Synthesis of 3-Formylfurans via a Silver(I)-Catalyzed Epoxide Ring-Opening/1,2-Acyl Migration/Cyclization Cascade

Article abstract of DOI:10.1002/adsc.201600938

By the design of suitable starting materials, a silver(I)-catalyzed epoxide ring-opening/1,2-acyl migration/cyclization cascade has been developed, which allowed us to systematically prepare unsymmetrical 3-formylfurans. Various 3-formylfurans were prepared in good to excellent yields. In addition, the distinct fluorescence properties of 3-formylfurans in solution and the solid state are disclosed. (Figure presented.).

Full text of DOI:10.1002/adsc.201600938

COMMUNICATIONS
DOI: 10.1002/adsc.201600938
Synthesis of 3-Formylfurans via a Silver(I)-Catalyzed Epoxide
Ring-Opening/1,2-Acyl Migration/Cyclization Cascade
Jing Wang,a Chen Shen,a Tao Wang,a,* Sheng Mo,a Xingxin Li,a
and Zunting Zhanga,*
a
School of Chemistry and Chemical Engineering, Shaanxi Normal University, No.620 West Chang’an Avenue, Xi’an
710119, Peopleꢀs Republic of China
E-mail: chemtao@snnu.edu.cn or zhangzunting@sina.com
Received: August 24, 2016; Revised: October 12, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600938.
Abstract: By the design of suitable starting materi-
als, a silver(I)-catalyzed epoxide ring-opening/1,2-
acyl migration/cyclization cascade has been devel-
oped, which allowed us to systematically prepare
unsymmetrical 3-formylfurans. Various 3-formylfur-
ans were prepared in good to excellent yields. In
addition, the distinct fluorescence properties of 3-
formylfurans in solution and the solid state are dis-
closed.
tions were also employed. Li reported the Pd/Cu-cata-
lyzed Sonogashira coupling/cyclization cascade to 3-
formylfurans (Scheme 1b).[3] In analogy to Vilsmeier–
Keywords: 1,2-acyl migration; cascade reaction; ep-
oxides; 3-formylfurans; silver catalysis
3-Formylfurans are core structures of some bioactive
natural products. Examples include Lophotoxin, Lo-
phodiol A, Leptolide and Pukalide.[1] In addition,
some of the 3-formylfuran derivatives exhibited anti-
proliferation effects against some cancer cells lines.[2]
As an functional group, the presence of a formyl
group facilities further transformations of the furan
moiety. Giving the importance of 3-formylfurans in
natural products and organic synthesis, the methodol-
ogy for their preparation is important in organic syn-
thesis. Traditionally, 3-formylfurans were obtained
either through the transformation of other functional
groups or by the direct formylation of furans. A typi-
cal example is the Vilsmeier–Haack reaction, which
was used to prepare 3-formylfuran derivative 1 dis-
playing anti-proliferation effects against two cancer
cell lines[2] (Scheme 1a). The product was obtained in
very low yield under harsh conditions. In the light of
atom economy, the Vilsmeier–Haack reaction is also
not satisfactory. In addition, when several electron-
rich groups were present, the formylation suffers from
the regioselectivity of more than one reaction site.
Scheme 1. Previous methods for the synthesis of 3-formylfur-
Beside the direct formylation of furans, cascade reac- ans.
