Reactivity of γ-hydroxy-α-acetylenic esters with amines: Facile synthesis of the optically active 4-amino-2(5H)-furanones

Article abstract of DOI:10.1021/jo802592h

A convenient synthesis of the optically active 4-amino-2(5H)-furanones is discovered by combining an asymmetric alkyne addition to aldehydes and a subsequent aliphatic amine addition. Both steps can be conducted at room temperature and the products are obtained with high enantioselectivity (84-90% ee). The 4-amino-2(5H)-furanones are also found to undergo very facile electrophilic substitution reactions.

Full text of DOI:10.1021/jo802592h

Reactivity of γ-Hydroxy-r,ꢀ-acetylenic Esters with Amines: Facile
Synthesis of the Optically Active 4-Amino-2(5H)-furanones
Li-Hong Zhou,†,‡ Xiao-Qi Yu,*,‡ and Lin Pu*,†
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904-4319, and Department of
Chemistry, Key Laboratory of Green Chemistry and Technology (Ministry of Education), Sichuan
UniVersity, Chengdu, China 610064
lp6n@Virginia.edu
ReceiVed NoVember 21, 2008
A convenient synthesis of the optically active 4-amino-2(5H)-furanones is discovered by combining an
asymmetric alkyne addition to aldehydes and a subsequent aliphatic amine addition. Both steps can be
conducted at room temperature and the products are obtained with high enantioselectivity (84-90% ee).
The 4-amino-2(5H)-furanones are also found to undergo very facile electrophilic substitution reactions.
Introduction
with a tetronic ester,4h addition of an amine to a γ-silyloxy-R,ꢀ-
acetylenic ester,4h and reaction of an amine with a 4-bromo-2(5H)-
furanone4i have also been used. Among the reported syntheses,
we consider the most direct method to be the addition of amines
to γ-hydroxy-R,ꢀ-acetylenic esters.4j,k In this reaction, the ꢀ-amine
addition is followed by γ-lactonization to readily generate the
4-amino-2(5H)-furanone products. Although racemic or achiral
4-amino-2(5H)-furanones have been prepared from this route,4j,k
the optically active products have not been obtained by using this
reaction.
2(5H)-Furanone (or γ-butenolide) structures are found to exist
in many natural and unnatural products. Derivatives of 2(5H)-
furanones have exhibited very diversebiological functions and
(3) Selected reports and reviews: (a) Carter, N. B.; Nadany, A. E.; Sweeney,
J. B. J. Chem. Soc., Perkin Trans. 1 2002, 2324–2342. (b) Bru¨ckner, R. Curr.
Org. Chem. 2001, 5, 679–718. (c) Raju, R.; Allen, L. J.; Le, T.; Taylor, C. D.;
Howell, A. R. Org. Lett. 2007, 9, 1699–1701. (d) Patil, S. N.; Liu, F. Org. Lett.
2007, 9, 195–198. (e) Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129,
778–779. (f) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. J. Am. Chem.
Soc. 2003, 125, 1192–1194. (g) Cho, C. W.; Krische, M. J. Angew. Chem., Int.
Ed. 2004, 43, 6689–6691. (h) Barleuenga, J.; Prado, A. D.; Santamaria, J.; Tomas,
M. Angew. Chem., Int. Ed. 2005, 44, 6583–6585. (i) Ma, S.; Lu, L.; Lu, P. J.
Org. Chem. 2005, 70, 1063–1065. (j) Hanessian, S.; Murray, P. J. Tetrahedron
1987, 43, 5055–5072. (k) Feringa, B. L.; de Lange, B.; Jansen, J. F. G. A.; de
Jong, J. C.; Lubben, M.; Faber, W. S.; Schudde, E. P. Pure Appl. Chem. 1992,
64, 1865–1871.
(4) (a) Ireland, R. E.; Brown, F. R., Jr. J. Org. Chem. 1980, 45, 1868–1880.
(b) Niwa, H.; Miyachi, Y.; Osamu Okamoto, O.; Uosaki, Y.; Yamada, K.
Tetrahedron Lett. 1986, 27, 4605–4608. (c) Niwa, H.; Okamoto, O.; Miyachi,
Y.; Uosaki, Y. J. Org. Chem. 1987, 52, 2941–2943. (d) Hart, D. J.; Sun, L.-Q.;
Kozikowski, A. P. Tetrahedron Lett. 1995, 36, 7787–7790. (e) Lee, J. Y.; Lee,
Y. S.; Chung, B. Y.; Park, H. Tetrahedron 1997, 53, 2449–2458. (f) Li, Y.-J.;
Lee, P.-T.; Yang, C.-M.; Chang, Y.-K.; Weng, Y.-C.; Liu, Y.-H. Tetrahedron
Lett. 2004, 45, 1865–1868. (g) Hiyama, T.; Oishi, H.; Suetsugu, Y.; Nishide,
K.; Saimoto, H. Bull. Chem. Soc. Jpn. 1987, 60, 2139–2150. (h) Schlessinger,
R. H.; Iwanowicz, E. J. Tetrahedron Lett. 1988, 29, 1489–1492. (i) Basler, B.;
Schuster, O.; Bach, T. J. Org. Chem. 2005, 70, 9798–9808. (j) Jones, E. R. H.;
Whiting, M. C. J. Chem. Soc. 1949, 1423–1430. (k) Mavrov, M. V.; Konyushkin,
L. D.; Simirskaya, N. I.; Zlotin, S. G. Russ. Chem. Bull. Int. Ed. 2005, 54, 2857–
2866.
