Chemoselective cross-coupling reactions with differentiation between two nucleophilic sites on a single aromatic substrate

Article abstract of DOI:10.1021/ol302571t

A new thiophene building block, containing both a stannyl group and a boronic ester, was prepared. From this starting material, a general, nucleophile-selective one-pot reaction was developed, exploiting the different reactivities of the Stille and Suzuki-Miyaura cross-coupling reactions. A series of aromatic electrophiles were used to demonstrate the high functional group tolerance.

Full text of DOI:10.1021/ol302571t

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5644–5647
Chemoselective Cross-Coupling
Reactions with Differentiation between
Two Nucleophilic Sites on a Single
Aromatic Substrate
Julian Linshoeft, Annika C. J. Heinrich, Stephan A. W. Segler, Paul J. Gates,† and
Anne Staubitz*
€
Otto-Diels-Institut fu€r Organische Chemie, Universitat Kiel,
Otto-Hahn-Platz 4, 24118 Kiel, Germany
astaubitz@oc.uni-kiel.de
Received September 18, 2012
ABSTRACT
A new thiophene building block, containing both a stannyl group and a boronic ester, was prepared. From this starting material, a general,
nucleophile-selective one-pot reaction was developed, exploiting the different reactivities of the Stille and SuzukiꢀMiyaura cross-coupling
reactions. A series of aromatic electrophiles were used to demonstrate the high functional group tolerance.
Transition metal catalyzed cross-coupling reactions
(CCRs) are among the most powerful tools in synthesis.1
They are crucial for the preparation of many complex
organic natural products,2 pharmaceuticals, and agro-
chemicals.3 In all these fields, heterocycles play an important
role but thiophenes are unquestionably the most impactful.4
The incorporation of thiophene into organic semiconduct-
ing materials for example is a highly active research area:5
Thiophenes and their derivatives are arguably the most
important monomers for semiconducting polymers6 and
oligomers5a,7 which find already widespread use in, for
example, plastic solar cells6a,8 and organic field effect transis-
tors.5a,7a,c,9 The exploration of their chemistry, in particular
their efficient functionalization, is therefore of great urgency.
The electrophiles used in CCRs have different reactivity,
which depends on the leaving group. Typically, a gradual
decrease in reactivity is observed for electrophiles containing
† School of Chemistry, University of Bristol, Bristol BS8 1TS, U.K.
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Chem., Int. Ed. 2012, 51, 5062. (c) Meijere, A. d.; Stang, P. J. Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim,
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Med. Chem. Lett. 2004, 14, 2817. (c) Majumdar, K. C.; Chattopadhyay,
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r
10.1021/ol302571t
Published on Web 11/02/2012
2012 American Chemical Society

