Iron(III) chloride-catalyzed synthesis of 3-carboxy-2,5-disubstituted furans from γ-alkynyl aryl- and alkylketones

Article abstract of DOI:10.1016/j.tet.2017.04.030

A mild, catalytic method for the synthesis of 3-carboxy-2,5-disubstituted furans is reported proceeding via a 5-exo-dig cycloisomerization reaction. The iron(III) chloride-catalyzed transformation of aryl- and alkyl β-ketoesters enables synthetic access t

Full text of DOI:10.1016/j.tet.2017.04.030

Accepted Manuscript
Iron(III) chloride-catalyzed synthesis of 3-carboxy-2,5-disubstituted furans from γ-
alkynyl aryl- and alkylketones
Alexander N. Golonka, Corinna S. Schindler
PII:
S0040-4020(17)30402-7
10.1016/j.tet.2017.04.030
TET 28631
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 October 2016
Revised Date: 10 April 2017
Accepted Date: 12 April 2017
Please cite this article as: Golonka AN, Schindler CS, Iron(III) chloride-catalyzed synthesis of 3-
carboxy-2,5-disubstituted furans from γ-alkynyl aryl- and alkylketones, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.04.030.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Iron(III) Chloride-Catalyzed Synthesis of 3-
Carboxy-2,5-disubstituted Furans from γ-
Alkynyl Aryl- and Alkylketones
Leave this area blank for abstract info.
Alexander N. Golonka and Corinna S. Schindler
University of Michigan, Department of Chemistry, Willard Henry Dow Laboratory, 930 North University Ave.,
Ann Arbor, MI 48109, US.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Iron(III) Chloride-Catalyzed Synthesis of 3-Carboxy-2,5-disubstituted Furans from γ-
Alkynyl Aryl- and Alkylketones
Alexander N. Golonka and Corinna S. Schindler
University of Michigan, Department of Chemistry, Willard Henry Dow Laboratory, 930 North University Ave., Ann Arbor, MI 48109, US.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A mild, catalytic method for the synthesis of 3-carboxy-2,5-disubstituted furans is reported
proceeding via a 5-exo-dig cycloisomerization reaction. The iron(III) chloride-catalyzed
transformation of aryl- and alkyl β-ketoesters enables synthetic access to functionalized furan
core structures found in many natural products and complex molecules of biological importance.
The method described herein, represents a mild and efficient alternative to currently available
reaction protocols.
Available online
Keywords:
iron(III) chloride
furan
2009 Elsevier Ltd. All rights reserved
.
heterocycle
Lewis acid catalysis
cembrane natural products
———
Corresponding author. Tel.: +1-734-763-6853; e-mail: corinnas@umich.edu

2
Tetrahedron
ACCEPTED MANUSCRIPT
2. Results and Discussion
1. Introduction
To identify an optimal set of reaction conditions for the synthesis
of 3-carboxy-2,5-disubstituted furans, we initially focused on the
evaluation of suitable Lewis acid catalysts upon conversion with
β-ketoester 8. When β-ketoester 8 was converted with iron(II)
and zinc(II) salts, no formation of furan 9 was observed (entries
1-3, Table 1). The strong Lewis acid AlCl316 was also not able to
promote the desired transformation under otherwise identical
reaction conditions (entry 4, Table 1). However, when alkyne 8
was subjected to catalytic amounts of iron(III)- and scandium(III)
triflate, the desired furan 9 was generated in 16% and 43% yield,
respectively (entries 5 and 6, Table 1). Catalytic amounts of both,
GaCl3 and InCl3 proved viable and resulted in the formation of 9
in up to 55% (entries 7 and 8, Table 1). The use of SnCl4 as a
Lewis acid catalyst further increased the yield of furan 9 to 70%
(entry 9, Table). Ultimately, 10 mol% of FeCl3 in dichloroethane
was identified as an optimal set of reaction conditions, resulting
in quantitative formation of the cycloisomerization product 9 in
95% yield (entry 10, Table 1). It is important to note that
conducting the reaction at higher concentration of 0.2M did not
affect the formation of furan 9 (entry 11, Table). However, higher
catalyst loadings of 20 mol% FeCl3 under otherwise identical
reaction conditions resulted in the formation of the desired
product with diminished yields of 73% (entry 12, Table 1).
Entries 5 and 13 in Table 1 suggest that hydration of the alkyne
moiety prior to cyclization is not necessary. The
cycloisomerization of substrate 8 leading to the desired furan 9
proved sensitive towards the reaction solvent. Non-coordinating
polar aprotic solvents were found to be optimal, while both
acetonitrile and tetrahydrofuran resulted in no formation of the
desired furan 9 (entries 15 and 16, Table 1).
