A convenient preparation of tetrahydrofuran-based diamines

Article abstract of DOI:10.1081/SCC-120037910

A convenient, three-step preparation of tetrahydrofuran-based diamines as combinatorial building blocks from 3,4-epoxytetrahydrofuran is described.

Full text of DOI:10.1081/SCC-120037910

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A Convenient Preparation of Tetrahydrofuran‐Based
Diamines
Gaifa Lai a
a Chemo Dynamics, Inc., 8‐7B Koster Blvd., Edison, Sayreville, New Jersey, 08837, USA
Version of record first published: 20 Aug 2006.
To cite this article: Gaifa Lai (2004): A Convenient Preparation of Tetrahydrofuran‐Based Diamines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:11, 1981-1987
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 11, pp. 1981–1987, 2004
A Convenient Preparation of
Tetrahydrofuran-Based Diamines†
*
Gaifa Lai
Chemo Dynamics, Inc., Sayreville, New Jersey, USA
ABSTRACT
A convenient, three-step preparation of tetrahydrofuran-based diamines
as combinatorial building blocks from 3,4-epoxytetrahydrofuran is
described.
Key Words: Tetrahydrofuran; Diamines; Amino groups.
As combinatorial chemistry plays an important role in new drug discov-
ery,[1,2] there is a growing need for a wide variety of structurally diversified
amines as combinatorial building blocks for the use in the library construction
in the effort to develop new therapeutically significant molecules. In view of
the fact that the tetrahydrofuran ring is a ubiquitous motif, which can be found
in many natural products with antitumor, antibiotic, and other biological
†Dedicated to the memory of Mom for her initiation and inspiration.
*
Correspondence: Gaifa Lai, 8-7B Koster Blvd., Edison, NJ 08837, USA; E-mail:
gflai2002@hotmail.com.
1981
DOI: 10.1081/SCC-120037910
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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1982
Lai
activities (e.g., burseran,[3] asiminocin,[4] and teurilene[5]), we were interested
in the conjunction of different substituted amino groups with this important
ring to construct a series of new tetrahydrofuran-based diamines 1a–1i
(Table 1). In this article, we report a convenient, three-step preparative
route to these new diamines from commercially available 3,4-epoxytetrahy-
drofuran, as shown in Sch. 1.
Thus, epoxide ring opening of commercially available 3,4-epoxytetrahy-
drofuran (2)a with morpholine or dimethylamine readily afforded the vicinal
amino alcohol 3a or 3b, respectively. Mesylation of the amino alcohols
with methanesulfonyl chloride and triethylamine in THF and subsequent treat-
ment with various amines smoothly furnished the corresponding vicinal dia-
mines 1a–1i in yields ranging from 55% to 87%. The results are
summarized in Table 1. The one-pot, two-step conversion of the amino alco-
hols to the diamines proceeded with retention of configuration[6,7] presumably
through a symmetric aziridinium species 5, providing racemic trans isomers. It
was important to add a certain amount of water just after addition of the amine
in order to facilitate the diamine formation step in cases where neat amine was
used (entries 3–5 and 7–9).[7a] Water may accelerate the formation of the
aziridinium intermediate 5. There was no nucleophilic attack on 5 by water.
However, when CH2Cl2 was used in place of THF as solvent, a small amount
of the byproduct 6a or 6b, resulting from nucleophilic attack of chloride, was
detected in the crude product. The diamine 1e was formed from selective sub-
stitution by the more nucleophilic thiol function instead of the amino group of
2-aminoethanethiol (entry 5). The assignment of its structure was further con-
firmed by acetylation with acetyl chloride and triethylamine in CH2Cl2 and
NMR analysis of the corresponding acetamide.
In summary, a convenient and practical preparation of a series of tetrahy-
drofuran-based diamines has been achieved in three steps from commercially
a3,4-Epoxytetrahydrofuran is available from Acros Organics now. This epoxide was
also prepared in this laboratory by treatment of 2,5-dihydrofuran with urea hydrogen
peroxide addition compound and phthalic anhydride in ethyl acetate at room
temperature.

