Transannular [4 + 2] Cycloaddition Reactions of Cobalt-Complexed Macrocyclic Dienynes

Article abstract of DOI:10.1021/acs.orglett.5b01984

The first transannular [4 + 2] cycloaddition reactions of macrocyclic dicobalt hexacarbonyl-dienyne complexes were demonstrated. Complexes were conveniently prepared through palladium(II)-catalyzed intramolecular oxidative cyclization of bis(vinylboronate esters) followed by complexation with dicobalt octacarbonyl. Transannular [4 + 2] cycloaddition reactions of the complexes occurred at lower temperatures and shorter times than transannular Diels-Alder reactions of metal-free dienynes. Intermolecular control reactions confirmed the effect of cobalt complexation on [4 + 2] cycloaddition reactions of unactivated alkynes and dienes.

Full text of DOI:10.1021/acs.orglett.5b01984

Letter
pubs.acs.org/OrgLett
Transannular [4 + 2] Cycloaddition Reactions of Cobalt-Complexed
Macrocyclic Dienynes
Sedef Karabiyikoglu and Craig A. Merlic*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
*
S Supporting Information
ABSTRACT: The first transannular [4 + 2] cycloaddition reactions of
macrocyclic dicobalt hexacarbonyl−dienyne complexes were demonstrated.
Complexes were conveniently prepared through palladium(II)-catalyzed
intramolecular oxidative cyclization of bis(vinylboronate esters) followed by
complexation with dicobalt octacarbonyl. Transannular [4 + 2] cyclo-
addition reactions of the complexes occurred at lower temperatures and shorter times than transannular Diels−Alder reactions of
metal-free dienynes. Intermolecular control reactions confirmed the effect of cobalt complexation on [4 + 2] cycloaddition
reactions of unactivated alkynes and dienes.
1
2
he transannular Diels−Alder (TADA) reaction is a poten1t
synthetic tool for building complex organic scaffolds.
underwent proximity-induced TADA reactions at room
temperature (Scheme 1).
13
T
TADA reactions are exploited in total syntheses due to their
2
versatility, atom economy, and unique stereoselectivity. Studies
Scheme 1. Previous Work on TADA
on spinosyn A biosynthesis led to the discovery of the first pure
Diels−Alderase enzyme that, in fact, catalyzes a transannular
3
Diels−Alder transformation. Although TADA reactions have
been widely investigated, utilization of transition metals to
promote or catalyze such transformations remains poorly
4
established.
Cobalt−alkyne complexes are versatile species with myriad
applications in synthetic chemistry. In addition to operating as
5
6
protected alkynes and stabilized propargyl cations, dicobalt
hexacarbonyl−alkyne complexes participate in several important
7
cycloaddition reactions. In particular, the [2 + 2 + 1]
cycloaddition known as the Pauson−Khand reaction (PKR) is
8
the most frequently studied. However, studies on other
cycloaddition reactions of alkyne−{Co (CO) } complexes,
2
6
To explore TADA reactivity of 14-membered alkynes, we
needed to synthesize dienyne 11 (Scheme 2). Trials to prepare
especially the [4 + 2] reaction, are scarce. The only reported
examples of [4 + 2] cycloaddition reactions with alkyne−
{
Co (CO) } complexes are (1) intermolecular tandem Diels−
2
6
Scheme 2. Preparation and TADA Reaction of 11
Alder/Pauson−Khand reactions of a few terminal alkyne
complexes with 1,3-cyclohexadiene and (2) intermolecular
9
Diels−Alder reactions with complexes of otherwise inaccessible
10
strained and reactive cyclic alkynes. Despite this limited
precedence, we postulated that [4 + 2] cycloaddition reactions of
dicobalt complexes would make structures unattainable via
metal-free Diels−Alder reactions accessible and that cobalt-
promoted TADA reactions would present a unique entry to both
organocobalt and macrocycle chemistry. Herein, we demonstrate
the first transannular [4 + 2] cycloadditions of macrocyclic
dienyne−{Co (CO) } complexes and the advantages over
2
6
metal-free TADA reactions.
