Palladium-catalyzed cross-coupling of 2-aryl-1,3-dithianes

Article abstract of DOI:10.1021/ol502428h

Palladium-catalyzed cross-coupling of aryl bromides with 2-aryl-1,3-dithianes is described. This methodology takes advantage of the relatively acidic benzylic proton of the dithiane, allowing it to act as a competent, polarity-reversed transmetalation reagent. This unique approach affords the ability to employ an orthogonal deprotection strategy, and practical routes to both diaryl ketones and diarylmethanes are illustrated. Cross-coupling of a range of aryl dithianes with aryl bromides, including scope and current limitations, is presented.

Full text of DOI:10.1021/ol502428h

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Cross-Coupling of 2‑Aryl-1,3-dithianes
Summer A. Baker Dockrey, Alicia K. Makepeace, and Jason R. Schmink*
Department of Chemistry, Bryn Mawr College, 101 North Merion Avenue, Bryn Mawr, Pennsylvania 19010-2899, United States
S
* Supporting Information
ABSTRACT: Palladium-catalyzed cross-coupling of aryl bromides with 2-aryl-1,3-dithianes is described. This methodology takes
advantage of the relatively acidic benzylic proton of the dithiane, allowing it to act as a competent, polarity-reversed
transmetalation reagent. This unique approach affords the ability to employ an orthogonal deprotection strategy, and practical
routes to both diaryl ketones and diarylmethanes are illustrated. Cross-coupling of a range of aryl dithianes with aryl bromides,
including scope and current limitations, is presented.
orey and Seebach first reported that 1,3-dithiane reagents
1
Ccould be used as acyl anion equivalents in 1965. When
dithianes reacted with an equivalent of n-butyllithium, the
corresponding anions could be quenched with various electro-
philes including primary and secondary alkyl halides, ketones,
aldehydes, esters, carbon dioxide, and acyl chlorides. Since this
seminal report, these versatile reagents have been widely
utilized in synthesis as a reversed polarity synthon (Figure 1).2
For example, Smith and co-workers developed anion relay
chemistry relying on the nucleophilic character of the dithiane.3
Figure 2. The pKa trends of transmetalation reagents in cross-coupling
reactions.
transformation.8 Recently, Walsh and co-workers have even
used the less activated diphenylmethane (pKa 32.3, DMSO9) as
a transmetalation reagent in Pd-catalyzed cross-coupling
reactions.10
On the other hand, metal catalystsespecially palladium
Figure 1. Umpolung reactivity of 1,3-dithianes.
can be sensitive to sulfur and susceptible to catalyst
poisoning.11 Yet, given the right catalyst environment,
palladium-catalyzed cross-couplings proceed without difficulty
in the presence of pendant thioethers.12 Furthermore, C−S
bond formation can be accomplished via cross-coupling that
requires the intermediate complex with a Pd−S bond to be
formed.13
Though this reactivity has been exploited over the years,
dithiane nucleophiles as transmetalation reagents in cross-
coupling reactions are conspicuously absent from the literature.
On one hand, extending known transition-metal-catalyzed
cross-coupling conditions to 1,3-dithiane derivatives should
be an obvious one (Figure 2). With a pKa of 30.7 (in DMSO),
2-phenyl-1,3-dithiane4 is essentially as acidic as, for example,
the α proton of ethyl acetate5 (29.5, DMSO) or aniline6 (30.6,
DMSO). Palladium-catalyzed α-arylation of esters has been
widely exploited,7 and the C−N cross-coupling Buchwald−
Hartwig reaction has been so thoroughly developed and
subsequently utilized to be considered a routine laboratory
Our group’s interest in polarity-reversed cross-coupling
chemistry arose from our and others’ recent work using
acylsilanes as cross-coupling reagents in palladium-catalyzed
cross-coupling reactions.14 At a preparative scale, the most
Received: July 17, 2014
Published: September 5, 2014
© 2014 American Chemical Society
4730
dx.doi.org/10.1021/ol502428h | Org. Lett. 2014, 16, 4730−4733

Organic Letters
Letter
a
straightforward synthesis of acylsilanes requires three steps
from commercially available aldehydes.15 While the first two
steps are robust and high yielding, the final synthetic step is
touchy at best due to the labile C(sp2)−Si bond. This limits the
modes of oxidative cleavage/hydrolysis to the acylsilane, and
the unfortunate result is the need to use superstoichiometric
mercury salts, followed by chromatographic purification of the
crude reaction mixture. Ultimately, it is the most reliable route,
as it leaves the C−Si bond intact where other known methods
for dithiane deprotection16 show a propensity to over oxidize to
the carboxylic acid during hydrolysis (Figure 3).
