Gold-Catalyzed Cycloisomerization and Diels-Alder Reaction of 1,6-Diyne Esters with Alkenes and Diazenes to Hydronaphthalenes and -cinnolines

Article abstract of DOI:10.1021/acs.orglett.5b01935

A method for the efficient preparation of hydronaphthalene and -cinnoline derivatives by Au(I)-catalyzed cycloisomerzation of 1,6-diyne esters followed by a Diels-Alder reaction with alkenes or diazenes under mild conditions at room temperature with catal

Full text of DOI:10.1021/acs.orglett.5b01935

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Cycloisomerization and Diels−Alder Reaction of 1,6-
Diyne Esters with Alkenes and Diazenes to Hydronaphthalenes and
-
cinnolines
§
§
§
†
,†,‡
Jianming Yan, Guan Liang Tay, Cuien Neo, Bo Ra Lee, and Philip Wai Hong Chan*
†
School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
‡
Department of Chemistry, University of Warwick, Coventry, CV4 7AL, United Kingdom
§
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
*
S Supporting Information
ABSTRACT: A method for the efficient preparation of
hydronaphthalene and -cinnoline derivatives by Au(I)-
catalyzed cycloisomerzation of 1,6-diyne esters followed by a
Diels−Alder reaction with alkenes or diazenes under mild
conditions at room temperature with catalyst loadings as low
as 1 mol % is described.
artially hydrogenated naphthalenes and cinnolines are
cycloisomerization of 1,n-diyne esters triggered by an initial 1,2-
acyloxy migration step (Scheme 1, eq 1). Building on these
6
P
potentially useful building blocks in organic synthesis and
1
drug discovery programs. As illustrated in Figure 1, the two
Scheme 1. Gold-Catalyzed Reactivities of 1,n-Diyne Esters
Figure 1. Examples of bioactive natural and synthetic compounds
containing the hydronaphthalene and -cinnoline core.
seminal works, we envisioned that the alkenyl gold carbenoid
species I, derived from Au(I)-catalyzed rearrangement of 1,6-
diyne ester 1, might be susceptible to a pathway involving 1,2-
3
4
hydride migration followed by deauration when R = CH R in
2
ring systems are also a key structural feature in a myriad of
bioactive natural and pharmacologically interesting com-
the substrate (Scheme 1, eq 2). Subsequent Diels−Alder
reaction of the ensuing triene intermediate II on subjecting it to
a dienophile would then be anticipated to deliver the bicyclic
2
pounds. For this reason, the targeting of elegant approaches
to these two cyclic compound classes with selective control of
substitution patterns by using readily accessible substrates
remains among one of the central themes in organic
8
,9
product. Herein we disclose the details of this chemistry that
offers an expedient and chemoselective synthetic route to
hydronaphthalenes and -cinnolines in good to excellent yields
under mild conditions at room temperature.
1
,3
chemistry.
,n-Diyne ester cycloisomerizations catalyzed by Au(I) and
1
We commenced our studies by examining the Au(I)-
catalyzed reactions of 1a with N-phenyl maleimide to establish
Au(III) complexes have been highlighted in a number of recent
studies as one of the most efficient and atom-economical
4
−7
methods for complex molecule synthesis in a single step. For
example, we and others reported the preparation of a variety of
carbocyclic and heterocyclic compounds from gold(I)-catalyzed
Received: July 6, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01935
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the reaction conditions (Table 1). This initially revealed that
treating the 1,6-diyne ester and dienophile (2 equiv) with 5 mol
Similarly, a final set of control reactions mediated by AuCl,
the Au(III) complex I, PtCl , or AgSbF were found to result in
either the recovery of the substrate or a mixture of
unidentifiable decomposition products (entries 13−16).
