Stereo- and Regiocontrolled Methylboration of Terminal Alkynes

Article abstract of DOI:10.1021/acs.orglett.8b01252

A scalable and operationally simple synthesis of trisubstituted alkenyl boronic esters has been achieved using a Zr-catalyzed carboalumination of terminal alkynes followed by in situ transmetalation with i-PrOBpin. The products are formed in good yields and with excellent regioselectivity and perfect stereoselectivity. The new procedure provides a significant improvement over the previously reported syntheses.

Full text of DOI:10.1021/acs.orglett.8b01252

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereo- and Regiocontrolled Methylboration of Terminal Alkynes
Oleksandr Zhurakovskyi, Rafael M. P. Dias, Adam Noble, and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
S
* Supporting Information
ABSTRACT: A scalable and operationally simple synthesis of trisubstituted alkenyl boronic esters has been achieved using a Zr-
catalyzed carboalumination of terminal alkynes followed by in situ transmetalation with i-PrOBpin. The products are formed in
good yields and with excellent regioselectivity and perfect stereoselectivity. The new procedure provides a significant
improvement over the previously reported syntheses.
erminal trisubstituted alkenyl boronates are highly
methods are desirable and have been reported. One-step
Timportant substrates in synthetic chemistry, with carboborations of terminal or internal alkynes are possible
under transition-metal catalysis with B2pin2 as the boron source
(Figure 1B).2a−c,6 However, while high regioselectivity can be
obtained with aryl-substituted alkynes, product ratios are
invariably lower with alkyl-substituted terminal alkynes.7−9
We considered the possibility of using intermediate alkenyl
alanes, generated from the well-established carboalumination of
alkynes,3a−c in a transmetalation process with trialkoxyboro-
nates. Such transmetalation processes (Al → B) are rare. In fact,
based on typical bond strengths, the transmetalation process is
expected to be strongly endothermic by 101 kJ/mol due
primarily to the high B−O bond strength and so should not
proceed.10,11 However, a limited precedent does exist. Hoveyda
showed that trialkoxyboronates could transmetalate alkenyl
alanes generated by a Ni-catalyzed addition of DIBAL-H to
terminal alkynes,12 and Thomas and Cowley reported that
pinacol borane was able to transmetalate alkenyl alanes
generated by a DIBAL-H addition to terminal alkynes.13
Herein, we report the successful development of this
reaction, which provides an operationally simple protocol to
convert terminal alkynes 1 into trisubstituted alkenyl boronates
3 in one pot using readily available chemicals. The
carboborations proceed with high regio- and stereoselectivities
and with improved yields when compared to previous
approaches (Figure 1C).
application in a variety of useful transformations, including
the Suzuki−Miyaura cross coupling,1a,b radical additions,1c−e
and transition-metal-free cross couplings.1f,g The required
boronate esters can be accessed from various precursors,
including alkynes,2a−c alkenes,2d−g epoxides,2h allenes,2i ke-
tones, and aldehydes.2j,k The carboboration of terminal alkynes
represents a particularly attractive method to access alkenyl
boronates due to the concomitant introduction of both alkyl
and boron groups. Historically, this transformation has been
achieved by initial carboalumination,3 followed by iodination,
isolation, and finally, borylation4,5 (Figure 1A). More direct
To test the feasibility of the Al → B transmetalation, we
prepared alkenyl alane 2a by a Cp2ZrCl2-catalyzed Negishi
carboalumination of 1-octyne (1a) with AlMe3 (Table 1). In
the same pot, treatment of alkenyl alane 2a with i-PrOBpin, a
cheap and widely available reagent, resulted in an extremely fast
formation of the desired alkenyl boronate 3a in high yield and
with excellent regioselectivity (rr 98:2). It was found that only
1.2 equiv of i-PrOBpin was required for complete borylation in
Received: April 19, 2018
Figure 1. Synthesis of alkenyl boronates from alkynes.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01252
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
H2O). Deliberate addition of 1 equiv of water to the reaction
mixture (entry 3)3h,i resulted in an exceedingly fast
