Cross-couplings of alkyl halides with heteroaromatic halides, in water at room temperature

Article abstract of DOI:10.1016/j.tetlet.2010.11.160

Zn-mediated, Pd-catalyzed cross-coupling reactions between heteroaromatic and alkyl halides can be done at room temperature in pure water using a commercially available Pd catalyst and PTS, a nanomicelle-forming amphiphile. Notably, zinc metal inserts selectively into a carbon sp³-halide bond, while palladium adds oxidatively to a carbon sp²-bond.

Full text of DOI:10.1016/j.tetlet.2010.11.160

Tetrahedron Letters 52 (2011) 2203–2205
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cross-couplings of alkyl halides with heteroaromatic halides, in water
at room temperature
Arkady Krasovskiy, Isabelle Thomé, Julien Graff, Valeria Krasovskaya, Paul Konopelski,
⇑
Christophe Duplais, Bruce H. Lipshutz
Department of Chemistry & Biochemistry, University of California, Santa Barbara, CA 93106, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Zn-mediated, Pd-catalyzed cross-coupling reactions between heteroaromatic and alkyl halides can be
done at room temperature in pure water using a commercially available Pd catalyst and PTS, a nanomi-
celle-forming amphiphile. Notably, zinc metal inserts selectively into a carbon sp3-halide bond, while
palladium adds oxidatively to a carbon sp2-bond.
Received 28 September 2010
Accepted 30 November 2010
Available online 5 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Warmest congratulations and very best
wishes on your very special 90th birthday.
Keywords:
Negishi-like cross-coupling
Pd catalysis
Heteroaromatic halides
Micellar catalysis
Green chemistry
Transition metal catalyzed reactions leading to formation of
Csp2–Csp3 bonds involving heteroaryl halides and alkyl halides
have been intensively studied by many groups.1 Such contributions
that also relate to the field of green chemistry deserve particular
mention. Notably, very active catalysts derived from iron salts have
been described in reactions of organozinc and organomagnesium
reagents with heteroaromatic halides.2 Organozinc reagents are
of increasing interest due to their well known tolerance of func-
tionality, such as ketones, aldehydes, nitriles, amides, etc., and
their commercial availability. Organozinc halides (e.g., RZnX) are
always fully fashioned prior to a coupling event, and are commonly
prepared by a zinc metal insertion into an organohalide precursor
(RX).3
We now present results suggestive of the scope and limitations
of this technology based on several representative heteroaromatic
bromides, together with alkyl iodides and bromides (Scheme 1).
As a model reaction, n-octyliodide and 2-methoxy-5-bromo-
pyridine were coupled using 2 mol % PdCl2(Ampos)2, along with
Zn powder and N,N,N0,N0-tetramethylethylenediamine (TMEDA).6
Several nonionic surfactants were screened (e.g., PTS, Brij 30, and
Solutol), as was the reaction in the absence of any amphiphile
(i.e., ‘on water’). As optimized in other studies (Heck,7 Suzuki–
Miyaura,8 and Ru-catalyzed olefin metathesis reactions9), 2 wt %
PTS in pure water appears to provide micelles that best accommo-
date both educts and catalyst (Table 1). Interestingly, addition of
inert highly lipophilic n-dodecane (2 equiv) was found to further
improve rate and conversion in these cross-coupling reactions (Ta-
ble 1, entries 1–2 and 7–8). Especially noteworthy are results in de-
gassed water. Thus, without surfactant, the rate of coupling was
the slowest observed (entry 7), while in the presence of the lipo-
philic additive (n-C12H26; entry 8), reaction rate and conversion
were second only to that seen in PTS/H2O (entry 1).