are important in the development of therapeutic agents.1 For
example, a few 4-substituted 2(5H)-furanones are found to be
potent antibiotics and have shown cytotoxicity against human colon
carcinoma and human melanoma.2 Extensive studies on the
synthesis of both chiral and achiral derivatives of 2(5H)-furanones
have been conducted.3,4 We are interested in the synthesis of chiral
4-amino-2(5H)-furanones. Previously, the intramolecular Wittig
reaction4a-e and [2,3]-Wittig rearrangement4f have been used to
prepare 4-amino-2(5H)-furanones. Other methods such as the
addition of an ester enolate to a nitrile,4g condensation of an amine
† University of Virginia.
‡ Sichuan University.
(1) Examples: (a) Van Quaquebeke, E.; Simon, G.; Andre’, A.; Dewelle, J.;
El Yazidi, M.; Bruyneel, F.; Tuti, J.; Nacoulma, O.; Guissou, P.; Decaestecker,
C.; Braekman, J.-C.; Kiss, R.; Darro, F. J. Med. Chem. 2005, 48, 849–856. (b)
Bousserouel, H.; Litaudon, M.; Morleo, B.; Martin, M.-T.; Thoison, O.; Nosjean,
O.; Boutin, J. A.; Renard, P.; Se´venet, T. Tetrahedron 2005, 61, 845–851. (c)
Dai, S.-J.; Tao, J.-Y.; Liu, K.; Jiang, Y.-T.; Shen, L. Phytochemistry 2006, 67,
1326–1330.
(2) Ortega, M. J.; Zubia, E.; Ocana˜, G. M.; Naranjo, S.; Salva`, J. Tetrahedron
2000, 56, 3963–3967.
10.1021/jo802592h CCC: $40.75
Published on Web 02/05/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2013–2017 2013

Zhou et al.
TABLE 1. Results for the Asymmetric Methyl Propiolate Addition
to Various Aldehydes Followed by Treatment with Benzylamine
SCHEME 1. Asymmetric Synthesis of an
4-Amino-2(5H)-furanone
Recently, we discovered a highly enantioselective reaction
of methyl propiolate with aldehydes by using 1,1′-bi-2-naphthol
(BINOL) in combination with ZnEt2, Ti(OiPr)4, and HMPA at
room temperature.5,6 This reaction allows the synthesis of
γ-hydroxy-R,ꢀ-acetylenic esters under very mild conditions with
excellent enantiomeric purity. We find that treatment of the
γ-hydroxy-R,ꢀ-acetylenic esters with aliphatic amines leads to
the facile synthesis of the optically active 4-amino-2(5H)-
furanones. These 4-amino-2(5H)-furanones are also found to
undergo electrophilic substitution under very mild conditions.
Herein, these results are reported.
Results and Discussion
We have conducted the reaction of methyl propiolate with
octanal in the presence of (S)-BINOL, ZnEt2, Ti(OiPr)4, and
HMPA to generate the corresponding γ-hydroxy-R,ꢀ-acetylenic
ester (Scheme 1).5b When this γ-hydroxy-R,ꢀ-acetylenic ester
is treated with 1.2 equiv of benzylamine in benzene at room
temperature, upon removal of the solvent, the 1H NMR spectrum
of the residue indicates the formation of the amine addition
product 1 as the major product. After chromatography on silica
gel eluted with 50% ethyl acetate in hexanes, compound 1
undergoes an intramolecular cyclization to form the 4-amino-
2(5H)-furanone 2. TLC analysis with silica gel plate shows that
the polarity of 2 is much greater than that of 1 and 1 is not
converted to 2 during the TLC analysis. Increasing the amount
of benzylamine to 1.4 equiv allows the lactonization to take
place immediately after the amine addition before column
chromatograph and it also reduces the overall reaction time.
Changing the solvent to THF gives lower yield and using
methanol gives similar yield as the use of benzene. Increasing
the reaction temperature or addition of DABCO as a catalyst
shows little influence on the reaction time and the product yield.
Thus, the combination of the asymmetric alkyne addition to
octanal with the subsequent treatment with 1.4 equiv of
benzylamine at room temperature gives the 4-amino-2(5H)-
furanone product 2 in 75% yield in two steps and with 84% ee.
