A practical method for the Reformatsky reaction of aldehydes

Article abstract of DOI:10.1055/s-2000-6378

Reformaksky reaction of aliphatic aldehydes has been performed successfully by the addition of BF₃·OEt₂ to a stirred suspension of aldehyde, bromo ester and Zn dust in aqueous THF. For aromatic aldehydes, addition of benzoyl peroxide is also required to effect the reaction.

Full text of DOI:10.1055/s-2000-6378

PAPER
561
A Practical Method for the Reformatsky Reaction of Aldehydes
Angshuman Chattopadhyay,* Avinash Salaskar
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai-400085, India
Fax +91(22)5505151; E-Mail: achat@apsara.barc.ernet.in
Received 2 November 1999; revised 2 December 1999
tion gave only a low yield of the product and aliphatic al-
dehydes failed to react.5a Subsequently, Reformatsky
reaction has been effected with low to moderate yield of
the required product when aromatic aldehydes were react-
ed with bromo esters in water mediated by In.4b In this
case also, aliphatic aldehydes failed to react. Recently,
Zn-mediated Reformatsky reaction has been performed
with a variety of aromatic aldehydes but with few aliphat-
ic ones, in the presence of saturated aqueous NH4Cl solu-
tion and other additives but in majority of the cases the
yield are not appreciable.2h However, this method gave
relatively poor yield of the desired product when ethyl
bromoacetate was treated with the aliphatic aldehydes.
Abstract: Reformaksky reaction of aliphatic aldehydes has been
performed successfully by the addition of BF3•OEt2 to a stirred sus-
pension of aldehyde, bromo ester and Zn dust in aqueous THF. For
aromatic aldehydes, addition of benzoyl peroxide is also required to
effect the reaction.
Key words: aqueous condition, boron trifluoride etherate, stereose-
lectivity, chemoselectivity, radical chain mechanism.
Carbon-carbon bond formation is the essence of synthetic
organic chemistry. In this regard numerous reactions in-
volving the addition of an organic halide to an electrophile
in presence of active metals are widely applied in organic
synthesis.1 Consequently, there has been tremendous de-
velopment of strategies allowing the reactions between
functionalized organometallics and carbonyls. Among
them, metal-mediated Reformatsky reaction has been tra-
ditionally considered as an important homologation reac-
tion as this produces a versatile and exploitable
functionality like d-hydroxy ester. In view of this, there
has been continuous effort till recently2 for the develop-
ment of practically viable methodologies to carry out this
reaction. Thus, a variety of metal-mediated Reformatsky
reactions have been reported using Zn,2b Ge,2c In,2d Sn,2e
Zn-Cu couple,2f ultrasound2g etc. However, the use of Zn
metal is more advantageous as powdered Zn is easily
available at low cost, with reasonably good reactivity and
hence amenable for handling in practical scale. It is note-
worthy that there has been a tremendous development of
organozinc reagents and their extensive utilization in or-
ganic synthesis.3
During our ongoing program on the synthesis of bioactive
compounds, we have done Zn-mediated allylation of
chiral aliphatic carbonyls7a-c in the presence of water fol-
lowing Luche’s procedure.6 Simultaneously, we utilized
this methodology for the propargylation of the carbon-
yls.7a,b However, our efforts to carry out Reformatsky ad-
dition of ethyl bromoacetate to several aliphatic as well as
aromatic aldehydes using this procedure proved unsuc-
cessful. We then found that the addition of BF3•OEt2 in-
stead of saturated aqueous NH4Cl solution to a stirred
suspension of Zn dust, an aldehyde and ethyl bromoace-
tate in aqueous THF (containing approx. 2% water) pro-
duced much more encouraging results (Scheme). Several
aliphatic and aromatic aldehydes were chosen as repre-
sentative examples. For aliphatic aldehydes (Table, En-
tries a-f), Reformatsky reaction has been effected
smoothly at reasonably faster rate showing their disap-
pearance (TLC) within 1-4 hours. Unfortunately, for aro-
matic aldehydes (Table, Entries g-k), the results are not
appreciable even after stirring the mixture under these re-
action conditions for a longer duration (40 h). We then ob-
served that the addition of a catalytic amount of benzoyl
peroxide and increased quantity of both Zn dust and bro-
mo ester effected a substantial progress of reaction which
goes to completion within 7-9 hours.
