Direct construction of bicyclic heterocycles by palladium-catalyzed domino cyclization of propargyl bromides

Article abstract of DOI:10.1021/ol800063d

The palladium-catalyzed domino cyclization of propargyl bromides having two nucleophilic functional groups Is described. Treatment of 1,7-dlamlno-5- bromohept-3-yne derivatives with catalytic Pd (PPh₃)₄ in the presence of NaH in MeOH gives the 2,7-diazabicyclo[4.3.0]non-5-enes in good yields. Interestingly, the regioselectivity of the reaction is completely controlled by the relative reactivity of the amine functional groups, irrespective of the position of the nucleophiles. The malonate derivative also undergoes domino cyclization to produce a hexahydroindole derivative.

Full text of DOI:10.1021/ol800063d

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1171-1174
Direct Construction of Bicyclic
Heterocycles by Palladium-Catalyzed
Domino Cyclization of Propargyl
Bromides
Hiroaki Ohno,*,† Akinori Okano,† Shohei Kosaka,‡ Koji Tsukamoto,§ Miyo Ohata,‡
Kotaro Ishihara,‡ Hatsuo Maeda,§ Tetsuaki Tanaka,*,‡ and Nobutaka Fujii*,†
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku,
Kyoto 606-8501, Japan, Graduate School of Pharmaceutical Sciences,
Osaka UniVersity, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan, and Department of
Pharmacy, Hyogo UniVersity of Health Sciences, 1-3-6 Minatojima, Chuo-ku,
Kobe 650-8530, Japan
hohno@pharm.kyoto-u.ac.jp; t-tanaka@phs.osaka-u.ac.jp; n-fujii@pharm.kyoto-u.ac.jp
Received January 10, 2008
ABSTRACT
The palladium-catalyzed domino cyclization of propargyl bromides having two nucleophilic functional groups is described. Treatment of 1,7-
diamino-5-bromohept-3-yne derivatives with catalytic Pd(PPh3)4 in the presence of NaH in MeOH gives the 2,7-diazabicyclo[4.3.0]non-5-enes in
good yields. Interestingly, the regioselectivity of the reaction is completely controlled by the relative reactivity of the amine functional groups,
irrespective of the position of the nucleophiles. The malonate derivative also undergoes domino cyclization to produce a hexahydroindole
derivative.
Palladium-catalyzed reactions of propargylic compounds
developed by Tsuji and co-workers are widely used as an
efficient tool for the introduction of two nucleophiles into a
substrate.1,2 The reaction with dual nucleophiles such as
acetoacetonates and diols forms cyclic products including
furans and dioxanes.1,3 Recent contributions in this area have
revealed that a combination of nucleophilic attacks by an
internal nucleophilic functional group and an appropriate
external nucleophile can be a convenient approach to car-
bapenems,4 furans,5 indoles,6 indenes,7 and cyclic carbonates.8
In contrast, there have been no reports of the direct
(3) (a) Minami, I.; Yuhara, M.; Tsuji, J. Tetrahedron Lett. 1987, 28,
629-632. (b) Geng, L.; Lu, X. Tetrahedron Lett. 1990, 31, 111-114. (c)
Labrosse, J.-R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1999, 40, 9025-
9028. (d) Labrosse, J.-R.; Lhoste, P.; Sinou, D. Org. Lett. 2000, 2, 527-
529. (e) Labrosse, J.-R.; Lhoste, P.; Sinou, D. J. Org. Chem. 2001, 66,
6634-6642. (f) Zong, K.; Abboud, K. A.; Reynolds, J. R. Tetrahedron
Lett. 2004, 45, 4973-4975.
(4) (a) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2001, 42, 4869-4873.
(b) Kozawa, Y.; Mori, M. J. Org. Chem. 2003, 68, 8068-8074. See also,
(c) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002, 43, 1499-1502.
(5) Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M. Tetrahedron Lett.
2004, 45, 1861-1864.
(6) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Org. Lett. 2006, 8, 2083-2086.
(7) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. Org.
Lett. 2006, 8, 5777-5780.
† Kyoto University.
‡ Osaka University.
§ Hyogo University of Health Sciences.
(1) (a) Tsuji, J.; Watanabe, H.; Minami, I.; Shimizu, I. J. Am. Chem.
Soc. 1985, 107, 2196-2198. (b) Minami, I.; Yuhara, M.; Watanabe, H.;
Tsuji, J. J. Organomet. Chem. 1987, 334, 225-242.
(2) For a review, see: Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. Engl.
1995, 34, 2589-2612.
10.1021/ol800063d CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/23/2008

