Preparation and reactions of 4-iodobutyl pinacolborate. Synthesis of substituted alkyl and aryl pinacolboronates via 4-iodobutyl pinacolborate utilizing tetrahydrofuran as the leaving group

Article abstract of DOI:10.1016/j.tetlet.2014.12.033

Iodine reacts with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin), under ambient reaction conditions in THF, to form the iodoalkylborate species 2-(4-iodobutoxy)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4-IboxBpin). Apparently, one-half equivalent of I₂ reacts with HBpin to form IBpin in pentanes, which in turn cleaves THF to form the 4-IboxBpin. Alkyl and aryl Grignard reagents, prepared under Barbier conditions, then react with 4-IboxBpin to form the corresponding alkyl and aryl pinacolboronates while reforming and liberating THF as the leaving group.

Full text of DOI:10.1016/j.tetlet.2014.12.033

Tetrahedron Letters 56 (2015) 3032–3033
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation and reactions of 4-iodobutyl pinacolborate. Synthesis
of substituted alkyl and aryl pinacolboronates via 4-iodobutyl
pinacolborate utilizing tetrahydrofuran as the leaving group
⇑
Chris L. Murphy, Aaron Hall, Emily J. Roberts, Matthew D. Ryan, Jacob W. Clary, Bakthan Singaram
Department of Chemistry and Biochemistry, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodine reacts with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin), under ambient reaction conditions
in THF, to form the iodoalkylborate species 2-(4-iodobutoxy)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Received 2 October 2014
Revised 1 December 2014
Accepted 5 December 2014
Available online 13 December 2014
2
(4-IboxBpin). Apparently, one-half equivalent of I reacts with HBpin to form IBpin in pentanes, which
in turn cleaves THF to form the 4-IboxBpin. Alkyl and aryl Grignard reagents, prepared under Barbier con-
ditions, then react with 4-IboxBpin to form the corresponding alkyl and aryl pinacolboronates while
reforming and liberating THF as the leaving group.
Keywords:
Borate
Published by Elsevier Ltd.
Boronate
Grignard
Barbier
Ether cleavage
Both arylboronic acids and arylboronates have widespread
application over a range of synthetic and biological processes.
using inexpensive reactants, such as Grignard reagents. Herein,
we report the results of our study on the reactions of Grignard
reagents with 2-(4-iodobutoxy)-4,4,5,5-tetramethyl-1,2,3-dioxa-
borolane [4-iodobutoxyBpin, (4-IboxBpin)] boron donor where tet-
rahydrofuran (THF) is extruded as the leaving group.
1
Among these are the use of boronic esters in cross-coupling reac-
2
tions, such as palladium- and copper(II)-mediated processes.
Pinacolboronates have also garnished tremendous attention as
coupling partners due to many factors, including their stability in
many different reaction conditions as well as easy handling and
purification. These compounds are often invaluable in the forma-
tion of complex structures and scaffolds of synthetic targets and
The most popular borate trapping method developed by Brown
and Cole must be performed at À78 °C and does not work efficiently
with Grignard reagents. Even 2-isopropoxy-4,4,5,5-tetramethyl-
1,2,3-dioxaborolane (iPrO-Bpin)works wellonly with organometallic
reagents when carried out at À78 °C and generates metal isopropox-
3
,4
used in stereospecific conversions to different functionalities.
1
2
Many methods exist for the synthesis of boronic esters, both
simple and functionalized, however each possesses drawbacks.
The most established method for this is the use of an aryllithium
or aryl Grignard reagent added to excess trialkylborate at À78 °C,
with trimethyl-, triethyl-, or triisopropylborate being the most
commonly used alkylborates.5 Other methods have since been
developed utilizing different boron sources, such as palladium- or
copper-catalyzed borylation of arylhalides with bis(pinacola-
ide byproducts. We sought to extend Brown–Cole boronate
synthesis to include inexpensive and green Grignard reagents.
Since iPrO-Bpin reacts as a boron donor with organometallic
1
2
reagents, we wanted to test the use of 4-iodobutyl-4,4,5,5-tetra-
methyl-1,2,3-dioxaborolane in the borate trapping reaction with
reagents such as organolithiums and Grignard reagents, preferably
at 25 °C. To test the feasibility of this approach, we began exploring
,6
the reaction of I
and B-H containing compounds, such as dialkylborane and diam-
inoborane, have been used to cleave cyclic ethers through the
2
and pinacolborane (HBpin). The reaction between
to)diboron (B
2
pin
2
), however only one Bpin moiety is incorporated
I
2
7
into the product. Borylation using other expensive transition met-
8
9
10
13–15
als, such as rhodium, ruthenium, and iridium also exist, includ-
ing processes utilizing aromatic C–H bond activation.11 We were
interested in developing a new method for the synthesis of pina-
colboronates that can be carried out under ambient conditions
intermediate formation of B-iodo derivatives.
We anticipated
that the reaction between I and HBpin in pentane would furnish
2
IBpin, which in turn should be capable of cleaving the THF ring
in a similar fashion. The resulting 4-iodobutylBpin compound
could be a potential boron donor in borylation reactions, driven
by the favorable recyclization of an iodobutoxide leaving group
to the neutral THF molecule.
⇑
Corresponding author. Tel.: +1 831 459 4002.
E-mail address: singaram@ucsc.edu (B. Singaram).
http://dx.doi.org/10.1016/j.tetlet.2014.12.033
040-4039/Published by Elsevier Ltd.
0

