Synthesis of polysubstituted naphthalenes by iron-catalyzed [2+2+2] annulation of grignard reagents with alkynes

Article abstract of DOI:10.1055/s-0032-1317077

Iron catalyzes the oxidative [2+2+2] annulation of an arylmagnesium compound with two molecules of an internal alkyne via C-H bond activation at 0 °C to produce polysubstituted naphthalene. Georg Thieme Verlag Stuttgart.New York.

Full text of DOI:10.1055/s-0032-1317077

LETTER
▌2381
lSetyternthesis of Polysubstituted Naphthalenes by Iron-Catalyzed [2+2+2] Annu-
lation of Grignard Reagents with Alkynes
Iron-Catalyzed [2+2+2] Annulation
Laurean Ilies, Arimasa Matsumoto, Motoaki Kobayashi, Naohiko Yoshikai,1 Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58006889; E-mail: nakamura@chem.s.u-tokyo.ac.jp
Received: 26.06.2012; Accepted after revision: 20.07.2012
1.2 mmol) as an oxidant in THF at 0 °C for one hour gave
Abstract: Iron catalyzes the oxidative [2+2+2] annulation of an
1,2,3,4-tetraphenylnaphthalene (3a) in 73% isolated
arylmagnesium compound with two molecules of an internal alkyne
yield, together with a small amount of carbometalated
via C–H bond activation at 0 °C to produce polysubstituted naph-
product 4. Note that one equivalent of PhMgBr was con-
sumed as a base that takes up the ortho-hydrogen atom, a
fraction was used for reduction of the iron salt to an active
iron species, and a fraction was used in a competing iron-
catalyzed oxidative homocoupling14 to produce a small
amount of biphenyl.
thalene.
Key words: alkynes, annulation, C–H bond activation, iron, naph-
thalene
Polycyclic aromatic compounds have received much
attention in materials science,2 resulting in considerable
interest in the development of new synthetic routes.3 An
attractive strategy to synthesize these compounds is the
annulation of simple starting materials4 to construct mo-
lecular complexity in an expeditious manner. For exam-
ple, the [2+2+2] annulation of a benzene fragment with
two molecules of alkyne5 represents a concise approach to
polysubstituted naphthalenes6 (cf. Scheme 1, conversion
of 1 and 2a to 3a); however, it typically relies on expen-
sive and toxic metal catalysts, such as Pd, Rh, or Ir, and
harsh reaction conditions. In concomitant work,7 one of us
has demonstrated that an arylindium reagent can be annu-
lated with two molecules of an internal alkyne using an
iron catalyst8 at 60 °C. We report here that iron catalyzes
the annulation of organomagnesium reagents with inter-
nal alkynes via C–H bond activation at 0 °C in the pres-
ence of an organic dihalide as a mild oxidant (Scheme 1).