In synthetic organic chemistry efforts are directed towards
the development of the reactions in wet solvent, aqueous
medium or salt solution,4,5 with a view to impart practical
viability. Morever, organic reactions in aqueous media
without using harmful solvents are of great current inter-
est specially in relation with the present environmental
concerns. Regarding Reformatsky reaction, the first ex-
amples in aqueous medium were reported in 1985 using
(bromomethyl)acrylic acid and metallic Zn to prepare
a-methylene-g-butyrolactones.4a Normal a-halocarboxyl-
ic esters did not react under these conditions. Since the
substrate of this reaction is an allylic halide, the reaction
should be regarded as an allylation reaction rather than a
Reformatsky reaction.
It has been generally observed that the reaction rate for ar-
omatic aldehydes is slower as compared with that of ali-
phatic aldehydes. This is in sharp contrast with all the
available reports where majority of the Reformatsky reac-
tions under wet condition have been performed smoothly
with aromatic aldehydes rather than aliphatic ones. In our
case, for aliphtic aldehydes the reactions are clean and
high yielding for the expected products without any prom-
inent dehydration of the resulting b-hydroxy esters. For
aromatic aldehydes that we have utilized, the general
yields are appreciable but slightly lower as compared to
A direct Reformatsky-type reaction took place when an
aromatic aldehyde was reacted with an a-bromo ester in
water, mediated either by zinc or tin. However, the reac-
Synthesis 2000, No. 4, 561–564 ISSN 0039-7881 © Thieme Stuttgart · New York

562
A. Chattopadhyay, A. Salaskar
PAPER
Table Reformatsky Reactions of Aldehydes
Entry
RCHO
BrCH2CO2R1
R1 = Et
Additive
none
Time (h)
1-2
Yield (%)
a
isobutanal
92
81
b
(R)-2,3-O-cyclohexylidene
glyceraldehyde
R1 = Me
none
2-3
c
d
e
f
citronellal
R1 = Et
R1 = Et
R1 = Et
R1 = Et
R1 = Et
R1 = Et
R1 = Et
R1 = Et
R1 = Et
none
3-4
3-4
3-4
3-4
7-8
8-9
8-9
8-9
7-8
70
88
85
84
81
76
75
66
78
heptanal
none
decanal
none
dodecanal
none
g
h
i
benzaldehyde
Bz2O2
Bz2O2
Bz2O2
Bz2O2
Bz2O2
4-chlorobenzaldehyde
4-methoxybenzaldehyde
2-methoxybenzaldehyde
1-naphthaldehyde
j
k
the average cases for aliphatic ones. This is probably due sufficiently active to react with ethyl bromoacetate which
to the formation of slight amount of side products caused has comparatively much less reactivity than those of allyl-
by prolonged stirring of the mixture in the presence of ic or propargylic bromides. The enhancement of the activ-
Lewis acid. However, there is considerable improvement ity of Zn dust in this case has been caused due to the
in the yields of the Reformatsky products of the aldehydes chemical erosion of the Zn surface after the addition of
(Table, Entries g, h and i) as compared to those in a report- Lewis acid (BF3•OEt2). However, the failure of the aro-
ed procedure.2h To our delight, when (R)-2,3-O-cyclohex- matic aldehydes to undergo Reformatsky reaction in pres-
ylideneglyceraldehyde (Table, Entry b), a potentially ence of such eroded Zn only, led to the speculation that the
useful chiron7a,c was used as substrate no deketalization reaction subsequently does not propagate through ionic
was observed. This is certainly advantageous for the sub- mechanism. The presence of the radical chain
sequent synthetic maneuvre as this requires selective ex- mechanism2h deserves consideration as the reactions have
ploitation of all the hydroxyl functionalities of the been facilitated considerably by the addition of benzoyl
resulting product. Furthermore, the addition has been peroxide. Nevertheless, the sluggishness of the reaction of
found to be highly anti selective (syn:anti = 2:98) by treat- aromatic aldehydes under this condition with respect to
ing methyl bromoacetate with 1b under similar condition. the aliphatic ones still remains a problem. Moreover,
This was evident by isolation of both diastereomers of the when several aliphatic and aromatic ketones were tried
product by column chromatography and comparing their we found them to be totally unreactive under this condi-
NMR data with those of the reported ones.8
tion. Hence, our method presents a good application for
conducting chemoselective Reformatsky reaction of alde-
hydes in the presence of ketones.
