The copper-catalysed Suzuki-Miyaura coupling of alkylboron reagents: disproportionation of anionic (alkyl)(alkoxy)borates to anionic dialkylborates prior to transmetalation

Article abstract of DOI:10.1039/c6cc05114f

We report the first example of Cu^I-catalysed coupling of alkylboron reagents with aryl and heteroaryl iodides that affords products in good to excellent yields. Preliminary mechanistic studies with alkylborates indicate that the anionic (alkoxy)(alkyl)borates, generated from alkyllithium and alkoxyboron reagents, undergo disproportionation to anionic dialkylborates and that both anionic alkylborates are active for transmetalation to a Cu^I-catalyst. Results from a radical clock experiment and the Hammett plot imply that the reaction likely proceeds via a non-radical pathway.

Full text of DOI:10.1039/c6cc05114f

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: P. Basnet, S.
Thapa, D. Dickie and R. giri, Chem. Commun., 2016, DOI: 10.1039/C6CC05114F.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C6CC05114F
Journal Name
COMMUNICATION
Copper‐Catalysed Suzuki‐Miyaura Coupling of Alkylboron
Reagents: Disproportionation of Anionic (Alkyl)(Alkoxy)borates to
Anionic Dialkylborates Prior to Transmetalaꢀon†
Received 00th January 20xx,
Accepted 00th January 20xx
Prakash Basnet, Surendra Thapa, Diane A. Dickie, and Ramesh Giri*[a]
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report the first example of CuI‐catalysed coupling of redox changes on CuI‐catalysts by organohalides for
a
alkylboron reagents with aryl and heteroaryl iodides that affords productive C‐C coupling pathway remains a daunting challenge
products in good to excellent yields. Preliminary mechanistic due to the subtle redox behaviour of Cu.9 The reactions are
studies with alkylborates indicate that the anionic further complicated by having an alkyl group on CuI‐catalysts
(alkoxy)(alkyl)borates, generated from alkyllithium and after transmetalation, which not only have the tendency to
alkoxyboron reagents, undergo disproportionation to anionic undergo

‐hydride elimination10 but also to engage in facile
11
dialkylborates and that both anionic alkylborates are active for disproportionation reactions9,
due to enhanced electron
transmetalation to a CuI‐catalyst. Results from a radical clock density on Cu in the alkylcopper(I) complexes.10a, 12 As such,
experiment and the Hammett plot imply that the reaction likely Cu‐catalysed cross‐coupling of alkylboron reagents with aryl
proceeds via a non‐radical pathway.
halides that requires redox changes on CuI (CuI/CuII or CuI/CuIII)
remains undeveloped.13 In this article, we present the first
example of Cu‐catalysed coupling of alkylboron reagents with
aryl and heteroaryl iodides, and its mechanistic studies.
The Suzuki‐Miyaura coupling of alkylboron reagents1 with aryl
halides has emerged as one of most powerful synthetic tools in
organic synthesis.2 Its versatility arises from the benign nature,
stability and remarkable functional group tolerance of the
alkylboron reagents.1 As such, this cross‐coupling is widely
We began our investigation by coupling B‐(2‐phenylpropyl)‐9‐
BBN (
1), generated in situ by the hydroboration of
‐methyl‐
styrene with 9‐BBN, with 1‐chloro‐4‐iodobenzene (
2) (Table 1).