Adv. Synth. Catal. 0000, 000, 0 – 0
1
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Haack formylation, the reaction also suffered from same time, we noticed that the rearrangement of a,b-
low atom economy and harsh conditions. In 2014, epoxy ketones under Lewis acidic conditions can
Hashmi and his co-workers developed an efficient afford b-keto aldehydes via a 1,2-acyl migration
gold-catalyzed[4] method, which gave 3-formylfurans (Scheme 2b).[8] Based on these two transformations,
under very mild conditions with high efficiency we hypothesized that the rearrangement of alkynyl
(Scheme 1c).[5] However, because of the use of pyri- a,b-epoxy ketones 2 would give the same b-keto alde-
dine N-oxide as oxygen transfer reagent, a stoichio- hyde intermediate A and the same final product as in
metric amount of pyridine as by-product was unavoid- Hashmiꢀs report (Scheme 2c). If this hypothesis could
able. In addition, when unsymmetrical starting materi- be realized, this reaction would provide an efficient
als were subjected to the standard conditions, two iso- method to systematically prepare unsymmetrical 3-
mers were obtained due to the lack of regioselectivity formylfurans. However, a main challenge that this hy-
(Scheme 1c). As part of our efforts on the synthesis of pothesis meets is the cyclization of alkynyl epoxides,
heterocycles,[6] we herein want to report the synthesis which is very easy to accomplish under mild condi-
of 3-formylfurans under mild conditions via a sil- tions (Scheme 2d).[9]
ver(I)-catalyzed epoxide ring-opening/1,2-acyl migra-
tion/cyclization cascade.
To prove the hypothesis, alkynyl a,b-epoxy
ketone[10] 2a was prepared and was subjected to vari-
Our hypothesis comes from Hashmiꢀs work and the ous conditions. Although a multi-step procedure was
rearrangement of epoxides. As depicted in Scheme 2a, required for the preparation of 2a, the formation of
in Hashmiꢀs work, a b-keto aldehyde was the key in- the epoxide by the use of hydrogen peroxide as stoi-
termediate for the 3-formylfuran synthesis.[5,7] At the chiometric oxidant is greener and a synthetic benefit,
compared to one equivalent of a pyridine N-oxide or
metal salts.[11] Lewis acids which were reported to be
effective in the rearrangement of a,b-epoxy ketones
were examined first (Table 1, entries 1–5). By the use
[8b]
[8c,d]
of Cu(OTf)2,[8a] Bi(OTf)3 and BF3·OEt2
as cata-
lyst, the reaction indeed afforded 3-formylfuran 3a as
main product. However, the yield was poor due to the
decomposition of the starting material. To our delight,
no competitive direct cyclization product 4 was ob-
served. Tris(pentafluorophenyl)boron was also exam-
ined, however, no desired product was formed
[8e]
(entry 4). AuCl3 gave 3a in a relative better yield
(entry 5). Fe(OTf)3 (entry 6) and AgOTf (entry 7)
were also screened, the later one delivered 3a in mod-
erate yield. This result inspired us to focus on silver
salts. Among the silver salts we examined (entries 7–
11), AgBF4 showed a great advantage in promoting
this reaction (entry 11). Further solvent screening (en-
tries 12–14) revealed that use of a coordinative sol-
vent resulted in deactivation of the catalyst (entry 14).
By literature investigation on silver catalysis,[12] we re-
alized that the solubility of the silver salts might
affect the reaction dramatically. In addition, the acidi-
ty of the catalyst might result in the decomposition of
starting material. One method to enhance the solubili-
ty of the silver salts, as well as neutralize their acidity,
is the use of ligands. Thus a variety of ligands was
screened. To our surprise, the addition of ligands in
a 1:1 ratio to silver salt totally prevented the reaction
(entries 15, 16). We carefully repeated the reaction
and it was found that a slight excess of the silver salts
over ligands made the reaction possible. In analogy,
Shi found that in gold catalysis an excess of silver
salts was necessary in some cases.[13] It was also found
that in silver catalysis the different ratio of ligands to
silver salts resulted in dramatic differences in catalytic
activation.[14] For example, Yamamoto and co-workers
Scheme 2. Our design and the main challenge.