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1983

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Scheme 1. Reaction conditions: (i) for 3a, morpholine (1.5 eq.), 75–808C; for 3b,
40% aqueous Me2NH solution (2 eq.), 55–608C; (ii) MsCl (1.1 eq.), Et3N (2 eq.),
THF, 215 to 2108C; (iii) amine (2 eq.), Et3N (2 eq.), H2O, rt.
available 3,4-epoxytetrahydrofuran with good overall yields. This efficient
sequence should prove useful in the synthesis of other related substituted
vicinal diamines.
EXPERIMENTAL
All reagents and solvents were purchased from Acros or Aldrich and used
without further purification. GC was performed using a Hewlett–Packard
5890A chromatograph equipped with a flame ionization detector. NMR spec-
tra were obtained with a Varian Gemini 300 spectrometer. Chemical shifts are
reported in parts per million (d) downfield from tetramethylsilane as the
internal standard. Melting points were taken in glass capillary tubes on a
Thomas-Hoover melting point apparatus and are uncorrected.
trans-3-Hydroxy-4-morpholinotetrahydrofuran (3a). A 500-mL,
three-necked, round-bottomed flask, equipped with a thermometer, a conden-
ser, a mechanic stirrer, and an addition funnel, was charged with morpholine
(152 mL, 1.74 mol, 1.5 eq.). The flask was heated to 75–808C, and 3,4-epoxy-
tetrahydrofuran (100 g, 1.16 mol) was added dropwise with agitation under
nitrogen over a period of 30 min. The mixture was then agitated at
75–808C for 3 hr when GC analysis indicated the complete consumption of
the starting material. Excess morpholine was removed under reduced pressure
and the brown oily residue was subjected to vacuum distillation to give 169 g
(84%) of trans-3-hydroxy-4-morpholinotetrahydrofuran (3a) as a white solid:
mp 51–538C, bp 145–1478C/0.5–0.6 mmHg; 98% GC purity; 1H NMR
(CDCl3) d 4.40 (m, 1H), 4.11 (m, 1H), 3.94 (m, 1H), 3.73 (m, 5H), 3.67
(m, 1H), 2.82 (m, 1H), 2.62 (m, 2H), 2.48 (m, 2H), 1.89 (s, 1H, OH);
13C NMR (CDCl3) d 73.3, 71.6, 66.8, 63.2, 54.9, 72.2; Anal. calcd. for
C8H15NO3: C, 55.47; H, 8.73; N, 8.09. Found: C, 55.41; H, 9.01; N, 7.92.
trans-3-(Dimethylamino)-4-hydroxytetrahydrofuran(3b). A 5-L, three-
necked, round-bottomed flask, equipped with a thermometer, a condenser, a
mechanic stirrer, and an addition funnel, was charged with 40% aqueous

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1985
dimethylamine solution (2.3L, 18.32 mol, 2 eq.). The solution was heated to
508C, and 3,4-epoxytetrahydrofuran (790g, 9.17mol) was added dropwise
with agitation under nitrogen, while the temperature being maintained at 50–
558C. After addition, the mixture was agitated at 50–558C under nitrogen over-
night. Excess dimethylamine and water were removed under reduced pressure
and the pale brown liquid residue was subjected to vacuum distillation to give
1.08kg (90%) of trans-3-(dimethylamino)-4-hydroxytetrahydrofuran (3b) as a
pale yellow liquid: bp 95–988C/0.4 mmHg; 99% GC purity; 1H NMR
(CDCl3) d 3.91 (m, 2H), 3.81 (m, 3H), 3.06 (m, 1H), 2.27 (s, 6H), 1.98 (s, 1H,
OH); 13C NMR (CDCl3) d 72.9, 71.6, 67.5, 66.1, 39.7; Anal. calcd. for
C6H13NO2: C, 54.94; H, 9.99; N, 10.68. Found: C, 55.11; H, 9.89; N, 10.91.
General Procedure for the One-Pot Preparation of Diamines
1a–1i from Amino Alcohol 3a or 3b
To a stirred solution of the amino alcohol 3a or 3b (1 mol) in THF (1 L)
was added triethylamine (280 mL, 2 mol, 2 eq.). After the mixture was cooled
to 2158C, a solution of methanesulfonyl chloride (85 mL, 1.1 mol, 1.1 eq.) in
THF (80 mL) was added dropwise with agitation under nitrogen over a period
of 1 hr, while the temperature being maintained below 2108C. The mixture
was then agitated at 215 to 2108C for 1 hr when TLC and GC analysis
showed that the mesylation was complete. Triethylamine (280 mL, 2 mol, 2
eq.), an amine (2 mol, 2 eq.), and water (80 mL) were added in turn with agita-
tion below 2108C. The resulting mixture was then agitated under nitrogen at
room temperature overnight. Water (300 mL) was added, and the organic layer
was separated. The aqueous layer was extracted with CH2Cl2 (2 ꢀ 500 mL).
The combined organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified by vacuum distilla-
tion. Their yields, boiling points, and purity were listed in Table 1.
1
1a. a colorless liquid; H NMR (CDCl3) d 4.02 (m, 1H), 3.98 (m, 1H),
3.74–3.70 (m, 5H), 3.51 (m, 2H), 2.61 (m, 3H), 2.48 (m, 2H), 1.48
(s, broad, 2H, NH2); 13C NMR (CDCl3) d 72.8, 72.1, 67.5, 64.4, 54.8, 52.7;
Anal. calcd. for C8H16N2O2: C, 55.79; H, 9.36; N, 16.27. Found: C, 55.67;
H, 9.22; N, 16.43.
1b. a pale yellow liquid; 1H NMR (CDCl3) d 4.05 (m, 2H), 3.77 (m, 4H),
3.66 (m, 2H), 3.23 (m, 1H), 2.78 (m, 1H), 2.67 (m, 2H), 2.51 (m, 2H), 2.48
(s, 3H); Anal. calcd. for C9H18N2O2: C, 58.04; H, 9.74. Found: C, 58.34;
H, 9.64.
1c. a colorless liquid; 1H NMR (CDCl3) d 5.88 (m, 1H), 5.19 (dd,
J ¼ 1.6, 17.2 Hz, 1H), 5.11 (dd, J ¼ 1.5, 11.8 Hz, 1H), 3.95 (m, 2H), 3.70
(m, 5H), 3.62 (m, 1H), 3.31 (m, 1H), 3.24 (m, 2H), 2.74 (m, 1H), 2.58

