Magnesium-mediated carbon-carbon bond formation in aqueous media: Barbier-Grignard allylation and pinacol coupling of aldehydes

Article abstract of DOI:10.1021/jo982497p

Magnesium-mediated Barbier-Grignard type alkylation of aldehydes with alkyl halides was studied in aqueous media. The reaction of aromatic aldehydes with allyl halides is highly effective with either THF or water as the reaction solvent but poor in a mixture of THF/water. It was found that the magnesium-mediated allylation of aldehydes with allyl bromide and iodide proceeds effectively in aqueous 0.1 N HCl or 0.1 N NH₄Cl. Aromatic aldehydes reacted chemoselectively in the presence of aliphatic aldehydes. An exclusive selectivity was also observed when both aliphatic and aromatic aldehyde functionalities are present in the same molecule. In the absence of allyl halides, aldehydes and ketones reacted with magnesium in aqueous 0.1 N NH₄Cl to form the corresponding pinacol coupling products in high yields. The effectiveness of the pinacol reaction was strongly influenced by the steric environment surrounding the carbonyl group. Aliphatic aldehydes and simple alkyl halides appear inert under the reaction conditions for either alkylation or the pinacol coupling reaction.

Full text of DOI:10.1021/jo982497p

3
230
J . Org. Chem. 1999, 64, 3230-3236
Ma gn esiu m -Med ia ted Ca r bon -Ca r bon Bon d F or m a tion in
Aqu eou s Med ia : Ba r bier -Gr ign a r d Allyla tion a n d P in a col
Cou p lin g of Ald eh yd es
Wen-Chun Zhang and Chao-J un Li*
Department of Chemistry, Tulane University, New Orleans, Louisiana 70118
Received December 23, 1998
Magnesium-mediated Barbier-Grignard type alkylation of aldehydes with alkyl halides was studied
in aqueous media. The reaction of aromatic aldehydes with allyl halides is highly effective with
either THF or water as the reaction solvent but poor in a mixture of THF/water. It was found that
the magnesium-mediated allylation of aldehydes with allyl bromide and iodide proceeds effectively
in aqueous 0.1 N HCl or 0.1 N NH Cl. Aromatic aldehydes reacted chemoselectively in the presence
4
of aliphatic aldehydes. An exclusive selectivity was also observed when both aliphatic and aromatic
aldehyde functionalities are present in the same molecule. In the absence of allyl halides, aldehydes
4
and ketones reacted with magnesium in aqueous 0.1 N NH Cl to form the corresponding pinacol
coupling products in high yields. The effectiveness of the pinacol reaction was strongly influenced
by the steric environment surrounding the carbonyl group. Aliphatic aldehydes and simple alkyl
halides appear inert under the reaction conditions for either alkylation or the pinacol coupling
reaction.
In tr od u ction
Carbon-carbon bond formation is the essence of or-
concerns, the use of water as a solvent for metal-mediated
carbon-carbon bond formations has generated consider-
able interest. Within the last several years, various
ganic synthesis. One of the most important steps in the
history of modern chemistry was the introduction by
metals have been developed to mediate Barbier-Grig-
nard type reactions.9 For a long time, we have been
1
Barbier and Grignard about a century ago of magnesium
intrigued by the possibility of performing classical Bar-
bier-Grignard reactions by using magnesium in water.
The study would possibly extend the scope of the aqueous
metal reaction and increase the understanding of the
mechanism of both the classical Barbier-Grignard and
the aqueous metal reactions. However, in view of the high
reactivity of organomagnesium reagents toward water
and moisture, it is doubtful that magnesium can be used
for such a purpose. Nevertheless, recently we observed
that the reaction of benzaldehyde with allyl iodide is also
2
for carbon-carbon bond formations through the addition
of an organometallic reagent to a carbonyl group. The
further study of magnesium-based reactions also sparked
the development of new reagents based on electronically
more negative and more positive metals, as well as
semimetallic elements for various synthetic purposes to
tailor reactivities and selectivities (chemo, regio, and
3
stereo). For carbonyl additions based on organomagne-
sium reagents, it is generally accepted that strict anhy-
drous reaction conditions are required for a smooth
4
highly effective in both aqueous 0.1 N NH Cl and dry
4
reaction. The presence of moisture delays the initiation
10
THF as the reaction solvent. This unusual observation
led us to examine the aqueous reaction mediated by
magnesium in detail. Historically, the allylation of car-
bonyl compounds with an organomagnesium reagent had
not been well-established for decades until Gilman and
McGlumphy developed a new procedure to prepare Grig-
nard reagents from allylic halides.11 Herein, we report
the studies of using magnesium for Barbier-Grignard
allylation and pinacol coupling of aldehydes in water.
and/or inhibits the reaction. Various methods, such as
5
dibromoethane or iodine initiators, mechanical activa-
6
7
tion, ultrasonic irradiations, and more recently, acti-
vated magnesium have been developed to help initiate
8
the reaction. Because of economical and environmental
(
1) Barbier, P. Compt. Rend. 1898, 128, 110. Barbier, P. J . Chem.
