Myers Magnesium-Halogen Exchange Chem 115

Review: • Unlike many lithium-halogen exchange protocols, only one equivalent of i-PrMgX is used
in typical experimental procedures.
Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.;
Ahn Vu, V. Angew. Chem., Int. Ed. Engl. 2003, 42, 4302.
• THF is the most common solvent. Ethyl ether has been employed as a solvent for
selective exchange of geminal dihalides to generate magnesium carbenoids.
General References on the Preparation and Reactions of Grignard Reagents:

Main Group Metals in Organic Synthesis, Yamamoto, H., Oshima, K., Eds.; John Wiley and
Sons: New York, 2004.
Handbook of Grignard Reagents, Silverman, G. S., Rakita, P. E., Eds.; Marcel Dekker:
New York, 1996.
• The reactivity of Grignard reagents is highly temperature dependant. Only highly reactive
electrophiles such as aldehydes and ketones react at significant rates below 0 °C. This
allows for the preparation of organomagnesium reagents containing cyano, nitro, ester,
and imine functional groups, provided that the rate of the exchange reaction is fast enough
to allow for exchange at temperatures below 0 °C.

Organomagnesium Methods in Organic Synthesis, Wakefield, B. J.; Academic Press:

San Diego, 1995. • The rate of magnesium-halogen exchange is accelerated by electron-withdrawing groups
on the aromatic ring, and is slowed by electron-donating groups:
Development and General Aspects:
I MgBr
RX + R'MgX' RMgX' + R'X i-PrMgBr
THF, –20 °C, 30 min
• Analogous to lithium-halogen exchange. The position of the equilibrium varies with the CO2CH3 CO2CH3
stabilities of the carbanion intermediates involved (sp >> sp2 >> sp3).
Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Ahn Vu, V.; Knochel, P.
Br Et2O MgBr + Synthesis 2002, 565.
+ EtMgBr EtBr
20 °C, 12 h
I MgBr

Prévost, C. Bull. Soc. Chim. Fr. 1931, 49, 1372. i-PrMgBr

THF, 25 °C, 1 h
• Although the first example was reported in 1931 (above), the preparation of Grignard
reagents via metal-halogen exchange has not been widely used until recently. Knochel and OCH3 OCH3
coworkers have demonstrated the functional-group tolerance of magnesium-halogen
exchange, which is now the method of choice for the preparation of highly functionalized Cali, P.; Begtrup, M. Synthesis 2002, 63.
organomagnesium reagents.
I MgCl
• i-PrMgCl or i-PrMgBr are the most common reagents. In most cases, these reagents can be
NO2 PhMgCl NO2
used interchangeably. i-PrMgBr is made by the Grignard reaction of isopropyl bromide
and magnesium turnings. It is less soluble than the chloride (solutions are ~0.8 M), and the
titre must be checked more often. i-PrMgCl is commercially available as a 2.0 M solution THF, –40 °C, 30 s
in THF or diethyl ether. NO2 NO2

• Solutions of i-PrMgX are titrated by the method of Paquette (Lin, H.-S.; Paquette, L. A. Synth. Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 1610.
Commun. 1994, 24, 2503.) According to this procedure, a flame-dried flask is charged with
menthol (a non-hygroscopic solid), 1,10-phenanthroline (indicator) and THF. The Grignard
reagent is then added until a distinct violet or burgundy color persists.

Jason Brubaker

1
• Aryl bromides undergo exchange more slowly than iodides, but electron-poor aryl bromides • Dibromides undergo regioselective exchange of the bromine ortho- to a chelating group.
can still react at temperatures below 0 °ˇC. Note also the compatibility of the amidine group with the exchange reaction.
I MgBr
i-PrMgBr N(CH3)2 N(CH3)2 N(CH3)2
CHO
–40 °C, 30 min N N N OH
NC Br i-PrMgBr NC MgBr Bu NC Bu
Br Br
THF, –10 °C, 1.5 h
Br Br Br
Bomond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1998, 37,
1701. 68%

Br MgBr Varchi, G.; Jensen, a. E.; Dohle, W.; Ricci, A.; Cahiez, G.; Knochel, P. Synlett 2001, 477.
F F i-PrMgBr F F

–78 °C, 30 min • Higher temperatures are required for the selective exchange with less effective chelators.
F F F F
F F OCH3 OCH3 OCH3
Br MgBr CO2H
Br MgBr i-PrMgCl CO2
F i-PrMgBr F
THF, 40 °C, 5 h
–10 °C, 1 h Br Br Br
F F
90%
F F
Nishiyama, H.; Isaka, K.; Itoh, K.; Ohno, K.; Nagase, H.; Matsumoto, K.; Yoshiwara, H.
Br MgBr J. Org. Chem. 1992, 57, 407.
F i-PrMgBr F