Table 1. Reaction Optimization
b
entry
ligand
none
base
solvent
t (°C) conv (%)
1
2
3
4
5
6
7
8
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
KOtBu
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
60
60
60
60
60
60
60
60
60
60
60
60
60
80
80
0
0
PPh3
dppe
0
dppp
0
dppf
44
36
0
DPEPhos
Xantphos
NiXantphos
NiXantphos
NiXantphos
NiXantphos
NiXantphos
NiXantphos
NiXantphos
NiXantphos
100
100
46
53
4
c
9
Figure 3. Streamlined route to diaryl ketones utilizing 1,3-dithianes.
10
11
12
13
14
KOtBu
It did not escape our notice, however, that to synthesize the
acylsilanes, a carbon center with the desired, reversed-polarity
characteristic has already been generated two steps prior! If
instead of completing the synthesis of the acylsilane, we
intercepted the dithiane anion under cross-coupling conditions,
we hypothesized that we could develop a novel methodology17
that is more atom-economical,18 requires fewer synthetic steps,
and affords orthogonal dithiane deprotection strategies.
Initial reaction optimization focused first on bidentate
phosphine ligands, as we hypothesized the palladium should
be less susceptible to sulfur poisoning. Indeed, bisphosphines
are routinely employed when carrying out palladium-catalyzed
C−S bond formation.19 Thus, our model reaction sought to
couple 2-phenyl-1,3-dithiane with bromobenzene using 5%
Pd(OAc)2 and 10% of various phosphine ligands.
KOtBu
toluene
CPME
CPME
CPME
KOtBu
58
100
100
KOtBu
d
15
KOtBu
a
1.0 mmol scale, 0.2 M, 2 equiv of LiHMDS or 3 equiv of KOtBu, 5%
Pd(OAc)2, 10% ligand. Liquid chromatography area percent. 5%
Pd(OAc)2, 5.0% NiXantphos. 2.5% Pd(OAc)2, 2.5% NiXantphos.
b
c
d
Table 2. Cross-Coupling Aryl Bromides with 2-Aryl-1,3-
a
Dithianes
b
entry
Ar1
Ar2
yield (%)
Due to the moderate acidity at the benzylic position, our
initial optimization utilized LiHMDS in THF. At 60 °C, dppe
and dppp showed no reactivity (Table 1, entries 3 and 4),
though both dppf and DPEPhos led to some of the desired
transformation (Table 1, entries 5 and 6). Interestingly, using
the bidentate Xantphos ligand afforded none of the desired
coupling,20 though using the closely related NiXantphos led to
complete consumption of both starting materials and
quantitative conversion to the desired product after 24 h. It
has been shown that under the basic reaction conditions,
NiXantphos is likely deprotonated, leading to a very electron-
rich palladium center.21 Additionally, van Leeuwen and co-
workers disclosed that NiXantphos has both a larger bite angle
and is more flexible than Xantphos.22 Investigations are
ongoing in our lab to try to ascertain which of these
phenomena, if either, leads to the observed difference in
reactivity.
Our optimized set of conditions employs 2.5% Pd(OAc)2
with 2.5% NiXantphos in CPME and uses 3.0 equiv of KOtBu.
Allowing the reaction to age at 80 °C for 24−48 h effected
complete conversion and moderate to good isolated yields of a
range of 2,2-diaryl-1,3-dithianes (Table 2).