The choice of ligand was crucial for this reaction (Table
1). In the absence of a ligand (Table 1, entry 2), only a
trace of the desired product 3a was obtained, together with
about 20% of carbometalated product 4. Diphosphine (Ta-
ble 1, entry 5) and carbene (Table 1, entry 6) ligands gave
the same result as when the reaction was performed in the
absence of any ligand (Table 1, entry 2), suggesting inef-
fective coordination of the active iron species. This obser-
vation stands in contrast to previous work using
arylindium reagents,7 where diphosphine ligands were the
most effective and 1,10-phenanthroline gave only a trace
amount of the desired product. A tridentate ligand (Table
Table 1 Investigation of the Reaction Conditions for the Annulation
of PhMgBr (1) with Diphenylacetylene (2a)a
Entry Conditions
Yield of 3a Yield of 4 Yield of 2a
(%)b
(%)b
(%)b
We previously reported that iron catalyzes the [4+2]
benzannulation between a biphenylmagnesium bromide
and an alkyne, probably via formation of a biphenyl ferra-
cycle.9 We conjectured that a similar ferracycle (B in
Scheme 1) might be formed via iron-catalyzed carbometa-
lation of an alkyne with an arylmagnesium reagent,10 fol-
lowed by base-assisted C–H bond activation.11 The
intermediate B could then undergo insertion of another al-
kyne,9 followed by oxidatively induced reductive
elimination12 to produce a polysubstituted naphthalene
(Scheme 1).13 After extensive experimentation (see the
Supporting Information for optimization studies), we
found that the reaction of phenylmagnesium bromide (1,
1.18 M in THF, 1.0 mL, 1.2 mmol) with diphenylacety-
lene (2a, 72 mg, 0.40 mmol) in the presence of Fe(acac)3
(0.04 mmol) as a catalyst, 1,10-phenanthroline (phen,
0.04 mmol) as a ligand, and 1,2-dichloroisobutane (DCIB,
1
standarda
68
1
10
21
19
3
6
63
55
43
61
60
72
38
2c
3c
4c
5c
6c
7
without ligand
Bipyd as ligand
terpyridinee as ligand
Dppff as ligand
IPr·HClg as ligand
without DCIB
12
0
2
24
21
9
1
2
8
Fe(acac)3 (5 mol%)
39
11
a Standard reaction conditions: diphenylacetylene (2a, 0.40 mmol),
PhMgBr (1, 1.2 mmol) in THF, Fe(acac)3 (0.04 mmol), 1,10-phenan-
throline (0.04 mmol), and 1,2-dichloroisobutane (1.2 mmol) in THF
at 0 °C for 1–3 h.
b Determined by GC in the presence of n-tridecane as an internal stan-
dard.
c Conditions: 2 equiv of 1,2-dichloroisobutane was used.
d Bipy = 2,2′-bipyridine.
SYNLETT 2012, 23, 2381–2384
Advanced online publication: 03.09.2012
e Terpyridine = 2,6-bis(2-pyridyl)pyridine.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
f Dppf = 1,1′-bis(diphenylphosphino)ferrocene.
g IPr·HCl = 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride.
DOI: 10.1055/s-0032-1317077; Art ID: ST-2012-U0548-L
© Georg Thieme Verlag Stuttgart · New York

2382
L. Ilies et al.
LETTER
Fe(acac)3 (10 mol%)
phen (10 mol%)
DCIB (3 equiv)
Ph
Ph
H
Ph
Ph
Ph
Ph
+
Ph
Ph
+
THF, 0 °C, 1 h
73%
MgBr
Ph
1 (3 equiv)
2a
3a
4 ca. 10%
+ [Fe]Cl2
Fe(III)
Cl
Cl
[Fe]
Ph
Ph
PhMgBr
H
Ph
Ph
[Fe]
[Fe]
Ph
Ph
Ph
PhH
Ph
Ph
Ph
A
B
C
Scheme 1
Table 2 Iron-Catalyzed Annulation of Arylmagnesium Compounds with Internal Alkynesa
Entry
1
Alkyne
ArMgBr
Product
Yield (%)b
4-XC6H4MgBr
3a
3b
73 X = H
X
X
X
X
X
2
47 X = Cl
X
X
3
4
3c
5
60 X = OMe
24 (38)c
n-Pr
n-Pr
n-Pr
n-Pr
PhMgBr
n-Pr
n-Pr
p-Anis
p-Anis
p-Anis
p-Anis
p-Anis
6
65 (56:44)e
p-Anis
p-Anisd
+
5
PhMgBr
6′
MeO
p-Anis
p-Anis
Ph
a Reaction conditions: alkyne (0.30–0.40 mmol), Grignard reagent (3 equiv), Fe(acac)3 (10 mol%), 1,10-phenanthroline (10 mol%), and 1,2-
dichloroisobutane (3 equiv) in THF at 0 °C for 1 h. See Supporting Information for details.
b Isolated yield.
c Determined by GC in the presence of n-tridecane as an internal standard.
d p-Anis = 4-methoxyphenyl.
e Determined by 1H NMR spectroscopy.