Soc. 1899, 76, Pt. 1, 323. Grignard, V. Compt. Rend. 1900, 130, 1322.
2) Kharasch, M. S.; Reinmuth, O. Grignard Reactions of Nonmetal-
lic Substances; Prentice-Hall: New York, 1954.
3) For representative monographs and reviews, see: Wakefield, B.
(
(
(8) For reviews, see: Rieke, R. D. Science 1989, 246, 1260. Bogdanov-
ic, B. Acc. Chem. Res. 1988, 21, 261. For a review on graphite-metal
compounds, see: Csuk, R.; Glanzer, I.; Furstner, A. Adv. Organomet.
Chem. 1988, 28, 85.
(9) For reviews, see: Li, C. J .; Chan, T. H. Organic Reactions in
Aqueous Media; J ohn Wiley & Sons: New York, 1997. Li, C. J .
Tetrahedron 1996, 52, 5643. Chan, T. H.; Isaac, M. B. Pure Appl. Chem.
1996, 68, 919. Lubineau, A.; Auge, J .; Queneau, Y. Synthesis 1994,
741. Lubineau, A.; Auge, J .; Queneau, Y. In Organic Synthesis in Water;
Grieco, P. A., Ed.; Blackie Academic & Professional: London, 1998.
Paquette, L. A. In Green Chemistry-Frontiers in Benign Chemical
Syntheses and Processes; Anastas, P. T., Williamson, T. C., Eds.; Oxford
University Press: New York, 1998. Li, C. J . ibid. Li, C. J . Chem. Rev.
1993, 93, 2023.
J . Organomagnesium Methods in Organic Synthesis, Best Synthetic
Methods series; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Academic Press: San Diego, 1995. Blomberg, C. The Barbier Reaction
and Related One-Step Processes; Springer-Verlag: New York, 1993.
Lai, Y. H. Synthesis 1981, 585. Courtois, G.; Miginiac, L. J . Organomet.
Chem. 1974, 69, 1. Normant, H. Adv. Org. Chem. 1960, 2, 1. Ioffe, S.
T.; Nesmeyanov, A. N. The Organic Compounds of Magnesium,
Beryllium, Calcium, Strontium and Barium; North-Holland: Amster-
dam, 1976.
(4) Wakefield, B. J . Organomagnesium Methods in Organic Syn-
thesis, Best Synthetic Methods series; Katritzky, A. R., Meth-Cohn, O.,
Rees, C. W., Eds.; Academic Press: San Diego, 1995.
(5) Pearson, D. E.; Cowan, D.; Beckler, J . D. J . Org. Chem. 1959,
2
4, 504.
(10) Li, C. J .; Zhang, W. C. J . Am. Chem. Soc. 1998, 120, 9102.
(11) Gilman, H.; McGlumphy, J . H. Bull. Soc. Chim. Fr. 1928, 43,
1322.
(6) Shaw, M. C. J . Appl. Mechanics 1948, 15, 37.
7) Sprich, J . D.; Lewandos, G. S. Inorg. Chim. Acta 1983, 76, L241.
(
1
0.1021/jo982497p CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/30/1999

Mg-Mediated C-C Bond Formation in Aqueous Media
J . Org. Chem., Vol. 64, No. 9, 1999 3231
Ta ble 1. Ma gn esiu m -Med ia ted Ba r bier -Gr ign a r d Allyla tion of Ben za ld eh yd e in Va r iou s Solven tsa
entry
allyl halide
solvent
mediator
3/4/benzyl alcohol (%)
conversion (%) of aldehyde
1
2
3
4
5
6
7
8
9
allyl bromide
allyl bromide
allyl bromide
allyl bromide
allyl bromide
allyl bromide
allyl bromide
allyl bromide
allyl iodide
THF/H2O (10:0.04)
THF/H2O (10:0.2)
THF/H2O (10:0.55)
THF/H2O (10:0.67)
THF/H2O (10:0.7)
H2O
0.1 N HCl
0.1 N NH4Cl
0.1 N NH4Cl
Mg/I2
Mg/I2
Mg/I2
Mg/I2
Mg/I2
Mg/I2
Mg/I2
Mg
100/0/0
100/0/0
98/0/0
9/43/4
0/0/0
13/2/1
28/66/6
41/52/7
58/34/8
quantitative
quantitative
98
56
0
16
quantitative
quantitative
quantitative
Mg
a
Entries 1-6, benzaldehyde:allyl halide:magnesium ) 1:3:20. Entries 7-9, benzaldehyde:allyl halide:magnesium ) 1:3:10 (the use of
a stoichiometric amount of magnesium resulted in a low conversion).
