Nucleophilic addition of arylmethylzinc reagents (ArCH2ZnCl) to formaldehyde: An easy access to 2-(hetro)arylethyl alcohols

Article abstract of DOI:10.1080/00397911.2017.1297458

The selective addition of arylmethylmagnesium halides with formaldehyde giving arylethyl alcohols is extremely challenging. To circumvent the difficulties, in the current communication, we have reported on the nucleophilic addition of benzyl zinc reagents derived from inexpensive and abundant benzyl chlorides to paraformaldehyde. The reaction investigated herein is hitherto unknown and was found to be selective, operationally simple, atom- and step-economical and high yielding to deliver phenethyl alcohols utilized as key perfumery ingredients in 60–83% yields. After successful establishment of the reaction condition, the reaction was also scaled up successfully to deliver a large-scale preparation of the phenethyl alcohol.

Full text of DOI:10.1080/00397911.2017.1297458

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Nucleophilic Addition of Arylmethylzinc Reagents
(
ArCH ZnCl) to Formaldehyde: An Easy Access to 2-
2
(Hetro)arylethyl Alcohols
V. P. Bhatt, S. D. Samant & Suhas Pednekar
To cite this article: V. P. Bhatt, S. D. Samant & Suhas Pednekar (2017): Nucleophilic Addition
of Arylmethylzinc Reagents (ArCH ZnCl) to Formaldehyde: An Easy Access to 2-(Hetro)arylethyl
2
Alcohols, Synthetic Communications, DOI: 10.1080/00397911.2017.1297458
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1297458
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Date: 06 March 2017, At: 10:48

Nucleophilic Addition of Arylmethylzinc Reagents (ArCH ZnCl) to Formaldehyde:
2
An Easy Access to 2-(Hetro)arylethyl Alcohols
1
1
2
V. P. Bhatt , S. D. Samant , Suhas Pednekar
1
Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai, India
2
Department of Chemistry, Ramnarain Ruia College, Matunga, Mumbai, India..
Corresponding author: V. P. Bhatt Email: vimal8481@gmail.com
Abstract
The selective addition of arylmethylmagnesium halides with formaldehyde giving
arylethyl alcohols is extremely challenging. To circumvent the difficulties, in the current
communication we have reported on the nucleophilic addition of benzyl zinc reagents
derived from inexpensive and abundant benzyl chlorides to paraformaldehyde. The
reaction investigated herein is hitherto unknown and was found to be selective,
operationally simple, atom- and step-economical and high yielding to deliver phenethyl
alcohols utilized as key perfumery ingredients in 60-83% yields. After successful
establishment of the reaction condition, the reaction was also scaled up successfully to
deliver a large scale preparation of the phenethyl alcohol.
Graphical Abstract
KEYWORDS: Zn reagents, Nucleophilic addition, 2-(hetro)arylethyl alcohols
INTRODUCTION
Due to indispensable requirement of route scouting in pharmaceuticals, natural products,
agrochemicals, commodity chemicals, and flavours and fragrances, the development of
new synthetic methodologies have indispensable requirement to accomplish the desired
1
synthetic requirements of the chemical industry. New reagents have been developed to
provide the desired novelty in terms of selectivity, reactivity, cost-effectiveness, atom-
1

and step-economy, environment benignness, high yield, and high functional group
compatibility.
Since last few decades organometallic chemistry has played pivotal role to accomplish
2
the desired synthetic goals. A large number of metals has been used to address the
3
challenges in synthesis. Organometallic addition to electrophiles is ubiquitous and
4
plethora of literature is available to demonstrate the versatility of such transformations.
More specifically, the addition of organometallic reagents to carbonyls to form new
carbon-carbon bonds has been studied extensively. Interestingly, the addition of a
nucleophile containing benzylic organometallic (ArCH M, M = metal) to an electron
2
deficient carbon is found to be challenging for the installation of benzylic (ArCH ) group
2
in organic compounds. Traditionally, the related organometallics are generated from their
corresponding benzylethers or benzyl halides by the reaction of an active metal, for
5
instance Li, Mg, Zn, Mn, Cd, Si. However, this methodology is not straightforward and
does poses several practical difficulties. The challenges associated with this type of
organometallics are their very high reactivity and lack of stability under normal
conditions.
2
-Arylethyl alcohols are common perfumery chemicals. 2-Phenylethyl alcohol is used
when rose odour is desired. It is used as a preservative in soap because of its stability
under basic conditions and antimicrobial property. It is also found in extracts of
champaca, neroli, geranium, ylang-ylang, rose, carnation, aleppo pine, hyacinth, and
6
orange blossom.
2