C.L. Murphy et al. / Tetrahedron Letters 56 (2015) 3032–3033
3033
After removal of the precipitate and subsequent aqueous work-
up, the corresponding 3-chlorophenyl pinacolboronate was con-
firmed as the product. Encouraged by this result, we tested this
1
. I
2
, pentane
5 °C, 30 min
O
O
O
B
2
B
H
I
O
O
O
2.
1
18
system with a range of aryl and haloaryl substrates (Table 1).
In summary, we have developed a method for synthesizing
alkyl and aryl pinacolboronates under Barbier conditions in good
to excellent yields. Through the course of this work, we discovered
a novel boron electrophile, 4-IboxBpin, synthesized via the ring
opening of THF by IBpin. 4-IboxBpin reacts readily with alkyl and
aryl Grignard reagents formed under Barbier conditions to produce
the corresponding alkyl and aryl pinacolboronates while extruding
THF as a leaving group. This is a significant improvement to older
synthetic methods as this reaction is performed at room tempera-
ture, utilizes inexpensive and green Grignard reagents, and liber-
ates neutral THF instead of a basic alkoxide group.
Figure 1. Synthesis of 4-IboxBpin (1).
O
B
MgBr
O
B
I
O
O
THF, 25°C, 1 h
O
1
1a
3%
9
Scheme 1. Reaction of 1 with preformed Grignard reagent.
BrMg
Cl
O
B
Supplementary data
O
B
Cl
O
I
MgBr(THF)
4
O
O
Et
2
O
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.12.
033.
-
78 °C, 1 h
2
Scheme 2. Addition of ArMgBr to 4-iodobutylBpin in Et O.
To test this, we began with the addition of HBpin to a solution of
in pentane, producing a dark purple solution. After 30 min of
stirring, THF was added and the solution decolorized over 3 h at
References and notes
I
2
1.
(a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513; (b)
Matteson, D. S. Stereodirected Synthesis with Organoboranes; Springer: Berlin,
1
13
11
2
5 °C. Analysis of the product by MS, H, C, and B NMR spec-
1995; (c) Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, 2005; (d) Suzuki, A.
troscopy indicated the formation of 4-4-iodobutylBpin (1, 4-IboxB-
Acc. Chem. Res. 1982, 15, 178; (e) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457; (f) Miyaura, N. Top. Curr. Chem. 2002, 219, 11.
1
6
pin) (Fig. 1).
2.
(a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
We then studied the potential of 1 as a boron donor by reacting
it with various Grignard reagents. Thus, addition of n-octylmagne-
sium bromide in THF to 1 at 25 °C afforded n-octylBpin in high
yield (Scheme 1).
To check the generality of this methodology and the leaving
group capability of iodobutoxide, we carried out the reaction of 1
with Grignards prepared under Barbier conditions. First, 4-IboxB-
pin was synthesized as described above in toluene and neat 1
4544; (b) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P. Tetrahedron
Lett. 1998, 39, 2933; (c) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett.
1998, 39, 2937; (d) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400; (e) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S.
Tetrahedron Lett. 2003, 44, 3863.
3.
Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2009, 48, 3565.
4. Rousch, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186.
5
6
7
.
.
.
Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316.
Brown, H. C.; Srebnik, M.; Cole, T. E. Organometallics 1986, 5, 2300.
Kleeberg, C.; Dang, L.; Lin, Z.; Marder, T. B. Angew. Chem., Int. Ed. 2009, 48, 5350.
was isolated by the evaporation of toluene and any excess THF
8. Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995.