Resu lts a n d Discu ssion
Sch em e 1
To start our investigation, we stirred allyl bromide with
benzaldehyde and magnesium turnings in aqueous 0.1
N HCl for 3 h at room temperature. TLC measurement
of the ether extract clearly showed a spot that cor-
responded to the desired allylation product. Subse-
reactions, but in the present study, the use of a catalytic
amount of various Lewis acids, such as InCl or Sc(OTf) ,
3 3
1
quently, H NMR measurement of the crude reaction
did not significantly affect the reaction.13 However,
changing the allyl bromide to allyl iodide further in-
creased the formation of the allylation product (58%).
Only a minute amount of the allylation product was
observed with allyl chloride. In the absence of 0.1 N HCl,
mixture showed about 28% of the allylation product (3),
together with 66% pinacol coupling product (4)12 and 6%
benzyl alcohol. This promising result prompted us to
examine factors that influence the reaction. Subse-
quently, we have examined in greater detail the effect of
the solvent system on the magnesium reaction by using
various combinations of water and THF as the reaction
solvent, together with a small amount of iodine to initiate
the reaction. To reflect the composition of the product
mixture, we extracted the reaction mixture with diethyl
ether after each reaction, dried the combined organic
layers over magnesium sulfate, and carefully removed
the low-boiling solvent in vacuo. In the case where no
organic cosolvent was involved, the reaction mixture was
0
4
.1 N NH Cl, or iodine, virtually no reaction was observed
with allyl bromide. Subsequent experiments also revealed
that in water alone and with iodine as the initiator, the
reaction of allyl bromide proceeded through an allyl
iodide intermediate (Scheme 1). The formation of such
an allyl iodide intermediate, however, is not necessary
4
in aqueous 0.1 N NH Cl or 0.1 N HCl.
To explain the unusual phenomenon of the solvent
change, we postulate that in freshly dried THF, the
normal reaction occurs between the organic halide and
magnesium, generating the magnesium reagent. Subse-
quent reaction with carbonyl compounds generates the
allylation product. However, in a homogeneous mixture
of THF and water, the water molecules would be evenly
distributed throughout the solution; hence, the contact
between water and the metal surface would prohibit the
formation of the organomagnesium reagent. The solvent
with ca. 7% water may correspond to the point where
the surface is completely covered by water molecules.
With water alone, allyl bromide might be squeezed onto
3
extracted with CDCl and the extract was examined
1
directly. H NMR measurements of the reaction products
under various solvent combinations revealed a very
interesting phenomenon. The results are listed in Table
1
. In freshly distilled THF dried over sodium/benzophe-
none, the reaction between benzaldehye, allyl bromide,
and magnesium turnings together with a small amount
of iodine occurred almost quantitatively, generating the
expected allylation product. The addition of a small
amount of water to the freshly dried THF did not affect
the progress of the reaction. The expected reaction
proceeded effectively until about 7% water in THF was
used, which suddenly blocked the reaction progress. After
repeating this several times, we identified a midpoint at
which ca. 56% conversion of the starting benzaldehyde
was observed. However, when the composition of the
solvent is changed to water alone, a smooth reaction
started again, generating the allylation product albeit
with a low conversion. The low conversion could be
attributed to the formation of magnesium hydroxide on
the metal surface, which blocks further reactions. Sub-
1
4
the metal surface as a result of hydrophobic effect.
Locally and microscopically, magnesium would not be in
direct contact with water but would be in contact with
allyl bromide. The formation of allylmagnesium can thus
occur as in dry organic solvents, which leads to the
generation of allylation products.
Subsequently, a variety of aldehydes were tested with
this allylation method (eq 1), and the results are listed
in Table 2.