Apparently, the most common method to introduce the hydroxymethyl group in a
compound is the reaction of a Grignard reagent and formaldehyde. The Grignard
reaction of benzyl magnesium chloride 1 and different carbonyl compounds has been
7
extensively investigated by Siegel and Benkeser, independently. However, this reaction
with formaldehyde gives largely side products rather than the desired compounds. The
reaction of 1 with formaldehyde 2 yields predominantly undesired o-tolyl carbinol 4 with
a trace of the desired 2-phenethyl alcohol (3a) (Scheme 1). The generation of the by-
products is largely depends on the mole equivalent of the formaldehyde and the Grignard
reagent used. Alternative methodologies for the synthesis of phenethyl alcohol are also
8
reported in the literature.
DISCUSSION
On the background of this unusual observation and our interest in the synthesis of
phenethyl alcohols, we set out to study this reaction. Our hypothesis was that as zinc is
less electropositive than magnesium, an organozinc reagent would be better suited to
react with formaldehyde to give the desired phenethyl alcohols (Pauling electronegativity
Mg 1.31, Zn 1.65). Therefore, the key objective of this work was to address the limitation
of this abnormal reactivity of benzyl magnesium chloride with electrophiles and
investigating the possibility of using benzyl zinc reagents for the synthesis of phenethyl
alcohols. Turbo Grignard reagent is also found to be a valuable tool in metal-halogen
exchange having extensive practical utility in the presence of reactive functional groups
9
such as esters, nitriles, ketones, and various unstable heteroaromatics.
3

Organozinc reagents show excellent reactivity with diverse electrophiles and also are
easy to handle. For example, their reactivity exploited in Reformatsky and Simmons-
1
0
Smith reactions. Apparently, organolithium and organomagnesium reagents have
1
1
significantly lower functional group compatibility than organozinc reagents.
Organozinc reagents have excellent functional group compatibility which can be
12
witnessed in their reactions with electrophile variants. The more the ionic character of
the carbon-zinc bond the more reactive is the reagent; due to more negative charge
1
3
located at the carbon attached to Zn. These considerations prompted us to use zinc in
the reaction of arylmethyl halides with formaldehyde, with specific objective of obtaining
2
-arylethylalcohols; the reaction would proceed through zinc intermediate ArCH ZnX.
2
At the outset, the reaction of benzyl chloride 5a or benzyl bromide 5b and
paraformaldehyde 7 was selected; the reaction gives 2-phenylethanol 3a via benzylzinc
chloride 6 (Scheme 2). In a reaction involving organozinc reagent, the quality of zinc
affects the reaction to a great extent. Zn dust was used for this reaction and was activated
1
4
as per the reported method. The reaction was carried out in different solvents using
different quantities of zinc, paraformaldehyde is used in excess (Table 1).
Benzyl bromide 5a (1.0 equiv) and activated Zn dust (1.0 equiv) were heated at 70 °C for
2
h. Paraformaldehyde 7 (3.0 equiv) was added slowly and the reaction mixture was
further heated at the same temperature for 6 h. After the work-up and purification 56%
isolated yield of 3a was obtained (Table 1, Entry 1). Increasing the quantity of Zn from
1
equiv to 1.5 equiv gave 65% yield of 3a (Table 1, Entry 2). While using 2.0 equiv of
4