The furan structural element is found in a variety of
biologically important natural products,1 pharmaceuticals2 and
functional materials.3 Furans also represent ubiquitous synthetic
building blocks4 capable of undergoing
a
variety of
transformations including cycloaddition reactions that proceed
with dearomatization of the furan moiety,5 resulting in the rapid
formation of molecular complexity.6 Several strategies have been
developed to access furans bearing different substitution
patterns,7 including the Feist-Benary condensation of β-
dicarbonyl derivatives with α-substituted ketones.8 During our
efforts towards the development of an iron(III)-catalyzed
carbonyl-olefin ring-closing metathesis reaction,9 we investigated
a
variety of β-ketoester derivatives bearing differential
substitution patterns in the α-position (Fig. 1). While the
prenylated β-ketoesters 1 resulted in the exclusive formation of
the 5- and 6-membered ring-closing metathesis products 2, the
formation of the analogous cyclobutene products was not
observed (A and B, Fig. 1). Instead, when β-ketoester 4 was
subjected to the optimized reaction conditions for carbonyl-olefin
metathesis, the corresponding 3,4-dihydro-2H-pyrans 5 were
isolated as the exclusive products of this transformation.10
Converting β-ketoester 6 bearing an alkyne instead of a prenyl
fragment under identical reaction conditions, led to the isolation
of a 3-carboxy-2,5-disubstituted furan 7 as a
Table 1: Optimization of Reaction Conditions
Fig. 1: Iron(III)-catalyzed cyclization reactions recently
developed.
new product of this transformation, albeit in low yield (C, Fig. 1).
3-carboxy-2,5-disubstituted furans represent key structural motifs
in many compounds of biological importance.11 Specifically, the
cembrane family of natural products,12 including pukalide,13
acerolide,14 and pseudopteranes A-E15 represents a large group of
macrocyclic diterpenes incorporating
a
3-carboxy-2,5-
disubstituted furan moiety. Based on our initial promising results,
we were interested in developing a synthetic approach to these
important structural motifs that would be sufficiently mild for
application in complex molecule synthesis. Herein, we describe
the development of a mild and efficient synthesis of 3-carboxy-
2,5-disubstituted furans from both aryl- and alkyl-β-ketoesters
relying on iron(III) chloride as Lewis acid catalyst.
Table 2: Substrate Scope for Aryl-β-ketoesters

3
electron-poor aryl ketones were tolerated well and resulted in
ACCEPTED MANUSCRIPT
the formation of the desired furans in up to 94% yield. However,
a diminished yield of 59% was observed when the corresponding
trimethoxysubstituted aryl ketone 16 was subjected to the
optimized reaction conditions, resulting in the formation of the
naphthoate byproduct 32 in 35% yield (entry 5, Table 2 and
Figure 2). Notably, aryl ketones incorporating thiophene and
naphthyl substituents resulted in the formation of the desired
products in 74% and 91% yield respectively (entries 8 and 7,
Table 2).
Fig. 2: Isolation of naphthoate byproduct upon conversion of 16.
Table 3: Alkyl-β-ketoesters as Substrates.
Importantly, the corresponding alkynes bearing alkyl substituents
on the ketone moiety proved viable substrates under the
optimized reaction conditions, resulting in the formation of the
desired products, albeit in diminished yields (entries 1 and 2,
Table 3). Moreover, 1,2-disubstituted alkynes 39 underwent the
desired iron(III) chloride-catalyzed cycloisomerization reaction
and formed furan 40 in 40% yield (entry 3, Table 3). A
Importantly, Brønsted acids such as pTsOH and HCl failed to
yield product 9 under otherwise identical reaction conditions
(entries 17 and 18, Table 1).
We next investigated the ability of substrates bearing
electronically and sterically differentiated aryl substituents to
undergo the desired cycloisomerization under the identified
optimal reaction conditions (Table 2). Both electron-rich and

4
Tetrahedron
mechanistic hypothesis for the iron(III)-catalyzed formation of
display spectral data in accordance with previously reported
ACCEPTED MANUSCRIPT
3-carboxy-2,5-disubstituted furans is shown in Figure 3. The
iron-enolate intermediate 43 is formed upon coordination of
FeCl3 to the carbonyl oxygen of 33, which subsequently
undergoes 5-exo-dig cycloisomerization to result in the O-
alkylated product 44. Subsequent aromatization leads to the
formation of the 3-carboxy-2,5-disubstituted furan products 34.
literature.
Ethyl 2-(4-methylbenzoyl)pent-4-ynoate (10)
To a solution of ethyl 3-oxo-3-(p-tolyl)propanoate (320 mg,
1.552 mmol) in dry DMF (3.1 mL) was added K2CO3 (236 mg,
1.707 mmol) followed by a solution of propargyl bromide in
PhMe (9.2 M, 0.202 mL, 1.862 mmol). The reaction mixture was
allowed to stir at ambient room temperature for 12 hours. The
reaction was transferred to a separatory funnel and diluted with
deionized water (20 mL) and the aqueous layer was extracted
with ethyl acetate (3x 20 mL). The combined organic layers were
sequentially washed with deionized water (20 mL) and brine (20
mL). The organic layer was dried over sodium sulfate then
concentrated in vacuo.The crude material was then purified by
flash column chromotography (3% EtOAc/Hexanes) to provide
10 (313 mg, 82%) as a yellow oil. IR (neat) 3286, 2922, 1733,
In summary, we have developed a mild and efficient reaction for
the synthesis of 3-carboxy-2,5-disubstituted furans proceeding
via iron(III)-catalyzed 5-exo-dig cycloisomerization of simple
alkyne substrates. The new method described herein tolerates
both electron-donating as well as electron-withdrawing aryl
ketone substrates as well as the corresponding alkyl ketone
analogs resulting in good to excellent yields of the desired furan
products. Moreover, this method reported relies on iron(III)
chloride as an environmentally benign and earth-abundant Lewis
acid catalyst.
