Regiocontrolled CuI-catalyzed borylation of propargylic- functionalized internal alkynes

Article abstract of DOI:10.1021/ja300627s

Good to excellent reactivity and regiocontrol have been achieved in the Cu^I-catalyzed borylation of dialkyl internal alkynes with bis(pinacolato)diboron. The presence of a propargylic polar group (OH, OR, SAr, SO₂Ar, or NHTs), in combination with PCy₃ as ligand, allowed maximizing the reactivity and site-selectivity (β to the propargylic function). DFT calculations suggest a subtle orbitalic influence from the propargylic group, matched with ligand and substrate size effects, as key factors involved in the high β-selectivity. The vinylboronates allowed the stereoselective synthesis of trisubstituted olefins, while allylic substitution of the SO₂Py group without affecting the boronate group provided access to formal hydroboration products of unbiased dialkylalkynes.

Full text of DOI:10.1021/ja300627s

Communication
pubs.acs.org/JACS
Regiocontrolled CuI-Catalyzed Borylation of Propargylic-
Functionalized Internal Alkynes
Abraham L. Moure, Ramon Gomez Arrayas,* Diego J. Cardenas, Ines Alonso, and Juan C. Carretero*
́
́
́
́
́
Departamento de Química Organ
́
ica, Facultad de Ciencias, Universidad Auton
́
oma de Madrid, Cantoblanco, 28049 Madrid, Spain
S
* Supporting Information
CuI-PCy3-catalyzed protocol for the regio- and stereocontrolled
B2(pin)2-borylation of propargylic functionalized dialkylalkynes.
The resulting vinylboronates were applied to the stereoselective
synthesis of trisubstituted alkenes via cross-coupling reactions.
Further elaboration of the borylation products without affecting
the boronate group via allylic substitution allowed widening the
current structural scope in the synthesis of vinylboronates.
Given the wide chemical versatility of sulfur compounds, we
envisioned that propargyl sulfur-containing species might have
a neighboring regiocontrolling effect in the CuI-catalyzed
borylation reaction with B2(pin)2. To test this hypothesis,
model sulfide 1 was subjected to Cu-catalyzed9 borylation
under the standard reported conditions10 (Table 1). In
ABSTRACT: Good to excellent reactivity and regiocon-
trol have been achieved in the CuI-catalyzed borylation of
dialkyl internal alkynes with bis(pinacolato)diboron. The
presence of a propargylic polar group (OH, OR, SAr,
SO2Ar, or NHTs), in combination with PCy3 as ligand,
allowed maximizing the reactivity and site-selectivity (β to
the propargylic function). DFT calculations suggest a
subtle orbitalic influence from the propargylic group,
matched with ligand and substrate size effects, as key
factors involved in the high β-selectivity. The vinyl-
boronates allowed the stereoselective synthesis of
trisubstituted olefins, while allylic substitution of the
SO2Py group without affecting the boronate group
provided access to formal hydroboration products of
unbiased dialkylalkynes.
Table 1. Ligand Screening in the Borylation of Alkyne 1
ne of the greatest challenges associated with selective
functionalization of alkynes via hydrometalation is the
O
control of the regioselectivity.1 Achieving high regiocontrol
generally relies on the use of alkynes with a marked bias in
either the size or the electronic characteristics of the acetylenic
substituents, such as terminal alkynes, aryl-substituted alkynes,
and conjugated enynes.1 In contrast, simple dialkylalkynes
without a strong electronic or steric bias (i.e., alkyl-CC-
alkyl′) often lead to unpractical regioisomeric mixtures. These
characteristics hold true in hydroboration reactions.1,2 The
catalytic hydroboration of terminal alkynes with B−H reagents2
is regarded as one of the most straightforward methods for
accessing vinylboronate reagents, which are highly versatile
building blocks endowed with numerous synthetic applica-
tions.3 The anti-Markovnikov addition was the usual
regiochemical outcome in the direct borylation of terminal
alkynes until the very recent work by Hoveyda and co-workers,
who devised a NHC-Cu-catalyzed borylation protocol with
bis(pinacolato)diboron [B2(pin)2], leading to functionalized
branched vinylboronates with high α-selectivity.4,5
a
a
entry
L
conv (%)
15
α/β ratio
1
2
3
4
5
6
7
8
−
<2 : >98
−
b
Xantphos
<2
b
dppf
<2
b
−
−
rac-Binap
Xphos
PPh3
<2
18
<2 : >98
<2 : >98
<2 : >98
25 : 75
50
c
d
PCy3
>98 (76)
60
P(t-Bu)3
a
b
1
Determined by H NMR from the crude mixture. Starting material
c
d
recovered. Reaction time 2 h. Yield after chromatography.
