A Gold-Catalyzed A3 Coupling/Cyclization/Elimination Sequence as Versatile Tool for the Synthesis of Furfuryl Alcohol Derivatives from Glyceraldehyde and Alkynes

Article abstract of DOI:10.1002/adsc.201500812

The reaction of glyceraldehyde with alkynes delivers furfuryl alcohol derivatives within only one reaction step in the presence of a gold(III) catalyst. The reaction cascade is initiated by an intermolecular gold-catalyzed A3 coupling sequence in which mo

Full text of DOI:10.1002/adsc.201500812

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DOI: 10.1002/adsc.201500812
A Gold-Catalyzed A3 Coupling/Cyclization/Elimination Sequence
as Versatile Tool for the Synthesis of Furfuryl Alcohol Derivatives
from Glyceraldehyde and Alkynes
a,b
a
a
a,
Jian Li, Matthias Rudolph, Frank Rominger, Jin Xie, *
a,c,
and A. Stephen K. Hashmi. *
Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,
a
Germany
Fax: (+49)-(0)6221-54-4205; phone: (+49)-(0)6221-54-8413; e-mail: xj850626@163.com or hashmi@hashmi.de
School of Pharmaceutical Engineering & Life Science and Jiangsu Key Laboratory of Advanced Catalytic Materials &
b
Technology, Changzhou University, 1 Gehu Road, Changzhou 213164, Peopleꢀs Republic of China
Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia
c
Received: August 31, 2015; Revised: October 27, 2015; Published online: January 5, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500812.
Abstract: The reaction of glyceraldehyde with al-
kynes delivers furfuryl alcohol derivatives within
only one reaction step in the presence of a gold(III)
catalyst. The reaction cascade is initiated by an in-
termolecular gold-catalyzed A3 coupling sequence
in which morpholine is used as additive. Intramolec-
ular cyclization and subsequent aromatization
under elimination of the amine then deliver the
target molecules. The protocol offers a valuable al-
ternative to the common routes that are based on
functionalization of already existing furan cores.
acids or esters, but these precursors often also have to
[8]
be prepared by several reaction steps. Despite the
impressive progress made in this area, the exploration
of new methods for the preparation of (5-arylfuran-2-
yl)methanols from readily available starting materials
is still highly desirable. While all these protocols are
based on chemical modifications of an already exist-
ing furan core, we envisioned that a completely differ-
ent disconnection might be possible.
Keywords: alcohols; aldehydes; alkynes; amines;
furans; gold
Furan derivatives are important structural motifs that
[1]
are found in a wide range of natural products, phar-
[
2]
[3]
maceuticals and functional materials. As a result,
numerous efficient synthetic methods for the synthesis
of substituted furan derivatives have been devel-
[
4]
oped. However, only limited protocols are reported
for the assembly of (5-arylfuran-2-yl)methanol, which
is an important building block in organic synthesis;
traditional methods are Pd-catalyzed reactions, such
[
5]
as the Suzuki–Miyaura coupling, the Stille coupling
[7]
[
6]
reaction and direct arylations of furfuryl alcohols
Scheme 1). However, due to the required prefunc-
(
tionalization of the applied starting substrates (such
as halides, arylboronic acids or other organometallic
reagents), these approaches can be challenging. An
alternative method to access (5-arylfuran-2-yl)metha- Scheme 1. Synthetic strategies for the synthesis of 2-furan-
nol derivatives is the reduction of 2-furanyl aldehydes, methanol.
Adv. Synth. Catal. 2016, 358, 207 – 211
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Jian Li et al.
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[a]
Table 1. Screening of the reaction conditions.
o
Entry
Catalyst
Solvent
Temperature [ C]
Yield [%] of 3a
1
2
3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
AuCl3
AuCl
CuI
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DCE
r.t.
60
80
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
17
53
20
39
0
31
19
0
0
0
0
15
13
0
0
0
[
[
b]
c]
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
PtCl2
PtCl4
TfOH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
Ph PAuCl
3
Ph PAuCl/AgOTf
3
IPrAuCl
IPrAuCl/AgOTf
IPrAuCl/AgNTf
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
trace
17
0
DCM
DMF
DMSO
MeCN
toluene
0
trace
23
41
MeOH/H O (9/1)
2
[a]
Reaction conditions: a solution of 1 (0.3 mmol), 2a (0.45 mmol), morpholine (0.45 mmol) and catalyst (5 mol%) was
stirred in the specified solvent (1.0 mL) and at the specified temperature for 20 h.