the Zn gave 98% GC conversion and 81% yield of the product (Table 1, Entry 3). For
further work 2.0 equiv of the Zn was used. Benzyl chloride is cheaper than benzyl
bromide and has wide ranging commercial availability. Therefore, the reaction using
benzyl chloride 5b (1.0 equiv) and Zn (2.0 equiv) was tested under optimized conditions.
The reaction gave 83% yield of 3a (Table 1, Entry 4). This result showed that benzyl
chloride also worked efficiently in the reaction.
Next, the effect of solvent on the reaction was studied. A representative set of ethereal
solvents, 2-methyl THF, 1,4-dioxane, methyl tert-butyl ether (MTBE), diethyl ether, and
cyclopentylmethyl ether (CPME) was screened for the reaction and the reaction was
o
carried out at 70 C (Entries 4-13). 2-Methyl THF and cyclopentylmethyl ether (CPME)
are considered as green solvents and can be used as suitable replacements of THF, when
a high temperature is required. The yield of 3a was in the range of 55-70%. 2-Methyl
THF and CPME did not make any significant impact on the product purity, and gave 70%
and 62% isolated yields of the product, while 1,4-dioxane gave less yield of the product
(Table 1, Entries 5-7).
The effect of temperature on the reaction was studied by performing the reaction first at
ambient temperature in diethyl ether. In this reaction only traces of the product were
formed (Table 1, Entry 8). For the other solvents, the solution was first heated at 70 °C
for 2 h and then cooled to ambient-temperature and stirred for 6 h at 70°C, after the
addition of paraformaldehyde (Table 1, Entries 9-12). The use of THF was found to be
advantageous and 76% yield of the product was obtained. 2-Methyl THF was almost
5

equally effective, while 1,4-dioxane and MTBE were poor solvents to carry out the
desired transformation. The reaction at 0°C showed no conversion of 5.
Paraformaldehyde depolymerises at 60°C. Thus, the optimized conditions were - benzyl
chloride (1.0 equiv), Zn dust (2.0 equiv), paraformaldehyde (3.0 equiv), solvent (30 mL),
and temperature (70°C), time (6 h).
To establish the scope of the reaction, selected versatile (het)arylmethyl chlorides were
reacted with paraformaldehyde in the presence of zinc, under the optimal conditions. The
substrates were benzyl chlorides bearing electron-donating and electron-withdrawing
groups, and were also heterylmethyl chlorides (Scheme 3). All the substrates underwent
the reaction smoothly. Ortho-, meta- and para- substituted benzyl chlorides gave good to
excellent yields of the products. Tolyl benzyl chlorides (ortho- & meta-) gave 3b and 3c
in 74% and 83% yields, respectively. 4-Bromo and 4-methoxy benzyl chlorides gave 3d
(54%) and 3e (81%). Fluoro- and trifluoromethyl groups containing compounds are
important in pharmaceuticals for drug designing. Using the optimized conditions, p-
fluoro and o-(trifluromethyl)benzyl chlorides were also found to be susceptible to give 3f
and 3g in 75% and 71% yield, respectively.
The issue of possible intramolecular competition between more than one chlorine present
in the same molecule was addressed by choosing 2,4-dichlorobenzyl chloride, which
gave 65% isolated yield of the products 3h, without any aromatic addition reaction.
Thus, this addition is highly selective for benzyl halides and not for the aryl halides.
Heterocyclic arylmethyl chlorides 2- and 4-pyridyl methyl chlorides gave59% and 71%
6

isolated yields of the products 3i and 3j, respectively. The low yield from these
compounds may be ascribed to Zn complexing also with adjacent heteroatom nitrogen.
The same possibility exists for the 2-chloromethyl derivatives of thiophene and furan.
Thus, thiophene and furan derivatives gave 3k and 3l in low yield of 45% and 49%,
respectively. Overall, it can be seen that a wide ranging functional group tolerance was
observed for the reaction of benzyl zinc chloride and paraformaldehyde in the presence of
zinc.
The success of this methodology prompted us to establish a large scale (100 g) practical
method for the preparation of the key perfumery ingredient phenethyl alcohol 3a. The
reaction of benzyl chloride with paraformaldehyde was carried out under the optimized
conditions and 71% isolated yield of phenethyl alcohol was obtained (Scheme 4).
In conclusion, the failure of benzyl magnesium halide to react with formaldehyde to give
the expected 2-phenylethyl alcohol gave impetus to the present work. Herein we
hypothesized that less electropositive zinc may effectively replace magnesium; i.e.
benzylzinc organometallic compound may react with formaldehyde to form the expected
2
-phenylethyl alcohol. Hence, we reacted benzyl bromide and benzyl chloride with zinc
followed by the reaction of formaldehyde. A range of substituted benzyl chlorides as well
heteryl methyl chlorides reacted smoothly and gave the expected products. This protocol
is more straightforward than the reported methods and gave high-yield of the phenethyl
alcohols. Moreover, this method is proven to be atom- and step-economical, high
yielding which can be easily scaled up.
7

