Palladium-Catalyzed Synthesis of Six-Membered Benzofuzed Phosphacycles via Carbon-Phosphorus Bond Cleavage

Article abstract of DOI:10.1021/ol503252t

The palladium-catalyzed synthesis of dibenzofused six-membered phosphacycles via carbon-phosphorus bond cleavage is developed. This method is compatible with a range of functional groups, such as esters, amides, and carbamates, which is in sharp contrast to the limitations of the classical method using organolithium reagents. (Figure Presented).

Full text of DOI:10.1021/ol503252t

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Synthesis of Six-Membered Benzofuzed
Phosphacycles via Carbon−Phosphorus Bond Cleavage
Katsuaki Baba,† Mamoru Tobisu,*,‡ and Naoto Chatani*,†
†Department of Applied Chemistry, Faculty of Engineering and ‡Center for Atomic and Molecular Technologies, Graduate School of
Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: The palladium-catalyzed synthesis of dibenzofused six-membered
phosphacycles via carbon−phosphorus bond cleavage is developed. This
method is compatible with a range of functional groups, such as esters, amides,
and carbamates, which is in sharp contrast to the limitations of the classical
method using organolithium reagents.
hosphole and its benzo-fused derivatives have recently
palladium-catalyzed method for the synthesis of phosphacyles 2
from triphenylphosphine derivative via the cleavage of the
carbon−phosphorus (C−P) bond (Scheme 1c). To our
knowledge, this reaction represents the first catalytic synthesis
of 2.4
P
attracted significant attention as promising organic materials
due to their unique optical and electronic properties.1 For
example, a dibenzo[b,d]phosphole skeleton 1 has frequently
been employed as a structurally rigid and electronically tunable
alternative of a biphenyl unit for incorporation into organic
materials (Scheme 1a).2 In contrast to the significant progress in
Recently, our group developed a palladium-catalyzed method
for the synthesis of phospholes from triphenylphosphine
derivatives through the cleavage of the C−P bond.5 This
catalytic method features (1) operational simplicity, (2) direct
use of readily available tertiary phosphines as the phosphorus
source, (3) excellent functional group compatibility, and (4) high
modularity of the incorporated aromatic ring. Given these
favorable attributes, we attempted to apply this C−P bond
cleavage strategy to the synthesis of six-membered phosphacycle
2. Thus, we envisioned that 2-phenoxytriphenylphosphine (5)
would react with a palladium(II) catalyst to form palladacycle 6,
which would eventually lead to the formation of phosphacycle 7
via C−P bond cleavage similar to phosphole synthesis (Scheme
2).5 However, the exposure of 5 to the conditions developed for
the synthesis of phospholes (i.e., 5 mol % of Pd(OAc)2, in
toluene, 160 °C, 12 h) delivered none of the desired cyclized
product 7, and the starting phosphine 5 was recovered
quantitatively. The unsuccessful result with 5 could be attributed
Scheme 1. Six-Membered Phosphacycles: Utility and
Synthesis
Scheme 2. Working Hypothesis
the preparative methods and applications of phospholes, the
chemistry of the corresponding six-membered phosphacycles is
much less explored,3 although they are expected to share many of
their unique physical properties. One obvious reason that
discourages the study of six-membered phosphacycles is the
limited methods available for their syntheses. The six-membered
phosphacycle 2 is typically assembled through a nucleophilic
substitution reaction between a dilithium species 3 and
dichlorophosphine 4 (Scheme 1b).3a,g,k,m However, the scope
of this method is severely limited by low functional group
compatibility and the air/moisture sensitivity of organolithium
reagents. Therefore, more general methods that allow for access
to elaborate derivatives are clearly needed. Herein, we describe a
Received: November 9, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503252t | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to problems with the assembly of the seven-membered
metallacyclic intermediate 6, compared with the six-membered
ring intermediate for phosphole synthesis during the cyclo-
palladation process. We surmised that the key intermediate 6
could also be generated by oxidative addition of halide 8 to
palladium(0), which should occur relatively easily in view of the
higher reactivity of the C−X bond compared with the C−H
bond.
Scheme 3. Palladium-Catalyzed Synthesis of Six-Membered
Phosphacycles
a,b
To verify the feasibility of our hypothesis, we initially examined
the palladium-catalyzed reaction of phosphine 9 (Table 1).
