Ruthenium-catalyzed cross-coupling of 7-azabenzonorbornadienes with alkynes. An entry to 3a,9b-dihydrobenzo[g]indoles

Article abstract of DOI:10.1021/jo702248r

(Chemical Equation Presented) Electron-rich half-sandwich ruthenium complex CpRuI(PPh₃)₂, generated in situ, catalyzed the coupling reaction of 7-azabenzonorbornadienes with alkynes to form 3a,9b-dihydrobenzo[g] indoles. This transfo

Full text of DOI:10.1021/jo702248r

Ruthenium-Catalyzed Cross-Coupling of 7-Azabenzonorbornadienes
with Alkynes. An Entry to 3a,9b-Dihydrobenzo[g]indoles
Alphonse Tenaglia* and Sylvain Marc
Laboratoire de Synthe`se Asyme´trique, UMR 6180 CNRS, UniVersite´ d’Aix-Marseille P. Ce´zanne,
Faculte´ des Sciences et Techniques de St. Je´roˆme, Case A62, AVenue Escadrille Normandie Niemen,
13397 Marseille Cedex 20, France
alphonse.tenaglia@uniV-cezanne.fr
ReceiVed October 17, 2007
Electron-rich half-sandwich ruthenium complex CpRuI(PPh3)2, generated in situ, catalyzed the coupling
reaction of 7-azabenzonorbornadienes with alkynes to form 3a,9b-dihydrobenzo[g]indoles. This
transformation involves the cleavage of one C-N bond of the bicyclic alkene and formation of two
(C-C and C-N) bonds at the acetylenic carbons. The scope and limitations of the reaction are addressed
according to the substitution patterns of the alkyne and of the substituent at the nitrogen atom of the
azabenzonorbornadiene.
Introduction
although these structures are interesting precursors of indoles
through mild oxidative processes. For instance, the unusual 3a,-
7a-dihydroindole framework (as a substructure of dihydrocar-
bazoles) has been available by stoichiometric transition-metal-
mediated processes such as the intramolecular amination of
tricarbonyl(η4-cyclohexa-1,3-diene)iron complexes5 or the di-
carbonyl(η5-cyclopentadienyl)cobalt-mediated intermolecular [2
+ 2 + 2] cycloaddition of alkynes to the pyrrole 2,3-double
The widespread indole nucleus present in natural products,1
as well as in therapeutic agents,2 still remains one of the most
attractive targets in heterocyclic synthesis. Besides traditional
synthetic routes,3 transition-metal-catalyzed methods4 provided
remarkable improvements regarding efficiency, structural varia-
tions, and functional group compatibility to this important class
of heterocycles. Hydroindoles have received less attention,
(4) For recent references, see: (a) Kusama, H.; Miyashita, Y.; Takaya,
J.; Iwasawa, N. Org. Lett. 2006, 8, 289-292. (b) McLaughlin, M.; Palucki,
M.; Davies, I. W. Org. Lett. 2006, 8, 3307-3310. (c) Ragaini, F.; Rapetti,
A.; Visentin, E.; Monzani, M.; Caselli, A.; Cenini, S. J. Org. Chem. 2006,
71, 3748-3753. (d) Jia, Y.; Zhu, J. J. Org. Chem. 2006, 71, 7826-7834.
(e) Clawson, R. W. J.; Deavers, R. E. I.; Akhmedov, N. G.; So¨derberg, B.
C. G. Tetrahedron 2006, 62, 10829-10834. (f) Shen, Z.; Lu, X. Tetrahedron
2006, 62, 10896-10899. (g) Fayol, A.; Fang, Y.-Q.; Lautens, M. Org. Lett.
2006, 8, 4203-4206. (h) Nagamochi, M.; Fang, Y.-Q.; Lautens, M. Org.
Lett. 2007, 9, 2955-2958. (i) Whitney, S.; Grigg, R.; Derrick, A.; Keep,
A. Org. Lett. 2007, 9, 3299-3302. (j) Barluenga, J.; Jime´nez-Aquino, A.;
Valde´s, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 1529-1532. (k)
Cariou, K.; Ronan, B.; Serge Mignani, S.; Fensterbank, L.; Malacria, M.
