Nickel-catalyzed intramolecular [3 + 2 + 2] cycloadditions of alkylidenecyclopropanes. A straightforward entry to fused 6,7,5-tricyclic systems

Article abstract of DOI:10.1021/ol502288x

A highly diastereo- and chemoselective intramolecular nickel-catalyzed cycloaddition of alkene- and alkyne-tethered alkynylidenecyclopropanes is reported. The method constitutes the first fully intramolecular [3 + 2 + 2] alkylidenecyclopropropane cycloadd

Full text of DOI:10.1021/ol502288x

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Intramolecular [3 + 2 + 2] Cycloadditions of
Alkylidenecyclopropanes. A Straightforward Entry to Fused 6,7,5-
Tricyclic Systems
†
‡
ez,*,†,§ and Jose
L. Mascaren
̃
as*,†
Lucía Saya, Israel Fernan
†
́
dez, Fernando Lop
́
́
́ ́ ́
Centro Singular de Investigacion en Química Biologica y Materiales Moleculares (CIQUS) and Departamento de Química Organica,
Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
‡
Departamento de Química Organ
́
ica I, Facultad de Ciencias Químicas, Universidad Complutense Madrid, 28040-Madrid, Spain
§
Instituto de Química Organ
S Supporting Information
́
ica General (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain
*
ABSTRACT: A highly diastereo- and chemoselective intra-
molecular nickel-catalyzed cycloaddition of alkene- and alkyne-
tethered alkynylidenecyclopropanes is reported. The method
constitutes the first fully intramolecular [3 + 2 + 2]
alkylidenecyclopropropane cycloaddition occurring via a prox-
imal cleavage of the cyclopropane and makes it possible to build
relevant 6,7,5-tricyclic frameworks in a single-pot reaction. Importantly, the reaction outcome is highly dependent on the
characteristics of the nickel ligands.
odern organic synthesis is increasingly demanding the
development of sustainable transformations that allow
(ACPs). We have demonstrated that alkynylidenecyclopropanes
M
can react with activated alkenes in the presence of Ni(COD) to
2
5
,6
readily available precursors to be converted into complex, target-
give 6,7-bicyclic systems (Scheme 1, c). While the reaction
works well with acrylates, it fails with β-substituted alkenes and
alkynes and is often accompanied by the competitive formation
of cycloadducts arising from intermolecular [3 + 2] annulations.
Considering the wide occurrence and enormous relevance of
bioactive diterpenes featuring 6,7,5-tricarbocycles and the well-
known difficulties to assemble these types of skeletons using
1
relevant products. In this context, transition-metal-catalyzed
multicomponent cycloadditions are particularly appealing
because they allow the assembly of cyclic systems from simpler
2
3
4
acyclic precursors. Along these lines, Saito and de Meijere
have developed several Ni-catalyzed [3 + 2 + 2] intermolecular
cycloadditions of alkylidenecyclopropanes with alkynes and/or
alkenes (Scheme 1, a,b). Although the reactions yield syntheti-
cally appealing cycloheptene systems, their success is associated
with the use of specifically activated alkylidenecyclopropanes
7
current synthetic methodologies, we investigated the viability of
a fully intramolecular [3 + 2 + 2] annulation (Scheme 1, d).
Herein we describe an efficient and chemoselective intra-
molecular [3 + 2 + 2] cycloaddition reaction that allows 6,7,5-
tricarbocyclic skeletons to be built in a single step. The method
constitutes the first intramolecular [3 + 2 + 2] cycloaddition
involving ACPs that proceeds by proximal cleavage of the
Scheme 1. Ni-Catalyzed [3 + 2 + 2] Cycloadditions
8
cyclopropane ring. We also provide DFT calculations that
qualitatively explain the experimental results and shed light on
the reaction mechanisms.