[
[
b]
20 mol% of morpholine was employed.
c]
Morpholine was absent.
We regarded the AuBr -catalyzed A3-coupling re- ature. At 608C, 53% of furan was obtained. As no
3
[
9]
action of terminal alkynes, aldehydes, and amines as morpholine is incorporated in the final product, we
ideal as it has already proven to be a powerful tool tested the reaction in the absence of morpholine, but
for the access to complex compounds from simple no reaction took place (entry 5). Even with only
[
10]
starting materials. By using an alkyne and glyceral- 20 mol% of morpholine, 39% of the target compound
dehyde as building blocks, an addition/condensation/ were collected which demonstrates that morpholine
cyclization strategy might deliver the desired product acts as a kind of co-catalyst but still the results with
in only one step. In continuation of our interest in stoichiometric amounts of this additive were higher
[
11]
gold-catalyzed syntheses of furans,
we herein dis- (entry 4). A brief screening of different catalysts re-
close a divergent approach for the construction of (5- vealed AuBr to be optimal for the A3-coupling reac-
3
arylfuran-2-yl)methanol through a gold(III)-catalyzed tion to furfuryl alcohols. Other counter ions at the
A3-coupling/cyclization cascade.
gold(III) center reduced the yield (entry 6) while no
Glyceraldehyde 1, morpholine and 1-ethynyl-4- conversion at all was obtained with Cu and Pt salts, as
methylbenzene 2a were selected as substrates for the well as by the use of TfOH (entries 8–11). Gold(I)
first model reaction. Our optimization studies are salts were also not suitable and only a minor conver-
summarized in Table 1. With AuBr as catalyst at sion was obtained with phosphane ligands (entry 12),
3
room temperature in MeOH, minor amounts of fur- while no reactivity was detected with NHC ligands
furyl alcohol 3a were collected (entry 1). Temperature (entry 14). In order to study the effect of solvent, the
variation (entries 2 and 3) showed that a higher yield reaction with the best catalyst (AuBr ) was carried
3
of 3a is achievable by a moderate raise of the temper- out in a variety of different solvents. In all cases
2
08
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A Gold-Catalyzed A3 Coupling/Cyclization/Elimination Sequence
[a]
Table 2. Synthesis of 5-subsititued furfuryl alcohols.
[a]
Reaction conditions: a solution of 1 (0.3 mmol), 3 (0.45 mmol), morpholine (0.45 mmol), and AuBr (5 mol%) was stirred
3
in MeOH (1.0 mL) at 608C for 20 h.
(
even in a mixture of MeOH and H O) the reaction
2
only led to 3a in low yield (entries 17–23).
Under the optimized conditions for the formation
of furfuryl alcohol derivative 3a, we explored the sub-
strate scope of this synthetic concept. As outlined in
Table 2, 2,5-disubstituted furan products 3 could be
obtained in good to moderate yields. The scope of the
reaction with respect to the alkyne was investigated.
The reaction of glyceraldehyde 1 with various alkynes
2
gave the corresponding products 3 in 25–71% isolat-
ed yields. Regarding the substrate scope, terminal al-
kynes with an electron-donating group attached to
the aromatic part, such as methyl (3a, 3c, 3d), ethyl
(
(
3e), butyl (3f), amyl (3g), tert-butyl (3h) and alkoxy
3i–k) are beneficial for an effective transformation.
In addition vinyl (3m), aliphatic (3n) and heterocyclic
substitutents (3o) at the alkyne part turned out to be
suitable starting materials as well. Finally, it should be
mentioned that electron-withdrawing substituents at
the arene core showed no reactivity under the opti- Scheme 2. Mechanistic experiments.
mized conditions. As a consequence methyl 1-ethynyl-
4
-(trifluoromethyl)benzene, 4-ethynylbenzoate, 4-
ethynylbenzonitrile and 1-bromo-4-ethynylbenzene as the solvent and d-3h was obtained, d-3h showed
did not yield the desired furans. deuterium incorporation in the C-4 position of the
To gain mechanistic insight, isotope labelling ex- furan product. It is reasonable to assume that this
periments using glyceraldehyde 1, morpholine and 1- deuterium is derived from a protodemetallation step
tert-butyl-4-ethynylbenzene 2h as the model reaction by the solvent. This indicates that a 4-aurated furan is
under
Scheme 2). As the solvent property significantly af- ble intermediate propargylamine 4 (that would be
fected the reaction outcome, CD OD was first utilized formed by an initial A3 coupling reaction) was pre-
standard
conditions
were
conducted an intermediate in the catalytic cycle. Next, the possi-
(
3
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209

Jian Li et al.
