Novel and efficient catalytic route for the syntheses of tetrahydrofurans useful in the preparation of neonicotinoid insecticides

Article abstract of DOI:10.1081/SCC-200051709

Neonicotinoids are good alternatives to the widely used organophosphate insecticides (OP) and have gained enormous importance because of their low toxicity in vertebrates. An environmentally benign route for the synthesis of 3-(hydroxy-methyl)tetrahydrofuran useful in the preparation of a neonicotinoid insecticide viz. MTI-446 is described. Principles of green chemistry such as hydroformylation, single-pot transketalization, and intramolecular cyclocondensation through catalytic reactions were adopted. The process reported here is superior to the existing methods with respect to lower salt formation and higher atom economy, and it was extended to the preparation of a novel intermediate, 3,3-bis(hydroxymethyl)tetrahydrofuran, conceived to be useful in the preparation of new insecticides.

Full text of DOI:10.1081/SCC-200051709

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Novel and Efficient Catalytic Route for the
Syntheses of Tetrahydrofurans Useful in the
Preparation of Neonicotinoid Insecticides
a b
a
a
Srinagesh Kumar Potluri
, A. Raghu Ramulu & M. Pardhasaradhi
a
Gas Based Chemicals and Organic Intermediates Division , Indian Institute
of Chemical Technology , Hyderabad, India
b
Department of Chemistry , Southern Methodist University , Fondren
Science Bldg., 3215 Daniel Avenue, Dallas, TX, 75275, USA
Published online: 21 Aug 2006.
To cite this article: Srinagesh Kumar Potluri , A. Raghu Ramulu & M. Pardhasaradhi (2005) Novel and Efficient
Catalytic Route for the Syntheses of Tetrahydrofurans Useful in the Preparation of Neonicotinoid Insecticides,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
35:7, 971-978, DOI: 10.1081/SCC-200051709
To link to this article: http://dx.doi.org/10.1081/SCC-200051709
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Synthetic Communications , 35: 971–978, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200051709
Novel and Efficient Catalytic Route for the
Syntheses of Tetrahydrofurans Useful in the
Preparation of Neonicotinoid Insecticides
Srinagesh Kumar Potluri, A. Raghu Ramulu, and M. Pardhasaradhi
Gas Based Chemicals and Organic Intermediates Division, Indian
Institute of Chemical Technology, Hyderabad, India
Abstract: Neonicotinoids are good alternatives to the widely used organophosphate
insecticides (OP) and have gained enormous importance because of their low
toxicity in vertebrates. An environmentally benign route for the synthesis of 3-(hydroxy-
methyl)tetrahydrofuran useful in the preparation of a neonicotinoid insecticide viz.
MTI-446 is described. Principles of green chemistry such as hydroformylation,
single-pot transketalization, and intramolecular cyclocondensation through catalytic
reactions were adopted. The process reported here is superior to the existing
methods with respect to lower salt formation and higher atom economy, and it was
extended to the preparation of a novel intermediate, 3,3-bis(hydroxymethyl)tetrahydro-
furan, conceived to be useful in the preparation of new insecticides.
Keywords: Catalytic reactions, hydroformylation, neonicotinoids, transketalization
INTRODUCTION
Neonicotinoids, a group of highly effective insecticides with less toxicity in
vertebrates, were launched in 1991. These insecticides cause profound
effects on nerve-impulse transmission through action on insect postsynaptic
Received in India December 9, 2004
Address correspondence to Srinagesh Kumar Potluri (present address), Department
of Chemistry, Southern Methodist University, Fondren Science Bldg., 3215 Daniel
Avenue, Dallas, TX 75275, USA. Tel.: (214)-768-4392; E-mail: spotluri@zyvex.com

