Synthesis of bicyclic p-diiodobenzenes via silver-catalyzed Csp-H iodination and ruthenium-catalyzed cycloaddition

Article abstract of DOI:10.1021/ja061619p

Highly substituted iodobenzenes were efficiently and regioselectively synthesized from readily available 1,6-diynes via two-step process consisting of silver-catalyzed Csp-H iodination and subsequent ruthenium-catalyzed [2 + 2 + 2] cycloaddition of result

Full text of DOI:10.1021/ja061619p

Published on Web 06/21/2006
Synthesis of Bicyclic p-Diiodobenzenes via Silver-Catalyzed
Csp-H Iodination and Ruthenium-Catalyzed Cycloaddition
Yoshihiko Yamamoto,*,† Kozo Hattori, and Hisao Nishiyama
Contribution from the Department of Applied Chemistry Graduate School of Engineering,
Nagoya UniVersity, Chikusa, Nagoya 464-8603, Japan
Received March 8, 2006; E-mail: omyy@apc.titech.ac.jp
Abstract: Highly substituted iodobenzenes were efficiently and regioselectively synthesized from readily
available 1,6-diynes via two-step process consisting of silver-catalyzed Csp-H iodination and subsequent
ruthenium-catalyzed [2 + 2 + 2] cycloaddition of resultant iododiynes. Some of the obtained iodobenzenes
were subjected to palladium-catalyzed C-C bond-forming reactions such as Mizoroki-Heck reaction,
Sonogashira reaction, and Suzuki-Miyaura coupling, giving highly conjugated molecules.
Introduction
Iodobenzenes are highly valuable intermediates in organic
synthesis.1 They are readily transformed into fine chemicals via
catalytic cross-coupling reactions,2 or tritium-labeled biologically
active compounds via catalytic hydrodehalogenation.3 Moreover,
p-diiodobenzenes were recently utilized as monomers for
functional polymers.4 Although chloro- and bromobenzenes have
been conventionally prepared by means of electrophilic aromatic
halogenation,5 the direct iodination of aromatic precursors is
problematic due to the low electrophilicity of molecular iodine.
Thus, aromatic iodination requires a Lewis acid activator or
oxidative and/or acidic reaction conditions, which hamper the
synthesis of iodobenzenes bearing labile functionalities.5,6 In
addition, when a substituted benzene is subjected to electrophilic
halogenation, the newly introduced halogen atom (X) is directed
to the ortho, para, or meta positions, depending on the nature
of the substituent (R) of the precursor (Figure 1A). Accordingly,
this substrate-directed regioselectivity makes the synthesis of
unsymmetrical halobenzenes difficult, often leading to a mixture
of some regioisomeric products.
Figure 1. (A) Conventional electrophilic aromatic halogenation (X )
halogen atom) and (B) novel two-step access to fused iodobenzenes 4 from
1,6-diynes 2, involving (step 1) silver-catalyzed iodination of 2 leading to
iododiynes 3, and (step 2) ruthenium-catalyzed cycloaddition of 3 with
acetylene, resulting in the formation of iodobenzenes 4.
To address these issues, we developed a novel, two-step
strategy to assemble p-diiodobenzenes as outlined in Figure 1B.
† Current address: Department of Applied Chemistry, Graduate School
of Science and Engineering, Tokyo Institute of Technology, O-okayama,
Meguro-ku, Tokyo 152-8552, Japan.
(1) Merkushev, E. B. Synthesis 1988, 923-937.
(2) Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang, P. J., Eds.;
Wiley: Weinheim, 1998.
(3) Nagasaki, T.; Sakai, K.; Segawa, M.; Katsuyama, Y.; Haga, N.; Koike,
M.; Kawada, K.; Takechi, S. J. Labeled Cpd. Radiopharm. 2001, 44, 993-
1004.
(4) (a) Bao, Z.; Chen, Y.; Cai, R.; Yu, L. Macromolecules 1993, 26, 5281-
5286. (b) Bao, Z.; Chan, W. K.; Yu, L. J. Am. Chem. Soc. 1995, 117,
12426-12435. (c) Schlu¨ter, S.; Frahn, J.; Karakaya, B.; Schlu¨ter, A. D.