1681, 1606, 1369, 1235, 1182, 1033 cm−1; H NMR (500 MHz,
1
CDCl3) δ 7.94 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 4.54
(t, J = 7.4 Hz, 1H), 4.16 (qd, J = 7.1, 2.8 Hz, 2H), 2.88 (dddd, J =
44.9, 17.0, 7.4, 2.6 Hz, 2H), 2.43 (s, 3H), 1.98 (t, J = 2.6 Hz, 1H),
1.18 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 192.9,
168.5, 145.0, 133.5, 129.6, 129.2, 80.8, 70.4, 61.9, 53.3, 21.9,
+
18.5, 14.1. HRMS (ESI+): MH+, found 245.1173. C15H17O3
requires 245.1172.
Ethyl 5-methyl-2-(p-tolyl)furan-3-carboxylate (11)
To an oven-dried vial and stir bar brought into a glove box
was added FeCl3 (3.2 mg, 0.02 mmol) then fitted with a Teflon
coated screw cap and removed from the glove box, and
maintained under an atmosphere of nitrogen. To this vial was
sequentially added DCE (1 mL) then compound 10 (49.0 mg,
0.20 mmol) by microliter syringe. The resulting solution was
allowed to stir at ambient room temperature for 48 h. The
reaction was then filtered through a plug of silica gel with DCM
(50 mL) as the eluent. Upon concentration the crude material was
purified by flash column chromatography to provide 4 (45 mg,
92% yield) as a colorless solid. IR (neat) 2924, 2153, 2035, 2016,
1702, 1617, 1548, 1502, 1474, 1442, 1352, 1320, 1289, 1272,
1238, 1210, 1189, 1134, 1112, 1090, 1032, 1020 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2
Hz, 2H), 6.41 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H),
2.34 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 164.0, 156.4, 150.9, 139.1, 128.9, 128.2, 127.4,
114.1, 108.8, 60.4, 21.6, 14.4, 13.5. HRMS (ESI+): MH+,
found 245.1172. C15H17O3+ requires 245.1172.
Fig.3:
Mechanistic hypothesis for the iron(III) chloride-
catalyzed cycloisomerization reaction.
3. Experimental section
Materials and Instrumentation. All chemicals were purchased
from commercial suppliers and were used as received unless
otherwise stated. Proton Nuclear Magnetic Resonance NMR (1H
NMR) spectra and carbon nuclear magnetic resonance (13C
NMR) spectra were recorded on a Varian Unity Plus 400, Varian
MR400, Varian vnmrs 500, Varian Inova 500, Varian Mercury
500, and Varian vnmrs 700 spectrometers. Chemical shifts for
protons are reported in parts per million and are references to the
NMR solvent peak (CDCl3: δ 7.26) and (CD2Cl2: δ 5.33).
Chemical shifts for carbons are reported in parts per million and
are referenced to the carbon resonances of the NMR solvent
(CDCl3: δ 77.16). Data are represented as follows: chemical shift,
integration, multiplicity (br = broad, s = singlet, d = doublet, t =
triplet, q = quartet, p = pentet, m = multiplet), and coupling
constants in Hertz (Hz). High resolution mass spectroscopic
(HRMS) data was recorded at the Mass Spectrometry Facility at
the Department of Chemistry of the University of Michigan in
Ann Arbor, MI on an Agilent Q-TOF HPLC-MS with ESI high
resolution mass spectrometer. Infrared (IR) spectra were obtained
using a Perkin Elmer Spectrum BX FT-IR spectrometer. IR data
are represented as frequency of absorption (cm-1).
Ethyl 2-(3,4-dimethoxybenzoyl)pent-4-ynoate (14)
Isolated as a yellow oil (392.6 mg, 36%); IR (neat) 2930,
2190, 2042, 1709, 1604, 1555, 1505, 1463, 1441, 1423, 1374,
1328, 1257, 1203, 1174, 1146, 1130, 1091, 1046, 1025 cm−1
;
1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 8.5, 2.0 Hz, 1H),
7.58 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.53 (t, J =
7.4 Hz, 1H), 4.17 (qd, J = 7.1, 1.3 Hz, 2H), 3.96 (s, 3H), 3.94
(s, 3H), 2.89 (dddd, J = 42.3, 17.0, 7.4, 2.6 Hz, 2H), 1.99 (t, J
= 2.6 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 191.7, 168.7, 154.1, 149.3, 129.1, 124.0, 110.9,
110.21, 80.9 , 70.4, 62.0, 56.3, 56.1, 53.1, 18.7, 14.2; HRMS
(ESI+): MH+, found 291.1230. C16H18O3+ requires 291.1227.
