Cyclocarbopalladation of alkynes: A stereoselective method for preparing dibenzoxapine containing tetrasubstituted exocyclic alkenes

Article abstract of DOI:10.1021/ol060289a

A palladium-catalyzed cascade carbometalation-cross coupling of alkyne route was developed for the preparation of tetrasubstituted exocyclic alkenes with high stereo- and regiocontrol. The effectiveness of this novel methodology was demonstrated by the sy

Full text of DOI:10.1021/ol060289a

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1685-1688
Cyclocarbopalladation of Alkynes: A
Stereoselective Method for Preparing
Dibenzoxapine Containing
Tetrasubstituted Exocyclic Alkenes
Hannah Yu,*,† Rachel N. Richey,† Matthew W. Carson,‡ and Michael J. Coghlan‡
Chemical Product Research and DeVelopment, Lilly Research Laboratories, Eli Lilly
and Company, Indianapolis, Indiana 46285, and DiscoVery Chemistry Research, Lilly
Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285
yu_hannah@lilly.com
Received February 2, 2006
ABSTRACT
A palladium-catalyzed cascade carbometalation-cross coupling of alkyne route was developed for the preparation of tetrasubstituted exocyclic
alkenes with high stereo- and regiocontrol. The effectiveness of this novel methodology was demonstrated by the synthesis of a number of
dibenzoxapines in sufficient quantities to support their further development.
Dibenzoxapine and dibenzosuberane derivatives have been
an interest of the pharmaceutical industry for a number of
years. Recently, a novel series of these tricyclic compounds
have been identified at Eli Lilly and Company as nuclear
hormone receptor modulators.1 To support their further
development, quantities of tetrasubstituted dibenzoxapine
derivatives, such as 1a-d (Figure 1), were needed.
The dibenzoxapine derivatives containing tetrasubstituted
alkene moieties (1a-d) represent a novel structure and also
pose a unique synthetic challenge. Although these tetrasub-
stituted dibenzoxapine derivatives could be prepared by
methods such as the Wittig reaction2 or simply dehydration
of a carbinol, the synthetic approaches are lengthy and often
limited in scope. In addition, a mixture of the (E)- and (Z)-
isomers is often produced. Since each geometric isomer may
exhibit different toxicological and pharmacological activities,
stereoselective syntheses of these targets are advantageous.
Our need to develop a practical stereoselective route led to
an investigation of the palladium-catalyzed tandem cycliza-
tion of 3a-d. The synthetic strategy was to incorporate a
key intramolecular carbometalation of alkynes to establish
the desired geometric relationship. The convergent approach
involved preparation of cyclization precursors 3a-d, which
could be derived from benzyl alcohols 4a-c and phenols
5a or 5b through either a one-step Mitsunobu reaction3 or a
two-step alkylation procedure (Figure 1). Benzyl alcohols
4a-c could be easily synthesized from the corresponding
aryl halides by using Sonogashira coupling.4
* To whom correspondence should be addressed.
† Chemical Product Research and Development.
‡ Discovery Chemistry Research.
(1) Coghlan, M. J.; Green, J. E.; Grese, T. A.; Jadhav, P. K.; Matthews,
D. P.; Steinberg, M. I.; Fales, K. R.; Bell, M. G. WO 2004/052847 A2,
2004.
(2) For a review of Wittig olefination, see: Maryanoff, B. E.; Reitz, A.
B. Chem. ReV. 1989, 89, 863.
(3) (a) Simon, C.; Hosztafi, S.; Makleit, S. J. Heterocycl. Chem. 1997,
34, 349. (b) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127. (c)
Mitsunobu, O. Synthesis 1981, 1.
(4) (a) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566. (b)
Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.
10.1021/ol060289a CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/15/2006