Adv. Synth. Catal. 0000, 000, 0 – 0
2
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst (5 mol%)
Solvent/Time
Yield[b]
1
2
3
4
5
6
7
8
Cu(OTf)2
Bi(OTf)3
BF3·OEt2
(C6F5)3B
AuCl3
Fe(OTf)3
AgOTf
AgSbF6
AgNTf2
AgPF6
DCM/5 h
DCM/7 h
DCM/8 h
DCM/25 h
DCM/2 d
DCM/0.5 h
DCM/17 h
DCM/16 h
DCM/18 h
DCM/7 h
DCM/7 h
toluene/10 h
DCE/12 h
CH3CN/10 h
DCM/18 h
DCM/24 h
DCM/5 h
DCM/18 h
DCM/4 h
DCM/3 h
DCM/18 h
17%
28%
10%
NR
33%
25%
52%
45%
49%
65%
70%
20%
61%
NR
9
10
11
12
13
14
15
16
17
18
19
20
21
AgBF4
AgBF4
AgBF4
AgBF4
PPh3(5 mol%)+AgBF4 (5 mol%)
NR
NR
SPhos (5 mol%)+AgBF4 (5 mol%)
PPh3(5 mol%)+AgBF4 (10 mol%)
SPhos (5 mol%)+AgBF4 (10 mol%)
(Cy)3P (5 mol%)+AgBF4 (10 mol%)
[4-MeOC6H5]3P (5 mol%)+AgBF4 (10 mol%)
BINAP (5 mol%)+AgBF4 (20 mol%)
75%
82%
75%
66%
74%
[a]
All reactions were carried out on a 0.3 mmol scale in 3 mL of solvent at room temperature in the dark, and the reactions
were quenched once the TLC analysis showed that the starting material 2a was completely consumed.
Yields of isolated products.
[b]
reported that an excess amount of silver salts to the for some changes in shape.[16] An HR-MS investiga-
phosphine ligand significantly raised the enantioselec- tion also did not give any clues on the exact catalytic
tivity of the product in the asymmetric Sakurai– species, which are still not clear.
Hosomi allylation.[15] To our delight, when the ligands
With the optimized conditions in hand, the scope of
were added in a 1:2 ratio to silver salts, the reaction the substrates was explored (Table 2). The epoxide
worked smoothly to afford 3a in good yields (en- ring-opening/1,2-acyl migration/cyclization cascade
tries 17–21). Among the ligands we examined, SPhos proved feasible for a variety of substrates. For sub-
(2-dicyclohexylphosphino-2’,6’-dimethoxy-1,1’-biphen-
strates prepared from a variety of ethanone deriva-
yl) gave the best result (entry 18). The decomposition tives (2a–2p), the reaction afforded 3-formylfurans 3
of starting material was prevented to some degree in good to excellent yields (55–98%). For substrates
due to the addition of ligands. The differences in reac- derived from acetophenones with various substituents
tion rate and the yields of product (entries 17–21) in- in the benzene ring (2a–2i), those bearing electron-
dicated that the ligands indeed played some role in withdrawing groups delivered the products (3b, 3c, 3d
the reaction. It was not the silver salt which was and 3i) in better yields than those bearing electron-
added in excess that catalyzed the reaction solely. donating groups (3g and 3h). Beside the acetophe-
Table 2 gives the yields of some products which were none derived substrates, 2-acetothiophene (2k and 2l),
obtained by the use of SPhos/AgBF4 (1:2) as catalyst 2-acetyl-1-methylpyrrole (2m), 2-acetofuran (2n) and
and AgBF4 as catalyst, respectively. In some cases, the 2-acetobenzofuran (2o) derived substrates also
use of SPhos/AgBF4 (1:2) as catalyst improved the worked smoothly affording the corresponding prod-
yields dramatically (3e, 3h, 3n, 3s, 3t). We tried to find ucts in good to excellent yields, respectively (3k–3o).
out the reason for the dramatic difference resulted by To our delight, an acetone derived starting material
ratio changes of ligands to silver salts. 31P NMR ex- 2p also worked well giving 3p in very good yield. The
periments were carried out, however, no obvious dif- substituents at the acetylenic terminus could be sub-
ferences of the chemical shifts were observed, except stituted by phenyl (3q–3t), thienyl (3u) and naphthyl
Adv. Synth. Catal. 0000, 000, 0 – 0
3
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 2. Substrate scope for the reaction.[a]
[a]
Unless otherwise noted, reactions were performed on 0.3 mmol scale in 3 mL of DCM with Sphos (5 mol%) and AgBF4
(10 mol%) at room temperature in the dark; the yields given are isolated yields.