utilized to synthesize
a variety of molecules including
Screening the reaction under a variety of conditions revealed
materials, pharmaceuticals, building blocks and natural
products.3
that the cross‐coupling proceeded successfully with 10 mol%
Table 1. Optimization of reaction conditions.a
Recently, Cu is emerging as a viable catalyst for the Suzuki‐
Miyaura coupling.4 Early work in this area focused on the
couplings of arylboronic acids with aryl iodides with a varying
degree of success.5 Lately, we showed that CuI ligated by o‐(di‐
tert‐butylphosphino)‐N,N‐dimethylaniline was an active
catalyst for the coupling of arylboronate esters with aryl
iodides and bromides.6 A similar catalytic reaction was also
developed by the Brown group by utilizing xantphos•CuCl as a
catalyst.7
Despite these promising developments in recent days for aryl‐
aryl couplings, significant challenges still persist in developing
Cu‐based protocols as general methods for C‐C bond
formation. One such challenge remains in the capability of Cu
to utilize alkylboron reagents as coupling partners. In
particular, formulating a reaction condition that is amenable to
both the transmetalation of alkylboron reagents8 and the
entry
variation from the standard conditions
None
yield (%)b
90 (73)
0
1
2
3
4
5
6
7
8
Without LiOtBu or CuI
LiOMe, K3PO4 or CsF instead of LiOtBu
DMSO, NMP, DMPU, DMF
toluene, dioxane, acetonitrile, THF
nOct‐B(OH)2 instead of 1
38‐52
13‐34
<1
0c
nOct‐B(OR)2 (4) instead of 1
4‐bromobenzotrifluoride instead of 2
37c,d
20e
a0.1 mmol scale reactions in 0.5 mL solvent. bGC yields with pyrene as a standard.
a. Department of Chemistry & Chemical Biology, The University of New Mexico,
Value in parenthesis is the isolated yield (10.0 mmol scale reaction at 120 °C). c4‐
Albuquerque, NM 87131, USA. E-mail: rgiri@unm.edu
.
†Electronic supplementary information (ESI) available: Experimental procedures,
Chlorophenyloctane as the product. d(OR)2
=
neopentylglycol ester. e4‐(2‐
characterization and crystallographic data, and the 1H and 13C NMR spectra of new
Phenylpropyl)benzotrifluoride as the product. 120 °C, 12 h.
compounds. CCDC 1457747-1457748. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
View Article Online
DOI: 10.1039/C6CC05114F
COMMUNICATION
Journal Name
CuI in HMPA at 80 °C when LiOtBu was used as a base and bromide (23), chloride (
afforded the coupled product in 90% GC yield in 48 h (entry also tolerates aryl iodides with ortho‐substituents (
1). However, a gram‐scale reaction (10 mmol) required 120 °C sterically hindered groups 15 as well as
and afforded the product in 73% isolated yield. The reaction alkylboron reagents ( 10).
3
) and thioether (12
,
14). The reaction
16) and
‐branched
3
5,

(
)
3, 5‐
did not proceed in the absence of either CuI or LiOtBu (entry The current conditions can also be applied for the coupling of
2). Other bases such as LiOMe, K3PO4 and CsF afforded the alkyl‐9‐BBN reagents with nitrogen‐based heteroaryl iodides
product
proceeded in moderate yields in DMSO, DMF, NMP and DMPU base for best product yields. Some substrates provide best
(entry 4). Only a trace of the product was formed in toluene, yields of products when DMF is used as a solvent (35 39). The
dioxane, acetonitrile and THF (entry 5). While n‐octylboronic reaction tolerates ‐branched alkylboron reagents (34 35) and
acid afforded no product, n‐octylboronate ester formed the functional groups such as halides 25 29 34 36 38),
coupled product in 37% yield (entries 6‐7). Using 4‐ unprotected amines (31), olefins (33) and ethers (37).
3 in moderate yields (entry 3). The reaction also (Table 3). However, these reactions require moist K3PO4 as a
3
‐

,
4
(
‐
,
,
‐
bromobenzotrifluoride instead of
low yield (entry 8).
2 also formed the product in
Table 3. Coupling of alkylboron reagents with (Het)ArI.a
Table 2. Coupling of alkylboron reagents with ArI.a
a1.0 mmol scale reactions run in 5 mL solvent. Values are isolated yields. b100 °C.
c48 h. dDMF as a solvent. e60 °C. f12 h.