The scope of the present procedure was next assessed with a
variety of 1,6-diyne esters and alkenes, and the results are
summarized in Scheme 2. Overall, these experiments
2
6
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Cycloisomerization of 1a−l Catalyzed by F and
a
Diels−Alder Reaction with Alkenes
b
entry
catalyst
solvent
CH Cl
yield (%)
1
2
3
4
5
6
7
A
B
C
D
64
39
58
50
13
52
80
79
50
69
33
62
f
2
2
2
2
2
2
2
2
2
CH Cl
2
CH Cl
2
CH Cl
2
Ph PAuNTf
3
CH Cl
2
2
E
CH Cl
2
F
CH Cl
2
c
8
d
F
CH Cl
2
9
F
(CH Cl)
2
2
e
10
11
12
13
14
15
16
F
PhMe
G
CH Cl
2
2
2
2
2
2
2
H
CH Cl
2
AuCl
I
CH Cl
2
CH Cl
g
2
PtCl2
AgSbF6
CH Cl
f
2
CH Cl
f
2
a
All reactions were conducted with 0.2 mmol of 1a and 0.4 mmol of
N-phenyl maleimide in the presence of 5 mol % of catalyst and 4 Å MS
b
(
100 mg) at room temperature for 24 h; Bz = benzyl. Isolated
c
product yield. Reaction performed with 3 equiv of N-phenyl
maleimide. Reaction temperature = 60 °C. Reaction temperature
d
e
f
1
=
110 °C. No reaction based on TLC or H NMR analysis of the
g
crude reaction mixture. Unknown side product(s) were obtained
1
based on H NMR analysis of the crude mixture.
a
All reactions were conducted at the 0.2 mmol scale with 5 mol % of F
%
of Au(I) phosphine catalyst A and 4 Å molecular sieves (MS)
and 2 equiv of dienophile in dichloromethane in the presence of 4 Å
in dichloromethane at room temperature for 24 h afforded 2aa
in 64% yield (entry 1). Lower product yields of 13−58% were
observed when A was replaced with the Au(I) phosphine
complexes B, C, D, or Ph PAuNTf as the catalyst (entries 2−
MS (100 mg) at room temperature for 24 h. Values in parentheses
b
denote isolated product yield. Reaction temperature = 60 °C for 18 h
followed by the addition of 1 equiv of AlEt Cl in 1,2-dichloroethane
2
c
for 1 h at room temperature. Reaction performed with 5 mol % of A.
3
2
5). A similar outcome was found for reactions catalyzed by the
NHC-gold(I) (NHC = N-heterocyclic carbene) complexes E,
G, and H (entries 6, 11, and 12). Subsequent studies showed
that repeating the reaction with the NHC−gold(I) complex F
as the catalyst gave the best result, providing the hydronaph-
thalene adduct in 80% yield (entry 7). Under these latter
catalytic conditions, an increase in the amount of the dienophile
from 2 to 3 equiv led to a comparable product yield (entry 8).
However, changing the solvent from dichloromethane to either
demonstrated that the Au(I) complex F-catalyzed reaction
conditions proved to be broad, affording a variety of substituted
hydronaphthalenes in 45−85% yield from the corresponding
1,6-diyne esters 1a−l and electron-deficient alkenes. Reactions
of 1,6-diyne esters containing a PNB (1b), Ac (1c), or Alloc
(1d) instead of a Bz migrating group with N-phenyl maleimide
were found to proceed well, providing the corresponding
bicycloadducts 2ba−da in 65−82% yield. Likewise, the Diels−
Alder reaction of the putative triene II generated in situ from
either 1a or 1b with other dienophiles such as N-(4-
1
,2-dichloroethane or toluene afforded 2aa in lower yields of 50
and 69% yield (entries 9 and 10).
B
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Letter
nitrophenyl)maleimide, maleic anhydride and tetracyano-
ethylene, 1,4-benzoquinone, and 1,4-naphthoquinone was
found to be well-tolerated. In these transformations, the
corresponding bi-, tri-, and tetracycloadducts 2ab−bd were
obtained in yields of 59−84%, and with the structure and
relative cis-stereochemistry of 2ba also being confirmed by
provided the corresponding nitrogen heterocycles 3gb and 3gc
in respective yields of 67 and 60%.