Angew. Chem., Int. Ed. 2007, 46, 1881-1884. (l) Trost, B. M.; McClory,
A. Angew. Chem., Int. Ed. 2007, 46, 2074-2077. (m) Ohno, H.; Ohta, Y.;
Oishi, S.; Fuji, N. Angew. Chem., Int. Ed. 2007, 46, 2295-2298. (n) Liu,
F.; Ma, D. J. Org. Chem. 2007, 72, 4844-4850. (o) Chiba, S.; Hattori, G.;
Narasaka, K. Chem. Lett. 2007, 36, 52-53. For reviews on Pd-catalyzed
indole syntheses, see: (p) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106,
4644-4680. (q) Patil, S.; Buolamwini, J. K. Curr. Org. Synth. 2006, 3,
477-498. (r) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873-2920.
(s) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry: A Guide
for the Synthetic Chemist; Pergamon: Oxford, 2000; Chapter 3, pp 73-
181. (t) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113-
1126.
(1) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New
York, 1970. (b) Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4, pp
313-376. (c) Sundberg, R. J. Indoles; Academic Press: London. 1996. (d)
Joule, J. A. In Science of Synthesis: Houben-Weyl Methods of Molecular
Transformations; Thomas, E. J., Ed.; Georg Thieme: Stuttgart, 2000; Vol.
10, pp 361-652. (e) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
1045-1075. (f) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843-
868 and references therein.
(2) (a) Tang, L.; Huger, F. P.; Klein, J. T.; Davis, L.; Martin, L. L.;
Shimshock, S.; Effland, R. C.; Smith, C. P.; Kongsamut, S. Drug DeV.
Res. 1998, 44, 8-13. (b) Wolff, M. C.; Benvenga, M. J.; Calligaro, D. O.;
Fuller, R. W.; Gidda, J. S.; Hemrick-Luecke, S.; Lucot, J. B.; Nelson, D.
L.; Overshiner, C. D.; Leander, J. D. Drug DeV. Res. 1997, 40, 17-34. (c)
Kuethe, J. T.; Wong, A.; Qu, C.; Smitrovich, J.; Davies, I. W.; Hughes, D.
L. J. Org. Chem. 2005, 70, 2555-2567. (d) Van Zandt, M. C.; Jones, M.
L.; Gunn, D. E.; Geraci, L. S.; Jones, J. H.; Sawicki, D. R.; Sredy, J.; Jacot,
J. L.; DiCioccio, A. T.; Petrova, T.; Mitschler, A.; Podjarny, A. D. J. Med.
Chem. 2005, 48, 3141-3152.
(3) (a) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875-
2911. (b) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry;
Stanley Thornes Ltd.: Cheltenham, 1995. (c) Gilchrist, T. L. J. Chem. Soc.,
Perkin Trans. 1 2001, 2491-2515. (d) Eicher, T.; Hauptmann S. The
Chemistry of Heterocycles; Thieme: Stuttgart, 1995; pp 99-110.
10.1021/jo702248r CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/15/2008
J. Org. Chem. 2008, 73, 1397-1402
1397

Tenaglia and Marc
TABLE 1. Ruthenium-Catalyzed Coupling of
SCHEME 1. Ruthenium-Catalyzed Cycloaddition of
Norbornadiene with Alkynes
N-Boc-7-Azabenzonorbornadiene 1a with Symmetrical Alkynes 2a
bond.6 The oxidative demetalation of the resulting complexes
provided free 3a,7a-dihydroindoles or indoles depending on the
reaction conditions. The formation of 3a,9b-dihydrobenzo[g]-
indoles through the thermal, uncatalyzed reaction of 7-azaben-
zonorbornadienes with alkynes was sporadically reported. These
reactions suffered from limitation to electron-deficient alkynes
such as DMAD.7 In this paper, we report the ruthenium-
catalyzed coupling of 7-azabenzonorbornadienes 1 with alkynes
2 to produce the 3a,9b-dihydro[g]indole framework8 using
CpRuI(PPh3)2 as a catalyst generated in situ.9 The scope and
limitations of the reaction are addressed according to the
substitution patterns of the alkyne and the substitution at the
nitrogen atom of the bicyclic alkene 1.10 In addition, the
synthetic utility of the reaction is illustrated with the mild
oxidative conversion of 3a,9b-dihydrobenzo[g]indoles to benzo-
[g]indoles.
