Gold-Catalyzed Reaction of ortho-Alkynylarylaldehydes with Conjugated Dienes: An Efficient Access to Highly Strained Tetracyclic Bridgehead Olefins

Article abstract of DOI:10.1002/chem.201601430

An unprecedented access to strained tetracyclic bridgehead alkenes by reaction of easily accessible ortho-alkynylarylaldehydes with conjugated dienes is described. The process involves a chemo- and stereo-selective, gold-catalyzed, tandem intermolecular [3+2] cycloaddition/Prins-type ring-closing reaction that allows generating structural complexity in a straightforward manner. This approach for the preparation of anti-Bredt compounds is synthetically superior to those previously reported: the procedure is easy to implement, operates under mild experimental conditions, is efficient, and exhibits a good substrate scope.

Full text of DOI:10.1002/chem.201601430

DOI: 10.1002/chem.201601430
Communication
&
Gold Catalysis
Gold-Catalyzed Reaction of ortho-Alkynylarylaldehydes with
Conjugated Dienes: An Efficient Access to Highly Strained
Tetracyclic Bridgehead Olefins
Ziping Cao,* Hongbo Zhu, Xin Meng, Laijin Tian, Xuejun Sun, Guang Chen, and
Jinmao You*[a]
Abstract: An unprecedented access to strained tetracyclic
bridgehead alkenes by reaction of easily accessible ortho-
alkynylarylaldehydes with conjugated dienes is described.
The process involves a chemo- and stereo-selective, gold-
Scheme 1. Examples of anti-Bredt structural motifs.
catalyzed, tandem intermolecular [3+2] cycloaddition/
Prins-type ring-closing reaction that allows generating
structural complexity in a straightforward manner. This ap-
ortho-Alkynylarylaldehydes have been widely studied as val-
uable substrates in synthetic organic chemistry. They represent,
for instance, some useful starting materials for the synthesis of
functionalized 1H-isochromene derivatives by reaction with
various nucleophiles.[4] With regard to metal-catalyzed transfor-
mations, Yamamoto and co-workers initially reported in 2002
the synthesis of naphthyl ketone derivatives by a AuCl3-cata-
lyzed benzannulation reaction of ortho-alkynylarylaldehydes.[5]
This transformation was shown to involve the initial formation
of a benzopyrylium key intermediate that subsequently under-
goes a [4+2] cycloaddition with an alkyne to produce the cor-
responding naphthyl ketone after a final fragmentation step.
Following this seminal work, several other studies involving
a [4+2] cycloaddition of the intermediate pyrylium ion were
reported (Scheme 2, path a).[6] In sharp contrast, the possibility
to implement an alternative intermolecular [3+2] cycloaddition
with concomitant generation of a gold carbene intermediate
has been less explored (Scheme 2, path b).[7]
proach for the preparation of anti-Bredt compounds is
synthetically superior to those previously reported: the
procedure is easy to implement, operates under mild ex-
perimental conditions, is efficient, and exhibits a good
substrate scope.
Strained bridgehead olefin compounds (1, S ꢀ8), also known
as anti-Bredt compounds, are unusual structural motifs that
have attracted the interest of chemists since the beginning of
the last century (Scheme 1).[1,2] From a synthetic point of view,
a variety of methods has been established so far for accessing
such types of molecules.[3] For instance, it has been reported
that bicyclo[4.2.1]non-6-enes (2) could be obtained either
through pyrolysis,[3h] by using a Wittig reaction,[3d,e] or by de-
carboxylation[3i] (Scheme 1). While such methods allow reasona-
ble access to strained bridgehead olefin structural motifs, they
suffer from a series of limitations. Substrates are generally not
readily available, experimental conditions are not very mild,
and the scope is often limited. As a consequence, a straightfor-
ward approach to this class of unique compounds would be of
high interest. Herein, we would like to report our investiga-
tions in this field which have led to the development of a new
gold-catalyzed tandem intermolecular [3+2] cycloaddition/
Prins-type ring-closing reaction for the efficient construction of
highly strained tetracyclic bridgehead olefins (3).
Scheme 2. Cycloaddition modes of ortho-alkynylbenzaldehydes in the pres-
ence of a gold catalyst.
