Preparation, thermal stability and carbonyl addition reactions of 2,5-difluorophenyl lithium and 2,5-difluorophenyl grignard

Article abstract of DOI:10.1055/s-2004-825592

The generation of 2,5-difluorophenyl lithium 2 by lithiation of 1,4-difluorobenzene with BuLi in THF, with and without amine additives, has been surveyed. Thermal stability data of the organolithium species 2 generated with and without TMEDA were determin

Full text of DOI:10.1055/s-2004-825592

1646
LETTER
Preparation, Thermal Stability and Carbonyl Addition Reactions of 2,5-
Difluorophenyl Lithium and 2,5-Difluorophenyl Grignard
P
reparatio
e
nand
U
se
o
r
f
2,5-Di
e
fluorophen
m
yl
L
ithium y P. Scott,* Sarah E. Brewer,* Antony J. Davies, Karel M. J. Brands
Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU,
UK
Fax +44(1992)452581; E-mail: jeremy_scott@merck.com
Received 24 February 2004
to 1-bromo-2,5-difluorobenzene (1.0 equiv) in THF as
Abstract: The generation of 2,5-difluorophenyl lithium 2 by lithia-
solvent, leading to a smooth exchange reaction between
–30 °C and –10 °C. HPLC assay yields based on either
tion of 1,4-difluorobenzene with BuLi in THF, with and without
amine additives, has been surveyed. Thermal stability data of the or-
ganolithium species 2 generated with and without TMEDA were
1,4-difluorobenzene, formed on protic quench, or on the
determined and the synthetic utility of 2 in the addition to aldehyde secondary alcohol adduct 4 (R1 = H, R2 = Ph) formed on
quenching with benzaldehyde,4 were typically >90% after
and ketone electrophiles is described. Preparation and stability of
the corresponding organomagnesium reagent 1, generated by
0.5 hours. Indeed the organomagnesium reagent so
bromine-magnesium exchange of 1-bromo-2,5-difluorobenzene
formed was stable for up to 4 hours within this tempera-
with isopropylmagnesium chloride, was also examined.
ture window, however the titre decreased on warming
Key words: metalations, organometallic reagents, addition reac-
tions, magnesium-bromine exchange, thermal stability
above +5 °C. Toluene was also found to be an excellent
less polar solvent for this bromine-magnesium exchange.
The organomagnesium reagent 1 generated in this manner
was satisfactory in subsequent additions to carbonyl elec-
As part of the development of a synthetic route amenable
trophiles from a chemical yield basis, however the high
to the multikilogram preparation of an investigational
cost of 1-bromo-2,5-difluorobenzene remained undesir-
drug candidate, we required the incorporation of a 2,5-di-
able for further scale-up. The possibility of direct metala-
fluorophenyl moiety by way of organometallic addition to
a carbonyl compound 3 (Scheme 1). We were particularly
drawn to the potential use of 2,5-difluorophenyl Grignard
reagent (1, X = Cl or Br) and 2,5-difluorophenyl lithium
reagent (2). In this letter we document efficient prepara-
tions and thermal stability data of 1 and 2, as well as
exemplifying the utility of organolithium 2 in the addition
tion of 1,4-difluorobenzene with BuLi was attractive
where, although cryogenic operating conditions would
likely be necessary,5 a net cost benefit would still result
from use of this raw material.6 Furthermore, an additional
cost saving would also likely result through the use of
BuLi rather than i-PrMgCl.
to aldehyde and ketone electrophiles.
Table 1 Lithiation Survey of 1,4-Difluorobenzene
F
Entry
BuLi
Solvent
Additive
(equiv)
Assay yield
(%)b
F
O
(equiv)a
solvent
R1
R2
+
R1
R2
additives
F
F
M
1
2
3
4
5
6
7
8
9
1.1
1.1
1.1
1.1
1.1
1.0
1.1
1.2
1.5
THF
DME
MTBE
THF
THF
THF
DME
THF
THF
None
95
81
30
95
90
85
89
90
86
HO
3
4
1: M = MgX
2: M = Li
None
Scheme 1
None
TMEDA (1.1)
PMDETA (1.1)c
DABCO (1.0)
TMEDA (1.1)
None
2,5-Difluorophenyl Grignard reagent 1 has been previous-
ly prepared by bromine-magnesium exchange reaction of
1-bromo-2,5-difluorobenzene using i-PrMgCl or i-Pr2Mg
in THF, although the former exchange was reported to be
sluggish at ambient temperature.1 Attracted by the safety
profile of the Knochel-type exchange reaction of electron
deficient aryl halides,2,3 we examined this process in
detail.