Ethyl 2-(3,4-dimethoxyphenyl)-5-methylfuran-3-carboxylate (15)
Isolated as a yellow oil (48.0 mg, 83%) IR (neat) 2930,
2190, 2042, 1709, 1604, 1555, 1505, 1463, 1441, 1423, 1374,
Known compounds 817, 917, 1218, 1318, 2019, 2618, 2718, 3520, 3621,
3718, 3818, 4022 and ethyl 2-acetylpent-4-ynoate23 were found to
1328, 1257, 1203, 1174, 1146, 1130, 1091, 1046, 1025 cm−1
;
1H NMR (700 MHz, CDCl3) δ 7.68 (d, J = 1.5 Hz, 1H), 7.61
(dd, J = 8.4, 1.2 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.41 (s,

5
1H), 4.28 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 2.35
(s, 3H), 1.33 (dd, J = 7.5, 6.8 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 164.1, 156.1, 150.5, 149.8, 148.5, 123.1, 121.3,
113.6, 111.5, 110.7, 108.9, 77.4, 77.2, 76.9, 60.4, 56.1 56.0,
129.4, 128.9, 128.1, 126.3, 115.6, 109.2, 60.7, 14.4, 13.5;
ACCEPTED MANUSCRIPT
HRMS (ESI+): MH+, found 265.0626. C14H14O3Cl+ requires
265.0626
Ethyl 2-(thiophene-2-carbonyl)pent-4-ynoate (22)
14.5, 13.5; HRMS (ESI+): MH+, found 291.1233 C16H19O3
+
requires 291.1227.
Isolated as a yellow oil (176.0 mg, 73%); IR (neat) 3280,
3103, 2978, 2182, 2161, 1982, 1732, 1658, 1517, 1411, 1356,
1272, 1239, 1176, 1956, 1020 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.89 (d, J = 3.8 Hz, 1H), 7.73 (d, J = 4.9 Hz, 1H),
7.20 – 7.14 (m, 1H), 4.40 (t, J = 7.5 Hz, 1H), 4.19 (q, J = 7.1
Hz, 2H), 2.90 (dddd, J = 39.3, 17.0, 7.5, 2.6 Hz, 2H), 1.99 (t,
J = 2.6 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR (175
MHz, CDCl3) δ 185.8, 168.1, 135.4, 133.8, 128.5, 70.62, 62.1,
54.6, 18.5, 14.1; HRMS (ESI+): MH+, found 237.0585.
C12H13O3S+ requires 237.0580.
Ethyl 2-(3,4,5-trimethoxybenzoyl)pent-4-ynoate (16)
Isolated as a white solid (557.2 mg, 58%); IR (neat) 3282,
2982, 2942, 2840, 2250, 2165, 2038, 19978, 1739, 1677,
1583, 1504, 1458, 1426, 1414, 1367, 1352, 1314, 1252, 1231,
1190, 1173, 1144, 1125, 1089, 1053, 1015 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.33 (s, 2H), 4.52 (t, J = 7.4 Hz, 1H),
4.18 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 6H), 2.90 (dddd, J
= 24.0, 9.6, 7.4, 2.7 Hz, 2H), 2.01 (t, J = 2.6 Hz, 1H), 1.21 (t, J =
7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 191.8, 168.6, 153.3,
131.0, 106.6, 80.8, 70.6, 62.1, 61.1, 56.4, 53.6, 18.6, 14.2;
Ethyl 5-methyl-2-(thiophen-2-yl)furan-3-carboxylate (23)
HRMS (ESI+): MH+, found 321.1334. C17H21O6 requires
321.1333.
+
1
Isolated as a green oil (35.0 mg, 74%); IR (neat) H NMR
(400 MHz, CDCl3) δ 8.00 (d, J = 3.7 Hz, 1H), 7.38 (d, J = 5.0
Hz, 1H), 7.09 (dd, J = 5.0, 3.9 Hz, 1H), 6.40 (s, 1H), 4.33 (q,
J = 7.1 Hz, 2H), 2.34 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 163.7, 151.6, 150.7, 132.0, 128.1,
127.4, 127.3, 113.1, 108.6, 60.5, 14.5, 13.4. HRMS (ESI+):
MH+, found 237.0583. C12H13O3S+ requires 237.0580.