9
72
S. K. Potluri, A. R. Ramulu, and M. Pardhasaradhi
[1]
nicotinic acetylcholine receptors (nAChR). Neonicotinoids have much
lower activity in vertebrate tissues than in insects because of differences in
[
2]
binding to nAChR subtypes. Reduced access to receptors in the central
nervous system (CNS) resulting from poor penetration of the blood–brain
barrier (BBB) is an additional factor that acts to reduce the toxicity of these
[
3,4]
insecticides in vertebrates.
neonicotinoid insecticide viz. MTI-446 (4) received “conventional reduced
Because of these advantages, very recently a
risk and OP alternative status” for cotton, leafy vegetables, ornamentals,
[
5,6]
turf, and public health uses.
As a part of our program directed toward the development of green tech-
nologies (using carbon monoxide) for the manufacture of pharmaceutically
[
7,8]
important intermediates,
extending similar studies for the synthesis of tetrahydrofurans useful in the
we have given considerable thought to
[9]
preparation of neonicotinoid insecticides.
3
-(Hydroxymethyl)tetrahydrofuran (3) is an important intermediate for
presented in Scheme 1
[10,11]
the preparation of MTI-446. Literature methods
[12]
for the synthesis of tetrahydrofuran 3 involves LiBH4 reduction
-carboethoxydiethylsuccinate (1) followed by cyclocondensation of the
resulting 2-hydroxymethyl-1,4-butanediol (2) using p-toluenesulphonic acid
PTSA). However, these reactions are all stoichiometric and have the
of
2
(
following disadvantages: 1) triol 2 has very high water solubility and is
difficult to isolate from aqueous solutions during workup, 2) use of LiBH4
to reduce three ester groups generates large quantities of salts, and 3) separa-
tion of soluble PTSA from the reaction mixture before 3 is isolated either by
solvent extraction or distillation.
In view of these disadvantages in the preparation of 3, it was highly
desirable to 1) develop a catalytic process, 2) use small quantities of NaBH4
to minimize the salt generation, and 3) employ an acid catalyst that can be
easily separated from the reaction mixture, thus avoiding aqueous workup.
This paper describes our preliminary results (Scheme 2) pertaining to the
efficient catalytic construction of 3-(hydroxymethyl)tetrahydrofuran (3) and
synthesis of 3,3-bis(hydroxymethyl)tetrahydrofuran (11). To the best of our
knowledge, compound 11 is hitherto not reported in the literature. Taking a
lead from 3, we conceived to synthesize a new group of neonicotinoid insecti-
cides starting from 11.
RESULTS AND DISCUSSION
Synthetic strategy presented in this paper describes the preparation of tetra-
hydrofurans 3 and 11 (Scheme 2). Accordingly, 7,12-dioxaspiro[5,6]dodec-
9
-ene was subjected to hydroformylation in presence of RhHCO(TPP)3
using syngas to provide 9-formyl-7,12-dioxaspiro[5,6]dodecane (5) in
3% yield. Reduction of aldehyde 5 in presence of NaBH4 gave
9

Synthesis of Tetrahydrofurans
973

Scheme 2. Reagents: (a) RhHCO(TPP) , CO/H , 130 bar, 1008C, toluene; (b) NaBH , MeOH, 3 h, 208C; (c) Amberlyst-15,
3
2
4
MeOH, 608C–1208C; (d) Et
3
N/CH
2
O, 308C; (e) Amberlyst-15, MeOH-H O, 608C.
2