We reported palladium(II)-catalyzed oxidative coupling of
bis(vinylboronate esters) as a mild and facile entry to macrocyclic
11
trienes and dienynes. This approach efficiently provided
strained cyclic substrates, some of which, such as 2, readily
Received: July 16, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01984
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
triyne 9 via classical S 2 reactions with various nucleophiles and
Table 1. Transannular [4 + 2] Reaction of Complex 17
N
electrophiles failed. Therefore, we subjected cobalt complex diol
6
,14
7
to a double Nicholas reaction. The resultant complex 8 was
easily converted to novel triyne 9 by Ce(NO ) (NH )
4 2
3
6
oxidation/decomplexation. Selective bis-hydroboration cata-
15
lyzed by Schwartz’s reagent afforded bis(vinylboronate ester)
0. A 16 h Pd(II)-catalyzed macrocyclization reaction of 10
formed macrocycle 11 in 31% yield and TADA reaction product
2 in 33% yield, indicating the facility of the room temperature,
1
a
b
entry
solvent
CH Cl
THF
temp (°C)
time (h)
promoter
yield (%)
1
1
2
3
4
5
6
7
8
2
2
25
25
25
80
80
25
25
25
168
120
72
18
12
0.5
4
1
2
proximity-induced TADA reaction of 14-membered dienyne
DMSO
TMTU
DMSO
TMTU
NMO
1
3
1 (Scheme 2). Decreasing the macrocyclization reaction time to
h afforded ring 11 in 68% yield as the principle product. Kinetic
toluene
THF
74
99
80
90
86
studies on isolated macrocycle 11 determined the TADA
toluene
16
reaction half-life to be 27 h at 21 °C. Thermal TADA reaction
gave complete conversion of 11 to 12 in 9.5 h at 50 °C.
We then shifted our focus to TADA reactions of larger dienyne
rings. Hydroboration of triyne 13 produced bis(vinylboronate
ester) 14 in good yield, and Pd(II)-catalyzed coupling reaction of
CH
CH
2
Cl
Cl
2
NMO
2
2
MeCN
21
NMO
a
DMSO and NMO were used in 6 equiv, and TMTU was used in 0.6
equiv. Yields are of isolated products. For entries 1−4, unreacted
complex 17 and/or decomplexed dienyne 15 was recovered.
b
1
4 smoothly formed macrocycle 15 in 63% yield (Scheme 3).
increased the yield to 90% (Table 1, entry 7). Acetonitrile
solvent, which was the choice of promoter/solvent in reported
cycloadditions of dicobalt complexes, did not affect the product
yield but dramatically slowed the reaction (Table 1, entry 8).
Next, 16-membered dienyne ring 20 was prepared via
hydroboration followed by Pd(II)-catalyzed macrocyclization
and tested for transannular [4 + 2] reactivity (Scheme 4). Metal-
Scheme 3. Preparation and TADA Reaction of 15
10
Scheme 4. Preparation and Attempted Metal-Free TADA
Reaction of Macrocyclic Dienyne 20
The 15-membered cyclic dienyne was considerably less reactive
than 14-membered dienyne 11 as the overnight macrocyclization
of 14 did not yield any of the expected TADA product. Stirring
1
5 at room temperature for 20 days produced tricyclic TADA
product 16 in a mere 4% yield. A thermal TADA reaction was
more effective as 16 was formed quantitatively upon heating 15
at 80 °C for 45 h (Scheme 3).
As the macrocycle size increases, the TADA reactivity clearly
decreases, and thus we investigated alternative transannular [4 +
2
] cycloaddition routes. Dicobalt hexacarbonyl complex 17 was
prepared via complexation of 15 with {Co (CO) } (Table 1).
free TADA reaction of 20 was not effective as tricyclic compound
21 was not formed even after heating 20 at 70 °C for 24 h or at 80
°C for 72 h. When macrocycle 20 was heated in toluene at 120 °C
for 72 h, only a trace amount of product was observed by TLC.
Clearly, this larger system no longer benefits from a proximity
effect, and lacking diene or dienophile activating groups, no
TADA reactivity was observed.
2
8
Dicobalt complex 17 did not form TADA product 16 even after 7
days at rt (Table 1, entry 1). The rate-determining step of the
PKR is decoordination of a CO ligand to provide an open
coordination site for an incoming alkene. To facilitate this
mechanistic step, various promoters are commonly employed.