In summary, a practical method for Reformatsky reaction
has been developed under aqueous condition. The novelty
of this method is due to its operational simplicity and
practical viability. Moreover, this appears to be a unique
procedure in the presence of water which is smoothly ap-
plicable for aliphatic aldehydes whose availability in dif-
ferent functional and stereochemical combination is very
well documented.
Reagents and conditions: a) Zn, BrCH2CO2R1, BF3•OEt2, aq THF;
b) Bz2O2
Scheme
From the above observations the mechanism of this meth-
odology remains inconclusive. However, the rate of Zn in-
sertion into the carbon-halide bond is a crucial factor that
depends on the reaction condition and mode of Zn activa-
tion. Hence, it can be concluded that the addition of satu-
rated aqueous NH4Cl solution can not make Zn dust
All experiments were conducted using unactivated 20 mesh Zn
powder. Aqueous THF was used as mentioned in the text. Reagent
grade aldehydes and bromo esters were used directly. NMR spectra
were recorded on a Bruker AC 200 spectrometer in CDCl3. Chemi-
cal shifts are expressed in ppm downfield from TMS. IR were re-
corded on a Perkin-Elmer 837 spectrometer.
Synthesis 2000, No. 4, 561–564 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Practical Method for the Reformatsky Reaction of Aldehydes
563
Reformatsky Reaction of Aldehydes in the Presence of
BF3•OEt2; General Procedure
Ethyl 3-Hydroxy-5-phenylpropanoate (2g)
IR (film): n = 3480, 3087, 1731, 1603 cm-1.
To a well stirred suspension of aldehyde (0.03 mol), Zn dust
(9.75 g, 0.15 g-atom for Entries a-f; 11.7 g, 0.18 g-atom for Entries
g-k), bromo ester (0.09 mol for Entries a-f; 0.12 mol for Entries g-
k) and benzoyl peroxide (10 mol% for Entries g-k) in moist THF
(80 mL) was added BF3•OEt2 (7.4 mL, 0.06 mol) in portions over a
period of 15 min. The mixture was stirred at r.t. for the period as
mentioned in the Table. It was then filtered and the residue was
washed with EtOAc. The organic layer was washed with dil aq HCl
(5%) to dissolve a turbid suspension, H2O, brine and dried. Solvent
removal and column chromatography [silica gel, 0-20% EtOAc in
petroleum ether of the residue afforded pure b-hydroxy ester.
1H NMR: d = 7.1-7.5 (5 H, m), 5.0 (1 H, t, J = 5 Hz), 4.15 (2 H, q,
J = 6 Hz), 2.95 (1 H, br s, OH), 2.55 (2 H, d, J = 7 Hz), 1.2 (3 H, t,
J = 6.5 Hz).
Ethyl 5-[4-Chlorophenyl]-3-hydroxypropanoate (2h)
IR (film): n = 3470, 3087, 1731, 1603 cm-1.
1H NMR: d = 7.3 (2 H, d, J = 8.4 Hz), 6.87 (2 H, d, J = 8.4 Hz), 5.07
(1 H, t, J = 5 Hz), 4.15 (2 H, q, J = 6 Hz), 2.95 (1 H, br s, OH), 2.68
(2 H, d, J = 7 Hz), 1.21 (3 H, t, J = 6.5 Hz).
Ethyl 3-Hydroxy-5-[4-methoxyphenyl]propanoate (2i)
IR (film): n = 3470, 3087, 1731, 1603 cm-1.
Ethyl 3-Hydroxy-4-methylpentanoate (2a)
1H NMR: d = 7.3 (2 H, d, J = 8.4 Hz), 6.87 (2 H, d, J = 8.4 Hz), 5.07
(1 H, t, J = 5 Hz), 4.15 (2 H, q, J = 6 Hz), 3.8 (3 H, s), 2.95 (1 H, br
s, OH), 2.66 (2 H, d, J = 7 Hz), 1.22 (3 H, t, J = 6.5 Hz).
bp 82-84 °C/10 Torr (Lit9 bp 79-80 °C/5 Torr).
