A convenient synthesis of 3,3-dimethylbutyraldehyde

Article abstract of DOI:10.1081/SCC-100106050

3,3-Dimethylbutyraldehyde is synthesized from the reaction of 1-chloro-3,3-dimethylbutane with DMSO in presence of a base and substoichiometric amounts of MX (M=Na, K; X=Br, I).

Full text of DOI:10.1081/SCC-100106050

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A CONVENIENT SYNTHESIS OF 3,3-
DIMETHYLBUTYRALDEHYDE
Zhi Guo a , Rachel Sawyer a & Indra Prakash b
a The NutraSweet Company , Research and Development, 601 E. Kensington Road, Mt.
Prospect, Illinois, 60056, U.S.A.
b The NutraSweet Company , Research and Development, 601 E. Kensington Road, Mt.
Prospect, Illinois, 60056, U.S.A.
Published online: 20 Aug 2006.
To cite this article: Zhi Guo , Rachel Sawyer & Indra Prakash (2001) A CONVENIENT SYNTHESIS OF 3,3-
DIMETHYLBUTYRALDEHYDE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:21, 3395-3399, DOI: 10.1081/SCC-100106050
To link to this article: http://dx.doi.org/10.1081/SCC-100106050
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SYNTHETIC COMMUNICATIONS, 31(21), 3395–3399 (2001)
A CONVENIENT SYNTHESIS OF
3,3-DIMETHYLBUTYRALDEHYDE
Zhi Guo, Rachel Sawyer, and Indra Prakash*
Research and Development, The NutraSweet
Company, 601 E. Kensington Road,
Mt. Prospect, Illinois 60056, USA
ABSTRACT
3,3-Dimethylbutyraldehyde is synthesized from the reaction
of 1-chloro-3,3-dimethylbutane with DMSO in presence of a
base and substoichiometric amounts of MX (M ¼ Na, K;
X ¼ Br, I).
Neotame (N-[N-(3,3-dimethylbutyl)-L-a-aspartyl]-L-phenylalanine-
L-methyl ester) is the next generation of non-nutritive sweetener from the
NutraSweet Company. Neotame has a sweetness intensity about 8000 times
that of sucrose and 30–40 times that of aspartame and is expected to have a
wide range of applications in food categories.1 A petition was submitted in
December 1998 to the US FDA for the general use of neotame as a sweet-
ener. Neotame is synthesized by reductive alkylation of aspartame with
3,3-dimethylbutyraldehyde (A) (Eq. 1).2
*Corresponding author.
3395
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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GUO, SAWYER, AND PRAKASH
In the process development of neotame, we have required large quan-
tities of high quality A. Although A can be purchased from various vendors,
it is advantageous from a supply standpoint to prepare A economically to
reduce the overall cost of neotame. Therefore it was decided to explore
economic synthetic routes to A.
It has been reported in the literature that A can be synthesized
from the hydrolysis of 1,1-dichloro-3,3-dimethylbutane,3 oxidation of 3,3-
dimethylbutanol,4 ozonolysis of 4,4-dimethyl-1-pentene,5 and reduction of
3,3-dimethylbutyl chloride.6 However, none of these methods were able to
meet our cost goals.
The oxidation of a primary alkyl chloride or bromide with dimethyl
sulfoxide (DMSO) to generate an aldehyde was described by Engel and
co-workers.7 The reaction was facilitated by addition of 1.5 equivalent of
sodium iodide. The reaction proceeds by formation of an alkyl iodide which
is oxidized by DMSO.
This methodology seems applicable to the synthesis of A from
1-chloro-3,3-dimethylbutane, which can be readily prepared from the con-
densation of ethylene with tert-butyl chloride using AlCl3 as a catalyst.8
However, the usage of 1.5 equivalent of iodide is still undesirable on an
industrial scale due to its cost.
We describe herein a procedure for the synthesis of A from 1-chloro-
3,3-dimethylbutane in the presence of a base and a substoichiometric
amount of alkali bromide or iodide (Eq. 2).
1-Chloro-3,3-dimethylbutane itself does not react with DMSO at an
appreciable rate without the addition of bromide or iodide. Alkali bromide

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3,3-DIMETHYLBUTYRALDEHYDE
3397
or iodide facilitates the reaction by the formation of 1-bromo-3,3-dimethyl-
butane or 1-iodo-3,3-dimethylbutane, which is subsequently oxidized by
DMSO to generate A. Since alkali bromide costs much less than alkali
iodide, it would be economically advantageous to use bromide in Eq. 2.
The reaction also works well with 1-bromo-3,3-dimethylbutane or 1-iodo-
3,3-dimethylbutane.
In a typical experiment, a mixture of 1-chloro-3,3-dimethylbutane,
DMSO, MX (M ¼ Na, K; X ¼ Br, I) and a base was loaded into a reactor
and heated to 130–140ꢀC with agitation for up to 14 h. The usage of alkali
bromide and iodide is about 50% and 10–50% (w/w) respectively. An excess
amount of a base, such as bicarbonate, carbonate, or zinc oxide, was used to
neutralize HCl. Dimethyl sulfide was formed and distilled from the mixture
during the reaction, which was terminated when > 95% of the 1-chloro-
3,3-dimethylbutane reacted. The reaction mixture was subsequently distilled
under house vacuum to yield the crude aldehyde product, which can be
purified by further fractional distillation and used for most organic syn-
theses. The crude aldehyde may also be purified through formation and
isolation of the solid A/sodium bisulfite adduct, Eq. 3. Regeneration from
a base such as sodium bicarbonate in aqueous media generates A with a
purity > 99%.
The final yield of A is 58% based on 1-chloro-3,3-dimethylbutane after
purification through the aldehyde/bisulfite adduct and regeneration.
Compound A produced from this process has been used successfully to
produce high quality neotame.
In conclusion, we have developed a cost-effective synthetic route to
3,3-dimethylbutyraldehyde (A), a precursor to neotame. This process is
robust and can be readily practiced on a commercial scale. We have also
demonstrated that iodide may not be necessary, at least in our case, for the
oxidation of primary alkyl chloride or bromide with DMSO to generate the
corresponding aldehyde.

