2
940
M. Myslinska et al. / Tetrahedron Letters 53 (2012) 2937–2941
Table 3
The most effective catalytic system turned out to be a combina-
tion of palladium acetate in a toluene–methanol mixture at ele-
vated temperatures with cesium carbonate as the base (entry 6).
These conditions were applied to the reaction of a series of aryl
Optimization of reaction conditions for palladium-catalyzed cross coupling reaction
Entry Reaction condition
Yielda
%)
(
1
6
1
2
1 mol % Pd(OAc)
1 mol % Pd(OAc)
2
, PPh
, PPh
3
, KOH, THF/MeOH (4:1), rt, 96 h
56
78
boronates with alkyl halides according to Scheme 10.
o
2
3
, KOH, THF/MeOH (4:1), 60 C,
The final results are depicted in Table 4. The reaction progress
was followed by TLC till the starting materials were consumed.
All final products were purified via flash column chromatography.
One of our goals was to determine the reactivity pattern in the cou-
pling reaction, with specific attention on the dioxaborinanes and
dioxaborolanes. At first we noticed that the six-member structure
of the dioxaborinanes provides better yields in the Suzuki coupling
than the five-member structure. The results are not surprising in
light of the significant hydrolytic stability of pinacol boronates.
In the series of the examined dioxaborinanes, 4,4,6-trimethyl-
72 h
3
4
5
6
1 mol % Pd(PhP
3
)
4
, K
2
CO
3
, dioxane, rt, 96 h
78
56
67
1 mol % Pd(OAc)
1 mol % Pd(OAc)
2
2
2
, Cs CO
2
, Cs CO
3
, THF/MeOH (4:1), rt, 48 h
3
, toluene/MeOH (4:1), rt, 96 h
o
1 mol % Pd(OAc)
2
, Cs
2
CO
3
, toluene/MeOH (4:1), 60 C, 6 h 89
a
Isolated yields.
O
B
[
1,3,2]dioxaborinane (hexylene glycol esters) derivatives afforded
O
Pd(OAc) (1 mol%)
2
R
X
better yields than their 5,5-dimethyl-[1,3,2]dioxaborinane (neo-
pentyl glycol) counterparts.
R
o
Cs CO , 60 C
2
3
Toluene/MeOH
3
9
40
41
Conclusion
Scheme 10. Optimized conditions for the palladium-catalyzed cross coupling
reaction of cyclic boronates.
In summary, we have shown that novel derivatives of glycol bo-
rates react efficiently in the reaction with Grignard reagents at
room temperature to yield their corresponding boronates. More-
over, these borates can also be utilized in reactions with organo-
lithium reagents via the hereby reported improved synthetic
protocol. We have provided evidence that the dioxaborinanes par-
ticipate readily in the Suzuki coupling in a similar fashion to pina-
col boronic acid esters, and most importantly do so with better
yields. In general, our results have illustrated that dioxaborinane
derivatives can be effectively utilized in chemical processes with
superior results over widely used and accepted, and more expen-
sive dioxaborolane analogs.
Table 4
Palladium-catalyzed Suzuki coupling reaction with alkoxy glycol borates
Entry Boron
compd
Reaction
time
Halide
Product10
Yielda
(%)
1
18
6
37
38
89
Br
N
2
18
10
71
N
4
2
4
3
3
4
5
22
26
26
4
6
4
37
37
42
38
38
43
95
95
92
References and notes
1. Miayaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
2. Hall, D. G. Boronic Acids; Wiley: New York, 2005.
Br
Ph
3.
4.
5.
Wong, K.-T.; Chien, Y.-Y.; Liao, Y.-L.; Lin, C.-C.; Chou, M.-Y.; Lueng, M.-K. J. Org.
Chem. 2002, 67, 1041–1044.
Ito, S.; Terazono, T.; Kubo, T.; Okujima, T.; Morita, N.; Murafuji, T.; Sugihara, Y.;
Fujimori, K.; Kawakami, J.; Tajiri, A. Tetrahedron 2004, 60, 5357–5366.
Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179–13184.
6
18
7
61
4
4
4
5
a
6. Whiting, M.; Harwood, K.; Hossner, F.; Turner, P. G.; Wilkinson, M. C. Org.
Process Res. Dev. 2010, 14, 820–831.