carboalumination (<10 min). However, the yield of alkenyl
boronate 3a dropped to 53%. The use of excess reagents (entry
4) did not alter the yield or regioselectivity but did accelerate
the carboalumination step. The Al → B exchange was extremely
fast, and a temperature increase was observed upon the
addition of i-PrOBpin to the alkenyl alane. This heat evolution
initially led to reduced yields (35−45%) when the reactions
were scaled up or performed on sensitive substrates (vide
infra), with products of protodemetalation accounting for the
remaining mass balance (entry 5). Thus, small-scale Al → B
exchange was performed by adding the i-PrOBpin at 0 °C
before allowing the reaction mixture to warm to room
temperature. Since the reaction was expected to be
endothermic based on bond strengths, the surprising exotherm
observed must be caused by other processes, such as the
formation of dimers or other oligomeric structures of the i-
PrOAlMe2 byproduct.14
Table 1. Reaction Optimization
a
entry
1
conditions
result
b
c
2 equiv of AlMe3, 0.2 equiv of Cp2ZrCl2,
reagent-grade CH2Cl2, 23 °C, 9 h; then 1.2
equiv of i-PrOBpin, 0−23 °C, 10 min
82% yield, rr 98:2
deviations from the above
2
3
anhydrous CH2Cl2 used
incomplete [Al]
70% yield, rr 97:3
addition of 1 equiv of H2O during
carboalumination; 2 equiv of i-PrOBpin
[Al] in <10 min
53% yield,
rr >99:1
4
5
3 equiv of AlMe3, 1 equiv of Cp2ZrCl2, anhyd [Al] in <10 min
CH2Cl2; then 3 equiv of i-PrOBpin, 4 h
80% yield,
rr >98:2
i-PrOBpin added at 23 °C
overheating,
significant
protodemetalation
b
We then applied the optimized carboboration conditions to a
range of alkynes to test its scope (Scheme 1). Nineteen alkynes
were reacted on a 0.5 mmol scale to give the alkenyl boronate
products in generally high yields (ca. 80%) and with excellent
regioselectivities (up to >98:2 rr). In many cases, the isolated
yields and/or regioisomeric ratios were significantly higher than
those previously reported. For example, trifluoromethylated
a
Reactions performed with 0.45 mmol of 1a. Isolated yield.
c
1
Measured by H NMR analysis of the crude reaction mixtures.
less than 10 min. The reaction did not require anhydrous
solvents (entry 2 vs 1), and in fact, the carboalumination step
was slightly faster in reagent-grade CH2Cl2 (∼500 ppm of
Scheme 1. One-Pot Synthesis of Alkenyl Boronates 3a−q
a
Reaction conditions: 1 (0.5 mmol), 2 equiv of AlMe3, 0.2 equiv of Cp2ZrCl2, reagent-grade CH2Cl2, 0−23 °C, 14 h; then 1.2 equiv of i-PrOBpin,
b
c
0−23 °C, 60 min. Yields are given for isolated products after SiO2 column chromatography. Regioisomeric ratios are given for crude reaction
mixtures and measured by H NMR spectroscopy. Carboalumination performed in the presence of 1 equiv of modified methylaluminoxane
(MMAO-12). Carboalumination performed for 96 h. Regioisomeric ratio after column chromatography.
d
1
e
f
B
DOI: 10.1021/acs.orglett.8b01252
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Letter
boronate 3q could not be prepared using the previously
reported copper-catalyzed carboboration.6a However, using our
method, 3q was formed in a synthetically viable 33% yield and
with excellent regioselectivity.
precooling the AlMe3/Cp2ZrCl2 mixture to 0 °C. After 14 h, i-
PrOBpin was added in one portion at −50 °C, and the mixture
was allowed to warm to 23 °C. The cryogenic cooling was
essential in order to obtain good yields on gram scale. When we
attempted to control the exotherm by slow addition of i-
PrOBpin at 0 °C, alkenyl boronate 3b was obtained in only
50% yield. Only when the borylating agent was added in one
portion could 82% of the product be obtained.20 Under these
conditions, compound 3b was isolated in 82% yield,17 3f in
79% yield,19 3t in 78%, but with improved regioselectivity,6n
and isoprenylated boronate 3l in 50% yield.18 In almost all
cases, significant improvements over the literature procedures
were achieved.
In summary, we have developed a straightforward synthesis
of terminal trisubstituted alkenyl boronates from nonactivated
terminal alkynes. The reaction uses cheap and easily available
commercial materials, does not require flame-dried glassware,
and is scalable to gram amounts. The reaction is applicable to a
broad range of alkyne substrates, and the products are formed
with good-to-excellent regioselectivities.