23 °C, 2 h Functional Groups Compatible with the Magnesium-Halogen Exchange:

F F
• Ester, benzylic chloride:
Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449. CO2CH3 CO2CH3 CO2CH3
Cl i-PrMgBr PhN C O
Cl
Ortho- Directing Groups: THF, –30 °C, 1 h –10 °C → 23 °C NPh
I MgBr
O
75%
• The presence of a chelating ortho- group facilitates exchange, increases the rate of
reaction, and allows for low-temperature exchange.
Delacroix, T.; Berillon, L.; Cahiez, G.; Knochel, P. J. Org. Chem. 2000, 65, 8108.
Et
O • Secondary alkyl tosylate:
Br BrMg
Br OTs
OCH2OEt i-PrMgBr O OCH2OEt O
O i-PrMgCl CuCN·2LiCl
CH3
THF, –30 °C, 2 h CuCN 2LiCl
NC NC NC THF, –20 °C, 1 h –20 → 25 °C EtO2C
EtO2C I
80% CH3
83%
Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Kneisel, F. F.; Monguchi, Y.; Knapp, K. M.; Zipse, H.; Knochel, P. Tetrahedron 2002, 43,
Ahn Vu, V. Angew . Chem., Int. Ed. Engl. 2003, 42, 4302. 4875.

Jason Brubaker

2
 • Unprotected anilines:
• Nitrile:
OH NH2 CHO
NHMgCl NH2 OH
NC I i-PrMgBr NC MgBr PhCHO NC
Ph I I 1. PhMgCl I MgCl I Bu
–30 °C, 5 min Bu
THF, –40 °C, 30 min
2. i-PrMgCl
89% –25 °C, 10 min
CN CN CN
• Tertiary amide: 71%
Varchi, G.; Kofink, C.; Lindsay, D. M.; Ricci, A.; Seconi, G.; Knochel, P. Chem. Commun. 2003, 396.
O O
Br
N i-PrMgBr • In the above example, phenyl magnesium chloride is first added because it is a strong
N
THF, –25 °C, 30 min base and as a magnesium-halogen exchange reagent it is less reactive than i-PrMgX.
I This allows for quantitative deprotonation before exchange.
81%
• Heteroaromatics:
Bomond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1998, 37,
1701. Conditionsa
Heterocycle (°C, h) Electrophile Product Yield (%)
• Amidine, note also the selective exchange of a diiodide:
Br
F F CO2Et
N(CH3)2 N(CH3)2 –40, 0.5 F F 80
N(CH3)2 Br
N N N F N F (CuCN added) F N F
I I i-PrMgBr I MgBr 1. CuCN·2LiCl
I
O
–20 °C, 5 min 2. S S OH
CH3 CH3 Br 25, 1.5 PhCHO 75
I O N N Ph
CO2Et CO2Et CO2Et
87%
Br Br Br CO2Et
Varchi, G.; Jensen, A. E.; Dohle, W.; Ricci, A.; Cahiez, G.; Knochel, P. Synlett 2001, 477. O
OEt –20, 1 OEt 59
N N N N
NC OEt
• Imine: CH3 CH3
I MgBr
i-PrMgBr 1. BiCl3 O OH
2. SiO2 Bi Br N Br –5, 1 PhCHO Br N 73
THF, 25 °C H Ph
3 Bn Bn
N N 34%
iPr iPr
–30, 1 Br 80
Br O CO2Et CO2Et
Murafuji, T.; Nishio, K.; Nagasue, M.; Tanabe, A.; Aono, M.; Sugihara, Y. Synthesis 2000, 1208. (CuCN added) O

a
• Imines can be used to mask aryl aldehydes during the magnesium halogen exchange. The i-PrMgBr (1.2 equiv), THF
low yield of the reaction sequence above is likely attributable to the second step of the
procedure. Abarbi, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449.

Jason Brubaker

3
• Nitro arenes:
• Nitro-substituted organometallic reagents are difficult to prepare through classical
NO2 NO2 NO2 methods. These electron-deficient arenes tend to undergo electron-transfer reactions,
I MgCl E
and direct oxidative addition with elemental magnesium or zinc often leads to reduction of
PhMgCl E+ the nitro group. This new procedure is the best method to date for the preparation of
FG FG FG nitroarene organometallics.
–40 °C, 5 min

• The nitro group must be ortho to the iodide exchanged. Meta- and para-nitro substituted
Nitro arene Electrophile Product Yield (%) aryl iodides give complex mixtures.

