Differentiating C-Br and C-Cl bond activation by using solvent polarity: Applications to orthogonal alkyl-alkyl negishi reactions

Article abstract of DOI:10.1002/anie.201100705

A pot to share: A C_alkyl-Cl bond can be rendered "dormant" or "active" in the Negishi alkyl-alkyl cross-coupling by a simple solvent polarity "switch" (see scheme). Adjustment from a 1:2 to a 2:1 solvent ratio of dimethylimidazolidinone: tetrahydrofuran enables orthogonal alkyl-alkyl Negishi cross-coupling strategies to be carried out on bifunctional bromochloroalkanes in one pot at room temperature.

Full text of DOI:10.1002/anie.201100705

Communications
DOI: 10.1002/anie.201100705
Orthogonal Cross-Couplings
À
À
Differentiating C Br and C Cl Bond Activation by Using Solvent
Polarity: Applications to Orthogonal Alkyl–Alkyl Negishi Reactions**
Niloufar Hadei, George T. Achonduh, Cory Valente, Christopher J. OꢀBrien, and
Michael G. Organ*
Orthogonal reactivity allows one to chemoselectively address
one of two reactive centers—both of which are capable of
undergoing the same chemical transformation, e.g., cross-
couplings—within a bifunctional starting material or inter-
mediate (Scheme 1). This is most commonly achieved by one
Scheme 1. General overview of orthogonal cross-coupling strategies.
of two methods: A) fine-tuning the reaction conditions (i.e.,
temperature, catalyst, additives, etc.) for each reactive center
Scheme 2. An overview of known orthogonal alkyl–alkyl cross-cou-
plings.
or B) protecting group chemistry. Method A is commonly
achieved by taking advantage of the differences in bond
[1]
[10]
[11]
enthalpies (CÀI > CÀBr @ CÀCl), and more recently has
example is known (Scheme 2, previous work). Kambe
and co-workers showed in a single example that 1-bromo-6-
chlorohexane could undergo sequential Kumada–Tamao–
Corriu cross-couplings using temperature as the orthogonal
[
2]
come to include the C ÀO bonds (i.e., aryl carboxylates,
aryl
[
3]
carbamates, carbonates, and sulfamates ) that can be effi-
ciently coupled in the presence of a Ni (but not Pd) catalyst,
lending itself to orthogonal reaction strategies.
Method B has been applied in the form of masked boronic
acids, including pinacol esters, BF K salts, N-methylimi-
and 1,8-diaminonaphthalene
dan)-borane derivatives. Strategies based on method B
[
4]
II
trigger in one-pot in the presence of a Cu catalyst. Examples
of this type are rare as specially designed, highly active
catalysts are typically required to couple unactivated alkyl
[
5]
[6]
3
[
7]
[12]
nodiacetic acid (MIDA),
(
fragments efficiently, with the trade-off that discrimination
[
8]
between CalkylÀBr and C ÀCl bonds is now less chemo-
alkyl
generally discount the possibility of one-pot reaction sequen-
ces due to the need for deprotection chemistry. However,
bifunctional organodiborane linchpins possessing two of these
boronic acid derivatives have been applied successfully in
various orthogonal cross-coupling strategies to form aryl–aryl
selective. For example, we have shown that NHC–Pd catalysts
(NHC = N-heterocyclic carbene), generated in situ from
either an imidazolium salt
[Pd-PEPPSI-IPr] (1), can effectively couple both unacti-
[
13]
[14]
or a pre-catalyst,
namely
[
15]
vated primary CalkylÀBr and C ÀCl bonds in the Negishi
alkyl
[16]
[
9]
or aryl–vinyl motifs. Largely absent from the literature are
examples of orthogonal alkyl–alkyl cross-couplings of two
unactivated alkyl fragments; to our knowledge, only one
reaction at room temperature. During the course of these
studies, however, we discovered a unique property that
allowed us to chemoselectively couple CalkylÀBr bonds in the
presence of CalkylÀCl bonds with alkylzinc reagents: that is,
solvent polarity. This is a valuable attribute of this reaction, as
it provides an opportunity for one-pot orthogonal alkyl–alkyl
cross-couplings of bifunctional bromochloroalkanes by a
solvent polarity “trigger” (Scheme 2). At its core, the chemo-
selectivity of these alkyl–alkyl Negishi cross-couplings
depend on the ratio of dimethylimidazolidinone (DMI, e =
[
*] Dr. N. Hadei, G. T. Achonduh, Dr. C. Valente, Dr. C. J. O’Brien,
Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, Ontario M3J 1P3 (Canada)
Fax: (+1)416-736-5936
E-mail: organ@yorku.ca
3
7.6) to tetrahydrofuran (THF, e = 7.5).