IR (film): n = 3479, 1732, 1371 cm-1.
1H NMR: d = 4.15 (2H, q, J = 6 Hz), 3.6-3.8 (1 H, m), 3.0 (1 H, br
s, OH), 2.4 (2 H, d, J = 6 Hz), 1.3-1.5 (1 H, m), 1.21 (3 H, t, J = 6
Hz), 0.9 (6 H, d, J = 6 Hz).
Ethyl 3-Hydroxy-5-[2-methoxyphenyl]propanoate (2j)
IR(film): n = 3470, 3087, 1731, 1603 cm-1.
1 H NMR: d = 7.4-6.8 (4 H, m), 5.37 (1 H, t, J = 5 Hz), 4.15 (2 H,
q, J = 6 Hz), 3.8 (3 H, s), 2.95 (1 H, br s, OH), 2.66 (2 H, d, J = 7
Hz), 1.24 (3 H, t, J = 6.5 Hz).
Methyl (4,5-O-Cyclohexylidene)-3,4,5-trihydroxypentanoate
(2b)
(i) Minor (3R, 4R)-isomer:
IR (film): n = 3519, 1731 cm-1.
1H NMR: d = 4.0-4.1 (2 H, m), 3.85-3.95 (1 H, m), 3.75-3.85 (1
H, m), 3.68 (3 H, s), 3.4 (1 H, br s, OH), 2.45 (2 H, s), 1.35-1.65
(10 H, m).
Anal. Calcd for C12H16O4: C 64.27, H 7.19. Found: C 64.55, H 7.42.
Ethyl 3-Hydroxy-3-[1-naphthalyl]propanoate (2k)
IR(film): n = 3466, 3067, 1735, 1623 cm-1.
1 H NMR: d = 8.2-7.2 (7 H, m), 5.79 (1 H, t, J = 5 Hz), 4.15 (2 H,
q, J = 6 Hz), 3.29 (1 H, br s, OH), 2.68 (2 H, d, J = 7 Hz), 1.24 (3
H, t, J = 6.5 Hz).
(ii) Major (3S, 4R)-isomer:
IR (film): n = 3525, 1734 cm-1.
Anal. Calcd for C15H16O3 : C 73.75, H 6.60. Found: C 73.38, H 6.38.
1H NMR: d = 3.95-4.1 (2 H, m), 3.8-3.95 (2 H, m), 3.68 (3 H, s),
3.0 (1 H, br s, OH), 2.70 (1 H, dd, J = 15.9, 8.0 Hz), 2.44 (1 H, dd,
J = 15.9, 8.0 Hz), 1.35-1.65 (10 H, m).
References
(1) (a) Fürstner, A. Angew. Chem. Int. Ed. Engl. 1993, 32, 164.
(b) Rieke, R. D., Science 1989, 246, 1260.
(c) Erdik, E., Tetrahedron 1987, 43, 2203
(2) (a) Furstner, A. Synthesis 1989, 571.
Ethyl 3-Hydroxy-5,9-dimethyldec-8-enoate (2c)
IR (film): n = 3520, 1735, 1376 cm-1.
1H NMR: d = 5.1-5.3 (1 H, m), 4.15 (2 H, q, J = 6 Hz), 3.6-3.8 (1
H, m), 3.0 (1 H, br s, OH), 1.9-2.5 (4 H, m), 1.65 (3 H, s), 1.58 (3
H, s), 1.2-1.4 (5 H, m), 0.86-1.0 (6 H, m).
(b) Rieke, R. D.; Uhm, S. J. Synthesis 1975, 452.
(c) Kagoshima, H.; Hashimoto, Y.; Oguro, D.; Saigo, K.
J.Org. Chem. 1998, 63, 691, and references cited therein.
(d) Chao, L.; Rieke, R. D. J. Org. Chem. 1975, 40, 2253.
(e) Harda, T.; Mukaiyama, T. Chem. Lett. 1982, 161.