[a] Dr. Z. Cao, H. Zhu, Dr. X. Meng, L. Tian, X. Sun, G. Chen, Prof. J. You
Key Laboratory of Life-Organic Analysis
Key Laboratory of Pharmaceutical Intermediates and
Analysis of Natural Medicine
In this context and following our continuous interest in the
use of gold catalysis for the synthesis of polycyclic com-
pounds,[8] we recently envisaged the reaction of a tethered
diene with an ortho-alkynylarylaldehyde in the presence of
a gold catalyst. We indeed hypothesized that an intermolecular
gold-catalyzed [3+2] cycloaddition step of the benzopyrilium
School of Chemistry and Chemical Engineering, Qufu Normal University
Qufu, 273165, Shandong (China)
E-mail: caozp_qfnu@163.com
jmyou6304@163.com
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under http://dx.doi.org/10.1002/
chem.201601430.
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Communication
ion with the diene could deliver a gold carbene intermediate
that would then ring-close with the unreacted alkene unit to
produce a fused polycyclic structure featuring a bridgehead
alkene moiety (Scheme 2, path b). This approach would not
only allow rapid and unprecedented access to highly strained
polycyclic bridgehead olefins, but would also further highlight
the potential of gold catalysis for the generation of structural
complexity from simple starting materials.[9]
present transformation (Table 1, entries 7–9). Lowering the re-
action temperature led to a lower yield of 3a without improv-
ing the diastereoisomeric ratio (Table 1, entry 10). Finally, the
loading of AuCl·SMe2 (11) could be reduced to 2 mol% and
diene 5a used in lower excess (3 equiv). Under these opti-
mized conditions, bridgehead olefin 3a could be isolated in
87% yield as a 9:1 mixture of diastereoisomers (Table 1,
entry 11).
o-Alkynylbenzylaldehyde 4a[10] and conjugated diene 5a[11]
were initially chosen as model substrates for our study
(Scheme 3). We were aware that their reaction in the presence
of a gold catalyst might lead to some selectivity issues. Indeed,
we found that the desired reaction pathway leading ultimately
to the polycyclic bridgehead alkene 3a could be in competi-
tion with: 1) the frequently encountered [4+2] cycloaddition
reaction 4a+5a!6 and 2) the intra- or intramolecular trap-
ping of the postulated gold carbene intermediate with an
alkene leading to cyclopropanes 7 and 8.[12] However, by
taking into account the reactivity of conjugated diene struc-
tures in such a type of transformation,[13] we considered that
the introduction of methyl groups at positions C2 and C3
could potentially favor the desired ring-closing reaction lead-
ing to 3a.
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst[b]
(4 mol%)
T
[8C]
t
[h]
Yield
[%][c]
1
2
3
4
5
6
7
8
9
AuCl3 (9)
23
23
23
40
23
23
23
23
40
0
2
4
1
73 (9:1)
61 (8:1)
88 (9:1)
0
18 (>20:1)
31 (>20:1)
0
NaAuCl4·2H2O (10)
AuCl·SMe2(11)
PPh3AuNTf2 (12)
IPrAuNTf2 (13)
SIPrAuNTf2 (14)
AgSbF6
AgNTf2
PtCl2
11
11
6
12
12
6
6
6
4
1
0
0
10
11[d]
60 (9:1)
87 (9:1)
23
[a] Unless otherwise noted, all reactions were carried out with 4a
(0.2 mmol), 5a (1.0 mmol, 5 equiv), and catalyst (4 mol%) in CH2Cl2
(2.0 mL). [b] Tf=trifluoromethanesulfonyl; IPr=1,3-bis(2,6-diisopropylphe-
nyl)imidazol-2-ylidene; SIPr=1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroi-
midazol-2-ylidene. [c] Yield of isolated products, the d.r. values were de-
termined by 1H NMR spectroscopy and given within parentheses.
[d] 2 mol% of AuCl·SMe2 (11) and 3 equivalents of 5a were used.
Scheme 3. Potential competitive pathways in the reaction of 4a with 5a.