We also conducted preliminary mechanistic studies and
proposed a catalytic cycle (Scheme 1). Based on our previous
studies of Cu‐catalysed Suzuki coupling6a and the literature
reports on conjugate addition and allylic substitution reactions
of alkylboron reagents,8 we believe that the current reaction
proceeds via initial transmetalation14 followed by coupling
with aryl iodides.10a, 12 The reaction conditions indicate that a
base is required for the success of the cross‐coupling (Table 1,
entries 1‐2). In order to probe the potential role of the base in
transmetalation of the alkyl‐9‐BBN reagents, we attempted to
synthesize the anionic n‐butyl‐9‐BBN borate complex 40 by
reacting nBuLi with MeO‐9‐BBN in THF (Scheme 2). The
reaction of MeO‐9‐BBN with alkyllithium reagents is generally
proposed to generate (alkyl)(OMe)‐9‐BBN species as the
transmetalating intermediates in the Suzuki‐Miyaura
coupling.15 However, we found that the in situ‐generated
borate complex 40 disproportionated to form di‐n‐butylborate
and dimethoxyborate complexes 41 and 42 in solution from
a1.0 mmol scale reactions run in 5 mL solvent. 5, 6 and 7 were run in 5.0 mmol
scale. Values are isolated yields. b120 °C. c24 h. d2 equiv of alkyl‐9‐BBN was used.
e3 equiv of K3PO4 with 20 L H2O used instead of LiOtBu. f80 °C. g36 h. h100 °C.
The reaction condition was applicable to the coupling of a
variety of alkyl‐9‐BBN reagents with aryl iodides (Table 2).
However, many substrates required moist K3PO4 as a base for
best product yields (16
higher temperatures (100‐120 °C) (
can be run in gram‐scale quantities (5 mmol) (5‐7
‐
24). Most substrates also required
16 20 24). The reaction
). The
5
‐
,
‐
reaction proceeds well with both the electron‐deficient and
electron‐rich aryl iodides affording the products in good to
excellent yields. Functional groups are tolerated on both the
alkylboron reagents and aryl iodides. Products are also formed
in good to excellent yields for the coupling of aryl iodides
containing sensitive and strongly coordinating functional
groups such as carbonyl (20), ester (21), nitrile (22, 24),
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C6CC05114F
Journal Name
COMMUNICATION
which the complex 42 was crystallized at –35 °C as colourless yield (entries 1‐2). Similar reactions by using 0.5 and 1.0
blocks.16 A similar result was also observed by 11B NMR when equivalents of the anionic complex 41 instead of the neutral n‐
the reaction was performed in HMPA as a solvent (see SI for butyl‐9‐BBN (43) furnished 39 in 48% and 95% yields,
details).17
respectively (entries 3‐4). When only 0.5 equivalent of the
anionic complex 41 was utilized in the presence of 0.5
equivalent of LiOMe, the product 39 was formed in 94% yield
by converting most of the butyl groups on the complex 41 into
39 (entry 5). In addition, when a mixture of 0.5 equivalents of
each of the anionic complexes 41 and 42 was reacted with 1‐
iodoisoquinoline, the product 39 was generated in 97% yield
(entry 6). These reactivity experiments indicate that both the
anionic alkylalkoxyborate and the anionic dialkylborate
complexes like 40 and 41 are capable of transmetalating to
CuI‐catalysts and that the complexes 41 and 42
comproportionate in solution during reaction to generate the
anionic complex 40, a species also generated immediately
after LiOMe coordinates to the neutral n‐butyl‐9‐BBN reagent.
Scheme 1. Proposed catalytic cycle.
These complexes were also synthesized independently
(Scheme 2). The anionic complex 41 was synthesized from the
reaction of 2 equivalents of n‐BuLi with Br‐9‐BBN in pentane.
