Improved synthesis of dialkylaminopyrrolines

Article abstract of DOI:10.1081/SCC-120021030

The literature synthesis of 5-dialkylamino-3,4-dihydro-2H-pyrroles from 5-methoxy-3,4-dihydro-2H-pyrrole has been much improved. In initial assays, the pyrrolinium salts obtained on alkylation of the dibutylaminoamidine are excellent "naked halide" catalysts.

Full text of DOI:10.1081/SCC-120021030

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Improved Synthesis of Dialkylaminopyrrolines
David A. Flosser a & Roy A. Olofson a
a The Pennsylvania State University, Department of Chemistry , University Park,
Pennsylvania, USA
Published online: 17 Aug 2006.
To cite this article: David A. Flosser & Roy A. Olofson (2003) Improved Synthesis of Dialkylaminopyrrolines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:12, 2045-2052, DOI:
10.1081/SCC-120021030
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 12, pp. 2045–2052, 2003
Improved Synthesis of Dialkylaminopyrrolines
*
David A. Flosser and Roy A. Olofson
The Pennsylvania State University, Department of
Chemistry, University Park, Pennsylvania, USA
ABSTRACT
The literature synthesis of 5-dialkylamino-3,4-dihydro-2H-pyrroles
from 5-methoxy-3,4-dihydro-2H-pyrrole has been much improved.
In initial assays, the pyrrolinium salts obtained on alkylation of
the dibutylaminoamidine are excellent ‘‘naked halide’’ catalysts.
Key Words: Dialkylaminopyrrolines; Amidininium salts; Naked
halide catalysts; Phase transfer catalysis; Chloroformates.
*Correspondence: Roy A. Olofson, The Pennsylvania State University,
Department of Chemistry, University Park, PA 16802, USA; E-mail:
rao3@psu.edu.
2045
DOI: 10.1081/SCC-120021030
Copyright & 2003 byMarcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2046
Flosser and Olofson
INTRODUCTION
Hexabutylguanidinium chloride (HBGCl) 1 is an economical ‘‘naked
chloride’’ catalyst with exceptional reactivity and high thermal stability.[1]
Resonance delocalization of the plus charge over four positions not
onlyis responsible for the heat stabilityof 1 but also seems to be a keyto
its high anionic reactivityin phase transfer processes. Although ‘‘fat solu-
bility’’ is a factor, steric shielding of the anion from the cation does not
seem to be important. When solubilityis not a significant problem, hexa-
methylguanidinium chloride (HMGCl) is nearly as active as 1.[1,2] In a
recent study, biguanidinium chlorides (þ charge spread over 5 N’s and 2
C’s) were onlyslightlymore effective than 1 as ‘‘naked chloride’’ cata-
lysts.[3] This led to the efforts reported here to prepare and test low cost
amidinium salts (þ spread over 2 N’s and 1 C) in this role.
RESULTS AND DISCUSSION
Because of its verylow cost and economical conversion to the acti-
vated 2-methoxypyrroline 2, 2-pyrrolidinone seemed an ideal reactant in
the preparation of the aminopyrroline precursor 3 of some desired ami-
dinium salts to test as catalysts.
While treatment of neat 2-pyrrolidinone with Me2SO4 afforded 2
in the reported 71% distilled yield,[4] problems were encountered
in the subsequent conversion of 2 to dibutylaminopyrroline 3.
2-Methoxypyrroline is reported to react with an equiv. of Me2NH.HCl
in ethanol at rt for 24 h to give 2-dimethylaminopyrroline in 84% yield