Ethyl 5-methyl-2-(3,4,5-trimethoxyphenyl)furan-3-carboxylate
(17)
Isolated as a white solid (38.1 mg, 59%); IR (neat) 3111,
2966, 2937, 2836, 2168, 2947, 2010, 1710, 1620, 1583, 1548,
1498, 1464, 1431, 1418, 1323, 1248, 1203, 1121, 1096, 1063,
Ethyl 2-(2-naphthoyl)pent-4-ynoate (24)
1036, 1004 cm−1; H NMR (400 MHz, CDCl3) δ 7.38 (s, 2H),
1
6.43 (d, J = 0.9 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.93 (s,
6H), 3.89 (s, 3H), 2.36 (d, J = 0.8 Hz, 3H), 1.33 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 164.0, 155.7, 153.0,
150.7, 139.0, 125.5, 114.4, 109.2, 105.6, 61.1, 60.556.4, 14.5,
Isolated as a yellow oil (255.3 mg, 30%); IR (neat) 3290,
2982, 1732, 1679, 1626, 1596, 1467, 1367, 1278, 1227, 1173,
1123, 1021 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H),
8.10 – 8.05 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.91 (dt, J =
14.5, 5.7 Hz, 2H), 7.68 – 7.55 (m, 2H), 4.74 (dd, J = 8.7, 6.1
Hz, 1H), 4.22 – 4.13 (m, 2H), 3.04 – 2.88 (m, 2H), 2.00 (q, J
= 2.5 Hz, 1H), 1.17 (dd, J = 8.4, 5.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 193.3, 168.5, 136.0, 133.4, 132.6, 131.2,
130.0, 129.1, 128.8, 127.9, 127.1, 124.3, 80.8, 70.6, 62.0,
53.4, 18.6, 14.1 HRMS (ESI+): MH+, found 281.1177,
C18H17O3+ requires 281.1172
+
13.5; HRMS (ESI+): MH+, found 321.1338. C17H21O6 requires
321.1333.
Ethyl 2-(4-chlorobenzoyl)pent-4-ynoate (18)
Isolated as a pale yellow solid (350 mg, 67%); IR (neat)
3263, 2987, 2242,2176, 2160, 2006, 1954, 1734, 1682, 1586,
1485, 1464, 1449, 1422, 1400, 1368, 1343, 1368, 1343, 1315,
1
1293, 1259, 1239, 1185, 1165, 1091, 1019, 1010 cm-1; H
Ethyl 5-methyl-2-(naphthalen-2-yl)furan-3-carboxylate (25)
NMR (500 MHz, CDCl3) δ 8.02 – 7.95 (m, 2H), 7.50 – 7.45
(m, 2H), 4.51 (t, J = 7.4 Hz, 1H), 4.21 – 4.13 (m, 2H), 2.89
(qdd, J = 17.0, 7.4, 2.6 Hz, 2H), 1.98 (t, J = 2.6 Hz, 1H), 1.18
(t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 192.3,
168.1, 140.6, 134.4, 130.4, 129.3, 80.5, 70.6, 62.2, 53.4, 18.5,
14.1, HRMS (ESI+): MH+, found 265.0631. C14H14O3Cl+
requires 265.0626.
Isolated as a yellow oil (51.0 mg, 91%); IR (neat) 2850,
1714, 1600, 1553, 1508, 1464, 1378, 1259, 1207, 1160, 1089,
1036 cm−1; 1H NMR (700 MHz, CD2Cl2) δ 8.52 (s, 1H), 8.05
(dd, J = 8.6, 1.7 Hz, 1H), 7.94 – 7.91 (m, 1H), 7.88 (dd, J =
12.3, 7.0 Hz, 2H), 7.55 – 7.51 (m, 2H), 6.50 (d, J = 0.9 Hz,
1H), 4.30 (q, J = 7.1 Hz, 2H), 2.41 (d, J = 0.8 Hz, 3H), 1.33
(t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 164.0,
160.0, 151.4, 133.5, 133.1, 128.9, 127.7, 127.62, 127.0, 126.8,
126.4, 125.1, 125.6, 115.0, 109.2, 60.6, 14.5, 13.6; HRMS
(ESI+): MH+, found 281.1178, C18H17O3+ requires 281.1172
Ethyl 2-(4-chlorophenyl)-5-methylfuran-3-carboxylate (19)
Isolated as a yellow oil (49.6 mg, 94%); IR (neat) 3110,
2983, 1716, 1617, 1570, 1544, 1485, 1443, 1407, 1373, 1309,
1283, 1215, 1189, 1132, 1088, 1033, 1016, 1004 cm−1; 1H
NMR (500 MHz, CDCl3) δ 7.94 (d, J = 8.7 Hz, 2H), 7.38 (d, J
= 8.7 Hz, 2H), 6.44 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.35 (s,
3H), 1.33 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 163.8,
154.8, 151.5, 134.9, 129.5, 128.6, 128.4, 115.1, 60.6, 14.4,
13.5; HRMS (ESI+): MH+, found 265.0624. C14H14O3Cl+
requires 265.0626.
Ethyl 2-(4-iodobenzoyl)pent-4-ynoate (28
)
Isolated as a yellow oil (213 mg, 80%); IR (neat) 2953,
2003, 1714, 1682, 1580, 1562, 1482, 1463, 1419, 1393, 1368,
1345, 1315, 1271, 1228, 1189, 1173, 1155, 1095, 1061, 1025,
1004 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz,
2H), 7.74 (d, J = 8.3 Hz, 2H), 4.49 (t, J = 7.4 Hz, 1H), 4.16
(qd, J = 7.1, 1.7 Hz, 2H), 2.88 (qdd, J = 17.0, 7.4, 2.6 Hz,
2H), 1.98 (t, J = 2.6 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H); 13C
NMR (175 MHz, CDCl3) δ 192.8, 168.1, 138.3, 135.3, 130.3,
102.3, 80.5, 70.7, 62.2, 53.3, 18.4, 14.1; HRMS (ESI+): MH+,
C14H14O3I+found 356.9981 requires 356.9982.