The reaction was carried out on the gram scale; 0.811 g of 3a were obtained from 1.026 g of 2a under the standard condi-
tions.
The yields given in the parentheses are isolated yields by the use of AgBF4 (5 mol%) as catalyst without addition of
SPhos as ligand.
[b]
[c]
groups (3v). In analogy to the above-mentioned re- however only complex mixtures were obtained due to
sults, the electron-deficient substrates afforded 3-for- the high reactivity of the starting material. A gram
mylfuran products (3q and 3r) in better yields than scale reaction of 2a was also carried out, delivering 3a
the electron-rich ones (3s and 3t). Unfortunately, in 79% yield.
when aromatic groups were replaced by an aliphatic
Interestingly, the obtained 3-formylfuran products
group (2w), no reaction was observed under the stan- showed distinct fluorescence properties both in solu-
dard conditions. Phenylhydrazine and hydroxylamine tion and in the solid state. Figure 1 and Figure 2 show
hydrochloride were added, respectively, to capture the emission spectra in ethanol solution and the solid-
the b-keto aldehyde intermediate A (Scheme 2c), state fluorescence of selected samples. As is demon-
Adv. Synth. Catal. 0000, 000, 0 – 0
4
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
silver salt in a 1:2 ratio was crucial for the generation
of the catalytic species. Various 3-formylfurans were
prepared in good to excellent yields. Interestingly, the
products showed distinct fluorescence properties both
in ethanol solution and in the solid state. The interac-
tion between ligands and silver salts, and investiga-
tions on 3-formylfurans with significant fluorescence
properties are currently in progress.
Experimental Section
General Procedure for the Synthesis of 3-Formyl-
furans
SPhos (6.2 mg, 0.015 mmol) and AgBF4 (5.8 mg, 0.03 mmol)
were dissolved in 1 mL of DCM and the mixture was stirred
at room temperature for 30 min in the dark under nitrogen.
To this solution, epoxide 2 (0.3 mmol) in 2 mL of DCM was
added. The resulting mixture was continually stirred at
room temperature in the dark until the epoxide was con-
sumed completely as determined by TLC analysis. After
that the solvent was removed and the crude product was pu-
rified via column chromatography on silica gel (petroleum
ether/ethyl acetate, 50:1) to afford 3-formylfurans in good
yields.
Figure 1. Normalized fluorescence emission spectra of se-
lected samples in EtOH (2ꢅ10À5 molLÀ1).
2,5-Diphenylfuran-3-carbaldehyde (3a):[5a] Yield: 82%;
1H NMR (400 MHz, CDCl3): d=10.17 (s, 1H), 7.83 (d, 2H,
J=7.7 Hz), 7.76 (d, 2H, J=7.7 Hz), 7.58–7.51 (m, 3H),
7.47–7.41 (m, 2H), 7.38–7.33 (m, 1H), 7.14 (s, 1H).
Acknowledgements
Financial support by the National Natural Science Founda-
tion of China (21502110, 21542002) and the Fundamental Re-
search Funds for the Central Universities (GK201503034) are
greatly appreciated. Chen Shen, Sheng Mo and Xingxin Li
appreciate the Undergraduate Qinzhu Research Program of
Shaanxi Normal University (KY2016YB046). We thank Prof.
Dr. Nan Li, Prof. Dr. Mingyu Yang and Prof. Dr. Na Zhao
(Shaanxi Normal University) for many helpful discussions.
We also thank Bing Zhang for reproducing the preparation
of 3g, 3h and 3n (Table 2).
Figure 2. Normalized fluorescence emission spectra of se-
lected samples in the solid state.
strated, these compounds show the green-blue fluo-
rescence both in ethanol and in the solid-state with
the emission maxima ranging from 460 nm to 520 nm.