under reduced pressure. Its 1H NMR spectrum indicated that no
9.
Murphy, J. M.; Lawrence, J. D.; Kawamura, K.; Incarvito, C.; Hartwig, J. F. J. Am.
Chem. Soc. 2006, 126, 13684.
residual THF was present. Anhydrous diethyl ether (Et
added, followed by dropwise addition of 3-chlorophenylmagne-
sium bromide in Et
O at À78 °C to quantitatively trap the liberated
THF. The reaction was stirred for 3 h, producing a white precipitate.
2
O) was then
10. Iverson, C. N.; Smith, M. R., III J. Am. Chem. Soc. 1999, 121, 7696.
11. Cho, J.-Y.; Iverson, C. N.; Smith, M. R., III J. Am. Chem. Soc. 2000, 122, 12868.
1
1
2. (a) Hoffmann, R. W.; Holzer, B.; Knopff, O. Org. Lett. 2001, 3, 1945–1948; (b)
Baron, O.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 3133.
3. Gilman, H.; Vernon, C. C. J. J. Am. Chem. Soc. 1926, 48, 1063.
2
1
An H NMR spectrum of the isolated precipitate in D
2
O showed the
14. Joshi, N. N.; Srebnik, M.; Brown, H. C. J. Am. Chem. Soc. 1988, 110, 6246–6248.
15. Srebnik, M.; Joshi, N. N.; Brown, H. C. Isr. J. Chem. 1989, 29, 229.
presence of THF, stemming from the release and subsequent cycli-
zation of iodobutoxide (Scheme 2).17
16.
General procedure for the synthesis of compound 1: To a mixture of anhydrous
pentane (8 mL) and (0.254 g, 1.0 mmol) under Ar was added neat
I
2
pinacolborane (0.29 mL, 2.0 mmol) dropwise over 1 min to provide a dark
purple solution. The mixture was stirred at 25 °C for 30 min. Anhydrous THF
(0.16 g, 2.0 mmol) was then added dropwise over 1 min with constant stirring
at 25 °C. The reaction was complete after 3 h, producing a clear solution, and
confirmed by the disappearance of pinacolborane starting material (d +27.7, d,
J = 173.9 Hz) and the appearance of a singlet at +30.6 ppm via 11B NMR. Brine
(1 mL) was then added. The reaction mixture was then transferred to a
separatory funnel and extracted with diethyl ether (3 Â 15 mL). The combined
Table 1
Synthesis of haloaryl pinacolboronates via 4-IboxBpin under Barbier
conditions
1
. Mg°, THF,
5°C, 3 h
2
O
O
R-Br
1
R
B
+
O
2
. HCl
organic layers were dried over anhydrous MgSO
4
, filtered, and dried in vacuo,
1
(
25 °C, 1 Torr) to afford compound 1. Clear oil; 97% yield (0.632 g). H NMR
PinB
Cl PinB
Cl PinB
(500 MHz, CDCl
3
) d 3.88 (t, J = 6.2 Hz, 2H), 3.20 (t, J = 7.0 Hz, 2H), 1.90 (m, 2H),
PinB
13
1
2
.67 (m, 2H), 1.22 (s, 12H). C NMR (125.7 MHz, CDCl
8.5, 23.3, 5.3. B NMR (160.4 MHz, CDCl
3
): d 81.5, 62.3, 30.9,
O
11
3
): d +22 (s). HRMS (ESI): m/z calcd
1
b
1h
O
3
for C10H20BIO 326.0550, found 326.0548.
Cl
17. For 1H NMR spectra, see Supplementary data.
7
9%
1e
79%
1
k
8
3%
18. General procedure for the synthesis of compounds 1a–1m: The following
procedure is representative. To a solution containing 4-IboxBpin (0.651 g,
PinB
S
68%
PinB
PinB
PinB
Cl
Cl
2.0 mmol) and anhydrous THF (8 mL) under Ar, Mg turnings (0.048 g,
Bpin
2.0 mmol) were added. The corresponding halide reagent (2.0 mmol) was
then introduced dropwise over 5 min with constant stirring at 25 °C. The
reaction was complete after 3 h, as evidenced by the disappearance of
1
i
1
c
8
5%
1
f
7
1%
1l
8
8%
PinB
61%
11
Cl
4-IboxBpin (d +21.6) via B NMR. 1 M HCl (3 mL) was then added to the
PinB
reaction flask and left to stir for 5 min. The reaction mixture was then
PinB
transferred to
a separatory funnel and extracted with diethyl ether
Cl
1
8
d
5%
(3 Â 15 mL). The combined organic layers were dried over anhydrous MgSO
4
,
1g
9%
1j
85%
1m
71%
filtered, and dried in vacuo, (25 °C, 1 Torr) to afford the corresponding
8
pinacolboronate.