[CAUTION: On heating, paraformaldehyde generates formaldehyde gas, safety
precautions need to be taken by using suitable personal protective equipments (PPEs) to
avoid the toxic effects of formaldehyde. This is particularly important while carrying out
a large scale operation. The reaction should be performed in a well-ventilated fume
hood.]
EXPERIMENTAL DETAILS
Phenethyl Alcohol (3a)
A two neck Schlenk flask equipped with a magnetic stirring bar and septum was heated
with heat gun (~400 °C) for 10 min under high vacuum. After cooling to room
temperature, the flask was flushed with argon (3 times). Zn-dust (654 mg, 2.0 equiv,
1
0.0 mmol) was added followed by THF (20 mL). 1,2-Dibromoethane (5 mol%) was
added and the reaction mixture was heated until ebullition occurs. After cooling to rt,
chlorotrimethylsilane (1 mol%) was added and the mixture was heated again till
ebullition occurs. The flask was again cooled to rt and benzyl chloride (633 mg, 5.0
mmol, 1 equiv) was added as a solution in THF (10 mL) and it was heated at 70 °C for 2
h and cooled to rt. Paraformaldehyde (450 mg, 3.0 equiv. 15.0 mmol) was slowly added
at rt and the flask was again heated at 70 °C for 6 h. The solution was cooled to rt and
saturated NH Cl solution was added. The phases were separated and the aqueous layer
4
was extracted with ethyl acetate (100 mL). The combined organic layer was washed with
water (20 mL), brine (10 mL) and then dried over Na SO . The solvents were evaporated
2
4
under reduced pressure and the residue was purified by silica gel column chromatography
8

using cyclohexane or cyclohexane/ethyl acetate as an eluent to obtain phenethyl alcohol
3a) (510 mg, 83%) as a colourless liquid. (b.p. 221-222 °C at 760 torr) (lit. 218-220 °C
(
1
5
at 760 torr). The physical data are consistent with the literature values.
ACKNOWLEDGEMENT
The authors are thankful to Sardar Patel University for providing analytical facility. The
authors are also thankful to the Ramnarain Ruia College for providing infrastructural
facility and project funding.
SUPPORTING INFORMATION
1
Full experimental detail, H NMR and mass spectra. This material can be found via the
“Supplementary Content” section of this article’s webpage.’
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1
2

Table 1: The reaction of benzyl chloride/bromide and formaldehyde in the presence of
zinc in different solvents.
Entry PhCH X Zn
Solvent
Temp
(°C)
Conversion Yield
2
a
b
(1 equiv) metal
of 5 (%)
of 3
(%)
56
(equiv)
1
2
3
4
5
6
7
8
9
1
1
1
1
PhCH Br 1
THF
70
70
70
70
70
70
70
62
70
96
98
75
59
65
-
2
PhCH Br 1.5
THF
65
2
PhCH Br 2.0
THF
81
2
PhCH Cl 2.0
THF
83
2
PhCH Cl 2.0
2-MeTHF
1,4-Dioxane
CPME
70
2
PhCH Cl 2.0
55
2
PhCH Cl 2.0
62
2
PhCH Cl 2.0
Diethyl ether Rt
traces
47
2
PhCH Cl 2.0
MTBE
70
70
70
70
0
52
79
75
52
ND
2
0
1
2
3
PhCH Cl 2.0
THF
76
2
PhCH Cl 2.0
2-MeTHF
1,4-Dioxane
THF
72
2
PhCH Cl 2.0
44
2
PhCH Cl 2.0
ND
2
Reaction conditions: PhCH X (X = Br of Cl) (5.0 mmol), paraformaldehyde (15.0
2
mmol), solvent (30 mL). All reactions were run for six hours after formation of benzyl
zinc reagent. ND: not detected.
a
b
GC conversion, Isolated yield.
1
3

Scheme 1. The addition of benzyl Grignard reagent to formaldehyde.
1
4

Scheme 2. The reaction of benzyl chloride/bromide with paraformaldehyde (PFA)
mediated by zinc.
1
5

Scheme 3. Products obtained in the reaction of different arylmethyl chlorides with
formaldehyde in the presence of zinc. Reaction condition: Arylmethyl chloride (5.0
mmol), Zn dust (10 mmol), THF (30 mL), paraformaldehyde (15 mmol), Time 6 h
1
6

Scheme 4. Large scale preparation of phenethyl alcohol.
1
7