Scale up of a ritter reaction

Article abstract of DOI:10.1021/op980211c

The Ritler reaction of secondary or tertiary alcohols with acrylonitrile provides easy access to acrylamides which would otherwise be difficult to prepare. A safe procedure for conducting this reaction is described.

Full text of DOI:10.1021/op980211c

Organic Process Research & Development 1999, 3, 232−234
Scale Up of a Ritter Reaction
Sou-Jen Chang*
Biocide Department, Rohm and Haas Company, 747 Norristown Road, Spring House, PennsylVania 19477
8
Abstract:
thiolation with thiourea (eq 1) according to the literature
The Ritter reaction of secondary or tertiary alcohols with
acrylonitrile provides easy access to acrylamides which would
otherwise be difficult to prepare. A safe procedure for conduct-
ing this reaction is described.
procedure. All literature references on the preparation of
Reaction between nitriles and alcohols or olefins to give
1
carboxylic amides, the Ritter reaction, is well documented.
This reaction is a very efficient way to prepare amides with
secondary or tertiary alkyl groups on the nitrogen. Modifica-
2
tion of the Ritter reaction allows primary alcohols to react
with nitriles when activated by trifluoromethanesulfonic
anhydride, complementing the traditional Ritter reactions.
Activation of olefins by electrophilic palladium(II) salts
N-cyclohexylacrylamide (2) as of 1984 involved adding
concentrated sulfuric acid to a mixture of acrylonitrile and
cyclohexanol. This worked reasonably well on a small
laboratory scale. When we scaled up this procedure to 2 mol
reactant scale, a violent reaction occurred several hours after
all the reagents had been mixed at room temperature, ejecting
most of the flask contents. Further search revealed an earlier
3
instead of strong acids was shown to be feasible, though less
successful. More recently, the Ritter reaction was elegantly
applied to the enantiospecific synthesis of 3-aza-bicyclic
4
compounds using chiral terpenes and to the chiral synthesis
5
6
9
of cis-aminoindanol. Surprisingly, Sohar et al. observed a
Ritter reaction with an unexpected retention of chirality at
the carbonium ion center. Application of the Ritter reaction
patent which described the violent nature of this particular
reaction. However, no other paper mentioned the runaway
or violent nature of the Ritter reaction, especially when
acrylonitrile was the substrate.
7
along with the sigmatropic rearrangement was also reviewed
for the synthesis of N-containing terpenes. These develop-
ments exemplified the significance of the Ritter reaction in
the preparation of a variety of compounds.
Seeking a safer way to perform this reaction, we realized
that there was a long induction period at room temperature
in the literature procedure due to the low instantaneous
9
As part of an effort to develop a practical process for
preparing a mildewcide, N-cyclohexylisothiazolone, we
needed to synthesize the starting N-cyclohexyl-3-mercapto-
propionamide (1). Compound 1 can be prepared by the Ritter
sulfuric acid-to-nitrile/alcohol ratio, until all the necessary
sulfuric acid had been added. We believed that the formation
of cyclohexyl carbonium ion was the rate-determining
step. The concentration of the acid is too low with respect
to that of the alcohol during acid addition. Therefore,
generation of cyclohexyl carbonium ion intermediate is very
slow until enough sulfuric acid is added. Presumably, the
rate of formation of the cyclohexyl carbonium ion is
first order in cyclohexanol and first order in sulfuric acid.
We used two different approaches to address these issues.
First, we kept the reaction temperature moderate through-
out the course of reagent addition to prevent buildup of
unreacted starting materials. Second, we maintained a
high and constant sulfuric-to-cyclohexanol ratio throughout
the addition. These two modifications ensured a reasonable
rate of carbonium ion formation and its reaction with
acrylonitrile.
reaction of acrylonitrile with cyclohexanol, followed by
*
Correspondence should be sent to the current address: CAPD Process
Research, Abbott Laboratories, D-54P, Bldg. R-14, 1401 N. Sheridan Rd., North
Chicago, IL 60064-4000.
(
(
(
(
1) For review of Ritter reactions, see: Krimen, L. I.; Cota, D. J. Org. React.
1
969, 17, 213.
2) Martinez, A. G.; Alvarez, R. M.; Vilar, E. T.; Fraile, A. G.; Hanack, M.;
Subramanian, L. R. Tetrahedron Lett. 1989, 30 (5), 581.
3) Hegedus, L. S.; Mulhern, T. A.; Asada, H. J. Am. Chem. Soc. 1986, 108,
Cyclohexanol was also successfully replaced with cyclo-
hexene to give acrylamide 2 with comparable yield. This
eliminated the need to thaw the cyclohexanol, which had
been stored outside in cold weather. The following methods
illustrate our improvements to this Ritter reaction.
6
224.
4) Samaniego, W. N.; Baldessari, A.; Ponce, M. A.; Rodriguez, J. B.; Gros,
E. G.; Caram, J. A.; Marschoff, C. M. Tetrahedron Lett. 1994, 35 (38),
6
967.
(
5) Senanayake, C. H.; Roberts, F. E.; DiMichele, L. M.; Ryan, K. M.; Liu,
J.; Fredenburgh, L. E.; Foster, B. S.; Douglas, A. W.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1995, 36 (23), 3993.
6) Sohar, P.; Mathre, D. J.; Blacklock, T. J. European Patent EP 0617037A1,
(
(
1
994.
(8) Bauer, L.; Welsh, T. L. J. Org. Chem. 1961, 26, 1443.
(9) Fugate, W. O.; D’Errico, M. J. U.S. Patent 3,151,157, 1964.
7) Ichikawa, Y. Yuki Gosei Kagaku Kyokaishi 1997, 55 (4), 281.
2
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10.1021/op980211c CCC: $18.00 © 1999 American Chemical Society and Royal Society of Chemistry
Published on Web 04/30/1999