Recently, we reported different selectivity issues of the
ruthenium-catalyzed cycloaddition between norbornadiene and
alkynes according to the nature of the ligands associated with
the metal. For instance, electron-rich half-sandwich ruthenium
complexes catalyzed the [2 + 2] cycloaddition to give cy-
clobutenes,9 whereas norbornadiene-coordinated ruthenium com-
plexes led exclusively to the [2 + 2 + 2] cycloaddition pathway
to produce deltacyclenes (Scheme 1).11
adduct(s) (yield)b
temp time
entry
alkyne
(°C)
(h)
3
4
1
2
3
4
5
6
7
8
9
2a R ) Et
2b R ) Ph
60
60
60
50
60
55
60
60
60
50
6
3aa (63%) 4aa (12%)
-
4ab (97%)
2c R ) CO2Me
2d R ) CH2OH
2e R ) CH2OMe
2f R ) CH2OBn
2g R ) CH2OMOM
2h R ) CH2OTBDMS
2i R ) CH2OAc
20
48
24
11
22
22
48
3ac (53%)c
3ad (88%)
3ae (80%)
3af (98%)
3ag (82%)
3ah (98%)
3ai (77%)
-
-
-
-
-
-
-
a Reaction conditions: 1a (0.5 mmol), alkyne (0.5 mmol), CpRuI(PPh3)2
(5 mol %), MeI (0.175 mmol) in dioxane (4 mL). b Isolated yields after
column chromatography. c Adduct 5 (20%) was also formed (see Scheme
2).
cyclobutenes13 or 1,3-cyclohexadienes,14 respectively. Alkynoates
reacted differently with nickel catalysts, leading to cis-2-alkenyl-
1,2-dihydronaphthylamines, through a reductive coupling oc-
curring with C-N bond cleavage.15
Results and Discussion
In continuation of these studies, it was anticipated that the
ruthenium-catalyzed reactions involving 7-azabenzonorborna-
dienes 1 were expected to afford exclusively [2 + 2] cycload-
ducts. Indeed, these reactions, leading to exo-cyclobutene
derivatives, have been reported to occur with cobalt catalysts.12
In the presence of nickel catalysts, [2 + 2] or [2 + 2 + 2]
cycloaddition pathways are observed depending on the structural
patterns of alkynes and the reaction conditions producing exo-
We initially examined the reaction of 7-azabenzonorborna-
diene 1a with hex-3-yne (2a) in the presence of CpRuCl(PPh3)2
(5 mol %) in dioxane at 60 °C, which afforded a complex
mixture of products and a low conversion. Carrying out the
reaction in the presence of methyl iodide (35 mol %) to generate
9
in situ CpRuI(PPh3)2 proved to be crucial to obtain the [2 +
2] cycloadduct 4aa (12%) and a new unsymmetrical adduct 3aa
in 63% yield.16 Interestingly, the beneficial effect of the iodo
ligand17 contrasted with the use of Cp*Ru(cod)I10 which turned
out to be completely inactive. The structure of 3aa was clearly
(5) (a) Kno¨lker, H.-J.; Baum, G.; Pannek, J.-B. Tetrahedron 1996, 52,
7345-7362. (b) Kno¨lker, H.-J.; Fro¨hner, W. Tetrahedron Lett. 1997, 38,
1535-1538. (c) Kno¨lker, H.-J.; Wolpert, M. Tetrahedron 2003, 59, 5317-
5322.
(6) (a) Sheppard, G. S.; Vollhardt, K. P. C. J. Org. Chem. 1986, 51,
5496-5498. (b) Grotjahn, D. B.; Vollhardt, K. P. C. J. Am. Chem. Soc.
1986, 108, 2091-2093.
(7) (a) Vernon, J. M.; Ahmed, M.; Kricka, L. J. J. Chem. Soc., Perkin
Trans. 1 1978, 837-842. (b) Duflos, J.; Queguiner, G. J. Org. Chem. 1981,
46, 1195-1198. (c) Duflos, J.; Queguiner, G. J. Heterocycl. Chem. 1984,
21, 49-51. (d) Cha, C.-K.; Tsou, C.-P. J. Org. Chem. 1990, 55, 2446-
2450.