Synlett 2012, 23, 2381–2384
© Georg Thieme Verlag Stuttgart · New York

LETTER
Iron-Catalyzed [2+2+2] Annulation
2383
p-Anis
Ph
Ph
Fe(acac)3 (10 mol%)
phen (10 mol%)
DCIB (3 equiv)
Ph
4-MeOC6H4MgBr
+
MeO
Ph
Ph
+
Ph
solvent, 0 °C, 2 h
Ph
Ph
Ph
7'
7
2a
42% (46:54)
12% (84:16)
solvent = THF
Et2O–PhH (9:1)
Scheme 2
1, entry 4) suppressed not only the desired reaction but ly, by chromatography, recrystallization, or sublimation.
also the initial carbometalation step, suggesting inactiva- We speculate that the reason for this poor regioselectivity
tion of the active species through strong coordination. In is the iron-catalyzed isomerization of alkene intermedi-
the absence of the oxidant (Table 1, entry 7), a stoichio- ates such as A in Scheme 1. We observed similar isomer-
metric amount of carbometalated product 4 was obtained, ization during an iron-catalyzed C–H activation
together with a trace amount of naphthalene 3a. Attempts reaction,11c when THF was found to accelerate the isom-
to decrease the catalyst loading (Table 1, entry 8) resulted erization reaction, whereas aromatic solvents retarded it.
in a sharp decrease in yield.
The selectivity of the present annulation reaction was also
found to depend on the solvent, and changing THF to a
mixture of diethyl ether and benzene resulted in an im-
proved regioselectivity, at the expense of lower conver-
sion (Scheme 2).
The electron density of the substrates did not significantly
affect the reaction (Table 2, entries 1–3). A chloride group
was tolerated well (Table 2, entry 2), and the five chlorine
atoms on 3b can serve as a platform for further function-
alization. A dialkylalkyne (Table 2, entry 4) could also be To evaluate the products for applications to organic elec-
used, albeit in lower yield. This also stands in contrast to tronic materials, we examined the standard physical prop-
the previous work using arylindium reagents,7 where di- erties of 3a–c; they are summarized in Table 3. These
alkylalkynes reacted the best and diarylalkynes gave low compounds show absorption maxima in the ultraviolet re-
yields. A limitation of the present reaction is the lack of gion, and increased electron density results in a red shift
regioselectivity, which surfaces as a problem when the al- of the absorption. The blue fluorescence of these com-
kyne and the Grignard reagent possess different aryl pounds is also red-shifted upon increased electron density,
groups (Table 2, entry 5). This limitation was found to be and the quantum yield of the methoxy-substituted 3c is
a severe obstacle to achieving versatility of this reaction also significantly higher (Table 3, entry 3). The electron-
unless the regioisomeric products can be separated readi- rich compound 3c showed a pseudoreversible electro-
Table 3 Physical Properties of Compounds 3a–c
Entry
1
Compound
λabs max
,
a (nm)
λem,maxa,b(nm)
Φfa,b
Eoxc (V)
3a X = H
296
354
0.06
1.04
X
X
X
X
283 (sh)
302 (sh)
2
3b X = Cl
362
0.06
–
X
0.81e
1.05
3
3c X = OMe
341 (sh)
379d
0.34d
a In CH2Cl2.
b Irradiated at λ = 300 nm. The absolute quantum yield was determined by a calibrated integrating-sphere system.
c Oxidation potential determined by cyclic voltammetry for a CH2Cl2 solution (0.5 mmol/L), using tetrabutylammonium perchlorate (0.1 mol/L)
as an electrolyte. The scan rate was 100 mV/s, three cycles per measurement. Glassy carbon was used as the working electrode, platinum wire
as the counter electrode and Ag+/Ag as a standard electrode. Eox refers to the anode potential for the irreversible reduction wave; its value was
determined by differential pulse voltammetry (DPV) and corrected from a ferrocene standard.
d Irradiated at λ = 330 nm.
e Pseudoreversible.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2381–2384

2384
L. Ilies et al.
LETTER
(5) Selected examples: (a) Herwig, W.; Metlesics, W.; Zeiss, H.