the leaving groups I > OTf > Br . Cl.10 This difference in
reactivity has enabled the development of selective CCRs
with respect to the electrophile.11 In contrast, nucleophile-
selective CCRs have rarely been reported and the few
reports that do exist are largely associated with nonaromatic
compounds.12 There are only a few examples in which the
difference in reaction rate between Stille and Suzukiꢀ
Miyaura cross-coupling has been used13 and only one
example of a chemoselective CCR involving an aromatic
compound containing both tin- and boron-based substitu-
ents at the same molecule.14 In that particular case, the
benzene derivative para-Bu3SnꢀC6H4ꢀB(OR)2 was cross-
coupled with two protected nucleosides for boron neutron
capture therapy, but generality was not demonstrated. One
possible reason for the striking neglect of nucleophile selective
CCRs is that methods for preparing appropriate aromatic
starting materials containing two different nucleophilic
groups are very rare in the literature.14 These starting materials
could be used for comparing the reactivity of different
metalgroups, M1 andM2 (1, Scheme 1), inCCRsand could
facilitate the preparation of novel molecules and materials
that were not accessible before. A particularly intriguing
prospect in this context would be the development of reac-
tions that are both electrophile- and nucleophile-selective at
the same time, for which work is ongoing in our laboratories.
Scheme 1. General Procedure for Chemoselective CCRs
Herein, we report the synthesis of a thiophene derivative
containing both tin- and boron-based substituents and its
use in the first systematic study of nucleophile-selective
CCRs involving aromatic compounds. This presents a
major challenge, as the nucleophilic groups are in chemi-
cally identical environments and chemoselectivity could
only be derived from the nucleophilic group itself, not from
any neighboring effects. We also show that the reaction
products, which contain the unreactive nucleophilic metal
component, can be used, in situ, in subsequent CCRs
involving a second electrophile Ar2ꢀX (Scheme 1).
(10) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
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J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369. (b) Bonnamour,
J.Piedrafita, M.; Bolm, C. Adv. Synth. Catal. 2010, 352, 1577.
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Scheme 2. Synthesis of Thiophene 1b (Pin = pinacol)
Org. Lett. 2004, 6, 3293. (e) Kienle, M.; Unsinn, A.; Knochel, P.
Angew. Chem., Int. Ed. 2010, 49, 4751. (f) Lou, S.; Fu, G. C. J. Am.
Chem. Soc. 2010, 132, 1264. (g) Mariampillai, B.; Herse, C.; Lautens,
M. Org. Lett. 2005, 7, 4745. (h) Martin, R.; Rivero, M. R.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2006, 45, 7079. (i) Mosrin, M.; Knochel, P.
Chem.;Eur. J. 2009, 15, 1468. (j) Shen, Q.; Hartwig, J. F. J. Am.
Chem. Soc. 2007, 129, 7734. (k) Wang, Y. F.; Deng, W.; Liu, L.; Guo,
Q. X. Chin. Chem. Lett. 2005, 16, 1197. (l) Wu, X.-F.; Anbarasan, P.;
Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49, 7316. In this
context, the chain growth SuzukiꢀHeck polymerization is of interest,
where dibromoaryl monomers react with potassium vinyl trifluoroborate
(Suzuki step) followed by a Heck reaction which carries the chain growth
(Heckstep)ina one-potreaction: (m) Grisorio, R.;Mastrorilli, P.; Nobile,
C. F.; Romanazzi, G.; Suranna, G. P.; Gigli, G.; Piliego, C.; Ciccarella,
G.; Cosma, P.; Acierno, D.; Amendola, E. Macromolecules 2007, 40,
4865. (n) Grisorio, R.; Suranna, G. P.; Mastrorilli, P. Chem.;Eur. J.
2010, 16, 8054.
Thiophene 1b was prepared in a one-pot reaction of bis-
(stannyl) thiophene 415 through monolithiation and in situ
LiꢀB exchange (Scheme 2). Purification of the crude product
turned out to be challenging due to contaminations with the
starting material 4 and bis(borylated) thiophene. The desired
product 1b was unstable to silica gel chromatography, but it
could be purified by fractional sublimation and was even-
tually isolated in good yields and could be stored in air at 5 °C
for at least 5 months without noticeable decomposition.
To establish reaction conditions for a chemoselective
CCR, we used 1-bromo-4-nitrobenzene (5a) as a test sub-
strate and Pd(PPh3)4 as a catalyst in toluene at 110 °C. After
16 h, we obtained product 2a in 70% yield following isolation
(Table 1, entry 6). The isolated product was used as a cali-
brant for the development of a GC method for reaction mon-
itoring and optimization. The conversion and the yield were
highly dependent on the solvent and temperature. At 110 °C,
although conversion for the reactions conducted in all sol-
vents was essentially quantitative, the corresponding yields
were significantly lower, owing to the formation of unidenti-
fied byproducts. The use of toluene and dioxane gave super-
ior yields (83% and 80% respectively, Table 1). DMF was
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73, 9657. (h) Lee, S. J.; Anderson, T. M.; Burke, M. D. Angew. Chem.,
Int. Ed. 2010, 49, 8860. (i) Singidi, R. R.; RajanBabu, T. V. Org. Lett.
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Org. Lett., Vol. 14, No. 22, 2012
5645

