Unexpected copper(II) catalysis: Catalytic amine base promoted β-borylation of α,β-unsaturated carbonyl compounds in water

Article abstract of DOI:10.1021/ol300575d

Using bis(pinacolato)diboron, catalytic amounts of Cu^II, and various amine bases in water under atmospheric conditions at rt, acyclic and cyclic α,β-unsaturated ketones and esters are β-borylated in up to 98% yield. Mechanistic investigations u

Full text of DOI:10.1021/ol300575d

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1918–1921
Unexpected Copper(II) Catalysis: Catalytic
Amine Base Promoted β-Borylation
of r,β-Unsaturated Carbonyl Compounds
in Water
Steven B. Thorpe, Joseph A. Calderone, and Webster L. Santos*
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, United States
santosw@vt.edu
Received March 6, 2012
ABSTRACT
Using bis(pinacolato)diboron, catalytic amounts of CuII, and various amine bases in water under atmospheric conditions at rt, acyclic and cyclic
R,β-unsaturated ketones and esters are β-borylated in up to 98% yield. Mechanistic investigations using UVꢀvis spectroscopy, 11B NMR, and
solvent kinetic isotope effect suggest that the role of the amine is not only to coordinate to CuII but also to activate a nucleophilic water molecule to
form the reactive sp2ꢀsp3 diboron complex.
Preparation of organoboronic acids and their derivatives
remains an active area of intense research because of their
functional group tolerance and remarkable versatility to be
Scheme 1. Metal Catalyzed Conjugate Borylation Approaches
converted into a wide variety of functional groups.1 In
particular, the SuzukiꢀMiyaura cross-coupling (SMC) reac-
tion provides a convenient route to construct difficult CꢀC
bonds. Although the use of SMC has become ubiquitous, the
cross-coupling of sp3 carbon centers remains a challenge.
Recent advances in this field include stereospecific cross-
coupling of secondary benzylic boronates,2 R-(acylamino)-
benzylboronic esters,3 nonbenzylic alkyl β-trifluoro-
carbonyl compounds: organometallic conjugate addition
to β-borylated compounds6 and transition metal-catalyzed
borylation.7 Among the transition metal-catalyzed methods,
the CuI-catalyzed conjugate borylation of electron deficient
olefins has garnered significant attention (Scheme 1).
Building on the pioneering work of Hosomi8 and Miyaura,9
Yun expanded the scope of substrates from unsaturated
boratohomoenolates,4 and alkyl-1,1-diboron compounds.5
Indeed, methods to prepare alkylboronic acid SMC sub-
strates are necessary to access increasingly more complex mol-
ecules. Two approaches currently exist for R,β-unsaturated
(1) (a) Hall, D. Boronic Acids: Preparation and Applications in
Organic Synthesis, Medicine and Materials, 2nd ed.; Wiley-VCH GmbH
& Co.: Weinheim, 2011. (b) Crudden, C. M.; Glasspoole, B. W.; Lata, C. J.
Chem. Commun. 2009, 6704–6716.
(6) Lee, J. C. H.; Hall, D. G. J. Am. Chem. Soc. 2010, 132, 5544–5545.
€
(7) (a) Schiffner, J. A.; Muther, K.; Oestreich, M. Angew. Chem., Int.
(2) Imao, D.; Glasspoole, B. W.; Laberge, V. r. S.; Crudden, C. M.
J. Am. Chem. Soc. 2009, 131, 5024–5025.
(3) Ohmura, T.; Awano, T.; Suginome, M. J. Am. Chem. Soc. 2010,
132, 13191–13193.
Ed. 2010, 49, 1194–1196. (b) Bonet, A.; Sole, C.; Gulyas, H.; Fernandez,
E. Curr. Org. Chem. 2010, 2, 2531–2548. (c) Mantilli, L.; Mazet, C.
ChemCatChem 2010, 2, 501–504.
(8) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett.
2000, 41, 6821–6825.
ꢀ
(4) (a) Sandrock, D. L.; Jean-Gerard, L.; Chen, C.-y.; Dreher, S. D.;
Molander, G. A. J. Am. Chem. Soc. 2010, 132, 17108–17110.
(b) Molander, G. A.; Petrillo, D. E. Org. Lett. 2008, 10, 1795–1798.
(5) Lee, J. C.; McDonald, R.; Hall, D. G. Nat. Chem 2011, 3, 894–9.
(9) (a) Takahashi, K.; Takagi, J.; Ishiyama, T.; Miyaura, N. Chem.