are still no reports on the preparation of seven-membered
rings through a palladium-catalyzed carbometalation-cross
coupling cascade with use of organometallics as the termi-
nating trapping species.7
The commercially available 3-nitrophenylboronic acid was
first used as the terminating species. Reaction between alkyne
3a and 3-nitrophenylboronic acid was attempted to optimize
the reaction conditions (Table 1). Modifying a literature
Table 1. Optimization Studiesa
temp
%
%
%
%
entry
catalyst
solvent
(° C) 3ab 6b 7b 2ac
1d
2
3
Pd(OAc)2/Ae tolueneh
Pd(OAc)2/Ae toluene
90
90
110
90
90
110
90
70
70
70
51
84
88
76
0
0
0
0
0
4
0
0
2
0
43
1
74
76
37
9
0
0
3
25
4
24 32
3
5
Pd(OAc)2
dioxane
0
0
4
Pd(OAc)2/Bf dioxane
Figure 1. Retrosynthetic approach to 1a-d.
5d
6d
7d
8
Pd(OAc)2/Ae n-BuOH
Pd(OAc)2
DMF
Pd(OAc)2/Ae DMF
The carbometalation of alkynes by organometallic reagents
is now widely used for the stereospecific synthesis of di-,
tri-, and even tetrasubstituted alkenes.5 The major advantage
of these reactions lies in their high stereo- and regioselec-
tivity, which enables them to add to the triple bond of various
alkynes. Another advantage of this approach is the generation
of a new organometallic species, a vinylic metal, which can
be further transformed in such a way that the overall result
is the one-pot positioning of two new substituents in a cis
or trans manner, depending on the organometallic reagent
used.5 In particular, intramolecular carbopalladation of
alkynes (cyclocarbopalladation) is a versatile approach to
various tetrasubstituted alkenes.6 The reaction generally
involves an initial cyclocarbopalladation followed by cross-
coupling of the vinylpalladium species with boron, tin, or
zinc organometallic species. The termination of the vinyl-
palladium species effectively converts the Pd(II) to Pd(0),
thus completing the catalytic cycle. The initial carbopalla-
dation generally follows the 5-exo-dig, 6-exo-dig, or 7-exo-
dig process. However, to the best of our knowledge, there
Pd(OAc)2/Ae DMF/ H2Oi
Pd(OAc)2/Ae dioxane/H2Oi
Pd(OAc)2/Bf dioxane/ H2Oi
9
10
11
12
0
0
0
2
33
Pd(OAc)2/Cg dioxane/ H2Oi 110
19 12 38
89
Pd(OAc)2
dioxane/ H2Oi
70
3
6
a All reactions were run with 2% catalyst, 1.2 equiv of 3-nitroboronic
acid, and 3 equiv of Na2CO3 for 12 h with total concentration at 0.1 M.
b Determined by reverse-phase HPLC. c Isolated yields. d Additional oli-
gomers and polymers were formed. Some of the oligomers and polymers
may not be HPLC detectable. e Ligand A: tri-o-tolyphosphine. f Ligand B:
triphenylphosphine. g Ligand C: 2-(dicyclohexylphosphino)biphenyl. h 1
equiv of Bu4NCl was added. i 4:1 v/v ratio.
procedure6f for the carbopalladation reaction, 3a and 3-ni-
trophenylboronic acid were heated in toluene at 90 °C for
12 h with 2 mol % Pd(OAc)2, 4 mol % tri-o-tolylphosphine,
1 equiv of tetrabutylammonium chloride, and 3 equiv of Na2-
CO3 (Table 1, entry 1). Significant amounts of starting
materials 3a and 3-nitrophenylboronic acid remained unre-
acted, along with the desired product 2a, direct Suzuki
coupling byproduct 6,8 3-nitroboronic acid dimerization
byproduct 7,9 and some oligomeric and polymeric byproducts
which were formed presumably due to the intermolecular
coupling between vinylic palladium intermediate and alkyne
(5) For reviews see: (a) Normant, J. F.; Alexakis, A. Synthesis 1981,
841. (b) Negishi, E. Acc. Chem. Res. 1987, 20, 65. (c) Knochel, P. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 4, p 865. (d) Marek, L.; Normant, J.
F. In Carbometallation Reactions in Metal Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P., Eds.; Wiley VCH: New York, 1998;
pp 271-337. (e) Fallis, A. G.; Forgione, P. Tetrahedron 2001, 5899. (f)
Mitchell, D.; Yu, H. Curr. Opin. Drug DiscoVery DeV. 2003, 6, 876.
(6) For representative examples, see: (a) Zhang, Y.; Negishi, E. J. Am.
Chem. Soc. 1989, 111, 3454. (b) Burns, B.; Grigg, R.; Sridharan, V.;
Stevenson, P.; Sukirthalingam, S.; Worakun, T. Tetrahedron Lett. 1989,
30, 1135. (c) Grigg, R.; Sandano, J. M.; Santhakumar, V.; Sridharan, V.;
Thangavelanthum, R.; Thornton, P. M.; Wilson, D. Tetrahedron 1997, 53,
11803. (d) Poli, G.; Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56,
5959. (e) Frewell, P.; Grigg, R.; Sansano, J. M.; Sridharan, V.; Sukirthal-
ingam, S.; Wilson, D.; Redpath, J. Tetrahedron 2000, 56, 7525. (f) Salem,
B.; Klotz, P.; Suffert, J. Org. Lett. 2003, 5, 845.
(7) For selective references of seven-membered ring formation through
the palladium-catalyzed cascade reaction, see: (a) References 6a and 6d.
(b) Grigg, R.; Savic, V.; Sridharan, V.; Terrier, C. Tetrahedron 2002, 58,
8613.
(8) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457. (b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reaction; Dieder-
ich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp
49-97.
(9) (a) Miyaura, N.; Suzuki, A. Main Group Met. Chem. 1987, 10, 295.
(b) Parrish, J. P.; Jung, Y. C.; Floyd, R. J.; Jung, K. W. Tetrahedron Lett.
2002, 43, 7899. (c) Lei, A.; Zhang, X. Org. Lett. 2002, 4, 2285. (d) Yoshida,
H.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2003, 44, 1541.
1686
Org. Lett., Vol. 8, No. 8, 2006