4
sequently, by using aqueous 0.1 N HCl or 0.1 N NH Cl
as the reaction solvent, a quantitative conversion was
observed that generated a mixture of the allylation and
pinacol coupling products. The use of aqueous 0.1 N NH
Cl as the solvent was found to be superior to the use of
.1 N HCl. Recently, various Lewis acids have been
reported to mediate aqueous Barbier-Grignard type
4
-
0
(13) For representing examples of using InCl
type reactions, see: Li, X. R.; Loh, T. P. Tetrahedron: Asymmetry 1996,
, 1535. For examples of using other Lewis acids for aqueous Barbier-
3
in aqueous Barbier-
7
type reactions, see: Kobayashi, S. In Organic Synthesis in Water;
Grieco, P. A., Ed.; Blackie Academic & Professional: London, 1998.
(14) Tanford, C. The Hydrophobic Effect: Formation of Micelles and
Biological Membranes, 2nd ed.; J ohn Wiley & Sons: New York, 1980.
Breslow, R. Acc. Chem. Res. 1991, 24, 159.
(
12) For a recent review on pinacol coupling, see: Wirth, T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 61. Robertson, G. M. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1991;
Vol. 3, Chapter 2.6.

3
232 J . Org. Chem., Vol. 64, No. 9, 1999
Ta ble 2. Allyla tion Rea ction Med ia ted by Ma gn esiu m in Aqu eou s Med iu m
Zhang and Li
It was found that various aromatic aldehydes are
allylated efficiently by allyl halides and magnesium in
aqueous 0.1 N NH Cl. It is noteworthy to mention that
aromatic aldehydes bearing various halogens were ally-
lated without any problem (entries 2-8). The allylations
of hydroxylated aldehydes also gave the allylation prod-
ucts in good yields (entries 9 and 11). Reaction of
potentials between aliphatic and aromatic aldehydes.15
Such a reactivity difference between an aromatic alde-
hyde and an aliphatic aldehyde suggests a useful chemose-
lectivity of the aqueous magnesium reaction.
To further investigate this, competitive studies were
carried out between an aliphatic and an aromatic alde-
hyde (eq 2). Under the standard reaction conditions, a
4
4
-hydroxybenzaldehyde under the standard conditions
led to the formation of the allylation product. The high
electron density of hydroxylated benzene led to formation
of some ether product (entry 11), which was reflected by
the decreased isolated yield. It is interesting to note that
although the allylation of 3-methoxybenzaldehyde was
equally successful (entry 12) in this reaction, the allyla-
tion of a similar substrate, 4-methoxybenzaldehyde, gave
the desired product in a much lower yield (entry 13). This
could be attributed to the difference in the reduction
potential of these two aldehydes. However, the reaction
of a cyano-substituted aldehyde gave rise to the formation
of a benzyl alcohol product almost in quantitative yield
(entry 14). This indicates that a delicate tuning of the
reduction potential of the aldehyde is needed in the
magnesium reaction. Instead of forming the correspond-
ing allylation product, a dark powder was generated in
the reaction of phthalic dicarboxaldehyde with ally iodide
single allylation product was generated when a mixture
of different aliphatic aldehydes (e.g., hexaldehyde, hept-
(15) The reduction potentials of aldehydes are affected by many
4
and magnesium in 0.1 N NH Cl, which appears to be a
factors. Under similar conditions, the half wave reduction potentials
of aliphatic aldehydes are more negative than those of aromatic
polymer as it is insoluble in any organic or inorganic
solvent (entry 15). In contrast, aliphatic aldehydes are
inert under the reaction conditions (entries 16-18). The
result could be attributed to the difference in reduction
3
aldehydes; for example, CH CHO (EtOH, pH ) 8, E1/2 ) -1.7 eV),
PhCHO (EtOH, pH ) 8, E1/2 ) -1.4 eV), see: Meites, L.; Zuman, P.
CRC Handbook Series in Organic Electrochemistry, Vol I-V; CRC
Press: Boca Raton, FL, 1977-1982.

Mg-Mediated C-C Bond Formation in Aqueous Media
J . Org. Chem., Vol. 64, No. 9, 1999 3233
aldehyde, or octaldehyde) and benzaldehyde was reacted
with allyl iodide. Such a selectivity appears similar to
our recently reported manganese-copper method.16 Aque-
Sch em e 2. Ra tion a le for Ma gn esiu m -Med ia ted
Ca r bon -Ca r bon Bon d F or m a tion in Wa ter via
Alexa n d er ’s Equ ilibr iu m
1
7
18
ous methodologies mediated by other metals (Zn, Sn,
1
9
and In ) all generated a 1:1 mixture of allylation
products of both aldehydes. As a comparison, a 1:1
mixture of products was also generated when the ally-
lation was performed with allylmagnesium bromide in
ether.