The existence of an electron-donating substituent on
the product resulted in a bathochromic shift of the
fluorescence emission spectrum both in solution and
in the solid state. For an example, the emission
maxima of 3t (503 nm) was observed with a 40-nm
red shift over 3a (463 nm) in ethanol solution. Given
the fact that the substituents on the 2- and 5-positions
of 3-formylfurans are diversified and easily changed,
the development of compounds with significant fluo-
rescence properties should be feasible by modification
of 3-formylfurans.
References
[1] a) W. Fenical, R. K. Okuda, M. M. Bandurraga, P.
Culver, R. S. Jacobs, Science 1981, 212, 1512–1514;
b) S. N. Abramson, J. A. Trischman, D. M. Tapiolas,
E. E. Harold, W. Fenical, P. Taylor, J. Med. Chem.
1991, 34, 1798–1804; c) M. Gutiꢂrrez, T. L. Capson,
H. M. Guzmꢃn, J. Gonzꢃlez, E. Ortega-Barrꢄa, E.
QuiÇoꢃ, R. Riguera, J. Nat. Prod. 2005, 68, 614–616.
[2] G. A. Soares, R. B. de Oliveira, S. F. de Andrade, R. J.
Alves, C. L. Zani, E. M. de Souza-Fagundes, Molecules
2010, 15, 12–26.
In conclusion, we have developed an efficient
method to systematically prepare unsymmetrical 3-
formylfurans. The addition of a phosphorus ligand to
[3] J. Yang, C. Wang, X. Xie, H. Li, E. Li, Y. Li, Org.
Biomol. Chem. 2011, 9, 1342–1346.
Adv. Synth. Catal. 0000, 000, 0 – 0
5
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
[4] For a review on such diynes in gold catalysis, see:
a) A. M. Asiria, A. S. K. Hashmi, Chem. Soc. Rev. 2016,
45, 4471–4503; for early results in gold catalysis, see:
b) A. S. K. Hashmi, L. Schwarz, J.-H. Choi, T. M. Frost,
Angew. Chem. 2000, 112, 2382–2385; Angew. Chem.
Int. Ed. 2000, 39, 2285–2288; c) A. S. K. Hashmi, T. M.
Frost, J. W. Bats, J. Am. Chem. Soc. 2000, 122, 11553–
11554.
[5] a) T. Wang, S. Shi, M. M. Hansmann, E. Rettenmeier,
M. Rudolph, A. S. K. Hashmi, Angew. Chem. 2014, 126,
3789–3793; Angew. Chem. Int. Ed. 2014, 53, 3715–3719;
b) T. Wang, L. Huang, S. Shi, M. Rudolph, A. S. K.
Hashmi, Chem. Eur. J. 2014, 20, 14868–14871; c) T.
Wang, S. Shi, M. Rudolph, A. S. K. Hashmi, Adv.
Synth. Catal. 2014, 356, 2337–2342.
[6] a) X. Yao, T. Wang, X. Zhang, P. Wang, B. Zhang, J.
Wei, Z. Zhang, Adv. Synth. Catal. 2016, 358, 1534–
1539; b) J. Wang, X. Yao, T. Wang, J. Han, J. Zhang, X.
Zhang, P. Wang, Z. Zhang, Org. Lett. 2015, 17, 5124–
5127.
[7] For an example of the conversion of b-keto aldehydes
to furans reported by Kirsch, see: M. H. Suhre, M.
Reif, S. F. Kirsch, Org. Lett. 2005, 7, 3925–3927.
[8] a) B. G. Jadhav, A. A. Vaidya, S. D. Samant, Lett. Org.
Chem. 2015, 12, 55–61; b) K. A. Bhatia, K. J. Eash,
N. M. Leonard, M. C. Oswald, R. S. Mohan, Tetrahe-
dron Lett. 2001, 42, 8129–8132; c) P. Mathew, D.
