route
to a series of 3-N-substituted and 5-alkyl-3-N-substituted
furan derivatives from acyclic precursors (Scheme 1).
Using literature procedures,[14–16] propargyl alcohol (1)
was first reacted with 3,4-dihydro-2H-pyran to form (2)
NH2
NH
⌬H = 0.061eV
O
O
Fig. 1.
© CSIRO 2002
10.1071/CH02178
0004-9425/02/120795

796
A. R. Lingham, T. J. Rook and H. M. Hügel
(i)
Table 1. Yields of 3-N-substituted furans (5)
OTHP
R1
R2R3NH
% yield
OH
(5)
(1)
(2)
a
b
c
d
e
f
g
h
i
Me
Me
Me
Me
Me
Me
Me
Me
Et
morpholine
96
90
95
84
diethylamine
diisopropylamine
pyrrolidine
dibenzylamine
ethylenediamine
n-butylamine
cyclohexylamine
morpholine
(ii)
73
O
73A
90A
86A
91
R1
OTHP
(3)
j
k
l
Et
Et
H
diethylamine
n-butylamine
morpholine
88
84A
67
(iii)
m
n
H
H
diethylamine
n-butylamine
64
R2
65A
R3
R2 R3
N
N
A The monosubstituted C3-amines were isolated as N-acetyl deriva-
(iv)
O
R1
tives.
OTHP
R1
O
(4)
(5)
R2
R2
Scheme 1. (i) 3,4-Dihydro-2H-pyran, POCl3; (ii) NaNH2 (R1CO)2O,
R1 = Me, Et; BunLi, DMF, R1 = H; (iii) R2R3NH; (iv) TFA in
1,2-dichloroethane, NaOH.
N
H
N
Ac
(Ac)2OA or AcClB
R1
R1
O
O
(5)
(6)
(Scheme 1), which was then converted into the tetrahydro-
pyran (THP)-protected keto alkynol (3) using sodamide and
acetic or propanoic anhydride [R1 = Me, Et], or BunLi and
dimethylformamide (DMF) [R1 = H]. Michael addition reac-
tions when R1 = Me, Et were performed neat by the addition
of equimolar amounts of the amine to (3). When R1 = H,
best yields were obtained when the reaction was performed
in dry tetrahydrofuran (THF) at 5◦C by the addition of (3)
to the amine. Most amines reacted exothermically during the
addition with the exception of the more hindered amines,
diisopropylamine and dibenzylamine, which required mild
heating and prolonged stirring in order to achieve optimal
yields. Gas chromatography (GC) and 1H nuclear magnetic
resonance (NMR) analysis of the crude Michael-addition
products indicated almost quantitative yields of enaminones
(4). It is of interest to note that the Michael-addition products
(4a)–(4k), where R1 = Me, Et, gave the E-isomer, whereas
products (4l) and (4m), whereR1 = H, gave the Z-isomer.The
Michael-addition product of (4n) gave a 2 : 1 mixture of E-
and Z-isomers. THP deprotection of (4) with trifluoroacetic
acid (TFA) and aqueous alkaline reaction workup resulted
in cyclization and dehydration to give the furans (5). Prod-
ucts which required no derivatization were directly isolated
in >95% purity (Table 1).
Scheme 2. A Where R2 = n-butyl, ethylene diamine. B Where R2 =
cyclohexylamine.
indicate that the aqueous workup is less efficient for more
hydrophobic amine substituents.
Aniline underwent Michael addition with the protected
keto alkynol (3) using the same general procedure as for
amines (c) and (e), and was also successfully cyclized to the
furan(5).Anefficientderivatizationmethodforthe N-(furan-
3-yl)aniline has not yet been found and the free amine is only
stable for 1–2 h in ethereal solution at room temperature.
Conclusion
In this paper we have presented a versatile and high yielding
synthesis of a range of 3-N-substituted and 5-alkyl-3-N-
substituted furans.
The methodology described allows for the introduction of
a variety of amine substituents in the 3-position, as well as
the selective introduction of alkyl groups in the 5-position.