The feasibility of the cycloaddition was assessed with
alkynylidenecyclopropane 1a (Table 1). Gratifyingly, treatment
of a toluene solution of 1a with Ni(COD) (10%), at rt for 24 h,
2
led to the desired [3 + 2 + 2] cycloadduct 2a, which was isolated
in 85% yield (Table 1, entry 1). The reaction was completely
diastereoselective, providing exclusively the isomer that retains
the trans stereochemistry of the parent alkene, and could be
significantly accelerated by slight heating at 40 °C (83% yield
after 2 h, entry 2). Moreover, the catalyst loading could be
decreased down to 5% without significantly compromising the
Received: August 1, 2014
Published: September 18, 2014
©
2014 American Chemical Society
5008
dx.doi.org/10.1021/ol502288x | Org. Lett. 2014, 16, 5008−5011

Organic Letters
Letter
Table 1. Preliminary Screening of the Intramolecular
Cycloaddition
PR catalysts (entries 4, 6, 7), the use of N-heterocyclic carbene
ligands such as IPr or IMes led to the exclusive formation of the
3
[
3 + 2 + 2] cycloadduct 2a, although the reaction rates were
significantly lower than that observed with just Ni(COD)2
entries 10 and 11 vs 2). The inhibition of the β-hydride
(
elimination pathway in these cases might be related to the
particular geometry of these bulky NHC ligands, which could
impede the adoption of the required syn-coplanar disposition of
the Ni and β-H atoms in the nickelacyclooctene intermediate of
10
type B.
Using Ni(COD) as the optimal catalytic system, we found
2
that ACP precursors 1b−1h, containing oxygen-, nitrogen-, or
carbon-based tethers participate in the reaction to give the
expected cycloadducts 2b−2h with complete diastereoselectivity
and good or excellent yields (Scheme 2).
a
entry
[Ni] (10%)
L (mol %)
t (°C) time (h) 2a (%) 3a (%)
1
2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
rt
24
2
85
83
80
0
0
0
40
40
40
40
40
40
40
40
40
40
b
3
4
0
4
5
6
7
8
9
PPh (20)
2
86
39
85
5
Scheme 2. Scope of the Intramolecular [3 + 2 + 2]
3
c
,
d
a
PPh (10)
24
4
0
Cycloaddition Reaction
3
PCy (20)
0
3
c
c
c
c
c
,
,
,
,
,
e
f
c
c
c
c
c
L1 (20)
2
9
dppe (10)
dppp (10)
IPr (20)
24
24
24
24
76
86
23
67
1
g
h
I
2
1
1
0
1
1
IMes (20)
1
a
1
a (0.2 M in toluene), [Ni(COD) ] (10%), L (%), at 40 °C. Full
2
1
conversions (determined by H NMR) and isolated yields of 2a and
3
b
c
a, unless otherwise noted. Carried out with Ni(COD) (5%). Yield
2
d
1
determined by H NMR with internal standard. 89% conversion.
e
f
g
h
6
7% conversion. 86% conversion. 90% conversion. 38% con-
I
version. 77% conversion.
rate and yield of the process (entry 3). In an attempt to further
understand the catalytic system, we analyzed the influence of
external ligands. Curiously, and in contrast to the intermolecular
a
, 0.2 M in toluene. Full conversions determined by 1H NMR.
b
1
5
processes, the use of PPh3 (20%) in combination with
Isolated yields of 2. Obtained from Z-1b.
Ni(COD) (10%) did not inhibit the reaction; however, instead
2
of providing the expected cycloadduct 2a, the reaction gave the
bicyclic triene 3a in 86% yield, (entry 4).
Importantly, in all cases the cycloadditions were completely
chemoselective since no traces of potentially competitive [3 + 2]
The formation of this triene can be rationalized in terms of a β-
hydride elimination step occurring on a hypothetical nickel-
acyclooctene intermediate of type B, which could alternatively
evolve to the desired cycloadduct 2a through a reductive
elimination step (Table 1). The use of equimolar amounts of
Ph P and Ni(COD) led to a significant decrease of the reaction
5
,11
adducts, or of other side products, were detected. Particularly
relevant are the cycloadditions of precursors that incorporate a
saturated hydrocarbon linkage between the ACP and the alkyne
(1g and 1h), as they generate tricarbocyclic scaffolds (2g and 2h)7
reminiscent of those present in naturally occurring diterpenes.
Of mechanistic significance, the reaction proved to be stereo-
especific, as the cycloaddition of a substrate containing a cis-
alkene, Z-1b, afforded 2b′, the complementary diastereoisomer
to that obtained from 1b. The structure and stereochemical
assignment of the adducts was performed by NMR, and in the
case of 2e, further verification was obtained by X-ray diffraction
analysis (Figure 1).
