Low-Temperature Formation of Functionalized Grignard Reagents from Direct Oxidative Addition of Active Magnesium to Aryl Bromides

Full text of DOI:10.1021/jo000413i

5428
J . Org. Chem. 2000, 65, 5428-5430
Sch em e 1
Low -Tem p er a tu r e F or m a tion of
F u n ction a lized Gr ign a r d Rea gen ts fr om
Dir ect Oxid a tive Ad d ition of Active
Ma gn esiu m to Ar yl Br om id es
J un-sik Lee, Raffet Velarde-Ortiz,† Albert Guijarro,‡
J oshua R.Wurst,§ and Reuben D. Rieke*
Department of Chemistry, University of NebraskasLincoln,
Ta ble 1. F or m a tion of F u n ction a lized Gr ign a r d
Rea gen ts a n d Th eir Rea ction s w ith Electr op h iles
Lincoln, Nebraska 68588-0304
rrieke@unlserve.unl.edu
Received March 21, 2000
In tr od u ction
Despite being 100 years old, the Grignard reagent still
plays a central role in synthetic chemistry today.1 How-
ever, few functionalized Grignard reagents have been
prepared due to the low functional group tolerance.2 In
1998, several functionalized aromatic and vinylic Grig-
nard reagents were prepared by iodine-magnesium
exchange using an excess of diisopropylmagnesium as
metalating agent at a low temperature (-40 °C). The
yields were excellent to moderate after reaction with allyl
bromide or benzaldehyde as electrophiles.3 However, the
thermodynamic nature of the equilibrium of exchange
limits the range of substrates to arylic and vinylic
halides. Moreover, the transmetalation failed to afford
functionalized Grignard reagents from brominated sub-
strates. Chromium salts can form functionalized orga-
nochromium compounds, but the chromium salts needed
a catalyst for the oxidative addition step and the func-
tionalized organochromium compounds reacted only with
aldehydes so far.4 We would like to report the use of
activated magnesium (Rieke Magnesium) to prepare
functionalized Grignard reagents from aryl bromides at
low temperatures (-78 °C). The Grignard reagents were
reacted with several electrophiles such as benzaldehyde,
benzoyl chloride, or allyl iodide. The reaction of the
Grignard reagents with acid chlorides yielded ketones.
Because the reactions were carried out at low tempera-
tures, we observed little or no addition to the ketones.5
The use of the functionalized Grignard reagents repre-
sents a straightforward method to synthesize polyfunc-
tionalized organic molecules.
a
b
Resu lts a n d Discu ssion
Isolated yields. CuI (10 mol %, based on the substrate) was
used.
In general, the low functional group tolerance of
Grignard reagents precludes the use of most groups in
the same molecule. However, if the oxidative addition
reaction is carried out at low temperatures (-78 °C), the
functionalized Grignard reagents are stable for a limited
time. Functionalized Grignard reagents were successfully
prepared by direct oxidative addition to aryl bromide
substrates containing a nitrile, ester, or chloride group
using highly active magnesium (Rieke magnesium) at low
temperature (-78 °C). The oxidative addition was rapid
even at this temperature and was completed in 15 min
(Scheme 1). The reaction with the electrophiles (PhCHO,
allyl iodide, and PhCOCl using 10% CuI) was carried out
†Present address: Department of Chemical Engineering, University
of NebraskasLincoln, Lincoln, NE 68588.
‡ Present address: Departamento de Quimica Organica, Univer-
sidad de Alicante, Ap. 99 E-03080, Alicante, Spain.
§ Present address: Department of Chemistry, University of
MinnesotasMorris, Morris, MN 56267.
(1) Grignard. V. C. R. Acad. Sci. 1900, 130, 1322.
(2) (a) Silverman, G. S.; Rakita, P. E. Handbook of Grignard-
reagents; Marcel Dekker: New York, 1996. (b) Burns, T. P.; Rieke, R.
D. J . Org. Chem. 1983, 48, 4141.
(3) Knochel, P.: Cahiez, G.; Boymond, L.; Rottlander, M. Angew.
Chem., Int. Ed. 1998, 37, 1701.
(4) (a) Takai, K.; Nitta, K.; Fujimura, O.; Utimoto, K. J . Org. Chem.
1988, 54, 4732. (b) Chen, C.; Tagami, K.; Kishi, Y. J . Org. Chem. 1995,
60, 5386. (c) Furstner, A.; Shi, N. J . Am. Chem. Soc. 1996, 118, 2533.