A range of aryl bromides was shown to engage in this
protocol, affording the cross-coupled product in fair to excellent
yields. The reaction tolerated the cross-coupling of aryl
bromide in the presence of aryl chlorides on either coupling
1
2
C6H5
C6H5
81
72
65
4-MeSC6H4
4-FC6H4
3
2-naphthyl
C6H5
c
4
C6H5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-MeC6H4
4-MeC6H4
4-FC6H4
75, 83
5
4-ClC6H4
86
99
89
83
6
4-MeSC6H4
7
2-naphthyl
8
4-FC6H4
c
9
3-MeOC6H4
72
10
11
12
13
14
15
16
17
18
19
20
21
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
4-MeC6H4
81
74
96
90
4-ClC6H4
c
4-t-BuC6H4
2-naphthyl
4-OCF3C6H4
6-bromoquinoline
3-bromopyridine
4-MeOC6H4
C6H5
72
61
c
72
c
30
6
d
67
3,4,5-(MeO)3C6H2
4-Cl
63
e
4-BrC6H4
71
a
b
1.0 mmol scale, 0.2 M, 3 equiv KOtBu. Isolated yield after column
chromatography. 48 h reaction time. The aryl iodide (1.2 equiv, 60
°C) was used. From 1,4-dibromobenzene.
c
d
e
4731
dx.doi.org/10.1021/ol502428h | Org. Lett. 2014, 16, 4730−4733

Organic Letters
Letter
reagent (Table 2, entries 5 and 13). When a full equivalent of
1,4-dibromobenzene is used, only a single coupling is observed
(via crude GC). An attempt to engage both electrophilic sites
by adding only 0.5 equiv led to a messy reaction mixture, and
still none of the disubstituted product was observed via GC or
1H NMR of the crude reaction mixture.
The cross-coupling proceeded smoothly with both moder-
ately electron-rich and electron-poor partners, though when
strong electron-withdrawing groups were a part of either the
aryl bromide or the dithiane, reactivity was attenuated.
Reactions run with a nitro, nitrile, or trifluoromethyl
functionality as part of either of the coupling partners provided
none of the desired products.
Additional initial limitations to this methodology include the
inability to engage with sterically demanding aryl halides; for
example, 2-bromotoluene or 2-bromoanisole showed no
conversion to the desired diaryl dithianes. While both 3-
bromopyridine and 6-bromoquinoline provided the expected
products, the introduction of the electron-poor pyridine ring
led to low isolated yields of 6 and 30%, respectively. Repeated
attempts were made to use phenyl triflate in lieu of the
bromide, though each was met with no observed cross-
coupling. Research into improving these current limitations is
ongoing.
Figure 4. Putative catalytic cycle.
Table 3. Synthesis of Benzophenones and Diarylmethanes
via Two-Step, One Pot Procedures
Aryl iodides could be used in place of aryl bromides (Table 2,
entry 19), though we found that direct application of the
general procedure consumed the 4-iodoanisole without
complete conversion of the aryl dithiane. However, decreasing
the temperature to 60 °C and using a slight excess of the iodide
afforded complete conversion of both starting materials and an
67% isolated yield of the title compound.
Interestingly, when this methodology was applied to 2-
benzyl-1,3-dithiane, a tandem elimination/ring opening fol-
lowed by a Pd-catalyzed C−S bond formation was observed
(Scheme 1). Initial data indicate that this new reaction proceeds
b
entry
Ar1
4-FC6H4
Ar2
yield (%)
a
benzophenones
1
2
3
4
5
6
7
8
9
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-FC6H4
66
52
55
3-MeC6H4
4-ClC6H4
c
4-MeSC6H4
65
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3-MeOC6H4
72
66
40
41
53
Scheme 1. Reaction with 2-Benzyl-1,3-dithiane
4-ClC6H4
4-t-BuC6H4
4-MeOC6H4
a
diarylmethanes
10
11
12
13
3-MeOC6H4
C6H5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-MeC6H4
54
50
53
38
3-MeC6H4
with a high degree of trans specificity. Further investigations
into this ring opening are underway, and the results will be
reported in due course.