[**] This work was supported by NSERC (Canada) and the ORDCF
(
Ontario).
Preliminarily, a competition experiment (Table 1) was
designed to evaluate the chemoselectivity in the alkyl–alkyl
Negishi reaction. The nBuZnBr for these studies was
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100705.
3
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Angew. Chem. Int. Ed. 2011, 50, 3896 –3899

Table 1: Effect of the DMI:THF solvent ratio on the chemoselectivity in
alkyl–alkyl Negishi cross-couplings of bromochloroalkanes.
Entry
DMI:THF
2
3
[%]
4
[%]
Apparent
selectivity
[
b]
[b]
[b]
[19]
[%]
(3:4)
1
2
3
4
5
1:2
1:1
2:1
3:1
1:0
9
–
–
–
61
61
58
49
42
5
12.2:1
5.1:1
2.9:1
2.6:1
2.5:1
12
20
19
17
10
[
17]
[
[
a] nBuZnBr (1.0m in DMI) was prepared according to Huo’s method.
b] Percent conversion was assessed by GCMS analysis using undecane
[
20]
as a calibrated internal standard.
Reactions were performed in
duplicate and the average conversions are reported.
prepared as a solution in DMI by oxidative addition of
activated Zn dust into nBuBr following a procedure reported
[17]
by Huo; this method of organozinc preparation is preferred
as it requires relatively little synthetic effort, is efficient and
[18]
produces no inorganic byproducts.
The optimal solvent
Figure 1. Alkyl–alkyl Negishi cross-couplings carried out at various
ratios of DMI:THF. The plot reveals solvent polarity dependence for
the coupling of alkyl bromides and chlorides. [a] For data points
ranging from 0–59% DMI, nBuZnBr in THF was used (0.5m, Rieke’s
method); 60–100% DMI, nBuZnBr in DMI was used (1.0m, Huo’s
mothod). [b] nBuZnCl (0.75m in THF) was prepared by transmetala-
ratio in the cross-coupling reaction involving 1-bromo-4-
chlorobutane and nBuZnBr was found to be 1:2 DMI:THF,
[
19]
where a 12.2:1 apparent selectivity (CalkylÀBr:C ÀCl) was
alkyl
[
22]
obtained (Table 1, entry 1); increasing the proportion of DMI
relative to THF was detrimental to the apparent selectivity
entries 2–5). Thus, while the same highly active catalyst
[
20]
tion of nBuMgCl with ZnCl . [c] Percent conversion was assessed by
2
(
GCMS analysis using undecane as a calibrated internal standard.
Reactions were performed in duplicate and the average conversions
are reported. [d] The activation threshold refers to the point at which
sufficient conversion is obtained; it is arbitrarily set at 30% for
illustrative purposes.
that is required in the cross-coupling of alkyl halide electro-
philes also leads to a reduction in the intrinsic reactivity
differences in CalkylÀX bonds, excellent chemoselectivity can
still be achieved with these bifunctional precursors through a
simple adjustment of the solvent polarity.
A more detailed study was conducted subsequently to
further delineate the observed solvent polarity effect
coupling reactions carried out with 1-chloro-3-phenylpro-
(
Figure 1). 1-Bromo-3-phenylpropane was subjected to
pane, LiCl and nBuZnCl in the presence of catalyst 1 (~ data
Negishi reaction conditions with nBuZnBr, catalyst 1, and
points) revealed a similar solvent polarity dependency, ruling
out the Finkelstein mechanism. These control reactions also
reveal that at a 1:2 DMI:THF solvent ratio, increasing the
reaction time to 24 h had little effect on the percent
conversion, indicating the reaction is truly switched off. At a
2:1 DMI:THF solvent ratio, a marked increase in percent
conversion was obtained when increasing the reaction time
from 2 to 24 h. Thus, the solvent polarity trigger is real and can
be used as an on/off switch in the cross-coupling reaction of
alkyl chlorides and bromides. These findings provide a
unique, and to our knowledge, unexplored approach to
orthogonal reactivity in bifunctional starting materials. A
solvent polarity “trigger” permits the chemoselective cross-
coupling of an CalkylÀBr bond in the presence of a dormant
CalkylÀCl bond, with the latter “activatable” simply by
[
18]
LiBr
DMI:THF (
at room temperature for 2 h in various ratios of
data points). Using pure THF, only a trace
&
amount of product was detected by GCMS analysis, however,
the conversions steadily increased as the proportion of DMI
was increased relative to THF, and plateaus at near quanti-
tative conversion at ca. 1:1 DMI:THF solvent ratio. The
analogous reaction, using 1-chloro-3-phenylpropane and
LiCl, remained mostly dormant at this solvent ratio, and
useful conversions were not observed until the proportion of
DMI was increased to establish ca. 2:1 DMI:THF solvent
ratio (* data points). To verify that the solvent polarity
dependence was not an artifact of a Finkelstein reaction with
À
Br (that arises from the use of nBuZnBr), wherein sub-
stitution first takes place and is followed by efficient cross-
coupling of the resultant alkyl bromide, nBuZnCl was
prepared. The Grignard reagent nBuMgCl was first formed
increasing the proportion of DMI in the reaction mixture.