Table 2. Carbometalation Terminated with Different Boronic
Acidsa
Table 3. Synthesis of Dibenzoxepin Derivatives 2a-e from
3a-e and 3-Nitroboronic Acida
a All reactions were run with 1.2 equiv of boronic acid, 3.0 equiv of
Na2CO3, and 1 mol % Pd(OAc)2 in 4:1 dioxane/water (0.1 M) at 100 °C
for 12 h. b Isolated yields after column chromatography.
starting material.10 Increasing the catalyst loading to 10 mol
% Pd(OAc)2 and 20 mol % tri-o-tolylphosphine and raising
the temperature to 110 °C did consume all of the starting
material 3a; however, a much lower yield of the desired
product was observed. As anticipated, elimination of the
tetrabutylammonium chloride resulted in a more incomplete
reaction (entry 2). Next, we investigated several additional
solvents, under both ligand and ligandless conditions (entries
3-7). Although none of these reactions gave a satisfactory
result, this initial screening indicated that substrate 3a is more
reactive in solvents with higher dielectric constants. With 2
mol % of catalyst, toluene and dioxane led to a significant
amount of starting material 3a, indicating that the insertion
of palladium to alkyne did not take place under the reaction
conditions. n-BuOH and DMF led to a faster palladium
insertion process and completed reactions. However, sig-
nificant amounts of oligomers and polymers were observed.
It is likely that under these conditions, the initial palladium
insertion was activated, but the subsequent transmetalation
between vinylic palladium and boronic acid did not occur
at a reasonable rate.
a All reactions were run with 1.2 equiv of boronic acid, 3.0 equiv of
Na2CO3, and 1 mol % Pd(OAc)2 in 4:1 dioxane/water (0.1 M) at 70 °C for
12 h unless otherwise indicated. b Isolated yields after column chromatog-
raphy. c 4:1 DMF/water (0.1 M) was used as solvent.
9).7a,11,12 In fact, a significant enhancement in the reaction
rate was observed when the reactions were conducted in
DMF/water (4:1 v/v) and dioxane/water (4:1 v/v). Both
reactions went to completion at 70 °C in less than 1 h
accompanied by only trace amounts of polymerization.
However, under these conditions the direct Suzuki coupling
product 6 predominated.
In an effort to find conditions where the alkyne insertion
would be faster than the direct Suzuki coupling, we continued
our investigation by using dioxane/water (4:1) as the solvent
with various ligands (entries 9-11). None of the ligands gave
the desired 2a/6 ratios, but we were pleased to find that under
the ligandless condition (entry 12), desired product 2a and
direct Suzuki coupling product 6 were obtained in an
excellent ratio of 29:1. Therefore, under this optimized
condition, 2 mol % Pd(OAc)2, 1.2 equiv of 3-nitroboronic
acid, and 3 equiv of Na2CO313 at 70 °C for 12 h, the desired
product 2a was isolated in 89% yield.
Since the coupling of a vinylic palladium species with
arylboronic acids is essentially a variant of the Suzuki cross-
coupling reaction, which is known to proceed much faster
in water when a hydroxide is present, we examined the
possibility of using water as the cosolvent (entries 8 and
(11) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(12) After the completion of this work, Larock et al. reported the synthesis
of tetrasubstituted olefins through an intermolecular carbopalladation
process. Water as cosolvent and ligandless conditions were also proved to
be critical, see: (a) Zhou, C. Z.; Larock, R. C. J. Org. Chem. 2005, 70,
3765. (b) Zhou, C.; Larock, R. C. Org. Lett. 2005, 7, 259. (c) Zhang, X.;
Larock, R. C. Org. Lett. 2003, 5, 2993. (d) Zhou, C.; Emrich, D. E.; Larock,
R. C. Org. Lett. 2003, 5, 1579.
(10) (a) Wu, G.; Rheingold, A. L.; Geig, S. L.; Heck, R. F. Organo-
metallics 1987, 6, 1941. (b) Reddy, K.; Rajender, S. K.; Lee, G. H.; Peng,
S. M.; Liu, S. T. Organometallics 2001, 20, 5557.
Org. Lett., Vol. 8, No. 8, 2006
1687