Table 1. Optimization Studies
entry
catalyst
Pd(OAc)2
additive
Zn
solvent
DMF
NMR yield (%)
1
2
3
4
5
6
7
8
9
10
19
56
28
36
53
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3·CHCl3
Pd(PPh3)4
DMF
(EtO)3SiH
DMF
Et3SiH
iPr3SiH
DMF
DMF
b
(Me3Si)3SiH
(Me3Si)3SiH
(Me3Si)3SiH
(Me3Si)3SiH
(Me3Si)3SiH
DMF
83 (86)
toluene
1,4-dioxane
DMF
81
76
70
81
DMF
a
Reaction conditions: 9 (0.20 mmol), catalyst (0.010 mmol), additive
b
a
(0.24 mmol), solvent (0.40 mL), for 12 h. Isolated yield.
Reaction conditions: bromide (0.30 mmol), Pd(OAc)2 (0.015
mmol), (Me3Si)3SiH (0.36 mmol), DMF (0.60 mL), at 130 °C for
b
c
12 h. Isolated yield. Substrate (0.30 mmol), Pd(OAc)2 (0.015
mmol), (Me3Si)3SiH (0.36 mmol), K3PO4 (0.36 mmol), DMF (0.60
mL), at 130 °C for 12 h.
Pleasingly, the expected cyclization occurred, when 9 in
conjunction with 5 mol % of Pd(OAc)2 was heated at 130 °C
for 12 h in DMF (entry 1). Because the cyclic phosphane product
was prone to oxidation upon workup, the yield of the product
was quantified by conversion to the corresponding oxide 10
(19% yield based on NMR analysis). Consideration of the
reaction mechanism led us to infer that the regeneration of an
active Pd(0) species after formation of the product is inefficient
under these conditions, and the catalyst turnover might be
improved by addition of a suitable reducing agent (see Scheme 6
for our mechanistic proposal). Indeed, addition of metallic zinc
was found to increase the yield of 10 to 56% (entry 2).
Hydrosilanes were also found to be effective reductants for this
cyclization reaction. Interestingly, the substituents on the silicon
atom had a profound impact on the efficiency of the reaction
(entries 3−6).6 The addition of a bulkier hydrosilane such as
(Me3Si)3SiH improved the yield, providing 86% of 10 (entry 6).
This catalytic cyclization could also be conducted in nonpolar
solvents, such as toluene and dioxane, without significant
decrease in yield (entries 8 and 9). In agreement with our
mechanistic hypothesis, palladium(0) complexes also served as
effective catalyst precursors (entries 9 and 10), which is in sharp
contrast to the results from our previous Pd(II)-catalyzed
phosphole synthesis.5
enabled the incorporation of aromatic and heteroaromatic rings
other than phenyl, allowing for the synthesis of π-extended
phosphacycles, such as those containing naphthalene and
carbazole (i.e., 22 and 23). In addition to the phenoxaphosphi-
nine scaffold, phenophosphazine derivative 24 could also be
prepared by using a nitrogen-tethered substrate.
Although we routinely isolated the products as the oxides, the
phosphorus center of the resulting phosphacycles can be
differently modified through a suitable post-treatment. For
example, treatment of phosphacycle 10 (prepared from 9) with
MeI produced the phosphonium salt 25 (Scheme 4). When the
substrate bearing a PPhBu group, i.e., 26 was exposed to the
catalytic conditions, a phenyl group, rather than a butyl group,
Scheme 4. Synthesis of Phosphonium Salt 25 and P-Alkyl
Derivative 27
With optimized reaction conditions in hand, we next examined
the scope of substrates for this catalytic cyclization reaction. As
depicted in Scheme 3, a wide range of functional groups was
tolerated. In particular, phosphacycles containing cyano, ester,
amide and carbamate groups (i.e., 13, 14, 16−19), which are
inaccessible by the classical method using organlithium reagents,
could be synthesized successfully. Our catalytic method also
B
dx.doi.org/10.1021/ol503252t | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
was eliminated exclusively to deliver a P-alkyl-substituted
phosphacycle 27.5
Our catalytic cyclization reaction was also applicable for the
synthesis of phosphole derivatives as shown in Scheme 5. In this
bond in the phosphonium C can be cleaved through oxidative
addition to the Pd(0) species,8 releasing a phosphacycle product
D and PhPdBr E. If intermediate E undergoes reductive
elimination of PhBr, an active Pd(0) species can be regenerated.