(8) Marc, S. Ph.D. Dissertation, University of Aix-Marseille, France,
2005.
(9) Tenaglia, A.; L. Giordano, L. Synlett 2003, 2333-2336.
(10) During the editing of this manuscript, a study on the cyclization of
7-azabenzonorbornadienes with alkynes producing dihydrobenzo[g]indoles
and/or [2 + 2] cycloadducts catalyzed by ruthenium complexes appeared.
The reaction scope was only limited to electron-poor alkynes such as
conjugated alkynoates; see: Burton, R. R.; Tam, W. Org. Lett. 2007, 9,
3287-3290.
(11) Tenaglia, A.; Giordano, L. Tetrahedron Lett. 2004, 45, 171-174.
(12) Chao, K. C.; Rayabarapu, D. K.; Wang, C.-C.; Cheng, C.-H. J. Org.
Chem. 2001, 66, 8804-8810.
1
established by H and 13C NMR spectroscopy,18 and the cis
stereochemistry of the fused rings was established by NOESY
experiment and was consistent with the H3a-H9b coupling
constant of 9.5 Hz.19 The yield of 3aa slightly decreased using
preformed CpRuI(PPh3)220 as a catalyst. The higher efficiency
of the in situ generated catalyst may be ascribed to the presence
(13) Huang, D. J.; Rayabarapu, D. K.; Li, L. P.; Sambaiah, T.; Cheng,
C.-H. Chem.sEur. J. 2000, 6, 3706-3713.
(14) (a) Huang, D.-J.; Sambaiah, T.; Cheng, C.-H. New J. Chem. 1998,
22, 1147-1149. (b) Sambaiah, T.; Huang, D.-J.; Cheng, C.-H. J. Chem.
Soc., Perkin. Trans 1 2000, 195-203. For a single example of Pd-catalyzed
cocyclotrimerization with benzynes, see: (d) Jayanth, T. T.; Jeganmohan,
M.; Cheng, C.-H. J. Org. Chem. 2004, 69, 8445-8450.
(15) Rayabarapu, D. K.; Cheng, C.-H. Chem.sEur. J. 2003, 9, 3164-
3169.
(16) No reaction was observed when a mixture of stoichiometric amounts
of 1a and 2a was refluxed in the absence of catalyst for 24 h in dioxane.
(17) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26-47.
(18) See the Supporting Information.
1398 J. Org. Chem., Vol. 73, No. 4, 2008

Ru-Catalyzed Cross-Coupling of 7-Azabenzonorbornadienes
TABLE 3. Ruthenium-Catalyzed Coupling of
N-Boc-7-Azabenzonorbornadiene 1a with Terminal Alkynes 7
SCHEME 2. Structure of Compounds 5, 6, and 10
TABLE 2. Ruthenium-Catalyzed Coupling of
N-Boc-7-Azabenzonorbornadiene 1a with Unsymmetrical Alkynes 2a
product(s) (yield)b
temp time
entry
alkyne
7a R ) Pr
(°C)
(h)
8
9
1
2
3
4
5
6
7
8
90
90
90
60
65
60
90
90
20
27
25
18
20
20
20
20
8aa (19%)
9aa (59%)
7b R ) (CH2)2CN
7c R ) OPh
8ab (23%) 9ab (56%)
8ac (10%) 9ac (73%)
8ad (23%) 9ad (69%)
7d R ) OBn
7e R ) OAc
7f R ) OCO2Et
7g R ) SO2Ph
7h R ) CMe2OH
8ae (91%)
8af (89%)
-
-
-
9ag (87%)
8ah (93%)
-
a Reaction conditions: 1a (0.5 mmol), alkyne (0.5 mmol), CpRuCl(PPh3)2
(5 mol %), MeI (0.175 mmol) in dioxane (4 mL). b Isolated yields after
column chromatography.
