Iron-Catalyzed [2+2+2] Annulation of Aliphatic Bridged 1,n-Enynes with Aldehydes for the Synthesis of Fused Pyrans

Article abstract of DOI:10.1002/ejoc.202000653

An iron-catalyzed [2+2+2] annulation of aliphatic bridged 1,n-enynes with aldehydes was developed. Aldehydes play a dual role as the precursors of acyl radicals to trigger the cascade cyclization but also as the radical acceptors to terminate the annulation. This two-in-one strategy overcomes the limitation in [2+2+m] cyclization that requires a rigid benzene skeleton as the essential linker, thus enabling the efficient synthesis of functionalized fused [5.6] and [6.6] pyran skeletons.

Full text of DOI:10.1002/ejoc.202000653

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Iron-Catalyzed [2+2+2] Annulation of Aliphatic Bridged 1,n-
Enynes with Aldehydes for Synthesis of Fused Pyrans
Authors: Tian Tian, Xin Wang, Leiyang Lv, and Zhiping Li
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000653
Link to VoR: https://doi.org/10.1002/ejoc.202000653
01/2020

10.1002/ejoc.202000653
European Journal of Organic Chemistry
COMMUNICATION
Iron-Catalyzed [2+2+2] Annulation of Aliphatic Bridged
1,n-Enynes with Aldehydes for Synthesis of Fused Pyrans
Tian Tian, Xin Wang, Leiyang Lv, Zhiping Li*
Abstract: Iron-catalyzed [2+2+2] annulation of aliphatic bridged
1,n-enynes with aldehydes was developed. Aldehydes play dual
roles that not only as the precursors of acyl radicals to trigger the
cascade cyclization but also as the radical accepters to terminate the
annulation. This two in one strategy overcomes the limitation in
[2+2+m] cyclization that requires rigid benzene skeleton as the
essential linker, thus enabling the efficient synthesis of functionalized
fused [5.6] and [6.6] pyran skeletons.
interested in further probing the reactivity of acyl radicals with
flexible aliphatic bridged 1,n-enynes, presuming that the two in
one strategy might help to overcome the adverse spatial
interaction in radical [2+2+2] annulation. Herein we report the
preliminary results of this hypothesis (Scheme 1c).
Transition metal-catalyzed [2+2+2] cycloaddition plays an
important role in six-membered ring synthesis, by which the
researchers can realize selective transformations that would
either be difficult or impossible by conventional organic
chemistry.[1] Tandem radical cyclization of 1,n-enynes is growing
rapidly as a useful method for the construction of carbocyclic and
heterocyclic skeletons.[2] The radical [2+2+2] annulation of
1,n-enynes is particularly interesting due to the one step access
to polycyclic skeletons[3], which are core structures of various
natural products, agrochemicals and pharmaceuticals. In 2013,
Li and co-workers reported the first tandem radical [2+2+2]
annulation by tactfully using benzene-linked 1,n-enynes as the
all-purpose substrates.[4] The key to the success is that the
linker benzene provides a rigid planar conformation that favors
the spatial interaction of radical intermediate with unsaturated
C=C and/or C≡C moiety (Scheme 1a).[5] By contrast, the
analogue cyclization involving flexible 1,n-enynes is mostly
restricted to the mono-annulation (Scheme 1b)[6], probably
because its relaxed configuration fails to the second cyclization.
Accordingly, radical [2+2+2] annulation of flexible aliphatic
bridged 1,n-enynes is a largely unexplored research area and
remains a big challenge.[7]
Fused [n.6] pyran compounds have superior antibacterial,
antiviral and antitumor activities.[8] However, the method for
synthesis of pyran skeleton mainly depends on [4+2]
Hetero-Diels-Alder reactions,[9] which is difficult to apply to
synthesize fused [n.6] pyrans. In 2016, we disclosed that
aldehydes were identified as ideal two-atom units to undergo
regioselective cascade radical [2+2+2] cyclization with
benzene-linked 1,7-enynes under FeCl2/di-tert-butyl peroxide
(DTBP) catalytic system.[5d] Aldehydes play dual roles in this
transformation, namely as both the precursors of acyl radicals to
trigger the cascade cyclization and the radical accepters to
terminate the annulation. Motivated by this finding, we became
Scheme 1. Radical-mediated 1,n-enynes cascade cyclizations.
We started the investigation using dimethyl malonate tethered
1,6-enyne 1a and benzaldehyde 2a as the model substrates to
optimize the reaction conditions (Table 1). Initially, a yield of 20%
of desired fused [5.6] pyran 3aa was obtained when FeCl2 was
selected as catalyst and (t-BuO)2 was used as the oxidant in
PhCl at 105 °C (entry 1). Screening ferrous salts with different
types of anions (entries 2-7), we found that the yield of 3aa was