However, such a C−halogen bond-forming reductive elimination
is known to be thermodynamically unfavorable.9 Thus, the
reaction only proceeded in low yield when the reaction was
conducted in the absence of a reducing agent (entry 1, Table 1).
Addition of hydrosilane can promote the regeneration of Pd(0)
by reductively cleaving Pd(II) intermediate E to benzene and
silyl bromide, similar to the process involved in the catalytic
reductive dehalogenation of aryl halides.10 When less bulky
hydrosilanes were used, reductive debromination of A occurs
competitively to form A′, thus resulting in a lower yield of the
desired cyclized product D. Bulky (Me3Si)3SiH effectively
discriminates Pd(II) intermediates B and E, allowing for the
exclusive formation of D.
Scheme 5. Palladium-Catalyzed Synthesis of Phosphole
a,b
Derivatives
Our method could be useful for the construction of a π-
extended ladder-type structure through double cyclization.
Bisphosphine 35 prepared from 34 was readily converted to 36
via successive cleavage of C−P bonds (Scheme 7).
a
Reaction conditions: substrate (0.30 mmol), Pd(OAc)2 (0.015
mmol), Et3SiH (0.36 mmol), DMA (0.60 mL), at 130 °C for 6 h.
b
c
Isolated yield. Corresponding bromides were used as starting
Scheme 7. Synthesis of π-Extended Phosphacycle 36
materials.
case, the use of the less bulky Et3SiH allowed for the formation of
phospholes in an efficient manner, presumably because the
formation of the six-membered metallacyclic intermediate occurs
more easily than the corresponding seven-membered ring, as in
6. Both bromides and triflates served as the appropriate
precursors for the palladium-catalyzed cyclization via C−P
bond cleavage. A brief survey of several biaryl substrates
demonstrated that a series of fused phosphole derivatives could
be synthesized in a similar manner. Unfortunately, the extension
of this method to the synthesis of seven-membered phospha-
cycles was unsuccessful (see the Supporting Information for
details).
A possible mechanism for the reaction is depicted in Scheme 6.
The oxidative addition of bromide A to the Pd(0) species initially
forms a seven-membered palladacycle B. Subsequent C−P bond-
forming reductive elimination from B generates a cyclic
phosphonium salt C, along with a Pd(0) species.7 The P−Ph
If the palladacycle intermediate that is capable of undergoing
C−P bond cleavage, such as B, can be assembled in an
intermolecular manner, the utility of the method would be
further enhanced. One way to achieve such a goal involves a
carbopalladation of bromide 37 across an alkyne, which should
eventually lead to the formation of the benzophosphole
derivative. A preliminary study revealed that our reaction design
could be realized by using a benzyne as the alkyne component.
Thus, the palladium-catalyzed reaction of bromide 37 with the
benzyne precursor 38 in the presence of CsF and hydrosilane
afforded the dibenzophosphole 29 in 24% yield (Scheme 8).11
Scheme 6. Possible Mechanism
Scheme 8. Intermolecular Assembly of Dibenzophosphole via
Catalytic C−P Bond Cleavage
In summary, the first catalytic method for the synthesis of P,X-
bridged biaryl derivatives was developed. The method features
C−P bond cleavage, which allows for the use of tertiary
phosphines as a stable and readily available phosphorus source. It
proved to be highly compatible with several functional groups
including esters, amides, and carbamates. This method over-
comes the limitation encountered in the classical method that
uses organolithium reagents. Applications of this method to the
C
dx.doi.org/10.1021/ol503252t | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Organometallics 2010, 29, 1210. P,N-bridged phosphacycles: (f) Free-
man, H. S.; Freedman, L. D. J. Org. Chem. 1981, 46, 5373. (g) Dodds, D.
L.; Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, J. G.; van Leeuwen,
P. W. N. M.; Kamer, P. C. J. Eur. J. Inorg. Chem. 2012, 1660. P,B-bridged
phosphacycles: (h) Agou, T.; Kobayashi, J.; Kawashima, T. Org. Lett.
2005, 7, 4373. (i) Agou, T.; Kobayashi, J.; Kawashima, T. Inorg. Chem.