Experimental
Unless noted, materials were obtained from Aldrich Chemical Co. and
used without further purification. Diethyl ether and THF were dried
first with CaH2, and then distilled from sodium/benzophenone before
use. 1H and 13C NMR spectra were recorded on a Varian Gemini 2000
(200 MHz) Fourier transform (FT) spectrometer, and were referenced
to CHCl3. FT-infrared (IR) spectra were recorded on a Perkin-Elmer
Spectrum 2000 Fourier transform IR spectrometer. Gas chromatography
mass spectra (GCMS) were recorded using a Hewlett Packard 5890 GC
with a BPX-5 column and a Hewlett Packard 5970 mass selective
detector.
3-Dialkylamino-substituted furans were stable as the free
bases and could be stored for long periods at 0◦C. 3-N-alkyl
substituted furans (5) (R3 = H) were stable in solution at
0◦C, and for characterization were isolated as their N-acetyl
derivatives (6) (Scheme 2).
When R1= alkyl (a)–(k), higher product yields were
obtained than for the unsubstituted R1 = H (l)–(n) series of
compounds.Amine substituents containing more hydrophilic
groups gave higher yields of cyclized product compared with
substituents containing bulkier organic groups. This may
3-(Tetrahydropyran-2-yloxy)prop-1-yne (2)[14]
Phosphorusoxytrichloride(100 mg)wasaddedtoamixtureofpropargyl
alcohol (8.4 g) and 3,4-dihydro-2H-pyran (12.6 g), and stirred whilst

Synthesis of Some 3-Furylamine Derivatives
797
cooling in an ice bath until no more heat evolved. It was then stirred
at room temperature for 2 h. Several NaOH pellets were added and the
3-(tetrahydropyran-2-yloxy)prop-1-yne was distilled directly from the
reaction vessel under vacuum (19 g, 90% yield), b.p. 28◦C/25 mmHg.
32.4, 52.8, 61.1, 63.1, 97.8, 99.9, 127.0, 127.6, 128.9, 136.7, 158.8,
195.6. Mass spectrum m/z 379 (M+•, 1%), 336 (1), 296 (2), 295 (13),
294 (6), 288 (5), 280 (2), 279 (2), 278 (5), 277 (5), 276 (2), 262 (2), 252
(3), 236 (4), 234 (3), 232 (2), 205 (11), 204 (79), 189 (2), 188 (16), 186
(8), 162 (11), 160 (2), 158 (2), 146 (5), 144 (5), 143 (2), 132 (2), 117
(2), 115 (2), 106 (2), 105 (2), 104 (2), 92 (16), 91 (100), 85 (26), 67 (4),
65 (6), 57 (4), 55 (2), 43 (5), 41 (4).
5-(Tetrahydropyran-2-yloxy)pent-3-yn-2-one (3, R1 = Me)[15]
3-(Tetrahydropyran-2-yloxy)prop-1-yne (28 g) was added dropwise
under an inert atmosphere to a stirred mixture of sodamide (7.8 g) in
anhydrous diethyl ether (150 mL).The mixture was then heated to reflux
for 5 h. The suspension was diluted with anhydrous ether (200 mL) and
poured into a vigorously stirred solution of acetic anhydride (20.4 g)
in anhydrous ether (300 mL), the temperature being kept between −5
and −10◦C. The mixture was allowed to reach room temperature and
the white solid was separated by filtration. The solvent was evaporated
under reduced pressure and any unreacted materials were removed using
a high vacuum oil pump and gentle heating on a water bath (60◦C). The
product was obtained as a red oil (25 g, 70%).
Compound (4c) was also prepared using the procedure described
above. Its characterization data is included in the Accessory material.