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Dialkylaminopyrrolines
2047
although the yield is only 43% in the same preparation of 5.[5] Reaction
of free Me2NH requires a month to get 71% of product.[5]
Because of its enhanced lipophilicity, 2-dibutylaminopyrroline 3
was the desired intermediate in the present research. However, since
Bu2NH.HCl is not commerciallyavailable, the reaction first was tried
with Bu2NH and an added equiv. of p-toluenesulfonic acid in ethanol
(rt, 24 h). No product was obtained, implying that the reaction either
required a weaker acid catalyst and/or a significant concentration of
free amine nucleophile. When the reaction also was unsatisfactorywith
0.1-0.2 equiv. of acetic acid (neat, rt-45ꢀC, 24 h, ca. 30% 3), Bu2NH.HCl
was made byadding HCl gas to Bu NH. The yields of 3 and its con-
2
geners, 4 and 5, under varying conditions using catalytic amounts of HCl
are summarized in Table 1.
Keyimprovements over the literature process include the elimination
of solvent thus simplifying workup and reduction in the amount of HCl
(note increase in the yield of 5 from 43% to 84%). From Table 1, it is
evident that HCl is a strong enough acid to be a good catalyst but not so
strong (like pTosOH) that there is no equilibrium with free amine. Above
a certain point, increasing the amount of acid reduces the yield. Also, the
optimum temperature and acid concentration are functions of amine
structure (likelydue to differences in basicityand polarity). Since possible
mechanisms for this process include several steps where both acid and
free amine (as nucleophile and as base) participate, the data are as might
be anticipated.
Table 1. Conversion of 2-methoxypyrroline to various 2-
dialkylaminopyrrolines.
Amine
(R2NH)a
HCl
(mol%)
Temp. Time
(ꢀC)
Distilled
yield (%)
No.
3
(h)
Dibutylamine
0.1
0.2
0.1
0.1
0.3
0.1
0.1
0.1
0.1
25
70
70
80
70
70
80
70
60
72
24
24
24
48
24
24
24
24
No reaction
80
54
62
79
95
4
5
Piperidine
63
84
Diethylamine
No reactionb
aRatio of amine plus its HCl salt to 2-methoxypyrroline is 1:1.
bDiethylamine hydrochloride is insoluble in the reaction
mixture at 60ꢀC but soluble at 70ꢀC.

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2048
Flosser and Olofson
When 3 was alkylated with bromooctadecane, the product salt 6
(54% yield) was stable above 200ꢀC (thermogravimetric analysis at
PPG). Alkylation of 3 with benzyl chloride afforded the amidinium salt
7 in 92% yield as an orange gum (used as 60% solution in o-dichloro-
benzene in catalyst studies). (When tested, other alkyl and substituted
benzyl salts had no advantages over 6 or 7.)
In a commerciallyvaluable process, SNPE has converted octanethiol
to its thiochloroformate 8 in 100% yield by treating the neat liquid with
[6]
phosgene in the presence of only0.2% mole HMGCl.
After flushing awayexcess phosgene and HCl with N followed
2
byvacuum evaporation, the product 8 was effectivelypure without
distillation (too little catalyst to see by NMR). With other ‘‘ClÀ’’
catalysts (R4NþClÀ, anion exchange resins, and ureas and their products
with phosgene, etc.), distillation always was required, because of
increased catalyst amount (>0.01 equiv.) and because yields were
variable with by-products present.[6] When this assaywas repeated with
0.25 mol% of the new amidinium catalyst 7 at rt for 8 h with triphosgene
as the phosgene source (converted to phosgene in the presence of
‘‘ClÀ’’[7]) the reaction again was quantitative, with 8>99% pure without
distillation.
Olofson and Martz together with Senet and co-workers at SNPE
obtained the industriallyimportant 1-chloroethly chloroformate
9 in
96% yield just by stirring acetaldehyde neat with phosgene in the
presence of 3 mol% of benzyltributylammonium chloride (rt/1 h).[2a,8]