Macromol. Chem. Phys. 2000, 201, 139-142.
(5) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry, 5th ed.;
Wiley: New York, 2001, Chapter 11, p 704, and references sited therein.
(6) Recently, mild and efficient aromatic iodination was reported, see:
Johnsson, R.; Meijer, A.; Ellervik, U. Tetrahedron 2005, 61, 11657-11663.
Also see iodonium-triggered cyclization leading to iodoarenes: (a) Gold-
finger, M. B.; Crawford, K. B.; Swager, T. M. J. Am. Chem. Soc. 1997,
119, 4578-4593. (b) Yao, T.; Campo, M. A.; Larock, R. C. J. Org. Chem.
2005, 70, 3511-3517. (c) Zhang, X.; Sarkar, S.; Larrock, R. C. J. Org.
Chem. 2006, 71, 236-243.
First, 1,6-diynes 2 are converted to diiododiynes 3 via the silver-
catalyzed Csp-H halogenation.7 Second, the cycloaddition of 3
with acetylene can be carried out in 1,2-dichloroethane (DCE)
at room temperature with our own protocol using a organoru-
thenium catalyst, Cp*RuCl(cod) (1: Cp* ) η5-pentamethyl-
cyclopentadienyl, cod ) 1,5-cyclooctadiene). The ruthenium-
catalyzed partially intramolecular alkyne cyclotrimerization has
proved to be highly selective and tolerant to a broad range of
functional groups.8 Overall, this two-step procedure allows us
to achieve catalytic assembly of bicyclic p-diiodobenzenes 4
with the exact control of the substitution pattern. Thus,
(7) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew. Chem. Int.
Ed. Engl. 1984, 23, 727-729.
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Synthesis of Bicyclic p-Diiodobenzenes
A R T I C L E S
Scheme 1
environmentally benign process with high atom- and step-
economy is realized as a result of the dramatic reduce of
chemical wastes such as stoichiometric amounts of an activator
for molecular iodine and undesired regioisomeric side products.9
To the best of our knowledge, transition-metal-catalyzed [2 +
2 + 2] cyclocotrimerization of iodoalkynes has not been
explored,10,11 whereas thermal and stoichiometric-metal-medi-
ated cyclotrimerization of chloroalkynes were reported previ-
ously.12,13d This is partly because low-valent transition metals
are capable of undergoing oxidative addition toward the Csp-I
bond in iodoalkynes, resulting in the formation of a transition
metal acetylide,13 which might be an intermediate for recently
reported catalytic homo-coupling of iodoalkynes.14 Although
the mild and regioselective methods to synthesize iodoarenes
have recently been reported,6,11d,f-g the Csp-H iodination/
cyclotrimerization strategy would provide a powerful route to
the bicyclic p-diiodobenzene framework, which is otherwise
difficult to be accessed.
perature for 30 min to give diiodobenzene 4a-I in 83% yield.
In a similar manner, the corresponding bromide 3a-Br, which
was obtained from 2a and N-bromosuccinimide (NBS) in high
yield, underwent the ruthenium-catalyzed cycloaddition with
acetylene to afford p-dibromobenzene 4a-Br in 77% yield.
Having confirmed the feasibility of our two-step protocol,
its generality was then explored as summarized in Table 1. Our
method well tolerated malononitrile, an ether or a sulfonamide
tether in diynes 2b-d, resulting in the formation of diiodides
4b-d over 60% overall yields (entries 1-3). It is noteworthy
that even simpler phthalan derivative 4c was unknown com-
pound, probably because conventional electrophilic aromatic
iodination conditions is incompatible to the acid-labile isoben-
zofuran structure. Protecting groups such as an acid labile ketal
in 2e and a benzyl ether in 2f were also compatible to the present
method (entries 4 and 5). When multiple benzene rings are
present in a single molecule, electrophilic iodination would result
in a mixture of several products. In our hand, spirocyclic
compound 4g bearing a fluorene moiety was successfully
obtained from diyne 2g in ca. 70% overall yield (entry 6). In a
similar manner, diynes 2h-j bearing a single terminal alkyne
moiety were transformed into unsymmetrical iodobenzenes
4h-j (entries 7-9). The most impressive is the synthesis of
p-iodobenzoate derivative 4j, because a meta-halogenated
product is expected for electrophilic halogenation of a benzene
derivative possessing an electron-withdrawing group such as
an ester. In striking contrast to these diynes, acetylacetone
derivative 2k and electron-deficient diyne 2l failed to undergo
Ag-catalyzed Csp-H iodination, resulting in the formation of
intractable materials.