(f) Santanielo, E.; Manzocchi, A. Synthesis 1977, 698.
(g) Han, B.; Boudjouk, P. J. Org. Chem. 1982, 47, 5030.
(h) Bieber, L. W.; Malvestiti, I.; Storch, E. C. J. Org. Chem.
1997, 62, 9065, and references cited therein.
(i) Tanaka, K.; Kishigami, S.; Toda, F. J. Org. Chem. 1991,
56, 4333.
Anal. Calcd for C14H26O3: C 69.38, H 10.81. Found: C 69.17, H
10.61.
Ethyl 3-Hydroxynonanoate (2d)
IR (film): n = 3520, 1735 cm-1.
1H NMR: d = 4.15 (2 H, q, J = 6 Hz), 3.6-3.8 (1 H, m), 2.8 (1 H, br
s, OH), 2.4 (2 H, d, J = 6Hz), 1.3-1.4 (10 H, m), 1.21 (3 H, t, J = 6
Hz), 0.91 (3 H, t, J = 6Hz).
Anal Calcd for C11H22O3: C 65.31, H 10.96. Found: C 65.54, H
10.72.
(3) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117
(4) (a) Mattes, H.; Benezra, C. Tetrahedron Lett 1985, 26, 5697.
(b) Chan, T. H.; Li, C. J.; Lee, M. C.; Wei, Z. Y. Can. J. Chem.
1994, 72, 1181.
Ethyl 3-Hydroxydodecanoate (2e)
IR (film): n = 3520, 1735 cm-1.
1H NMR: d = 4.15 (2 H, q, J = 6 Hz), 3.6-3.8 (1 H, m), 2.9 (1 H, br
s, OH), 2.4 (2 H, d, J = 6 Hz), 1.3 1.4 (10 H, m), 1.21 (3 H, t, J = 6
Hz), 0.91 (3 H, t, J = 6 Hz).
(5) (a) Li, C-J Chem. Rev. 1993, 93, 2023.
(b) Li, C-J Tetrahedron 1996, 52, 5643.
(c) Mulzer, J.; Attenbach, H.; Braun, M.; Reissig, H. Organic
Synthesis Highlights; VCH: Weinheim, 1991; pp 71.
(d) Grieco, P. Ed. Organic Reactions in Water; Chapman &
Hall: London, 1998.
Anal. Calcd for C14H28O3: C 68.81, H 11.55. Found: C 68.59, H
11.77.
Ethyl 3-Hydroxytetradecanoate (2f)
(6) (a) Petrier, C.; Luche, J. L. J. Org. Chem. 1985, 50, 910.
(b) Einhorn, C.; Luche, J. L. J. Organomet. Chem. 1987, 322,
177.
(7) (a) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104.
(b) Chattopadhyay, A.; Dhotare, B. Tetrahedron: Asymmetry
1998, 9, 2715.
IR (film): n = 3520, 1735 cm-1.
1H NMR: d = 4.15 (2 H, q, J = 6 Hz), 3.6-3.8 (1 H, m), 2.9 (1 H, br
s, OH), 2.4 (2 H, d, J = 6Hz), 1.3 1.4 (10 H, m), 1.21 (3 H, t, J = 6
Hz), 0.91 (3 H, t, J = 6Hz).
Anal. Calcd for C16 H32 O3: C 70.54, H 11.84. Found: C 70.28, H
11.68.
(c) Chattopadhyay, A.; Dhotare, B.; Hassrajani, S. J. Org.
Chem. 1999, 64, 6874.
Synthesis 2000, No. 4, 561–564 ISSN 0039-7881 © Thieme Stuttgart · New York

564
A. Chattopadhyay, A. Salaskar
PAPER
(8) Orsini, F.; Leccioli, C. Tetrahedron: Asymmetry 1997, 8,
4011.
Article Identifier:
1437-210X,E;2000,0,04,0561,0564,ftx,en;Z08199SS.pdf
(9) Sugimura, T.; Yoshikawa, M.; Yoneda, T.; Tai, A. Bull. Soc.
Chem. Jpn. 1990, 63, 1080
Synthesis 2000, No. 4, 561–564 ISSN 0039-7881 © Thieme Stuttgart · New York