Ethyl 2-(3-chlorophenyl)-5-methylfuran-3-carboxylate (21)
Isolated as a yellow oil (38.5 mg,73%); IR (neat) 2981,
2157, 1714, 1596, 1549, 1469, 1446, 1428, 1376, 1267, 1279,
1206, 1136, 1093, 1078, 1032, 1007 cm−1; 1H NMR (700
MHz, CDCl3) δ 7.99 (s, 1H), 7.90 (dt, J = 7.1, 1.8 Hz, 1H),
7.36 – 7.32 (m, 2H), 6.45 (d, J = 1.0 Hz, 1H), 4.29 (q, J = 7.1
Hz, 2H), 2.36 (d, J = 0.9 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C
NMR (175 MHz, CDCl3) δ 163.7, 154.1, 151.8, 134.1, 131.8,
Ethyl 2-(4-iodophenyl)-5-methylfuran-3-carboxylate (29)
Isolated as yellow solid; (66.0 mg, 93%); IR (neat) 3091,
2981, 2957, 2184, 2050, 1705, 1615, 1583, 1562, 1539, 1479,

6
Tetrahedron
ACCEPTED MANUSCRIPT
1441, 1398, 1373,1308, 1271, 1236, 1214, 1190, 1132, 1119,
Isolated as an orange oil (190.0 mg, 66%); IR (neat) 2927.0,
1093, 1064, 1028, 1001 cm−1; 1H NMR (500 MHz, CDCl3) δ
7.74 (s, 4H), 6.43 (s, 1H), 4.28 (d, J = 7.1 Hz, 2H), 2.34 (s,
3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
163.8, 154.9, 151.6, 137.3, 129.7, 129.6, 115.3, 109.2, 95.2,
60.6, 14.4, 13.5. HRMS (ESI+): MH+, C14H14O3I+ found
356.9983 requires 356.9982.
2232.0, 1737.8, 1715.4, 1593.1, 1515.7, 1339.8, 1222.0, 1175.0,
1149.0, 1107.0, 1014.1 cm−1; 1H NMR (400 MHz, CDCl3) δ
8.15 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 4.30 – 4.20
(m, 2H), 3.78 (t, J = 7.4 Hz, 1H), 3.06 – 2.86 (m, 2H), 2.34 (s,
3H), 1.36 – 1.18 (m, 3H); 13C NMR (176 MHz, CDCl3) δ
200.88, 168.10, 147.02, 132.48, 130.23, 123.62, 91.97, 80.84,
62.11, 58.26, 29.62, 18.51, 14.24; HRMS (ESI+): MNa+,
Ethyl 3-(3-iodophenyl)-3-oxo-propanoate (30)
+
C20H17NNaO5 found 312.0843 requires 312.0842
Isolated as a yellow oil (433 mg, 41%); IR (neat) 2978, 2181,
1982, 1970, 1732,1688, 1561, 1416, 1368, 1230, 1172, 1063,
1027 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.99
(d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 7.9
Hz, 1H), 4.50 (t, J = 7.4 Hz, 1H), 4.22 – 4.12 (m, 2H), 2.95 –
2.82 (m, 2H), 1.99 (t, J = 2.6 Hz, 1H), 1.20 (t, J = 7.1 Hz,
3H); 13C NMR (175 MHz, CDCl3) δ 192.1, 168.0, 142.7,
137.9, 137.8, 130.5, 128.1, 94.6, 80.5, 70.7, 62.2, 53.3, 18.4,
14.1. HRMS (ESI+): MH+, C14H14O3I+ found 356.9980 requires
356.9982.
Ethyl 2-methyl-5-(4-nitrobenzyl)furan-3-carboxylate (42)
Isolated as a colorless solid (2.9 mg, 5%); IR (neat) 3131.0,
3111.1, 3084.2, 2987.0, 2923.2, 2851.7, 1714.7, 1597.8, 1578.9,
1515.0, 1428.5, 1386.2, 1346.1, 1276.1, 1231.7, 1207.8, 1079.4,
1016.3 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8.4
Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 6.32 (s, 1H), 4.26 (q, J =
7.1 Hz, 2H), 4.00 (s, 2H), 2.52 (s, 3H), 1.33 (t, J = 7.1 Hz,
3H).; 13C NMR (176 MHz, CDCl3) δ 164.11, 158.95, 150.40,
147.06, 145.22, 129.66, 124.02, 114.39, 108.11, 60.30, 34.16,
14.51, 13.91. δ; HRMS (ESI+): MH+, C20H18NO5 found
+
Ethyl 2-(3-iodophenyl)-5-methylfuran-3-carboxylate (31)
290.1022 requires 290.1023.