construction of bicyclic heterocycles by domino cyclization
using propargylic substrates having two nucleophilic func-
tional groups.
1, this domino cyclization could afford four types of bicyclic
products 6-9, depending on (1) which nucleophilic site (NuA
and NuB) would participate in the first cyclization (path A
vs B) and (2) which carbon (distal or proximal) would be
attacked on the second cyclization (path C vs D and E vs
F). Herein we describe the domino cyclization of propargyl
bromides 2 having two nitrogen functional groups to form
fused azacycles of the type 6 and 8. The remarkable effect
of the nucleophilicity of NA and NB on the outcome as well
as the stereochemical course of the reaction is also presented.
To avoid the regioselectivity issue during the first cycliza-
tion (path A vs B, Scheme 1), we investigated the reaction
of propargyl bromide 10a containing two hydroxy groups
tethered by two carbon atoms (Scheme 2). Use of this starting
During the course of our studies directed toward elucidat-
ing efficient cyclization reactions of allenic compounds,9 we
found that bromoallenes can act as allyl dication equivalents
in the presence of palladium(0) and alcohol. This reactivity
has been shown to be extremely useful for the synthesis of
medium-sized heterocycles10 as well as bicyclic sulfamides11
by successive bond formation. In light of this chemistry, we
envisioned that the domino cyclization of bromoallenes 1
having two nucleophilic sites (NuA and NuB) might lead to
bicyclic compounds by domino cyclization (Scheme 1).
Scheme 1. Reaction Course of Palladium-Catalyzed Domino
Cyclization of Allenyl/Propargyl Bromides 1 and 2
Scheme 2. Formation of Furan Derivatives by
Monocyclizationa
a Reaction conditions: for 10a, 14, and 15: Pd(PPh3)4 (5 mol
%), NaH (2.5 equiv), MeOH, 60 °C; for 10b: Pd2(dba)3‚CHCl3
(2.5 mol %), dppe (10 mol %), dioxane, 80 °C.
However, since efficient chemoselective preparation of 1,3-
disubstituted bromoallenes of the type 1 via conventional
bromination methods has proven to be difficult,12 we turned
our attention to the reaction of propargyl bromides 2, which
can be considered as a synthetic equivalent of bromoallenes
in the palladium-catalyzed reaction.13 As shown in Scheme
material has the advantage of allowing the production of a
highly symmetrical allenylpalladium intermediate. The bro-
mide 10a was readily prepared through the addition of the
acetylide of a protected but-3-yn-1-ol to a hydroxypropanal
derivative followed by bromination of the resulting protected
propargyl alcohol with CBr4 and PPh3 in the presence of
imidazole. Unfortunately, treatment of 10a with Pd(PPh3)4
(5 mol %) in the presence of in situ generated NaOMe
(standard conditions for cyclization of bromoallenes)10,11 gave
the furan derivative 11 in 62% yield. The reaction of the
carbonate 10b with Pd2(dba)3‚CHCl3 (2.5 mol %)/dppe (10
mol %) in dioxane also afforded 11 in 48% yield, without
promoting the desired domino cyclization. Formation of the
furan 11 can be rationalized through a â-hydride elimination
from the π-allylpalladium intermediate 12 followed by
aromatization of the diene 13. Similar results were obtained
with amino alcohol derivatives 14 and 15, both leading to
furan 16 in moderate yields. However, these unsuccessful
results clearly show that the anion of the hydroxy group of
14 and 15 is more reactive than that of the tosylamide group,
irrespective of their location (R1 or R2). Thus, both NuA and
(8) (a) Yoshida, M.; Ihara, M. Angew. Chem., Int. Ed. 2001, 40, 616-
619. (b) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem. Soc.
2003, 125, 4874-4881.
(9) (a) Ohno, H.; Hamaguchi, H.; Tanaka, T. Org. Lett. 2001, 3, 2269-
2271. (b) Ohno, H.; Ando, K.; Hamaguchi, H.; Takeoka, Y.; Tanaka, T. J.
Am. Chem. Soc. 2002, 124, 15255-15266. (c) Ohno, H.; Miyamura, K.;
Takeoka, Y.; Tanaka, T. Angew. Chem., Int. Ed. 2003, 42, 2647-2650. (d)
Ohno, H.; Mizutani, T.; Kadoh, Y.; Miyamura, K.; Tanaka, T. Angew.
Chem., Int. Ed. 2005, 44, 5113-5115. (e) Ohno, H.; Aso, A.; Kadoh, Y.;
Fujii, N.; Tanaka, T. Angew. Chem., Int. Ed. 2007, 46, 6325-6328.
(10) (a) Ohno, H.; Hamaguchi, H.; Ohata, M.; Tanaka, T. Angew. Chem.,
Int. Ed. 2003, 42, 1749-1753. (b) Ohno, H.; Hamaguchi, H.; Ohata, M.;
Kosaka, S.; Tanaka, T. J. Am. Chem. Soc. 2004, 126, 8744-8754.
(11) (a) Hamaguchi, H.; Kosaka, S.; Ohno, H.; Tanaka, T. Angew. Chem.,
Int. Ed. 2005, 44, 1513-1517. (b) Hamaguchi, H.; Kosaka, S.; Ohno, H.;
Fujii, N.; Tanaka, T. Chem.-Eur. J. 2007, 13, 1692-1708.
(12) For example, treatment of propargyl alcohols with CuBr‚SMe2 in
the presence of LiBr gave a mixture of allenyl/propargyl bromides.
(13) The reactivities of allenic and propargylic compounds are not
necessarily the same. For example, propargyl bromides and carbonates are
more reactive than bromoallenes toward SN2 reactions and alcoholysis,
respectively.10b
1172
Org. Lett., Vol. 10, No. 6, 2008