accordance with literature precedents,4−7 we noticed a strong
dependence of the reactivity upon the nature of the ligand.
Very poor reactivity (15% conversion), yet a very high β-
selectivity, were observed in the absence of ligand (entry 1).
Typical bidentate phosphines such as Xantphos,11 dppf, or
( )-Binap were totally ineffective (entries 2−4). A scan of the
recent literature revealed that the level of reactivity and
regiocontrol in addition reactions to alkynes can be optimized
by adjusting the steric and electronic properties of mono-
dentate phosphine or NHC ligands.4−7,12−14 Xphos13 and PPh3
ligands promoted the β-selective borylation, albeit with
unpractical conversions (18% and 50%, respectively, entries 5
The regiocontrolled borylation of internal unsymmetrical
alkynes represents an even greater challenge because of their
lower reactivity and difficult regiocontrol. Indeed, only recently
have the first two successful reports on highly regioselective
borylation of internal alkynes appeared.6−8 Both are elegant
examples of CuI-catalyzed B2(pin)2-borylation of electronically
biased internal alkynes, such as 1-aryl-1-alkynes6 and 1,3-
enynes.7 In contrast, a general procedure for the highly
regiocontrolled hydroboration of simple dialkylalkynes remains
an unmet challenge. Herein we present an operationally trivial,
Received: January 26, 2012
Published: April 13, 2012
© 2012 American Chemical Society
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Communication
and 6). To our delight, the reactivity was greatly enhanced with
the more donating PCy3 ligand (full conversion after 2 h at rt)
while maintaining the excellent β-regiocontrol (entry 7). In
contrast, the bulkier P(t-Bu)3 was much less reactive (60%
conversion) and regioselective (α/β = 25 : 75; entry 8).
A variety of propargylic functional groups with various steric
and electronic properties provided uniformly good reactivity
and very high regiocontrol (generally >98% β-selectivity, Table
2). A potentially coordinating 2-pyridylsulfide group had no
least hindered alkyne terminus. Accordingly, the 3-heptyne,
with a reduced steric bias, led to much poorer regiocontrol and
similar low yield (43 : 57 mixture, 37%, entry 13).
Structural variation at the alkyl acetylenic substituent (R1)
was also found to be viable (Scheme 1). For example, alkyl
a
Scheme 1. Other Propargylic-Substituted Internal Alkynes
Table 2. β-Borylation in Propargylic-Substituted 2-Butynes
a
b
c
entry
FG
product
α/β ratio
yield (%)
1
S(2-Py)
SO2Ph
SO2(2-Py)
OH
3
<2 : >98
<2 : >98
<2 : >98
<2 : >98
<2 : >98
<2 : >98
<2 : >98
<2 : >98
10 : 90
82
78
80
2
4
3
5
d
4
6
69
5
OBn
7
78
79
76
82
6
OPh
8
a
b
Yield of β-regioisomer after chromatographic separation. Yield in
7
OTBDMS
OTIPS
OAc
9
the mixture of regioisomers.