Although the γ-hydrogen of the γ-hydroxy-R,ꢀ-acetylenic ester
is of significant acidity, no racemization is observed in the
presence of the amine base.
a The total yield of the two steps.
generate optically active 4-amino-2(5H)-furanones. As the
results summarized in Table 1 show, the desired products are
obtained in good yields (all the yields are the total of the two
steps) and high enantiomeric purity. The reaction works well
for linear and branched aliphatic aldehydes. Good enantiose-
lectivity is also observed for a few aromatic aldehydes. In entry
7, a racemic chiral aldehyde is used that gives a 1:1 mixture of
two diastereomers with good enantiomeric purity for each
diastereomer. No optically active 4-amino-2(5H)-furanones were
prepared by the reaction of amines with chiral propargylic
alcohols before, although the racemic or achiral products were
obtained from the reaction of amines with achiral or racemic
γ-hydroxy-R,ꢀ-acetylenic esters.4j,k
As shown in Table 1, the enantiomeric purity of the products
generated from the asymmetric methyl propiolate addition to
the aliphatic and aromatic aldehydes is maintained in the
subsequent reaction with benzylamine to form the 4-amino-
2(5H)-furanones. However, we find that the reaction of ben-
zylamine with the γ-hydroxy-R,ꢀ-acetylenic esters derived from
other aromatic aldehydes such as 1-naphthaldehyde and 2-fural-
dehyde led to the racemized 4-amino-2(5H)-furanones. It is not
clear yet what contributes to the racemization and formation of
free radicals during the amine addition might be involved.
We have also studied the reactivity of racemic alkyl- and
aryl-substituted γ-hydroxy-R,ꢀ-acetylenic esters in the presence
of a variety of primary and secondary amines. The results are
summarized in Table 2. Entries 1-6 show that both primary
and secondary amines can react with the γ-hydroxy-R,ꢀ-
acetylenic esters to generate the 4-amino-2(5H)-furanones with
good yields. In entries 7 and 8, a racemic chiral amine is used
that gives the products in good yields with 1.1-1.4:1 diaster-
eomeric ratio. In entry 9, the optically pure amino ester is used,
which gives the product with 1.3:1 diastereomeric ratio.
We have examined the two-step reaction of methyl propiolate
with a variety of aldehydes and then with benzylamine to
(5) (a) Gao, G.; Wang, Q.; Yu, X.-Q.; Xie, R.-G.; Pu, L. Angew. Chem., Int.
Ed. 2006, 45, 122–125. (b) Rajaram, A. R.; Pu, L. Org. Lett. 2006, 8, 2019–
2021.
(6) Other reports on the asymmetric propiolate addition to aldehydes: (a)
Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc. 2006, 128,
8–9. (b) Yang, F.; Xi, P.; Yang, L.; Lan, J.; Xie, R.; You, J. S. J. Org. Chem.
2007, 72, 5457–5460. (c) Lebel, H.; Parmentier, M. Org. Lett. 2007, 9, 3563–
3566.
2014 J. Org. Chem. Vol. 74, No. 5, 2009

ReactiVity of γ-Hydroxy-R,ꢀ-acetylenic Esters with Amines
TABLE 2. Results for the Reaction of γ-Hydroxy-r,ꢀ-acetylenic
Esters with Various Amines
SCHEME 3. Reactions with Boc2O
C-C bond on a 4-amino-2(5H)-furanone ring under very mild
conditions. These halogenation and acylation of 2 demonstrate
that the 3-position of the 4-amino-2(5H)-furanone is very
electron rich and susceptible to electrophilic substitution.
Preparation of compounds 3 and 4 makes it possible to further
derivatize the 4-amino-2(5H)-furanones on the ring.
In contrast to the reaction with trifluoroacetic anhydride, when
2 is treated with (Boc)2O in the presence of DMAP at room
temperature, the N-protected product 5 is obtained in 99% yield
(Scheme 3).4i When 3 is treated with (Boc)2O in the presence
of DMAP at room temperature, it also gives the N-protected
product 6 in 96% yield. However, the electron-withdrawing
effect of the Boc group in 5 makes this compound unreactive
toward bromine.
a
n
Prepared from the treatment of methyl propiolate with BuLi at -78
°C followed by the addition of the aldehyde.7 b The total yield of the
alkyne addition and the amine addition. c The diasteromeric ratio.
SCHEME 2. Reactions of 2 with Br2 and (CF3CO)2O
In summary, we have discovered a convenient synthesis of
the optically active 4-amino-2(5H)-furanones by combining an
asymmetric alkyne addition to aldehydes and a subsequent
aliphatic amine addition. Both steps are conducted at room
temperature and the products are obtained with high enantiose-
lectivity. The 4-amino-2(5H)-furanones are also found to
undergo very facile electrophilic substitution reactions.
Experimental Section
We have investigated the reactivity of the 4-amino-2(5H)-
furanones. When the racemic compound 2 is treated with Br2
in methylene chloride solution at 0 °C, the 3-brominated product
3 is obtained in 91% yield (Scheme 2). Previously, the
General Data. Dichloromethane was dried by passing through
activated alumina columns under nitrogen. All solvents were stored
over molecular sieves. All liquid aldehydes were distilled prior to
use.