Recently, we have shown that Suzuki–Miyaura cross-couplings
of heteroaromatic halides can be carried out in water as the only
reaction medium.4 Our approach takes advantage of homogeneous
micellar catalysis within nanoparticle reactors using the commer-
cially available amphiphile PTS (PTS = polyoxyethanyl
a-tocophe-
ryl sebacate) that form spontaneously in aqueous media.5 Using
this approach, Pd-catalyzed, Zn-mediated Negishi-like cross-cou-
pling reactions between aromatic bromides and alkyl iodides in
the absence of a stoichiometrically preformed organometallic cou-
pling partner can also efficiently be conducted in 2 wt % PTS/H2O at
room temperature.6
Several 2-, 3-, and 4-bromopyridines were screened in their
cross-coupling reactions with n-octyliodide (Table 2). Water-solu-
ble unsubstituted bromopyridines led to traces of desired products
Zn, TMEDA
cat. PdCl2(Amphos)2
FG-Alkyl-X
X = I, Br
Br-HetAr-FG'
FG-Alkyl-HetAr-FG'
surfactant/H2O, rt
⇑
Corresponding author. Tel.: +1 805 893 2521; fax: +1 805 893 8265.
E-mail address: Lipshutz@chem.ucsb.edu (B.H. Lipshutz).
Scheme 1. Cross-couplings between alkyl and heteroaromatic halides.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.160

2204
A. Krasovskiy et al. / Tetrahedron Letters 52 (2011) 2203–2205
Table 1
reactions with alkyl iodides of varying chain length. Superior con-
Effect of surfactant on the cross-coupling reactiona
versions and isolated yields were observed with the more lipo-
philic n-decyliodide (Table 3, entries 3, 8, and 11). The low
isolated yield of 3-butylthiophene (entry 1) can be attributed to
losses due to its high volatility. Interestingly, here again addition
of n-dodecane to the cross-coupling reactions with shorter chain
alkyl halides led to higher isolated yields (entries 4 vs 5 and 6 vs
7). Additionally, dramatic decreases of competitive Zn-insertion
into the heteroaromatic bromides, rather than the alkyl iodides,
were observed in the presence of n-dodecane. Thus, cross-coupling
of 3-bromobenzo[b]thiophene with n-butyliodide and n-heptyl
iodide (entries 4–7) produced substantial amounts of benzo[b]thi-
ophene (14% and 9%, respectively), while in the presence of
n-dodecane the amount of this protio-quenched by-product was
only 2–3%. The role of the hydrocarbon may be that of a carrier,
where its greater lipophilicity dissolves some of the substrate
and presents this solution for entry into the lipophilic core of a
nanomicelle. Reactions with 3-bromoquionoline (entries 9–11)
led to inseparable mixtures of desired product with that from a
Chichibabin10 1,2-addition. Moreover, these couplings were fur-
ther complicated by partial reduction of the cross-coupled product
to 1,2,3,4-tetrahydroquinoline derivatives.
Zn/TMEDA
Br
n-C8H17
PdCl2(Amphos)2
n-C8H17
I
+
Surfactant/H2O
O
N
O
N
rt, 24 h
Cl
PdCl2(Amphos)2
=
Me2N
P
Pd
Cl
P
NMe2
Entry
Surfactant
PTS
Conversionb
1
2
3
4
5
6
7
8
98 (82)c
>99 (89)c
68
PTS + n-C12H26 (2 equiv)
Triton X-100
TPGS-750 M
75
55
75
Solutol
Brij 30
None
47 (47)c
78 (75)c
None + n-C12H26 (2 equiv)
a
Reaction conditions: n-C8H17I (0.75 mmol), bromopyridine (0.25 mmol), 2%
PdCl2(Amphos)2, zinc powder (1 mmol), TMEDA (1.25 mmol), surfactant/H2O
(1.5 mL), rt, 24 h.
b
Conversion was measured by GC–MS as a ratio between starting 5-bromo-2-
To further explore the scope of these Pd-catalyzed, Zn-mediated
cross-coupling reactions, several other heteroaromatic bromides
and functionalized alkyl halides were examined (Table 4). We
found that benzo[b]thiophene, thiophene, furane, pyrrole, indole,
and quinoline derivatives participated smoothly together with
functionalized primary and secondary alkyl halides. Functional
groups, such as an aliphatic and aromatic ketone, ester, ether, chlo-
ride, Boc, TBS, and benzyl-protected alcohols are tolerated within
the starting halides.
methoxypyridine and product.
c
After 12 h.