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Dialkylaminopyrrolines
2049
Also, the yield of 9 was 98% after an h with only0.5 mol% of
HBGCl.[2a] When this reaction was repeated using 4 mol% of 7 with
triphosgene as the phosgene source (0ꢀC/3 h), the yield of 9 was quanti-
tative. The assayalso afforded pure 9 with 3 mol% of 6 as the catalyst.
However, in both assays side products (acetaldehyde trimer) became
significant when the catalyst concentration was reduced.
In conclusion, an understanding of the factors involved has per-
mitted substantial improvement of the literature route to dialkylamino-
pyrrolines 3-5. The salts 6 and 7 obtained on alkylation of 3 have useful
activityas ‘‘naked halide’’ catalysts.
EXPERIMENTAL
1H and 13C (proton decoupled) NMR spectra were recorded on a
Bruker WP 200, DPX 300, or AMX 360 spectrometer. Mass spectral
(MS) data were obtained at 70 eV on a Kratos MS-9/50 double-focusing
high resolution mass spectrometer.
5-Dialkylamino-3,4-dihydro-2H-pyrroles 3–5
A neat mixture of 5-methoxy-3,4-dihydro-2H-pyrrole 2 (4.95 g,
0.0500 mol), Bu2NH (5.17 g, 0.0400 mol), and Bu2NH.HCl (1.65 g,
0.0100 mol, 20 mol%) (anhyd HCl bubbled into ethereal Bu2NH) was
stirred at 70ꢀC for 24 h. The cooled mixture was neutralized with 21%
NaOEt in ethanol (0.75 g, 0.011 mol), then concentrated and distilled to
obtain, after a 1.0 g forerun of dibutylamine, 7.80 g (80% yield) of pure 3,
b.p.: 100ꢀC at 1.5 mm. 1H NMR (CDCl3): ꢀ 3.66 (t, 2H, J ¼ 7.4 Hz), 3.22
(t, 4H, J ¼ 7.5 Hz), 2.49 (t, 2H, J ¼ 7.9 Hz), 2.0–1.8 (m, 2H), 1.6–1.2 (m,
8H), 0.92 (t, 6H, J ¼ 7.4 Hz). 13C NMR (CDCl3): ꢀ 167.8, 56.6, 48.6, 31.7,
30.6, 24.0, 20.3, 14.0. MS (EI): m/z (%) 196 (Mþ, 29), 181 (9), 167 (26),
139 (18).
Reaction as above of 2 (4.95 g, 0.0500 mol), piperidine (3.83 g,
0.0450 mol), and piperidine.HCl (0.61 g, 0.0050 mol, 10 mol%) at 70ꢀC
for 24 h, followed byneutralization with 21% NaOEt/EtOH (0.41 g,
0.006 mol) afforded 7.20 g (95% yield) of pure 4, b.p.: 90–91ꢀC at
2.5 mm (lit.[5]: 90–91ꢀC at 2.5 mm). H NMR (CDCl3): ꢀ 3.65 (t, 2H,
1
J ¼ 7.1 Hz), 3.4–3.2 (m, 4H), 2.48 (t, 2H, J ¼ 8.2 Hz), 2.1–1.8 (m, 2H),
1.7–1.4 (m, 6H). 13C NMR (CDCl3): ꢀ 168.4, 56.5, 47.2, 31.4, 25.7, 24.6,
23.7. MS (EI): m/z (%) 152 (Mþ, 100).