NuB with appropriate carbon tethers in the palladium complex
3 (Scheme 1) can readily react with the central carbon of
the propargylic moiety.
Next, the reaction of diamine derivative 17a was inves-
tigated (Scheme 3). Fortunately, treatment of 17a with 5 mol
1. As shown in entries 1 and 2, the reaction of propargyl
carbonate 17b under aprotic conditions15 gave a lower yield
of 18 (38%) than the reaction of the bromide 17a in MeOH.
The reaction of the bromide 20 having tosyl- and nosylamide
groups afforded the bicyclic product 21 in 79% yield (entry
3), in which the tosylamide group is incorporated into the
five-membered ring.16 Interestingly, the same product was
obtained in 87% yield from the bromide 22 which has a
nosylamide group on the carbon close to the bromine atom
(entry 4). These results show that the tosylamide group
participates in the first cyclization to form a five-membered
ring, which is followed by the second cyclization by the
nosylamide, irrespective of their location. When bis-nosyl-
amide 23 was employed in the domino cyclization, the
corresponding bicyclic product 24 was obtained in 91% yield
(entry 5). The malonate derivative 25 was successfully
converted to hexahydroindole dicarboxylate derivative 26 in
78% yield. This result can be partly attributed to steric
hindrance of the malonate moiety which hampers the first
cyclization.
Scheme 3. Domino Cyclization of Diamine Derivatives 17a
% of Pd(PPh3)4 in the presence of NaH (2.5 equiv) in MeOH
afforded the desired bis-cyclized product 18 in 89% yield.
This enamine is relatively unstable, and complete isomer-
ization to the dihydropyrrole derivative 19 having an ethene
diamide moiety proceeded in CDCl3 within 48 h at room
temperature.14
To expand the synthetic utility of this domino cyclization,
conversion to a fused pyrrole derivative was then investigated
(Scheme 4). The domino cyclization of 17a and 20 using
The results of the palladium-catalyzed domino cyclization
using selected diamine derivatives are summarized in Table
Scheme 4. Synthesis of Fused Pyrrole Derivatives
Table 1. Domino Cyclization of Diamine and
(Aminoalkyl)malonate Derivativesa
acidic workup (4% HCl) directly gave the dihydropyrrole-
fused bicyclic compounds 19 and 27 both in good yields.
DDQ-mediated oxidation of these compounds easily afforded
the desired fused pyrroles 28.
Finally, the stereochemical course of the domino cycliza-
tion was examined using syn- and anti-29 derived from
L-valine (Scheme 5). The reaction of syn-29 under the
Scheme 5. Domino Cyclization of syn- and anti-29
a Unless otherwise stated, the reactions were carried out with Pd(PPh3)4
(5 mol %), NaH (2.5 equiv) in MeOH at 60 °C. b Yields of isolated products.
c The reaction was carried out with Pd2(dba)3‚CHCl3 (2.5 mol %)/dppe (10
mol %) in dioxane.
standard conditions using Pd(PPh3)4 (5 mol %) and in situ
generated NaOMe in MeOH gave 30 (57%) and 31 (10%),
both in a stereoselective manner.17 Quite interestingly, the
Org. Lett., Vol. 10, No. 6, 2008
1173