Table 2
Zn-mediated couplings of bromopyridines with n-octyl iodidea
Zn/TMEDA
n-C8H17
PdCl2(Amphos)2
n-C8H17
I
+
R
R
Br
2% PTS/H2O
N
N
rt, 48 h
Competitive Zn-insertion into 3-bromobenzo[b]thiophene and
2-bromo-5-benzoylfuran resulting in the corresponding protio-
quenched heteroaromatic halides was observed, even with highly
reactive ethyl 4-iodobutanoate, accounting for the modest yields
obtained (entries 1 and 5). With the bromoindole and bromopyr-
role framework, nitrogen protection is necessary (entries 6–9). In
such cases, N-protected 2-, 3-, and 5-bromoindoles readily partic-
ipate in cross-coupling reactions with both alkyl bromides and al-
kyl iodides affording excellent yields of desired products (entries
Entry
Py-Br
R
Product
Yieldb (%)
1
2
3
H
Traces
62
99
R
R
N
3-OMe
6-OMe
N
2
Br
Br
n-C8H17
n-C8H17
4
5
6
7
H
2-Me
2-OMe
6-OMe
Traces
28
62
85
3
R
R
R
N
N
Br
n-C8H17
8
9
10
11
12
H
2-Me
2-Me
2-CH2Bn
2-OMe
Traces
31
4
75c
71
89
R
Table 3
N
N
Effect of alkyl halide lipophilicity on cross-couplingsa
a
Zn/TMEDA
Reaction conditions: n-C8H17I (0.75 mmol), bromopyridine (0.25 mmol), 2%
PdCl2(Amphos)2
PdCl2(Amphos)2, zinc powder (1 mmol), TMEDA (1.25 mmol), surfactant/H2O
n-CnH2n+1
I
+
n-CnH2n+1−HetAr
HetAr-Br
(1.5 mL), rt, 48 h.
2% PTS/H2O
rt, 48 h
b
Isolated yields.
n-C12H26 (2 equiv) was added to the reaction mixture.
c
Entry
HetAr-Br
n
Product
Yieldb (%)
(entries 1, 4, 8). Interestingly, even slight increases in lipophilicity
(entry 4 vs 5, and 8 vs 9) resulted in higher levels of conversion and
isolated yields, while adding an additional benzyl group (compare
entries 9 and 11) led to full conversion and good isolated yield of
alkylated pyridine (entry 11). Combinations of various methoxy
substituted bromopyridines and n-octyliodide afforded the desired
pyridine derivatives in good-to-excellent yields (entries 2, 3, 6, 7,
and 12). Addition of 2 equiv of n-dodecane proved to be essential
for cross-coupling reactions with insufficiently lipophilic 2-
methyl-4-bromopyridine (entry 9 vs 10). With n-octyl bromide
low conversions were observed even after a week of stirring, while
all attempts to introduce secondary alkyl halides led to low iso-
lated yields due to competitive Wurtz-type homocoupling.
Br
n-CnH2n+1
1
2
3
4
7
10
22
69
78
S
S
Br
n-CnH2n+1
4
5
6
7
8
4
4
7
7
47
70c
84
89c
91
S
S
10
9
10
11
4
7
10
41d
Br
n-CnH2n+1
58d
68d
N
N
a
Reaction conditions: alkyl halide (2 mmol), heteroaromatic bromide
(0.5 mmol), 2% PdCl2(Amphos)2, Zn powder (3 mmol), TMEDA (2 mmol), 2% PTS/
H2O (1.5 mL), rt, 24 h.
b
Increasing the lipophilicity of the nucleophile can also impact
yields dramatically. Thus 3-bromothiophene, 3-bromobenzo[b]thi-
ophene, and 3-bromoquinoline were subjected to cross-coupling
Isolated yields, average of two runs.
n-C12H26 (2 equiv) was added to the reaction mixture.
c
d
GC yield.