(53%) an unexpected adduct 5 (20%) (Scheme 2). In contrast
with these observations, the reaction of 1a with diphenylethyne
2b gave exclusively the [2 + 2] cycloadduct 4ab in 97% yield
(Table 1, entry 2). The reaction with bisphosphate 2j (R )
CH2OP(O)(OEt)2 (not shown in Table 1)) required a higher
temperature (90 °C) and afforded, instead of adduct 3aj (R )
OP(O)(OEt)2), the dienol phosphate 6 (38%) (Scheme 2) as a
single diastereomer.
To address the selectivity issues of the coupling reactions,
unsymmetrical alkynes with different electronic properties were
examined in cross-coupling reactions of 1a (Table 2).
The ring-opening adducts 3 were exclusively observed with
propargylic alcohols 2k,l and propargylic phenyl ether 2m
although obtained in moderate yields (Table 2, entries 1-3)
from complex reaction mixtures. Even the 1,3-diyne 2n is
incorporated satisfactorily, affording 3an (48%) and the cy-
clobutene 4an (15%) (Table 2, entry 4). Dihydrobenzoindoles
3 were formed as single regio- and stereoisomers with the most
polar group located at the carbon atom vicinal to the nitrogen
group (entries 1-3). Phenyl-substituted alkynes afforded ex-
clusively (Table 2, entries 5-7) the [2 + 2] cycloadducts. The
same trend was observed with diphenylethyne 2b (see Table 1,
entry 2).
The successful application of internal alkynes in the ruthenium-
catalyzed coupling reaction prompted us to examine the reaction
with terminal alkynes (Table 3). So far, ruthenium-catalyzed
intermolecular [2 + 2] cycloadditions of norbornadienes with
terminal alkynes are less efficient with respect to internal alkynes
and give aromatic compounds as byproducts.22 In our hand,
ruthenium-catalyzed intermolecular [2 + 2] cycloadditions of
norbornadienes failed when terminal alkynes were involved.23
We were pleased to observe that the coupling of 1a with terminal
alkynes 7 afforded the dihydrobenzoindoles 8 and/or isomers 9
adduct(s) (yield)b
temp
(°C)
time
(h)
entry
alkyne
3
4
1
2
3
4
5
6
7
2k
2l
2m
2n
2o
2p
2q
60
60
60
60
60
60
60
19
48
5.5
26
21
15
20
3ak (42%)
3al (35%)
3am (52%)
3an (48%)
-
-
-
-
4an (15%)
4ao (83%)
4ap (98%)
4aq (98%)
-
-
a Reaction conditions: 1a (0.5 mmol), alkyne (0.5 mmol), CpRuI(PPh3)2
(5 mol %), MeI (0.175 mmol) in dioxane (4 mL). b Isolated yields after
column chromatography.
of excess MeI. Halogenoalkanes are able to coordinate the metal
center of cyclopentadienylruthenium complexes via σ-donation
of a halogen lone pair.21 The resulting complexes easily undergo
ligand substitution with common coordinating solvents to
produce the corresponding solvento complexes which promote
coordination of the reactants more easily. Therefore, the catalyst
combination CpRuCl(PPh3)2/MeI was conveniently used for
further studies. Under these reaction conditions, the cyclization
of 1a with various symmetrical alkynes 2c-i afforded the
expected dihydrobenzoindoles 3ac-ai in moderate to good
yields (Table 1).
The best results were observed with but-2-yn-1,4-diol (2d)
(entry 4) and the corresponding bisethers 2e-h (entries 5-8)
and bisacetate 2i (entry 9). The reaction of dimethylacetylene
dicarboxylate (DMAD) 2c (entry 3) afforded along with 3ac
(19) Typical vicinal coupling constants of 5-9 Hz were observed for
related cis-fused bicyclic compounds. The corresponding trans isomers
exhibit J values of 20-24 Hz; see: Barinelli, L. S.; Nicholas, K. M. J.
Org. Chem. 1988, 53, 2114-2117 and references therein.
(20) (a) Blackmore, T.; Bruce, M. I.; Stone, F. G. A. J. Chem. Soc. 1971,
2376-2382. (b) For an alternative synthesis, see ref 8.
(21) Kulawiec, R. J.; Faller, J. W.; Crabtree, R. H. Organometallics 1990,
9, 745-755.
(22) Mitsudo, T.; Naruse, H.; Kondo, T.; Ozaki, Y.; Watanabe, Y. Angew.
Chem., Int. Ed. Engl. 1994, 33, 580-581.