2006, 45, 9137. P,Si-bridged phosphacycles: (j) Tsuji, H.; Komatsu, S.;
Kanda, Y.; Umehara, T.; Saeki, T.; Tamao, K. Chem. Lett. 2006, 35, 758.
(k) Ren, Y.; Baumgartner, T. Chem.Asian J. 2010, 5, 1918. P,CO-
bridged phosphacycles: (l) Gray, M.; Chapell, B. J.; Taylor, N. J.;
Snieckus, V. Angew. Chem., Int. Ed. 1996, 35, 1558. (m) He, X.; Lin, J.-B.;
Kan, W. H.; Baumgartner, T. Angew. Chem., Int. Ed. 2013, 125, 9160.
(4) Catalytic synthesis of a related 5,6-dihydrophosphanthridine was
recently reported during the course of our studies: Chen, Y.-R.; Duan,
W.-L. Synthesis 2014, 46, 1067.
synthesis of other heterocycles through carbon−heteroatom
bond cleavage are currently being investigated in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and details pertaining to the
characterization of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tobisu@chem.eng.osaka-u.ac.jp.
*E-mail: chatani@chem.eng.osaka-u.ac.jp.
Notes
(5) Baba, K.; Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52,
11892.
(6) A varying amount (∼30%) of reductive debrominated byproduct
was formed with less bulky hydrosilanes.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(7) (a) Migita, T.; Nagai, T.; Kiuchi, K.; Kosugi, M. Bull. Chem. Soc. Jpn.
1983, 56, 2869. (b) Hinkle, R. J.; Stang, P. J.; Kowalski, M. H. J. Org.
Chem. 1990, 55, 5033. (c) Kwong, F. Y.; Chan, K. S. Chem. Commun.
2000, 36, 1069. (d) Kwong, F. Y.; Chan, K. S. Organometallics 2000, 19,
2058. (e) Kwong, F. Y.; Chan, K. S. Organometallics 2001, 20, 2570.
(8) Catalytic reactions of triarylphosphines that involve the cleavage of
a C−-P bond: (a) Kwong, F. Y.; Chan, K. S. Chem. Commun. 2000, 36,
1069. (b) Kwong, F. Y.; Chan, K. S. Organometallics 2000, 19, 2058.
(c) Kwong, F. Y.; Chan, K. S. Organometallics 2001, 20, 2570.
(d) Hwang, L. K.; Na, Y.; Lee, J.; Do, Y.; Chang, S. Angew. Chem., Int. Ed.
2005, 44, 6166. (e) Ma, M.-T.; Lu, J.-M. Tetrahedron 2013, 69, 2102.
(f) Li, Z.; Zhou, H.; Xu, J.; Wu, X.; Yao, H. Tetrahedron 2013, 69, 3281.
See also ref 5. Undesired incorporation of an aryl group of
triarylphosphine-based ligands via C-P bond cleavage has also been
observed in several catalytic processes (g) Garrou, P. E. Chem. Rev. 1985,
85, 171. (h) Macgregor, S. A. Chem. Soc. Rev. 2007, 36, 67.
(9) Reductive elimination of ArBr from ArPdBr was only observed
when sterically hindered alkylphosphine was added as a ligand: (a) Roy,
A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232. (b) Roy, A. H.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 13944. (c) Roy, A. H.;
Hartwig, J. F. Organometallics 2004, 23, 1533.
(10) (a) Fowley, L. A.; Michos, D.; Luo, X.-L.; Crabtree, R. H.
Tetrahedron Lett. 1993, 34, 3075. (b) Boukherroub, R.; Chatgilialoglu,
C.; Manuel, G. Organometallics 1996, 15, 1508.
■
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” from The Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
Japan, and ACT-C from JST, Japan. K.B. expresses his special
thanks for a JSPS Research Fellowship for Young Scientists. We
also thank the Instrumental Analysis Center, Faculty of
Engineering, Osaka University, for assistance with the MS and
HRMS.
REFERENCES
(1) Reviews: (a) Baumgartner, T.; Rea
■
́
u, R. Chem. Rev. 2006, 106,
4681. (b) Matano, Y.; Imahori, H. Org. Biomol. Chem. 2009, 7, 1258.
(c) Fukazawa, A.; Yamaguchi, S. Chem.Asian J. 2009, 4, 1386.
