An improved synthesis of 4-aminobutanenitrile from 4-azidobutanenitrile and comments on room temperature stability

Article abstract of DOI:10.1080/00397911.2020.1832527

4-Aminobutanenitrile (1) is an important synthetic intermediate for neurological disorder therapeutics including Parkinson’s and Alzheimer’s diseases, and is an industrial precursor to pyrroline and pyrrolidine. Synthesis of 1 by Co(II) catalyzed reduction of 4-azidobutanenitrile (2) with NaBH₄, or by a one-pot Staudinger reduction of 2 in THF, was low yielding. ¹H-NMR analysis of the Staudinger reduction revealed the formation of iminophosphorane intermediate (3) after 22 h at rt, and that increasing the reaction temperature from rt to 40 °C promoted hydrolysis of 3 to 1. A modified Staudinger reduction of 2 involving pyridine as solvent, addition of water 3 h after triphenylphosphine, and a temperature increase to 40 °C, gave rise to 1 in 69% yield. 1 is unstable at rt, thus the hydrochloride salt of 1 (1?HCl) was prepared by bubbling HCl_(g) through a solution of 1 in chloroform. 1?HCl is stable at rt and is hence the preferred form for storage.

Full text of DOI:10.1080/00397911.2020.1832527

Synthetic Communications
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Chemistry
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An improved synthesis of 4-aminobutanenitrile
from 4-azidobutanenitrile and comments on room
temperature stability
Patrick K. Capon , Thomas D. Avery , Malcolm S. Purdey & Andrew D. Abell
To cite this article: Patrick K. Capon , Thomas D. Avery , Malcolm S. Purdey & Andrew D. Abell
(2020): An improved synthesis of 4-aminobutanenitrile from 4-azidobutanenitrile and comments on
room temperature stability, Synthetic Communications, DOI: 10.1080/00397911.2020.1832527
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https://doi.org/10.1080/00397911.2020.1832527
An improved synthesis of 4-aminobutanenitrile from
4-azidobutanenitrile and comments on room
temperature stability
Patrick K. Capona,b,c , Thomas D. Averya,b,c , Malcolm S. Purdeya,b,c , and
Andrew D. Abella,b,c
aDepartment of Chemistry, School of Physical Sciences, The University of Adelaide, Adelaide, Australia;
bInstitute for Photonics and Advanced Sensing (IPAS), The University of Adelaide, Adelaide, Australia;
cAustralian Research Council Centre of Excellence for Nanoscale BioPhotonics (CNBP), Adelaide, Australia
ABSTRACT
ARTICLE HISTORY
Received 2 September 2020
4-Aminobutanenitrile (1) is an important synthetic intermediate for
neurological disorder therapeutics including Parkinson’s and
Alzheimer’s diseases, and is an industrial precursor to pyrroline and
pyrrolidine. Synthesis of 1 by Co(II) catalyzed reduction of 4-azidobuta-
nenitrile (2) with NaBH4, or by a one-pot Staudinger reduction of 2 in
THF, was low yielding. 1H-NMR analysis of the Staudinger reduction
revealed the formation of iminophosphorane intermediate (3) after
22 h at rt, and that increasing the reaction temperature from rt to
40 ꢀC promoted hydrolysis of 3 to 1. A modified Staudinger reduction
of 2 involving pyridine as solvent, addition of water 3 h after triphenyl-
phosphine, and a temperature increase to 40 ꢀC, gave rise to 1 in 69%
yield. 1 is unstable at rt, thus the hydrochloride salt of 1 (1ꢁHCl) was
prepared by bubbling HCl(g) through a solution of 1 in chloroform.
1ꢁHCl is stable at rt and is hence the preferred form for storage.
KEYWORDS
Aminonitriles; nuclear
magnetic resonance
spectroscopy; stability;
staudinger reduction
GRAPHICAL ABSTRACT
CONTACT Prof. Andrew D. Abell
andrew.abell@adelaide.edu.au
Australian Research Council Centre of Excellence
for Nanoscale BioPhotonics (CNBP), Adelaide, Australia.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