Synthesis of Tetrahydrofurans
-hydroxymethyl-7,12-dioxaspiro[5,6]dodecane (6) in 98% yield.
975
[7,8]
9
Trans-
ketalization of alcohol 6 followed by cyclocondensation in one pot, using
methanol and Amberlyst-15 as catalysts, resulted in 3-(hydroxymethyl)tetra-
hydrofuran (3) in 90% yield. Compound 5 was subjected to hydroxymethyla-
tion using CH O/TEA and the resulting intermediate 7, without further
2
purification and characterization, was reduced using NaBH in methanol to
4
afford 9,9-bis(hydroxymethyl)-7,12-dioxaspiro[5,6]dodecane (8) in 95%
yield. Similarly, transketalization and cyclocondensation of 8 in a single
step resulted in 3,3-bis(hydroxymethyl)tetrahydrofuran (11) and a minor by-
product 2,7,14-trioxadispiro[4.2.5.2]pentadecane (10). The by-product 10
was separated and purified by column chromatography and subsequently
cleaved into the required product 11 in 95% overall yield using aqueous
methanol and Amberlyst-15 catalyst. In the synthesis of tetrahydrofurans 3
and 11, the initial transketalization reaction was performed at 608C for 2 h,
excess methanol and dimethoxycyclohexane were distilled off, and the cyclo-
condensation was affected by heating the residue to 1208C. It is assumed that
spiro by-product (10) is formed by dehydration of the intermediate (9).
The stability of rigid six-membered spiro-1,3-dioxane (9) compared to
flexible seven-membered spiro-1,3-dioxepane (8) is the driving force for the
formation of intermediate 9. This justification has precedence in our work
[7,8]
on the synthesis of antiviral acyclonucleoside intermediates. Compounds
0 and 11 are unprecedented in the literature and herein we present their
1
synthesis and characterization.
From the green chemistry standpoint, introduction of formyl group
by catalytic hydroformylation using syngas and its reduction using relatively
lesser quantities of NaBH renders our process a distinct synthetic advantage
4
by lowering salt formation. Moreover, use of heterogeneous acid catalyst (for
single-pot transketalization and cyclocondensation) does not require water
wash. On the other hand, the acid catalyst is simply filtered and the product
distilled. The process presented here is environmentally friendly and much
superior to the reported route for synthesis of 3 and is amenable for commer-
cial exploitation. In addition, the byproduct cylohexanone was recovered and
reused.
In conclusion, synthesis of novel tetrahydrofurans 3 and 11 through a
three-step catalytic route starting from very common reactants is described.
The process presented here has greater atom economy when compared to
the literature methods. Furthermore, catalytic reduction of aldehyde (5) and
use of continuous reaction for hydroformylation are being explored to make
the preparation of 3 more efficient. Although representative neonicotinoids
[
13]
have high margins of safety,
development of less toxic and more potent
insecticides depends greatly on the availability of new and diverse tetrahydro-
furan skeletons such as 11. Synthesis and biological evaluation of new
neonicotinoid insecticides derivable from tetrahydrofuran 11 are underway
and the findings at this stage are somewhat provisional.

9
76
S. K. Potluri, A. R. Ramulu, and M. Pardhasaradhi
EXPERIMENTAL
General Directions
1
13
H-NMR (200 MHz) and C-NMR (50 MHz) spectra were recorded on a
Varian FT (Gemini) instrument, using tetramethyl silane (TMS) as the
internal standard. The chemical shifts are expressed in d scale. The abbrevia-
tions such as s, d, t, m, and b refer to singlet, doublet, triplet, multiplet, and
broad respectively. Mass spectra were recorded on VG Micromass 7070 H
(
EI and CI) instruments. Elemental analyses were recorded on a Perkin-
Elmer 240C-CHN analyzer. Completion of the reaction and purity of the
synthesized compounds were checked by TLC performed on silica gel
(
catalyst, RhHCO(TPP) , was purchased from Aldrich. Hydroformylation
acmes) plates, using iodine and H SO for visualizing the spots. Rhodium
2 4
3
reaction was carried out in an Andreas Hofer autoclave.
Formyl-7,12-dioxaspiro[5,6]dodecane (5): 7,12-Dioxaspiro[5,6]dodec-
9-ene (101 g, 0.6 mol), triphenyl phosphine (5.0 g, 0.018 mol), toluene
(100 ml), and the conventional hydroformylation catalyst RhHCO(TPP)3
(1.25 g, 0.001 mol) were taken into an autoclave. It was heated to 1008C
with syngas under 130 bar for 4 h. The reaction product after evaporation of
the solvent was distilled at 110–1138C/1 torr to give 9-formyl-7,12-dioxaspiro
[
5,6]dodecane (5) (110 g) as colorless liquid in 93% yield.
1
H-NMR (CDCl ) d 1.30–1.75 (m, 12H, 6 ꢀ CH ), 2.42 (m, 1H,
3
2
CHCHO), 3.55 (m, 2H, OCH ), 3.95 (m, 2H, OCH ), and 9.68 (s, 1H,
2
2
1
3
CHO). C-NMR (CDCl ) d 2.63, 22.74, 25.27, 33.24, 33.41 (5 ꢀ CH ),
3
2
2
8.43 (OCH CH ), 51.31 (CHCHO), 58.84 (OCH ), 59.54 (OCH ), 101.17
2 2 2 2
þ
(
spiro C), and 202.22 (CHO). MS (EI) m/z (%): 198 (M , 48), 169 (100),
155 (52). Anal. calcd. for C H O : C, 66.64; H, 9.15. Found: C, 66.68;
H, 9.12.
11 18 3
9
-Hydroxymethyl-7,12-dioxaspiro[5,6]dodecane (6): To a solution of
-formyl-7,12-dioxaspiro[5,6]dodecane (5) (100 g, 0.5 mol) in methanol
100 ml) was added in small portions NaBH4 (6.3 g, 0.16 mmol) while
9
(
stirring the solution and maintaining the temperature below 108C. After
complete addition, the reaction mixture was stirred for 3 h at 208C. The
product residue obtained after evaporation of methanol was treated with
water (20 ml), extracted into solvent ether (250 ml), and was distilled at 96–
1008C/0.3 torr to give 9-hydroxymethyl-7,12-dioxaspiro[5,6]dodecane (6)
(
98 g) as colorless viscous liquid in 98% yield.
1
H-NMR (CDCl ) d 1.35–1.58 [m, 10H, (CH ) ], 1.70 (m, 1H,
3
2 5
CHCH OH), 1.80 (m, 2H, CH CH), 3.58 (d, 2H, J ¼ 4 Hz, CH OH), and
2
2
2
1
3
3
4
.70–3.82 (m, 4H, 2 ꢀ OCH ). C-NMR (CDCl ) d 22.5, 25.1, 31.9, 33.4,
2
3
1.4 (CH , CHCH OH), 59.0 (CH OH), 62.2, 62.7 (2 ꢀ OCH ), and 100.8
2 2 2 2
þ
(spiro C). MS (EI); m/z (%): 200 (M , 30), 157 (100), 99 (38), 85 (50).
Anal. calcd. for C H O : C, 65.97; H, 10.07. Found: C, 65.94; H, 10.02.
1
1 20 3

