A convenient synthesis of 3,3-dimethylbutyraldehyde

Article abstract of DOI:10.1081/SCC-100103254

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-100103254

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A CONVENIENT
SYNTHESIS OF 3,3-
DIMETHYLBUTYRALDEHYDE
a
a
b
Zhi Guo , Rachel Sawyer & Indra Prakash
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: 16 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,
31:5, 667-671, DOI: 10.1081/SCC-100103254
To link to this article: http://dx.doi.org/10.1081/SCC-100103254
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SYNTHETIC COMMUNICATIONS, 31(5), 667–671 (2001)
A CONVENIENT SYNTHESIS OF
,3-DIMETHYLBUTYRALDEHYDE
3
Zhi Guo, Rachel Sawyer, and Indra Prakash*
Research and Development, The NutraSweet Company,
01 E. Kensington Road, Mt. Prospect, Illinois 60056, USA
6
ABSTRACT
3
,3-Dimethylbutyraldehyde is synthesized from the reac-
tion 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-ꢀ-aspartyl]-L-phenylalanine 1-
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
1
to have a wide range of applications in food categories. A petition was
submitted in December 1998 to the US FDA for the general use of neotame
as a sweetener. Neotame is synthesized by reductive alkylation of aspartame
2
with 3,3-dimethylbutyraldehyde (A) (Eq. 1).
*
Corresponding author.
6
67
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

6
68
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
3
the hydrolysis of 1,1-dichloro-3,3-dimethylbutane, oxidation of 3,3-
4
5
dimethylbutanol, ozonolysis of 4,4-dimethyl-1-pentene, and reduction of
6
3
,3-dimethylbutyl chloride. 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
7
co-workers. 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
densation of ethylene with tert-butyl chloride using AlCl as a catalyst.
-chloro-3,3-dimethylbutane, which can be readily prepared from the con-
8
3
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
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 130–140 C with agitation for up to 14 hours. The usage of

3
,3-DIMETHYLBUTYRALDEHYDE
669
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 sub-
sequently distilled under house vacuum to yield the crude aldehyde product,
which can be purified by further fractional distillation and used for
most organic syntheses. 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-dimethylbutyraldehyde (A), a precursor to neotame. This process is
3
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.
EXPERIMENTS
Preparation of 1-Chloro-3,3-dimethylbutane
8
This compound was synthesized according to the literature. The
catalyst used in the reaction, AlCl , may react with tert-butyl chloride at
3
room temperature to generate an inactive material. It is desirable to add
AlCl at low temperature and to introduce ethylene as soon as possible after
the catalyst dissolves.
3

6
70
GUO, SAWYER, AND PRAKASH
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 g sodium bicarbonate, 1.0 g NaI and 20 g DMSO-d .
6
ꢀ
1
The mixture was stirred and heated to 140 C for 2.5 hours. H 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-d .
6
ꢀ
1
The mixture was stirred and heated to 140 C for 4.5 hours. H NMR
indicated that the yield of 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 135–140 C under nitrogen atmosphere for 12–14 hours, during
which some low boiling material (mostly dimethyl sulfide) was collected in
9
ꢀ
a receiver. The reaction mixture was cooled to below 40 C and distilled
under house vacuum to collect 31.6 g crude product (80% 3,3-dimethyl-
butyraldehyde) 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
ꢀ
minutes with vigorous agitation at 0–5 C. A white solid precipitated upon
addition of the bisulfite solution. The thus formed slurry was stirred for
another 80 minutes with ice cooling followed by filtration. The solid was
washed with 100 ml MTBE and 2 ꢁ 100 ml 60/40 (vol./vol.) MTBE/metha-
ꢀ
nol and dried in a house vacuum oven (40 C) 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
671
ꢀ
3
,3-dimethylbutylraldehyde and water (b.p. 82–85 C). Phase separation
1
0
gave 18.0 g 3,3-dimethylbutyraldehyde. The overall yield is 58% based on
-chloro-3,3-dimethyl-butane. The purity of the aldehyde is >99% by GC.
b.p. 106 C. H NMR (DMSO-d ): ꢁ 1.01 (s, 9H), 2.24 (d, 2H), 9.75 (t, 1H).
1
ꢀ
1
6
REFERENCES AND NOTES
1
2
. Nofre, C.; Tinti, J.-M. US Patent, 5480668, 1996.
. (a) Nofre, C.; Tinti, J.-M. US Patent, 5510508, 1996; (b) Prakash, I. US
Patent, 5728862, 1998; (c) Prakash, I.; Bishay, I.; Schroeder, S. Synth.
Commun. 1999, 29, 4461.
3
4
. Schmerling, I. J. Amer. Chem. Soc. 1946, 68, 1650.
. (a) Wiberg, K.B.; Squires, R.R. J. Amer. Chem. Soc. 1981, 103, 1650;
(
5
b) Cheung, C.K.; Wedinger, R.S.; le Noble, W.J. J. Org. Chem. 1989,
4, 570.
5
6
7
8
9
. Whitmore, F.C.; Homeyer, A.H. J. Amer. Chem. Soc. 1933, 55, 4557.
. Pospisek, J.; Blaha, K. Collect Czech. Chem. Comm. 1987, 52, 514.
. Dave, P.; Byun, H.-S.; Engel, R. Synth. Comm. 1986, 16, 1343.
. Branstrom, A. Acta Chem. Scand. 1959, 13, 611.
. Alternatively 1-chloro-3,3-dimethylbutane was added drop-wise
over a period of several hours into a preheated mixture of 1-chloro-
3
1
,3-dimethylbutane, sodium bromide, zinc oxide and DMSO at
ꢀ
ꢀ
30–140 C. This mixture continued to be heated at 130–140 C for a
total of 12–14 hours and was subsequently subjected to a similar work
up procedure to produce 3,3-dimethylbutyraldehyde with similar
yields.
1
0. 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 U.S.A. June 7, 2000