Alkynes bonded to primary (1b), secondary (1c), and even
tertiary carbon centers (1d) reacted equally well (the slightly
reduced yield of 3d can be explained by the volatility of the
starting material, bp 37−38 °C15), thus demonstrating that the
reaction tolerates the full spectrum of steric demand.
Conjugation of the alkyne to an alkene or an aromatic ring
slowed the carboalumination step (1i: 20 h; 1j: 96 h), but the
overall yield and regioselectivity remained high. Silyl ethers (1g,
1h) and alkyl chlorides (3e) were well tolerated, although
slightly reduced regioselectivity (rr 89:11) was observed for the
two-carbon-tethered silyl ether 3g, presumably arising from the
O → Al coordination.
The success of the overall transformation depended on the
ability to perform the initial carboalumination and thus
followed the general trends known for this reaction.3b,c In
particular, the presence of sterically accessible Lewis basic sites
interfered with this step (1o−s). For example, almost no
reaction was observed for ester 1p, even when 4 equiv of AlMe3
were used or when the reaction mixture was heated at 60 °C in
1,2-dichloroethane. Pleasingly, the reactivity of this substrate,
and others bearing Lewis basic functional groups, could be
dramatically improved by the addition of modified methyl-
aluminoxane (MMAO-12, 1 equiv).16 Thus, the ester 3p was
obtained in 69% yield (rr 95:5, improved to >98:2 by
chromatography). Silyl ether 3g was formed with rr 93:7,
compared with 89:11 for the additive-free reaction. On the
other hand, 3-pyridyl alkyne 1s yielded no desired boronate,
even in the presence of MMAO-12, with products of ring
methylation observable by GCMS and NMR.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01252.
General reaction procedures, characterization data, and
NMR spectra for alkenyl boronates 3 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: v.aggarwal@bristol.ac.uk.
ORCID
The utility of the carboalumination−borylation sequence was
further demonstrated by performing gram-scale reactions
(Scheme 2). We targeted four substrates, for which direct
comparisons with the literature protocols could be
made.6n,17−19 Carboalumination was smoothly performed on
a 6 mmol scale, the slight exotherm being controlled by
Oleksandr Zhurakovskyi: 0000-0002-2096-2202
Rafael M. P. Dias: 0000-0002-0780-8382
Adam Noble: 0000-0001-9203-7828
Varinder K. Aggarwal: 0000-0003-0344-6430
Notes
Scheme 2. Gram-Scale Synthesis of Alkenyl Boronates
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC (EP/I038071/1), the H2020 ERC
(670668), and the University of Bristol for financial support.
R.M.P.D. is grateful to the CAPES Foundation for a fellowship
(Grant No. 88881.120469/2016-01).
REFERENCES
■
(1) Suzuki−Miyaura cross coupling: (a) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457−2483. (b) Kotha, S.; Lahiri, K.; Kashinath,
D. Tetrahedron 2002, 58, 9633−9695. Radical additions: (c) Noble,
A.; Mega, R. S.; Pflasterer, D.; Myers, E. L.; Aggarwal, V. K. Angew.
̈
Chem., Int. Ed. 2018, 57, 2155−2159. (d) Silvi, M.; Sandford, C.;
Aggarwal, V. K. J. Am. Chem. Soc. 2017, 139, 5736−5739.
(e) Guennouni, N.; Lhermitte, F.; Cochard, S.; Carboni, B.
Tetrahedron 1995, 51, 6999−7018. Transition-metal-free cross
couplings: (f) Armstrong, R. J.; Sandford, C.; García-Ruiz, C.;
Aggarwal, V. K. Chem. Commun. 2017, 53, 4922−4925. (g) Armstrong,
R. J.; Aggarwal, V. K. Synthesis 2017, 49, 3323−3336.
(2) Synthesis of boronate esters from alkynes: (a) Yoshida, H. ACS
Catal. 2016, 6, 1799−1811. (b) Barbeyron, R.; Benedetti, E.; Cossy, J.;
Vasseur, J. J.; Arseniyadis, S.; Smietana, M. Tetrahedron 2014, 70,
a
Reagents and conditions: 1 (6 mmol), 2 equiv of AlMe3, 0.2 equiv of
Cp2ZrCl2, CH2Cl2, 0−23 °C, 14 h; then 1.2 equiv of i-PrOBpin, −50
to +23 °C, 1 h.