J. Org. Chem, Vol. 73, No. 4, 2008 1399

Tenaglia and Marc
SCHEME 3. DDQ-Promoted Oxidation of 3a,9b-Dihydrobenzo[g]indoles to Benzo[g]indoles
TABLE 4. Effect of the Substitution at the Nitrogen of
7-Azabenzonorbornadienes 1 on the Ru-Catalyzed Coupling with
Alkynes 2a
SCHEME 4. Proposed Mechanism for the Ru-Catalyzed
Formation of Dihydrobenzo[g]indoles
SCHEME 5. Proposed Mechanism for the Ru-Catalyzed
Formation of Adduct 5
adduct(s), yieldb
temp
(°C)
time
(h)
entry
alkene
alkyne
3
4
1
1a
1b
1a
1b
1a
1b
2a
2a
2e
2e
2i
60
90
50
60
90
90
50
8
65
22
6
3aa (63%)
3ba (5%)d
3ae (84%)
3be (79%)
3ai (77%)
3bi (86%)
4aa (12%)
4ba (63%)
-
-
-
-
2c
3
4
5
6
2i
6
a Reaction conditions: 1a (0.5 mmol), alkyne (0.5 mmol), CpRuCl(PPh3)2
(5 mol %), MeI (0.175 mmol) in dioxane (4 mL). b Isolated yields after
column chromatography. c No reaction occurred at 60 °C. d Yield determined
1
by H NMR.
bond isomers 9aa-ad as single regio- and stereoisomers.
Propargylic acetate 7e (Table 3, entry 5) or mixed carbonate 7f
(Table 3, entry 6) afforded exclusively 8ae (91%) or 8af (89%),
respectively. In contrast, the propargylic phenylsulfone 7g
provided only the vinyl sulfone 9ag (87%) (Table 3, entry 7).
An X-ray crystallographic analysis secured both the structure
and the stereochemistry of 9ag.24 Tertiary propargylic alcohol
7h proved to be stable under the reactions conditions,25
providing exclusively 8ah in 93% yield (entry 8).
Variation in the substitution of the nitrogen atom of 7-aza-
benzonorbornadienes was also examined in these reactions
(Table 4). The reactions of 1a or 1b, bearing the tertiary
carbamate at the bridgehead position, with alkynes 2e and 2i,
afforded the dihydroindoles in good yields (Table 4, entries
as single diastereomers in good overall yields (78-92%). The
reactions proceeded with complete regioselectivity giving ad-
ducts with the alkyl and/or alkenyl substituent at the C-2
position. Interestingly, the competitive [2 + 2] cycloaddition
reaction observed so far was totally suppressed.
Alkyl-substituted alkynes 7a,b (Table 3, entries 1 and 2) and
propargylic ethers 7c,d (Table 3, entries 3 and 4) gave the
adducts 8aa-ad as minor products, and the E-exocyclic double
(23) A notable exception was recently reported in the case of the
ruthenium-catalyzed vinylcyclopropanation of norborn(adi)enes using ter-
tiary propargylic carboxylates. See: Tenaglia, A.; Marc, S. J. Org. Chem.
2006, 71, 3569-3575.
1400 J. Org. Chem., Vol. 73, No. 4, 2008

Ru-Catalyzed Cross-Coupling of 7-Azabenzonorbornadienes
SCHEME 6. Proposed Mechanism for the Ru-Catalyzed Formation of Adduct 6
3-6). Unexpectedly, an inversion of selectivity between the
dihydroindole and the [2 + 2] adduct was observed for reactions
of 1a or 1b with hex-3-yne (2a) (entries 1 and 2). All of the
reactions carried out with 1c bearing the tosyl group at the
nitrogen atom afforded only 4-methyl-N-naphthalen-1-ylben-
zenesulfonamide (10) (Scheme 2), resulting from the isomer-
ization of 1c.
bond to form complex III. Insertion of the alkyne into the
metal-carbon bond27 would give the ruthenacycle IV which
upon reductive elimination would release 5 (Scheme 5).
The formation of adduct 6, depicted in Scheme 6, presumably
arose through a regio- and stereoselective 1,4-elimination of
diethyl phosphonate from the putative intermediate 3aj under
the reaction conditions.