Lett. 2000, 29, 126–127. (b) Takahashi, K.; Ishiyama, T.; Miyaura, N.
J. Organomet. Chem. 2001, 625, 47–53.
r
10.1021/ol300575d
Published on Web 03/19/2012
2012 American Chemical Society

ketones and esters to include more challenging R,β-unsa-
turated amides.10 Catalytic asymmetric variants as well as
metal-free conditions have also been developed.7a,11
Although other transition metals (Pt,12 Pd,13 Rh,14 Ni,15
and Zn16) were effective as catalysts, CuI-catalyzed reports
dominate the literature in part because copper is an
inexpensivemetaland itsreactivitycan be tunedbyaltering
the ligands. Bis(pinacolato)diboron (B2pin2) is widely used
asthe boron source ina majorityofreports; however, other
reagents such as pinacolatodiisopropanolaminatodiboron17
and tetrahydroxydiborane18 can be used as alternatives.
Despite the great number of reports detailing the in-
stallation of boron on the β-carbon of an R,β-unsaturated
carbonyl, most reaction conditions have disadvantages:
some are uneconomical (employing expensive ligands and
a high catalyst loading), others are harsh (strong base such
as tert-butoxide is required), and more importantly, the
reactions are air-sensitive, often requiring the use of a
glovebox or Schlenck techniques. Thus, there is a need
for a more efficient and convenient method for the synth-
esis of alkylboronic acids. Herein we report an amine base
promoted β-borylation protocol of R,β-unsaturated car-
bonyls in water and open to air. In addition, we demonstrate
the first CuII-catalyzed β-borylation reaction and provide
mechanistic insight to the efficient borylation reaction.
Previous work in our laboratory17established that com-
plexation of B2pin2 by a Lewis base is necessary for the
in situ formation of an activated diboron.19 Hence, we began
our investigation by screening suitable additives that can
affect the borylation reaction in water without any organic
cosolvent.20 Preliminary studies indicated that amine bases
are inefficient in catalyzing the β-borylation reaction in
organic solvents in the presence of copper. Surprisingly, we
found that addition of a catalytic amount of inexpensive,
commercially available amines allowed the efficient con-
version of 2-cyclohexenone 1 to the corresponding bora-
tohomoenolate 2 in the presence of CuCl2 in water (Table 1).
Table 1. Screening of Additives and Reaction Conditionsa
entry
base additive
conv %b
1
benzylamine
piperidine
triethylamine
TMEDA
98.2
96.6
95.0
98.2
95.6
98.1
>99.9
98.4
97.5
99.8
97.8
76.9
17.7
99.8
20.3
42.9 (0d)
86.0
86.0
2
3
4
5
DBU
6
pyridine
7
4-picoline
8
3-picoline
9
2,6-lutidine
DMAPc
10
11
12
13
14
15
16
17
18
imidazole
quinoline
2,20-bipyridinec
proton sponge
none
4-picoline
sodium acetate
sodium hydroxide
a Reaction conditions: B2pin2 (1.1 equiv), 2-cyclohexen-1-one (1.0
equiv), and amine (2 mol %) were added to a 1-dram, PTFE vial with a
magnetic stir bar. 1.5 mL of a stock CuCl2 (1.72 mM) solution in water
was added and stirred vigorously for 1 h at rt. b Conversions determined
by GC analysis. c Amine was dissolved in THF before addition. d In the
absence of CuCl2 using nuclease-free or Milli-Q water.
(10) Mun, S.; Lee, J. E.; Yun, J. Org. Lett. 2006, 8, 4887–4889.
(11) (a) Lee, J. E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145–147.
(b) Lillo, V.; Prieto, A.; Bonet, A.; Dıaz-Requejo, M. M.; Ramırez, J.;
´ ´
In marked contrast to CuI-catalyzed β-borylation in
organic solvents,9b,10,11,11f,17a,17c,18,21 the current protocol
is most efficient with a CuII source (vide infra).22 CuII salts
are especially convenient because of their high solubility in
water and resistance to oxidation upon exposure to air.
Gratifyingly, we found that a variety of primary, second-
ary, and tertiary aliphatic amines provided excellent con-
version to 2 (entries 1ꢀ4). Use of a strong base was also
effective (entry 5). Heteroaromatic amines performed
better on average than aliphatic amines, with 4-picoline
giving the highest conversion (entries 6ꢀ11). Quinoline
showed decreased activity, likely due to decreased solubi-
lity in water (entry 12). On the other hand, 2,20-bipyridine
gavea significantly lower conversion, possibly asa resultof
ꢀ
ꢀ
Perez, P. J.; Fernandez, E. Organometallics 2008, 28, 659–662. (c) Chen,
I. H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2009, 131, 11664–11665. (d) Lillo, V.; Bonet, A.; Fernandez, E. Dalton
Trans. 2009, 2899–2908. (e) Lee, K. S.; Zhugralin, A. R.; Hoveyda, A. H.
