Iridium-Catalyzed Formal [4 + 1] Cycloaddition of Biphenylenes with Alkenes Initiated by C-C Bond Cleavage for the Synthesis of 9,9-Disubstituted Fluorenes

Article abstract of DOI:10.1021/acs.orglett.6b00619

An Ir-catalyzed intermolecular reaction of biphenylenes as a C4 unit with various alkenes as a C1 unit gave 9,9-disubstituted fluorenes in moderate to high yields. Preliminary mechanistic studies revealed that this formal [4 + 1] cycloaddition probably pr

Full text of DOI:10.1021/acs.orglett.6b00619

Letter
pubs.acs.org/OrgLett
Iridium-Catalyzed Formal [4 + 1] Cycloaddition of Biphenylenes with
Alkenes Initiated by C−C Bond Cleavage for the Synthesis of
9,9‑Disubstituted Fluorenes
Hideaki Takano,† Kyalo Stephen Kanyiva,‡ and Takanori Shibata*,†,§
†Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo,
Shinjuku, Tokyo 169-8555, Japan
‡International Center for Science and Engineering Programs (ICSEP), Waseda University, 3-4-1 Okubo, Shinjuku, Tokyo 169-8555,
Japan
§JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
S
* Supporting Information
ABSTRACT: An Ir-catalyzed intermolecular reaction of
biphenylenes as a C4 unit with various alkenes as a C1 unit
gave 9,9-disubstituted fluorenes in moderate to high yields.
Preliminary mechanistic studies revealed that this formal [4 +
1] cycloaddition probably proceeds via C−C bond cleavage,
alkene insertion, β-hydrogen elimination, intramolecular alkene
insertion, and then reductive elimination. An example of enantioselective reaction was also disclosed.
Scheme 1. Formal Cycloadditions of
Dibenzometallacyclopentadiene as a C4 Unit Derived from
Biphenylene
enerally, a carbon−carbon (C−C) single bond is inactive
Gand cannot be directly used in organic synthesis.
However, C−C bonds found in small ring compounds such
as cyclopropane and cyclobutane can be cleaved due to their
ring strain. In particular, transition metal complexes can realize
oxidative cleavage of such C−C single bonds under relatively
mild reaction conditions to give metallacycles. Therefore,
various types of transition-metal-catalyzed synthetic trans-
formations of small ring compounds initiated by C−C bond
activation have been reported.1,2 Biphenylene is a typical
substrate that reacts with transition metal complexes to form
dibenzometallacyclopentadiene and, thus, often used as a C4
unit (Scheme 1). For example, nickel- or platinum-catalyzed
homocoupling of biphenylene gives o,o,o,o-tetraphenylene as a
formal [4 + 4] cycloadduct (path a).3,4 The iridium- or
rhodium-catalyzed reaction of biphenylene with alkynes and
nitriles affords phenanthrenes and phenanthridines, respectively
(path b).5−7 We reported asymmetric variants, where an
iridium-catalyzed enantioselective formal [4 + 2] cycloaddition
of biphenylene with ortho-substituted arylalkynes gave axially
chiral phenanthrene derivatives (path c).8
Herein we report a new pattern of formal [4 + 1]
cycloaddition (path d):9−11 Ir-catalyzed reaction of bipheny-
lenes with alkenes as a C1 unit provides a variety of 9,9-
disubstituted fluorenes in moderate to high yields. The reaction
mechanism involving inter- and intramolecular alkene in-
sertions is also discussed.
We first examined the reaction of biphenylene (1a) with
styrene (2a) in the presence of an Ir catalyst prepared in situ
from [Ir(cod)Cl]2 and 2,2′-bis(diphenylphosphino)-1,1′-bi-
phenyl (BIPHEP) in xylene at 135 °C (Scheme 2). While
the expected [4 + 2] cycloadduct could not be detected at all,
fluorene derivative 3aa was obtained in moderate yield, where
styrene was incorporated as a C1 unit to construct a
cyclopentadiene ring.12
Received: March 4, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00619
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Organic Letters
Letter
Scheme 2. Reaction of Biphenylene (1a) with Styrene (2a)
Table 2. Formal [4 + 1] Cycloaddition of Biphenylene (1a)
with Various Alkenes 2
a
To improve the yield of the formal [4 + 1] cycloadduct 3aa,
we screened several reaction conditions (Table 1). When
a
Table 1. Screening of Reaction Conditions
a
entry
ligand
solvent
xylene
yield (%)
1
2
3
4
5
BINAP
DPPF
83
xylene
NR
NR
44
b
PPh3
xylene
BINAP
BINAP
BINAP
BINAP
1,4-dioxane
PhCl
5
c
6
d
xylene
ND
71
7
xylene
a
Conditions: 1a (0.10 mmol), 2a (0.40 mmol), [Ir(cod)Cl]2 (0.010
b
mmol), ligand (0.020 mmol). Triphenylphosphine (40 mol %) was
used. [Rh(cod)Cl]2 was used in place of [Ir(cod)Cl]2. Conditions:
c
d
[Ir(cod)Cl]2 (2.5 mol %), BINAP (5.0 mol %), 4 days.
racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP)
was used as a ligand, most of the biphenylene (1a) was
consumed and a higher yield was achieved (entry 1). In
contrast, no reaction proceeded when using other ligands such
as 1,1′- bis(diphenylphosphino)ferrocene (DPPF) and
triphenylphosphine (entries 2 and 3). The solvent effect was
very large, and xylene was the best among three solvents
(entries 1, 4, and 5). In the present reaction, the Rh counterpart
was ineffective (entry 6). The amount of the catalyst could be
reduced to 5 mol %, but a longer reaction time was required
(entry 7).
a
Condition: 1a (0.10 mmol), 2 (0.40 mmol), [Ir(cod)Cl]2 (0.010
b
mmol), BINAP (0.020 mmol). Byproduct 4ah was obtained in 27%
yield.
Under the optimum conditions indicated in entry 1 of Table
1, various alkenes were subjected to the formal [4 + 1]
cycloaddition (Table 2). We first examined styrene derivatives
2b−f possessing various substituents at the para position
(entries 1 and 2). Although 4-chlorostyrene (2b) gave the
corresponding product 3ab in moderate yield because of low
conversion of 1a, 4-fluorostyrene (2c) gave 3ac in high yield. In
addition to phenyl and methyl groups, a methoxy group was
also tolerated, and the corresponding products 3ad−3af were
obtained in moderate to high yields. 3-Methoxystyrene (2g)
was also a good coupling partner, but 2-methoxystyrene (2h)
was not, and the yield of cycloadduct 3ah was low along with
the formation of uncyclized product 4ah having an exo olefin
moiety, which is possibly derived from a reaction intermediate
as we discuss later (entry 2). Vinylsilanes 2i and 2j and
allylsilane 2k also reacted with biphenylene (1a) to give 9-
silylated and 9-silylmethylated fluorenes 3ai−3ak (entries 3 and
4). Finally, 1-nonene (2l) as a simple alkene was examined, and
9,9-dialkylated fluorene 3al was obtained in 63% yield (entry
5).13
Next, we examined the scope of biphenylene derivatives 1b−
1f using styrene (2a) as a standard alkene (Table 3). The
formal [4 + 1] cycloaddition of 1-phenylbiphenylene (1b)
proceeded to give 3ba quantitatively (entry 1). Methyl and
trimethylsilyl substituents were tolerable, and 4-substituted
fluorenes 3ca and 3da were obtained (entries 2 and 3). The
reaction of benzo[a]biphenylene (1e) with styrene also
proceeded smoothly to afford 7,7-disubstituted benzo[c]-
fluorene 3ea14 in 68% yield (entry 4). Notably, the sterically
less hindered single bond of biphenylenes was selectively
cleaved, and regioisomeric fluorenes could not be detected in
all entries. The reaction of benzo[b]biphenylene (1f)
proceeded to give 3fa, but in low yield probably because of
instability of 1f under the reaction conditions (entry 5).
B
DOI: 10.1021/acs.orglett.6b00619
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Organic Letters
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Table 3. Formal [4 + 1] Cycloaddition of Biphenylene
Derivatives 1 with Styrene (2a)
Scheme 3. Proposed Mechanism
a
Scheme 4. Mechanism Studies
a
Condition: 1 (0.10 mmol), 2a (0.40 mmol), [Ir(cod)Cl]2 (0.010
b
mmol), BINAP (0.020 mmol). The reaction time was 4 h.