A primary experiment was performed by treating at room
temperature a solution of o-alkynylbenzylaldehyde 4a and 2,3-
dimethylbutadiene (5a, 5 equiv) in dichloromethane with
4 mol% of AuCl3 (9). We were delighted to observe the rapid
formation (2 h) of the fused tetracyclic product 3a, which
could be isolated in 73% yield as a 9:1 mixture of diastereoiso-
mers (Table 1, entry 1).[14] Notably the reaction was surprisingly
highly selective; no trace of compound 6 or cyclopropanes 7
We then performed the scope of the reaction and first stud-
ied the possibility to use various ortho-alkynylarylaldehydes
(Table 2). It was found that the procedure could be successfully
applied to a large panel of enynals (4a–u). The corresponding
strained tetracyclic bridgehead olefins (3a–u) were obtained in
generally high yield (51-99%) and diastereoselectivity (9:1 to
>20:1). While enynals 4b and 4d–h, possessing substituents
of various electronic nature at the 4-, 5-, and 6-positions of the
aromatic ring, smoothly gave the desired products, the reac-
tion of substrate 4c, bearing a strong electron-donating
group, was almost inefficient (Table 2, entries 1–8). With regard
to the substitution pattern of the R2 group attached to the
alkyne moiety, it was shown that the reaction could be per-
formed with a similar efficiency whatever the electronic nature
of the substituent at the para position of the aromatic ring
(73–99% yield, 18:1 to 1:0 diastereoselectivity, Table 2, en-
tries 9–11 and 13–18). meta-Substituted enynals (4s and 4t)
were also suitable substrates (Table 2, entries 19 and 20). A
limit in reactivity was observed when the sterically hindered
ortho-substituted substrate 4u was employed. In this case, an
elevated temperature and a longer reaction time were re-
quired to produce 3u in acceptable yield and good selectivity
1
and 8 could be detected by H NMR spectroscopy analysis of
the reaction mixture (Scheme 3). We then focused our atten-
tion on the optimization of the experimental reaction condi-
tions. Results of this study are reported in Table 1. While
NaAuCl4·2H2O (10) could also promote the formation of 3a
(Table 1, entry 2), the best result in terms of reaction rate and
yield was obtained when AuCl·SMe2 (11) was used as the cata-
lyst (Table 1, entry 3). [Ph3PAuNTf2] gold complex (12), which
possesses a phosphine ligand, was completely inefficient even
at the elevated temperature (Table 1, entry 4); gold(I) com-
plexes 13 and 14 bearing an N-heterocyclic carbene ligand
were also far less reactive than 11 (Table 1, entries 5 and 6). It
was also shown that other transition-metal salts, such as
AgSbF6, AgNTf2 and PtCl2, were not suitable catalysts for the
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Table 2. Scope of the reaction with various ortho-alkynylarylaldehydes
4.[a]
Table 3. Scope of the reaction with various conjugated dienes 5.[a]
Entry
Substrate
Product
Yield [%][b]
1
2
3[c]
4
5
6
7
8
4a (R1 =H)
3a
3b
3c
3d
3e
3 f
87 (9:1)
85 (>20:1)
<10
84 (10:1)
95 (>20:1)
95 (12:1)
76 (>20:1)
81 (>20:1)
4b (R1 =4-Me)
4c (R1 =5-MeO)
4d (R1 =4-F)
4e (R1 =5-F)
4 f (R1 =5-Cl)
4g (R1 =5-CF3)
4h (R1 =6-F)
3g
3h
9
10
11
12[d]
4i (R2 =4-MeOC6H4)
4j (R2 =4-MeC6H4)
4k (R2 =4-FC6H4)
4l (R2 =nBu)
3i
3j
3k
3l
91 (>20:1)
95 (>20:1)
84 (>20:1)
0
[a] see Table 2, footnote [a] and [b]. [b] 4 mol% of AuCl·SMe2 (11) and
5 equivalents of 5 f were used.
tetracyclic skeleton of the molecule, and the relative stereo-
chemistry of the methyl group at position C11 (Figure 1, left
part).[16] The polycyclic compound features a funnel-shaped ar-
chitecture with a bridgehead alkene (C14=C13) being twisted
from planarity by 40.85(2)8 (dihedral angle of C11-C13-C14-C4)
(Figure 1, right part). The relative configurations of other prod-
ucts (Tables 2 and 3) were tentatively assigned by analogy with
that of 3n.