(5) (a) Sato, F.; Inoue, M.; Oguro, K.; Sato, M. Tetrahedron Lett.
1979, 44, 4304. (b) Eberle, M. K.; Kahle, G. G. Tetrahedron Lett. 1980,
21, 2303.
o
at low temperatures (-78, -40 C) within ca. 1 h, and
the yields were good to moderate (Table 1).
When ethyl or methyl arylcarboxylates were used, i.e.,
ethyl 3-bromobenzoate, the Grignard reagent did not
10.1021/jo000413i CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/26/2000

Notes
J . Org. Chem., Vol. 65, No. 17, 2000 5429
form at -78 oC. A possible explanation might be the
coordination of the ester group to the magnesium surface,
blocking the active sites of the metal and thus preventing
the oxidative addition step. Raising the temperature to
neat films unless otherwise stated. GC/MS were performed by
the Nebraska Center for Mass Spectrometry at the University
of NebraskasLincoln.
All manipulations were carried out under an argon atmo-
sphere on a dual manifold vacuum/argon system. The prepuri-
fied-grade argon was further purified by passage over a BASF
R3-11 catalyst column at 150 °C, a phosphorus pentoxide
column, and a column of granular potassium hydroxide. Tet-
rahydrofuran was distilled immediately before use from Na/K
alloy under an atmosphere of argon.
Analytical thin-layer chromatography was performed on a
silica gel plate (60 F254). The product spots were visualized with
either UV light (254 nm) or by staining a solution of phospho-
molybdic acid in ethanol. Flash chromatography was performed
using silica gel (230-400 mesh). Rieke magnesium (Mg*) was
purchased from Rieke Metals, Inc. All other reagents were
purchased from commercial suppliers and used without further
purification.
o
-50 C permits the formation of the organomagnesium
reagent. However, at the higher temperatures, more
byproducts were formed, which limited the scope of the
reaction. Other bidentate substrates containing groups
of increased polarity, such as amides, failed to react with
active magnesium at low temperature. A highly temper-
ature-dependent equilibrium of adsorption-desorption of
the functionalized group on the metal surface and active
sites seems to be responsible for the capricious reactivity
displayed by the halogenated substrates.
tert-Butyl arylcarboxylates proved to be good candi-
dates for the preparation of functionalized Grignard
reagents. The bulky ester group most likely prevented
the coordination of the ester to the magnesium surface.
The reactivity of the three isomers of the Grignard
reagents also displayed important differences. Only the
para-isomer gave moderate yields in the reaction with
benzaldehyde. Entry 4 demonstrates that the highly
reactive magnesium displays unusual selectivity in mod-
erate yield.
The coupling reactions with the benzoyl chloride and
allyl iodide required the addition of 10% CuI as catalyst
to yield the corresponding ketone and allyl derivatives.
In the absence of copper iodide catalyst, the above two
electrophiles gave only low yields of the expected prod-
ucts. 1,2-Dibromoethane was used to remove the excess
of magnesium when benzoyl chloride or allyl iodide was
used as electrophiles (entries 6 and 7) and it did not react
with the Grignard reagents under the given reaction
conditions.
Typ ica l P r oced u r e for th e P r ep a r a tion of th e Cor r e-
sp on d in g Gr ign a r d Rea gen ts. To an oven-dried 50 mL
centrifuge tube, equipped with a Teflon-coated magnetic stirring
bar and septum, was added, under an atmosphere of prepurified
argon, Mg* (3.0 mmol) in dry THF (5 mL) via syringe. This
mixture was cooled to -78 oC, and the organic substrate (1 mmol)
was added dropwise with stirring via syringe. After 15 min the
electrophile (1.1 mmol) was added in the same fashion at -78
o
oC. The temperature was increased to -40 C for the reaction of
the nitrile substrate with the benzoyl chloride and allyl iodide.
Reaction progress was monitored by gas chromatography of
hydrolyzed reaction aliquots. After
2 h, the reaction was
quenched with saturated aqueous NH4Cl. The aqueous layers
were extracted with diethyl ether three times. The organic layers
were then combined, dried with MgSO4, and filtered. The solvent
was removed under vacuum. The crude product obtained was
purified by flash chromatography.