J. Am. Chem. Soc. 2009, 131, 7253–5. (f) Bonet, A.; Gulyas, H.;
Fernandez, E. Angew. Chem., Int. Ed. 2010, 49, 5130–4.
(12) (a) Lawson, Y. G.; Lesley, M. J. G.; Norman, N. C.; Rice, C. R.;
Marder, T. B. Chem. Commun. 1997, 2051–2052. (b) Abu Ali, H.;
Goldberg, I.; Srebnik, M. Organometallics 2001, 20, 3962–3965. (c) Bell,
N. J.; Cox, A. J.; Cameron, N. R.; Evans, J. S. O.; Marder, T. B.; Duin,
M. A.; Elsevier, C. J.; Baucherel, X.; Tulloch, A. A. D.; Tooze, R. P.
Chem. Commun. 2004, 1854–1855.
ꢀ
ꢀ
(13) Bonet, A.; Gulyas, H.; Koshevoy, I. O.; Estevan, F.; Sanau, M.;
ꢀ
ꢀ
Ubeda, M. A.; Fernandez, E. Chem.;Eur. J. 2010, 16, 6382–6390.
(14) (a) Kabalka, G. W.; Das, B. C.; Das, S. Tetrahedron Lett. 2002,
43, 2323–2325. (b) Shiomi, T.; Adachi, T.; Toribatake, K.; Zhou, L.;
Nishiyama, H. Chem. Commun. 2009, 5987–5989.
(15) Hirano, K.;Yorimitsu, H.;Oshima, K. Org. Lett. 2007, 9, 5031–5033.
(16) Kajiwara, T.; Terabayashi, T.; Yamashita, M.; Nozaki, K.
Angew. Chem., Int. Ed. 2008, 47, 6606–6610.
(17) (a) Gao, M.; Thorpe, S. B.; Santos, W. L. Org. Lett. 2009, 11,
3478–3481. (b) Thorpe, S. B.; Guo, X.; Santos, W. L. Chem. Commun.
2011, 47, 424–426. (c) Gao, M.; Thorpe, S. B.; Kleeberg, C.; Slebodnick,
C.; Marder, T. B.; Santos, W. L. J. Org. Chem. 2011, 76, 3997–4007.
(18) Molander, G. A.; McKee, S. A. Org. Lett. 2011, 13, 4684–4687.
(21) (a) Chea, H.; Sim, H. S.; Yun, J. Adv. Synth. Catal. 2009, 351, 855–
858. (b) Sim, H.-S.; Feng, X.; Yun, J. Chem.;Eur. J. 2009, 15, 1939–1943.
(c) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 982–983.
(d) Fleming, W. J.; Muller-Bunz, H.; Lillo, V.; Fernandez, E.; Guiry, P. J.
Org. Biomol. Chem. 2009, 7, 2520–4. (e) Chen, I. H.; Kanai, M.; Shibasaki,
M. Org. Lett. 2010, 12, 4098–4101. (f) Feng, X.; Yun, J. Chem. Commun.
2009, 6577–6579. (g) Park, J. K.; Lackey, H. H.; Rexford, M. D.; Kovnir,
K.; Shatruk, M.; McQuade, D. T. Org. Lett. 2010, 12, 5008–5011.
(22) During the submission of this manuscript, Cu(OTf)2 was re-
ꢀ
ꢀ
(19) Pubill-Ulldemolins, C.; Bonet, A.; Bo, C.; Gulyas, H.; Fernandez,
E. Chem.;Eur. J. 2012, 18, 1121–1126.
ꢀ
ported as a catalyst: Ibrahem, I.; Breistein, P.; Cordova, A. Angew.
Chem., Int. Ed. 2011, 50, 12036–12041.
(20) Chea, H.; Sim, H. S.; Yun, J. Bull. Korean Chem. Soc. 2010, 31,
551–552.
Org. Lett., Vol. 14, No. 7, 2012
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rigid bidentate binding to copper (entry 13).23 A proton
sponge also provided excellent conversion (entry 14). As
expected, the reaction was sluggish in the absence of amine
or copper (entries 15ꢀ16). As shown in entry 16, when the
reaction was run using in-house deionized water, a back-
ground conversion of 43% resulted, suggesting a possibi-
lity of transition-metal-free reaction. However, analysis of
the deionized water revealed 40 ppb Cu by ICP-MS, an
indication that a minute level of copper is capable of
catalyzing the transformation.
catalyzing the reaction (vide supra) because of the fast
oxidation of CuI by molecular oxygen (entry 8).26 Taken
together, these studies suggest that CuII is the active
catalyst under aqueous conditions and that CuII may be
the active catalyst for reactions run under organic solvents.
Scheme 2. CuII-Catalyzed Boryl Conjugate Addition with
Acyclic and Cyclic R,β-Unsaturated Ketones and Estersa
Table 2. Screening of Copper Sources and Stoichiometrya
4-picoline
entry
Cu source
(mol %)
conv %b
1
2
3
4
5
6
7
8
CuCl2
2%
5%
2%
5%
5%
5%
5%
5%
<1
CuCl2
72.8
39.9
89.5
84.0
78.3
77.4
33.5
CuSO4
CuSO4
Cu(OAc)2
Cu(BF4)2
CuCl
c
CuSO4
a Reaction conditions identical to Table 1. b Conversion determined
by GC analysis. c With 20 mol % sodium ascorbate.
a Reaction conditions: B2pin2 (1.1 equiv), 1 (1.0 equiv), and 4-picoline
(0.05 equiv) were added to a 5 mL round-bottomed flask with a magnetic
stir bar. CuSO4 (1 mol %) dissolved in 3 mL of deionized water was added,
and the reaction was stirred vigorously for 1ꢀ3 h at rt. bChalcone was
dissolved in minimal THF before addition. cNMR yield. dPreparative scale.
Although many amines participate as good additives, we
chose 4-picoline for further optimization since it gave the
highest conversion. When a more sterically demanding
substrate, 3-methylcyclohexenone (3), was used (Table 2),
the desired product 4 was only observed in good conver-
sion with 1:5 Cu/amine stoichiometry (compare entry 1 vs 2).
A further survey of copper sources revealed that a more
water-soluble CuSO4 resulted in excellent conversion and
that other copper(II) sources were also effective (entries
3ꢀ6). We were surprised to discover that CuII was an
effective borylation catalyst since, to the best of our
knowledge, only CuI catalyst systems have been reported.
To investigate the CuII catalysis, the reaction was run with
CuCl with good conversion(entry 7);however, thisresultis
misleading because CuI disproportionates (to Cu0 and
CuII) in water and provides a CuII source.24 To further
confirm that CuI is not the active catalyst, CuSO4 was
reduced in situ to CuI in the presence of excess sodium
ascorbate.25 As expected, the conversion decreased; how-
ever trace CuII is likely still present that is capable of
Withthe optimized conditionsin hand (Table2, entry 4),
we explored the scope and limitations of this reaction with
a
variety of R,β-unsaturated carbonyl compounds
(Scheme 2). For example, borylated acyclic ketones 6ꢀ9
were synthesized in good to excellent yield (up to 98%
isolated yield). Furthermore, a conjugated dienone was
regiospecifically borylated on the β-position to afford 10.
Cyclic enones (2, 4, and 11) were also readily transformed
in good yields; cyclopentenone resulted in a moderate yield
as the pinacol ester 11, but conversion to the trifluorobo-
rate salt 11a significantly improved the isolated product
yield. To our delight, R,β-unsaturated esters also generated
borylated products in good to excellent yields (12ꢀ15). A
limitation of the reaction is evident with tert-butyl croto-
nate (16), which afforded the product in only 46% yield as
the potassium trifluoroborate salt 16a. To demonstrate the
practical utility of the developed protocol, we performed
reactions on a preparative scale. Indeed, the borylated
products (2, 6, 9, 13, and 15) were efficiently formed in
yields within experimental error of the small scale version.
Moreover, the products in Scheme 1 were isolated by
(23) Ozutsumi, K.;Kawashima, T.Inorg. Chim. Acta 1991, 180, 231–238.
(24) A distinct difference in the physical appearance of the copper
sources was observed. For example, a gray/black precipitate appeared
with CuCl while CuSO4 was a homogeneous pale blue solution.
(25) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–9. (b) Wang, Q.; Chan,
T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am.
Chem. Soc. 2003, 125, 3192–3193.
(26) Martell Arthur, E. Chelates of Ascorbic Acid. In Ascorbic Acid:
Chemistry, Metabolism, and Uses; American Chemical Society: 1982; Vol.
200, pp 153ꢀ178.