Mathew, C. V. Asokan, Synth. Commun. 2007, 37, 661–
665; d) E. Hasegawa, S. Arai, E. Tayama, H. Iwamoto,
J. Org. Chem. 2015, 80, 1593–1600; e) V. Gudla, R. Ba-
lamurugan, Tetrahedron Lett. 2012, 53, 5243–5247.
[9] a) A. S. K. Hashmi, P. Sinha, Adv. Synth. Catal. 2004,
346, 432–438; b) A. Blanc, K. Tenbrink, J.-M. Weibel, P.
Pale, J. Org. Chem. 2009, 74, 4360–4363; c) A. Blanc,
K. Tenbrink, J.-M. Weibel, P. Pale, J. Org. Chem. 2009,
74, 5342–5348; d) M. Yoshida, M. Al-Amin, K. S. Mat-
suda, Tetrahedron Lett. 2008, 49, 5021–5023; e) D.
Miller, J. Chem. Soc. C 1969, 12–15; f) J. Y. Kang, B. T.
Connell, J. Org. Chem. 2011, 76, 2379–2383; g) M.
Yoshida, M. Al-Amin, K. Shishido, Synthesis 2009,
2454–2466.
[10] For metal-catalyzed reactions of 1-(1-alkynyl)oxiranyl
ketones, please see: a) T. Wang, J. Zhang, Chem. Eur. J.
2011, 17, 86–90; b) T. Wang, C.-H. Wang, J. Zhang,
Chem. Commun. 2011, 47, 5578–5580.
[11] Lei reported the facile synthesis of polysubstituted
furans promoted by 2.0 equiv. of silver salts, see: C. He,
S. Guo, J. Ke, J. Hao, H. Xu, H. Chen, A. Lei, J. Am.
Chem. Soc. 2012, 134, 5766–5769.
[12] For reviews, please see: a) Q.-Z. Zheng, N. Jiao, Chem.
Soc. Rev. 2016, 45, 4590–4627; b) Z. Li, C. He, Eur. J.
Org. Chem. 2006, 4313–4322; c) M. ꢆlvarez-Corral, M.
MuÇoz-Dorado, I. Rodrꢄguez-Garcꢄa, Chem. Rev. 2008,
108, 3174–3198; d) Y. Yamamoto, Chem. Rev. 2008,
108, 3199–3222; e) M. Naodovic, H. Yamamoto, Chem.
Rev. 2008, 108, 3132–3148; f) A. Yanagisawa, T. Arai,
Chem. Commun. 2008, 1165–1172.
[13] a) D. Wang, R. Cai, S. Sharma, J. Jirak, S. K. Thumma-
napelli, N. G. Akhmedov, H. Zhang, X. Liu, J. L. Pe-
tersen, X. Shi, J. Am. Chem. Soc. 2012, 134, 9012–9019;
b) Y. Su, Y. Zhang, N. G. Akhmedov, J. L. Petersen, X.
Shi, Org. Lett. 2014, 16, 2478–2481.
[14] a) Y. Su, M. Lu, B. Dong, H. Chen, X. Shi, Adv. Synth.
Catal. 2014, 356, 692–696; b) J. M. Alderson, A. M.
Phelps, R. J. Scamp, N. S. Dolan, J. M. Schomaker, J.
Am. Chem. Soc. 2014, 136, 16720–16723.
[15] M. Wadamoto, N. Ozasa, A. Yanagisawa, H. Yamamo-
to, J. Org. Chem. 2003, 68, 5593–5601.
[16] TLC (thin-layer chromatography) intuitively shows the
differences between two cases (with or without li-
gands), for TLC traces and the 31P NMR spectrum, see
the Supporting Information, S80 and S82.
Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Synthesis of 3-Formylfurans via a Silver(I)-Catalyzed
Epoxide Ring-Opening/1,2-Acyl Migration/Cyclization
Cascade
7
Adv. Synth. Catal. 2016, 358, 1 – 7
Jing Wang, Chen Shen, Tao Wang,* Sheng Mo, Xingxin Li,
Zunting Zhang*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!