Halogen-lithium exchange versus deprotonation: synthesis of diboronic acids derived from aryl-benzyl ethers

Article abstract of DOI:10.1016/j.tetlet.2006.12.076

Lithiation of a series of aryl benzyl ethers containing halogen substituents (-F, -Br, -I) was investigated. The resultant mono- and diorganolithium intermediates were converted into the corresponding aldehydes or diboronic acids in good yields. The dilit

Full text of DOI:10.1016/j.tetlet.2006.12.076

Tetrahedron Letters 48 (2007) 1169–1173
Halogen–lithium exchange versus deprotonation: synthesis
of diboronic acids derived from aryl–benzyl ethers
*
Tomasz Kli s´ and Janusz Serwatowski
Warsaw University of Technology, Department of Chemistry, Noakowskiego 3, 00-664 Warsaw, Poland
Received 16 October 2006; revised 5 December 2006; accepted 13 December 2006
Available online 8 January 2007
Abstract—Lithiation of a series of aryl benzyl ethers containing halogen substituents (–F, –Br, –I) was investigated. The resultant
mono- and diorganolithium intermediates were converted into the corresponding aldehydes or diboronic acids in good yields. The
dilithiation of aryl benzyl ethers containing a reactive hydrogen atom and halogen atom capable of halogen–lithium exchange pro-
ceeds quantitatively in THF at À50 °C. It was found that mono aryllithiums formed in the reaction can remove the reactive hydro-
gen atom from a molecule of aryl benzyl ether thus decreasing the yield of dilithiated species. This effect does not occur when t-BuLi
is used instead of n-BuLi.
Ó 2006 Published by Elsevier Ltd.
The formation of dilithiated organometallic compounds
is interesting for two reasons: they can be used as start-
ing materials for the synthesis of more advanced organic
compounds and studying their formation can reveal
knowledge about the mechanism of lithiation. In this
Letter, we present the results of our studies on lithiation
of aryl benzyl ethers (ABEs) containing –F, –Br and –I
substituents. The successful dilithiation of ABEs opens
the way to the synthesis of diboronic acids, a group of
compounds which have found many applications in
undergoes HLE to give the more stable 2-lithio species.5
It was found recently that fluorine activates bromine
more strongly than a methoxy group, however, nonacti-
vated iodine undergoes HLE easier than an activated
6
bromine atom. Our previous work on metallation of
fluorinated ABEs possessing reactive hydrogen atoms
at different positions confirmed that the acidity of the
hydrogen was the most important factor directing the
regioselectivity rather than –O–Li–Bu complex forma-
7
tion. The presence of other factors such as temperature
1
–3
8
organic synthesis and in analytical chemistry. Lithiation
of organic compounds can occur via deprotonation
and solvent is also crucial for selective lithiation. The
ABEs used for this study can be lithiated in more than
one position and depending on the structure, the reac-
tion can occur via HLE or a deprotonation mechanism,
but in some cases both the mechanisms occur simulta-
neously. Our work demonstrates that a small change
in the structure of the ABE requires completely different
conditions to obtain dilithiated species selectively. The
resultant lithiated ABEs were converted into the corre-
sponding benzaldehydes or diboronic acids.
(
(
ortho lithiation) or via a halogen–lithium exchange
HLE) mechanism. It is generally accepted that fluorine
atoms accelerate ortho lithiation and Br or I atoms
undergo HLE easily. Ziegler showed that amongst butyl
halides only iodine and bromine derivatives underwent
rapid halogen–lithium exchange with n-butyllithium in
4
diethyl ether. The presence of an activating group is
essential for both ortho lithiation and HLE. The activat-
ing group increases the acidity of the ortho hydrogen as
in fluorobenzenes, forming entropy saving complexes
like in anisoles or stabilizing the newly formed organo-
lithium compound (e.g., 2,5-dibromonitrobenzene) which
Regioselective bromine–lithium exchange in 2-bromo-
9
,10
anisole as well as in 2-bromotoluene is well known.
It was interesting to determine the regioselectivity of
the HLE in 1 as this compound contains both 2-bromo-
anisole and 2-bromotoluene moieties. These two bro-
mine atoms should demonstrate different reactivities as
only one of them is activated by an oxygen atom.