13
14
15
16
17
18
19
20
21[d]
4m (R2 =4-MeC6H4)
4n (R2 =4-MeOC6H4)
4o (R2 =4-BnOC6H4)
4p (R2 =4-FC6H4)
4q (R2 =4-ClC6H4)
4r (R2 =4-CNC6H4)
4s (R2 =3-MeC6H4)
4t (R2 =3-ClC6H4)
4u (R2 =2-MeC6H4)
3m
3n
3o
3p
3q
3r
3s
3t
3u
96 (>20:1)
85 (>20:1)
80 (>20:1)
99 (18:1)
99 (>20:1)
73 (1:0)
85 (>20:1)
99 (>20:1)
51 (>20:1)
[a] Unless otherwise noted, all reactions were carried out with
4
(0.2 mmol), 5a (0.6 mmol, 3 equiv), and 11 (2 mol%) in CH2Cl2 (2.0 mL).
[b] Yield of isolated products, the ratio of the isomers given within paren-
theses. [c] For 24 h. [d] At 408C for 12 h.
(Table 2, entry 21). Finally, it was proven that the procedure
could not be applied to the use of alkyl substituted alkynes as
shown by the complete unreactivity of enynal 4l (Table 2,
entry 12).
Figure 1. X-ray structure of bridgehead alkene (3n) (left part). Hydrogen
atoms have been omitted for clarity. Structure of the bridgehead alkene unit
(right part).
The possibility to vary the nature of the conjugated diene
was next evaluated. As seen from the results compiled in
Table 3, mono-substituted isoprene (5b), as well as di-substi-
tuted diene (5d), and even tri-substituted diene (5 f) were suit-
able reaction partners, thus expanding the applicability of the
transformation. The corresponding strained tetracyclic bridge-
head alkenes were efficiently obtained with high chemo- and
stereo-selectivity (Table 3, 3eb, 3 fb, 3ed and 3ef). It should
be noted, however, that the reaction could not be performed
with 1,3-pentadiene (5c) and 2,4-hexadiene (5e). In these
cases, the reaction led to the formation of a mixture of uniden-
tifiable decomposition products (Table 3, 3ec and 3ee).[15]
Fortunately, the X-ray crystal structure of product 3n could
be obtained, thus confirming unambiguously the anti-Bredt
A mechanistic proposal for the formation of 3a is shown in
Scheme 4.[17] The alkyne–gold complex A, generated in situ by
coordination of 11 with 4a, could initially produce the dipolar
intermediate B as previously proposed (Scheme 2).[5] A subse-
quent stereoselective endo-type [3+2] cycloaddition of dipole
B with diene 5a could lead to a new gold intermediate, which
can be represented under two reactive forms C or C’. The pro-
nounced carbocationic nature of this intermediate[18,19] can
then favor a Prins-type cyclization that would produce carbo-
cation D.[20] The final formation of the bridgehead alkene prod-
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In summary, we have developed an efficient approach to the
synthesis of highly strained tetracyclic bridgehead olefins from
readily available ortho-alkynylarylaldehydes and conjugated
dienes by gold catalysis. The reaction is easy to set up, oper-
ates under mild experimental conditions with a low loading of
catalyst. It is more general, efficient and stereoselective when
compared to the other previously reported methods to access
strained polycyclic bridgehead olefins. The transformation has
been proposed to involve a gold-catalyzed intermolecular
[3+2] cycloaddition/Prins-type ring-closing sequence that
allows the formation of no less than six bonds and three rings.
The detailed mechanistic investigations and further extensions
of this methodology are currently underway in our laboratory.
Acknowledgements
We are grateful for funding from NSFC (21402106, 21475075,
21475074),
Shandong
Natural
Science
Foundation
(ZR2014BQ024, ZR2013BM007), and the Project-sponsored by
SRF for ROCS, SEM, Shandong Higher Educational Science and
Technology Program (J15LA02), and Research Start-up Founda-
tion of Qufu Normal University (bsqd20130115).
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Keywords: alkynylbenzylaldehyde · bridgehead · diene · gold ·
polycycles
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Published online on May 24, 2016
Chem. Eur. J. 2016, 22, 9125 – 9129
www.chemeurj.org
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