An intramolecular discrimination study was also car-
ried out on a compound bearing both aromatic and
aliphatic carbonyl groups. Allylation of dialdehyde 516
under the identical conditions mediated by magnesium
resulted in 50% yield of the allylation product 616 (eq 3).
A complete chemoselectivity20 was observed in which the
allylation only occurred on the aromatic carbonyl. This
result again resembles the manganese-copper method.
The use of terminally substituted ally halides, e.g.,
Young and Roberts25 (represented by the symbol S
The radical intermediate could lead to the formation of
2′).26
E
1
-chloro-2-butene, 3-methyl-1-chloro-2-butene, cinnamyl
27
1
,6-hexadiene, pinacol product, and benzyl alcohol.
To gain mechanistic information on the present reac-
chloride, and ethyl 4-bromocrotonate, generated a com-
plicated mixture of products which again resembled the
Mn-Cu reaction.16 In addition, the possibility of reactions
tion, several experiments were performed, which can be
generalized as follows: (1) The allylation process in
between aldehydes and alkyl halides, e.g., CH
3
I and
aqueous 0.1 N NH
mixture was extracted with CDCl
4
Cl was interrupted. The reaction
C
2
H
5
I, was also examined by using magnesium as a
1
3
, and a H NMR
mediator in water. The reactions did not generate the
alkylation product but gave mainly the pinacol products.
The mechanism of the classical magnesium-mediated
spectrum was taken directly. The measurement shows
the formation of the three products (allylation, pinacol,
and benzyl alcohol), reflecting our previous experiments.
Barbier and Grignard reactions have been studied in-
In addition, 1,5-hexadiene was clearly formed. No pro-
tensively by several groups.2
1,22
It is generally believed
pene formation was detected with 1H NMR. However,
that the radicals on the metal surface are involved in the
organomagnesium reagent formation.21 There is still no
conclusion as to the freedom of these free radicals.22 For
the Barbier allylation of carbonyl compounds with mag-
nesium in anhydrous solvent, it is believed that the
reaction of allyl bromide on the metal surface generates
an organometallic intermediate that is in equilibrium
with the charge-separated form and the radical form, as
proposed by Alexander (Scheme 2).23 These two forms will
also lead to either the protonation of the carbanion
GC-MS analysis of the gaseous component collected
during the reaction did reveal the presence of propene.
(2) Aliphatic aldehydes do not react under the present
reaction conditions, which implies that the reduction
potential of the aldehyde is important. (3) Although the
allylation products can also be observed by using allyl
chloride in these types of reactions, it is not as reactive
as either allyl bromide or allyl iodide. No reaction was
observed with nonactivated alkyl halides. For that mat-
ter, halogen substituents on the aromatic rings did not
complicate the reaction. This implies that the reduction
potential of the halide is also critical to the reaction. On
the basis of these observations, we propose an alternative
mechanism (Scheme 3) for the aqueous magnesium
reaction. The transfer of electrons from magnesium to
the allyl halide (path a), the aldehyde (path b), or both
generates the corresponding radical anions 7 and 8. Then,
reaction of either 7 with the aldehyde or 8 with the allyl
halide generates the corresponding allylation product 3.
(
overall reduction of the halide) or Wurtz-type coupling,24
whereas the intermediate reacts with aldehydes through
the usual six-membered ring mechanism, as proposed by
(16) Li, C. J .; Meng, Y.; Yi, X. H.; Ma, J . H.; Chan, T. H. J . Org.
Chem. 1997, 62, 8632. Li, C. J .; Meng, Y.; Yi, X. H.; Ma, J . H.; Chan,
T. H. J . Org. Chem. 1998, 63, 7498.
(
17) Nokami, J .; Otera, J .; Sudo, T.; Okawara, R. Orgnometallics
1
983, 2, 191.
(
(
(
(
18) Petrier, C.; Luche, J . L. J . Org. Chem. 1985, 50, 910.
19) Li, C. J .; Chan, T. H. Tetrahedron Lett. 1991, 32, 7017.
20) Trost, B. M. Science 1985, 227, 908.
21) Gomberg, M.; Bachmann, W. E. J . Am. Chem. Soc. 1927, 49,
2
36.
(24) For a recent review, see: Billington, D. C. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 1.
(25) Young, W. G.; Roberts, J . D. J . Am. Chem. Soc. 1946, 68, 1472.
(26) Felkin, H.; Roussi, G. Tetrahedron Lett. 1965, 4153. Benkeser,
R. A.; Broxterman, W. E. J . Am. Chem. Soc. 1969, 91, 5162. Sakurai,
H.; Kudo, Y.; Miyoshi, H. Bull. Chem. Soc. J pn. 1976, 49, 1433.