The usefulness of this ruthenium-catalyzed coupling was
demonstrated through the facile conversion of 3a,9b-dihy-
drobenzo[g]indoles 3al, 8af, and 3bg to the corresponding
benzo[g]indoles 11, 12, and 13, respectively, under mild
oxidative conditions in the presence of DDQ (Scheme 3). Under
these conditions, allylic alcohol 3al reacted smoothly at
room temperature in the presence of 2 equiv of DDQ to give
the 2-formylbenzo[g]indole 11, whereas 8af proved to be
reluctant to oxidation and required 5 equiv of DDQ for com-
pletion of the reaction affording the benzo[g]indole 12 in 79%
yield.
In summary, we have developed the ruthenium-catalyzed
cross-coupling reactions of azabenzonorbornadienes and alkynes
that resulted in a formal [3 + 2] annulation reaction to afford
3a,9b-dihydrobenzo[g]indoles. The competitive ruthenium-
catalyzed [2 + 2] cycloaddition is suppressed in reactions
involving terminal alkynes. The synthetic utility of the reaction
was demonstrated by the conversion of the 3a,9b-dihydrobenzo-
[g]indoles into benzo[g]indoles functionalized on the hetero-
cyclic ring for further structural modifications.
Experimental Section
A mechanistic rationale accounting for the formation of the
dihydrobenzoindoles is proposed in Scheme 4. The catalytic
cycle starts with the formation of the coordinatively unsaturated
CpRuI by dissociation of the phosphine ligands from CpRuI-
(PPh3)2. The oxidative coupling of the reactants to the metal
center would give the ruthenacyclopentene I. Reductive elimina-
tion of the metal species would form the [2 + 2] adduct, while
â(N)-elimination would allow the formation of ruthenadehy-
dropiperidine II, which upon reductive elimination might release
the dihydrobenzoindole and the active species CpRuI. The cross-
coupling regioselectivity observed with unsymmetrical alkynes,
including terminal ones, is worth being mentioned. The presence
of a propargylic oxygen substituent able to coordinate to the
metal center favors carbon-carbon bond formation to the distal
acetylenic carbon in ruthenacyclopentene I.26 Interestingly, in
the couplings of 1a with terminal alkynes (Table 3), the
orientation of the alkyne in the coupling step is not affected by
the absence of such a substituent.
Typical Procedure for the Coupling of 1a with 2h as a
Representative Example: CpRuCl(PPh3)2 (18.2 mg, 0.025 mmol)
and dioxane (2 mL) were placed in a flame-dried Schlenk flask. A
solution of 1a (121.7 mg, 0.5 mmol) and 2h (157.3 mg, 0.5 mmol)
in dioxane (2 mL) and MeI (11.7 µL, 0.175 mmol) were added at
once, and the mixture was stirred at 60 °C for 22 h. After removal
of the solvent under reduced pressure, the residue was purified by
column chromatography over silica gel (AcOEt/hexanes 1/19) to
give 273 mg (98% yield) of 3ah as a colorless oil.
(3aR*,9bS*)-tert-Butyl 2,3-bis[(tert-butyldimethylsilanyloxy)-
methyl]-3a,9b-dihydro-1H-benzo[g]indole-1-carboxylate (3ah):
Rf (AcOEt/hexanes 1/19) 0.48; IR (neat) ν 3038, 2955, 2857, 1702,
1671, 1472, 1365, 1250, 1169, 1059, 836, 775 cm-1; 1H NMR (200
MHz, CDCl3) δ 7.49 (m, 1H), 7.15 (m, 2H), 6.97 (m, 1H), 6.40
(d, J ) 9.8 Hz, 1H), 5.97 (dd, J ) 6.1, 9.7 Hz, 1H), 5.61 (d, J )
9.7 Hz, 1H), 4.62 (br d, J ) 13.1 Hz, 1H), 4.50 (br d, J ) 13.3 Hz,
1H), 4.47 (d, J ) 12.3 Hz, 1H), 4.09 (d, J ) 12.3 Hz, 1H), 3.88
(m, 1H), 1.55 (s, 9H), 0.91 (s, 9H), 0.75 (s, 9H), 0.07 (s, 6H),
-0.16 (s, 3H), -0.23 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 153.8
(s), 136.8 (s), 133.7 (s), 132 (s), 127.9 (2 × d), 127.4 (2 × d),
126.0 (d), 124.4 (d), 123.7 (s), 80.5 (s), 60.3 (d), 58.1 (t), 57.0 (t),
41.5 (d), 28.4 (3 × q), 25.9 (3 × q), 25.7 (3 × q), 18.3 (s), 18.1(s),
-5.3 (q), -5.4 (q), -5.6 (q), -5.7 (q). Anal. Calcd for C31H51-
NO4Si2: C, 66.74; H, 9.21; N, 2.51. Found: C, 66.83; H, 9.21; N,
2.57.