8
10
11
12
13
14
e
9
76
groups bulkier than methyl such as propyl, isobutyl, or
phenethyl are well accommodated, preserving high regiocontrol
10
11
12
13
NHTs
<2 : >98
12 : 88
15 : 85
89
f
CH2OBn
2-pentyne
3-heptyne
72
f
(products 16−18, from 93 to >98% β-selectivity).15
A
30
g
f
cyanopropyl group could be installed with somewhat lower
regioselectivity (19, 87% β). Similar β-selectivity (86%) was
also observed in the borylation of 2-hexynol and its OTBS-
protected derivative (products 20 and 21), as well as the 5-
phenyl-2-pentynol (product 22, 84% β). Interestingly, the β-
selectivity was restored to α/β = <2 : >98 in the case of the
bulkier secondary alcohol derivatives (R2 = Me or Ph, products
23−25), suggesting the modulating role of steric effects in the
main regiochemical control exerted by the propargylic
moiety.16
15
43 : 57
37
a
b
1
0.26 mmol scale in substrate. Determined by H NMR from the
crude mixture. Isolated product after chromatography. Reaction
carried out in the absence of MeOH. In pure β-regioisomer after
chromatographic separation. Yield in the mixture of regioisomers. α/
β-site selectivity not assigned.
c
d
e
f
g
impact on reactivity or regioselectivity (entry 1), nor did the
bulkier and more electrophilic sulfonyl substrates (products 4
and 5, 78−80% yield, entries 2 and 3). Oxygenated propargyl
derivatives proved also to be suitable, which is interesting given
the availability of propargyl alcohols and the synthetic utility of
the resulting allylic alcohols. The parent 2-butynol was
successfully transformed into the β-vinylboronate 6, bearing
an allylic hydroxyl group (69%, entry 4). A series of propargyl
alcohol derivatives delivered the corresponding vinylboronates
in reasonable yields (76−82%), irrespective of the substituents
attached to the oxygen (Bn, Ph, TBDMS, TIPS, or even the
challenging Ac,14 entries 5−9). Only the acetyl-protected
substrate gave a lower regiocontrol (α/β = 10 : 90). This
general trend in both reactivity and regioselectivity was also
observed for the N-Ts-protected propargylamine (product 11,
α/β = <2 : >98, entry 10). This set of homogeneous results
suggests that the observed regioselectivity profile is not derived
from direct coordination of the propargylic function to copper.
With regard to other types of internal alkynes, the
homopropargyl benzyl-protected 3-pentynol derivative pro-
vided the corresponding β-vinylboronate with good, albeit
significantly lower regiocontrol (13, α/β = 12 : 88, entry 11)
than the propargyl derivative (entry 5). The borylation of a
non-functionalized internal alkyne such as 2-pentyne was much
less efficient (30% yield) and led to an inseparable 15 : 85
mixture of α/β vinylboronates (14, entry 12), showing a
background steric regiocontrol favoring the borylation at the
Despite the borylation reaction was routinely run at 0.26
mmol scale, we confirmed that the process is amenable to 10-
fold scale-up without loss of chemical efficiency, such as in the
case of products 4 (2.05 mmol, 76%), 7 (2.50 mmol, 85%), and
17 (1.64 mmol, 92%). Additionally, we found that the CuI
catalyst loading can be reduced to 3 mol % with comparable
efficiency (product 17, 1.64 mmol, 87% yield, α/β = <2 : >98).