(27) Ashby, E. C.; Goel, A. B. J . Am. Chem. Soc. 1977, 99, 310.
(22) Lawrence, L. M.; Whitesides, G. M. J . Am. Chem. Soc. 1980,
1
1
02, 2493. Walborsky, H. M.; Zimmermann, C. J . Am. Chem. Soc. 1992,
14, 4996. Walling, C. Acc. Chem. Res. 1991, 24, 255. Garst, J . F. Acc.
Chem. Res. 1991, 24, 95. Walborsky, H. M. Acc. Chem. Res. 1990, 23,
86.
23) Alexander, E. R. Principles of Ionic Organic Reactions; J ohn
Wiley & Sons: New York, 1950; p 188.
2
(

3
234 J . Org. Chem., Vol. 64, No. 9, 1999
Zhang and Li
Sch em e 3. Alter n a tive Ra tion a le for Ma gn esiu m -Med ia ted Ca r bon -Ca r bon Bon d F or m a tion in Wa ter
The allylation product can also be formed between the
radical anions 7 and 8. Reaction of 7 with the allyl halide
gives the Wurtz-coupling product 10; reaction of 8 with
the aldehyde gives pinacol product 4. The reaction of
these radical anions with water led to the corresponding
reduced products 9 and 11.
In42 have also been found to promote the aqueous reaction
under ultrasonic radiation and manganese in acidic
conditions.1
5,16
When benzaldehyde was reacted with
Cl, the corresponding
magnesium in aqueous 0.1 N NH
4
pinacol coupling product was obtained in high yield. The
use of water alone as the reaction solvent was also
effective; however, it resulted in a low conversion of the
starting material. The use of aqueous 0.1 N HCl as
solvent also decreased the yield of the desired pinacol
coupling products. Other aryl aldehydes (eq 4) were
The encouraging results obtained from the allylation
reaction led us to investigate the pinacol coupling reac-
2
8
tion mediated by magnesium under aqueous conditions.
Although discovered well over a century ago, the pinacol
coupling reaction is still one of the most important
reactions for the formation of carbon-carbon bonds.12
Traditionally, pinacol couplings have been effected by
2
9
30
using metals such as sodium, lithium, or magnesium-
(
I) iodide21 (and Rieke Mg ) under strictly anhydrous
31
conditions. Other reagents used for such a reaction
3
2
33
34
35
include chromium or vanadium, SmI
2
38
,
Ce-I
SnH,36 Al(Hg), and Rieke Mn, as well as the
3
2
,
Yb,
coupled similarly to obtain the corresponding diols 2
37
Bu
versatile TiCl
(Table 3). Aromatic aldehydes bearing halogens (bromo,
3
-based reducing agents (the McMurry
chloro, fluoro) were coupled without any complication in
product formation. Furfural coupled equally well under
the reaction conditions. The couplings of aryl ketones
were also successful (entries 15 and 16). An aliphatic
aldehyde, however, was inert under the reaction condi-
tions (entry 11). The magnesium-mediated pinacol cou-
pling in water appears strongly affected by steric effects.
The position of the substituents present on the aromatic
rings shows a dramatic effect on the course of the
reaction. Although no substantial difference was observed
between meta- or para-substituted aromatic aldehydes
pinacol coupling).39 Recently, pinacol coupling reactions
mediated by Ti(III) in aqueous media have been inten-
sively investigated.40 Other metals such as Zn-Cu or
41
(
28) Zhang, W. C.; Li, C. J . J . Chem. Soc., Perkin Trans. 1 1998,
3
131.
(
(
(
29) Nelsen, S. F.; Kapp, D. C. J . Am. Chem. Soc. 1986, 108, 1265.
30) Pradhan, S. K.; Thakker, K. R. Tetrahedron Lett. 1987, 28, 1813.
31) Furstner, A.; Csuk, R.; Rohrer, C.; Weidmann, H. J . Chem. Soc.,
Perkin Trans. 1 1988, 1729.
(
32) Conant, J . B.; Cutter, H. B. J . Am. Chem. Soc. 1926, 48, 1016.
33) Namy, J . L.; Souppe, J .; Kagan, H. B. Tetrahedron Lett. 1983,
4, 765.
34) Imamoto, T.; Kusumoto, T.; Hatanaka, Y.; Yokoyama, M.
Tetrahedron Lett. 1982, 23, 1353.
35) Hou, Z.; Takamine, K.; Fujiwara, Y.; Taniguchi, H. Chem. Lett.
987, 2061.