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Scheme 3. Proposed mechanism for the formation of furans.
pared and isolated by using a copper catalyst and and AuBr
(5 mol%) in methanol (2 mL) was stirred at
08C for 20 h. After completion of the reaction (observed
3
6
then treated under the standard reaction condition
with the gold catalyst. Indeed the target compound 3h
was collected in 69% yield. This strongly suggests that
an A3-coupling reaction of the substrates 1, 2g and
morpholine stands at the beginning of the reaction
cascade.
on TLC), the solvent was evaporated under reduced pres-
sure to obtain the crude mixture. The residue was purified
by silica-gel column chromatography (ethyl acetate/petrole-
um ether=1/10–1/4) to afford the pure product 3. The ob-
tained product was analyzed by H NMR, C NMR and
HR-MS.
1
13
[12]
Based on these experiments, we propose
the
mechanism illustrated in Scheme 3 for the formation
of the furans 3. An initial AuBr -catalyzed A3-cou-
3
pling of 1 with 2 and morpholine generates the inter- References
mediate 4. This homopropargylic alcohol 4 then un-
[
13]
dergoes an intramolecular cyclization
which after
[1] a) A. Boto, L. Alvarez, in: Heterocycles in Natural
Product Synthesis, (Eds.: K. C. Majumdar, S. K. Chatto-
padhyay), Wiley-VCH, Weinheim, 2011; b) J. Kobaya-
shi, D. Watanabe, N. Kawasaki, M. Tsuda, J. Org.
Chem. 1997, 62, 9236–9239.
protodemetallation delivers dihydrofuran intermedi-
ate B’. Aromatization by elimination of the amine
[
14]
then leads to the final product 3.
In summary, we have established a new Au(III)-cat-
alyzed A3-coupling/cyclization cascade to afford
furan-2-ylmethanol derivatives. This versatile protocol
enables easy access towards the target products from
abundantly available alkynes and aldehydes as start-
ing materials and is operated under mild reaction con-
ditions. With regard to the synthetic efficiency it is
important to note that the functionalized furfuryl al-
cohols are formed in one synthetic step and not by
post-functionalizations of a preformed furan system.
Three new bonds are formed overall, thus a yield of
[
2] a) J. B. Sperry, D. L. Wright, Curr. Opin. Drug Discov.
Devel. 2005, 8, 723–740; b) Y. Wang, Y.-C. Luo, X.-Q.
Hu, P. -F. Xu, Org. Lett. 2011, 13, 5346–5349.
[
3] Selected examples: a) A. Gandini, M. N. Belgacem,
Prog. Polym. Sci. 1997, 22, 1203–1379; b) C. C. Wu,
W. Y. Hung, T. L. Liu, L. Z. Zhang, T. Y. Luh, J. Appl.
Phys. 2003, 93, 5465–5471; c) E. Ripaud, D. Demeter,
T. Rousseau, E. Boucard-Cetol, M. Allain, R. Po, P.
Leriche, J. Roncali, Dyes Pigm. 2012, 95, 126–133.
[4] Reviews: a) X. L. Hou, H. Y. Cheung, T. Y. Hon, P. L.
Kwan, T. H. Lo, S. Y. Tong, H. N. C. Wong, Tetrahedron
1
998, 54, 1955–2020; b) T. L. Gilchrist, J. Chem. Soc.
5
1% is equivalent to an average efficiency of 80% for
Perkin Trans. 1 1999, 2849–2866; c) A. V. Gulevich,
A. S. Dudnik, N. Chernyak, V. Gevorgyan, Chem. Rev.
each bond formation, the best yield of 71% even to
an average of 91%. Therefore we believe that this
protocol offers an attractive alternative to existing
protocols for the synthesis of these valuable building
blocks.
2
013, 113, 3084–3213; d) K.-S. Yeung, Z. Yang, X.-S.