A. Krasovskiy et al. / Tetrahedron Letters 52 (2011) 2203–2205
2205
Table 4
In summary, in situ formation of organozinc halides and their
subsequent cross-couplings with a variety of water-insoluble het-
eroaromatic bromides have been shown to take place in water at
room temperature. These Pd-catalyzed cross-couplings are effi-
cient, and occur under ‘green’ conditions where neither organic
solvents nor external energy in the form of heating or cooling are
needed.
General procedure: In a 5 mL round-bottom flask under argon
containing zinc powder (197 mg, 3 mmol) and PdCl2(Amphos)2
(7 mg, 0.01 mmol) was added 2% PTS solution in water (1.5 mL).
N,N,N0,N0-Tetramethylethylenediamine (TMEDA, 232 mg, 2 mmol)
was added at rt followed by the addition of the alkyl halide
(2 mmol) and the heteroaromatic halide (0.5 mmol). The flask
was stirred vigorously at rt for the indicated time. The product
was extracted with EtOAc.11 Silica gel (1 g) was added to the com-
bined organic phase and solvents were removed under vacuum.
The resulting dry, crude silica was introduced on top of a silica
gel chromatography column to purify the product.
Representative Zn-mediated couplings between alkyl halides and heteroaromatic
bromides in water at room temperaturea
Zn/TMEDA
PdCl2(Amphos)2
+
FG-Alkyl-X
X = I, Br
Br-HetAr-FG'
CO2Et
FG-Alkyl-HetAr-FG'
OTBS
2% PTS/H2O, rt
Entry
1c
Product (yieldb)
Entry
6c
Product (yieldb)
S
N
TIPS
(74%)
CO2Et
(86%)
Ph
R
N
Boc
2c
7c
S
S
(69%)
R = H (90%)
R = Cl (93%)
Acknowledgments
Cl
We are grateful to the NIH for financial support, and Johnson
Matthey for generously supplying palladium catalyst PdCl2(Am-
phos)2. I.T. also thanks the DAAD for a short-term fellowship and
gratefully acknowledges the support of Prof. Carsten Bolm.
3c
8d
N
O
Boc
(97%)
(82%)
Boc
O
N
References and notes
4d
9d,e
S
1. (a) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525; (b) Terao, J.;
Kambe, N. Acc. Chem. Res. 2008, 41, 1545; (c) Sherry, B. D.; Fürstner, A. Acc.
Chem. Res. 2008, 41, 1500; (d) Frisch, A.; Beller, M. Angew. Chem., Int. Ed. 2005,
44, 674; (e) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656; (f)
Nakamura, M.; Ito, S. In Modern Arylation Methods; Ackermann, L., Ed.; Wiley;
Weinheim, 2009; (g) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. J.
Org. Chem. 2005, 70, 8503; (h) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ,
M. G. Org. Lett. 2005, 7, 3805; (i) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G.
Angew. Chem., Int. Ed. 2006, 45, 3656; (j) Organ, M. G.; Avola, S.; Dubovyk, I.;
Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Valente, C. Chem. Eur. J. 2006, 12,
4749.
2. (a) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199; (b) Fürstner, A.; Leitner, A.;
Méndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856; (c) Fürstner, A.;
Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609; (d) Martin, R.; Fürstner, A.
Angew. Chem., Int. Ed. 2004, 43, 3955; (e) Nakamura, M.; Matsuo, K.; Ito, S.;
Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686; (f) Nagano, T.; Hayashi, T. Org.
Lett. 2004, 6, 1297; (g) Bedford, R. B.; Bruce, D. W.; Frost, R.; Hird, M. Chem.
Commun. 2005, 4161; (h) Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E.