Similarly, the anionic complex 42 was prepared from the
reaction of MeO‐9‐BBN with LiOMe in MeOH. These
complexes were characterized by 1H, 13C and 11B NMR
spectroscopies. The structures of 41 (as a 12‐crown‐4 adduct)
and 42 (as a THF adduct) were further confirmed by X‐ray
crystallography (Figure 1). We also prepared n‐butyl‐9‐BBN
Table 4. Reactions of borates 41‐43 with 1‐iodoisoquinoline.
entry
organoboron complexes
base
GC yield (%)
1
n‐Bu‐9‐BBN (43) (1.0 equiv)
none
trace
94
(43) from the reaction of 1 equivalent of n‐BuLi with Br‐9‐BBN
2
3
4
5
6
n‐Bu‐9‐BBN (43) (1.0 equiv) LiOMe (1 equiv)
in pentane and characterized by NMR spectroscopy (Scheme
2).
Complex 41 (0.50 equiv)
Complex 41 (1.0 equiv)
none
none
48
95
Complex 41 (0.50 equiv) LiOMe (0.5 equiv)
41 + 42 (0.50 equiv each) none
94
97
We further explored to determine if aryl radicals were involved
in the current reaction. We utilized o‐allyloxyiodobenzene (44
)
as a radical probe which is known to undergo cyclization in
DMSO at room temperature at a rate constant of 9.8 × 109 s‐1
through the generation of the corresponding aryl radical.18
Scheme 2. Synthesis of organoboron complexes 41‐43.
When the radical probe 44 was reacted with the alkyl‐9‐BBN
1
under the standard conditions at 120 °C for 12 h, only the
direct coupling product 45 was formed in 64% isolated yield
(Scheme 3). The cyclized products, arising from either
cyclization‐hydrogen atom abstraction/iodine atom transfer
18
19
(46
)
or cyclization/coupling (47
)
through the generation of
41•2(12-crown-4)
42•THF (dimer)
o‐allyloxyphenyl radical, were not observed. This experiment
indicates that the current reaction does not involve free aryl
radicals as intermediates.20
Figure 1. X‐ray structures of the complexes 41•2(12‐crown‐4)
and 42•THF (dimer). Selected bond lengths (Å) and angles (°).
41•2(12‐crown‐4): B1‐C1, 1.6512(18); B1‐C9, 1.6520(18); C1‐B1‐C9,
109.96(10). 42•THF (dimer): O1‐B1, 1.5125(18); O2‐B1, 1.5145(18);
O2‐Li1, 1.853(3); O1‐B1‐O2, 108.83(11).
With different species of fully characterized alkylboron
reagents in hand, we then investigated their reactivity with 1‐
iodoisoquinoline (Table 4). As expected, the reaction of n‐
Scheme 3. Radical clock experiment.
butyl‐9‐BBN
(43) with 1‐iodoisoquinoline afforded the
We further obtained
quantitatively the effects of electronic changes in iodoarenes
on the rates of their reactions with alkyl‐9‐BBN . A plot of log
a
Hammett plot to measure
butylated product 39 only in trace amounts while the addition
of 1 equivalent of LiOMe as a base furnished 39 in 94% GC
1
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
View Article Online
DOI: 10.1039/C6CC05114F
COMMUNICATION
Journal Name
6
(a) S. K. Gurung, S. Thapa, A. Kafle, D. A. Dickie, R. Giri, Org.
Lett. 2014, 16, 1264; (b) S. K. Gurung, S. Thapa, B. Shrestha,
R. Giri, Org. Chem. Front. 2015, 2, 649.
Y. Zhou, W. You, K. B. Smith, M. K. Brown, Angew. Chem. Int.
Ed. 2014, 53, 3475.
For selected examples of Cu‐catalysed conjugate and allylic
reactions of alkylboron reagents, see: (a) K. Takatsu, R.
Shintani, T. Hayashi, Angew. Chem. Int. Ed. 2011, 50, 5548;
(b) M. Yoshida, H. Ohmiya, M. Sawamura, J. Am. Chem. Soc.