DFT calculations provided insight into the reasons for the
observed regioselectivity. According to the accepted mecha-
nism, formation of the B−C bond takes place in the
coordination sphere of a boryl-Cu complex formed by initial
transmetalation. We focused on the boryl-cupration of 4-
methoxy-2-butyne coordinated to (pin)B-Cu-PCy3, considering
the complete phosphine ligand structure. Optimizations were
performed with CPCM model in toluene (see Supporting
Information for details).17 Coordination of the alkyne may
afford two different stereoisomeric trigonal complexes, Iα and
Iβ, leading to the alkenylboronate regioisomers IIα and IIβ
(Scheme 2). Both Cu−C(2) and Cu−C(3) distances are very
similar in Iβ, in spite of the unsymmetrical nature of the alkyne
(2.016 and 2.073 Å, respectively). In contrast, Cu−C(2) is
significantly longer than Cu−C(3) in Iα (2.187 and 2.032 Å,
respectively), which is 1.8 kcal mol−1 more stable than Iβ.18
Location of both transition states (TS, Figure 1) for the
insertion of the alkyne into the Cu−B bond allowed us to
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Journal of the American Chemical Society
Communication
Scheme 2. Energy Profile for the Two Possible Boryl
Cuprations of the Coordinated Alkyne
Scheme 3. Synthetic Applications of the Vinylboronates
a
Further elaboration of the products without affecting the
boronate group via nucleophilic allylic displacement of the
directing functionality allowed widening the scope of the
vinylboronate synthesis. This concept was realized in the FeII-
catalyzed allylic substitution of the 2-pyridylsulfone 17 with
PhMgBr, affording the new vinylboronate 28 (53% yield,
unoptimized, Scheme 3). Remarkably, this reaction shows the
compatibility of the pinacolboronate group with Grignard
reagents under metal catalysis24 and, to the best of our
knowledge, represents the first example of a Fe-catalyzed
nucleophilic displacement of allylic sulfones with Grignard
reagents.25
a
Optimized structures in toluene (M06/6-31G(d) (C,H,B,O,P),
LANL2DZ (Cu), CPCM model). Relative G values at 298 K (kcal
mol−1).
In conclusion, we have disclosed a highly regiocontrolled
B2(pin)2/CuI-catalyzed borylation of dialkylalkynes. The
effectiveness of this method relies on the subtle electronic
bias provided by a functional group at the propargylic position
of the alkyne substrate, along with the use of the PCy3 as ligand.
Functionalized vinylboronates bearing a variety of sulfur,
oxygen, and nitrogen groups at the allylic position are obtained
in good yields and good to excellent β-selectivity. DFT
calculations on the whole catalyst system are in agreement with
the observed regioselectivity. The resulting products have been
applied to the stereocontrolled synthesis of trisubstituted
olefins via cross-coupling reactions. Further elaboration of the
vinylboronates via FeII-catalyzed sulfonyl allylic substitution
with Grignard reagents provides formal hydroboration products
of unbiased dialkyl-substituted alkynes.
Figure 1. Molecular structure of the transition states TSα and TSβ.
Representative distances (Å) are indicated.
obtain the corresponding activation energies, which are low
(6.1 and 10.6 kcal mol−1 for β and α pathways, respectively)
and in agreement with the experimentally observed regiose-
lectivity. Thus, TSβ lies 2.7 kcal mol−1 below TSα. The carbon
atom that binds to B strongly interacts with Cu in the TS, the
Cu−C distances being shorter than those found in the starting
complexes.19 The lower energy pathway involves formation of
an earlier TS (TSβ), with a longer C−B distance (2.273 vs
2.186 Å for TSα). NBO analysis reveals a strong donor−
acceptor interaction between boron and the π*(C−C) alkyne
orbital in both TSs. Interestingly, analysis of the HOMO of
TSβ shows that the O atom orbitals also participate in this MO,
along with those of the alkyne and boryl moieties. Such
participation is much smaller in TSα, suggesting that this effect
could lay at the basis of the β-regiocontrol (see schemes in
Supporting Information). Therefore, the main reason for the
observed regioselectivity seems to be the result of orbital
control rather than merely steric effects.20,21
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental and computational details as well as spectroscopic
and analytical data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
ramon.gomez@uam.es; juancarlos.carretero@uam.es
■
Notes
The authors declare no competing financial interest.
This formal hydroboration protocol offers an efficient
approach to the stereocontrolled synthesis of multisubstituted
alkenes22 via cross-coupling reactions of the resulting products
(Scheme 3). For example, the Suzuki reaction of sulfide 3 with
bromobenzene afforded the corresponding trisubstituted olefin
26 in 72% yield. The Cu-promoted coupling with alcohols,
recently reported by the group of Merlic23 on terminal
vinylboronates, was found to be applicable to the branched
vinylboronate 7, leading to the allyl vinyl ether 27 (67% yield).