3,4-(OCH2O)C6H3
a
b
1.0 mmol scale. Two-step isolated yield after column chromatog-
raphy. Trace amount of the oxidized methyl thioether was detected in
the crude H NMR.
c
1
Our putative mechanism for this new transformation
conforms well to other cross-coupling mechanisms. In
particular, we suspect that the transmetalation/ligand exchange
step is similar to α-carbonyl arylation, whereby precoordination
to the catalytic center of the extant nucleophile (here, sulfur)
increases the acidity of the C2 carbon of the dithiane, assisting
in transmetalation. We have begun kinetic studies in order to
more fully understand this mechanism (Figure 4).
Differential deprotection of the diaryl dithianes afforded
benzophenones or diarylmethanes. After cross-coupling, the
crude reaction mixture could be taken on to the next step
directly where the dithiane was oxidatively hydrolyzed23 to
afford the substituted benzophenones in good yield over two
steps (Table 3). Alternatively, the crude reaction mixture could
be taken up in ethanol and refluxed overnight in the presence of
Raney nickel to afford diarylmethanes in good yield. The
flexibility of the removal of the dithiane to access two important
compounds classes should make this an attractive methodology
in small molecule synthesis.
In conclusion, we have reported the first palladium-catalyzed
cross-coupling of 2-aryl-1,3-dithianes with a range of aryl
bromides using a Pd(OAc)2/NiXantphos catalyst system. After
cross-coupling, the pendant dithiane can either be cleaved with
Raney nickel to afford diarylmethanes or hydrolyzed to afford
substituted benzophenones in good yields. Work is being
pursued to expand the scope of this reaction to include
heteroaryl bromides and aryl and heteroaryl triflates. Finally, we
have begun to examine the interesting tandem ring opening,
C−S bond formation encountered when employing 2-benzyl-
1,3-dithianes.
4732
dx.doi.org/10.1021/ol502428h | Org. Lett. 2014, 16, 4730−4733

Organic Letters
Letter
Canivet, C.; Spindler, J.-F.; Perrio, S.; Beslin, P. Tetrahedron 2005, 61,
5253.
ASSOCIATED CONTENT
■
S
* Supporting Information
(14) (a) Schmink, J. R.; Krska, S. W. J. Am. Chem. Soc. 2011, 133,
19574. (b) Cunico, R. F.; Maity, B. C. Org. Lett. 2002, 4, 4357.
(c) Cunico, R. F.; Pandey, R. K. J. Org. Chem. 2005, 70, 9048.
(d) Ramgren, S. D.; Garg, N. K. Org. Lett. 2014, 16, 824. (e) For a
metal-free approach, see: Ito, K.; Tamashima, H.; Iwasawa, N.;
Kusama, H. J. Am. Chem. Soc. 2011, 133, 3716.
(15) (a) Zhang, H.-J.; Priebbenow, D. L.; Bolm, C. Chem. Soc. Rev.
2013, 42, 8540. (b) Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc.
Rev. 1990, 19, 147.
(16) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; John Wiley & Sons, Inc.: New York, 2007;
pp 482−500.
(17) We were able to find one instance of the attempted cross-
coupling of aryl iodides at the 2-position of 1,3-dithianes: McFarlane,
M. T. Metal-Catalyzed Cross-Coupling Reactions with Dithiolanes and
Dithianes. M.S. Thesis, University of Manitoba, Winnipeg, Canada,
2012.
(18) Trost, B. M. Science 1991, 254, 1471.
(19) For a review, see: Eichman, C. C.; Stambuli, J. P. Molecules
2011, 16, 590.
(20) Repeated attempts were made under various reaction
conditions, but Xantphos never affected the desired transformation.
(21) Zhang, J.; Bellomo, A.; Trongsiriwat, N.; Jia, T.; Carroll, P. J.;
Dreher, S. D.; Tudge, M. T.; Yin, H.; Robinson, J. R.; Schelter, E. J.;
Walsh, P. J. J. Am. Chem. Soc. 2014, 136, 6276.