J. Am. Chem. Soc. 1959, 81, 6203. (b) Sakakibara, T.;
Tanaka, Y.; Yamasaki, S.-I. Chem. Lett. 1986, 797. (c) Wu,
G.; Rheingold, A. L.; Geib, S. J.; Heck, R. F.
chemical oxidation wave at 0.81 V, whereas 3a showed an
irreversible wave at 1.04 V, and the electron-deficient
compound 3b was not oxidized within the potential win-
dow of dichloromethane, indicating stabilization of the
radical cation by the electron-donating methoxy groups.
Organometallics 1987, 6, 1941. (d) Pena, D.; Pérez, D.;
Guitián, E.; Castedo, L. J. Am. Chem. Soc. 1999, 121, 5827.
(e) Yasukawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am.
Chem. Soc. 2002, 124, 12680. (f) Kawasaki, S.; Satoh, T.;
Miura, M.; Nomura, M. J. Org. Chem. 2003, 68, 6836.
(g) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72,
5362. (h) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M.
Angew. Chem. Int. Ed. 2008, 47, 4019. (i) Wu, Y.-T.; Huang,
K.-H.; Shin, C.-C.; Wu, T.-C. Chem.–Eur. J. 2008, 14, 6697.
(j) Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2009, 11, 5198. (k) Fukutani, T.; Hirano, K.; Satoh, T.;
Miura, M. J. Org. Chem. 2011, 76, 2867.
In conclusion, we have developed an iron-catalyzed
[2+2+2] annulation reaction of arylmagnesium com-
pounds with internal alkynes under oxidative conditions,
a reaction that proceeds through C–H bond activation at
0 °C to produce polysubstituted naphthalenes. Efforts to
control the regioselectivity of this reaction and to expand
the reaction scope toward creation of organic
semiconductors15 are under way.
(6) de Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L.
Tetrahedron 2003, 59, 7.
Typical Procedure (Scheme 1)
(7) Adak, L.; Yoshikai, N. Tetrahedron 2012, 68, 5167.
(8) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev.
2004, 104, 6217. (b) Enthaler, S.; Junge, K.; Beller, M.
Angew. Chem. Int. Ed. 2008, 47, 3317. (c) Plietker, B. Iron
Catalysis in Organic Chemistry; Wiley-VCH: Weinheim,
2008. (d) Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008,
41, 1500. (e) Czaplik, W. M.; Mayer, M.; Cvengros, J.;
Jacobi von Wangelin, A. ChemSusChem 2009, 2, 396.
(f) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75,
6061. (g) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011,
111, 1293.
Diphenylacetylene (2a, 72 mg, 0.40 mmol), 1,2-dichloroisobutane
(0.14 mL, 1.2 mmol), Fe(acac)3 (15 mg, 0.04 mmol), 1,10-phenan-
throline (8 mg, 0.04 mmol), and THF (2.0 mL) were placed in an
oven-dried Schlenk tube, under argon. A THF solution of PhMgBr
(1.0 mL, 1.18 mol/L, 1.2 mmol) was added to the mixture over
5 min at 0 °C. The reaction mixture immediately turned from red-
brown to purple. After stirring for 1 h, a 1 M aq solution of HCl was
added. After extraction with toluene three times, the combined or-
ganic layers were concentrated under reduced pressure to obtain a
pale-orange solid. The crude material was purified by silica gel col-
umn chromatography (eluent: hexane–toluene = 3:2) to afford
1,2,3,4-tetraphenylnaphthalene (3a) as a white solid (63 mg, 73%).