ACKNOWLEDGMENTS
Dedicated to Prof. Miguel A. Miranda on the occasion of his
60th birthday. This work was supported by the Ministerio de
■
Ciencia e Innovacion
2010-15927) and the Consejerıa de Educacio
́
(MICINN, CTQ2009-07791 and CTQ
́
́
n de la
Comunidad de Madrid (programme AVANCAT, S2009/
PPQ-1634). A.L.M. thanks the UAM for a predoctoral
fellowship. We also thank Johnson Matthey PLC for a supply
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Journal of the American Chemical Society
of Pd(OAc)2 and the Centro de Computacion
Communication
(17) See Supporting Information for calculations on analogous
complexes obtained by either substitution of PCy3 with PMe3 or
replacement of the alkyne with 2-pentyne.
́
Cientıfica de la
́
UAM for generous allocation of computer time.
(18) Natural charge for C (2) is always lower than for C (3), and the
difference between the two C atoms is higher for Iβ (Δq = 0.13) than
for Iα (Δq = 0.04), suggesting a higher reactivity toward boryl ligand
to afford the β product.
REFERENCES
■
(1) Review on hydrometallation of alkynes: Trost, B. M.; Ball, Z. T.
Synthesis 2005, 853.
(19) Molecular orbital analysis of copper−alkyne interactions:
(a) Mori, S.; Nakamura, E. Angew. Chem., Int. Ed. 2000, 39, 3750.
(b) Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 4, 2339.
(20) Recent example on the influence of electronic factors on
regioselectivity in the hydrosilylation of propargylic- and homopro-
pargylic-functionalized internal alkynes: (a) Rooke, D. A.; Ferreira, E.
M. Angew. Chem., Int. Ed. 2012, 51, 3225. For an example on reductive
coupling of propargylic alcohol derivatives with aldehydes: (b) Malik,
H. A.; Chaulagain, M. R.; Montgomery, J. Org. Lett. 2009, 11, 5734.
(21) As expected, modelization of the reaction with 2-pentyne as
substrate, lacking the propargylic functional group, predicted low
regiocontrol.
(22) Review on the stereoselective synthesis of substituted alkenes:
(a) Negishi, E.-i.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori,
H. Acc. Chem. Res. 2008, 41, 1474. Recent reports: (b) Nishihihara, Y.;
Okada, Y.; Jiao, J.; Suetsugu, M.; Lan, M.-T.; Kinoshita, M.; Iwasaki,
M.; Takagi, K. Angew. Chem., Int. Ed. 2011, 50, 8660 and references
cited therein.
(2) Reviews on hydroboration of alkynes: (a) Brown, H. C.;
Campbell, J. B., Jr. Aldrichim. Acta 1981, 14, 3. (b) Beletskaya, I.;
Pelter, A. Tetrahedron 1997, 53, 4957. Pioneering hydroboration with
pinacolborane: (c) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org.
Chem. 1992, 57, 3482. Review on metal-catalyzed reactions of
organoboron reagents: (d) Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81,
1535.
(3) Reviews on applications of vinylboronates in cross-coupling:
(a) Hall, D. G. Boronic Acids: Preparation and Applications in Organic
Synthesis and Medicine; Wiley-VCH: Weinheim, 2005. (b) Miyaura, N.
Bull. Chem. Soc. Jpn. 2008, 81, 1535.
(4) (a) Jang, H.; Zhugralin, A. R.; Lee, Y.; Hoveyda, A. H. J. Am.
Chem. Soc. 2011, 133, 7859. See also: (b) Lee, Y.; Jang, H.; Hoveyda,
A. H. J. Am. Chem. Soc. 2009, 131, 18234.
(5) Pioneering B2(pin)2-borylation under stoichiometric CuI:
(a) Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem.
2001, 625, 47. Cu-catalyzed B2(pin)2-borylation of phenylacetylene
that affords the terminal vinylboronate: (b) Lee, J. E.; Kwon, J.; Yun, J.