Results and Discussion
Scope and Limitations of Sequential Ag-Catalyzed Csp-H
Iodination/Ru-Catalyzed Cycloaddition. Upon treatment with
N-iodosuccinimide (NIS) in the presence of 10 mol % AgNO3
in N,N-dimethylformamide (DMF) at room temperature, dipro-
pargylmalonate 2a was converted to diiododiyne 3a-I in 92%
yield (Scheme 1).15 Subsequently, 3a-I was treated with the
ruthenium catalyst under acetylene atmosphere at room tem-
(8) (a) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc.
2003, 125, 12143-12160. (b) Yamamoto, Y.; Kinpara, K.; Saigoku, T.;
Nishiyama, H.; Itoh, K. Org. Biomol. Chem. 2004, 2, 1287-1294. (c)
Yamamoto, Y.; Saigoku, T.; Nishiyama, H.; Itoh, K. Org. Biomol. Chem.
2005, 3, 1768-1775. (d) Yamamoto, Y.; Ishii, J.; Nishiyama, H.; Itoh, K.
J. Am. Chem. Soc. 2005, 127, 9625-9631. (e) Yamamoto, Y.; Ishii, J.;
Nishiyama, H.; Itoh, K. Tetrahedron 2005, 61, 11501-11510.
(9) For atom-economy: (a) Trost, B. M. Science 1991, 254, 1471-1476. (b)
Trost, B. M. Angew. Chem. Int. Ed. 1995, 34, 259-281. For step-
economy: (c) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theory
and Applications; Hudlicky, T., Ed.; JAI: Greemwich, 1993; Vol. 2, p
27-66. (d) Wender, P. A.; Handy, S.; Wright, D. L. Chem. Ind. (London)
1997, 765-769.
(10) (a) Shore, N. E.; In ComprehensiVe Organic Synthesis, Trost, B. M.;
Fleming, I.; Paquette, L. A., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp
1129-1162. (b) Grotjahn, D. B. In ComprehensiVe Organometallic
Chemistry II; Hegedus, L. S., Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon: Oxford, 1995; Vol. 12, pp 741-770. (c) Saito, S.;
Yamamoto, Y. Chem. ReV. 2000, 100, 2901-2915. (d) Yamamoto, Y. Curr.
Org. Chem. 2005, 9, 503-519. (e) Kotha, S.; Brahmachary, E.; Lahiri, K.
Eur. J. Org. Chem. 2005, 4741-4767.
(11) Several examples of transition-metal-catalyzed or -mediated Pauson-Khand
reaction, [2 + 2] and [4 + 2] cycloadditions, and cycloisomerizations of
haloalkynes have recently been reported, see: (a) Balsells, J.; Moyano,
A.; Riera, A.; Perica`s, M. A. Org. Lett. 1999, 1, 1981-1984. (b) Villeneuve,
K.; Riddell, N.; Jordan, R. W.; Tsui, G. C.; Tam, W. Org. Lett. 2004, 6,
4543-4546. (c) Yoo, W.-J.; Allen, A.; Villeneuve, K.; Tam, W. Org. Lett.
2005, 7, 5853-5856. (d) Miura, T.; Iwasawa, N. J. Am. Chem. Soc. 2002,
124, 518-519. (e) Fu¨rstner, A.; Mamane, V. Chem. Commun. 2003, 2112-
2113. (f) Odedra, A.; Wu, C.-J.; Pratap, T. B.; Huang, C.-W.; Ran, Y.-F.;
Liu, R.-S. J. Am. Chem. Soc. 2005, 127, 3406-3412. (g) Lin, M.-Y.;
Maddirala, S. J.; Liu, R.-S. Org. Lett. 2005, 7, 1745-1748. (h) Lo, C.-Y.;
Kumar, M. P.; Chang, H.-K.; Lush, S.-F.; Liu, R.-S. J. Org. Chem. 2005,
70, 10482-10487.