We propose the reaction mechanism of this formal [4 + 1]
cycloaddition in Scheme 3. The reaction is initiated by oxidative
addition of the Ir(I) catalyst to the C−C single bond of
biphenylene (1a) to give iridacyclopentadiene II. The insertion
of alkene 2 leads to seven-membered metallacycle III. Next, β-
hydrogen elimination proceeds prior to reductive elimination,
which affords a [4 + 2] cycloadduct, and iridium hydride
species IV is formed. Intramolecular alkene insertion along with
the formation of a five-membered ring and subsequent
reductive elimination afford 9,9-disubstituted fluorene 3 and
regenerates the Ir catalyst. The existence of intermediate IV was
supported by the formation of byproduct 4ah in entry 2 of
Table 2.
To reinforce our speculation, we investigated the reaction of
1,8-dimethylbiphenylene (1g) with styrene (2a), where two
methyl groups can facilitate the reductive elimination from
intermediate IV due to their bulkiness (eq 1 in Scheme 4). As a
result, a significant amount of exo olefin compound 4ga was
obtained as we expected, in addition to [4 + 1] cycloadduct
3ga.15 When the reaction was conducted in the presence of
excess amounts of deuterated water, deuteration of the methyl
proton was observed (eq 2). When styrene-d8 was used, almost
perfect transfer of the vinylic protons to the methyl group in
the product was observed (eq 3).
As a preliminary application of this protocol, we examined an
enantioselective reaction of benzo[a]biphenylene (1e) with
styrene (2a) (Scheme 5). Among several chiral ligands,16 xyl-
BINAP could induce moderate enantioselectivity, and benzo-
Scheme 5. Enantioselective Reaction
C
DOI: 10.1021/acs.orglett.6b00619
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Letter
(b) Korotvick
M. Synthesis 2016, 48, 987.
̌
a, A.; Frejka, D.; Hampejsova,
́
Z.; Císaro
̌
va,
́
I.; Kotora,
[c]fluorene 3ea with an all-carbon quaternary stereogenic
center was obtained in high yield.
(8) Shibata, T.; Nishizawa, G.; Endo, K. Synlett 2008, 2008, 765.
(9) For iron carbonyl complex mediated formal [4 + 1] cycloaddition
of biphenylene with carbon monoxide, see: Berris, B. C.;
Hovakeemian, G. H.; Lai, Y.-H.; Mestdagh, H.; Vollhardt, K. P. C. J.
Am. Chem. Soc. 1985, 107, 5670.
(10) For a catalytic formal [4 + 1] cycloaddition of biphenylene with
bis(trimethylsilyl)ethyne as a C1 unit via a 1,2-silyl shift, see: Iverson,
C. N.; Jones, W. D. Organometallics 2001, 20, 5745.
In summary, we developed an Ir-catalyzed formal [4 + 1]
cycloaddition initiated by C−C bond cleavage of biphenylenes.
Various alkenes could be used as a C1 unit, and 9,9-
disubstituted fluorenes were obtained.17 This unprecedented
transformation probably includes β-hydrogen elimination
between intermolecular and intramolecular alkene insertion.
Synthetic applications including asymmetric synthesis are to be
studied in due course in our laboratory.
(11) For recent examples of catalytic [4 + 1] cycloaddition, see:
(a) Inami, T.; Sako, S.; Kurahashi, T.; Matsubara, S. Org. Lett. 2011,
13, 3837. (b) Chen, J.-R.; Dong, W.-R.; Candy, M.; Pan, F.-F.; Jorres,
̈
ASSOCIATED CONTENT
■
M.; Bolm, C. J. Am. Chem. Soc. 2012, 134, 6924. (c) Wang, Y.;
Muratore, M. E.; Rong, Z.; Echavarren, A. M. Angew. Chem., Int. Ed.
2014, 53, 14022. (d) Kumar, M.; Bagchi, S.; Sharma, A. RSC Adv.
2015, 5, 53592. (e) Takamatsu, K.; Hirano, K.; Miura, M. Org. Lett.
2015, 17, 4066. (f) Shi, T.; Guo, X.; Teng, S.; Hu, W. Chem. Commun.
2015, 51, 15204.
(12) The β-carbon of an acrylate α,β-double bond was used as a C1
unit; see: Ozawa, T.; Horie, H.; Kurahashi, T.; Matsubara, S. Chem.
Commun. 2010, 46, 8055.
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00619.