3
2
rate (39% yield after 24 h), although the selectivity toward the
triene 3a was preserved (entry 5). A more donating phosphine
such as PCy (20%) also favored the formation of 3a, which in
3
this case was isolated in 85% yield after 4 h (entry 6). On the
other hand, a less donating phosphine such as (p-CF Ph) P
3
3
partially restored the [3 + 2 + 2] cycloaddition pathway,
providing a 1:5.7 mixture of 2a and 3a in 60% overall yield (entry
7
). Interestingly, the β-hydride elimination pathway could be
We then analyzed the viability of using 2π-reactants other than
alkenyl esters as reaction components. While electronically
unactivated alkenes or allenes failed to participate in the process,
the alkyne-containing precursors 1i and 1j did react in the
completely suppressed by using bidentate phosphines such as
dppe or dppp; however, full conversions were not reached even
after 24 h at 40 °C when using these phosphines (entries 8 and
9
). The ability of the bisphosphine ligands to inhibit the β-
presence of Ni(COD) (10%) but instead of leading to the
2
hydride elimination pathway is consistent with the lack of vacant
sites at the metal owing to the bidentate coordination of the
ligand. Curiously, and contrary to the performance of Ni(0)/
expected tricycles, we obtained the cyclooctatetraenes 4i and 4j
12
in modest yields (Table 2, entries 1 and 2). Notably, the use of
Ph P (20%) in combination with Ni(COD) (10%) switches
9
3
2
5
009
dx.doi.org/10.1021/ol502288x | Org. Lett. 2014, 16, 5008−5011

Organic Letters
Letter
Scheme 3. Calculated Profile for the Reaction of 1l and
14
[
Ni(CH CH ) ], with or without PMe
2
2 2
3
Figure 1. X-ray structure of 2e.
a
Table 2. Use of Alkynes as Third Cycloaddition Components
time
(h)
entry
R, 1
X
Y
L (mol %)
2, (%)
4, (%)
1
2
3
4
5
6
7
Me, 1i
Me, 1j
Me, 1i
Me, 1j
Me, 1i
Me, 1j
H, 1k
C(E)2
NTs
O
O
O
O
O
O
O
1.5
1.5
1.5
1.5
1.5
2
4i, 44
4j, 34
4i, 10
4i, 2
C(E)2
NTs
PPh (20)
2i, 50
2j, 36
2i, 65
2j, 60
2k, 74
3
PPh (20)
3
⧧
−1
C(E)2
IPr (20)
IPr (20)
pathway through transition state TS1c [ΔΔG = 7.1 kcal·mol ],
whereas the second carbometalation, through transition states of
type TS2, shows again a lower energy barrier when occurring via
NTs
C(E)2
PPh (20)
3
3
a
⧧
−1
Conditions: 1 (0.2 M in toluene), [Ni(COD) ] (10%), L (%). Full
conversions after the indicated time. Isolated yields of 2 and 4. E =
CO Et.
TS2c [ΔΔG = 6.9 kcal·mol ]. Thus, the presence of the
external phosphine ligand seems to clearly favor the migratory
insertion steps, thereby reducing the overall energetic barrier of
the [3 + 2 + 2] process, a result that is in consonance with the
2
2
16
experimental observations.
The final reductive elimination step (IVc → Vc) proceeds via
TS3c with a very low activation barrier of 1.8 kcal·mol− (Scheme
1
4
, blue profile). The analogue step from IVb is similarly feasible
completely the outcome of the reaction, restoring the [3 + 2 + 2]
cycloaddition process. Thus, under these conditions, 1i and its
NTs counterpart 1j provided, after 1.5 h at rt, the expected
tricycles in 50% and 36% yield, respectively, together with traces
of the cyclooctatetraene products 4 (entries 3 and 4).
Gratifyingly, the use of the NHC ligand IPr allowed the yields
of the [3 + 2 + 2] cycloadducts to be improved to 65% and 60%,
⧧
−1
(
ΔG = 1.2 kcal·mol ; Supporting Information, Scheme S1).
Scheme 4. Calculated Reductive and β-H Elimination
Pathways for IVc
14
13
respectively (entries 5 and 6). On the other hand, the
cycloaddition could also be achieved employing a terminal alkyne
as third component (e.g., 1k, entry 7). It is worth mentioning that
in the reactions of entries 3−7 the β-hydride elimination
products 3i−k were never detected by NMR of the
corresponding crude mixtures.