ABE 1 was subjected to the HLE reactions (Table 1,
entries 1 and 2). We found that in diethyl ether solvent
Keywords: Lithiation; Aryl–benzyl ethers; Butyllithium; Diboronic
acid.
*
Corresponding author. Tel.: +48 22 6607575; fax: +48 22 6282741;
e-mail addresses: ktom@ch.pw.edu.pl; tomasz_klis@wp.pl
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.12.076

1170
T. Kli s´ , J. Serwatowski / Tetrahedron Letters 48 (2007) 1169–1173
Table 1. Preparation of functionalized ABEs via halogen–lithium exchange or deprotonation and subsequent DMF or B(OEt)
3
quench
Entry
1
ABE
RLi
Solvent, temperature (°C)
Products
Br
O
Br
OHC
O
Br OHC
O
CHO
n-BuLi
Et
2
O, À60
1
1a (87%)
1b (13%)
Br
Br
O
O
Br
Br
OHC
O
CHO
2
3
4
5
2n-BuLi
2n-BuLi
2n-BuLi
2n-BuLi
THF, À40
THF, À40
1
1
1b (98%)
(OH) B
O
B(OH)2
2
1c (96%)
Br
O
OHC
O
Et
2
O, À60
O, À60
2
I
2a (95%)
CHO
Br
O
(OH)
2
B
O
Et
2
2
I
2b (97%) B(OH)2
O
Br
O
CHO
6
7
F
F
n-BuLi
Et
2
O, À40
F
3
3h (95%)
O
Br
OHC
F
O
CHO
3t-BuLi
THF, À50
3
3f (96%)
O
O
Br
Br
(OH) B
O
B(OH)2
2
8
9
F
F
3t-BuLi
2n-BuLi
THF, À50
THF, À50
F
3
3i (95%)
OHC
F
O
OHC
F
O
CHO
3
3g (35%)
3f (45%)
F
O
CHO
F
O
Br
10
2n-BuLi
THF, À50
OHC
F
F
4
4a (92%)
B(OH)2
F
O
Br
F
O
11
2n-BuLi
THF, À50
F
(OH)
2
B
F
4
4b (71%)

T. Kli s´ , J. Serwatowski / Tetrahedron Letters 48 (2007) 1169–1173
1171
both bromines compete for n-BuLi but mainly the bro-
mine ortho to the oxygen atom (87%) is replaced with
lithium to give the corresponding aldehyde after DMF
quench. However, the nonactivated bromine atom ortho
to the methylene group also undergoes HLE providing
the dilithiated species which gives the respective dialde-
hyde (13%) after DMF quench. Similar results were ob-
tained with 2 mol of n-BuLi. Attempted application of
THF as solvent and increasing the temperature to
À40 °C activated the bromine atom on the benzylic aro-
matic of 1 and the reaction with 2 mol equiv of n-BuLi
gave the dialdehyde exclusively after DMF quench.
rine are not reactive enough to be removed by interme-
diates analogous to 3b. The successful dilithiation of 4
enabled the synthesis of the respective diboronic acid
4b using B(OEt) as an electrophile (entry 11). It should
3
be noted that the temperature for lithiation of 3 and
4 should not be higher than À50 °C because of the
potential decomposition of the lithiated species via an
1
3
aryne.
In conclusion, the dilithiation of ABEs is efficient pro-
vided that precautions are observed concerning the
choice of solvent, alkyllithium reagent and temperature.
ABEs containing a nonactivated bromine atom can be
dilithiated selectively via bromine–lithium exchange in
THF at À40 °C. On the other hand, replacement of
the nonactivated bromine with iodine enables HLE in
diethyl ether at À60 °C. ABEs which can be lithiated
simultaneously by deprotonation and HLE, require the
use of THF to obtain the dilithiated compound and
the temperature must not be higher than À50 °C to
avoid aryne formation. In ABEs containing very reac-
tive hydrogen atoms, t-BuLi should be used as the lith-
iating reagent to avoid deprotonation by the newly
formed aryllithiums. The dilithiated ABEs obtained
can be easily converted into diboronic acids using
The use of B(OEt) as an electrophile resulted in the
3
respective diboronic acid in excellent yield (entry 3).
We also investigated the HLE of 2 using 2 equiv of
n-BuLi, and in this case, quantitative replacement of
the bromine and iodine atoms was observed in diethyl
ether at À60 °C and the respective dialdehyde or di-
boronic acid was isolated following DMF or B(OEt)
3
quench (Table 1, entries 4 and 5). At this point, we
can state that the selective dilithiation of 1 and 2 via
HLE is feasible and depends on the correct choice of
solvent and temperature.