Following this study, a general one-pot double alkyl–alkyl
Negishi orthogonal reaction sequence (Scheme 3) was
devised whereby a bifunctional bromochloroalkane was
from nBuCl and Mg turnings, and subsequent transmetalation
À
with ZnCl provided nBuZnCl free from any Br . Cross-
2
Angew. Chem. Int. Ed. 2011, 50, 3896 –3899
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3897

Communications
[
[
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[
[
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K. Gooßen, C. Stanciu, Angew. Chem. 2009, 121, 3621 – 3624;
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[
[
[
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Scheme 3. Substrate study for one-pot, orthogonal alkyl–alkyl Negishi
cross-couplings that rely on a change in solvent polarity to achieve the
2
orthogonality. Subsequent to the first cross-coupling, R ZnBr was
[
added to the same pot as a solution in DMI (1.0m) that effectively
alters the DMI:THF solvent ratio that “activates” the CalkylÀCl bond to
[
10] Unactivated bromochloroalkanes were used previously in a two-
pot orthogonal cross-coupling strategy, wherein the first cross-
coupling was an aryl–alkyl or alkyl–alkyl Kumada–Tamao–
Corriu reaction, and the subsequent reaction was a Sonogashira
cross-coupling. The intrinsic reactivity of the CÀBr bond relative
to the CÀCl bond acted as the orthogonal “trigger”. See: O.
cross-coupling. Yields of isolated product are reported, unless indi-
cated otherwise, along with the per-step average for the two cross-
couplings. [a] Percent conversion was assessed by GCMS analysis
using undecane as a calibrated internal standard.
Vechorkin, D. Barmaz, V. Proust, X. Hu, J. Am. Chem. Soc. 2009,
131, 12078 – 12079.
[11] J. Terao, H. Todo, S. A. Begum, H. Kuniyasu, N. Kambe, Angew.
Chem. 2007, 119, 2132 – 2135; Angew. Chem. Int. Ed. 2007, 46,
dissolved in THF along with catalyst 1 and 3.2 equiv of LiBr.
A solution of nBuZnBr (1.0m in DMI) was added subse-
quently to achieve a final solvent ratio of 1:2 DMI:THF. After
2086 – 2089.
2
4 h, the second alkylzinc reagent (1.0m in DMI) was added
[
12] For reviews on alkyl–alkyl cross-couplings, see: a) A. C. Frisch,
M. Beller, Angew. Chem. 2005, 117, 680 – 695; Angew. Chem. Int.
Ed. 2005, 44, 674 – 688; b) F. Glorius, Angew. Chem. 2008, 120,
to attain a final solvent ratio of 2:1 DMI:THF such that the
dormant CÀCl bond was rendered active by the change in
solvent polarity. For optimal results, the second cross-
8474 – 8476; Angew. Chem. Int. Ed. 2008, 47, 8347 – 8349; c) A.
[
21]
coupling required an additional 6.4 equiv of LiCl.
This
Rudolph, M. Lautens, Angew. Chem. 2009, 121, 2694 – 2708;
Angew. Chem. Int. Ed. 2009, 48, 2656 – 2670.
one-pot orthogonal reaction sequence provided access to
aliphatic derivatives 5–11 in good yields at room temperature.