P r epar ation of 1,1-Dim eth yleth yl 4-br om oben zoate (1a).6
Potassium tert-butoxide (3.4 g, 30 mmol) in ethyl ether (30 mL)
was added dropwise into a 100 mL flask containing ethyl ether
(50 mL) and 4-bromobenzoyl chloride (4.5 g, 32 mmol) in an ice
water bath. Almost immediately a white precipitate formed,
indicating the formation of KCl salt. After 1 h of reaction, the
mixture was washed with saturated NaHCO3 and saturated
NaCl. The organic layer was dried with MgSO4 and filteredd.
Removal of the solvent afforded a colorless oil (8.1 g, 95%) of
1a : Rf ) 0.72 (silica, 20% EtOAc in hexanes); IR (cm-1, CDCl3)
1727 (CdO), 1159 (C-O); 1H NMR (300 MHz, CDCl3) δ 1.59 (S,
9H), 7.54 (app d, J ) 8.6 Hz, 2H), 7.85 (app d, J ) 8.6 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 28.74, 81.84, 128.00, 131.50, 131.60,
132.03, 165.38; HREI (M)+ calcd for C11H1379BrO2 256.0099,
found C11H1379BrO2 256.0100.
Finally, bromochlorobenzene is also an adequate sub-
strate for this low-temperature chemistry (entry 8). We
tested several additives, such as Me2AlCl, LiBr, or
TMSCl, on an attemp to enhance the reactivity of the
resulting Grignard reagent. However, the presence of
these additional Lewis acids failed to increase the yields.
When ethyl alkylcarboxylates were used, i.e., ethyl
6-bromobenzoate, some Grignard reagent was formed at
o
-78 C along with two major nonidentified byproducts,
and some of the starting material still remained. From
these data, we can conclude that simple alkyl esters are
not suitable candidates for functionalized Grignard re-
agent preparation. Even when the functionalized Grig-
nard reagents were made, they reacted with the ester
group either in an intra- or intermolecular way. tert-Butyl
11-bromoundecanoate reacted with active magnesium to
afford excellent yields of the corresponding Grignard
reagent at -78 °C within 15 min, but the yield of reaction
with the benzaldehyde was poor (∼30%).
P r ep a r a tion of 4-Br om op h en yl 2,2-Dim eth ylp r op a n oa te
(1b). Trimethylacetyl chloride (6.3 g, 52 mmol) in ethyl ether
(30 mL) was added dropwise into a 100 mL flask containing ethyl
ether (50 mL), triethylamine (15.2 g, 150 mmol), and 4-bro-
mophenol (8.7 g, 50 mmol) in an ice water bath. Almost
immediately a white precipitate formed, indicating the formation
of triethylamine chloride salt. After 1 h of reaction, the mixture
was washed with dilute HCl and saturated NaHCO3. The
organic layer was dried with MgSO4 and filtered. Removal of
the solvent afforded a white solid (8.1 g, 95%) of 1b: mp 59-60
°C (Et2O); Rf ) 0.72 (silica, 10% EtOAc in hexanes); IR (cm-1
,
CDCl3) 1761 (CdO), 1125 (C-O); 1H NMR (300 MHz, CDCl3) δ
1.36 (s, 9H), 6.96 (app d, J ) 9.0, 2H), 7.49 (app d, J ) 9.0, 2H);
13C NMR (75 MHz, CDCl3) δ 27.04, 39.06, 118.58, 123.30, 132.34,
150.12, 176.71; HREI (M)+ calcd for C11H1379BrO2 256.0099,
found C11H1379BrO2 256.0100.
P r ep a r a tion of 3-Br om op h en yl 2,2-Dim eth ylp r op a n oa te
(1c). Trimethylacetyl chloride (3.9 g, 32 mmol) in ethyl ether
(30 mL) was added dropwise into a 100 mL flask containing ethyl
ether (50 mL), triethylamine (12.1 g, 120 mmol), and 3-bro-
mophenol (5.2 g, 30 mmol) in an ice water bath. Almost
immediately a white precipitate formed, indicating the formation
of triethylamine chloride salt. After 1 h of reaction, the mixture
was washed with dilute HCl and saturated NaHCO3. The
In summary, several functionalized Grignard reagents
containing an ester, nitrile, or chloride have been pre-
pared at low temperature and their reactivities were
studied. The reported procedures involving the use of
highly reactive magnesium expands the well-known
methodologies of Grignard reagent preparation.