3-Diethylamino-4-(tetrahydropyran-2-yloxy)but-2-enal (4m)
4-(Tetrahydropyran-2-yloxy)but-2-ynal(0.5g)wasaddeddropwiseover
15 min to a solution of diethylamine (0.22 g) in dry THF (40 mL) at
5◦C. The solution was allowed to reach room temperature and was
stirred for an additional 4 h. The solvent was removed under vacuum
to afford 3-diethylamino-4-(tetrahydropyran-2-yloxy)but-2-enal (4m)
(94%, GCMS). δH (200 MHz; CDCl3) 1.18 (6H, t, J 7.1), 1.90–1.40
(8H, m), 3.32 (4H, q, J 7.0), 3.53 (1H, m), 3.80 (1H, m), 4.58 (2H, s),
4.66 (1H, m), 5.24 (1H, d, J 8.3), 9.62 (1H, d, J 8.3). 13C NMR
(200 MHz; CDCl3) 12.8, 19.5, 25.4, 30.5, 44.4, 59.8, 62.7, 98.1, 102.8,
159.7, 187.5. Mass spectrum m/z 241 (M+•, 1%), 212 (1), 208 (2), 207
(5), 182 (2), 158 (3), 157 (9), 156 (28), 147 (2), 142 (5), 141 (18), 140
(30), 139 (3), 138 (3), 129 (6), 128 (75), 126 (10), 125 (2), 124 (23),
122 (8), 114 (3), 113 (13), 112 (52), 110 (14), 108 (2), 105 (2), 100 (6),
99 (4), 98 (18), 97 (6), 96 (14), 95 (2), 94 (4), 86 (9), 85 (88), 84 (33),
83 (19), 82 (18), 81 (4), 80 (3), 74 (4), 73 (10), 72 (19), 71 (19), 70 (55),
69 (24), 68 (19), 67 (28), 58 (21), 57 (57), 56 (42), 55 (44), 54 (22), 53
(8), 45 (4), 44 (28), 43 (54), 42 (65), 41 (100).
The same method, as outlined above, was used to produce 6-
(tetrahydropyran-2-yloxy)hex-4-yn-3-one (3, R1 = Et), using propanoic
anhydride.
4-(Tetrahydropyran-2-yloxy)but-2-ynal (3, R1 = H)[16]
3-(Tetrahydropyran-2-yloxy)prop-1-yne (7 g) was dissolved in dry
THF (100 mL) and the solution cooled to −40◦C under nitrogen.
n-Butyllithium (1.6 M in hexane, 32 mL) was added dropwise and the
solution was stirred at between −30◦C and −40◦C for 30 min. Anhy-
drous DMF (7.8 mL, 100 mmol) was added at once and the solution was
allowed to warm to room temperature. Stirring was continued at room
temperature for an additional 30 min, and the solution was then poured
into a vigorously stirred biphasic solution of 10% KH2PO4 (250 mL)
and diethyl ether (200 mL) at 5◦C. The organic layer was separated and
the aqueous layer was extracted with diethyl ether (2 × 75 mL). The
combined organic phases were dried, filtered, and concentrated to leave
4-(tetrahydropyran-2-yloxy)but-2-ynal (7 g, 84%) as a yellow viscous
oil which was warmed on a water bath (60◦C) under high vacuum to
remove starting materials.
Compounds (4l) and (4n) were also prepared using the proce-
dure described above. Their characterization data are included in the
Accessory material.
Hydrolysis of THP-Protecting Group and Cyclization to Furan
4-(5-Methylfuran-3-yl)morpholine (5a)
Anhydrous trifluoroacetic acid (2 mL) was added to 4-morpholino-5-
(tetrahydropyran-2-yloxy)pent-3-en-2-one (0.5 g) in 1,2-dichloroethane
(20 mL). The solution was then stirred for 40 min at room temperature
and gradually became deep red in colour.The organic layer was extracted
with distilled H2O (4×50 mL) and the combined aqueous extracts were
extracted once with chloroform. Crushed ice (100 g) was added to the
aqueous layer followed by an excess of conc. aq. NaOH. The aqueous
solution was extracted while still cold with ether (3×75 mL), the organic
layer dried with MgSO4 and then evaporated to leave 4-(5-methylfuran-
Michael Addition of Amines to Alkynone (3)
4-Morpholino-5-(tetrahydropyran-2-yloxy)pent-3-en-2-one (4a)
Morpholine (0.24 g) was added dropwise with stirring to neat 5-
(tetrahydropyran-2-yloxy)pent-3-yn-2-one (3) (0.5 g) while cooling in
a cold water bath (10◦C). The viscous oil was then allowed to stir at
room temperature for 2 h to afford compound (4a) (98%, GCMS). δH
(200 MHz; CDCl3) 1.90–1.40 (6H, m), 2.10 (3H, s), 3.35 (4H, m), 3.55
(1H, m), 3.73 (4H, t, J 5.0 ), 3.85 (1H, m), 4.68 (1H, m), 4.71 (1H, d, J
11.9), 5.20 (1H, s), 5.29 (1H, d, J 11.9). 13C NMR (200 MHz; CDCl3)
20.2, 25.5, 31.0, 32.3, 47.0, 60.8, 63.5, 66.6, 98.2, 100.0, 158.8, 195.9.
Mass spectrum m/z 269 (M+•, 3%), 210 (4), 186 (11), 185 (100), 184
(39), 170 (15), 169 (16), 168 (28), 167 (12), 166 (4), 157 (5), 156 (52),
154 (8), 152 (15), 150 (6), 143 (8), 142 (89), 140 (4), 138 (7), 137 (5),
136 (3), 127 (12), 126 (60), 124 (9), 114 (9), 112 (9), 110 (9), 109 (12),
108 (4), 98 (5), 97 (8), 96 (7), 92 (5), 86 (16), 85 (38), 84 (13), 83 (9),
82 (6), 81 (4), 80 (4), 70 (5), 69 (5), 68 (6), 67 (15), 57 (12), 56 (8), 55
(15), 54 (5), 43 (25), 42 (5), 41 (15).
–1
3-yl)morpholine (5a) in high purity and yield. IR (neat)/cm 3140w,
2960s, 2918s, 2855s, 2820s, 2760m, 1755m, 1681s, 1621s, 1555m,
1451s, 1397s, 1379s, 1359m, 1332m, 1302m, 1258s, 1228m, 1178m,
1161m, 1116s. δH (200 MHz; CDCl3) 2.22 (3H, s), 2.87 (4H, m), 3.81
(4H, m), 5.86 (1H, s), 6.82 (1H, s). 13C NMR (200 MHz; CDCl3) 14.0,
50.8, 66.6, 100.2, 123.9, 141.7, 152.5. Mass spectrum m/z 169 (19%),
168 (56), 167 (M+•, 78), 166 (6), 154 (3), 153 (8), 152 (12), 139 (4), 138
(10), 137 (6), 136 (8), 125 (3), 124 (8), 122 (8), 112 (7), 111 (34), 110
(83), 109 (100), 108 (12), 97 (2), 96 (4), 95 (4), 94 (6), 84 (4), 83 (4), 82
(11), 81 (15), 80 (16), 79 (4), 73 (3), 72 (2), 70 (4), 69 (4), 68 (4), 67 (6),
66 (5), 65 (3), 59 (2), 58 (2), 57 (5), 56 (4), 55 (9), 54 (8), 53 (8), 52 (3),
51 (4), 45 (9), 44 (49), 43 (15), 42 (10), 41 (18). High-resolu•tion mass
spectrum (HRMS) Found [M]+•, 168.1019. C9H14NO2 [M]+ requires
168.1025.
Compounds (4b), (4d), (4f)–(4k) were also prepared using the pro-
cedure described above. Their characterization data are included in the
Accessory material.
Cyclizations of all products (5b)–(5n) were performed using this
procedure. Their characterization data are included in the Accessory
material.
4-Dibenzylamino-5-(tetrahydropyran-2-yloxy)pent-3-en-2-one (4e)
Dibenzylamine (0.54 g) was added to 5-(tetrahydropyran-2-yloxy)pent-
3-yn-2-one(3)(0.5 g)andstirredfor45mininawarmwaterbath(70◦C).
The oil was allowed to stir for an additional 8 h at room temperature to
give compound (4e) (97%, GCMS). δH (200 MHz; CDCl3) 1.76–1.30
(6H, m), 1.95 (3H, s), 3.44 (1H, m), 3.78 (1H, m), 4.49 (4H,ABq, J 5.7),
4.74 (1H, m), 4.87 (1H, d, J 11.5), 5.20 (1H, s), 5.28 (1H, d, J 11.5),
7.40–7.07 (10H, m). 13C NMR (200 MHz; CDCl3) 19.9, 25.5, 30.8,
Accessory Material
Copies of the accessory material are available, until
January 2008, from Australian Journal of Chemistry—
an International Journal for Chemical Science (website:
www.publish.csiro.au/journals/ajc/AcessMat.cfm).

798
A. R. Lingham, T. J. Rook and H. M. Hügel
Acknowledgments
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We thank Dr Julie Niere, Dr Peter McKay, and Dr GaryAmiet
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tation, and Dr John Zdysiewicz for assistance with organic
nomenclature.
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