(
2
(compare entries 3 and 4, 6 and 7, 9 and 10), the presence
(
of ortho-substituents increased the formation of the
benzyl alcohol product (entries 2, 5, and 8). A similar
increase in the amount of the benzyl alcohol product was
observed with increase in the size of the ortho-substitu-
ents. When two substituents were present (entry 13), no
pinacol coupling product was obtained; only complete
reduction of the aldehyde (to give the benzyl alcohol
product) was observed.
(
1
(
(
(
(
36) Hays, D. S.; Fu, G. C. J . Am. Chem. Soc. 1995, 117, 7283.
37) Hulce, M.; LaVaute, T. Tetrahedron Lett. 1988, 29, 525.
38) Rieke, R. D.; Kim, S. H. J . Org. Chem. 1998, 63, 5235.
39) For reviews, see: Furstner, A.; Bogdanovic, B. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2443. McMurry, J . E. Chem. Rev. 1989, 89,
513. Kahn, B. E.; Rieke, R. D. Chem. Rev. 1988, 88, 733.
40) Clerici, A.; Porta, O. Tetrahedron Lett. 1982, 23, 3517. Clerici,
A.; Porta, O. J . Org. Chem. 1982, 47, 2852. Gansauer, A. Chem.
Commun. 1997, 457. Clerici, A.; Porta, O.; Riva, M. Tetrahedron Lett.
1
(
In the notable report by Gomberg and Bachmann,21 the
1
981, 22, 1043 and references cited therein. Barden, M. C.; Schwartz,
J . J . Am. Chem. Soc. 1996, 118, 5484.
41) Delair, P.; Luche, J . L. J . Chem. Soc., Chem. Commun. 1989,
98. See also: Tsukinoki, T.; Kawaji, T.; Hashimoto, I.; Mataka, S.;
2
use of a Mg/MgI (1:1) mixture in anhydrous benzene or
ether for carbonyl coupling was rationalized through the
(
3
Tashiro, M. Chem. Lett. 1997, 235. Tanaka, K.; Kishigmi, S.; Toda, F.
J . Org. Chem. 1990, 55, 2981.
(42) Lim, H. J .; Keum, G.; Kang, S. B.; Chung, B. Y.; Kim, Y.
Tetrahedron Lett. 1998, 39, 4367.

Mg-Mediated C-C Bond Formation in Aqueous Media
J . Org. Chem., Vol. 64, No. 9, 1999 3235
Ta ble 3. P in a col Cou p lin g Med ia ted by Ma gn esiu m in Aqu eou s Med iu m
Sch em e 4. P ostu la ted Mech a n ism for
Ma gn esiu m -Med ia ted P in a col Cou p lin g a n d
Red u ction of Ca r bon yl Com p ou n d s
4
reactions in aqueous 0.1 N NH Cl. The product formation
of the aqueous magnesium-mediated reactions strongly
depends on the reduction potential of the substrates and
the steric environment of the reaction site. Nonactivated
organic halides and aliphatic aldehydes are not reactive
under the present conditions. Thus, in aqueous medium,
magnesium offers a high chemoselectivity toward aro-
matic aldehydes in the allylation of carbonyl compounds
and in the pinacol coupling reaction. The product forma-
tion of the pinacol coupling was strongly influenced by
the presence of substituents around the carbonyl group.
Increased congestion around the carbonyl inhibits the
carbon-carbon bond formation. We are presently explor-
ing this new reactivity and selectivity in synthetic
application.
formation of magnesium(I) iodide (MgI) and the coupling
of radical intermediates. In the present investigation, no
magnesium salt was present, thus indicating the appar-
ent occurrence of the reaction through a different mech-
anism. We tentatively rationalize the experimental re-
sults in the aqueous conditions by Scheme 4. During the
reaction, there are two potential pathways competing
with each other generating either the pinacol coupling
product (path a) or the benzyl alcohol product (path b).
The increase in steric hindrance around the carbonyl
would destabilize the transition state in the formation
of the pinacol product (route a), which results in an
increase in the formation of the benzyl alcohol product.
In conclusion, we found magnesium to be effective for
mediating both carbonyl allylation and pinacol coupling
Exp er im en ta l Section
Anhydrous reactions were performed under an atmosphere
of nitrogen. THF was distilled from sodium/benzophenone
ketyl when used as reaction solvent. Water was deionized
before use. Magnesium turnings were purchased from Fisher
and used directly as received. All other chemicals were also
used without additional purification. Flash chromatography
employed E. Merck silica gel (Kiesegel 60, 230-400 mesh)
1
purchased from Scientific Adsorbents. H NMR measurements
3
were conducted at 400 MHz in CDCl . Mass spectra were
obtained at the Center of Instrumental Facility of Tulane
University. All compounds involved in the studies are known
ones.