bromination of 4-amino-2(5H)-furanones with NBS8a as well
8b-d
General Procedure for the Preparation of 4-Amino-5-
substituted-2(5H)-furanones. (a) To a stirred solution of (S)-
BINOL (0.243 g, 0.5 mmol, 40 mol %), HMPA (0.44 mL, 2.5
mmol), and methyl propiolate (0.425 mL, 5.0 mmol) in methylene
chloride (15 mL) under nitrogen is slowly added ZnEt2 (0.523 mL,
5.0 mmol). After the solution is stirred at room temperature for
16 h, Ti(OiPr)4 (0.370 mL, 1.25 mmol) is added and the stirring is
continued for another hour. Then, an aldehyde (1.25 mmol, neat)
is added in one portion and the reaction is allowed to proceed at
room temperature for 4 h. Ammonium chloride (saturated aqueous)
is added to quench the reaction, and the mixture is extracted with
methylene chloride and dried with sodium sulfate. After column
chromatography on silica gel eluted with 10% ethyl acetate in
hexanes, an optically active γ-hydroxy-R,ꢀ-acetylenic ester product
is isolated. (b) A solution of the optically active γ-hydroxy-R,ꢀ-
acetylenic ester product prepared in step a (2 M in benzene) and
an amine (1.4 equiv) is stirred under nitrogen at room temperature
for 5-24 h. After the reaction is completed as shown by TLC, the
solvent is evaporated and the product is obtained after column
as the iodination with ICl or I(py)2BF4
were conducted to
give the 3-halogenated products, but the direct bromination with
Br2 was not reported. We have also studied the reaction of
compound 2 with trifluoroacetic anhydride. At room temperature
in methylene chloride solution, 2 reacts with trifluoroacetic
anhydride to give a C-acylated product 4 in 95% yield rather
1
than an N-acylated product (Scheme 2). The H NMR spectra
of both 3 and 4 show the disappearance of the vinyl proton
singlet of 2 at δ 4.67 for the substitution at the 3-position. The
acylation at the 3-position of a 4-amino-2(5H)-furanone is
unprecedented and it allows the direct construction of a new
(7) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980, 45,
28–29.
(8) (a) Schlessinger, R. H.; Pettus, T. R. R.; Springer, J. P.; Hoogsteen, K.
J. Org. Chem. 1994, 59, 3246–3247. (b) Matsuo, K.; Ishida, S.; Takund, Y.
Chem. Pharm. Bull. 1994, 42, 1149–1150. (c) Campos, P. J.; Arranz, J.;
Rodriguez, M. A. Tetrahedron Lett. 1997, 38, 8397–8400. (d) Kim, J. M.; Na,
J. E.; Kim, J. N. Tetrahedron Lett. 2003, 44, 6317–6318.
J. Org. Chem. Vol. 74, No. 5, 2009 2015

Zhou et al.
chromatography on silica gel eluted with 50% ethyl acetate in
hexanes. The enantiomeric purity of the product is determined by
using HPLC-Chiralcel OD or AD column.
OD-H column; solvent: 90:10 hexanes:isopropanol; flow rate: 1
mL/min; retention time: tminor1 ) 5.1 min, tminor2 ) 31.8 min, tmajor1
) 36.9 min, and tmajor2 ) 37.8 min. The NMR spectra show a
mixture of two diastereomers: 1H NMR (300 MHz, CDCl3) δ
7.37-7.26 (m, 5H), 5.10 (br, 1H), 4.81 (m), 4.72 (m), 4.28 (d, J )
5.4 Hz, 2H), 1.67-1.40 (m, 1H), 1.09 (d, J ) 6.9 Hz), 0.96 (t, J
) 7.5 Hz), 0.92 (t, J ) 7.5 Hz), 0.77 (d, J ) 6.6 Hz). 13C NMR
(75 MHz, CDCl3) δ 175.2, 169.2, 168.8, 136.5, 128.9, 128.1, 127.6,
127.5, 83.6, 83.4, 82.7, 80.6, 49.2, 37.5, 37.4, 26.6, 21.4, 15.7, 11.9,
11.3. HRMS (ESI) calcd for C15H19NO2 + H+ 246.1494, found
246.1491.
Characterization of the 4-Amino-5-substituted-2(5H)-fura-
nones Products: 4-(Benzylamino)-5-heptylfuran-2(5H)-one, 2
(P1): 75% overall yield, and 84% ee determined by HPLC analysis:
chiralcel AD-H column; solvent: 95:5 hexanes:isopropanol; flow
rate: 1 mL/min; retention time: tminor ) 22.1 min and tmajor ) 27.0
min. 1H NMR (300 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 5.15 (br,
H), 4.77 (dd, J ) 7.5, 3.3 Hz, 1H), 4.67 (s, 1H), 4.28 (d, J ) 5.1
Hz, 2H), 1.85 (m, 1H), 1.61 (m, 1H), 1.45-1.26 (m, 10H), 0.87 (t,
J ) 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 175.6, 170.9, 136.7,
128.6, 127.6, 127.3, 81.3, 78.6, 48.8, 33.0, 31.7, 29.2, 29.0, 23.9,
22.5, 14.0. HRMS (ESI) calcd for C18H25NO2 + H+ 288.1964,
found 288.1967.