The observation of azabicyclic adduct 5 (Table 1, entry 3
and Scheme 2) when 1a reacted with DMAD 2c suggested that
the insertion of 2c into the bridgehead C-N bond of 1a occurred
during its formation. A plausible mechanism may involve the
coordination of this highly electron-deficient alkyne to the
electron-rich ruthenium center. This species would undergo
oxidative addition with the benzylic and allylic bridgehead C-N
Typical Procedure for the Oxidation of Dihydrobenzo[g]-
indole to Benzo[g]indole: DDQ (1-5 equiv) was added to a
solution of 3a,9b-dihydrobenzo[g]indole (1 equiv) in dry Et2O. The
mixture was stirred at room temperature until complete conversion
(monitored by TLC) and concentrated under reduced pressure. The
residue was purified by column chromatography to afford the
corresponding benzo[g]indole.
(24) CCDC-655677 contains the supplementary crystallographic data.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: (internat.) +44-1223-336-
033; or e-mail: deposit@ccdc.cam.ac.uk]. See also the Supporting Informa-
tion.
(25) The propensity of tertiary propargylic alcohols to form ruthenium
allenylidene complexes is known. See: Rigaut, S.; Touchard, D.; Dixneuf,
P. H. Coord. Chem. ReV. 2004, 248, 1585-1601.
(26) Trost, B. M.; Indolese, A. F.; Mu¨ller, T. J. J.; Treptow, B. J. Am.
Chem. Soc. 1995, 117, 615-623.
(27) For insertion of DMAD into a Pd-heteroatom bond, see: (a)
Yagyu, K.; Osakada, K.; Brookhart, M. Organometallics 2000, 19, 2125-
2129. (b) Sugoh, K.; Kuniyasu, H.; Kurosawa, H. Chem. Lett. 2002, 106-
107.
J. Org. Chem, Vol. 73, No. 4, 2008 1401

Tenaglia and Marc
tert-Butyl 3-butyl-2-formyl-1H-benzo[g]indole-1-carboxylate
(11) was obtained as a colorless oil: Rf (hexanes/AcOEt 9/1) 0.35;
1H NMR (200 MHz, CDCl3) δ 10.12 (s, 1H), 8.43 (m, 1H), 7.92
(m, 1H), 7.63 (m, 2H), 7.54 (m, 2H), 3.11 (t, J ) 7.5 Hz, 2H),
1.74 (s, 9H), 1.72 (m, 2H), 1.46 (m, 2H), 0.97 (t, J ) 7.2 Hz, 3H);
13C NMR (50 MHz, CDCl3) δ 179.8 (d), 152.0 (s), 134.1 (s), 133.3
(s), 132.8 (s), 131.7 (s), 129.2 (d), 126.4 (d), 126.0 (d), 124.7 (s),
124.0 (d), 122.8 (d), 122.2 (s), 118.8 (d), 86.1 (s), 33.8 (t), 27.5 (3
x q), 23.6 (t), 22.7 (t), 13.8 (q). Anal. Calcd for C22H25NO3: C,
75.19; H, 7.17; N, 3.99. Found: C, 75.31; H, 7.13; N, 3.75.
Acknowledgment. The authors would like to thank the
CNRS for financial support, and Dr. I. De Riggi (ECM,
Universite´ P. Cezanne, Marseille) for help with the NMR.
Supporting Information Available: Experimental procedures,
cif file for compound 9ag, and characterization data of all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO702248R
1402 J. Org. Chem., Vol. 73, No. 4, 2008