Gen er a l P r oced u r e for Allyla tion of Ald eh yd es. To a
mixture of benzaldehyde (200 mg, 1.89 mmol) and allyl iodide
4
(950 mg, 5.67 mmol) in aqueous 0.1 N NH Cl (10 mL) were

3
236 J . Org. Chem., Vol. 64, No. 9, 1999
Zhang and Li
added magnesium turnings (1 g, 41.6 mmol). The mixture was
stirred at room temperature for 12 h. The reaction was
of this research. We also thank Profs. H. Ensley and R.
Schmehl for discussions.
3
quenched by aqueous 1 N HCl and extracted with CDCl . The
1
extract was dried briefly over magnesium sulfate and the H
NMR spectrum of the extract was taken. The measurement
shows benzaldehyde (0), the allylation product (58%), the
pinacol coupling product (34%), and benzyl alcohol (8%). The
crude product was purified through flash column chromatog-
raphy on silica gel (hexanes-ethyl acetate) to give the desired
allylation product (139 mg, 50%).
Registr y Nu m ber s (su p p lied by a u th or ). 1-phenyl-
3
5
-buten-1-ol, 936-58-3; 1-(2-furanyl)-3-buten-1-ol, 6398-
1-2; 1-(4-chlorophenyl)-3-buten-1-ol, 14506-33-3; 1-(2-
chlorophenyl)-3-buten-1-ol, 24165-66-0; 1-(3-chlorophenyl)-
3
7
-buten-1-ol, 67472-21-3; 1-(1-naphthyl)-3-buten-1-ol,
2551-06-5; 1-(4-methoxyphenyl)-3-buten-1-ol, 24165-60-
Gen er a l P r oced u r e for P in a col Cou p lin g of Ald e-
h yd es. A suspension of benzaldehyde (20 mg, 1.89 mmol) and
magnesium turning (1 g, 41.67 mmol) in aqueous 0.1 N NH -
4
4; 1-(3-methoxyphenyl)-3-buten-1-ol, 156091-01-9; 1-(3-
bromophenyl)-3-buten-1-ol, 114095-73-7; 4-hydroxymeth-
ylbenzaldehyde, 52010-97-6; 1-(4-hydroxyphenyl)-3-buten-
Cl (10 mL) was stoppered and stirred overnight (vigorously)
under an atmosphere of air and at room temperature. The
reaction was quenched with 3 N aqueous HCl and extracted
with ethyl acetate (3 × 20 mL). The combined organic layers
1
5
0
1
-ol, 109272-34-6; 1-(4-cyanophenyl)-3-buten-1-ol, 71787-
3-6; 1,2-bis(4-methoxyphenyl)-1,2-ethanediol, 4464-76-
; 1,2-bis(2-fluorophenyl)-1,2-ethanediol, 165677-46-3;
,2-bis(3-fluorophenyl)-1,2-ethanediol, 177981-31-6; 1,2-
3
were washed with saturated aqueous NaHCO solution and
brine, dried over magnesium sulfate, and filtered. The filtrate
was concentrated in vacuo to give a crude material, which was
purified by flash chromatography on silica gel to afford the
pinacol product (162 mg, 80%) as a white crystalline solid.
bis(4-fluorophenyl)-1,2-ethanediol, 119441-86-0; 1,2-bis-
phenyl-1,2-ethanediol, 492-70-6; 1,2-bis(2-chlorophenyl)-
1,2-ethanediol, 71776-59-5; 1,2-bis(3-chlorophenyl)-1,2-
ethanediol, 37580-83-9; 1,2-bis(4-chlorophenyl)-1,2-
ethanediol, 38152-44-2; 1,2-bis(p-tolyl)-1,2-ethanediol,
Ack n ow led gm en t. We are grateful for the support
provided by the NSF-EPA joint program for a Sustain-
able Environment. Acknowledgment is also made to the
donors of the Petroleum Research Fund (administered
by the American Chemical Society), LEQSF, and the
NSF Early CAREER Award program for partial support
2
3
4133-59-3; 1,2-bis(1-naphthenyl)-1,2-ethanediol, 116204-
9-8; 1,2-bis(2-furanyl)-1,2-ethanediol, 4464-77-1; 2,3-
diphenyl-2,3-butanediol, 1636-34-6; 2,3-bis[4-methoxy-
phenyl]-2,3-butanediol, 21985-99-9.
J O982497P