achieved in 53% when acetylacetonato (acac-) was used as the
anion of the ferrous salt (entry 7). It should be noted that the
reaction gave a yield of 38% 3aa in the absence of a metal
catalyst (entry 8), indicating that the iron catalyst increased the
efficiency of the reaction. The solvent had a prominent effect on
the reaction efficiency (entries 9-13). For example, when PhCl
was replaced by PhMe, a decreased yield (42%) was obtained
(entry 9). Other solvents such as MeCN, EtOAc, DCE and DMF
turned out to be less effective for this transformation (entries
10-13). Subsequently, we tested other oxidants such as tert-butyl
hydroperoxide (TBHP), tert-butyl peroxybenzoate (TBPB) and
benzoyl peroxide (BPO), while no improved result was observed
(entries 14-16). When half amount of Fe(acac)2 was used, it was
found that the yield remained almost the same (entry 17 vs 7).
Furthermore, the increased product yield (67%) was obtained
upon increasing the (t-BuO)2 to 5.0 equivalents (entry 18).
[*]
T. Tian, X. Wang, L. Lv, Prof. Dr. Z. Li
Department of Chemistry
Renmin University of China
Beijing 100872 (P.R. China)
E-mail: zhipingli@ruc.edu.cn
Homepage: http://chem.ruc.edu.cn/ligroup/index.html
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.202000653
European Journal of Organic Chemistry
COMMUNICATION
Control experiment revealed that no 3aa was detected in the
absence of oxidant (entry 19). Upon these screenings, we
established the optimized reaction conditions using Fe(acac)2 as
the catalyst and (t-BuO)2 as the oxidant in PhCl at 105 oC for 3 h
(entry 18).
product. The result suggested that a stable tertiary radical is
essential for the desired cycloaddition. In addition, the skeletons
of 1,6-enynes including other malonates and 1,3-dione were
applied smoothly and delivered the desired products (3an, 3ao
and 3ap).
Table 1. Optimization of the reaction conditions[a]
Table 2. Scope of 1, 6-enynes (1) [a] [b]
Entry
Catalyst
[O]
Sovent
Yield (%)[b]
1
FeCl2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
TBHP
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhMe
MeCN
EA
20
29
31
49
50
52
53
38
42
8
2
FeBr2
3
Fe(OAc)2
FeCl3
4
5
Fe2(CO)9
Fe(Cp)2(Bz)2
Fe(acac)2
—
6
7
8
9
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
10
11
12
13
14
15
16
17[c]
18[c] [d]
19[c]
6
DCE
DMF
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
trace
trace
9
TBPB
34
11
55
67
0
BPO
(t-BuO)2
(t-BuO)2
—
[a] Reaction conditions: 1 (0.3 mmol),2a (1.5 mmol), Fe(acac)2 (1.25 mol %),
(t-BuO)2 (1.5 mmol), PhCl (3.0 mL), 105 oC, 3 h, under N2 unless otherwise
noted. [b] Reported yield were based on 1 and determined by 1H NMR using an
internal standard; isolated yields are given in parentheses.
[a] Reaction conditions: 1a (0.3 mmol), 2a (1.5 mmol), catalyst (2.5 mol%),
oxidant (0.75 mmol), solvent (3.0 mL), 105 oC, 3 h, under N2 unless otherwise
noted. [b] NMR yields were determined by 1H NMR using an internal standard.
[c] Catalyst is 1.25 mol%. [d] Oxidant (1.5 mmol).
Next, the scope of the annulation was examined with respect
to the aldehydes (Table 3). The electron-rich aldehydes, such as
p-anisyl aldehyde, p-tolualdehyde, and p-tert-butyl benzaldehyde,
reacted smoothly with 1,6-enyne 1a to afford the target products
3ba-3da in 41-63% yields. The aldehydes with a halogen atom
(-F, -Cl, -Br) underwent the radical [2 + 2 + 2] annulation to give
the fused pyrans 3ea-3ga efficiently. The cyano group (-CN) on
the ring of benzaldehyde was also tolerated and 3ha was
obtained in 38% yield. Steric hindrance on the meta-position of
the aldehyde eroded the efficiency of this transformation (3ia).
Biphenyl formaldehyde (3ja), 2-naphthaldehyde (3ka) and
thiophene-2-carbaldehyde (3la) were tested as suitable
substrates for the current annulation. However, aliphatic
aldehydes were not applicable under the standard conditions due
to the competitive decarbonylation reaction.
With the optimal reaction conditions established, the scope of
1,6-enynes was investigated by the reactions with benzaldehyde
2a (Table 2). This [2+2+2] annulation was applicable to a series
of flexible 1,6-enynes. Both electron-donating (Me, OMe) and
electron-withdrawing groups (Cl, CO2Me, CN) at the
para-position of the alkyne components were viable in the
reaction (3ab-3af). The reduced yields were obtained for alkynes
bearing substituents at the meta- and ortho-positions (3ag and
3ah), probably for the steric hindrance. 2-Naphthyl and 2-thiophyl
substituted alkynes were well tolerated under the standard
conditions, giving the corresponding products 3ai and 3aj in 58%