4-(Benzylamino)-5-phenylfuran-2(5H)-one, P8: 78% overall
yield, and 90% ee determined by HPLC analysis: chiralcel AD-H
column; solvent ratio: 90:10 hexanes: isopropanol; flow rate: 1 mL/
min; retention time: tminor ) 24.3 min and tmajor ) 29.1 min. [R]21
D
1
-26.7 (c 0.41, THF). H NMR (300 MHz, CDCl3) δ 7.47-7.12
4-(Benzylamino)-5-butylfuran-2(5H)-one, P2: 70% overall yield,
and 87% ee determined by HPLC analysis: chiralcel OD-H column;
solvent: 90:10 hexanes:isopropanol; flow rate: 1 mL/min; retention
(m, 10H), 5.61 (s, 1H), 4.80 (s, 1H), 4.72 (br, 1H), 4.24 (t, J ) 5.4
Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 174.6, 169.2, 136.2, 134.9,
129.6, 129.1, 128.7, 127.9, 127.2, 127.1, 82.2, 80.3, 49.0. HRMS
(ESI) calcd for C17H15NO2 + H+ 266.1181, found 266.1187.
4-(Benzylamino)-5-o-tolylfuran-2(5H)-one, P9: 57% overall
yield, and 90% ee determined by HPLC analysis: chiralcel OD-H
column; solvent: 90:10 hexanes: isopropanol; flow rate: 2 mL/min;
time: tmajor ) 37.3 min and tminor ) 47.3 min. [R]21 14.2 (c 0.30,
D
1
THF). H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 4.97
(br, 1H), 4.77 (dd, J ) 7.8, 3.3 Hz, 1H), 4.70 (s, 1H), 4.29 (d, J )
5.4 Hz, 2H), 1.83 (m, 1H), 1.61 (m, 1H), 1.45-1.31 (m, 4H), 0.89
(t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 175.9, 171.3,
136.7, 128.4, 127.3, 127.0, 80.5, 78.7, 48.5, 32.5, 25.9, 22.1, 13.7.
HRMS (ESI) calcd for C15H19NO2 + H+ 246.1494, found 246.1497.
4-(Benzylamino)-5-octylfuran-2(5H)-one, P3: 31% overall yield,
and 83% ee determined by HPLC analysis: chiralcel OD-H column;
solvent: 90:10 hexanes:isopropanol; flow rate: 1 mL/min; retention
1
retention time: tminor ) 33.4 min and tmajor ) 53.8 min. H NMR
(300 MHz, CDCl3) δ 7.30-7.08 (m, 9H), 5.81 (s, 1H), 5.55 (br,
1H), 4.66 (s, 1H), 4.23 (d, J ) 3.6 Hz, 2H), 2.34 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 174.8, 169.4, 137.4, 136.4, 132.6, 130.5, 129.0,
128.2, 127.2, 126.9, 126.0, 81.8, 77.4, 48.4, 18.6. HRMS (ESI)
calcd for C18H17NO2 + H+ 280.1338, found 280.1338.
time: tmajor ) 26.7 min and tminor ) 37.2 min. [R]21 15.7 (c 0.20,
D
1
THF). H NMR (300 MHz, CDCl3) δ 7.33-7.30 (m, 5H), 5.96
4-(Benzylamino)-5-(4-methoxyphenyl)furan-2(5H)-one, P10:
67% overall yield, and 90% ee determined by HPLC analysis:
chiralcel AD-H column; solvent: 90:10 hexanes: isopropanol; flow
rate: 1 mL/min; retention time: tminor ) 34.9 min and tmajor ) 44.3
(br, 1H), 4.77 (m, 1H), 4.56 (s, 1H), 4.26 (d, J ) 5.1 Hz, 2H),
1.87 (m, 1H), 1.60 (m, 1H), 1.36-1.24 (m, 12H), 0.87(m, 3H).
13C NMR (75 MHz, CDCl3) δ 175.4, 170.6, 136.6, 128.7, 127.7,
127.3, 81.6, 78.6, 48.9, 33.0, 31.8, 29.4, 29.3, 29.2, 24.0, 22.6, 14.1.
HRMS (ESI) calcd for C19H27NO2 + H+ 302.2115, found 302.2118.
4-(Benzylamino)-5-isobutylfuran-2(5H)-one, P4: 51% overall
yield, and 85% ee determined by HPLC analysis: chiralcel AD-H
column; solvent: 90:10 hexanes:isopropanol; flow rate: 1 mL/min;
retention time: tminor ) 18.2 min and tmajor ) 22.5 min. [R]21D 17.8
(c 0.20, THF). 1H NMR (300 MHz, CDCl3) δ 7.51-7.27 (m, 5H),
5.18 (br, 1H), 4.79 (dd, J ) 6.3, 3.9 Hz, 1H), 4.65 (s, 1H), 4.27 (d,
J ) 5.4 Hz, 2H), 2.00 (m, 1H), 1.55 (m, 2H), 0.964 (d, J ) 6.6
Hz, 3H), 0.957 (d, J ) 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ 175.0, 170.9, 136.4, 128.9, 128.0, 127.5, 81.8, 77.1, 49.1, 42.7,
24.9, 23.5, 21.5. HRMS (ESI) calcd for C15H19NO2 + H+ 246.1494,
found 246.1491.
1
min. H NMR (300 MHz, CDCl3) δ 7.32-6.89 (m, 9H), 5.58 (s,
1H), 4.80 (s, 1H), 4.70 (br, 1H), 4.25 (t, J ) 5.4 Hz, 2H), 3.81 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 174.7, 169.3, 160.5, 136.3,
128.8, 128.7, 127.8, 127.3, 126.8, 114.4, 82.3, 80.1, 55.3, 49.0.