We were next interested in comparing the relative
directing potential of fluorine and oxygen with respect
to the nonactivated bromine atom. We employed ABE
B(OEt) . Obviously, the synthetic potential of all the de-
3
scribed lithiation experiments is not limited to the exam-
ples presented in this Letter and appears to be an
interesting synthetic tool for the synthesis of other di-
boronic acids.
3
, where one of the hydrogen atoms is flanked by fluo-
rine and oxygen atoms and can be removed by deproto-
1
1,12
nation while the bromine atom can undergo HLE.
The reaction of 3 with n-BuLi in diethyl ether at
À40 °C followed by DMF quench afforded the respec-
tive monoaldehyde (entry 6). This result shows that in
diethyl ether only the HLE occurs at a reasonable rate.
Surprisingly, treatment of 3 with 2 equiv of n-BuLi in
THF at À50 °C followed by DMF quench did not give
the pure dialdehyde, instead a mixture of two products
A typical procedure for dilithiation of ABEs and reaction
with B(OEt) : To a cooled (À68 °C) solution of n-butyl-
3
lithium (0.05 mol) in 100 mL of THF, 1 (0.025 mol) dis-
solved in 20 mL of THF was added dropwise with
stirring while maintaining the temperature below
À60 °C. The reaction mixture was slowly warmed to
À40 °C and maintained at this temperature for 20 min.
The resultant solution was cooled to À68 °C and then
1
was formed (entry 9) as confirmed by analysis of the H
NMR spectrum where two methylene singlets at 5.13
and 5.24 ppm were observed. The mass spectrum
showed the presence of two molecular ions: m/z = 230
and m/z = 258 which correspond to structures 3f and
B(OEt) (0.05 mol) was added maintaining the tempera-
3
ture below À60 °C. Following addition, the reaction
mixture was allowed to warm to À40 °C and water
(100 mL) and 3 M sulfuric acid (20 mL) were added to
make the mixture slightly acidic. The organic phase
was separated and the aqueous phase was extracted with
ether (30 mL). Drying followed by evaporation of the
combined organic solutions left a solid which was
washed with water and hexane to give 1c as colourless
3
g. However, application of t-BuLi (1:3) as base at
À50 °C yielded 3f quantitatively (entry 7) and the use
of B(OEt) as an electrophile gave the respective di-
3
boronic acid (entry 8). The lithiation of 4 can also occur
via HLE or deprotonation because of the presence of
the strongly activating fluorine atoms and the bromine.
Contrary to lithiation of 3, treatment of 4 with 2 equiv
of n-BuLi followed by DMF quench occurred cleanly to
give 4a in satisfactory yield (entry 10). The difference
between the reactivity of 3 and 4 with n-butyllithium
is caused most probably by the presence of the reactive
hydrogen atom flanked by fluorine and oxygen atoms in
1
powder, mp 151–152 °C. H NMR (400 MHz, acetone-
d ) d 7.78 (m, 3H), 7.49 (m, 2H), 7.39 (m, 2H), 7.31
6
1
3
(m, 2H), 7.11 (m, 2H), 6.95 (m, 1H), 5.45 (s, 2H).
C
NMR (100 MHz, acetone-d ) d 164.87, 142.03, 137.27,
6
135.52, 132.99, 130.54, 129.15, 128.06, 121.45, 112.41,
1
1
71.05. B NMR (200 MHz) d 29.5. Analysis: Anal.
3
. According to our hypothesis, this atom shows such
Calcd for C H B O : C, 57.43; H, 5.17. Found: C,
1
3
14
2
5
high reactivity that it can be removed not only by
n-butyllithium but also by the intermediates 3b or 3c
containing C–Li bonds. As a result, the reactions pro-
vide a mixture of 3f and 3g (Scheme 1). The reaction
of 3 with t-BuLi proceeds cleanly as t-BuLi is a stronger
base than 3b and removes the reactive hydrogen atom
more rapidly. The reaction of 4 with n-BuLi occurs
cleanly because the hydrogen atoms ortho to the fluo-
57.59, H, 5.24.