and 53% yields, respectively. Notably, 1,6-enyne containing
trimethylsilyl (TMS) was also compatible with the reaction
conditions (3ak). Importantly, when the CO2Me substituent at the
acrylate moiety was replaced by a Ph group or CO2Et group, the
corresponding products 3al and 3am could be obtained in 43%
and 55% yield, respectively. However, when this position is
replaced by H atom, this reaction failed to give the desired
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10.1002/ejoc.202000653
European Journal of Organic Chemistry
COMMUNICATION
case of TEMPO applied (see S19 in Supporting Information).
These outcomes indicated that the [2+2+2] annulation was most
likely initiated by the formation of acyl radical from aldehyde.
Table 3. Scope of aldehydes (2) [a] [b]
On the basis of the results and previous reports,[2-6] a
possible reaction mechanism for this [2+2+2] annulation is
illustrated in Scheme 2. Initially, di-tert-butyl peroxide oxidizes
FeII to FeIII under heating conditions and decomposes into t-BuO-
and t-BuO•, which abstracts H of aldehyde (2a) C-H bond
delivers the acyl radical A and t-BuOH. The regioselective
addition of A across the C=C bond of the enyne 1a affords the
radical intermediate B, which further undergoes cyclization with
the C≡C bond to give the vinyl radical intermediate C. The newly
introduced carbonyl as an inner-sphere radical acceptor that
enables the efficient 6-endo-trig addition of vinyl radical to give
intermediate D.[10,11] Irreversible oxidation of D to E by FeIII and
final deprotonation by t-BuO- delivers the annulation product 3aa.
[a] Reaction conditions: 1a (0.3 mmol),2 (1.5 mmol), Fe(acac)2 (1.25 mol %),
(t-BuO)2 (1.5 mmol), PhCl (3.0 mL), 105 oC, 3 h, under N2 unless otherwise
noted. [b] Reported yield were based on 1a and determined by 1H NMR using
an internal standard; isolated yields are given in parentheses.
To expand the scope of the substrates, we found that
malonate-bridged 1,7-enynes (4a and 4b) could also be applied
under the standard reaction conditions (eqs 1 and 2). The
desired isochromene derivatives (5aa and 5ab) were obtained in
60% and 49% yields,respectively. This is the first report on the
synthesis of fused [6.6] pyran skeleton starting from a flexible
aliphatic enynes.
In order to investigate the possible reaction pathways, some
control experiments were carried out (eqs 3-5). The results
showed that the reactions of 1,6-enyne 1a with benzaldehyde 2a
were completely suppressed in the presence of radical inhibitors
including (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO),
butylated hydroxytoluene (BHT) and 1,1-diphenylethylene. In
addition, the TEMPO-acyl radical adduct was obtained in the
Scheme 2. Proposed mechanism
In summary, we have discovered an iron-catalyzed radical
[2+2+2] annulation of aliphatic bridged 1,n-enynes with
aldehydes. In this transformation, aldehydes play dual roles that
not only as the precursors of acyl radicals to trigger the cascade
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10.1002/ejoc.202000653
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annulation. With this two in one strategy in hand, we have
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enabled the one-step, efficient synthesis of various fused [5.6]
and [6.6] pyran molecules. Further studies on the mechanism
and applications of aldehydes as two-atom units in cascade
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Financial support from the National Science Foundation of China
(21672259).
Keywords: Iron catalysis • [2+2+2] Cycloaddition • 1,n-Enyne •
Aldehyde • Fused pyran
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10.1002/ejoc.202000653
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Entry for the Table of Contents (Please choose one layout)
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Tian Tian, Xin Wang, Leiyang Lv,
Zhiping Li*
Page No. – Page No.
Iron-Catalyzed [2+2+2] Annulation of
Aliphatic Bridged 1,n-Enynes with
Aldehydes for Synthesis of Fused
Pyrans
Two-in-One: Iron-catalyzed [2+2+2] annulation of aliphatic bridged 1,n-enynes with aldehydes was developed. Aldehydes play dual
roles that not only as the precursors of acyl radicals to trigger the cascade cyclization but also as the radical accepters to terminate the
annulation. This two in one strategy overcomes the limitation in [2+2+m] cyclization that requires rigid benzene skeleton as the
essential linker, thus enabling the efficient synthesis of functionalized fused [5.6] and [6.6] pyran skeletons.
This article is protected by copyright. All rights reserved.