A tentative mechanism for the present Au(I)-catalyzed
cycloisomerization/Diels−Alder transformation is outlined in
Scheme 4. Initially, this could involve activation of 1 by
10
single crystal X-ray analysis. The presence of other aryl motifs
1e,f) at the p-nitrobenzoyl carbon center or an n-hexyl (1g),
Scheme 4. Proposed Mechanism for the Au(I)-Catalyzed
Cycloisomerization/Diels−Alder Reaction of 1a−l with
Electron-Deficient Dienophiles
(
3
phenethyl (1h), or ether (1i,j) group at the R position of the
,6-diyne ester were found to have minimal influence on the
1
course of the reaction. Under the present protocol, these
reactions gave the corresponding hydronaphthalene derivatives
2
ea−ja in 72−85% yield. The only exceptions were the
reactions of 1,6-diyne esters containing a Bn (1k) or
sulfonamide (1l) moiety. The former required a reaction
temperature of 60 °C for the cycloisomerization step followed
by the addition of AlEt Cl to promote the Diels−Alder reaction
2
with N-(4-nitrophenyl)maleimide to give 2ka in 45% yield. In
the case of the latter, the gold(I) phosphine complex A-
catalyzed reaction was found to furnish 2la in 72% yield and
with fewer impurities than the analogous transformation
mediated by the NHC−gold(I) complex F. On other hand,
no other cycloaddition products arising from a possible
competitive Diels−Alder reaction at the ring diene motif of
the posited triene intermediate were observed by TLC analysis
1
and H NMR spectroscopic measurements of the crude
reaction mixtures. This was further corroborated by repeating
the large-scale reaction of 1a (1.5 g) with N-phenyl maleimide
imide in the presence of 1 mol % of F under the present
protocol, which gave 2aa as the only product in 75% yield (1.7
g).
With 1,6-diyne esters 1a and 1g as representative examples,
the scope of this new Au(I)-catalyzed cycloisomerization/
Diels−Alder reaction method was further examined with
diazene dienophiles (Scheme 3). By applying the NHC−
gold(I) complex F-catalyzed protocol, this revealed the
reactions of 1a and 1g with diisopropyl azodicarboxylate gave
the corresponding hydrocinnolines 3aa and 3ga in 62 and 65%
yield, respectively. Under similar conditions, experiments of 1g
with diethyl azodicarboxylate or di-tert-butyl azodicarboxylate
coordination of the gold catalyst to the CC bond of the
6
substrate to give the gold(I)-coordinated species III. This
triggers syn-1,2-migration of the acyloxy moiety in the
organogold adduct to give the gold carbenoid complex V via
the 1,3-dioxol-1-ium species IV. Addition of the gold carbenoid
moiety to the remaining alkyne moiety in this newly formed
adduct might afford the cyclopropene VI. Further activation of
the CC bond of the bicyclic intermediate may give the
gold(I)-coordinated complex VII, which is susceptible to
electrophilic ring opening to afford the second gold carbenoid
species VIII. A subsequent 1,2-hydride shift followed by
protodeuteration of the ensuing putative organogold inter-
mediate IX would then deliver the 1-vinylcyclohexa-1,3-diene
adduct II that undergoes the Diels−Alder reaction with the
dienophile to afford 2 or 3. The proposed involvement of the
triene intermediate is consistent with our findings for the
control reactions depicted in Scheme 5. Subjecting 1a with 5
Scheme 3. Cycloisomerization of 1a and 1g Catalyzed by F
a
and Diels−Alder Reaction with Diazenes
Scheme 5. Control Experiment with 1a and N-Phenyl
Maleimide
mol % of Au(I) catalyst F and 4 Å MS in dichloromethane at
room temperature for 2 h provided the 1-vinylcyclohexa-1,3-
diene 4aa (II in Schemes 1 and 4) in 85% yield. Treatment of
this cycloadduct with N-phenyl maleimide (2 equiv) and 4 Å
MS in dichloromethane at room temperature for 24 h then gave
the expected Diels−Alder reaction product 2aa in 90% yield.
a
All reactions were conducted at the 0.2 mmol scale with 5 mol % of F
and 2 equiv of dienophile in dichloromethane in the presence of 4 Å
MS (100 mg) at room temperature for 24 h. Values in parentheses
denote isolated product yield.