None
a Titre = 2.3 M (hexane).
The optimal procedure involved dropwise exothermic ad-
dition of i-PrMgCl (0.96 equiv of a 2.0 M THF solution) b HPLC assay after 60 min age at –70<T<–65 °C, quenching into 10
equiv PhCHO in THF.
c PMDETA = N,N,N¢,N¢,N¢¢-Pentamethyldiethylenetriamine.
SYNLETT 2004, No. 9, pp 1646–1648
2
2.
0
7.
2
0
0
4
Advanced online publication: 18.05.2004
DOI: 10.1055/s-2004-825592; Art ID: D05404ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation and Use of 2,5-Difluorophenyl Lithium
1647
2,5-Difluorophenyl lithium (2) has been previously ac- Table 3 Thermal Stability of 2 in THF with TMEDAa
cessed by bromine-lithium exchange reaction of 1-bromo-
Entry
Temp (°C)
–60
Time (min)
Assay yield (%)b
2,5-difluorobenzene with BuLi in THF.7 Direct lithiation
of 1,4-difluorobenzene by BuLi,8a s-BuLi,8b or the super-
base combination BuLi/t-BuOK,8c has also been reported,
although no rigorous stability or assay data were docu-
mented in any of these preparations of 2.9 Consequently,
we undertook a survey of the lithiation of 1,4-difluoroben-
zene with BuLi and a variety of solvent and additive com-
binations (Table 1). A standard protocol, involving
charging BuLi to a precooled ethereal solution with or
without the appropriate amine modifier, followed by addi-
tion of 1,4-difluorobenzene, was employed to generate an
approximately 0.5 M solution.
1
2
3
4
25
80
80
82
72
33
–53
–45
130
220
–40
a Conditions: 1.0 equiv BuLi, 1.0 equiv TMEDA, THF, ca. 0.5 M.
b HPLC assay.
Table 4 Carbonyl Additions of Organolithium 2 and Grignard 1
Entry Carbonyl electrophile Yield of 2,5-difluorophenyl adduct (%)a
Of those solvents surveyed, THF proved superior
(Table 1, entries 1–3), with lithiation equally efficient
with or without TMEDA10 (95% assay yield, entries 1, 4).
TMEDA appeared the optimal additive in THF (entries
4–6) whilst also apparently enhancing lithiation in DME
(entries 2, 7). A survey of the BuLi stoichiometry for lithi-
ation in THF indicated 1.1 equivalents to be sufficient to
achieve lithiation of 95% assay yield; higher charges were
deleterious (entries 1, 8, 9).
t-BuCHO
1
2
3
73b
92b
90b
PhCHO
OHC
N
4
5
84,b 90,c 89d
86b
O
O
O
O
Ph
Based on our initial survey, we selected THF as solvent
to evaluate the thermal stability of 2, with or without
TMEDA (Table 2 and Table 3). The organolithium 2 was
generated at an initial cryogenic temperature, then
allowed to warm over a period of several hours. In both in-
stances, 2 was found to degrade significantly5 on warming
above –45 °C (Table 2, entries 3, 4; Table 3, entries 2, 3).
However an experiment in which 2 was generated with
1.1 equivalents BuLi, 1.1 equivalents TMEDA in THF
and held below –60 °C, indicated a stable titre for up to 4
hours.