HRMS (ESI) calcd for C18H17NO3 + H+ 296.1287, found 296.1279.
4-(Butylamino)-5-phenylfuran-2(5H)-one, P11: 81% overall
yield. 1H NMR (300 MHz, CDCl3) δ 7.40-7.27 (m, 5H), 5.56 (s,
1H), 4.73 (s, 1H), 4.59 (br, 1H), 3.05 (p, 2H), 1.47 (sextet, 2H),
1.24 (m, 2H), 0.86 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ 175.2, 169.8, 135.3, 129.3, 128.8, 127.1, 80.2, 80.0, 44.8, 30.1,
19.7, 13.4. HRMS (ESI) calcd for C14H17NO2 + H+ 232.1338,
found 232.1334.
4-(Butylamino)-5-heptylfuran-2(5H)-one, P12: 75% overall
yield. 1H NMR (300 MHz, CDCl3) δ 5.97 (br, 1H), 4.74 (dd, J )
7.5, 3.3 Hz, 1H), 4.51 (s, 1H), 3.08 (m, 2H), 1.86 (m, 1H), 1.57
(m, 3H), 1.38-1.23 (m, 12H), 0.91 (t, J ) 7.5 Hz, 3H), 0.84 (t, J
) 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 175.7, 171.0, 80.0,
78.5, 44.8, 33.1, 31.7, 30.4, 29.2, 29.1, 24.0, 22.5, 20.0, 14.0, 13.6.
HRMS (ESI) calcd for C15H27NO2 + H+ 254.2122, found 254.2115.
4-(Dihexylamino)-5-phenylfuran-2(5H)-one, P13: 87% overall
yield. 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 5H), 5.70 (s,
1H), 4.76 (s, 1H), 3.13-2.89 (m, 4H), 1.61-0.86 (m, 22H). 13C
NMR (75 MHz, CDCl3) δ 174.3, 169.1, 135.6, 129.4, 129.0, 127.7,
82.0, 80.0, 50.9, 50.7, 50.6, 31.2, 28.0, 26.0, 22.3, 13.8. HRMS
(ESI) calcd for C22H33NO2 + H+ 344.2590, found 344.2588.
4-(Dihexylamino)-5-heptylfuran-2(5H)-one, P14: 88% overall
4-(Benzylamino)-5-isopropylfuran-2(5H)-one, P5: 62% overall
yield, and 84% ee determined by HPLC analysis: chiralcel OD-H
column; solvent: 90:10 hexanes: isopropanol; flow rate: 1 mL/min;
1
retention time: tminor ) 34.7 min and tmajor ) 38.6 min. H NMR
(300 MHz, CDCl3) δ 7.38-7.26 (m, 5H), 4.86 (br, 1H), 4.76 (s,
1H), 4.69 (d, J ) 2.4 Hz, 1H), 4.29 (d, J ) 5.1 Hz, 2H), 2.03
(heptet d, J ) 6.9, 2.7 Hz, 1H), 1.15 (d, J ) 6.9 Hz, 3H), 0.83 (d,
J ) 6.6 Hz, 3H) (contains ∼9% impurity that cannot be removed).
13C NMR (75 MHz, CDCl3) δ 175.9, 169.8, 136.7, 128.7, 127.7,
127.4, 82.6, 82.3, 49.0, 30.6, 19.4, 13.5. HRMS (ESI) calcd for
C14H17NO2 + H+ 232.1332, found 232.1333.
4-(Benzylamino)-5-cyclohexylfuran-2(5H)-one, P6: 69% over-
all yield, and 86% ee determined by HPLC analysis: chiralcel OD-H
column; solvent: 90:10 hexanes: isopropanol; flow rate: 1 mL/min;
retention time: tmajor ) 34.7 min and tminor ) 38.3 min; [R]21D 14.2
(c 0.26, THF). 1H NMR (300 MHz, CDCl3) δ7.37-7.29 (m, 5H),
5.16 (br, 1H), 4.69 (s, 1H), 4.65 (d, J ) 1.8 Hz, 1H), 4.28 (d, J )
5.4 Hz, 2H), 1.71 (m, 6H), 1.47 (m, 1H), 1.20 (m, 4H). 13C NMR
(75 MHz, CDCl3) δ 176.0, 169.8, 136.8, 128.5, 127.5, 127.2, 82.6,
81.7, 48.8, 40.1, 29.8, 26.3, 25.8, 25.6, 23.7. HRMS (ESI) calcd
for C17H21NO2 + H+ 272.1651, found 272.1656.
1
yield. H NMR (300 MHz, CDCl3) δ 4.80 (dd, J ) 6.9, 2.4 Hz,
1H), 4.53 (s, 1H), 3.07 (m, 4H), 1.87 (m, 1H), 1.55-1.26 (m, 27H),
0.88 (m, 9H). 13C NMR (75 MHz, CDCl3) δ 174.7, 170.9, 82.5,
77.7, 50.6, 33.8, 31.7, 31.4, 29.2, 29.0, 26.4, 24.2, 22.54, 22.49,
14.0, 13.9. HRMS (ESI) calcd for C23H43NO2 + H+ 366.3372,
found 366.3369.