Experimental procedure, characterization, and NMR
copies of all new compounds (PDF)
(13) The reaction of 1a with disubstituted alkenes, such as cis-
stilbene and norbornene, did not give [4 + 1] cycloadducts.
(14) The structure of 3ea was determined by NOESY analyses (see
Supporting Information).
(15) The obtained 4ga was subjected to the reaction, but the
formation of 3ga could not be detected.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tshibata@waseda.jp.
Notes
(16) Table S1 in Supporting Information.
The authors declare no competing financial interest.
(17) (a) Debroy, P.; Shukla, R.; Lindeman, S. V.; Rathore, R. J. Org.
Chem. 2007, 72, 1765. (b) Gilot, J.; Abbel, R.; Lakhwani, G.; Meijer, E.
W.; Schenning, A. P. H. J.; Meskers, S. C. J. Adv. Mater. 2010, 22,
E131. (c) Lakhwani, G.; Meskers, S. C. J. J. Phys. Chem. Lett. 2011, 2,
1497.
ACKNOWLEDGMENTS
■
This work was supported by ACT-C from JST (Japan).
REFERENCES
■
(1) For selected reviews, see: (a) Rybtchinski, B.; Milstein, D. Angew.
Chem., Int. Ed. 1999, 38, 870. (b) Activation of Unreactive Bonds and
Organic Synthesis. In Topics in Organometallic Chemistry; Murai, S.,
Ed.; Springer: Berlin, 1999. (c) Small Ring Compounds in Organic
Synthesis VI. In Topics in Current Chemistry; de Meijere, A., Ed.;
Springer: Berlin, 1999. (d) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610.
(e) Murakami, M.; Matsuda, T. Chem. Commun. 2011, 47, 1100.
(f) C−C Bond Activation. In Topics in Current Chemistry; Dong, G.,
Ed.; Springer: Berlin, 2014. (g) Souillart, L.; Cramer, N. Chem. Rev.
2015, 115, 9410. (h) Li, H.; Shi, Z. J. In Catalysis in C−C Activation in
Homogeneous Catalysis for Unreactive Bond Activation; Shi, Z.-J., Ed.;
John Wiley & Sons, Inc.: New York, 2014; p 575.
(2) For recent examples, see: (a) Ding, L.; Ishida, N.; Murakami, M.;
Morokuma, K. J. Am. Chem. Soc. 2014, 136, 169. (b) Souillart, L.;
Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 9640. (c) Breunig, J. M.;
Gupta, P.; Das, A.; Tussupbayev, S.; Diefenbach, M.; Bolte, M.;
Wagner, M.; Holthausen, M. C.; Lerner, H.-W. Chem. - Asian J. 2014,
9, 3163. (d) Shaw, M. H.; McCreanor, N. G.; Whittingham, W. G.;
Bower, J. F. J. Am. Chem. Soc. 2015, 137, 463. (e) Masarwa, A.; Weber,
M.; Sarpong, R. J. Am. Chem. Soc. 2015, 137, 6327. (f) Yu, J.; Yan, H.;
Zhu, C. Angew. Chem., Int. Ed. 2016, 55, 1143.
(3) (a) Schwager, H.; Spyroudis, S.; Vollhardt, K. P. C. J. Organomet.
Chem. 1990, 382, 191. (b) Edelbach, B. L.; Lachicotte, R. J.; Jones, W.
D. J. Am. Chem. Soc. 1998, 120, 2843.
(4) Synthesis of azatetraphenylene: Masselot, D.; Charmant, J. P. H.;
Gallagher, T. J. Am. Chem. Soc. 2006, 128, 694.
(5) A pioneering example of a Ni-mediated reaction: Eisch, J. J.;
Piotrowski, A. M.; Han, K. I.; Kruger, C.; Tsay, Y. H. Organometallics
1985, 4, 224.
(6) Ni-catalyzed reactions: (a) Edelbach, B. L.; Lachicotte, R. J.;
Jones, W. D. Organometallics 1999, 18, 4040. (b) Schaub, T.; Backes,
M.; Radius, U. Organometallics 2006, 25, 4196.
(7) For Ir- or Rh-catalyzed reactions, see: (a) Korotvick
̌
a, A.;
Císarova, I.; Roithova, J.; Kotora, M. Chem. - Eur. J. 2012, 18, 4200.
̌
́
́
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DOI: 10.1021/acs.orglett.6b00619
Org. Lett. XXXX, XXX, XXX−XXX