We proposed that PKR promoters might also activate trans-
annular [4 + 2] cycloaddition reactions, thus systems commonly
used for PKR substrates were screened. DMSO/THF and
TMTU (1,1,3,3-tetramethylthiourea)/toluene systems were
ineffective at rt (Table 1, entries 2 and 3), but experiments at
17
Dicobalt complex 22 was prepared and subjected to
transannular [4 + 2] cycloaddition conditions that were
successful but highly dependent on the promoter/solvent
composition (Table 2). NMO was ineffective at rt or at 80 °C
(Table 2, entries 1 and 2). When heat was used as the sole
promoter product, yields were low (Table 2, entries 3 and 4).
While toluene/TMTU provided a quantitative conversion of 15
to tricycle 16 (Table 1, entry 5), it failed to promote formation of
tricycle 21. Higher yields of 21 were achieved with TMTU and
18
8
0 °C produced the desired TADA product in 74 and 99% yields,
respectively (Table 1, entries 4 and 5). The reaction times
indicated that the dicobalt-promoted TADA reaction was
considerably more facile than the cobalt-free TADA reaction
(Table 1, entry 5, vs Scheme 3). An exceptionally impressive
19
result was obtained when the cycloaddition was performed with
the stronger promoter NMO. Although dienyne ring 15 was
unreactive at rt (Scheme 3), complex 17 formed product 16 in
benzene solvent (Table 2, entry 6) . Finally, product 21 was
successfully synthesized in an 86% yield with a THF/DMSO
system (Table 2, entry 7).
8
6
0% yield in just 30 min when treated with NMO (Table 1, entry
). Increasing the reaction time for complete consumption of 17
Products 16 and 21 were obtained from the cobalt-promoted
reactions as single diastereomers, and they were predicted to
B
DOI: 10.1021/acs.orglett.5b01984
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Transannular [4 + 2] Reaction of Complex 22
Scheme 6. Possible Transannular PKR Products
a
b
entry
solvent
temp (°C)
time (h)
promoter
yield (%)
1
2
3
4
5
6
7
CH Cl2
25
80
48
48
96
17
24
12
18
NMO
NMO
14
17
21
25
2
into the dicobalt−alkyne moiety to undergo a 1,3-shift and
subsequent reductive elimination faster than CO insertion.
Since tricycles 12, 16, and 21 bear 1,4-cyclohexadiene rings,
aromatization might be anticipated, especially when heated with
oxidants. However, aromatization products derived from 12 and
DCE
toluene
80−100
140
100
70
(n-Bu) O
2
toluene
benzene
THF
TMTU
TMTU
DMSO
51
86
2
1 were not observed. The aromatized form of 16 was detected
80
1
a
by H NMR only in trials involving heating with cobalt and
oxidizing promoters. Since 16 is synthesized via dicobalt-
promoted [4 + 2] reaction at rt, aromatization can be avoided.
Finally, we tested intermolecular dicobalt-promoted [4 + 2]
cycloadditions. These control reactions used dienes and
dienophiles not activated with electron-donating or -withdrawing
components similar to TADA substrates 11, 15, 20, and 25.
Dienophiles 3-hexyne and 1,4-dipropoxybut-2-yne (35) were
reacted with 2,3-dimethylbuta-1,3-diene, but thermal Diels−
Alder products were not formed (Scheme 7). However, dicobalt
NMO and DMSO were used in 6 equiv, and TMTU was used in 0.6
b
equiv (entry 5) and in 2 equiv (entry 6). Yields are of isolated
products. For entry 1, unreacted complex 22 and decomplexed 20
were recovered. For entries 2−6, recovered 22 and 20 were detected
with unidentifiable decomposition products.
1
have cis stereochemistry. H NMR analysis determined that
thermal metal-free TADA reaction of dienyne 15 and trans-
annular [4 + 2] cycloaddition reaction of dicobalt complex 17
formed the same diastereomer of 16. Thus, the stereochemistry
of tricylic products 16 and 21 from cobalt-promoted reactions
were assigned as cis.
We next turned to a transannular cycloaddition of a larger
dienyne ring. The 18-membered ring 25 was synthesized from
bis(vinylboronate ester) 24 in 42% yield by Pd(II)-catalyzed
macrocyclization (Scheme 5). Like dienyne 20, 25 was inert in a
Scheme 7. Dicobalt-Promoted Intermolecular [4 + 2]
Reactions
Scheme 5. Preparation and Attempted TADA Reactions of
Macrocyclic Dienyne 25
complexes 33 and 36 were reactive, and [4 + 2] adducts 34 and
3
7 were formed at rt (Scheme 7). A competing PKR was not
16
observed from 36, and only a trace was detected from 33.
thermal TADA reaction; after heating at 120 °C for 72 h, no
desired tricycle 26 was formed. Complex 27 was prepared and
subjected to a transannular [4 + 2] reaction with various
promoters, but no product was observed. The lack of reactivity
may be due to steric interference by the extended methylene
chains.