Isolated yields.
7.
Demory, E.; Blandin, V.; Einhorn, J.; Chavant, P. Y. Org. Process Res. Dev. 2011, 15,
10–716.
7
the lithiation reaction can be carried out with n-butyllithium in-
8
.
Andersen, M. W.; Hildebrandt, B.; Köster, G.; Hoffmann, R. W. Chem. Ber. 1989,
122, 1777–1782.
General procedure for reaction with Grignard reagents: Preparation of 4,4,6-
stead of pyrophoric t-butyllithium reagent which has to be used
in the case of N-(tert-butoxycarbonyl)-anilines.12 Secondly, N-piva-
9.
trimethyl-2-phenyl-[1,3,2]dioxaborinane (26): To a solution of 2-isopropoxy-
loylanilines (29) are easier to prepare as the protection of less
nucleophilic aromatic amines with di-tert-butyl dicarbonate
4,4,6-trimethyl-[1,3,2] dioxaborinane (10) (5.58 g, 30 mmol, 1.5 equiv) in dry
THF (15 ml) under an argon atmosphere a solution of phenylmagnesium
bromide (1 M in THF, 20 mmol) was added dropwise via addition funnel at
room temperature. The reaction mixture was allowed to stir at ambient
temperature for 2 h. The reaction flask was then cooled to 0 °C and an aqueous
solution of hydrochloric acid (1 N, 30 ml) was added dropwise. After the
addition was completed the reaction mixture was allowed to warm to ambient
temperature for 1 h. The organic layer was then separated from water layer.
The latter aqueous phase was extracted with ethyl acetate (3 Â 30 ml). The
combined organic layers were dried using magnesium sulfate. The volatiles
were removed under reduced pressure and the residue was purified using flash
chromatography on silica gel (5% ethyl acetate:hexanes) to obtain the title
13
(
2
Boc O) is not as efficient as that of aliphatic amines. Due to
the instability of prepared in situ organolithium species, we
decided to initiate the ortho-lithiation process at À40 °C. However,
the key addition of the organoborate electrophile in this case was
1
4
performed at À20 °C. This higher temperature is more amenable
to large scale process chemistry and especially useful to those
facilities using glycol based heat transfer systems. The directed
ortho-lithiation results are summarized in Table 2.
compound in 98% yield. 1H NMR (400 MHz, CDCl
.40 (t, J = 7.3 Hz, 1H), 7.36 (t, J = 7.9 Hz, 2H), 4.36 (m, 1H), 1.87 (dd, J = 13.9 Hz,
3
): d 7.84 (d, J = 7.3 Hz, 2H),
N-pivaloylanilines (29) were prepared from their corresponding
anilines and electrophilic pivaloyl chloride according to the known
literature procedures in almost quantitative yields and in a short
7
J = 3.3 Hz, 1H), 11.62 (t, J = 11.7 Hz, 1H), 1.41 (d, J = 6.5 Hz, 6H), 1.38 (d,
1
13
J = 7.4 Hz, 3H). B NMR (128.3 MHz, CDCl
CDCl
0. Snieckus, V. Chem. Rev. 1990, 90, 879–887.
3
): d À26.8. C NMR (100.6 MHz,
3
): d 133.6, 130.2, 127.3, 70.8, 64.9, 45.9, 31.2, 28.1, 23.1.
1
5
time. With a variety of organoboronates in hand, we wanted to
study their performance in the palladium-catalyzed cross coupling
reaction. We have optimized the coupling reaction conditions
based on a model reaction between 4-bromobenzonitrile (37)
and phenyl boronic acid pinacol ester (18) as shown in Scheme
1
11. All of the products in the Table 1 are known compounds and their NMR data
are consistent with the literature data.
1
1
2. Stanetty, P.; Koller, H.; Mihovilovic, M. J. Org. Chem. 1992, 57, 6833–6837.
3. Vilaivan, T. Tetrahedron Lett. 2006, 47, 6739.
14. General procedure for reaction with organolithium reagents: Preparation of N-[4-
chloro-2-(4,4,6-trimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-2,2-dimethyl-
9. The findings are summarized in Table 3.