4-(Dibenzylamino)-5-phenylfuran-2(5H)-one, P15: 87% over-
all yield. 1H NMR (300 MHz, CDCl3) δ 7.37-6.98 (m, 15H), 5.85
(s, 1H), 5.01 (s, 1H), 4.34-4.17 (m, 4H). 13C NMR (75 MHz,
CDCl3) δ 173.7, 169.9, 134.8, 129.4, 129.0, 128.5, 128.0, 127.6,
4-(Benzylamino)-5-sec-butylfuran-2(5H)-one, P7: 53% overall
yield, and 84% and 87% ee determined by HPLC analysis: chiralcel
2016 J. Org. Chem. Vol. 74, No. 5, 2009

ReactiVity of γ-Hydroxy-R,ꢀ-acetylenic Esters with Amines
126.8, 84.4, 80.0, 53.4. HRMS (ESI) calcd for C24H21NO2 + H+
356.1651, found 356.1646.
over 2 h. After the reaction is completed as shown by TLC, the
solvent is evaporated, and the product is obtained in 95% overall
yield after column chromatography eluted with 50% ethyl acetate
in hexanes. 1H NMR (300 MHz, CDCl3) δ 9.92 (br, 1H), 7.46-7.29
(m, 5H), 5.10 (dd, J ) 7.5, 1.8 Hz, 1H), 4.62 (d, J ) 6.3 Hz, 1H),
2.01 (m, 1H), 1.62 (m, 1H), 1.44-1.23 (m, 10H), 0.87 (t, J ) 6.6
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 179.3, 176.6 (q, JC-F ) 38
Hz), 167.1, 134.0, 129.4, 129.0, 127.0, 115.9 (q, JC-F ) 286 Hz),
92.6, 75.7, 49.3, 32.5, 31.5, 28.9, 28.8, 24.1, 22.4, 13.9. HRMS
(ESI) calcd for C20H24F3NO3 + H+ 384.1787, found 384.1784.
Preparation and Characterization of tert-Butyl Benzyl(2-
heptyl-5-oxo-2,5-dihydrofuran-3-yl)carbamate, 5. To a stirred
solution of 4-(benzylamino)-5-heptylfuran-2(5H)-one (0.3 mmol,
86 mg) and DMAP (0.36 mmol, 44 mg) in CH2Cl2 (20 mL) was
added Boc2O (0.36 mmol, 78 mg). After the reaction is completed
as shown by TLC, the solvent is evaporated, and the product is
obtained in 99% yield after column chromatography eluted with
25% ethyl acetate in hexanes. 1H NMR (300 MHz, CDCl3) δ
7.36-7.15 (m, 5H), 5.68 (s, 1H), 5.21 (s, 2H), 4.94-4.68 (m, 2H),
1.93 (s, 1H), 1.58-1.25 (m, 20H), 0.87 (t, J ) 5.4 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 172.2, 167.0, 151.3, 135.6, 128.8, 127.7,
126.2, 98.4, 84.2, 81.4, 52.7, 33.5, 31.6, 29.1, 28.9, 27.8, 24.7, 22.5,
14.0. HRMS (ESI) calcd for C23H33NO4 + Na+ 410.2307, found
410.2301.
4-(Dibenzylamino)-5-heptylfuran-2(5H)-one, P16: 89% overall
1
yield. H NMR (300 MHz, CDCl3) δ 7.37-7.13 (m, 10H), 5.02
(dd, J ) 7.5, 2.4 Hz, 1H), 4.81 (s, 1H), 4.42-4.25 (m, 4H), 2.00
(m, 1H), 1.65 (m, 1H), 1.47 (m, 2H), 1.30-1.21 (m, 8H), 0.86 (t,
J ) 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.1, 171.8, 135.1,
128.9, 127.9, 127.0, 84.7, 77.8, 53.3, 33.8, 31.5, 28.9, 24.3, 22.4,
13.9. HRMS (ESI) calcd for C25H31NO2 + H+ 378.2433, found
378.2435.
5-Heptyl-4-(1-phenylethylamino)furan-2(5H)-one, P17: 86%
1
overall yield. H NMR (300 MHz, CDCl3) δ 7.35-7.22 (m, 5H),
5.97 (d, J ) 5.7 Hz, 1H), 4.78 (dd, J ) 4.2, 3.3 Hz, 1H), 4.39 (s,
1H), 4.34 (m, 1H), 1.89 (m, 1H), 1.60 (m, 1H), 1.56 (d, 3H),
1.27-1.23 (m, 10H), 0.87 (t, J ) 6.0 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 175.1, 169.1, 142.1, 128.8, 127.7, 125.8, 82.9, 78.5, 55.2,
33.1, 31.7, 29.2, 29.1, 24.0, 22.9, 22.6, 14.0. HRMS (ESI) calcd
for C19H27NO2 + H+ 302.2120, found 302.2115.