not a suitable solvent, and THF, acetonitrile, and pyridine
also gave low yields (see Supporting Information (SI)).
Table 2. Chemoselective Cross-Coupling with Varying Catalyst,
Reaction Time, and Temperaturea
Table 1. Optimization Studies for Chemoselective CCRs with
Varying Solvent and Temperaturea
a 5a (1.0 equiv), 1b (1.1 equiv), Pd(PPh3)4 (5 mol %). b Conversion;
based on 5a. c Determined by GC (multiple point internal standard
method). d Yield of isolated product: 70%.
To establish mild conditions that minimize the forma-
tion of byproducts, we tested a variety of catalysts for the
reaction in toluene (Table 2) and dioxane (see SI). By
reducing the reaction time from 16 to 5 h, not only was the
starting material completely consumed but also the pro-
duct was obtained in essentially quantitativeyield (Table 2,
entry 2). [Pd(dppe)Cl2]16 was a poorer catalyst than
[Pd(PPh3)4]: even after a reaction time of 72 h, the yield
was only 61% (Table 2, entries 3ꢀ5). Although the use of
[Pd(PtBu3)2], [Pd(dppf)Cl2], and Pd(OAc)2/SPhos16 re-
sulted in excellent conversions at 110 °C, decomposition
ofthe product wasmostlikely the problem (Table2, entries
6ꢀ14). However, when using the Pd(OAc)2/SPhos cata-
lyst, this problem could be avoided by reduction of the
reaction time to 80 min (Table 2, entry 12). To ensure that
the cross-coupling was compatible with temperature-
sensitive compounds, we optimized the reaction also at a
lower temperature. When the reaction was carried out at
65 °C for 4 h, the product 2a was obtained in 98% yield
(Table 2, entry 18). However, when we attempted to isolate
the product by using column chromatography or sublima-
tion, we were unable to obtain the product without contam-
ination with the SPhos ligand. To simplify the purification of
the product, the loading of the Pd(OAc)2/SPhos catalyst was
reduced to 1 mol % and, following the reaction at 65 °C over
the course of 18 h, the product was obtained in excellent yield
(Table 2, entry 19; for further details, see the SI).
a 5a (1.0 equiv), 1b (1.1 equiv), Pd source (5 mol %), SPhos (10 mol %
for entries 12ꢀ18). b Conversion; based on 5a. c Determined by GC
(multiple point internal standard method). d 1 mol % Pd(OAc)2,
2 mol % SPhos. dppe = 1,2-bis(diphenylphosphino)ethane; dppf =
1,10-bis(diphenylphosphino)ferrocene; SPhos
sphino-20,60-dimethoxy-biphenyl.
= 2-dicyclohexylpho-
amounts of the corresponding products were observed by
GC/MS. Increasing the reaction temperature to 110 °C did
not improve the yield of product in the case of 2-bromo-
pyridine; however, we found that 3-bromopyridine reacted
smoothly within 6 h under these conditions, giving 2e in
81% yield upon isolation (Table 3, entry 5).
The origin of this behavior could be the deactivation of
the catalyst through its binding with the N-atom of the
substrate.17 The use of electron-neutral electrophiles, such
as bromobenzene and 1-bromonaphthalene, also gave the
corresponding products in good yields, 83% and 91%,
respectively; however, the use of 1-bromonaphthalene
required a longer reaction time (40 h) for completion
(Table 3, entries 9 and 10), presumably owing to steric
hindrance. Furthermore, electron-richarylbromides could
also be employed as electrophiles for the nucleophile-
selective CCR (Table 3, entries 11ꢀ13); however, the use
of amine 5k gave the product in moderate yield.18 In all the
reactions, the transformation was fully chemoselective
with respect to the stannyl and boronic ester functional
groups. The reason for this is that, in the case of Suzuki reac-
tions, a base has to be added for the reaction to take place.
With optimized conditions established, the scope of the
reaction was explored by using a variety of (hetero)aryl
bromides (Table 3). To avoid the potential for product
decomposition, reactionswere performedat65°C. The use
of electron-deficient benzene and furan derivatives gave
good to excellent yields of the corresponding products
(76ꢀ98%; Table 3, entries 1ꢀ3 and 6ꢀ8). However, close
to no conversion was observed when 2- or 3-bromo-
pyridine was used (Table 3, entries 4 and 5) and only trace
(17) Solano, C.; Svensson, D.; Olomi, Z.; Jensen, J.; Wendt, O. F.;
€
Warnmark, K. Eur. J. Org. Chem. 2005, 3510.
(18) The tertiary amine 5k showed a low yield of 37% due to a low
conversion. Longer reaction times and reflux conditions did not lead to
higher conversion. A reason could be the binding of the amine to the Pd.
For more information about tertiary amines used as ligands for Pd, see:
(a) Li, J.-H.; Liu, W.-J. Org. Lett. 2004, 6, 2809. (b) Li, Y.; El-Sayed,
M. A. J. Phys. Chem. B 2001, 105, 8938.0.
(16) dppe = 1,2-bis(diphenylphosphino)ethane; dppf = 1,10-bis-
(diphenyl-phosphino)ferrocene; SPhos = 2-dicyclohexylphosphino-
20,60-dimethoxybiphenyl.
5646
Org. Lett., Vol. 14, No. 22, 2012