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2050
Flosser and Olofson
Similar reaction of 2 (5.94 g, 0.0600 mol), Et2NH (3.29 g, 0.0450 mol),
and Et2NH.HCl (0.55 g, 0.0050 mol, 10 mol%) (Aldrich) at 70ꢀC for 24 h,
then neutralization with 21% NaOEt/EtOH (0.41 g, 0.006 mol) yielded
5.90 g (84%) of pure 5, b.p.: 98–101ꢀC at 25 mm (lit.[5]: 98–101ꢀC at
25 mm). 1H NMR (CDCl3): ꢀ 3.67 (t, 2H, J ¼ 7.2 Hz), 3.32 (q, 4H,
J ¼ 6.9 Hz), 2.51 (t, 2H, J ¼ 8.3 Hz), 2.0–1.9 (m, 2H), 1.13 (t, 6H,
J ¼ 7.2 Hz).
N-Alkylpyrrolinium Halides 6, 7
A mixture of 3 (2.5 g, 0.013 mol) and 1-bromooctadecane (5.3 g,
0.016 mol) in CH3CN (20 mL) was stirred at 90ꢀC (18 h) and then con-
centrated. A solution of the residue in CH2Cl2 (65 mL) was extracted with
water (2 ꢁ 65 mL), dried (Na2SO4), concentrated, and the remaining resi-
due dried in vacuo (60ꢀC); then trituated in hexane and dried in vacuo for
18 h to obtain 3.7 g (54% yield) of pure 6, m.p.: 75–78ꢀC. 1H NMR
(CDCl3): ꢀ 3.97 (t, 2H, J ¼ 7.2 Hz), 3.6–3.3 (m, 8H), 2.3–2.1 (m, 2H),
1.9–1.7 (m, 6H), 1.5–1.2 (m, 34H), 1.1–0.8 (m, 9H). IR (NaCl): 2368
(sh, w), 1669 cmÀ1 (s). Thermogravimetric analysis (PPG): stable above
200ꢀC.
A solution of 3 (8.9 g, 0.045 mol) and benzyl chloride (7.5 g,
0.059 mol) in CH3CN (30 mL) was stirred at 90ꢀC overnight. After con-
centration, the remaining orange gum was dried in vacuo at 60ꢀC for 2 h,
then dissolved in CH2Cl2 (50 mL), extracted with water (2 ꢁ 15 mL), and
back extracted with CH2Cl2 (2 ꢁ 15 mL). The combined organic layers
were dried (Na2SO4) and concentrated, and the orange gum was trituated
in ether and dried in vacuo at 80ꢀC overnight to obtain 13.3 g (92% yield)
of pure 7. 1H NMR (CDCl3): ꢀ 7.6–7.2 (m, 6H), 4.98 (s, 2H), 4.00 (t, 2H,
J ¼ 7.2 Hz), 3.6–3.3 (m, 6H), 2.4–2.3 (m, 2H), 2.0–1.6 (m, 4H), 1.5–1.1 (m,
4H), 1.1–0.7 (m, 6H). When the water wash was skipped, 7 was contami-
nated with the HCl salt of 3.
Catalyst Evaluations
A 60% solution of 7 (0.020 g, 0.062 mmol, 0.25 mol%) in o-dichloro-
benzene was added to stirred, cooled (0ꢀC, ice bath) triphosgene (3.0 g,
0.010 mol) under a –70ꢀC condenser. After 5 min, octanethiol (3.7 g,
0.025 mol) (Aldrich) was injected into the yellow liquid and the mixture
stirred for 8 h under the À70ꢀC condenser. The excess phosgene was
flushed awaywith N (20–30 s) followed byshort vacuum evaporation
2

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Dialkylaminopyrrolines
2051
1
to yield pure 1-octyl thiochloroformate 8. H NMR (CDCl3, 300 MHz):
ꢀ 2.93 (t, 2H, J ¼ 6.0 Hz), 1.7–1.6 (m, 2H), 1.5–1.2 (m, 10H), 0.89 (t, 3H).
13C NMR (CDCl3): ꢀ 166.0, 34.0, 31.8, 29.1, 29.0, 28.7, 28.6, 22.7, 14.1.
A 60% solution of 7 (0.10 g, 0.30 mmol, 0.7 mol%) in o-dichloro-
benzene was added to stirred, cooled (À20ꢀC bath) triphosgene (5.1 g,
0.017 mol) and acetaldehyde (1.9 g, 0.043 mol) under a À20ꢀC condenser.
After 15 min, more of the catalyst (0.47 g, 1.4 mmol, 3.3 mol%) solution
was added. The bath temperature was increased (ice bath), and
the mixture was stirred at this temperature for 3 h under the À20ꢀC
condenser. When the excess phosgene was removed with an N2 stream,
1-chloroethyl chloroformate 9 was obtained in quantitative yield.
1H NMR (CDCl3): ꢀ 6.48 (q, 1 H, J ¼ 6.0 Hz), 1.88 (d, 3H, J ¼ 6.3 Hz).
1
13C NMR (CDCl3): ꢀ 148.5, 85.9, 24.4. Yield determined by H NMR
(360 MHz) analysis using the benzylic H’s of the catalyst at ꢀ 4.91 as
an internal standard.
Because the stirred, cooled (0ꢀC) mixture of triphosgene (2.1 g,
0.0067 mol) and 6 (0.32 g, 0.60 mmol, 3 mol%) contained two solids,
acetaldehyde (5 drops) was added to initiate reaction. After 5 min, the
remaining acetaldehyde (0.89 g, 0.020 mol) was added, and the mixture
was stirred at 0ꢀC (3 h). The excess phosgene was evacuated with N2 to
yield 9 free of side products (1H NMR analysis).
ACKNOWLEDGMENTS
We thank PPG Industries for partial support of this research and Dr.
C. Kreutzberger of PPG for advice and arranging the thermogravimetric
analysis.
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2052
Flosser and Olofson
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Received in the USA October 17, 2002