(d) Romero-Nieto, C.; Baumgartner, T. Synlett 2013, 24, 920. (e) Stolar,
M.; Baumgartner, T. Chem.Asian. J. 2014, 9, 1212. (f) Baumgartner,
T. Acc. Chem. Res. 2014, 47, 1613.
(2) For examples, see: (a) Chen, R.-F.; Zhu, R.; Fan, Q.-L.; Huang, W.
Org. Lett. 2008, 10, 2913. (b) Fukazawa, A.; Hara, M.; Okamoto, T.; Son,
E.-C.; Xu, C.; Tamao, K.; Yamaguchi, S. Org. Lett. 2008, 10, 913.
́ ́ ́
(c) Dienes, Y.; Eggenstein, M.; Karpati, T.; Sutherland, T. C.; Nyulaszi,
L.; Baumgartner, T. Chem.Eur. J. 2008, 14, 9878. (d) Kira, A.;
Shibano, Y.; Kang, S.; Hayashi, H.; Umeyama, T.; Matano, Y.; Imahori,
H. Chem. Lett. 2010, 39, 448. (e) Yin, J.; Chen, R.-F.; Zhang, S.-L.; Ling,
Q.-D.; Huang, W. J. Phys. Chem. A 2010, 114, 3655. (f) Fukazawa, A.;
Kiguchi, M.; Tange, S.; Ichihashi, Y.; Zhao, Q.; Takahashi, T.; Konishi,
T.; Murakoshi, K.; Tsuji, Y.; Staykov, A.; Yoshizawa, K.; Yamaguchi, S.
Chem. Lett. 2011, 40, 174. (g) Ren, Y.; Baumgartner, T. J. Am. Chem. Soc.
2011, 133, 1328. (h) Bruch, A.; Fukazawa, A.; Yamaguchi, E.;
Yamaguchi, S.; Studer, A. Angew. Chem., Int. Ed. 2011, 50, 12094.
(i) Matano, Y.; Saito, A.; Fukushima, T.; Yokudome, Y.; Suzuki, F.;
Sakamaki, D.; Kaji, H.; Ito, A.; Tanaka, K.; Imahori, H. Angew. Chem., Int.
Ed. 2011, 50, 8016. (j) Ren, Y.; Kan, W. H.; Henderson, M. A.; Bomben,
P. G.; Berlinguette, C. P.; Thangadurai, V.; Baumgartner, T. J. Am. Chem.
Soc. 2011, 133, 17014. (k) Ren, Y.; Baumgartner, T. Dalton Trans. 2012,
41, 7792. (l) Cen, H.; Delaunay, W.; Li, J.; Wang, Z.; Bouit, P.-A.;
(11) The reaction of 37 with diphenylacetylene and 4-octyne produced
no desired product under the standard conditions.
́
Tondelier, D.; Geffroy, B.; Mathey, F.; Duan, Z.; Reau, R.; Hissler, M.
Org. Lett. 2013, 15, 330. (m) Ren, Y.; Biegger, F.; Baumgartner, T. J.
Phys. Chem. C 2013, 117, 4748. (n) He, X.; Woo, A. Y. Y.; Borau-Garcia,
J.; Baumgartner, T. Chem.Eur. J. 2013, 19, 7620.
(3) P,O-bridged phosphacycles: (a) Mann, F. G.; Millar, I. T. J. Chem.
Soc. 1953, 3746. (b) Granoth, I.; Levy, J. B.; Symmes, J. C. J. Chem. Soc.,
Perkin Trans. 2 1972, 697. (c) Bronger, R. P. J.; Bermon, J. P.; Herwig, J.;
Kamer, P. C. J.; van Leeuwen, P. W. N. M. Adv. Synth. Catal. 2004, 346,
789. (d) Tschan, M. J.-L.; Garcia-Suarez, E. J.; Freixa, Z.; Launay, H.;
Hagen, H.; Benet-Buchholz, J.; van Leeuwen, P. W. N. M. J. Am. Chem.
Soc. 2010, 132, 6463. (e) Zuidema, E.; Goudriaan, P. E.; Swennenhuis,
B. H. J.; Kamer, P. C.; van Leeuwen, P. W. N. M.; Lutz, M.; Spek, A. L.
D
dx.doi.org/10.1021/ol503252t | Org. Lett. XXXX, XXX, XXX−XXX