N
a Yields are unoptimised and refer to isolated chromatographically
homogeneous materials, except entry 4 (HPLC assay yields).
b Conditions: Aldehyde/ketone added to 1.4–1.8 equiv organolithium
2 in THF/TMEDA at –70 °C and aged 1 h.
c Conditions: Ketone in THF added to 1.8 equiv of organolithium 2 in
THF at –70 °C and aged 1 h.
d Conditions: Ketone in THF added to 1.4 equiv of Grignard 1 at
–30 °C and aged 1 h warming to 0 °C.
were determined by HPLC assay of the crude reaction
mixtures prior to purification and in all three reaction
manifolds were excellent (84–90%).12
Table 2 Thermal Stability of 2 in THF without TMEDAa
Entry
Temp (°C)
–70
Time (min)
60
Assay yield (%)b
In summary, we have developed high yielding and practi-
cal procedures for the preparation of 2,5-difluorophenyl
Grignard (1) and 2,5-difluorophenyl lithium (2). The ther-
mal stability data obtained for 1 and 2 indicate that orga-
nolithium 2 degrades in THF at temperatures above –45
°C with or without TMEDA. In this instance the use of the
Grignard reagent 1, which is stable for a period of up to 4
hours below –10 °C, may be beneficial. The utility of 2
was exemplified through high yielding addition to a num-
ber of aldehyde and ketone substrates. Altogether, the data
reported herein should facilitate the introduction of the
2,5-difluorophenyl moiety by organometallic carbonyl
1
2
3
4
5
95
90
91
83
76
–60
120
–45
180
–35
210
–25
240
a Conditions: 1.1 equiv BuLi, THF, ca. 0.5 M.
b HPLC assay.
With efficient lithiation protocols in hand, we evaluated addition processes and provide a useful starting point for
the utility of 2, in the presence of TMEDA, in the addition optimisation of related addition reactions.
to a number of carbonyl electrophiles (Table 4).11 In all
cases, isolated yields were excellent (73–92%) for both
the aldehydes (entries 1–3) and potentially enolisable ke-
tones (entries 4, 5) employed. A direct comparison of the
addition of organolithium 2, with and without TMEDA,
and of Grignard 1 to cyclohexanedione mono-ethylene
ketal was also performed (entry 4). In this instance yields
Preparation of 2,5-Difluorophenyl Grignard (1):
1-Bromo-2,5-difluorobenzene (157.3 g, 0.82 mol) was diluted with
THF (500 mL), degassed with vacuum/N2 cycles (3 ×) and cooled
to –30 °C. Isopropyl magnesium chloride (2.0 M in THF, 400 mL,
0.80 mol) was added dropwise over 20 min at T<–10 °C. After a 30
min age at –20<T<–10 °C, HPLC assay4 indicated a 92% yield.
Synlett 2004, No. 9, 1646–1648 © Thieme Stuttgart · New York

1648
J. P. Scott et al.
LETTER
Preparation of (2,5-Difluorophenyl)(phenyl)methanol (4:
R1 = H, R2 = Ph):
(7) (a) Ong, H. H.; Profitt, J. A.; Anderson, V. B.; Kruse, H.;
Wilker, J. C.; Geyer, H. M. III. J. Med. Chem. 1981, 24, 74.
(b) Bridges, A. J.; Patt, W. C.; Stickney, T. M. J. Org. Chem.
1990, 55, 773. (c) We have found MTBE to be an excellent
alternative to THF for this bromine-lithium exchange.
(8) (a) Nichols, D. A. J. Chem. Soc. (A) 1969, 10, 1471.
(b) Morrow, G. W.; Swenton, J. S.; Filppi, J. A.;
TMEDA (7.1 mL, 47.1 mmol) was diluted with THF (40 mL), de-
gassed with vacuum/N2 cycles (3 ×) and cooled to –70 °C. BuLi
(47.1 mmol, 18.8 mL of 2.5 M in hexane solution) was added drop-
wise over 10 min such that T<–60 °C. Following a 10 min age
whilst recooling to –71 °C, 1,4-difluorobenzene (4.84 g, 42.4
mmol) was added dropwise such that –71<T<–68 °C (15 min addi-
tion). After aging at this temperature for a further 1.5 h, benzalde-
hyde (2.5 g, 23.6 mmol) was added dropwise over 15 min and the
resultant mixture aged 1 h. HOAc (3 mL) was then added and the
reaction warmed to ambient temperature before partitioning be-
tween 2 M HCl (50 mL) and isopropyl acetate (50 mL). The organic
layer was washed with H2O (2 × 25 mL), evaporated in vacuo and
purified by silica gel chromatography to give the title compound as
Wolgemuth, R. L. J. Org. Chem. 1987, 52, 713.