Mechanistically, a 1,3-shift from a 5-membered to a 7-membered
cobaltocycle leading to [4 + 2] adducts should be favored by
converting the carbon bonded to cobalt from tertiary to primary.
Key to the success of these reactions was incorporation of the
mild promoter MeCN as reaction solvent and slow addition of
NMO. Under these conditions, we could avoid using high
equivalents of diene. These results suggest that dicobalt-
promoted [4 + 2] cycloaddition reactions may be more feasible
than previously thought and deserve further exploration.
In conclusion, we demonstrated the first transannular [4 + 2]
cycloaddition reactions of dicobalt hexacarbonyl alkyne com-
plexes. Transannular Diels−Alder reactions of 14-, 15-, 16-, and
18-membered cyclic dienynes, efficiently synthesized via Pd(II)-
catalyzed macrocyclizations, were investigated. Dicobalt-pro-
moted transannular cycloadditions were significantly more
effective than metal-free thermal TADA reactions, and
competing PKRs were not observed. Intermolecular control
One reason for the paucity of dicobalt-promoted [4 + 2]
cycloaddition examples is the high propensity for PKR to occur.
{
Co (CO) }−alkyne complexes are known to undergo facile
2
6
9,20
intermolecular PKR with dienes.
Moreover, acyclic dienyne
dicobalt hexacarbonyl complexes were shown to prefer PKR over
21
dicobalt-promoted intramolecular [4 + 2] cycloadditions. In
our studies, dicobalt promoted transannular [4 + 2] cyclo-
addition reactions showed impressive selectivity, and no
transannular PKR products 28, 29, or 30 were detected (Scheme
6). This may be due to conformational effects and a propensity
for the intermediate cobaltocycle resulting from alkene insertion
C
DOI: 10.1021/acs.orglett.5b01984
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactions confirmed the ability to select [4 + 2] cycloaddition
reactions over PKR.
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ASSOCIATED CONTENT
Supporting Information
■
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*
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J. P.; Martin, V. S. Molbank 2008, 2008, 562. (c) Ni, R.; Mitsuda, N.;
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01984.
1
(
(
190.
15) (a) Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127.
b) Wang, Y. D.; Kimball, G.; Prashad, A. S.; Wang, Y. Tetrahedron Lett.
Experimental details and spectral data for isolated
products (PDF)
NMR Spectra (PDF)
2
(
005, 46, 8777.
16) For experimental results, see Supporting Information.
AUTHOR INFORMATION
Corresponding Author
(17) Cambeiro, X. C.; Pericas, M. A. In The Pauson−Khand Reaction
Scope, Variations and Applications; Torres, R. R., Ed.; Wiley & Sons:
Chichester, U.K., 2012; pp 23−49.
■
*
E-mail: merlic@chem.ucla.edu.
Notes
(18) (a) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z.
Org. Lett. 2005, 7, 593. (b) Ishaq, S.; Porter, M. J. Synth. Commun. 2006,
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6, 547. (c) Turlington, M.; Yue, Y.; Yu, X.; Pu, L. J. Org. Chem. 2010, 75,
The authors declare no competing financial interest.
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941. (d) Chung, Y. K.; Lee, B. Y. Organometallics 1993, 12, 220.
(
19) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry;
ACKNOWLEDGMENTS
■
Wiley-VCH: Weinheim, Germany, 2003.
We thank the ACS Petroleum Research Fund (48564-AC1) and
UCLA for support of this work.
(20) Becheanu, A.; Bell, T.; Laschat, S.; Baro, A.; Frey, W.; Steinke, N.;
Fischer, P. Z. Naturforsch. 2006, 37, 589.
(21) (a) Park, K. H.; Choi, S. Y.; Kim, S. Y.; Chung, Y. K. Synlett 2006,
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27. (b) Odedra, A.; Lush, S.−F.; Liu, R.−S. J. Org. Chem. 2007, 72, 567.
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DOI: 10.1021/acs.orglett.5b01984
Org. Lett. XXXX, XXX, XXX−XXX