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were recorded at 300
MHz, and 13C NMR spectra were recorded at 75 MHz. Internal
1
standards used in H NMR spectra were TMS (δ 0.00) and CDCl3
(δ 7.27) and in 13C NMR was the center peak of CDCl3 (δ 77.7).
Infrared spectra were obtained using an FTIR spectrometer as
(6) Taylor, E. C.; Ray, P. S. J . Org. Chem. 1988, 53, 35.

5430 J . Org. Chem., Vol. 65, No. 17, 2000
Notes
organic layer was dried with MgSO4 and filtered. Removal of
the solvent afforded a colorless oil (8.3 g, 97%) of 1c: Rf ) 0.72
(silica, 10% EtOAc in hexanes); IR (cm-1, CDCl3) 1757 (CdO),
1159(C-O); 1H NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 7.08-
7.14 (m, 2H), 7.30-7.36 (m, 1H), 7.59-7.62 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 27.12, 39.17, 116.11, 123.63, 127.01, 128.30,
133.24, 148.35, 175.90; HREI (M)+ calcd for C11H1379BrO2
256.0099, found C11H1379BrO2 256.0100.
P r ep a r a tion of 2,4-Dibr om op h en yl 2,2-Dim eth ylp r o-
p a n oa te (1d ). Trimethylacetyl chloride (3.9 g, 32 mmol) in ethyl
ether (30 mL) was added dropwise into a 100 mL flask contain-
ing ethyl ether (50 mL), triethylamine (12.1 g, 120 mmol), and
2,4-dibromophenol (8.0 g, 30 mmol) in an ice water bath. Almost
immediately a white precipitate formed, indicating the formation
of triethylamine chloride salt. After 1 h of reaction, the mixture
was washed with dilutr HCl and saturated NaHCO3. The organic
layer was dried with MgSO4 and filtered. Removal of the solvent
afforded a colorless oil (9.6 g, 95%) of 1d : Rf ) 0.65 (silica, 10%
EtOAc in hexanes); IR (cm-1, neat) 1755 (CdO), 1159(C-O); 1H
NMR (300 MHz, CDCl3) δ 1.39 (s, 9H), 6.98 (d, J ) 8.7 Hz, 1H),
7.44 (dd, J ) 8.7, 2.3 Hz, 1H), 7.75 (d, J ) 2.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 27.11, 39.26, 117.16, 119.13, 124.88, 131.40,
135.60, 147.68, 175.71; HREI (M)+ calcd for C11H1279Br2O2
333.9204, found C18H2079Br2O2 333.9204.
(m, 9H); 13C NMR (75 MHz, CDCl3) δ 27.05, 38.98, 75.59, 119.44,
120.44, 123.75, 126.63, 127.62, 128.46, 129.26, 143.31, 145.49,
151.10, 177.10; HREI (M)+ calcd for C18H20O3 284.1412, found
284.1414.
2,2-Dim eth yl-2-br om o-4-((h yd r oxyp h en yl)m eth yl)p h en -
ylp r op ion a te (2d ): Rf ) 0.42 (silica, 20% EtOAc in hexanes);
1
IR (cm-1, neat) 3499 (OH), 1755 (CdO), 1140 (C-O); H NMR
(300 MHz, CDCl3) δ 1.37 (s, 9H), 3.08 (br s, 1H), 5.66 (s, 1H),
6.99 (d, J ) 8.3 Hz, 1H), 7.21-7.34 (m, 6H), 7.58 (d, J ) 1.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 27.82, 39.92, 75.71, 116.75,
124.10, 127.23, 127.26, 128.58, 129.30, 131.91, 143.59, 143.70,
148.11, 176.97; HREI (M)+ calcd for C18H1979BrO3 362.0518,
found C18H1979BrO3 362.0519.
4-(Hyd r oxyp h en yl)m eth yl-ben zon itr ile (2e):7 1H NMR
(300 MHz, CDCl3) δ 3.13 (br s, 1H), 5.80 (s, 1H), 7.27-7.38 (m,
5H), 7.47 (app d, J ) 8.1 Hz, 2H), 7.56 (app d, J ) 8.1 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 76.16, 111.56, 119.56, 127.38,
127.71, 128.89, 129.52, 132.92, 143.52, 149.76.