Improved Ritter Reaction
3-mercaptopropionamide in chorobenzene (72.4% yield by
potency assay).
Method A. An inert solvent (e.g., monochlorobenzene)
was charged to the reactor and heated to 45-50 °C.
Concentrated sulfuric acid and a premixed mixture of
acrylonitrile and cyclohexanol were simultaneously added
to the flask via two separate addition funnels at such a rate
that addition times for both reagents were the same. After
the addition, the mixture was warmed to complete the
reaction. In this method, the product mixture may be taken
directly to the thiolation step to give mercaptopropionamide
Method A: Preparation of N-Cyclohexylacrylamide
(2) Using Cyclohexene. A homogeneous mixture of acry-
lonitrile (50 g, 0.94 mol) and cyclohexene (77.4 g, 0.94 mol)
was added to a stirred volume of monochlorobenzene (220
mL) at 45 °C while concentrated sulfuric acid (192 g, 98%)
was added from another addition funnel. The rate of the
addition was adjusted such that the pot temperature was kept
at 45-55 °C. The addition time was kept at about 30 min
for both reagents. After the addition, the mixture was heated
at 60 °C for an additional 3 h. The mixture was cooled to
ambient temperature, and the chlorobenzene was removed
under reduced pressure. The resulting brown liquid was
poured into stirred ice water (2 L) and mixed for 2 h at room
temperature. The white precipitate was filtered and washed
with cold water until the filtrate was no longer acidic. The
wet product cake was dried in a vacuum oven at 55 °C to
yield the desired N-cyclohexylacrylamide (2). Yield was
1
in the same solvent. This mercaptoamide solution may, in
turn, be used in the chlorination step to prepare the desired
isothiazolone biocide.10
Method B (Solvent-Free Process). All or part of the
requisite concentrated sulfuric acid was charged to the reactor
and heated to 45-50 °C. A premixed mixture of acrylonitrile
and cyclohexanol along with any remaining sulfuric acid was
added via two separate addition funnels at such a rate as to
maintain the reaction temperature at 45-50 °C. After the
addition(s), the mixture was warmed to reaction completion.
The mixture can be quenched with water, and the acrylamide
product can be filtered and dried, or it can be directly treated
with thiourea to give the mercaptopropionamide 1.
131.2 g (90.9%). This material was used directly for the next
step without further purification.
Method B: Preparation of N-Cyclohexylacrylamide
(2). Sulfuric acid (95.8%, 46.0 g, 0.45 mol) was placed in a
Both methods provide a higher starting temperature for
facile generation of the cyclohexyl carbonium ion and its
trapping with acrylonitrile. A stoichiometric or an excess
amount of the sulfuric acid is also present at all times during
the addition to ensure reactant consumption. There is no
buildup of unreacted starting materials which might lead to
violent eruption after all the reactants are mixed in either
method. Both methods scaled up smoothly in the pilot plant
and successfully provided the N-cyclohexyl-3-mercaptopro-
jacketed 3-L, three-neck flask and heated to 45 °C. A mixture
of acrylonitrile (94.5 g, 1.783 mol) and cyclohexanol (180.2
g, 1.802 mol) was prepared and added to the flask simulta-
neously with additional sulfuric acid (95.8%, 322.3 g, 3.151
mol) using two addition funnels, keeping the temperature at
4
5-55 °C during the addition. At the end of the addition,
the brown solution was heated to 60 °C for 3 h to complete
the reaction. The mixture was then poured into 3 L of ice
water with constant stirring. The white precipitate that formed