The above examples, besides proving a robust catalytic method
for the synthesis of 6,7,5-fused tricycles, represent a new
demonstration of the power of ligand tuning in metal-catalyzed
reactions. To get information on the reaction mechanism and, in
particular, to gain insights into the effect of the external ligand in
the [3 + 2 + 2] cycloaddition of enediynes like 1i−k, we carried
out a DFT study using the substrate 1l and Ni(CH CH ) and
We also calculated a plausible pathway involving a β-hydride
elimination to give a tetraene of type 3 (Scheme 4, red profile). In
consonance with the experimental results for the cycloaddition of
1k (Table 2, entry 7), the process leading to VIIc (which
proceeds via IVc′, a rotamer of IVc that has the required syn-
2
2 2
14
PMe as model reactants (Scheme 3). The computational data
3
support a mechanism initiated by insertion of the nickel complex
into the proximal C−C bond of the cyclopropane to give the
nickelacyclobutane intermediate Ia, which readily evolves to Ib
by exergonic coordination of the terminal alkyne or to Ic if
⧧
disposition for the β-H elimination) is kinetically [ΔΔG = 3.5
−1
⧧
−1
kcal·mol ] and thermodynamically [ΔΔG = 7.3 kcal·mol ]
disfavored over that forming the cycloadduct Vc (Scheme 4, blue
profile). In contrast, we have found that the pathways leading to
the products 2g and 3g are clearly competitive (Supporting
Information, Scheme S2). This is in qualitative agreement with
the experimental observation of products arising from a β-H
elimination pathway, when the reaction of a dienyne like 1a is
15
coordinated to PMe3. Interestingly, the following carbometa-
lation steps that provide the nickelacyclohexenes of type II and
the subsequent nickelacyclooctenes IV are significantly more
favored when the nickel bears a coordinated phosphine. Indeed,
analysis of the activation barriers for the first carbometalation
leading to intermediates of type II shows a preference for the
5
010
dx.doi.org/10.1021/ol502288x | Org. Lett. 2014, 16, 5008−5011

Organic Letters
Letter
carried out in the presence of monodentate phosphines (Table 1,
entries 4−6).
(7) (a) Rigby, J. H. Stud. Nat. Prod. Chem. 1993, 12, 233. (b) Wender,
P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997, 119, 7897.
(c) Ovaska, T. V.; Reisman, S. E.; Flynn, M. A. Org. Lett. 2001, 3, 115.
In summary, we have developed a Ni(0)-catalyzed [3 + 2 + 2]
cycloaddition between an alkylnylidenecyclopane and a tethered
alkene or alkyne. The cycloaddition, which proceeds via proximal
cleavage of the cyclopropane and takes place with excellent
chemo- and stereoselectivity, generates three new C−C bonds
and provides a straightforward approach to synthetically
appealing 6,7,5-fused tricyclic systems. Importantly, the results
demonstrate that the reaction rate and outcome depends on the
nickel ligands and that it is even possible to switch among
different products by changing their electronic characteristics
and denticity. These interesting ligand effects might be relevant
to other nickel-catalyzed processes.
(d) Paquette, L.; Gallou, F.; Zhao, Z.; Young, D. G.; Liu, J.; Yang, J.;
Friedrich, D. J. Am. Chem. Soc. 2000, 122, 9610. (e) Wender, P. A.;
Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J.
Am. Chem. Soc. 1997, 119, 12976. (f) Jackson, S. R.; Johnson, M. G.;
Mikami, M.; Shiokawa, S.; Carreira, E. M. Angew. Chem., Int. Ed. 2001,
4
0, 2694.
(8) Previously reported Pd- and Rh-catalyzed intramolecular [3 + 2 +
2] cycloadditions of ACPs proceed through distal opening: (a) Bhargava,
G.; Trillo, B.; Araya, M.; Lopez, F.; Castedo, L.; Mascarenas, J. L. Chem.
́
̃
Commun. 2010, 46, 270. For Rh, see: (b) Evans, P. A.; Inglesby, P. A. J.
Am. Chem. Soc. 2008, 130, 12838. (c) Evans, P. A.; Inglesby, P. A.;
Kilbride, K. Org. Lett. 2013, 15, 1798. (d) Araya, M.; Gulías, M.;
̃
́ ́
Fernandez, I.; Bhargava, G.; Castedo, L.; Mascarenas, J. L.; Lopez, F.