Isolated as a yellow oil (45.0 mg, 63%); IR (neat) 2981, 2193,
2145, 1982, 1712, 1613, 1589, 1564, 1546, 1467, 1444, 1417,
1376, 1244, 1207, 1137, 1069, 1027 cm−1; 1H NMR (700 MHz,
CDCl3) δ 8.30 (t, J = 1.6 Hz, 1H), 7.99 – 7.96 (m, 1H), 7.68
(dd, J = 6.7, 1.2 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 6.44 (d, J =
0.9 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.35 (d, J = 0.8 Hz,
3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ
163.7, 153.8, 151.8, 137.8, 136.8, 132.1, 129.8, 127.4, 115.6,
109.2, 93.8, 60.7, 14.4, 13.5; HRMS (ESI+): MH+, found
356.9981 C14H14O3I+ requires 356.9982 .
Acknowledgments
We thank the Petroleum Research Fund (PRF#54688-DNI1),
the University of Michigan Office of Research and the
NIH/National Institute of General Medical Sciences (GM118644)
for financial support.
References and notes
1. a) Fenical, W.; Okeeda, R.K.; Basnadurraga, M.M.; Culver, P.;
Jacobs, R.S. Science 1981, 212, 1512; b) Look, S.A.; Burch, M.T.;
Fenical. W.; Qi-tai, Z.; Clardy, J. J. Org. Chem. 1985, 50, 5741.
2. a) Baumann, M.; Baxendale, I.R.; Ley, S.V.; Nikbin, N. Beilstein
J. Org. Chem. 2011, 7, 442; b) Banerjee, R.; HKS, K.; Banerjee,
M. Int. J. Rev. Life. Sci. 2012, 2, 7.
3. a) Gandini, A.; Belgacem, M.N. Monomers, Polymers and
Composites from Renewable Resources, 2008, 115-152; b) Li, Y.;
Chen, H.; wan, Y.; Li, N.; xu, Q.; He, J.; Chen, D.; Wang, L.; Lu,
J. Adv. Funct. Mater. 2015, 25, 4246.
4. a) Boto, A. and Alvarez, L. (2011) Furan and Its Derivatives, in
Heterocycles in Natural Product Synthesis (eds K. C. Majumdar
and S. K. Chattopadhyay), Wiley-VCH Verlag GmbH & Co.
KGaA, Weinheim, Germany; b) Yeung, K.-S. Top. Heterocycl.
Chem. 2012, 29, 47.
5. Bur, S. and Padwa, A. (2014) [4+2] Cycloaddition Chemistry of
Substituted Furans, in Methods and Applications of Cycloaddition
Reactions in Organic Syntheses (ed N. Nishiwaki), John Wiley &
Sons, Inc., Hoboken, New Jersey.
Ethyl 1-hydroxy-5,6,7-trimethoxy-4-methyl-2-naphthoate (32)
Isolated as a colorless solid (22.6 mg, 35%); IR (neat) 3109.9,
2936.2, 2830.1, 1656.3, 1623.1, 1600.6, 1581.2, 1499.8, 1470.2,
1444.4, 1399.1, 1354.1, 1313.7, 1281.2, 1246.3, 1201.7, 1121.8,
1
1093.9, 1063.6, 1019.0 cm−1; H NMR (400 MHz, CDCl3) δ
11.81 (s, 1H), 7.59 (s, 1H), 7.39 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H),
4.01 (s, 3H), 3.99 (s, 3H), 3.92 (s, 3H), 2.74 (s, 3H), 1.45 (t, J =
7.1 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 171.16, 157.99,
152.31, 150.68, 145.17, 127.61, 124.12, 124.05, 122.69,
105.07, 99.73, 61.48, 61.43, 61.10, 56.02, 23.13, 14.44.
+
HRMS (ESI+): MH+, C17H21O6 found 321.1332 requires
321.1332.
Ethyl 2-acetyl-5-(4-methoxyphenyl)pent-4-ynoate (39)
To a 25 mL round bottom flask with magnetic stir bar and
septa was sequentially added CuI (19.1 mg, 0.10 mmol)
Pd(PPh3)4 (5.0 mg, 0.005 mmol), triethylamine (7.1 mL), 1-iodo-
4-methoxybenzene (234 mg, 1,0 equiv.) and ethyl 2-acetylpent-4-
ynoate (168.0 mg, 1 mmol). The reaction mixture was allowed to
stir for 4 h, filtered through a pad of Celite, and concentrated in
vacuo. The resulting crude material was purified by column
chromatography to afford 39 (220.7 mg, 80%) as a yellow oil. IR
(neat) 2929, 1738, 1715, 1606, 1568, 1509, 1464, 1358, 1289,
1244, 1172, 1106, 1030 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.29 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 4.24 (q, J =
7.1 Hz, 2H), 3.79 (s, 3H), 3.76 (t, J = 7.6 Hz, 1H), 2.92 (d, J =
7.5 Hz, 2H), 2.33 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 201.7, 168.5, 159.5, 133.1, 115.5, 114.0,
84.3, 82.4, 61.9, 58.8, 55.4, 29.8, 18.7, 14.3; HRMS (ESI+):
6. a) Schindler, C.S.; Carreira, E.M. Chem. Soc. Rev. 2009, 38, 3222;
b) Armaly, A.M.; DePorre, Y.C.; Groso, E.J.; Riehl, P.S.
Schindler, C.S. Chem. Rev. 2015, 115, 9232.