In conclusion, orthogonal reactivity of bifunctional and
unactivated bromochloroalkanes was possible in a double
Negishi alkyl–alkyl cross-coupling strategy. The orthogonality
was made possible by a relatively simple solvent polarity
[13] a) N. Hadei, E. A. B. Kantchev, C. J. OꢀBrien, M. G. Organ, Org.
Lett. 2005, 7, 3805 – 3807; b) N. Hadei, E. A. B. Kantchev, C. J.
OꢀBrien, M. G. Organ, J. Org. Chem. 2005, 70, 8503 – 8507;
c) C. J. OꢀBrien, E. A. B. Kantchev, G. A. Chass, N. Hadei, A. C.
Hopkinson, M. G. Organ, D. H. Setiadi, T.-H. Tang, D.-C. Fang,
Tetrahedron 2005, 61, 9723 – 9735.
“
trigger”, lending itself to a one-pot approach. To our
[
14] M. G. Organ, S. Avola, I. Dubovyk, N. Hadei, E. A. B. Kantchev,
knowledge, this is the first general strategy for orthogonal
alkyl–alkyl cross-couplings, and the first to use solvent
polarity as the orthogonal trigger. We are currently inves-
tigating the rationale behind the solvent polarity-mediated
chemoselectivity of the alkyl–alkyl Negishi reaction.
C. J. OꢀBrien, C. Valente, Chem. Eur. J. 2006, 12, 4749 – 4755.
[15] PEPPSI is an acronym for pyridine-enhanced precatalyst
preparation, stabilization, and initiation; IPr refers to the NHC
ligand. [Pd-PEPPSI-IPr] is commerically available through
Aldrich (Product # 669032). For reviews on [Pd-PEPPSI]
catalysts, see: a) M. G. Organ, G. A. Chass, D.-c. Fang, A. C.
Hopkinson, C. Valente, Synthesis 2008, 2776 – 2797; b) ref. [16].
16] C. Valente, M. E. Belowich, N. Hadei, M. G. Organ, Eur. J. Org.
Chem. 2010, 4343 – 4354.
17] S. Huo, Org. Lett. 2003, 5, 423 – 425.
Received: January 27, 2011
Revised: February 18, 2011
Published online: March 25, 2011
[
[
[
18] Inorganic salts, such as LiBr or LiCl, have been found to have a
significant effect on the alkyl–alkyl Negishi reaction. For studies
relating to this topic, see: G. T. Achonduh, N. Hadei, C. Valente,
Keywords: alkyl–alkyl coupling · cross-coupling ·
.
Negishi reaction · orthogonal reactions · solvent polarity
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S. Avola, C. J. OꢀBrien, M. G. Organ, Chem. Commun. 2010, 46,
109 – 4111.
19] The term “apparent selectivity” is used as there is the
intermediate (4-chlorobutyl)zinc bromide couples with 2 to
some extent. Trace quantities of 1,4-dibromobutane (Finkel-
stein) and dodecane (coupling each site on 2) are observed in
some entries. For the GCMS chromatograms of each entry, see
Figure S2 in the Supporting Information.
4
[
opportunity for a Finkelstein reaction to occur with the C
À
alkyl
À
Cl bond and free Br to produce the corresponding alkyl
bromide. This side reaction has the net effect of increasing the
amount of 4, thus leading to a decrease in the observed or
apparent selectivity. Although this side reaction has not been
fully quantified, our observations indicate that it is minor in its
contribution to 4.
[21] Whereas 3.2 equiv of LiBr or LiCl is sufficient for the first cross-
coupling, the second cross-coupling requires 6.4 equiv to achieve
optimal conversions. For optimization studies, see Table S1 in
the Supporting Information.
[22] LiX is a byproduct in Riekeꢀs method for organozinc formation.
When Rieke organozincs are utilized, the total effective
equivalents of LiX are reported. For the preparation of Rieke
organozincs, see: a) L. Zhu, R. M. Wehmeyer, R. D. Rieke, J.
Org. Chem. 1991, 56, 1445 – 1453; b) R. D. Rieke, M. V. Hanson,
J. D. Brown, Q. J. Niu, J. Org. Chem. 1996, 61, 2726 – 2730.
[
20] The mass balance of 2 for each entry in Table 1 is attributed
primarily to quenched (4-chlorobutyl)zinc bromide (volatility of
1
-chlorobutane hinders quantification, b.p. 77–788C), which is
the product of disproportionation of nBuZnBr with 2. Trace
< 5%) quantities of 1,8-dichlorooctane are observable in the
GCMS chromatograms of each entry, suggesting that the
(
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