2012, 134, 11896; (c) K. Hojoh, Y. Shido, H. Ohmiya, M.
Sawamura, Angew. Chem. Int. Ed. 2014, 53, 4954; (d) Y. Shi,
values of the ratio of initial rates of p‐XC6H4I (X = OMe, Me, F,
Cl and CF3) to PhI against the corresponding

‐values of the
value of
substituents showed a linear curve (R2 = 0.99) with a

7
8
+1.33 (Figure 2).21 This result is consistent with the reaction of
aryl halides with electron‐rich metals via oxidative addition
pathway.22
0.8
CF3
0.6
0.4
0.2
0
Cl
B. Jung, S. Torker, A. H. Hoveyda, J. Am. Chem. Soc. 2015
137, 8948.
,
F
9
(a) J. K. Kochi, Acc. Chem. Res. 1974, 7, 351; (b) J. K. Kochi, J.
Organomet. Chem. 2002 653, 11; (c) K. M. Smith,
Organometallics 2005, 24, 778.
H
,
Me
-0.2
10 (a) M. D. Janssen, K. Köhler, M. Herres, A. Dedieu, W. J. J.
Smeets, A. L. Spek, D. M. Grove, H. Lang, G. van Koten, J. Am.
Chem. Soc. 1996, 118, 4817; (b) A. Miyashita, T. Yamamoto,
A. Yamamoto, Bull. Chem. Soc. Jpn. 1977, 50, 1109; (c) J. K.
Kochi, K. Wada, M. Tamura, J. Am. Chem. Soc. 1970, 92,
6656.
OMe
-0.4
-0.4 -0.2
0
0.2
0.4
0.6

Figure 2. The Hammett plot.
In summary, we have developed the first Cu‐catalysed Suzuki‐
Miyaura coupling of alkylboron reagents with aryl and
heteroaryl iodides. Alkylboron reagents generated in situ by
hydroboration of olefins can be used directly without further
purification. We also conducted mechanistic studies with
discrete reaction intermediates, which indicate that anionic
(alkyl)(alkoxy)borates, generated from alkyllithium and
alkoxyboron reagents, undergo disproportionation to anionic
dialkylborates prior to transmetalation to CuI‐catalysts.
Moreover, the results obtained from the radical clock
experiment and the Hammett plot indicate that the reaction
proceeds via a non‐radical route.
11 X. Ribas, D. A. Jackson, B. Donnadieu, J. Mahía, T. Parella, R.
Xifra, B. Hedman, K. O. Hodgson, A. Llobet, T. D. P. Stack,
Angew. Chem. Int. Ed. 2002, 41, 2991.
12 For stable alkylcopper(I) complexes containing ‐hydrogens,
see: a) ref. 10a; (b) K. Moriya, M. Simon, R. Mose, K.
Karaghiosoff, P. Knochel, Angew. Chem. Int. Ed. 2015, 54,
10963; (c) A. Miyashita, A. Yamamoto, Bull. Chem. Soc. Jpn.
1977, 50, 1102; (d) T. Stein, H. Lang, J. Organomet. Chem.
2002, 664, 142.
13 For a reaction of alkylboron reagents with primary alkyl
halides via a redox neutral SN2 process, see: C.‐T. Yang, Z.‐Q.
Zhang, Y.‐C. Liu, L. Liu, Angew. Chem. Int. Ed. 2011, 50, 3904.
14 (a) A. M. Whittaker, R. P. Rucker, G. Lalic, Org. Lett. 2010, 12,
3216; (b) T. Ohishi, M. Nishiura, Z. Hou, Angew. Chem. Int.
Ed. 2008, 47, 5792.
15 (a) J. A. Marshall, M. P. Bourbeau, J. Org. Chem. 2002, 67,
2751; (b) T. Hu, N. Takenaka, J. S. Panek, J. Am. Chem. Soc.
2002, 124, 12806; (c) S. Bonazzi, O. Eidam, S. Güttinger, J.‐Y.