(c) Schlosser, M.; Katsoulos, G.; Takagishi, S. Synlett 1990,
747.
(9) An ab initio study encompassing 2,5-difluorophenyl lithium
(2) has been reported, see: Streitweiser, A.; Abu-Hasanyan,
F.; Neuhaus, A.; Brown, F. J. Org. Chem. 1996, 61, 3151.
(10) (a) Chalk, A. J.; Hoogeboom, T. J. J. Organomet. Chem.
1968, 11, 615. (b) For a discussion of the role of TMEDA as
additive, see: Collum, D. A. Acc. Chem. Res. 1992, 25, 448.
(11) All new compounds gave satisfactory spectroscopic and/or
elemental data:
1
a white solid (4.8 g, 92%). Mp 60–61 °C. H NMR (400 MHz,
CD2Cl2): d = 7.44–7.30 (6 H, m), 7.05–6.95 (2 H, m), 6.12 (1 H, s),
2.48 (1 H, br s). 13C NMR (100 MHz, CD2Cl2): d = 159.0 (d, J = 242
Hz), 155.6 (d, J = 242 Hz), 142.4, 133.0 (dd, J = 7, 16 Hz), 128.6,
128.0, 126.4, 116.4 (dd, J = 9, 25 Hz), 115.2 (dd, J = 9, 16 Hz),
114.0 (dd, J = 5, 25 Hz), 69.6. Anal. Calcd for C13H10F2O: C, 70.90;
H, 4.58; F, 17.25. Found: C, 70.91; H, 4.58; F, 17.37.
1-(2,5-Difluorophenyl)-2,2-dimethylpropan-1-ol
(colourless oil): 1H NMR (400 MHz, CD2Cl2): d = 7.25–7.20
(1 H, m), 7.06–6.93 (2 H, m), 4.80 (1 H, d, J = 4.0 Hz), 2.04
(1 H, d, J = 4.0 Hz), 0.96 (9 H, s). 13C NMR (100 MHz,
CD2Cl2): d = 158.3 (d, J = 259 Hz), 156.0 (d, J = 257 Hz),
131.3 (dd, J = 7, 16 Hz), 115.8 (dd, J = 9, 27 Hz), 115.5 (dd,
J = 5, 22 Hz), 114.9 (dd, J = 9, 24 Hz), 74.3, 36.2, 25.4.
Anal. Calcd for C11H14F2O: C, 65.98; H, 7.05; F, 18.98.
Found: C, 65.99; H, 7.13; F, 18.61.
References
(1) (a) Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett.
1999, 40, 7449. (b) For a recent review, see: Knochel, P.;
Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.;
Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem. Int. Ed.
2003, 42, 4302.
(2) Leazer, J. L.; Cvetovich, R.; Tsay, F.-R.; Dolling, U.;
Vickery, T.; Bachert, D. J. Org. Chem. 2003, 68, 3695.
(3) Halogen-magnesium exchange reactions employing
organomagnesium ate complexes have been reported:
(a) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J.
Org. Chem. 2001, 66, 4333. (b) Mase, T.; Houpis, I. N.;
Akao, A.; Dorziotis, I.; Emerson, K.; Hoang, T.; Iida, T.;
Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.; Kawasaki, M.; Lang,
F.; Lee, J.; Lynch, J.; Maligres, P.; Molina, A.; Nemoto, T.;
Okada, S.; Reamer, R.; Song, J. Z.; Tschaen, D.; Wada, T.;
Zewge, D.; Volante, R. P.; Reider, P. J.; Tomimoto, K. J.
Org. Chem. 2001, 66, 6775.
(4) An aliquot was quenched into 10 equiv of PhCHO in THF at
ambient and assayed versus authentic adduct 4 (R1 = H,
R2 = Ph) by reverse phase HPLC with UV detection at 210
nm on a Zorbax SB Phenyl 250 × 4.6 mm column.