was filtered, washed with water until the filtrate was no
longer acidic, and dried in a vacuum oven at 55 °C to yield
N-cyclohexylacrylamide (2, 242.4 g, 88% yield) as white to
off-white solids; mp 109-110 °C.
10
pionamide for the manufacture of an isothiazolone biocide.
Method B provides a solvent-free process, an attractive
feature when the starting nitrile/alcohol (or alkene) is a liquid.
Experimental Section
General Procedure for Preparing N-Cyclohexyl-3-
mercaptopropionamide (1) from N-Cyclohexylacrylamide
All starting materials were either commercial grades or
purchased from Aldrich Chemical Co. and used without
further purification. Commercial grade sulfuric acid of 95-
(2). A mixture of N-cyclohexylacrylamide (15.3 g, 0.1 mol),
concentrated hydrochloric acid (19.4 g, 37.6%), thiourea (7.6
g, 0.1 mol), and water (10 g) was heated to 60 °C for 2 h.
The mixture was cooled to 20 °C, and aqueous sodium
hydroxide (50%, 16 g) was slowly added under nitrogen,
keeping the temperature below 30 °C. The resulting mixture
was heated to 60 °C for 1 h and extracted with methylene
chloride (2 × 50 mL). Removal of methylene chloride
afforded N-cyclohexyl-3-mercaptopropionamide (1, 16.9 g),
which was purified by vacuum distillation at 0.095 mmHg/
98% concentration was equally suitable for the reactions.
All melting points were uncorrected.
Method A: Preparation of N-Cyclohexyl-3-mercap-
topropionamide (1). A premixed solution of acrylonitrile/
cyclohexanol (13.3 g, 0.25 mol/25.1 g, 0.25 mol) and
concentrated sulfuric acid (51.1 g, 95.8%, 0.5 mol) were
added through two addition funnels into a flask containing
chlorobenzene (60 g) at 45-55 °C. The mixture was then
heated to 60-70 °C for 3-5 h and cooled to 20 °C. After
the mixture was cooled, water (150 g) was added slowly.
After the mixture was stirred for 30 min, thiourea (19 g,
130 °C to yield pure N-cyclohexyl-3-mercaptopropionamide
(13.7 g, yield 73.3%); mp 73.5-75.5 °C.
Note: Mercaptopropionamides are susceptible to air
0.25 mol) was added, and the mixture was warmed to 60 °C
oxidation to give the corresponding disulfide. The thiolation
reaction, during and after treatment with sodium hydroxide,
should be carried out under a blanket of nitrogen.
Preparation of N-(2-Methyl-2-butyl)methacrylamide.
A premixed solution of 2-methyl-2-butene (7.0 g, 0.1 mol)
and methacrylonitrile (6.7 g, 0.1 mol) was added to a stirred
solution of concentrated sulfuric acid (98%, 10.0 g) in acetic
for 1 h. Upon cooling of the mixture to 20 °C, aqueous
sodium hydroxide solution (50%, 80 g, 1 mol) was added
between 20 and 60 °C under nitrogen, and the mixture was
held at 60 °C for 1 h. The organic layer was separated and
washed with warm water to yield 33.9 g of N-cyclohexyl-
(10) Chang, S. J. U.S. Patent 4,868,310, 1989.
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acid (50 mL) at 10 °C. The addition rate was adjusted such
that the pot temperature was maintained at 10-20 °C. After
the addition, the mixture was allowed to stir overnight at
room temperature. The brown thick liquid was poured into
centrated to an oil. Distillation of the crude product at 10
mmHg yielded N-(2-methyl-2-butyl)methacrylamide (10.1 g,
65%); bp 84 °C.
2
1
00 g of ice water, and the product was extracted with 2 ×
Received for review August 14, 1998.
OP980211C
00 mL of methylene chloride. The methylene chloride
solution was dried over sodium sulfate, filtered, and con-
234
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Vol. 3, No. 3, 1999 / Organic Process Research & Development