Wach, I. Zemp, U. Kutay, K. Gademann, J. Am. Chem. Soc.
2010, 132, 1432.
16 Since LiOMe is insoluble in most organic solvents, we could
not generate similar complexes from nBu‐9‐BBN and LiOMe.
However, previous studies indicated that the (allyl)(OMe)‐9‐
BBN complex generated from allyl‐9‐BBN and KOMe also
We thank the and the University of New Mexico (UNM) and
the National Science Foundation (NSF CHE‐1554299) for
financial support, and upgrades to the NMR (NSF grants
CHE08‐40523 and CHE09‐46690) and MS Facilities. The Bruker
X‐ray diffractometer was purchased via an NSF CRIF:MU award
to UNM (CHE04‐43580).
underwent disproportionation to complexes similar to 41
See: Furstner, A.; Seidel, G. Synlett 1998, 161‐162.
‐42.
Notes and references
17 (a) M. R. Uehling, S. T. Marionni, G. Lalic, Org. Lett. 2012, 14,
362; (b) H. Ohmiya, U. Yokobori, Y. Makida, M. Sawamura,
Org. Lett. 2011, 13, 6312.
18 A. Annunziata, C. Galli, M. Marinelli, T. Pau, Eur. J. Org.
Chem. 2001, 2001, 1323.
19 For a previous example that showed evidence for aryl
radicals via cascade cyclization/coupling of the radical probe
44 with a Cu‐amido complex, see: S. E. Creutz, K. J. Lotito, G.
C. Fu, J. C. Peters, Science 2012, 338, 647.
1
For reviews, see: (a) A. Suzuki, Angew. Chem. Int. Ed. 2011,
50, 6722; (b) A. J. J. Lennox, G. C. Lloyd‐Jones, Chem. Soc.
Rev. 2014, 43, 412; (c) R. Jana, T. P. Pathak, M. S. Sigman,
Chem. Rev. 2011, 111, 1417; (d) C. Valente, S. Çalimsiz, K. H.
Hoi, D. Mallik, M. Sayah, M. G. Organ, Angew. Chem. Int. Ed.
2012, 51, 3314.
2
For recent selected examples, see: (a) T. P. Blaisdell, J. P.
Morken, J. Am. Chem. Soc. 2015, 137, 8712; (b) D. N. Primer,
I. Karakaya, J. C. Tellis, G. A. Molander, J. Am. Chem. Soc.
2015, 137, 2195; (c) L. Li, S. Zhao, A. Joshi‐Pangu, M. Diane,
M. R. Biscoe, J. Am. Chem. Soc. 2014, 136, 14027.
20 For a previous example that showed evidence for the lack of
aryl radicals via direct coupling of the radical probe 44 with a
Cu‐amido complex, see: J. W. Tye, Z. Weng, A. M. Johns, C. D.
Incarvito, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 9971.
3
4
For reviews, see: (a) A. M. Rouhi, Chem. Eng. News 2004, 82,
49; (b) J.‐P. Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651.
For reviews, see: (a) S. Thapa, B. Shrestha, S. K. Gurung, R.
Giri, Org. Biomol. Chem. 2015, 13, 4816; (b) I. P. Beletskaya,
A. V. Cheprakov, Coord. Chem. Rev. 2004, 248, 2337.
(a) M. B. Thathagar, J. Beckers, G. Rothenberg, J. Am. Chem.
Soc. 2002, 124, 11858; (b) J.‐H. Li, D.‐P. Wang, Eur. J. Org.
Chem. 2006, 2006, 2063.
21 Substituent constants ( values) were adopted from C.
Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165‐195.
22 For the Hammett plots for the oxidative addition of ArI to Pd,
see: (a) J.‐F. Fauvarque, F. Pflüger, M. Troupel, J. Organomet.
5
Chem. 1981
, 208, 419; (b) C. Amatore, F. Pfluger,
Organometallics 1990, 9, 2276.
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins