Palladium-catalyzed borylation of primary alkyl bromides

Article abstract of DOI:10.1021/jo301156e

A mild Pd-catalyzed process for the borylation of alkyl bromides has been developed using bis(pinacolato)diboron as a boron source. This process accommodates the use of a wide range of functional groups on the alkyl bromide substrate. Primary bromides react with complete selectivity in the presence of a secondary bromide. The generality of this approach is demonstrated by its extension to the use of alkyl iodides and alkyl tosylates, as well as borylation reactions employing bis(neopentyl glycolato)diboron as the boron source.

Full text of DOI:10.1021/jo301156e

Subscriber access provided by Columbia Univ Libraries
Note
Palladium-Catalyzed Borylation of Primary Alkyl Bromides
Amruta Joshi-Pangu, Xinghua Ma, Mohamed Diane, Sidra Iqbal,
Robert J Kribs, Richard Huang, Chao-Yuan Wang, and Mark R. Biscoe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301156e • Publication Date (Web): 10 Jul 2012
Downloaded from http://pubs.acs.org on July 13, 2012
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 14
The Journal of Organic Chemistry
Palladium-Catalyzed Borylation of Primary Alkyl Bromides
1
2
3
4
5
6
Amruta Joshi-Pangu, Xinghua Ma, Mohamed Diane, Sidra Iqbal, Robert J. Kribs, Richard Huang, Chao-
Yuan Wang, and Mark R. Biscoe*
7
8
9
Department of Chemistry, The City College of New York, 160 Convent Ave., New York, NY 10031
Email of corresponding author: mbiscoe@ccny.cuny.edu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Abstract: A mild Pd-catalyzed process for the borylation of alkyl bromides has been developed using
bis(pinacolato)diboron as a boron source. This process accommodates the use of a wide range of
functional groups on the alkyl bromide substrate. Primary bromides react with complete selectivity in
the presence of a secondary bromide. The generality of this approach is demonstrated by its extension to
the use of alkyl iodides and alkyl tosylates, as well as borylation reactions employing bis(neopentyl
glycolato)diboron as the boron source.
Over the past few decades, the Suzuki-Miyaura cross-coupling reaction has become a workhorse
for the construction of carbon-carbon bonds.1-3 The majority of such reactions involves the use of aryl or
vinylboron nucleophiles. In comparison, methods that allow the general use of alkylboron nucleophiles
in Suzuki-Miyaura cross-coupling reactions have remained far less developed.4,5 A major focus of the
research in our laboratory is the development of new methods for carbon-carbon bond formation via
metal-catalyzed cross-coupling reactions using alkyl nucleophiles.6-8 For such transformations,
alkylboron reagents constitute ideal nucleophiles. The high covalency of the carbon-boron bond
typically makes alkylboron reagents air and moisture stable, configurationally stable, and compatible
with a diverse range of functional groups.9,10 Thus, the development of new cross-coupling methods that
enable the general use of alkylboron reagents is an attractive synthetic goal.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 14
Classically, organoboron reagents have been generated via borylation of the corresponding
lithium or magnesium reagents, or via the hydroboration of a terminal olefin.11 More recently,
significant progress has been made towards the development of new, milder methods to generate
organoboron reagents for use in synthesis. Particular attention has been focused on the preparation of
alkyl and aryl boronic ester derivatives via transition metal-catalyzed processes. Notable examples
include the metal-catalyzed hydroboration of alkenes,12-16 metal-catalyzed C-H activation/borylation
sequences,17-25 and metal-catalyzed β-borylation of α,β-unsaturated compounds.26-30 With the aim of
developing a mild and general method to generate primary alkylboronate esters for use in cross-coupling
reactions, we explored the possiblity of using bis(pinacolato)diboron as a boron source in the Pd-
catalyzed borylation of alkyl halides. An analogous strategy has been successfully applied to the
formation of arylboronic esters from aryl halides.31-33 However, a method to effect the direct Pd-
catalyzed borylation of alkyl halides has not been reported.34-36 Herein, we report a Pd-catalyzed method
for the selective borylation of primary alkyl bromides. This process displays excellent functional group
tolerance and can be extended to the use of alkyl iodides and alkyl tosylates. Additionally, we have
demonstrated that bis(neopentyl glycolato)diboron can be successfully employed as the boron source
with nominal variation of the standard reaction conditions.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Initial ligand screening revealed that trialkylphosphines were most effective in the Pd-catalyzed
borylation of (3-bromopropyl)benzene. This is consistent with the reported ability of trialkylphosphine-
ligated palladium(0) complexes to undergo oxidative addition into primary alkyl halides.37-39 Products
resulting from alkyl halide reduction and β-hydride elimination constituted the major side-products
observed during reaction optimization. There was no evidence for protodeboronation of the
alkylboronic esters products over the course of the reactions. Our final, optimized conditions are
displayed in Table 1. The use of t-Bu2MeP•HBF4 as a supporting ligand resulted in the highest yields. t-
BuOH and DMA were the most effective solvents for this transformation. K3PO4 was the most effective
base, though K2CO3 could also be used successfully. While the addition of exogenous water was found
ACS Paragon Plus Environment

Page 3 of 14
The Journal of Organic Chemistry
to be essential for efficient conversion, only a nominal variation in GC yield was observed when 3 equiv
H2O was used in place of 15 equiv H2O.
1
2
3
4
5
6
7
8
Table 1. Optimization of Standard Reaction Conditions
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Yields and selectivities determined by GC with dodecane as an internal standard.
Using the optimized conditions displayed in Table 1, alkylboronate esters were generated cleanly
in high yields from a wide range of functionalized primary alkyl bromides (Table 2). Alkyl bromide
substrates bearing functional groups including nitriles, alcohols, ethers, esters, amides, and imides were
successfully borylated.40 The presence of heterocyclic substituents on the alkyl bromide substrate was
also well tolerated. 1-Bromo-5-chloropentane underwent selective borylation at the bromide. Although
primary alkyl chlorides did not undergo efficient borylation under these conditions, alkyl iodides and
alkyl tosylates were viable electrophiles. As these reactions proceeded, we observed no evidence of
transmetallation of the pinacol alkylboronate ester produced in the reaction.
Table 2. Pd-Catalyzed Borylation of Primary Alkyl Bromidesa
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 14
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Alkyl bromide (1 mmol), bis(pinacolato)diboron (1.2 mmol); average yield of 2 runs. b Using alkyl iodide. c Using alkyl
tosylate. d 0.75 mmol scale. e 3 mol % PCy3•HBF4. f 1.5 mol % Pd2(dba)3, 9 mol % PCy3•HBF4.
In contrast to nickel- and copper-catalyzed processes which can undergo oxidative addition via
radical processes,35,36,41,42 Pd(0) complexes generally undergo oxidative addition with alkyl halides via
direct nucleophilic displacement of the halide leaving group.37-39 As a result, the use of Pd catalysis is
generally limited to primary electrophiles. Fortunately, this mechanism for oxidative addition can be
exploited to achieve the chemoselective borylation of molecules bearing multiple halide groups. Using
1,4-dibromopentane (4) as an electrophile (Scheme 1), we observed that a primary bromide could indeed
be selectively borylated in the presence of a remote secondary bromide. This reaction occurred
efficiently, with no detectable trace of borylation at the secondary bromide.
Scheme 1. Selective Borylation of Primary Bromidea
a Alkyl bromide (1 mmol), bis(pinacolato)diboron (1.2 mmol); average yield of 2 runs.
ACS Paragon Plus Environment

Page 5 of 14
The Journal of Organic Chemistry
To broaden the utility of our borylation method, we have developed methods to convert the crude
1
2
pinacol boronate products to other boronate derivatives (Table 3). After borylation of (3-
bromopropyl)benzene via the standard conditions of Table 1, transformation of the resulting pinacol
boronate ester to a trifluoroboronate (6a), boronic acid (6b), and propylene glycol boronate (6c) was
readily achieved without isolation of the pinacol boronate intermediate.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Direct Preparation of Boronate Ester Derivativesa
a Alkyl bromide (0.75 mmol); average yield of 2 runs. b KHF2, MeOH, rt, 2 h. c NaIO4, HCl(aq), THF/H2O, rt, 3 h. d footnote
c, then 1,3-propanediol, benzene, reflux, 12 h.
It has been demonstrated that transmetallation of an aryl group from a pinacol boronate ester to
palladium occurs significantly more slowly than transmetallation of an aryl group from a neopentyl
glycol boronate ester.43 Consistent with this trend, Pd-catalyzed borylation reactions that form pinacol
alkylboronate esters showed no sign of post-borylation transmetallation of the alkyl group, while
neopentyl glycol alkylboronate esters generated by an analogous process displayed evidence of
subsequent transmetallation of the alkyl group. However, with minor modifications, we successfully
developed a process to achieve the Pd-catalyzed cross-coupling of alkyl bromides and bis(neopenyl
glycolato)diboron (7) with minimal transmetallation of the generated alkylboronate ester (8) (Table 4).
Although yields for the reactions were lower than those for the formation of the corresponding pinacol
alkylboronate esters, the general success of this reaction underscores the broad utility of our process, and
suggests that alkyl boronate compounds may be successfully formed from the Pd-catalyzed cross-
coupling reaction of alkyl electrophiles with other diboron reagents.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
Table 4. Pd-Catalyzed Borylation of Alkyl Bromides Using Bis(neopentyl glycolato)diborona
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Alkyl bromide (0.2 mmol), bis(pinacolato)diboron (0.22 mmol); average yield of 2 runs.
In conclusion, we have developed a mild process for the Pd-catalyzed borylation of primary
alkyl electrophiles using bis(pinacolato)diboron as a boron source. The reaction is highly tolerant of
reactive functional groups, requires low catalyst loadings, and accommodates the use of alkyl bromide,
iodide, and tosylate electrophiles. Primary bromides react with complete selectivity over secondary
bromides. The ability to easily convert the pinacol alkylboronate esters directly into boronic acids,
trifluoroboronates, and other boronate esters broadens the utility of this method. Finally, we have
demonstrated that our borylation process is not exclusive to the use of bis(pinacolato)diboron as a boron
source, and can be extended to the use of other diboron reagents.
Experimental Section.
Toluene and THF (unstabilized) were transferred to separate 20 L solvent-delivery kegs and vigorously
purged with argon for 2 h. The solvents were further purified by passing them under argon pressure
through two packed columns of neutral alumina (for THF) or through neutral alumina and copper (II)
oxide (for toluene). All other reagents and solvents were used as received unless otherwise noted. Flash
chromatography was performed using silica gel (ultra pure grade). Nuclear magnetic resonance spectra
1
were recorded on a 500 MHz instrument. All H NMR experiments are reported in δ units, parts per
million (ppm), and were measured relative to the signals for residual chloroform (7.26 ppm), dimethyl
13
sulfoxide (2.50 ppm) or acetonitrile (1.94 ppm). All C NMR spectra are reported in ppm relative to
deuterochloroform (77.2 ppm), dimethyl sulfoxide (39.5 ppm) or acetonitrile (118.3 ppm) and were
1
obtained with H decoupling. All GC analyses were performed on a gas chromatograph with an FID
ACS Paragon Plus Environment

Page 7 of 14
The Journal of Organic Chemistry
detector using a 25 m x 0.20 mm capillary column with cross-linked methyl siloxane as the stationary
phase.
1
2
3
4
5
6
7
8
9
General procedure for borylation of primary alkyl bromides with bis(pinacolato)diboron.
Pd2(dba)3 (4.6 mg, 0.005 mmol), di-tert-butyl(methyl)phosphonium tetrafluoroborate (7.4 mg, 0.03
mmol), (BPin)2 (305 mg, 1.2 mmol) and K3PO4•H2O (460 mg, 2 mmol) were weighed out on the
benchtop in an oven-dried 10 mL screw top test tube with stir bar. The test tube was sealed using a
screw cap lined with a teflon septum. With stirring begun, the test tube was evacuated (100 mTorr), and
backfilled three times with argon using a needle attached to a vacuum manifold. The alkyl bromide (1
mmol) was then added to the test tube via a microsyringe, followed by degassed tertiary butyl alcohol (3
mL) and degassed water (0.25 mL). If the alkyl bromide was a solid, it was weighed out after
K3PO4•H2O before evacuating the test tube. The test tube was sealed with electrical tape and the reaction
mixture was stirred overnight on the benchtop at 60 ºC with no additional argon pressure. N.B.: Ensure
that K3PO4•H2O does not clump while the reaction is in progress. If clumping becomes problematic,
K2CO3 may be used in place of K3PO4•H2O. The reaction mixture was quenched through the addition of
saturated aqueous NH4Cl (5 mL). The resulting mixture was then poured into a separatory funnel and
extracted with diethyl ether (3 x 20 mL). The combined organic layers were washed with brine and dried
over Na2SO4. The crude product was purified by column chromatography.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for borylation of primary alkyl bromides with bis(neopentylglycolato) diboron.
Pd2(dba)3 (1.83 mg, 0.002 mmol), di-tert-butyl(methyl)phosphonium tetrafluoroborate (3 mg, 0.012
mmol), (BNeop)2 (54 mg, 0.24 mmol) and anhydrous K3PO4 (85 mg, 0.4 mmol) were weighed out in the
glove-box in an oven-dried 10 mL screw top test tube with stir bar. The test tube was sealed using a
screw cap lined with a teflon septum. The reaction was stirred on a stir plate and alkyl bromide (0.2
mmol) was then added to the vial via a microsyringe. Degassed tertiary butyl alcohol (1mL) and
degassed water (20 µL) were then added under argon, outside of the glove box. The test tube was sealed
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
with an electrical tape and the reaction mixture was stirred for 5 hours on the benchtop at 80 ºC with no
additional argon pressure. The reaction mixture was quenched through the addition of saturated aqueous
NH4Cl (ca. 4 mL). The resulting mixture was then poured into a separatory funnel and extracted with
diethyl ether (3 x 10 mL). The combined organic layers were washed with brine and dried over Na2SO4.
The crude product was purified by column chromatography.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4,4,5,5-Tetramethyl-2-(3-phenylpropyl)-1,3,2-dioxaborolane (3a).44 The general procedure
was employed. A reddish yellow liquid (236 mg, 96%) was isolated by column chromatography (98:2
Hex:Ether). 1H NMR (500 MHz, CDCl
Hz, 2H), 1.76 (app. quint., J = 7.5 Hz, 2H), 1.26 (s, 12H), 0.85 (t, J = 7.5 Hz, 2H) ppm. 13C NMR (125
) δ: 142.8, 128.6, 128.3, 125.7, 83.0, 38.69, 26.2, 24.9, 11 (B-CH2, br) ppm. 11B (MHz,
3
) δ: 7.27 (t, J = 7.5 Hz, 2H), 7.16-7.20 (m, 3H), 2.63 (t, J = 7.5
MHz, CDCl
3
CDCl3) δ: 33.3 ppm.
2-Isopentyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3b).45 The general procedure was
employed. A yellow liquid (147 mg, 74%) was isolated by column chromatography (99:1 Hex:Ether).
1H NMR (500 MHz, CDCl
6.5 Hz, 6H), 0.74 (t, J = 8.5 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl
3
) δ: 1.45 (m, J = 6.5 Hz, 1H), 1.21-1.3 (m, 2H), 1.23 (s, 12H), 0.84 (d, J =
3
) δ: 83.0, 33.1, 30.4, 25.0, 22.4
ppm. The carbon atom directly attached to the boron atom was not detected, likely due to quadrupolar
broadening. 11B (MHz, CDCl3) δ: 33.3 ppm.
6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-1-ol (3c).35 The general procedure was
employed. A brownish liquid (139 mg, 61%) was isolated by column chromatography (gradient from
80:20 to 75:25 Hex:EtOAc). 1H NMR (500 MHz, CDCl
2H), 1.38-1.45 (m, 2H), 1.29-1.36 (m, 4H), 1.24 (s, 12H), 0.77 (t, J = 7.5 Hz, 2H) ppm. 13C NMR (125
3
) δ: 3.63 (app. q, J = 6.5 Hz, 2H), 1.53-1.59 (m,
MHz, CDCl ) δ: 83.0, 63.2, 32.8, 32.2, 25.6, 24.9, 24.0 ppm. The carbon atom directly attached to the
3
boron atom was not detected, likely due to quadrupolar broadening. 11B (MHz, CDCl3) δ: 33.2 ppm.
4,4,5,5-Tetramethyl-2-(2-(thiophen-2-yl)ethyl)-1,3,2-dioxaborolane (3d).35 The general
procedure was employed. An orange-yellow liquid (149 mg, 63%) was isolated by column
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
chromatography (98:2 Hex:Ether). 1H NMR (500 MHz, CDCl
(m, 1H), 6.79 (m, 1H), 2.96 (t, J = 8 Hz, 2H), 1.24 (m, 14H), ppm. 13C NMR (125 MHz, CDCl
3
) δ: 7.08 (dd, J = 5 Hz, 1.5 Hz, 1H), 6.88
1
2
3
3
) δ:
4
5
6
7
8
147.9, 126.6, 123.5, 122.7, 83.3, 24.9, 24.5 ppm. The carbon atom directly attached to the boron atom
was not detected, likely due to quadrupolar broadening. 11B (MHz, CDCl3) δ: 32.9 ppm.
6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hexanenitrile (3e).35 The general procedure
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
was employed. A golden yellow liquid (214 mg, 96%) was isolated by column chromatography
1
(gradient from 95:5 to 93:7 Hex:Ether). H NMR (500 MHz, CDCl
3
) δ: 2.30 (t, J = 7 Hz, 2H), 1.63
(quint., J = 7.0 Hz, 2H), 1.40-1.43 (m, 4H), 1.22 (s, 12H), 0.76 (t, J = 7.0 Hz, 2H) ppm. 13C NMR (125
11
) δ: 119.9, 83.1, 31.3, 25.2, 24.9, 23.2, 17.1, 11 (B-CH2, br) ppm. B (MHz, CDCl3) δ:
MHz, CDCl
3
33.1 ppm.
Ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butanoate (3f). The general procedure
was employed with following modification: The ligand used in this reaction is
tricyclohexylphosphonium tetrafluoroborate (11 mg, 0.03 mmol). A bright yellow liquid (215 mg, 89%)
was isolated by column chromatography (95:5 Hex:Ether). 1H NMR (500 MHz, CDCl
) δ: 4.10 (q, J = 7
3
Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 1.74 (app. quint., J = 7.5 Hz, 2H), 1.23-1.26 (m, 15H), 0.81 (t, J = 8
13
Hz, 2H) ppm. C NMR (125 MHz, CDCl
3
) δ: 173.8, 83.1, 60.2, 36.7, 24.8, 19.8, 14.4, 11 (B-CH2, br)
+
ppm. 11B (MHz, CDCl3) δ: 32.8 ppm. HRMS (EI+): Calcd (C12H23BO4 ) 242.1689; Found 242.1700.
2-(2-Cyclohexylethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3g).46 The general procedure
was employed with following modifications: Pd2(dba)3 (14 mg, 0.015 mmol),
tricyclohexylphosphonium tetrafluoroborate ligand (33 mg, 0.09 mmol). A pale yellow liquid (198 mg,
1
83%) was isolated by column chromatography (98:2 Hex:Ether). H NMR (500 MHz, CDCl
3
) δ: 1.61-
1.72 (m, 5H), 1.11-1.31 (m, 18H), 0.83 (app. q, J = 12 Hz, 2H), 0.75 (t, J = 8.5 Hz, 2H) ppm. 13C NMR
(125 MHz, CDCl
33.4 ppm.
3
) δ: 83.0, 40.1, 33.1, 31.5, 26.9, 26.6, 24.9, 20 (B-CH2, br) ppm. 11B (MHz, CDCl3) δ:
2-(5-Chloropentyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3h).47 The general procedure
was employed with following modification: The ligand used in this reaction is
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
tricyclohexylphosphonium tetrafluoroborate (11 mg, 0.03 mmol). A yellowish orange liquid (211 mg,
91%) was isolated by column chromatography (98:2 Hex:Ether) 1H NMR (500 MHz, CDCl
1
2
3
3
) δ: 3.50 (t,
4
5
J = 7 Hz, 2H), 1.75 (app. quint., J = 7 Hz, 2H), 1.41 (m, 4H), 1.23 (s, 12H), 0.77 (t, J = 7 Hz, 2H) ppm.
6
13C NMR (125 MHz, CDCl ) δ: 83.1, 45.2, 32.6, 29.6, 24.9, 23.4, 11 (B-CH2, br) ppm. 11B (MHz,
3
7
8
9
CDCl3) δ: 32.9 ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)decanamide (3i). The general procedure
was employed. A white solid (279 mg, 94%) was isolated by column chromatography (95:5
CH2Cl2:MeOH). 1H NMR (500 MHz, CDCl
(m, 2H), 1.22-1.26 (m, 22H), 0.76 (t, J = 7.5 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl
3
) δ: 5.32 (broad d, 2H), 2.21 (t, J = 7.5 Hz, 2H), 1.60-1.66
3
) δ: 175.6, 83.0,
36.1, 32.6, 29.62, 29.50, 29.46, 29.38, 25.7, 25.0, 24.1 ppm. The carbon atom directly attached to the
boron atom was not detected, likely due to quadrupolar broadening. 11B (MHz, CDCl3) δ: 33.7 ppm.
Anal. Calcd. for C16H32BNO3: C, 64.65; H, 10.85. Found: C, 64.41; H, 10.99.
4,4,5,5-Tetramethyl-2-(4-phenoxybutyl)-1,3,2-dioxaborolane (3j).48 The general procedure
was employed. A bright yellow liquid (259 mg, 94%) was isolated by column chromatography (99:1
Hex:Ether). 1H NMR (500 MHz, CDCl
) δ: 7.26 (dt, J = 7.5 Hz, 1 Hz, 2H), 6.88-6.93 (m, 3H), 3.95 (t, J
3
= 6.5 Hz, 2H), 1.80 (quint., J = 6.5 Hz, 2H), 1.59 (quint., J = 8Hz, 2H), 1.25 (s, 12H), 0.86 (t, J = 8 Hz,
13
2H) ppm. C NMR (125 MHz, CDCl ) δ: 159.3, 129.5, 120.5, 114.6, 83.1, 67.8, 31.9, 25.0, 20.7 ppm.
3
The carbon atom directly attached to the boron atom was not detected, likely due to quadrupolar
broadening. 11B (MHz, CDCl3) δ: 33.1 ppm.
2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)isoindoline-1,3-dione (3k). The
general procedure was employed with following modification: tricyclohexylphosphonium
tetrafluoroborate (11 mg, 0.03 mmol) was used as ligand. A brown liquid (260 mg, 79%) was isolated
1
by column chromatography (gradient from 85:15 to 80:20 Hex:Ether). H NMR (500 MHz, CDCl
3) δ:
7.80 (dd, J = 8.5 Hz, 3 Hz, 2H), 7.67 (dt, J = 8.5 Hz, 2.5 Hz, 2H), 3.64 (t, J = 7.5 Hz, 2H), 1.66 (quint., J
13
= 7.5 Hz, 2H), 1.44 (quint., J = 8 Hz, 2H), 1.20 (s, 12H), 0.79 (t, J = 7.5 Hz, 2H) ppm. C NMR (125
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
MHz, CDCl3) δ: 168.5, 133.9, 132.3, 123.2, 83.1, 38.0, 31.2, 24.9, 21.4, 11 (B-CH2, br) ppm. 11B (MHz,
CDCl3) δ: 33.0 ppm. Anal. Calcd. for C18H24BNO4: C, 65.67; H, 7.35. Found: C, 65.45; H, 7.28.
2-(4-Bromopentyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5). The general procedure was
employed. A bright yellow liquid (219 mg, 79%) was isolated by column chromatography (98:2
1
2
3
4
5
6
7
8
9
Hex:Ether). 1H NMR (500 MHz, CDCl
1.80 (m, 1H), 1.70 (d, J = 7 Hz, 3H), 1.48-1.66 (m, 2H), 1.24 (s, 12H), 0.73-0.84 (m, 2H) ppm. 13C
3
) δ: 4.13 (app. sextet, J = 6.5 Hz, 1H), 1.82-1.90 (m, 1H), 1.73-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (125 MHz, CDCl
3
) δ: 83.1, 51.6, 43.8, 26.5, 24.9, 22.3, 10 (B-CH2, br) ppm. 11B (160 MHz,
+
CDCl3) δ: 33.2 ppm. HRMS (EI+): Calcd (C11H22BBrO2 – CH3 ) 261.0661; Found 261.0656.
Potassium 3-phenyl-trifluoroboratopropane (6a).35 The general procedure was employed. A
white solid (118mg, 70 %) 1H NMR (500 MHz, DMSO) δ: 7.20-7.23 (t, J = 7.5 Hz, 4H), 7.08- 7.12 (m,
3H), 2.45 (t, J = 8.0 Hz, 2H), 1.40 (app. quint., J = 7.5 Hz, 2H), 0.02 (m, 2H) ppm. 13C NMR (125 MHz,
DMSO) δ: 144.1, 128.3, 127.9, 124.9, 28.25, 28.24, 20 (B-CH2, br) ppm. 11B (160 MHz, DMSO) δ: 9.3
ppm.
3-Phenylpropylboronic acid (6b).49 The general procedure was employed. A yellowish white
solid (109 mg, 89 %) 1H NMR (500 MHz, DMSO) δ: 7.40 (s, 2H), 7.25 (t, J = 8 Hz, 2H), 7.13-7.16 (m,
3H), 2.50 (m, 2H), 1.60 (app. quint., J = 7.5 Hz, 2H), 0.60 (t, J = 8.0 Hz, 2H) ppm. 13C NMR (125 MHz,
CD3CN) δ: 143.9, 129.4, 129.1, 126.5, 39.2, 27.3 ppm. The carbon atom directly attached to the boron
atom was not detected, likely due to quadrupolar broadening. 11B (160 MHz, CD3CN) δ: 37.0 ppm.
2-(3-Phenylpropyl)-1,3,2-dioxaborinane (6c).50 The general procedure was employed. (92 mg,
1
60%) H NMR (500 MHz, CD3CN) δ: 7.24-7.27 (m, 2H), 7.13-7.18 (m, 3H), 3.95 (t, J = 5.0 Hz, 4H),
2.58 (t, J = 7.5 Hz, 2H), 1.90 (quint., J = 6.0 Hz, 2H), 1.68 (quint., J = 8.0 Hz, 2H), 0.73 (t, J = 8.0 Hz,
2H) ppm. 13C NMR (125 MHz, CD3CN) δ: 143.1, 128.7, 128.2, 125.6, 61.7, 38.7, 27.5, 26.1, 11 (B-CH2,
br) ppm. 11B (160 MHz, CDCl3) δ: 29.9 ppm.
5,5-Dimethyl-2-(3-phenylpropyl)-1,3,2-dioxaborinane (8a). The general procedure was
employed. A yellowish liquid (32 mg, 70%) was isolated by column chromatography (90:10 Hex:
Ether). 1H NMR (500 MHz, CD3CN) δ: 7.24-7.27 (m, 2H), 7.14-7.19 (m, 3H), 3.57 (s, 4H), 2.60 (t, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 14
13
8 Hz, 2H), 1.70 (app. quint., J = 8 Hz, 2H), 0.95 (s, 6H), 0.76 (t, J = 8 Hz, 2H) ppm. C NMR (125
MHz, CD3CN) δ: 143.1, 128.7, 128.3, 125.6, 72.1, 38.9, 31.8, 29.9, 26.3, 22.0, 15 (B-CH2, br) ppm. 11B
(160 MHz, CDCl3) δ: 29.7 ppm. Anal. Calcd. for C14H21BO2: C, 72.44; H, 9.12. Found: C, 72.45; H,
9.23.
1
2
3
4
5
6
7
8
9
Ethyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)butanoate (8b). The general procedure was
employed. A yellow liquid (28 mg, 62%) was isolated by column chromatography (90:10 Hex:Ether).
1H NMR (500 MHz, CD3CN) δ: 4.11 (q, J = 7 Hz, 2H), 3.58 (s, 4H), 2.29 (t, J = 7.5 Hz, 2H), 1.70 (app.
quint., J = 7.5 Hz, 2H), 1.25 (t, J = 7 Hz, 3H), 0.95 (s, 6H), 0.75 (t, J = 8 Hz, 2H) ppm. 13C NMR (125
MHz, CD3CN) δ: 174.1, 72.1, 60.2, 36.9, 31.8, 29.8, 22.0, 19.9, 14.4, 14 (B-CH2, br) ppm. 11B (160
MHz, CDCl3) δ: 29.4 ppm. HRMS (FAB+): Calcd (for C11H21BO4 + H+) 229.1611; Found 229.1622.
6-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)hexanenitrile (8c). The general procedure was
employed. A yellow liquid (18 mg, 42%) was isolated by column chromatography (90:10 Hex:Ether).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (500 MHz, CDCl
) δ: 3.59 (s, 4H), 2.32 (t, J = 7.5 Hz, 2H), 1.65 (app. quint., J = 7 Hz, 2H),
3
1.37-1.47 (m, 4H), 0.95 (s, 6H), 0.72 (t, J = 8 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3) δ: 120.1, 72.1,
31.8, 31.4, 29.8, 25.4, 23.3, 22.0, 17.2, 14 (B-CH2, br) ppm. 11B (160 MHz, CDCl3) δ: 29.4 ppm.
HRMS (FAB+) Calcd (for C11H20BNO2 + H+) 210.1665; Found 210.1660.
Acknowledgment. We thank The National Institutes of Health (1SCGM096932-01), The City
College of New York (CCNY), The Alfred P. Sloan Foundation, and PSC-CUNY for financial support.
We gratefully acknowledge the National Science Foundation for an instrumentation grant (CHE-
0840498). Acknowledgement is additionally made to the donors of the American Chemical Society
Petroleum Research Fund (50307-DNI1) for partial support of this research. Finally, we thank BASF
for their generous gift of (BPin)2.
1
Supporting Information Available: H, 13C, and 11B NMR spectra for all products. This
information is available free of charge via the Internet at http://pubs.acs.org.
References and Footnotes.
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
1 Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds., Wiley-VCH: New York, 2004.
2 Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
1
2
3
4
3 Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
5
6
7
8
4 Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 4544.
5 Jana, R.; Pathak, T. P.; Sigman, M. S. Chem Rev. 2011, 111, 1417.
9
6 Joshi-Pangu, A.; Ganesh, M.; Biscoe, M. R. Org. Lett. 2011, 13, 1218.
7 Joshi-Pangu, A.; Wang, C.-Y.; Biscoe, M. R. J. Am. Chem. Soc. 2011, 133, 8478.
8 Joshi-Pangu, A.; Biscoe, M. R. Synlett 2012, 23, 1103.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9 Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem. Int. Ed. 2000, 39, 4414.