1
Compound 1b: mp 117–119 °C. H NMR (400 MHz,
CDCl ) d 10.62 (s, 1H), 10.17 (s, 1H), 7.86 (m, 3H),
3
7.69 (m, 1H), 7.56 (m, 2H), 7.10 (m, 2H), 5.66 (s, 2H).
1
3
C NMR (100 MHz, CDCl ) d 193.43, 189.51, 160.58,
3
138.43, 136.04, 134.93, 132.69, 128.92, 128.07, 127.07,
125.03, 121.13, 113.05, 67.98. Analysis: Anal. Calcd

1172
T. Kli s´ , J. Serwatowski / Tetrahedron Letters 48 (2007) 1169–1173
n
-BuLi
BuBr
C H
4
10
O
Br
Li
O
Br
O
Li
F
F
+
F
3
3
a
3b
n-BuLi
n-BuLi, 3b
n
-BuLi, 3b, 3c
O
Li
O
Li
O
Li
F
+
F
+
+
F
BuBr
C H
3
a
4
10
3
e
3d
3
c
1. DMF
+
2. H O/H
2
1
2
. DMF
+
. H O/H
2
OHC
F
O
OHC
F
O
CHO
3
g
3f
Scheme 1. The sequence of lithiations providing the mixture of 3f and 3g.
for C H O : C, 75.01; H, 5.00. Found: C, 74.66; H,
NMR (100 MHz, CDCl ) d 193.65, 186.83, 163.99 (d,
1
5
12
3
3
5
.01.
J = 260 Hz), 160.50, 138.02, 136.25, 135.16, 134.46,
1
32.44, 128.04, 127.11, 114.28, 108.86, 108.66, 68.72.
1
Compound 2a: mp 126–128 °C. H NMR (400 MHz,
Analysis: Anal. Calcd for C H FO : C, 69.78; H,
4.26. Found: C, 69.51; H, 4.30.
1
5
11
3
CDCl ) d 10.67 (s, 1H), 10.02 (s, 1H), 7.92 (m, 2H),
3
7
1
.86 (m, 1H), 7.62 (m, 2H), 7.54 (m, 1H), 7.07 (m,
H), 7.02 (m, 1H), 5.28 (s, 2H). C NMR (100 MHz,
1
3
1
Compound 3h: mp 42–44 °C. H NMR (400 MHz,
CDCl ) d 191.65, 189.29, 160.36, 142.78, 136.04,
CDCl ) d 10.18 (s, 1H), 7.90 (s, 1H), 7.78 (m, 1H),
3
3
1
6
35.89, 130.02, 128.73, 127.27, 125.02, 121.29, 112.73,
7.65 (m, 1H), 7.55 (m, 1H), 7.25 (m, 1H), 6.80 (m,
1H), 6.70 (m, 2H), 5.52 (s, 2H). C NMR (100 MHz,
1
3
9.48. Analysis: Anal. Calcd for C H O : C, 75.01;
1
5
12
3
H, 5.00. Found: C, 74.92; H, 4.98.
CDCl ) d 193.20, 163.61 (d, J = 243 Hz), 159.72,
3
1
38.91, 134.22, 134.09, 132.92, 130.29, 127.99, 127.47,
1
Compound 2b: mp 150–152 °C. H NMR (400 MHz,
110.53, 107.96, 102.69, 67.95. Analysis: Anal. Calcd
for C H FO : C, 73.06; H, 4.78. Found: C, 72.45; H,
acetone-d ) d 7.91 (m, 2H), 7.82 (m, 1H), 7.49 (m,
6
14 11
2
2
2
1
1
H), 7.40 (m, 1H), 7.11 (m, 1H), 6.98 (m, 1H), 5.24 (s,
4.91.
1
3
H), 3.06 (d, 4H). C NMR (100 MHz, acetone-d ) d
6
1
64.65, 139.61, 137.39, 135.36, 133.13, 127.73, 121.76,
Compound 3i: mp 142–144 °C. H NMR (400 MHz,
acetone-d ) d 7.73 (m, 1H), 7.55 (m, 1H), 7.38 (m,
1
1
12.42, 70.94. B NMR (200 MHz) d 29.1. Analysis:
6
Anal. Calcd for C H B O : C, 57.43; H, 5.17. Found:
C, 57.46; H, 5.20.