1920
Org. Lett., Vol. 14, No. 7, 2012

simple extraction (except for water-soluble 11) because
the alkene starting materials were consumed and any
excess B2pin2 decomposed into water-soluble pinB-OH.
Although the current conditions cannot yet be extended to
R,β-unsaturated amides, tetrahydroxydiborane as the bor-
on source provided a moderate yield of 6 upon treatment
with pinacol (Scheme 3).
Scheme 3. Two-Step BorylationꢀProtection with Tetrahy-
droxydiborane
Figure 1. 11B NMR spectra of B2pin2 in (A) 4-picoline, (B)
water, and (C) water with 4-picoline (1.0 equiv) at 4 °C.
Scheme 4. Pinacol Boronic Acid: Not the Boron Source
To gain insight into the effect of an amine base on the
CuII-catalyzed reaction in water, we performed 11B NMR
experiments at 4 °C (Figure 1). Investigation in neat
4-picoline suggests that the amine does not participate in
Lewis acidꢀbase coordination because a single boron
chemical shift is observed at 31 ppm, indicative of uncom-
plexed B2pin2 (Figure 1A). This result is not surprising
since B2pin2 is sterically hindered, and 4-picoline has only
been observed to coordinate with more Lewis acidic bis-
(catecholato)diboron.27 Furthermore, when water28 was
used as the NMR solvent, only B2pin2 and its decomposi-
tion product, pinBOH (confirmed by independent
synthesis), were detected (Figure 1B and 1C). To ensure
that pinBOH was not a reactive intermediate, the proce-
dure was performed using pinBOH as the boron source,
and no product was detected (Scheme 4). UVꢀvis mea-
surements with increasing stoichiometry of 4-picoline/CuII
revealed the expected coordination of amine tocopper; i.e.,
successive coordination of 4-picoline to copper results in a
blue shift in the spectrum (see Supporting Information
(SI)).29 We also determined that the reaction was efficient
when the amine was exchanged with NaOAc, NaOH, and
the noncoordinating proton sponge (Table 1, entries 14,
17ꢀ18). Furthermore a solvent kinetic isotope effect (H2O
vs D2O) of 1.9 was determined, suggesting a possible
deprotonation in the rate determining step (see SI).30 On
thebasisoftheseobservations, itis plausibletosuggest that
the role of the amine is twofold: (1) to form a stable
Figure 2. Proposed mechanism.
4-picoline-CuII complex and/or (2) to act as a Bronsted
base to activate a nucleophilic water molecule and gener-
ate, in situ, an sp2ꢀsp3 diboron that is capable of transme-
talation with copper (Figure 2). The resulting ‘boryl-
copper’ species then undergoes boryl conjugate addition.
In conclusion, we have developed an efficient and prac-
tical catalytic method for the preparation of alkylboronates
in good to excellent yields (up to 98%). To the best of our
knowledge, this is the first report of a CuII-catalyzed method
for this reaction using water as the solvent and open to air.
We also provided evidence for the role of catalytic amine in
the mechanism of the reaction. Further extension and
application of this method is currently underway.
(27) (a) Clegg, W.; Dai, C. Y.; Lawlor, F. J.; Marder, T. B.; Nguyen,
P.; Norman, N. C.; Pickett, N. L.; Power, W. P.; Scott, A. J. Dalton
Trans. 1997, 839–846. (b) Clegg, W.; Elsegood, M. R. J.; Lawlor, F. J.;
Norman, N. C.; Pickett, N. L.; Robins, E. G.; Scott, A. J.; Nguyen, P.;
Taylor, N. J.; Marder, T. B. Inorg. Chem. 1998, 37, 5289–5293.
(28) Water has been used as a reaction medium with B2pin2: Kokatla,
H. P.; Thomson, P. F.; Bae, S.; Doddi, V. R.; Lakshman, M. K. J. Org.
Chem. 2011, 76, 7842–7848.
(29) Leussing, D. L.; Hansen, R. C. J. Am. Chem. Soc. 1957, 79,
4270–4273.
(30) We could not exclude a rate determining protonation step of Cu-
enolate when performed in organic solvent (see ref 10), which has been
supported by theoretical calculation: Dang, L.; Lin, Z. Y.; Marder, T. B.
Organometallics 2008, 27, 4443–4454.
Acknowledgment. We gratefully acknowledge financial
support from the Thomas F. Jeffress and Kate Miller
Jeffress Memorial Trust and ACS Petroleum Research
Fund. B2pin2 was a generous gift from AllyChem.
Supporting Information Available. Experimental de-
tails and spectral data of all compounds synthesized. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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