Chem. Commun. 2008, 733.
(23) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am.
Chem. Soc. 2010, 132, 1202.
(6) (a) Kim, H. R.; Jung, I. G.; Yoo, K.; Jang, K.; Lee, E. S.; Yun, J.;
Son, S. U. Chem. Commun. 2010, 46, 758. (b) Ryung, H.; Yun, J. Chem.
Commun. 2011, 47, 2943. For an example of regioselective
hydroboration on a sterically biased tert-butyl-substituted internal
alkyne, see ref 6b.
(7) Sasaki, Y.; Horita, Y.; Zhong, C.; Sawamura, M.; Ito, H. Angew.
Chem., Int. Ed. 2011, 50, 2778.
(8) Examples on carboboration of internal alkynes: (a) Daini, M.;
Suginome, M. Chem. Commun. 2008, 5224. (b) Suginome, M.;
Shirakura, M.; Yamamoto, A. J. Am. Chem. Soc. 2006, 128, 14438.
(9) No reaction was observed in the absence of CuI catalyst.
(10) Reviews on asymmetric CuI-catalyzed borylation of conjugated
(24) Pinacolboronates have been found to be incompatible with
Grignard reagents under Cu catalysis: Lee, J. C. H.; Hall, D. G. J. Am.
Chem. Soc. 2010, 132, 5544.
(25) Cu-catalyzed substitution of allyl sulfones with non-stabilized
́ ́
nucleophiles: (a) Llamas, T.; Gomez Arrayas, R.; Carretero, J. C. Adv.
Synth. Catal. 2004, 346, 1651. (b) Trost, B. M.; Merlic, C. A. J. Am.
Chem. Soc. 1988, 110, 5216. (c) Julia, M.; Righini, A.; Verpeaux, J.-N.
Tetrahedron 1983, 39, 3283.
alkenes: (a) Schiffner, J. A.; Muther, K.; Oestreich, M. Angew. Chem.,
́
Int. Ed. 2010, 49, 1194. (b) Mantilli, L.; Mazet, C. ChemCatChem
2010, 2, 501. Application to α,β-unsaturated sulfones: (c) Moure, A.
L.; Gom
6701.
́ ́
ez Arrayas, R.; Carretero, J. C. Chem. Commun. 2011, 47,
(11) For CuI/Xantphos-catalyzed B2(pin)2-borylation, see ref 7.
(12) Ligand effect in CuI-catalyzed B2(pin)2-diborylation of alkynes:
Yoshida, H.; Kawashima, S.; Takemoto, Y.; Okada, K.; Ohshita, J.;
Takaki, K. Angew. Chem., Int. Ed. 2012, 51, 235.
(13) Use of X-phos in regioselective hydrosilylation of terminal
alkynes: McLaughlin, M. G.; Cook, M. J. Chem. Commun. 2011, 47,
11104.
(14) Propargylic carbonates are transformed into allenylboronates
under the Cu(O-t-Bu)/Xantphos catalyst system: Ito, H.; Sasaki, Y.;
Sawamura, M. J. Am. Chem. Soc. 2008, 130, 15774.
(15) In accordance with literature precedent,6 complete opposite α-
regioselectivity was observed in the borylation of an aryl-substituted
internal alkyne under the same optimized reaction conditions:
(16) Selected examples of regioselective addition (other than
borylation) to internal alkynes: (a) Liu, P.; Montgomery, J.; Houk,
K. N. J. Am. Chem. Soc. 2011, 133, 6956. (b) Bausch, C. C.; Patman, R.
L.; Breit, B.; Krische, M. J. Angew. Chem., Int. Ed. 2011, 50, 5687.
(c) Kawasaki, Y.; Ishikawa, Y.; Igawa, K.; Tomooka, K. J. Am. Chem.
Soc. 2011, 133, 20712. (d) Liu, P.; McCarren, P.; Cheong, P. H.-Y.;
Jamison, T. F.; Houk, K. N. J. Am. Chem.Soc. 2010, 132, 2050.
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