7. For representative examples, see: a) MaGee, D.I.; Leach, J.D.
Tetrahedron Lett. 1997, 38, 8129; b) Wipf, P.; Rahman, L.T.;
Rector, S.R. J. Org. Chem. 1998, 63, 7132; c) Marshall, J.A.; Zou,
D. Tetrahedron Lett. 2000, 41, 1347; d) Arcadi, A.; Cacchi, S.;
Fabrizi, G.; Marinelli, F.; Parisi, L.M. Tetrahedron 2003, 59,
4661; e) Imagawa, H.; Kurisaki, T.; Nishizawa, M. Org. Lett.
2004, 6, 3679; f) Ji, W.-h.; Pan, Y.-m.; Zhao, S.-y.; Zhan, Z.-p.
Synlett 2008, 19, 3046; g) Barluenga, J.; Riesgo, L.; Vicente, R.;
López, L.A.; Tomás, M. J. Am. Chem. Soc. 2008, 130, 13528; h)
Tsuji, H.; Yamagata, K.-i.; Ueda, Y.; Nakamura, E. Synlett 2011,
7, 1015; i) Saito, A.; Enomoto, Y.; Hanzawa, Y. Tetrahedron Lett.
2011, 52, 4299; j) Rodríguez, A.; Moran, W.J. Tetrahedron Lett.
2011, 52, 2605.
8. a) Feist, F. Chem. Ber. 1902, 35, 1545; b) Benary, E. Ber. 1911,
44, 489; c) Bisagni, E.; Marquet, J.P.; Andre-Louisfert, J.;
Cheutin, A.; Feinte, F. Bull. Soc. Chim. Fr. 1967, 2796; d)
Cambie, R.C.; Moratti, S.C.; Rutledge, P.S.; Woodgate, P.D.
Synth. Commun. 1990, 20, 1923.
+
MH+, C16H19O4 found 275.1279 requires 275.1278.
Ethyl 2-acetyl-5-(4-nitrophenyl)pent-4-ynoate (41)

7
9. a) This work was first reported as Ludwig, J.R.; Gianino, J.B.;
ACCEPTED MANUSCRIPT
Schindler, C. Abstracts of Papers, 250th ACS National Meeting &
Exposition, Boston, MA, United States, August 16th-20th, 2015,
ORGN-388; b) Ludwig, J.R.; Zimmerman, P.M.; Gianino, J.B.;
Schindler, C.S. Nature 2016, 533, 374.
10. Watson, R.B.; Golonka, A.N.; Schindler, C.S. Org. Lett. 2016, 18,
1310.
11. a) Paquette, L.A.; Doherty, A.M.; Rayner, C.M. J. Am. Chem. Soc.
1992, 114, 3910; b) Marshall, J.A.; Bartley, G.S.; Wallace, E.M. J.
Org. Chem. 1996, 61, 5729; c) Paterson, I.; Gardner, M.; Banks,
B.J. Tetrahedron 1989, 45, 5283; d) Paterson, I.; Brown, R.E.;
Urch, C.J. Tetrahedron Lett. 1999, 40, 5807.
12. Yang, B.; Zhou, X.-F.; Liu, X.-P.; Liu, J.; Peng, Y.; Yang, X.-W.;
Liu, Y. Curr. Org. Chem. 2012, 16, 1512.
13. Missakian, M.G.; Burreson, B.J.; Scheuer, P.J. Tetrahedron 1975,
31, 2513.
14. Montalvo, D.; Amade, P.; Funel-Le Bon, C.; Fernández, R.;
Reyes, F. Nat. Prod. Res. 2006, 20, 548.
15. a) Kate, A.S.; Aubry, I.; Tremblay, M.L.; Kerr, R.G. J. Nat. Prod.
2008, 71, 1977; b) González, Y.; Doens, D.; Santamaría, R.;
Ramos, M.; Restrepo, C.M.; Barros de Arruda, L.; lleonart, R.;
Gutiérrez, M.; Fernández, P.L. PLoS ONE 2013, 8, e84107.
16. a) Satchell, D.P.N.; Satchell, R.S. Chem. Rev. 1969, 69, 251; b)
Jensen, W.B. Chem. Rev. 1978, 78, 1.
17. Imagawa, H.; Kurisaki, T.; Nishizawa, M.; Org. Lett., 2004, 6,
3679.
18. Tsuji, H.; Yamagata, K.; Ueda, Y.; Nakamura, E.; Synlett
2011, 1015.
19. Chen, Y.; Wang, H.; Wang, Y.; Luo, H.; Xu, P.; Adv. Synth.
Catal. 2010, 352, 1163.
20. Gao, L.; Kang, B.C.; Hwang, G.; Ryu, D.O.; Angew. Chem.Int.
Ed. 2012, 51, 8322.
21. Jonas, F.; Stetter, H.; Chem. Ber. 1981, 114, 564.
22. Schmidt, D.; Malakar, C.; Beifuss, U.; Org. Lett., 2014, 16, 4862.
23. Nakamura, K.; Miyai, T.; Nagar, A.; Oka, S.; Bull. Chem. Soc.
Jpn., 1989, 62, 1179.
Supplementary Material
1H and 13C NMR spectra for all new compounds prepared in
the course of these studies are provided in the Supplementary
Material of this manuscript.