To understand the scope of this cyclization, alkyne 3a was
next reacted with different arylboronic acids bearing both
electron-donating and electron-withdrawing groups. The
results summarized in Table 2 indicated that the reaction was
fairly general in scope as electron density in boronic acid
had little effect on reaction yield. In all cases, excellent ratios
of desired compounds (8a-f, 1a) versus direct coupling
products were obtained (>25:1). The excellent selectivity
could be explained by assuming that the desired cascade
reaction is sterically favored over the undesired direct
coupling reaction. A moderate yield (59%) was obtained
when m-methylsulfonylaminophenyl boronic acid was used
(Table 2, entry 7). The reduced yield resulted from competi-
tive deboronation,14 which was observed only in this case
where a sulfonamide group was present.
Similar reaction conditions used for the preparation of 2a
were applied to the formation of nuclear hormone modulators
2b-e15 (Table 3). Both electron-donating groups (entry 3)
and electron-withdrawing groups (entry 4) could be employed
in the aromatic ring directly connected to the alkyne to afford
the desired dibenzoxapine derivatives. The same strategy was
also used in the synthesis of dibenzoxapine derivative with
the opposite olefin isomer (entry 5). In all cases, the desired
compounds were isolated as single stereoisomers. As an-
ticipated, the eight-membered-ring product was not observed,
indicating the regioselectivity was dictated by the 7-exo-dig
nature of the process rather than the steric effect as in the
intermolecular reactions.16 It was also noteworthy that the
reaction proceeded with high catalyst turnover rate. The
reaction was more efficient with 0.5 mol % than 5 mol %
Pd(OAc)2.
With stereodefined tetrasubstituted exocyclic alkenes 2a-d
in hand, the final targets 1a-d were prepared uneventfully
via a nitro group reduction followed by a sulfonation
procedure (79-89% yield). Because of steric hindrance, the
tetrasubstituted alkenes were generally inert to various
hydrogenation conditions.
In summary, the palladium-catalyzed intramolecular alkyne
carbometalation reaction has proven to be a practical means
for preparing dibenzoxapine containing tetrasubstituted exo-
cyclic alkenes. High regio- and stereocontrol was obtained
in all cases. Employing phosphine-free Pd(0) catalyst and
water as the cosolvent afforded the target compounds in
excellent yields. The practical utility of this novel method
was demonstrated on the kilogram scale to afford the desired
dibenzoxapine with over 70% yield.
Acknowledgment. We would like to thank Professors
Marvin Miller and William Roush and Drs. Tony Zhang,
Scott May, Carmen Somoza, Marvin Hansen, Stan Kolis,
and David Mitchell for helpful discussions.
Supporting Information Available: Complete experi-
mental details along with spectroscopic data for all new
molecules synthesized. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) Since all of the above optimization was carried out with Na2CO3
as base, we also investigated the effect of base on the reaction results. CsF,
NaHCO3, K2CO3, and KHCO3 were used to replace Na2CO3 under the
optimized conditions. They all afforded good 2a/6 selectivity, but the yield
is generally lower.
OL060289A
(14) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(15) It was necessary to convert 2b to final target 1b soon after isolation.
2b could undergo a light-catalyzed isomerization during storage.
(16) (a) Cacchi, S. J. Organomet. Chem. 1999, 576, 42. (b) Larock, R.
C. J. Organomet. Chem. 1999, 576, 111. (c) Roesch, K. R.; Zhang, H.;
Larock, R. C. J. Org. Chem. 2001, 66, 8042.
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Org. Lett., Vol. 8, No. 8, 2006