isomeric anti-29 afforded the same products, although the
major isomer was 31 (30: 21%; 31: 49%). These results
suggest that the stereochemistry of the substrates is not
reflected in that of the products, although it affects the
regioselectivity, i.e., which nitrogen attacks the central carbon
of the allenylpalladium intermediate in the first cyclization.
Formation of 30 and 31 from syn-29 can be explained as
follows (Scheme 6). Attack of palladium(0) to syn-29 from
would form a fused palladacyclobutene intermediate 34.19
Protonation of 34 leads to the allylpalladium complex 35,
which is in a state of equilibrium with the π-allylpalladium
intermediate 36. The second anti-cyclization from the
resulting π-allylpalladium intermediate 36 by the more
hindered nitrogen atom would give the major isomer 30 in
a stereoselective manner.20 On the other hand, the domino
cyclization in the opposite order through the first cyclization
by the more hindered nitrogen atom (path B) will form the
minor isomer 31 in a similar manner. Although the produc-
tion of the same isomers 30 and 31 from anti-29 should
involve inversion of the configuration through the sequence
of these steps which requires further consideration,21 these
stereochemical outcomes demonstrate an interesting aspect
of the palladium-catalyzed domino cyclization of propargyl
bromides.
Scheme 6. Stereochemical Course of the Cyclization of
syn-29
In conclusion, we have developed a novel domino cycli-
zation of propargyl bromides having two nucleophilic sites
catalyzed by palladium(0). The regioselectivity of the reac-
tion depends on the relative reactivities of the nucleophilic
moieties, irrespective of their location. This domino cycliza-
tion provides convenient access to fused bicyclic compounds
such as hexa- or tetrahydro-1H-pyrrolo[3,2-b]pyridine de-
rivatives as well as hexahydroindole derivatives.
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Encouragement of Young Scientists (A)
(H.O.) and for Scientific Research (B) (T.T.) from the
Ministry of Education, Culture, Sports, Science.
Supporting Information Available: Representative ex-
perimental procedures, characterization data of all new
compounds, and a crystallographic information file for 30.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL800063D
(18) (a) Ogoshi, S.; Tsutsumi, K.; Nishiguchi, S.; Kurosawa, H. J.
Organomet. Chem. 1995, 493, C19-C21. (b) Tsutsumi, K.; Ogoshi, S.;
Nishiguchi, S.; Kurosawa, H. J. Am. Chem. Soc. 1998, 120, 1938-1939.
(c) Tsutsumi, K.; Kawase, T.; Kakiuchi, K.; Ogoshi, S.; Okada, Y.;
Kurosawa, H. Bull. Chem. Soc. Jpn. 1999, 72, 2687-2692.
(19) (a) Casey, C. P.; Nash, J. R.; Yi, C. S.; Selmeczy, A. D.; Chung,
S.; Powell, D. R.; Hayashi, R. K. J. Am. Chem. Soc. 1998, 120, 722-733.
(b) Ogoshi, S.; Kurosawa, H. J. Synth. Org. Chem. Jpn. 2003, 61, 14-23.
Formation of a palladacyclobutene intermediate in a related reaction has
been well rationalized by DFT calculation. (c) Labrosse, J.-R.; Lhoste, P.;
Delbecq, F.; Sinou, D. Eur. J. Org. Chem. 2003, 2813-2822.
(20) For related chirality transfer in the reaction of the propargylic
compounds via palladacyclobutene intermediates, see: Yoshida, M.; Fujita,
M.; Ihara, M. Org. Lett. 2003, 5, 3325-3327.
the opposite face of the bromine atom gives an allenylpal-
ladium(II) intermediate 32. After formation of the π-prop-
argylpalladium complex 33,18 the first cyclization by the less-
hindered nitrogen atom on the methylene carbon (path A)
(21) For example, unfavorable steric repulsions around the isopropyl
group in 36′ and 39′ (respective epimers of 36 and 39) might hamper the
second cyclization (see the graphic below), which assist isomerization of
these intermediates to 36 and 39 via an inversion of configuration.
(14) However, isolation and characterization of the bicyclic compounds
of the type 18, some of which are crystaline compounds, are possible.
(15) The reaction of 17b under the standard conditions in MeOH
promoted methanolysis to give propargyl alcohol in 77% yield.
(16) The structure of 21 was confirmed by acid-mediated isomerization,
oxidation to 28b (Scheme 4) followed by deprotection of the nosyl group.
For more details, see the Supporting Information.
(17) The unambiguous structure assignment for 30 and 31 was made by
X-ray analysis and NOE experiment (see the Supporting Information).
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Org. Lett., Vol. 10, No. 6, 2008