Synlett 2005, 126, 1794; (i) Bedford, R. B.; Betham, M.; Bruce, D. W.;
Danopoulos, A. A.; Frost, R.; Hird, M. J. Org. Chem. 2006, 71, 1104; (j) Cahiez,
G.; Habiak, V.; Duplais, C.; Moyeux, A. Angew. Chem., Int. Ed. 2007, 46, 4364; (k)
Cahiez, G.; Duplais, C.; Moyeux, A. Org. Lett. 2007, 9, 3253; (l) Czaplik, W. M.;
Mayer, M.; von Wangelin, J. Angew. Chem., Int. Ed. 2009, 48, 607.
3. (a) Knochel, P.; Leuser, H.; Gong, L.-Z.; Perone, S.; Kneisel, F. F. In Handbook of
Functionalized Organometallics; Knochel, P., Ed.; Wiley; Weinheim, 2005; (b)
Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 6040.
N
(64%)
O
(89%)
CO2Et
Ph
CO2Et
d,e
5c,f
10
N
O
(61%)
(71%)
a
Reaction conditions: alkyl halide (2 mmol), heteroaromatic bromide
(0.5 mmol), 2% PdCl2(Amphos)2, zinc powder (3 mmol), TMEDA (2 mmol), 2% PTS/
H2O (1.5 mL), rt, 24 h.
b
Isolated yields.
From alkyl iodide.
From alkyl bromide.
c
d
e
48 h.
f
n-C12H26 (2 equiv) was added to the reaction mixture. Without additive 62%
isolated yield.
7–9). Cross-coupling with 3-bromoquinoline (entry 10) was
complicated with the formation of the Chichibabin11 1,2-addition
products. Unfortunately, under these conditions various bromoim-
idazoles, bromopyrazoles, and 2-bromothiophene were problem-
atic and resulted in low conversions under a variety of conditions.
Extension of this methodology to pseudo-halides has been doc-
umented in the form of couplings involving quinolin-8-yl trifluoro-
methanesulfonate and the corresponding nonaflate with n-decyl
bromide (Scheme 2). In both cases clean formation of the desired
alkylated quinoline was observed, although the isolated yield
was somewhat higher for the more lipophylic nonaflate derivative.
Curiously, n-decyliodide, under otherwise identical conditions,
gave low levels of conversion and significant amounts of alkyl
4. Lipshutz, B. H.; Abela, A. R. Org. Lett. 2008, 10, 5329.
5. Lipshutz, B. H.; Ghorai, S. Aldrichim. Acta 2008, 41, 59.
6. Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem. Soc. 2009, 131, 15592.
7. Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329.
8. Lipshutz, B. H.; Petersen, T. B.; Abela, A. R. Org. Lett. 2008, 10, 1333.
9. (a) Lipshutz, B. H.; Aguinaldo, G. T.; Ghorai, S.; Voigtritter, K. R. Org. Lett. 2008,
10, 1325; (b) Lipshutz, B. H.; Ghorai, S.; Aguinaldo, G. T. Adv. Synth. Catal. 2008,
350, 953.
10. Chichibabin, A. E.; Zeide, O. A. Zr. Russ. Fiz. Khim. Obshch. 1914, 46, 1212.
11. Alternatively, the reaction mixture was diluted with ethyl acetate and diethyl
ether and filtered through a plug of silica gel. Silica gel was additionally
washed with 100 mL of ethyl acetate and 100 mL diethyl ether. Organic
solvents were removed in vacuo and product was isolated by column
chromatography.
halide reduction and Wurtz-type homo-coupled product n-C20H42
.
n-C10H21
X
R = Tf; X = I, 48h, < 20%
R = Tf; X = Br, 72h, 68%
R = Nf; X = Br, 72h, 74%
Zn/TMEDA
cat. PdCl2(Amphos)2
2% PTS/H2O, rt
N
N
OR
n-C10H21
Scheme 2. Zn-mediated couplings of quinolin-8-yl triflate and nonaflate.