Peng, X.-L. Hou, Prog. Heterocycl. Chem. 2011, 23,
181–216; e) T. Graening, F. Thrun, in: Comprehensive
Heterocyclic Chemistry III, Vol. 3, (Eds.: A. R. Katritz-
ky, C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor),
Elsevier, Oxford, 2008, pp 497–569.
[
[
5] M. E. Jung, J.-M. Ku, L. Dub, H. Hu, R. A. Gatti,
Experimental Section
Bioorg. Med. Chem. Lett. 2011, 21, 5842–5848.
6] B. Martín-Matute, C. Nevado, D. J. Cµrdenas, A. M.
Echavarren J. Am. Chem. Soc. 2003, 125, 5757–5766.
7] D. Ghosh, H. M. Lee, Org. Lett. 2012, 14, 5534–5537.
8] a) C. Paizs, M. I. Tosa, L. C. Bencze, Heterocycles 2011,
82, 1217–1228; b) U. E. Hille, C. Zimmer, C. A. Vock,
R. W. Hartmann, ACS Med. Chem. Lett. 2011, 2, 2–6.
General Procedure; Synthesis of 5-Subsititued Furan-
[
[
2-ylmethanol 3
In
a
one-necked flask,
a
solution ofglyceraldehyde
1
(0.3 mmol), morpholine (4.5 mmol), alkyne 2 (4.5 mmol)
2
10
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A Gold-Catalyzed A3 Coupling/Cyclization/Elimination Sequence
[
9] For selected contributions, see: a) C. M. Wei, C.-J. Li, J.
Am. Chem. Soc. 2003, 125, 9584–9585; b) C. M. Wei,
C.-J. Li, Synlett 2004, 1472–1483; c) B. Yan, Y. Liu, Org.
Lett. 2007, 9, 4323–4326; d) J. Li, L. Liu, D. Ding, J.
Sun, Y. Ji, J. Dong, Org. Lett. 2013, 15, 2884–2887; e) S.
Shi, T. Wang, V. Weingand, M. Rudolph, A. S. K.
Hashmi, Angew. Chem. 2014, 126, 1166–1170; Angew.
Chem. Int. Ed. 2014, 53, 1148–1151; for a related Cu-
catalyzed furan synthesis see also: f) W. Fan, S. Ma,
Eur. J. Org. Chem. 2015, 2015, 3531–3539.
Rudolph, A. S. K. Hashmi, Angew. Chem. Int. Ed.
2014, 53, 3715–3719; Angew. Chem. 2014, 126, 3789–
3793; for the first gold-catalyzed formation of furans,
see: e) 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; f) A. S. K. Hashmi,
T. M. Frost, J. W. Bats, J. Am. Chem. Soc. 2000, 122,
11553–11554.
[12] A. S. K. Hashmi, Angew. Chem. 2010, 122, 5360–5369;
Angew. Chem. Int. Ed. 2010, 49, 5232–5241.
[
[
10] V. A. Peshkov, O. P. Pereshivkoa, E. V. Van der Eycken,
[13] For an efficient gold-catalyzed cyclization of homopro-
pargylic alcohols see also: V. Belting, N. Krause, Org.
Lett. 2006, 8, 4489–4492.
[14] For related furan formations, see: a) M. Egi, K. Azechi,
S. Akai, Org. Lett. 2009, 11, 5002–5005; b) A. Aponick,
C.-Y. Li, J. Malinge, E. F. Marques, Org. Lett. 2009, 11,
4624–4627; c) R. K. Minkler, N. A. Isley, D. J. Lippin-
cott, N. Krause, B. H. Lipshutz, Org. Lett. 2014, 16,
724–726.
Chem. Soc. Rev. 2012, 41, 3790–3807.
11] Recent work: a) A. Zeiler, M. Ziegler, M. Rudolph, F.
Rominger, A. S. K. Hashmi, Adv. Synth. Catal. 2015,
3
57, 1507–1514; b) T. Wang, L. Huang, S. Shi, M. Ru-
dolph, A. S. K. Hashmi, Chem. Eur. J. 2014, 20, 14868–
4871; c) T. Wang, S. Shi, M. Rudolph, A. S. K.
1
Hashmi, Adv. Synth. Catal. 2014, 356, 2337–2342; d) T.
Wang, S. Shi, M. M. Hansmann, E. Rettenmeier, M.
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