C
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Organic Letters
Letter
8431−8452. (c) Yun, J. Asian J. Org. Chem. 2013, 2, 1016−1025.
From alkenes: (d) Takahashi, K.; Takagi, J.; Ishiyama, T.; Miyaura, N.
Chem. Lett. 2000, 29, 126−127. (e) Kiesewetter, E. T.; O’Brien, R. V.;
Yu, E. C.; Meek, S. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2013, 135, 6026−6029. (f) Morrill, C.; Grubbs, R. H. J. Org. Chem.
2003, 68, 6031−6034. (g) Kirai, N.; Iguchi, S.; Ito, T.; Takaya, J.;
Iwasawa, N. Bull. Chem. Soc. Jpn. 2013, 86, 784−799. From epoxides:
(h) Murray, S. A.; Luc, E. C. M.; Meek, S. J. Org. Lett. 2018, 20, 469−
472. From allenes: (i) Meng, F.; Jung, B.; Haeffner, F.; Hoveyda, A.
H. Org. Lett. 2013, 15, 1414−1417. From ketones and aldehydes:
(j) Stephens, T. C.; Pattison, G. Org. Lett. 2017, 19, 3498−3501.
(k) Matteson, D. S.; Moody, R. J. Organometallics 1982, 1, 20−28.
(3) Carboalumination reviews: (a) Negishi, E. I. ARKIVOC 2011,
34−53. (b) Normant, J. F.; Alexakis, A. Synthesis 1981, 1981, 841−
870. (c) Negishi, E.; Kondakov, D. Y. Chem. Soc. Rev. 1996, 25, 417.
Seminal publications: (d) Van Horn, D. E.; Negishi, E. J. Am. Chem.
Soc. 1978, 100, 2252−2254. (e) Negishi, E.; Okukado, N.; King, A. O.;
Van Horn, D. E.; Spiegel, B. I. J. Am. Chem. Soc. 1978, 100, 2254−
2256. (f) Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc.
1985, 107, 6639−6647. Mechanistic studies: (g) Yoshida, T.; Negishi,
E. J. Am. Chem. Soc. 1981, 103, 4985−4987. Water-promoted
carboaluminations: (h) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl.
1993, 32, 1068−1071. (i) Wipf, P.; Nunes, R. L.; Ribe, S. Helv. Chim.
Acta 2002, 85, 3478−3488.
(11) (a) Dean, J. A., Ed. Bond Dissociation Energies. In Lange’s
Handbook of Chemistry, 15th ed; McGraw-Hill: New York, 1999; pp
329−330. (b) King, R. B., Crabtree, R. H., Lukehart, C. M., Atwood,
D. A., Scott, R. A., Eds. Bond Energies. In Encyclopedia of Inorganic
Chemistry; Wiley, 2006; DOI: 10.1002/0470862106.id098.
(12) Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10961−
10963.
(13) Bismuto, A.; Thomas, S. P.; Cowley, M. J. Angew. Chem., Int. Ed.
2016, 55, 15356−15359.
(14) The additional Al−O bonds formed in the dimerization of i-
PrOAlMe2 may contribute to the exotherm observed. See: Allan, J. F.;
Clegg, W.; Elsegood, M. R. J.; Henderson, K. W.; McKeown, A. E.;
Moran, P. H.; Rakov, I. M. J. Organomet. Chem. 2000, 602, 15.
̌
(15) Duris,
Rodriguez, F.; Ballereau, S.; Gen
2016, 22, 6676−6686.
̌
A.; Daïch, A.; Santos, C.; Fleury, L.; Ausseil, F.;
́
isson, Y.; Berkes, D. Chem. - Eur. J.
̌
(16) Kaminsky, W. Macromol. Chem. Phys. 1996, 197, 3907−3945.
(17) Hieda, Y.; Choshi, T.; Fujioka, H.; Hibino, S. Eur. J. Org. Chem.
2013, 2013, 7391−7401.
(18) Salvaggio, F.; Hodgkinson, J. T.; Carro, L.; Geddis, S. M.;
Galloway, W. R. J. D.; Welch, M.; Spring, D. R. Eur. J. Org. Chem.
2016, 2016, 434−437.
(19) Chen, J. L. Y.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2014, 53,
10992−10996.
(20) It is possible that the excess alkenyl alane intermediate 2 reacts
with the newly formed boronate 3 when i-PrOBpin is added slowly.