(5) (a) ortho-Halophenyl lithiums are well known benzyne
precursors at elevated temperatures, see inter alia: Kessar, S.
V. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I.; Paquette, L. A., Eds.; Pergamon Press: Oxford,
1991, Vol. 4, Chap. 2.3, 483–515. (b) Attempts to
characterise the degradation products by LCMS were
unsuccessful.
(2,5-Difluorophenyl)(pyridin-3-yl)methanol: Mp 102–
104 °C. 1H NMR (400 MHz, CD2Cl2): d = 8.34–8.31 (1 H,
m), 8.32–8.20 (1 H, m), 7.65–7.61 (1 H, m), 7.27–7.22 (1 H,
m), 7.18–7.13 (1 H, m), 6.92–6.83 (2 H, m), 5.30 (1 H, br s).
13C NMR (100 MHz, CD2Cl2): d = 159.0 (dd, J = 2, 241 Hz),
155.4 (dd, J = 2, 240 Hz), 148.3, 147.6, 138.8, 134.6, 132.6
(dd, J = 7, 16 Hz), 123.7, 116.4 (dd, J = 8, 24 Hz), 115.4 (dd,
J = 8, 24 Hz), 113.9 (dd, J = 5, 25 Hz), 67.0 (d, J = 3 Hz).
Anal. Calcd for C12H9F2NO: C, 65.16; H, 4.10; N, 6.33; F,
17.18. Found: C, 65.04; H, 4.09; N, 6.43; F, 17.15.
8-(2,5-Difluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol: Mp
112–114 °C. 1H NMR (400 MHz, CDCl3): d = 7.27–7.21 (1
H, m), 7.00–6.85 (2 H, m), 3.95 (4 H, s), 2.42 (1 H, br s),
2.36–2.28 (2 H, m), 2.15–2.03 (2 H, m), 1.88–1.70 (4 H, m).
13C NMR (100 MHz, CDCl3): d = 158.6 (d, J = 259 Hz),
156.2 (d, J = 258 Hz), 136.8 (dd, J = 6, 13 Hz), 117.3 (dd,
J = 8, 27 Hz), 114.6 (dd, J = 9, 24 Hz), 113.7 (dd, J = 5, 26
Hz), 108.2, 71.6, 64.3, 34.2, 30.3. Anal. Calcd for
C14H16F2O3: C, 62.22; H, 5.97; F, 14.06. Found: C, 62.33; H,
5.98; F, 14.02.
1-Benzyl-4-(2,5-difluorophenyl) piperidin-4-ol: Mp 63–
65 °C. 1H NMR (400 MHz, CD2Cl2): d = 7.42–7.26 (6 H, m),
7.12–6.93 (2 H, m), 3.60 (2 H, s), 2.83–2.76 (2 H, m), 2.54–
2.46 (2 H, m), 2.42–2.32 (2 H, m), 2.20 (1 H, br s), 1.78–1.72
(2 H, m). 13C NMR (100 MHz, CD2Cl2): d = 158.7 (d,
J = 253 Hz), 156.3 (d, J = 254 Hz), 138.9, 137.0 (dd, J = 7,
13 Hz), 129.0, 128.1, 126.9, 117.3 (dd, J = 9, 27 Hz), 114.7
(dd, J = 9, 24 Hz), 113.8 (dd, J = 5, 26 Hz), 70.6, 63.0, 49.0,
36.3. Anal. Calcd for C18H19F2NO: C, 71.27; H, 6.31; N,
4.62. Found: C, 71.29; H, 6.31; N, 4.63.
(6) For example, Aldrich 2003 catalogue prices: 1-Bromo-2,5-
difluorobenzene (24795-2) £648/mol, £3.36/g; 1,4-
difluorobenzene (D10220-2) £88/mol, £0.77/g.
(12) Addition reactions of organolithium 2 to the carbonyl
substrates illustrated, other than 1,4-cyclohexanedione
mono-ethylene ketal, have not been evaluated in the absence
of TMEDA.
Synlett 2004, No. 9, 1646–1648 © Thieme Stuttgart · New York