The present protocol can be carried out with an increased
scale (Table 1, entry 2). Actually, Ag-catalyzed iodination of 5
mmol of 2c gave 4 mmol of 3c, which was then treated with 5
mol % 1 under acetylene atmosphere for 30 min to deliver 1.4
g of 4c (76% overall yield). The second cycloaddition step can
also be conducted with a higher concentration, reducing an
amount of solvent waste. Upon treatment of 4 mmol of 3c with
1 and acetylene in 10 mL of DCE (0.4 M), 1.3 g of 4c was
obtained (87%), although the completion of the reaction requires
1 h.
(12) (a) Tanaka, R.; Zheng, S.-Q.; Kawaguchi, K.; Tanaka, T. J. Chem. Soc,
Perkin Trans. 1980, 2, 1714-1720. (b) Ballester, M.; Castan˜er, J.; Riera,
J.; Tabernero, I. J. Org. Chem. 1986, 51, 1413-1419.
(13) (a) Su¨nkel, K. J. Organomet. Chem. 1988, 348, C12-C14. (b) Klein, H.-
F.: Beck-Hemetsberger, H.; Reitzel, L.; Rodenha¨user, B.; Cordier, G. Chem.
Ber. 1989, 122, 43-51. (c) Su¨nkel, K.; Birk, U.; Robl, C. Organometallics
1994, 13, 1679-1687. (d) Su¨nkel, K.; Birk, U. Polyhedron 1999, 18, 3187-
3197.
(14) Damle, S. V.; Seomoon, D.; Lee, P. H. J. Org. Chem. 2003, 68, 7085-
7087.
(15) The iododiynes obtained in this study can be handled safely at ambient
temperature under air, although iodo-1,3-butadiyne was reported to be
explosive (see: Schlubach, H. H.; Franzen, V. Liebigs Ann. 1951, 573,
115-120.).
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A R T I C L E S
Yamamoto et al.
Table 1. Synthesis of Halodiynes 3 and Halobenzenes 4 from
Diynes 2a
Scheme 3
Scheme 4
substituted diiodide 5c was also obtained in 70% yield from 3c
and diphenylacetylene albeit with an increased catalyst loading
of 15 mol %. To examine the regioselectivity of the cycload-
dition step, unsymmetrical iododiyne 3h was allowed to react
with 1-hexyne to give rise to an inseparable mixture of
regioisomers 5d and 5d′ in 80% combined yield with the 60:
40 ratio (Scheme 3).
We next turned our attention to completely intramolecular
cyclotrimerization of a triyne. Applying the silver-catalyzed
Csp-H iodination to symmetrical triyne 6 gave 7 in 81% yield,
which was then treated with 15 mol % 1 in DCE at room
temperature for 24 h to afford desired tricyclic o-diiodobenzene
8 in 60% yield (Scheme 4).
Application of p-Diiodobenzene to Dual Cross-Coupling
Reactions. To demonstrate the utility of p-diiodobenzene
products obtained from this study, we further carried out some
cross-coupling reactions of representative product 4e as sum-
marized in Scheme 5. Diiodobenzene 4e was subjected to
Mizoroki-Heck reaction with styrene using the Pd2(dba)3/S-
Phos (S-Phos: 2-dicyclohexylphosphino-2′,6′-dimethoxybiphen-
yl)16 catalyst system in DMF/Et3N at 85 °C for 24 h to afford
9 in 67% yield. Sonogashira reaction of 4e with ethynylbenzene
was conducted under standard conditions to obtain 10 in
excellent yield. Moreover, 4e also underwent Suzuki-Miyaura
coupling with phenylboronic acid under unhydrous conditions
with the Pd2(dba)3/S-Phos catalyst system, resulting in the high
yield formation of 11.
a Diynes 2 (2 mmol) were treated with 10 mol % AgNO3 and NIS (3
equiv) in DMF (12 mL) at room temperature for 3 h. Iododiynes 3 (0.3
mmol) were treated with 5 mol % (15 mol % for entry 8) 1 in DCE (3.5
mL) under acetylene atmosphere at room temperature for 30 min (1 h for
entry 8). b Yields from 5 mmol of diynes 2c. c Yield from 4 mmol of 3c.
d A small amount of 2j was remained intact.