that the boronic ester products in the above nucleophile-
selective CCRs could react with a second electrophile in a
one-pot transformation. This was accomplished by adding
5-bromofuraldehyde as the second electrophile, water, and
K3PO4 as a base to the reaction mixture upon completion of
the Stille CCR and subsequently stirring the reaction
mixture at 100 °C for 3 h. The yields of the products 3 were
uniformly high for different aryl bromides (Table 4).
Table 3. Stille CCR of (Hetero)aryl Bromides with 1ba
Table 4. Chemoselective One-Pot Successive CCRs of
Thiophene 1ba
a (i) 1b (1.0 equiv), 5 (1.0 equiv), Pd(OAc)2 (1 mol %), SPhos (2 mol %),
toluene, 65 °C, 18 h. (ii) 5-Bromofuraldehyde (1.0 equiv), K3PO4 (2.0 equiv),
water, 100 °C, 3 h. b Yields of isolated products.
In conclusion, we prepared a thiophene dinucleophile 1b
with both a trialkyltin group and a boronic ester at the 2
and 5-positions, respectively. With this compound, we
established conditions for nucleophile-selective CCRs,
that is, conditions that allow a selective Stille CCR involv-
ing substrates that contain a boronic ester substituent.
The resulting products, which contain the boronic ester
group, were used in the same pot in a subsequent Suzukiꢀ
Miyaura CCR. We are currently developing efficient syn-
theses of a wide variety of aryl and heteroaryl substrates
containing both tin- and boron-based substituents for their
employment in nucleophile-selective CCRs.
a Pd(OAc)2 (1 mol %), SPhos (2 mol %). b Yields of isolated products.
c 6 h, reflux. d 40 h, 65 °C.
Acknowledgment. This work was supported by the
Fonds der Chemischen Industrie (FCI). J.L. and A.H.
thank the Deutsche Bundesstiftung Umwelt (DBU) for a
Ph.D. scholarship.
The latest analysis on the effect of OHꢀ ions has shown
their role to be threefold: First, they are reagents for
the formation of the reactive trans-[ArPd(OH)(L)2] from
the unreactive trans-[ArPd(X)(L)2], the product of oxida-
tive addition. Second, the reductive elimination step is also
accelerated by the reaction of OHꢀ with trans-[ArPdAr0(L)2].
Third, the addition of a base can also have a retarding effect
Supporting Information Available. Experimental pro-
cedures, all GC optimization reactions, and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ 19
by the formation of Ar0B(OH)4
.
Because the Pd(OAc)2/SPhos catalyst is also known to be
(20) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (c)
Barder, T.E.;Biscoe, M. R.;Buchwald,S. L.Organometallics 2007, 26, 2183.
very effective for SuzukiꢀMiyaura CCRs,20 we envisioned
(19) Amatore, C.; Jutand, A.; Le Duc, G. Chem.;Eur. J. 2011, 17,
2492.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
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