Synthesis of Tetrahydrofurans
977
3
-(Hydroxymethyl)-tetrahydrofuran (3): A mixture of 9-hydroxy-
methyl-7,12-dioxaspiro[5,6]dodecane (6) (100 g, 0.5 mol), methanol (100 ml)
and Amberlyst-15 (5 g) was heated to reflux and methanol distilled out. The
residue was then heated to 1208C and maintained for 0.5 h. The catalyst was
filtered and the residue distilled at 90–948C/7 torr to give 3-(hydroxymethyl)-
tetrahydrofuran (46 g) as colorless liquid in 90% yield.
1
H-NMR (CDCl ) d 1.60 (m, 1H, J ¼ 13 Hz, J ¼ 7 Hz, CH CH), 1.98
3
2
(
m, 1H, J ¼ 7 Hz, CH CH), 2.19 (m, 1H, D O exchangeable, OH), 2.40
2 2
2
2
(
m, 1H, J ¼ 13 Hz, J ¼ 7 Hz, CHCH OH), 3.45–3.62 (m, 4H, 2 ꢀ OCH ),
1
3
and 3.68–3.88 (m, 2H, CH OH). C-NMR (CDCl ) d 28.4, 41.2 (CH CH);
2
3
2
þ
4.1, 67.6, and 70.4 (OCH , CH OH). MS (EI) m/z (%): 102 (M , 10), 101
2 2
6
(
100), 84 (50).
9
-Formyl-9-hydroxymethyl-7,12-dioxaspiro[5,6]dodecane (7): To the
stirred solution of 9-formyl-7,12-dioxaspiro[5,6]dodecane (5) (50 g, 0.252 mol)
in benzene (50 ml) were added triethylamine (25.5 g, 0.252 mol) and 37% of
formaldehyde solution (21 g, 0.252 mol) in small portions at room temperature,
and the stirring was continued for 72h. The aqueous phase was removed,
organic phase was dried over anhydrous Na SO , and the solvent was evapor-
2
4
ated under reduced pressure to give a dense syrup.
,9-Bis(hydroxymethyl)-7,12-dioxaspiro[5,6]dodecane (8): To a solution
of 9-formyl-9-hydroxymethyl-7,12-dioxaspiro[5,6] dodecane (7) (20 g,
.087 mol) in methanol (50 ml) was added NaBH4 (2.0 g, 0.052 mol) in
9
0
small portions while stirring the solution and maintaining the temperature
below 108C. After complete addition, stirring continued for 3 h at 208C.
The reaction mixture was treated with water (20 ml) and the product
extracted into ethylacetate/ether. The combined solvent extracts were dried
over anhydrous Na SO and evaporated under reduced pressure to give
2
4
9
Recrystallization from ethylacetate gave (19.1 g) pure crystalline compound
,9-bis(hydroxymethyl)-7,12-dioxaspiro[5,6] dodecane (8) as a white solid.
1
in 95% yield. Mp 135–1378C. H-NMR [CDCl ) d 1.40–1.60 [bs, 10H,
3
(
CH ) ; 2H, CH C], 3.45 (s, 4H, 2 ꢀ CH OH), and 4.08–4.20 (m, 4H,
2
5
2
2
1
3
2
ꢀ OCH ). C-NMR (CDCl ) d 22.75, 25.41, 33.12, 33.47, 42.91 (CH ,
2
3
2
C), 57.12 (2 ꢀ CH OH), 63.03, 63.35 (2 ꢀ OCH ), and 100.51 (spiro C).
2 2
þ
MS (EI); m/z (%): 230 (M , 43), 187 (100), 115 (43).
,3-Bis(hydroxymethyl)tetrahydrofuran (11): A mixture of 9,9-
3
bis(hydroxymethyl)-7,12-dioxaspiro[5,6]dodecane (8) (50 g, 0.217 mol),
methanol (20 ml), and Amberlyst-15 (1 g) was heated to reflux and
methanol distilled off. The residue was then heated to 1208C and continued
for 0.5 h. The catalyst was filtered, and the filtrate was evaporated to
give liquid product. The crude product was purified by column chromato-
graphy; eluting with 1:9 EtOAc/hexane gave the by-product (10) as a
colorless liquid and gradually increasing the polarity to 1:1 EtOAc/hexane
gave 3,3-bis(hydroxymethyl)tetrahydrofuran (11) as colorless liquid (25.7 g)
in 90% yield.