1H), 7.29 (m, 2H), 6.85 (d, 1H), 6.65 (t, J = 8.4 Hz,
1
3
14
2
5
13
1H), 5.35 (s, 2H), 3.09 (s, 2H), 3.07 (s, 2H). C NMR
100 MHz, acetone-d6) 166.83 (d, J = 240 Hz),
163.87, 142.03, 135.22, 132.37, 130.45, 128.60, 127.77,
(
d
1
Compound 3f: mp 161–163 °C. H NMR (400 MHz,
1
1
CDCl ) d 10.57 (s, 1H), 10.14 (s, 1H), 8.03 (m, 1H),
108.49, 108.34, 71.52. B NMR (200 MHz) d 29.3.
3
7
.90 (m, 1H), 7.73 (m, 1H), 7.58 (m, 1H), 7.52
Analysis: Anal. Calcd for C H FB O : C, 53.89; H,
4.49. Found: C, 53.96, H, 4.59.
1
3
13
2
5
1
3
(
m, 1H), 6.95 (m, 1H), 6.79 (m, 1H), 5.64 (s, 2H).
C

T. Kli s´ , J. Serwatowski / Tetrahedron Letters 48 (2007) 1169–1173
1173
1
Compound 4a: mp 106–108 °C. H NMR (400 MHz,
References and notes
1. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
CDCl ) d 10.26 (s, 1H), 10.22 (s, 1H), 7.90 (m, 2H),
.69 (m, 1H), 7.59 (m, 2H), 7.04 (m, 1H), 5.67 (s, 2H).
C NMR (100 MHz, CDCl ) d 192.88, 185.69, 163.61
d, J = 243 Hz), 159.72, 138.27, 134.12, 133.78, 133.08,
28.50, 128.05, 123.10, 121.79, 113.02, 73.69. Analysis:
Anal. Calcd for C H F O : C, 65.23; H, 3.62. Found:
3
7
1
3
2
3
4
. Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron
997, 53, 16463–16470.
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0, 2147–2152.
. Ziegler, K.; Colonius, H. Liebigs Ann. Chem. 1930, 479,
36.
3
1
(
1
6
1
5
10
2
3
C, 65.16; H, 3.72.
1
5
6
. Voss, G.; Gerlach, H. Chem. Ber. 1989, 122, 1199.
. Dabrowski, M.; Kubicka, J.; Lulinski, S.; Serwatowski, J.
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1
Compound 4b: mp 142–143 °C. H NMR (400 MHz,
acetone-d ) d 7.74 (m, 1H), 7.51 (m, 1H), 7.38 (m,
6
2
2
1
1
1
H), 7.28 (m, 1H), 6.97 (m, J = 9.4 Hz, 1H), 5.42 (s,
7. Chodakowski, J.; Klis, T.; Serwatowski, J. Tetrahedron
Lett. 2005, 46, 1963–1965.
13
H), 3.19 (s, 4H). C NMR (100 MHz, acetone-d ) d
6
8
. Katsoulos, G.; Takagishi, S.; Schlosser, M. Synlett 1991,
31.
60.95 (m, J = 250 Hz), 158.34 (m, J = 248 Hz),
7
42.03, 135.34, 130.47, 130.31, 129.40, 129.00, 123.30,
1
1
9. Gilman, H.; Langham, W.; Jacoby, A. L. J. Am. Chem.
Soc. 1939, 61, 106.
12.61, 77.01. B NMR (200 MHz) d 29.0. Analysis:
Anal. Calcd for C H F B O : C, 50.73; H, 3.90.
Found: C, 50.93; H, 3.94.
1
3
12
2
2
5
1
1
1
1
0. Gilman, H.; Langham, W.; Moore, F. W. J. Am. Chem.
Soc. 1940, 62, 2327–2335.
1. Kirsch, P.; Bremer, M. Angew. Chem., Int. Ed. 2000, 39,
4
217.
Acknowledgements
2. Klis, T.; Serwatowski, J.; Wojcik, D. Appl. Organomet.
Chem. 2006, 20, 677–682.
3. Hegedus, L.; Lipshutz, B.; Nozaki, H.; Reetz, M.;
Rittmeyer, P.; Smith, K.; Totter, F.; Yamamoto, H.
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1995.
This work was supported by the Warsaw University of
Technology. The support from the Aldrich Chemical
Co., Inc, Milwaukee, WI, USA, through donation of
chemicals and equipment is gratefully acknowledged.