The spectral data were in agreement with those reported in the liter-
ature.16 1H NMR (500 MHz, CDCl3): δ = 7.66–7.62 (m, 2 H), 7.41–
7.37 (m, 2 H), 7.27–7.17 (m, 10 H), 6.88–6.80 (m, 10 H). 13C NMR
(125 MHz, CDCl3): δ = 140.2, 139.3, 138.6, 138.1, 131.7, 131.0,
127.2, 126.7, 126.3, 126.1, 125.6, 125.0. GC–MS (EI): m/z (%) =
433 (38), 432 (100) [M+], 355 (14), 77 (25).
(9) Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc.
2011, 133, 6557.
(10) (a) Hojo, M.; Murakami, Y.; Aihara, H.; Sakuragi, R.; Baba,
Y.; Hosomi, A. Angew. Chem. Int. Ed. 2001, 40, 621.
(b) Shirakawa, E.; Yamagami, T.; Kimura, T.; Yamaguchi,
S.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 17164.
(c) Zhang, D.; Ready, J. M. J. Am. Chem. Soc. 2006, 128,
15050. (d) Yamagami, T.; Shintani, R.; Shirakawa, E.;
Hayashi, T. Org. Lett. 2007, 9, 1045.
Acknowledgment
(11) (a) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E.
J. Am. Chem. Soc. 2008, 130, 5858. (b) Yoshikai, N.;
Matsumoto, A.; Norinder, J.; Nakamura, E. Angew. Chem.
Int. Ed. 2009, 48, 2925. (c) Ilies, L.; Asako, S.; Nakamura,
E. J. Am. Chem. Soc. 2011, 133, 7672. (d) Ilies, L.;
Kobayashi, M.; Matsumoto, A.; Yoshikai, N.; Nakamura, E.
Adv. Synth. Catal. 2012, 354, 593. (e) Ilies, L.; Konno, E.;
Chen, Q.; Nakamura, E. Asian J. Org. Chem. 2012, 7, in
press; DOI: 10.1002/ajoc.201200042.
We thank MEXT for financial support [KAKENHI Specially Pro-
moted Research No. 22000008 to E. N., and Grant-in-Aid for
Young Scientists (B) No. 23750100 to L.I.]. A.M. thanks the Japan
Society for the Promotion of Science for Young Scientists for a Re-
search Fellowship (No. 21-8684).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
(12) Yoshikai, N.; Asako, S.; Yamakawa, T.; Ilies, L.; Nakamura,
E. Chem.–Asian J. 2011, 6, 3059.
m
iotSrat
ungIifoop
r
t
(13) A mechanism involving two successive carbometalations to
generate a dienyliron species, followed by cyclization
through base-assisted C–H bond activation cannot be
excluded.
(14) (a) Cahiez, G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M.
Org. Lett. 2005, 7, 1943. (b) Nagano, T.; Hayashi, T. Org.
Lett. 2005, 7, 491. (c) Cahiez, G.; Moyeux, A.; Buendia, J.;
Duplais, C. J. Am. Chem. Soc. 2007, 129, 13788.
(15) (a) Tsuji, H.; Mitsui, C.; Ilies, L.; Sato, Y.; Nakamura, E.
J. Am. Chem. Soc. 2007, 129, 11902. (b) Ilies, L.; Tsuji, H.;
Sato, Y.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 4240.
(c) Zhu, X.; Mitsui, C.; Tsuji, H.; Nakamura, E. J. Am.
Chem. Soc. 2009, 131, 13596.
References and Notes
(1) Current address: Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371,
Singapore.
(2) (a) Harvey, R. G. Polycyclic Aromatic Hydrocarbons;
Wiley-VCH: New York, 1997. (b) Grimsdale, C. G.;
Müllen, K. Angew. Chem. Int. Ed. 2005, 44, 5592.
(c) Anthony, J. E. Angew. Chem. Int. Ed. 2008, 47, 452.
(3) Feng, X.; Pisula, W.; Müllen, K. Pure Appl. Chem. 2009, 81,
2203.
(4) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901.
(16) Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2009, 11, 5198.
Synlett 2012, 23, 2381–2384
© Georg Thieme Verlag Stuttgart · New York