C
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Organic Letters
Letter
Added to this is the observed relative cis-stereochemistry of the
product that would be in good agreement with Diels−Alder
reactions involving a trans,trans-1,3-diene.
In summary, we have elucidated an efficient one-pot Au(I)-
catalyzed cycloisomerization/Diels−Alder reaction process for
the construction of hydronaphthalene and -cinnoline deriva-
tives from 1,6-diyne esters and electron-deficient dienophiles.
Efforts to explore the scope and synthetic applications of this
transformation to other carbocyclic and heterocyclic systems
are in progress and will be reported in due course.
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*
S
́
́
̃
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01935.
initial 1,2-acyloxy migration step: (a) Liu, J.; Chen, M.; Zhang, L.; Liu,
Y. Chem. - Eur. J. 2015, 21, 1009. (b) Rao, W.; Chan, P. W. H. Chem. -
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W.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Adv. Synth. Catal.
Detailed experiment procedures, characterization data
1
13
and H and C NMR spectra for all starting materials
and products (PDF)
2
014, 356, 680. (d) Oh, C. H.; Kim, J. H.; Piao, L.; Yu, J.; Kim, S. Y.
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CIF file of 2ba (CIF)
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̈
sel, P.; Rudolph, M.; Rominger, F.; Hashmi, A. S.
AUTHOR INFORMATION
Corresponding Author
■
*
(
via an initial 1,3-acyloxy migration step: (a) Rao, W.; Susanti, D.;
Ayers, B. J.; Chan, P. W. H. J. Am. Chem. Soc. 2015, 137, 6350. (b) Li,
D.; Rao, W.; Tay, G. L.; Ayers, B. J.; Chan, P. W. H. J. Org. Chem.
E-mail: phil.chan@monash.edu; P.W.H.Chan@warwick.ac.uk.
Notes
2
014, 79, 11301. (c) Yu, Y.; Yang, W.; Rominger, F.; Hashmi, A. S. K.
The authors declare no competing financial interest.
Angew. Chem., Int. Ed. 2013, 52, 7586. (d) Hashmi, A. S. K.; Yang, W.;
Yu, Y.; Hansmann, M. M.; Rudolph, M.; Rominger, F. Angew. Chem.,
Int. Ed. 2013, 52, 1329. (e) Rao, W.; Koh, M. J.; Kothandaraman, P.;
Chan, P. W. H. J. Am. Chem. Soc. 2012, 134, 10811. (f) Chen, Y.;
Chen, M.; Liu, Y. Angew. Chem., Int. Ed. 2012, 51, 6493. (g) Shi, H.;
Fang, L.; Tan, C.; Shi, L.; Zhang, W.; Li, C.-C.; Luo, T.; Yang, Z. J. Am.
Chem. Soc. 2011, 133, 14944. (h) Leboeuf, D.; Simonneau, A.; Aubert,
C.; Malacria, M.; Gandon, V.; Fensterbank, L. Angew. Chem., Int. Ed.
2011, 50, 6868. (i) Zhang, D.-H.; Yao, L.-F.; Wei, Y.; Shi, M. Angew.
Chem., Int. Ed. 2011, 50, 2583. (j) Luo, T.; Schreiber, S. L. J. Am.
Chem. Soc. 2009, 131, 5667.
ACKNOWLEDGMENTS
■
This work was supported by the School of Chemistry, Monash
University and Department of Chemistry, University of
Warwick (Start-Up Grants) as well as by the Ministry of
Education of Singapore (Tier 2 grant, MOE2013-T2-1-060).
We thank Dr. Yongxin Li (Nanyang Technological University)
for providing the X-ray crystallographic data reported in this
work.
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