5-Phenyl-4-(1-phenylethylamino)furan-2(5H)-one, P18: 80%
overall yield. 1H NMR (300 MHz, CDCl3) δ 7.44-7.23 (m, 10H),
5.57 (s, 1H), 4.75 (br, 1H), 4.62 (s, 1H), 4.35 (p, 1H), 1.39 (d, J )
6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.9, 142.0,
135.0, 129.7, 129.0, 128.7, 127.6, 127.4, 125.4, 83.6, 80.4, 55.1,
23.3. HRMS (ESI) calcd for C18H17NO2 + H+ 280.1338, found
280.1338.
Preparation and Characterization of tert-Butyl Benzyl(4-
bromo-2-heptyl-5-oxo-2,5-dihydrofuran-3-yl)carbamate, 6. To
a stirred solution of 4-(benzylamino)-3-bromo-5-heptylfuran-2(5H)-
one (3; 0.5 mmol, 183 mg) in CH2Cl2 (20 mL) was added DMAP
(0.6 mmol, 73 mg) and Boc2O (0.6 mmol, 131 mg). After the
reaction is completed as shown by TLC, the solvent is evaporated,
and the product is obtained in 96% yield after column chromatog-
Methyl 2-(2-heptyl-5-oxo-2,5-dihydrofuran-3-ylamino)-2-phe-
1
nylacetate, P19: 71% overall yield. H NMR (300 MHz, CDCl3)
δ 7.38-7.33 (m, 5H), 5.83 (d, J ) 5.4 Hz, 1H), 4.91 (d, J ) 5.4
Hz, 1H), 4.78 (dd, J ) 4.5, 3.0 Hz, 1H), 4.44 (s, 1H), 3.76 (s, 3H),
1.87 (m, 1H), 1.64 (m, 1H), 1.46 (m, 2H), 1.30-1.28 (m, 8H),
0.88 (t, J ) 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.1,
170.6, 167.1, 134.7, 129.2, 127.0, 84.9, 78.4, 61.1, 53.3, 33.1, 31.7,
29.2, 29.0, 24.1, 22.6, 14.0. HRMS (ESI) calcd for C20H27NO4 +
H+ 346.1055, found 346.2010.
Preparation and Characterization of 4-(Benzylamino)-3-
bromo-5-heptylfuran-2(5H)-one, 3. To a stirred solution of
4-(benzylamino)-5-heptylfuran-2(5H)-one (0.3 mmol, 86 mg) in
CH2Cl2 (20 mL) at 0 °C was added dropwise a solution of Br2 (0.3
mmol, 0.015 mL) in CH2Cl2 (10 mL) over 10 min. After the reaction
is completed by TLC, the solvent is evaporated and the product is
obtained in 91% yield after column chromatography eluted with
50% ethyl acetate in hexanes. 1H NMR (300 MHz, CDCl3) δ
7.41-7.27 (m, 5H), 5.40 (br, 1H), 4.86 (dd, J ) 7.5, 2.7 Hz, 1H),
4.62 (d, J ) 6.0 Hz, 2H), 1.93 (m, 1H), 1.62 (m, 1H), 1.42-1.24
(m, 10H), 0.86 (t, J ) 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
169.9, 164.3, 137.0, 129.0, 128.1, 127.1, 78.1, 74.0, 47.6, 33.1,
31.6, 29.02, 28.96, 23.9, 22.5, 14.0. MS calcd for C18H24BrNO2 +
H+ 365.1, found 366.0.
1
raphy eluted with 25% ethyl acetate in hexanes. H NMR (300
MHz, CDCl3) δ 7.33-7.27 (m, 5H), 5.47 (dd, J ) 8.7, 2.4 Hz,
1H), 5.06 (m, 2H), 1.47 (m, 9H), 1.29-1.16 (m, 12H), 0.86 (t, J )
6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 168.2, 161.4, 151.7,
136.8, 128.5, 127.9, 127.6, 83.9, 81.8, 77.2, 49.9, 32.2, 31.5, 28.8,
28.6, 27.8, 24.5, 22.4, 13.9. HRMS (ESI) calcd for C23H32BrNO4
+ Na+ 488.1412, found 488.1401.
Acknowledgment. Partial support of this work from the U.S.
National Science Foundation (CHE-0717995), the donors of the
Petroleum Research Fund, administered by the American
Chemical Society, the National Science Foundation of China
(Nos. 20725206 and 20732004), and the Specialized Research
Fund for the Doctoral Program of Higher Education in China
are gratefully acknowledged. L.H.Z. also thanks the fellowship
from the China Scholarship Council [No.(2007)3020].
Supporting Information Available: The 1H/13C NMR, mass
spectra, and HPLC plots of the new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Preparation and Characterization of 4-(Benzylamino)-5-
heptyl-3-(2,2,2-trifluoroacetyl)furan-2(5H)-one, 4. To a stirred
solution of 4-(benzylamino)-5-heptylfuran-2(5H)-one (0.3 mmol,
86 mg) in CH2Cl2 (20 mL) was added dropwise a solution of
trifluoroacetic anhydride (0.4 mmol, 0.015 mL) in CH2Cl2 (10 mL)
JO802592H
J. Org. Chem. Vol. 74, No. 5, 2009 2017