NO2 NO2 OH • PhMgCl is necessary for a successful reaction. More reactive Grignard reagents such as
I i-PrMgCl give complex mixtures.
PhCHO Ph 87
• For successful reactions with reactive electrophiles such as allyl bromides and acid halides,
transmetallation of the organomagnesium intermediate with CuCN·2LiCl is necessary.
NO2 NO2 OH
• Pd-catalyzed Negishi cross-coupling reactions are possible after transmetallation with
I
ZnBr2:
PhCHO Ph 94
O
NO2 CO2Et 1= P
1. mesitylMgBr, –40 °C, 5 min NO2
3
CN CN I 2. ZnBr2, –40 °C, 5 min
NO2 3. Pd(dba)2 (5 mol %) CO2Et
NO2 OH
NC 1 (10 mol %), 2 (1.5 equiv) NC 2=
I
Ph –40 → 23 °C, 3 h 73% I
PhCHO 72

CH3O CH3O • In the case above, mesityl magnesium bromide is used to prevent competing oxidative
NO2 NO2 OH addition of the aryl iodide generated in the magnesium-iodide exchange reaction.
I
cHexCHO cHex 64
Magnesium-Halogen Exchange of Vinyl Iodides:
EtO2C EtO2C
1. i-PrMgBr, THF
NO2 NO2 O 25 °C, 18 h
Ph
I I 2. PhCHO
PhCOBr Ph 76 OH
60%
EtO2C EtO2C
1. i-PrMgBr, THF Ph
Ph –70 °C, 12 h CH3O
NO2 NO2 OH CH3O
Ph
I 2. PhCHO
PhCHO Ph 81 I
OH
O2N O2N 95%
NO2
NO2 Rottlander, M.; Boymond, L.; Cahiez, G.; Knochel, P. J. Org. Chem. 1999, 64, 1080.
CO2Et
I
Br • Vinyl Iodides are also suitable substrates for magnesium-halogen exchange. Higher
CO2Et 74
O2N temperatures and longer reaction times are required, which limits the functional-
I group tolerance of this method.

Sapountzis, Ioannis; Knochel, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 1610. • When the vinyl iodide is substituted with electron-withdrawing groups or chelating
heteratoms, the rate of exchange is enhanced.

Jason Brubaker

4
Alternative, More Reactive Reagent Combinations for Magnesium-Halogen Exchange: • Enhanced Reactivity by Addition of Lithium Chloride to i-PrMgCl prior to exchange (1 equiv):

• Lithium Trialkyl Magnesium Ate Complexes: OH

Br 1. i-PrMgCl·LiCl
THF, 0 °C, 2 h Ph

OH NC 2. PhCHO NC
1. Bu3MgLi (1.2 equiv)
I 81%
THF, –78 °C, 0.5 h C6H13
2. C6H13CHO Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2004, 43, 3333.
CH3O CH3O
94%
1. i-PrMgCl·LiCl
THF, –40 °C, 7 h
C6H13 C6H13 O
Br 1. Bu3MgLi (1.2 equiv) I
THF, 0 °C, 0.5 h 2. DMF
H
2. 71%
CH3O Br CH3O
84%
1. i-PrMgCl·LiCl
I THF, –40 °C, 7 h
I
2. EtCHO
Br 1. i-PrBu2MgLi (1.2 equiv) I OH
THF, –78 °C, 1 h
t-BuO Et
t-BuO 2. Br 84%
O CuCN·2LiCl O 66%
Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215.

• Addition of LiCl to the Grignard reagent produces a more active magnesium-halogen

1. i-PrBu2MgLi (1.2 equiv)
THF, 0 °C, 1 h
exchange reagent
C10H21 C10H21
I TMS
2. TMSCl • It has been proposed that LiCl breaks up aggregates of organomagnesium reagents.
93%
• This more active reagent combination is successful in the exchange of the ortho-phenoxy
aryl iodide shown below:
Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333.

• The lithium trialkyl magnesiates are prepared in situ by the addition of an alkyl lithium CO2Et 1. CH3MgCl, LiCl
(2 equiv) to an alkyl magnesium halide (1 equiv). THF, –30 °C, 0.5 h CO2Et
2. i-PrMgCl
–30 °C, 0.5 h
• Magnesiates exhibit a reactivity somewhere between alkyllithium and alkylmagnesium Ph
I 3. PhCHO
reagents.
OH
• The exchange reaction is faster and less sensitive to electronic effects (arene substitution). OH OH
62%
• In accord with their greater reactivity, aryl magnesiates show less funtional group tolerance.
Kopp, F.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2004, 2288.

Jason Brubaker