10 Crudden, C. M.; Glasspoole, B. W.; Lata, C. J. Chem. Commun. 2009, 6704.
11
Hall, D. G. “Structures, Properties, and Preparation of Boronic Acid Derivatives” in Boronic Acids: Preparation and
Applications in Organic Synthesis and Medicine; Hall, D. G., Ed., Wiley-VCH: Weinheim, 2005, pp. 1-99.
12 Burgess, K.; Ohlmeyer, M. J. Chem. Rev. 1991, 91, 1179.
13 Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992, 114, 6671.
14 Burgess, K.; van der Donk, W. A.; Westcott, S. A.; Marder, T. B.; Baker, R. T.; Calabrese, J. C. J. Am. Chem. Soc. 1992,
114, 9350.
15 Beletskaya, I.; Pelter, A. Tetrahedron 1997, 53, 4957.
16 Edwards, D. R.; Crudden, C. M.; Yam, K. Adv. Synth. Catal. 2005, 347, 50.
17 Chen, H. Y.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995.
18 Shimada, S.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B. Angew. Chem. 2001, 113, 2226.
19 Cho, J. -Y.; Tse, M. K.; Holmes, D.; Maleczka, Jr., R. E.; Smith III, M. R. Science 2002, 295, 305.
20 Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Baker, R. T.; Calabrese, J. C. Chem. Rev. 2010, 110, 890.
21 Yamamoto, T.; Morita, T.; Takagi, J.; Yamakawa, T. Org. Lett. 2011, 13, 5766.
22 Hartwig, J. F. Acc. Chem. Res. 2012, 6, 864.
23 Ros, A.; Lopez-Rodriguez, R.; Estepa, B.; Alvarez, E.; Fernandez, R.; Lassaletta, J. M. J. Am. Chem. Soc. 2012, 134, 4573.
24 Yu, J. -Q.; Dai, H. -X. J. Am. Chem. Soc. 2012, 134, 134.
25Xiao, B.; Li, Y. -M.; Liu, Z. -J.; Yang, H. -Y.; Fu, Y. Chem. Commun. 2012, 48, 4854.
26 O’Brien, M.; Lee, K. -S.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10630.
27 Schiffner, J. A.; Muthner, K.; Oestreich, M. Angew. Chem. Int. Ed. 2010, 49, 1194.
28 Sasaki, Y.; Zhong, C.; Sawamura, H.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226.
29 Molander, G. A.; McKee, S. A. Org. Lett. 2011, 13, 4684.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
30 Thorpe, S. B.; Calderone, J. A.; Santos, W. Org. Lett. 2012, 14, 1918.
Page 14 of 14
1
2
3
4
31 Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447.
32 Furstner, A.; Seidel, G. Org. Lett. 2002, 4, 541.
5
6
33 Billingsley, K. L.; Barder, T. E.; Buchwald, S. L. Angew. Chem. Int. Ed. 2007, 46, 5359.
7
8
34
While the work contained in this manuscript was in progress, processes for the Cu-catalyzed borylation of alkyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
electrophiles were reported. See references 39-40.
35 Yang, C. -T.; Zhang, Z. -Q.; Tajuddin, H.; Wu, C. -C.; Liang, J.; Liu, J. -H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T.
B.; Liu, L. Angew. Chem. Int. Ed. 2012, 51, 528.
36 Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890.
37 Netherton, M. R.; Dai, C.; Neuschütz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099.
38 Netherton, M. R.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 3910.
39 Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 5749.
40
When substrates bearing remote alkenes and alkynes were employed, significant background diborylation of the alkene or
alkyne was observed. See: Bonet, A.; Pubill-Ulldemolins, C.; Bo, C.; Gulyás, H.; Fernández, E. Angew. Chem. Int. Ed. 2011,
50, 7158.
41 Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360.
42 Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2656.
43 Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116.
44 Lata, C. J.; Crudden, C. M. J. Am. Chem. Soc. 2010, 132, 131.
45 Chen, H.; Hartwig, J. F. Angew. Chem. Int. Ed. 1999, 38, 3391.
46 Guennouni, N.; Lhermitte, F.; Cochard, S.; Carboni, B. Tetrahedron 1995, 51, 6999.
47 Pereira, S.; Srebnik, M. J. Am. Chem. Soc. 1996, 118, 909.
48 Biedrzycki, M.; Scouten, W. H.; Biedrzycka, Z. J. Organomet. Chem. 1992, 431, 255.
49 Falck, J. R.; Bondlela, M.; Venkataraman, S. K.; Srinivas, D. J. Org. Chem. 2001, 66, 7148-7150.
50 Pei, W.; Krauss, I. J. J. Am. Chem. Soc. 2011, 133, 18514.
ACS Paragon Plus Environment