Scheme 2
As above, Ag-catalyzed Csp-H iodination/Ru-catalyzed cy-
cloaddition/Pd-catalyzed cross-coupling sequences effectively
assembled conjugated molecules from readily available starting
materials. In particular, the combination with Suzuki-Miyaura
coupling provides a powerful access to functionalized oligo-p-
phenylenes, which would find wide applications to molecular
The monoalkyne component is not limited to acetylene.
Diiododiyne 3c was allowed to react with 1-hexyne or phenyl-
acetylene (1.5 equiv) in the presence of 5 mol % 1 at ambient
temperature for 4-5 h to afford pentasubstituted benzenes 5a
and 5b in 83% and 80% yields, respectively (Scheme 2). Fully
(16) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2004, 43, 1871-1876.
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Synthesis of Bicyclic p-Diiodobenzenes
A R T I C L E S
Scheme 5
Scheme 6
electronics.17 In this context, we finally attempted the modular
synthesis of penta- and hexa-p-phenylenes from diiodobenzenes
and biarylboronic acid ester 12,18 all of which were prepared
by using the Cp*RuCl-catalyzed cycloaddition technology.19 At
the outset, diiodobenzene 4e was subjected to the coupling with
boronate 12 under the above anhydrous conditions (2.5 mol %
Pd2(dba)3, 11 mol % S-Phos, 4 equiv K3PO4, toluene, 110 °C,
24 h). The desired pentaphenylene was, however, obtained only
in a trace amount, and 40% of 4e was recovered intact. This
was probably because cyclic esters of arylboronic acids are less
reactive than the parent acids. Thus, 4e was allowed to react
with 12 in toluene/H2O under otherwise identical conditions
(Scheme 6). As a result, 4e was completely consumed for 15 h
and penta-p-phenylene 13 was obtained in 50% isolated yield.
Toward the synthesis of the hexa-p-phenylene, we next
designed diiodobiaryl 16 as a diiodide module (Scheme 7). The
Ag-catalyzed Csp-H iodination of malonate-derived tetrayne 14
delivered cycloaddition precursor 15 in high yield, which was
subsequently treated with 15 mol % 1 under acetylene atmo-
sphere at room temperature to give desired 16 in 87% yield.
Thus, prepared 16 was finally allowed to react with boronate
module 12 under the optimized conditions to afford hexa-p-
phenylene albeit in a moderate yield (36%) along with recovered
16 (13%).
(17) (a) Martin, R. E.; Diedrich, F. Angew. Chem. Int. Ed. 1999, 38, 1350-
1377. (b) Segura, J. L.; Mart´ın, N. J. Mater. Chem. 2000, 10, 2403-2435.
(18) Yamamoto, Y.; Hattori, K.; Ishii, J.; Nishiyama, H. Tetrahedron 2006, 62,
4294-4305.
(19) For examples of cyclotrimerization of polyynes, leading to oligo-p-
phenylenes, see: McDonald, F. E.; Smolentsev, V. Org. Lett. 2002, 4, 745-
748.
Summary
In conclusion, we successfully developed a novel regio-
defined route to bicyclic iodobenzenes from readily available
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A R T I C L E S
Scheme 7
Yamamoto et al.
diynes via the Ag-catalyzed Csp-H iodination/Cp*RuCl-
catalyzed cycloaddition sequence. One of the obtained p-
diiodobenzenes was utilized as a halide component for cross-
coupling reactions such as Mizoroki-Heck reaction, Sonogashira
reaction, and Suzuki-Miyaura coupling. Moreover, we achieved
the modular synthesis of penta- and hexa-p-phenylenes by
Suzuki-Miyaura coupling of a diiodobenzene or diiodobiaryl
with a biarylboronic acid ester.
Acknowledgment. This research was partially supported by
the Ministry of Education, Science, Sports and Culture, Japan,
Grant-in-Aid for Young Scientists (A), 17685008.
Supporting Information Available: Experimental procedures
and analytical data for products. These materials are available
free of charge via Internet at http://pubs.acs.org.
JA061619P
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