4-Ben zoyl-ben zon itr ile (2f):8 1H NMR (300 MHz, CDCl3) δ
7.52 (app t, J ) 7.5, 2H), 7.65 (app t, J ) 7.5, 1H), 7.79 (app d,
J ) 7.5, 2H), 7.80 (app d, J ) 8.7, 2H), 7.88 (app d, J ) 8.7, 2H);
13C NMR (75 MHz, CDCl3) δ 116.32, 118.64, 129.27, 130.69,
130.87, 132.81, 133.95, 136.93, 141.84, 195.65.
4-(2-P r op en yl)-ben zon itr ile (2g):9 1H NMR (300 MHz,
CDCl3) δ 3.44 (d, J ) 6.6 Hz, 2H), 5.10 (dd, J ) 16.7, 1.5 Hz,
1H), 5.13 (dd, J ) 10.2, 1.5 Hz, 1H), 5.92(ddt, J ) 16.7, 10.2,
6.6 Hz, 1H) 7.29 (app d, J ) 8.4 Hz, 2H), 7.57 (app d, J ) 8.1,
2H); 13C NMR (75 MHz, CDCl3) δ 40.67, 110.53, 117.77, 119.56,
129.95, 132.75, 136.19, 146.22.
1,1-Dim eth yleth yl 4-((h yd r oxyp h en yl)m eth yl)ben zoa te
(2a ): mp 84-85 °C (EtOAc); Rf ) 0.51 (silica, 20% EtOAc in
hexanes); IR (cm-1, CDCl3) 3493 (OH), 1711 (CdO), 1162 (C-
O); 1H NMR (300 MHz, CDCl3) δ 1.59 (s, 9H), 3.06 (br s, 1H),
5.89 (s, 1H), 7.27-7.36 (m, 5H), 7.45 (app d, J ) 8.3 Hz, 2H),
7.96 (app d, J ) 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 28.86,
76.50, 81.74, 126.87, 127.33, 128.47, 129.28, 130.27, 131.67,
144.13, 149.06, 166.43; HREI (M)+ calcd for C18H20O3 284.1412,
found 284.1415.
4-Ch lor o-r-p h en ylben zen em eth a n ol (2h ):10 1H NMR (300
MHz, CDCl3) δ 3.05(br s, 1H), 5.60(s, 1H), 7.16-7.30 (m, 9H);
13C NMR (75 MHz, CDCl3) δ 76.17, 127.28, 128.53, 128.63,
129.28, 129.33, 133.90, 142.92, 144.10.
4-((Hyd r oxyp h en yl)m eth yl)p h en yl 2,2-d im eth ylp r op a n -
oa te (2b): Rf ) 0.48 (silica, 20% EtOAc in hexanes); IR (cm-1
,
Ack n ow led gm en t. We are grateful to the National
Science Foundation for support of this work.
CDCl3) 3493 (OH), 1756 (CdO), 1140 (C-O); 1H NMR (300 MHz,
CDCl3) δ 1.38 (s, 9H), 2.89 (br s, 1H), 5.75 (s, 1H), 7.03 (app d,
J ) 8.7 Hz, 2H), 7.36 (app d, J ) 8.7 Hz, 2H), 7.27-7.38 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 27.83, 39.76, 76.26, 122.09,
127.30, 128.28, 128.32, 129.18, 141.95, 144.36, 150.98, 177.90;
HREI (M)+ calcd for C18H20O3 284.1412, found 284.1409.
2,2-Dim eth yl-3-((h yd r oxyp h en yl)m eth yl)p h en ylp r op io-
J O000413I
(7) Uchiyama, M.; Kameda, M.; Mishima, O.; Yokoyama, N.; Koike,
M.; Kondo, Y.; Sakamoto, T. J . Am. Chem. Soc. 1998, 120, 4934.
(8) Rieke, R. D.; Klein, W. R.; Wu, T. J . Org. Chem. 1993, 58, 2492.
(9) Nakanishi, K.; Mizuno, K.; Otsuji, Y. Bull. Chem. Soc. J pn. 1993,
66, 2371.
(10) Pouchert, C. J . The Aldrich Library of NMR Spectra, 2nd ed.;
Aldrich Chemical Co.: Wisconsin, 1983; Vol. I, p 927A.
n a te (2c): Rf ) 0.46 (silica, 20% EtOAc in hexanes); IR (cm-1
,
CDCl3) 3490 (OH), 1750 (CdO), 1145 (C-O); 1H NMR (300 MHz,
CDCl3) δ 1.37 (s, 9H), 2.69 (br s, 1H), 5.78 (s, 1H), 6.96-7.36