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(m, 2H), 2.47 (m, 2H), 1.32 (s, broad, 1H, NH); Anal. calcd. for C11H20N2O2:
C, 62.23; H, 9.50. Found: C, 62.49; H, 9.29.
1
1d. a colorless liquid; H NMR (CDCl3) d 3.98–3.94 (m, 2H), 3.72
(m, 6H), 3.42 (m, 1H), 2.73 (m, 1H), 2.62 (m, 2H), 2.47 (m, 2H), 2.10
(m, 1H), 1.69 (s, broad, 1H, NH), 0.47 (m, 2H), 0.37 (m, 2H); Anal. calcd.
for C11H20N2O2: C, 62.23; H, 9.50. Found: C, 62.42; H, 9.39.
1
1e. a colorless liquid; H NMR (CDCl3) d 4.20 (m, 1H), 3.92 (m, 1H),
3.81 (m, 1H), 3.75 (m, 5H), 3.29 (m, 1H), 2.92 (m, 3H), 2.68 (m, 4H), 2.49
(m, 2H), 1.55 (s, broad, 2H, NH2); Anal. calcd. for C10H20N2O2S: C, 51.69;
H, 8.68; N, 12.06. Found: C, 51.46; H, 9.02; N, 12.43.
1
1f. a colorless liquid; H NMR (CDCl3) d 4.00 (m, 2H), 3.68 (m, 1H),
3.49 (m, 2H), 2.51 (m, 1H), 2.29 (s, 6H), 1.45 (s, broad, 2H, NH2); Anal.
calcd. for C6H14N2O: C, 55.35; H, 10.84. Found: C, 55.65; H, 10.98.
1
1g. a pale yellow liquid; H NMR (CDCl3) d 3.96–3.92 (m, 2H), 3.70
(m, 1H), 3.62 (m, 1H), 3.49 (t, J ¼ 7.2 Hz, 2H), 3.36 (s, 3H), 3.26 (m, 1H),
2.77 (m, 2H), 2.70 (m, 1H), 2.28 (s, 6H), 1.68 (s, broad, 1H, NH); Anal.
calcd. for C9H20N2O2: C, 57.42; H, 10.71. Found: C, 57.74; H, 10.81.
1
1h. a colorless liquid; H NMR (CDCl3) d 3.93–3.91 (m, 2H), 3.68
(m, 2H), 3.38 (m, 1H), 2.67 (m, 1H), 2.20 (s, 6H), 2.13 (m, 1H), 1.81
(s, broad, 1H, NH), 0.47 (m, 2H), 0.36 (m, 2H); Anal. calcd. for C9H18N2O:
C, 63.49; H, 10.66. Found: C, 63.54; H, 10.39.
1i. a colorless liquid; 1H NMR (CDCl3) d 7.30 (d, J ¼ 8.7 Hz, 2H), 7.00
(d, J ¼ 8.7 Hz, 2H), 3.95–3.88 (m, 2H), 3.74 (d, 2H), 3.68 (m, 2H), 3.24
(m, 1H), 2.69 (m, 1H), 2.24 (s, 6H), 1.31 (s, broad, 1H, NH); Anal. calcd.
for C13H19FN2O: C, 65.52; H, 8.04; N, 11.76. Found: C, 65.67; H, 8.29;
N, 11.89.
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Received in the USA November 2, 2003

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