Detailed experimental procedures and characterization data for
1
all compounds. H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jschmink@brynmawr.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.K.M. and S.B.D. acknowledge the Charles Casey Under-
graduate Research Fellowship for funding support. Bryn Mawr
College and the Isabel H. Benham Fund for Faculty Research
are acknowledged for funding support. The authors acknowl-
edge the National Science Foundation for a Major Research
Instrumentation award (CHE-0958996), which paid for the
NMR spectrometer used in these studies. The authors
acknowledge Mr. Jesse McAtee (University of Delaware) for
HRMS data.
(22) van der Veen, L. A.; Keeven, P. H.; Schoemaker, G. C.; Reek, J.
N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Lutz, M.; Spek, A.
L. Organometallics 2000, 19, 872.
REFERENCES
■
(1) (a) Seebach, D.; Corey, E. J. Angew. Chem., Int. Ed. Engl. 1965, 4,
1077. (b) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231.
(23) For reaction conditions, see Supporting Information.
(2) (a) Grobel, B. T.; Seebach, D. Synthesis 1977, 6, 357. (b) Page, P.
̈
C. B.; Van Niel, M. B.; Prodger, J. C. Tetrahedron 1989, 45, 7643.
(c) Kolb, M. In Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; John Wiley & Sons: Chichester, UK, 1995; Vol. 5, p 2983.
́
For a review, see: (d) Yus, M.; Najera, C.; Foubelo, F. Tetrahedron
2003, 59, 6147. (e) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18,
239.
(3) (a) Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365.
(b) Smith, A. B., III; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.;
Sfouggatakis, C.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 14435.
(c) Smith, A. B., III; Pitram, S. M. Org. Lett. 1999, 1, 2001. (d) Smith,
A. B.; Kim, D. S. Org. Lett. 2004, 6, 1493. (e) Smith, A. B., III; Xiang,
M. J. Am. Chem. Soc. 2006, 128, 66.
(4) Bordwell, F. G.; Bares, J. E.; Bartmess, J. E.; Drucker, G. E.;
Gerhold, J.; McCollum, G. J.; Van der Puy, M.; Vanier, N. R.;
Matthews, W. S. J. Org. Chem. 1977, 42, 326.
(5) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1981, 46, 4327.
(6) Bordwell, F. G.; Algrim, D.; Vanier, N. R. J. Org. Chem. 1977, 42,
1817.
(7) (a) Johanasson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed.
2010, 49, 676. (b) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545.
(c) Biscoe, M. R.; Buchwald, S. L. Org. Lett. 2009, 11, 1773. (d) Hama,
T.; Hartwig, J. F. Org. Lett. 2008, 10, 1549. (e) Lloyd-Jones, G. C.
Angew. Chem., Int. Ed. 2002, 41, 953.
(8) (a) Muci, A. R.; Buchwald, S. L. Practical Palladium Catalysts for
C−N and C−O Bond Formation. In Cross-Coupling Reactions: A
Practical Guide. Miyaura, N., Ed.; Springer: Berlin, 2002; pp 131−209.
(b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (c) Surry, D. S.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
(9) Bordwell, F. G.; Matthews, W. S.; Vanier, N. R. J. Am. Chem. Soc.
1975, 97, 442.
(10) Zhang, J.; Bellomo, A.; Creamer, A. D.; Dreher, S. D.; Walsh, P.
J. J. Am. Chem. Soc. 2012, 134, 13765.
(11) Dunleavy, J. K. Platinum Met. Rev. 2006, 50, 110.
(12) For examples, see: (a) Li, G. Y. J. Org. Chem. 2002, 67, 3643.
(b) Bolliger, J. L.; Frech, C. M. Adv. Synth. Catal. 2010, 352, 1075.
(13) (a) Migata, T.; Shimizu, T.; Asami, Y.; Shiobara, J.-i.; Kato, Y.;
Kosugi, M. Bull. Chem. Soc. Jpn. 1980, 53, 1385. (b) Mispelaere-
4733
dx.doi.org/10.1021/ol502428h | Org. Lett. 2014, 16, 4730−4733