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GUO, SAWYER, AND PRAKASH
EXPERIMENTS
Preparation of 1-chloro-3,3-dimethylbutane. This compound was
synthesized according to the literature.8 The catalyst used in the reaction,
AlCl3, may react with tert-butyl chloride at room temperature to generate
an inactive material. It is desirable to add AlCl3 at low temperature and to
introduce ethylene as soon as possible after the catalyst dissolves.
Reaction of 1-chloro-3,3-dimethylbutane with DMSO/NaI. A 100 ml
round bottom flask was loaded with 2.0 g 1-chloro-3,3-dimethylbutane,
2.0 sodium bicarbonate, 1.0 g NaI and 20 g DMSO-d6. The mixture was
stirred and heated to 140ꢀC for 2.5 h. 1H NMR indicated that 62%
1-chloro-3,3-dimethylbutane was converted to 3,3-dimethylbutyraldehyde.
Reaction of 1-chloro-3,3-dimethylbutane with DMSO/KBr. A 100 ml
round bottom flask was loaded with 3.1 g 1-chloro-3,3-dimethylbutane,
2.1 sodium bicarbonate, 1.5 g KBr and 18 g DMSO-d6. The mixture was
stirred and heated to 140ꢀC for 4.5 h. H NMR indicated that the yield of
1
3,3-dimethylbutyraldehyde was 70%.
Reaction of 1-chloro-3,3-dimethylbutane with DMSO/NaBr. A 500 ml
round bottom flask fitted with a distillation setup was loaded with 46.1 g
1-chloro-3,3-dimethylbutane, 23 g sodium bromide, 20 g zinc oxide and
276 g DMSO. The mixture was stirred and heated with an oil bath to
135–140ꢀC under the nitrogen atmosphere for 12–14 h, during which some
low boiling material (mostly dimethyl sulfide) was collected in a receiver.9
The reaction mixture was cooled to below 40ꢀC and distilled under house
vacuum to collect 31.6 g crude product (80% 3,3-dimethylbutyraldehyde) in
a new receiver.
Purification of crude 3,3-dimethylbutyraldehyde. To a mixture of 30.6 g
of the above described crude product (80% 3,3-dimethylbutyraldehyde) and
240 ml methyl tert-butyl ether (MTBE) was added drop wise 30 g sodium
bisulfite in 60 ml water over a period of 20 min with vigorous agitation at
0–5ꢀC. A white solid precipitated upon addition of the bisulfite solution.
The thus formed slurry was stirred for another 80 min with ice cooling
followed by filtration. The solid was washed with 100 ml MTBE and
2 ꢁ 100 ml 60/40 (vol/vol) MTBE/methanol and dried in a house vacuum
oven (40ꢀC) overnight. The weight of the dry solid is 48.0 g. 40.0 g of this dry
solid, 22 g sodium bicarbonate and 200 ml water were loaded into a 250 ml
round bottom flask. This mixture was heated to boiling and distilled to yield
an azeotropic mixture of 3,3-dimethylbutyraldehyde and water (b.p.
82–85ꢀC). Phase separation gave 18.0 g 3,3-dimethylbutyraldehyde.10 The
overall yield is 58% based on 1-chloro-3,3-dimethylbutane. The purity of
the aldehyde is >99% by GC. b.p. 106ꢀC. H NMR (DMSO-d6): d 1.01
1
(s, 9H), 2.24 (d, 2H), 9.75 (t, 1H).

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REFERENCES
1. Nofre, C.; Tinti, J.-M. US Patent 1996, 5480668.
3399
2. (a) Nofre, C.; Tinti, J.-M. US Patent 1996, 5510508; (b) Prakash, I. US
Patent 1998, 5728862; (c) Prakash, I.; Bishay, I.; Schroeder, S. Synth.
Commun. 1999, 29, 4461.
3. Schmerling, I. J. Amer. Chem. Soc. 1946, 68, 1650.
4. (a) Wiberg, K.B.; Squires, R.R. J. Amer. Chem. Soc. 1981, 103, 1650.
(b) Cheung, C.K.; Wedinger, R.S.; le Noble, W.J. J. Org. Chem. 1989,
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8. Branstrom, A. Acta Chem. Scand. 1959, 13, 611.
9. Alternatively 1-chloro-3,3-dimethylbutane was added drop-wise over a
period of several hours into a preheated mixture of 1-chloro-3,3-
dimethylbutane, sodium bromide, zinc oxide and DMSO at 130–140ꢀC.
This mixture continued to be heated at 130–140ꢀC for a total of
12–14 h and was subsequently subjected to a similar work up procedure
to produce 3,3-dimethylbutyraldehyde with similar yields.
10. 3,3-Dimethylbutyraldehyde may be oxidized by air into 3,3-dimethyl-
butyracid. Cautions should be taken to limit its contact with air during
3,3-dimethylbutyraldehyde’s handling and storage.
Received in the USA January 21, 2001

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