9
78
S. K. Potluri, A. R. Ramulu, and M. Pardhasaradhi
1
H-NMR (CDCl ) d 1.66 (t, 2H, J ¼ 9 Hz, CH C), 3.57–3.67 (m, 6H,
3
2
1
3
2
ꢀ CH OH, OCH C), 3.82 (t, 2H, J ¼ 9 Hz, OCH CH ).
C-NMR
2
2
2
2
(
CDCl ) d 31.50, 49.50 (CH C), 65.84, 67.40, and 72.74 (2 ꢀ OCH ,
3
2
2
þ
2
ꢀ CH OH). MS (CI, acetone) m/z (%): 133 [(M þ H) , 83], 115 (35),
2
101 (33), and 43 (100). Anal. calcd. for C H O : C, 62.58; H, 9.63.
Found: C, 62.63; H, 9.57.
1
2 22 4
1
,7,14-Trioxadispiro[4.2.5.2]pentadecane (10): H-NMR (CDCl3)
2
d 1.34–1.47 f[b, 6H, (CH ) ], 1.53–1.67 [m, 4H, (CH ) ]g, 1.71–1.81
2
3
2 2
1
3
(
b, 2 H, CH C), and 3.60–3.77 (m, 8H, 4 ꢀ CH O). C-NMR (CDCl ,) d:
2
2
3
2
2.39, 25.55, 30.26, 32.83, 34.49, 42.87 (CH ), 66.16, 67.12, 67.58, 73.05
2
þ
(
OCH ); 74.91 and 97.90 (spiro C). MS (EI) m/z (%): 212 (M , 13), 183
2
(
C, 67.91; H, 9.47.
10), and 169 (100). Anal. calcd. for C H O : C, 67.89; H, 9.50. Found:
1
2 20 3
ACKNOWLEDGMENTS
We are grateful to UGC–New Delhi for providing fellowships to S.K.P. and
A.R.R. We thank CSIR–New Delhi and IICT–Hyderabad for providing the
facilities to work.
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