Chem.Eur. J. 2014, 20, 10255. For a review on cycloaddition strategies
to seven-membered carbocycles, see: (e) Battiste, M. A.; Pelphrey, P.
M.; Wright, D. L. Chem.Eur. J. 2006, 12, 3438.
ASSOCIATED CONTENT
Supporting Information
■
*
S
(9) Bidentate bisphosphine ligands have also been shown to suppress
Experimental details and characterization data, including X-ray
structures and further DFT calculations. This material is available
free of charge via the Internet at http://pubs.acs.org.
β-H elimination processes in different types of transition-metal-
catalyzed cycloadditions: (a) Jiao, L.; Lin, M.; Yu, Z.-X. Chem. Commun.
2
010, 46, 1059. (b) Jiao, L.; Lin, M.; Yu, Z.-X. J. Am. Chem. Soc. 2011,
1
33, 447. (c) Lin, M.; Kang, G.-Y.; Guo, Y.-A.; Yu, Z.-X. J. Am. Chem. Soc.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
2012, 134, 398.
(10) Hong, X.; Liu, P.; Houk, K. N. J. Am. Chem. Soc. 2013, 135, 1456.
(
Pd-catalyzed [3 + 2 + 2] cycloadditions of ACPs; see ref 8a. For [3 + 2]
cycloadditions of ACPs, see: (a) Delgado, A.; Rodríguez, J. R.; Castedo,
11) [3 + 2] Side products are also typically observed in intramolecular
E-mail: fernando.lopez@csic.es.
E-mail: joseluis.mascarenas@usc.es.
Notes
L.; Mascaren
Gulias, M.; Castedo, L.; Mascaren
c) Trillo, B.; Gulias, M.; Lopez, F.; Castedo, L.; Mascaren
Synth. Catal. 2006, 348, 2381.
12) (a) Related [2 + 2 + 2 + 2] cycloadditions of non-symmetrical
̃
as, J. L. J. Am. Chem. Soc. 2003, 125, 9282. (b) Duran
as, J. L. Org. Lett. 2005, 7, 5693.
as, J. L. Adv.
́
, J.;
The authors declare no competing financial interest.
̃
(
́
̃
ACKNOWLEDGMENTS
This work was supported by the Spanish MINECO (SAF2010-
0822-C02-01/02, CTQ2010-20714-C02-01/BQU, CTQ2013-
4303-P and CSD2007-00006, Consolider-Ingenio), the ERDF,
the Xunta de Galicia (GRC2010/12, GR2013-041, INCITE09
09084PR), and the ERC (Adv. Grant. 340055). We thank Dr.
■
2
4
(
bisdiynes had been previously described by Wender et al. using [(dme)
NiBr2]/Zn as catalyst, although the reported regioselectivity was
complementary to that of 4i and 4j; see ref 6d and Wender, P. A.;
Christy, J. P. J. Am. Chem. Soc. 2007, 129, 13402. (b) 1,6-Enynes have
also been shown to participate in Ni-catalyzed [2 + 2 + 2 + 2]
cycloadditions; see: Chai, Z.; Wang, H.-F.; Zhao, G. Synlett 2009, 1785.
Under the current conditions we did not observed these potential side
products. (c) The structure of 4j was also confirmed by X-ray analysis;
see the Supporting Information.
2
G. Bhargava (Punjab Technical University) for initial work and
the Orfeo-Cinqa network.
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■
(
13) The structure of 2j could also be confirmed by X-ray analysis; see
the Supporting Information.
14) Calculations carried out at the PCM(toluene)-M06/def2-SVP//
(
(
(
(
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(
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(
15) The initial step from 1l to Ia, not shown in Scheme 3, is identical
to that previously published in ref 5.
16) (a) The presence of these external ligands might also disfavour
(
the [2 + 2 + 2 + 2] pathway by impeding the coordination of the second
diyne. (b) The first carbometallation step was also calculated from
species Ia and, eventually, led to IIIb through a similar activation barrier
than that from Ib. See the Supporting Information for details.
&
(
(
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5
011
dx.doi.org/10.1021/ol502288x | Org. Lett. 2014, 16, 5008−5011