Rapid addition of i-PrOBpin diminishes the extent of this side reaction
at the cost of rapid heat evolution, which is controlled by precooling
the reaction mixture to −50 °C.
(4) Miyaura borylation: (a) Ishiyama, T.; Murata, M.; Miyaura, N. J.
Org. Chem. 1995, 60, 7508−7510. Review: (b) Kubota, K.; Iwamoto,
H.; Ito, H. Org. Biomol. Chem. 2017, 15, 285−300.
(5) (a) Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J. Org. Chem.
2002, 67, 5176−5183. (b) Li, W.; Nelson, D. P.; Jensen, M. S.;
Hoerrner, R. S.; Cai, D.; Larsen, R. D.; Reider, P. J. J. Org. Chem. 2002,
67, 5394−5397.
́
(6) Cu-catalyzed carboboration: (a) Alfaro, R.; Parra, A.; Aleman, J.;
García Ruano, J. L.; Tortosa, M. J. Am. Chem. Soc. 2012, 134, 15165−
15168. (b) Liu, P.; Fukui, Y.; Tian, P.; He, Z.-T.; Sun, C.-Y.; Wu, N.-
Y.; Lin, G.-Q. J. Am. Chem. Soc. 2013, 135, 11700−11703. (c) Yoshida,
H.; Kageyuki, I.; Takaki, K. Org. Lett. 2013, 15, 952−955. (d) Kageyuki,
I.; Yoshida, H.; Takaki, K. Synthesis 2014, 46, 1924−1932. (e) Semba,
K.; Bessho, N.; Fujihara, T.; Terao, J.; Tsuji, Y. Angew. Chem., Int. Ed.
2014, 53, 9007−9011. (f) Zhou, Y.; You, W.; Smith, K. B.; Brown, M.
K. Angew. Chem., Int. Ed. 2014, 53, 3475−3479. (g) Bidal, Y. D.;
Lazreg, F.; Cazin, C. S. J. ACS Catal. 2014, 4, 1564−1569. (h) Su, W.;
Gong, T.-J.; Lu, X.; Xu, M.-Y.; Yu, C.-G.; Xu, Z.-Y.; Yu, H.-Z.; Xiao, B.;
Fu, Y. Angew. Chem., Int. Ed. 2015, 54, 12957−12961. (i) Kubota, K.;
Iwamoto, H.; Yamamoto, E.; Ito, H. Org. Lett. 2015, 17, 620−623.
(j) Bin, H.-Y.; Wei, X.; Zi, J.; Zuo, Y.-J.; Wang, T.-C.; Zhong, C.-M.
ACS Catal. 2015, 5, 6670−6679. (k) Itoh, T.; Shimizu, Y.; Kanai, M. J.
Am. Chem. Soc. 2016, 138, 7528−7531. (l) Su, W.; Gong, T.-J.; Zhang,
Q.; Zhang, Q.; Xiao, B.; Fu, Y. ACS Catal. 2016, 6, 6417−6421.
(m) Kageyuki, I.; Osaka, I.; Takaki, K.; Yoshida, H. Org. Lett. 2017, 19,
830−833. (n) Mun, B.; Kim, S.; Yoon, H.; Kim, K. H.; Lee, Y. J. Org.
Chem. 2017, 82, 6349−6357.
(7) Other methods include bromoboration of alkynes with BBr3
followed by esterification and Negishi coupling,8 and Ni- or Pd-
catalyzed intramolecular boration of tethered alkynes.9
(8) (a) Wang, C.; Tobrman, T.; Xu, Z.; Negishi, E. Org. Lett. 2009,
11, 4092−4095. (b) Negishi, E. I.; Tobrman, T.; Rao, H.; Xu, S.; Lee,
C. T. Isr. J. Chem. 2010, 50, 696−701.
(9) (a) Yamamoto, A.; Suginome, M. J. Am. Chem. Soc. 2005, 127,
15706−15707. (b) Suginome, M.; Yamamoto, A.; Murakami, M. J. Am.
Chem. Soc. 2003, 125, 6358−6359. (c) Daini, M.; Yamamoto, A.;
Suginome, M. J. Am. Chem. Soc. 2008, 130, 2918−2919.
(10) Using the standard bond energies,11 one can estimate the Al→B
exchange to be endothermic with ΔH298 = + 101 kJ/mol:
D
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