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P. K. CAPON ET AL.
Introduction
Aminonitriles are common structural features in a wide range of bioactive compounds,
as was recently reviewed by Fleming et al.[1] Specifically, 4-aminobutanenitrile (1, see
Fig. 1) is an important synthetic intermediate of neurological disorder therapeutics
including those treating Parkinson’s and Alzheimer’s diseases,[2] and in the industrial
production of pyrroline and pyrrolidine.[3,4] Furthermore, 1 is commonly used in epoxy
resins or as an oil additive,[5] and the characteristic spectroscopic signature of its com-
ponent nitrile (infrared and Raman spectroscopy bands in the 2250–2230 cmꢂ1
range)[6,7] provides an opportunity for spectroscopic identification. For example, 1 can
be used to functionalize carboxylic acid decorated nanomaterials via amide bond forma-
tion, with the nitrile available for spectroscopic validation of functionalization (unpub-
lished work in our laboratory).
In this article, we investigate the synthesis and subsequent stability of 4-aminobutane-
nitrile (1). Its synthesis has been reported previously by reduction of the corresponding
azide, 4-azidobutanenitrile (2). A Staudinger reduction of 2 to 1 was reported by Yuan
and Silverman in 2006,[2] while Fringuelli et al.[8] reported a cobalt(II) catalyzed reduc-
tion of 2 to 1 with NaBH4 in water. In our hands, these procedures were not reprodu-
cible, with little to no product formation observed. Furthermore, in the cases when 1
was obtained, we found it to be unstable at rt in the laboratory, with pure samples
forming a complex mixture over 2–3 days. Here, we discuss these issues in detail and
report an improved Staudinger reduction of 2 to provide 1, including formation of the
hydrochloride salt, 1ꢁHCl.
Results and discussion
Synthesis design and optimization
The key starting material 4-azidobutanenitrile (2) was obtained from 4-bromobutaneni-
trile on reaction with sodium azide (see Supplementary Information),[2] and subsequent
reduction to 1 was attempted under a variety of conditions as shown in Table 1 (reac-
tions Cobalt #1–#3). Attempted reduction with a cobalt(II) chloride hexahydrate catalyst
and NaBH4, in water at rt, gave rise to a quantitative recovery of 2, contrary to the lit-
erature report[8] of a 98% yield of 1 after 10 min (Scheme 1, top route). Extension of
the reaction time up to 1 h did not result in any formation of 1. The addition of surfac-
tant cetyltrimethylammonium bromide (CTABr), as described in the original manu-
script[8] for use with hydrophobic azides (2 is insoluble in water), also returned starting
material 2 without evidence of amine 1. Finally, cobalt(II) catalyst crushed into a fine
powder with a mortar and pestle was used in the reduction to provide increased catalyst
surface area, however, this reaction also returned 2 only.
Figure 1. Structures of 4-aminobutanenitrile (1) and key starting material 4-azidobutanenitrile (2)
with carbon atoms numbered.

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Table 1. Summary of the literature reactions attempted to reduce 4-azidobutanenitrile (2) to 4-ami-
nobutanenitrile (1).
Reaction
Conditions
Result
Cobalt #1 (as per literature)[8]
NaBH4 (2 equiv.), CoCl2.6H2O (0.1
equiv.), water, rt, 10 min to 1 h
NaBH4 (2 equiv.), CoCl2.6H2O (0.1
equiv.), CTABr (0.1 equiv.) water,
rt, 10 min
NaBH4 (2 equiv.), CoCl2.6H2O (0.1
equiv., crushed into a fine
powder), water, rt, 10 min
Triphenylphosphine (1 equiv.), water
(2% v/v), THF, rt, 18 h
Recovered starting material (2)
Cobalt #2
Recovered starting material (2)
Recovered starting material (2)
5% yield of 1
Cobalt #3
Staudinger #1 (as per literature)[2]
Scheme 1. Reduction reactions of 4-azidobutanenitrile (2) to 4-aminobutanenitrile (1). Co(II) catalyzed
reaction resulted in recovery of 2, while the Staudinger reduction in THF was repeatedly low yielding
and required a tedious workup. New conditions were developed for the Staudinger reduction in
anhydrous pyridine to obtain product 1 in > 69% yield. The new conditions contain a simplified
work up and have been scaled up to 26 mmol of starting material 2.
Next, the Staudinger reduction of 2 to 1 was attempted as per literature conditions
(Table 1, entry Staudinger #1 and Scheme 1, central route).[2] Azide 2 was stirred in
THF with 2% (v/v) water and 1 equiv. of triphenylphosphine at rt overnight. The litera-
ture work up was followed, with solvent removed and the residue taken up in ethyl
acetate, followed by extraction of the organic layer with 1 M HCl, adjustment of the
aqueous layer to pH 12 with 1 M NaOH, and extraction with ethyl acetate, then finally
solvent removal to isolate 1 in only 5% yield. The fact that 1 was obtained, albeit in low
yield, prompted further investigation of the reaction progress.
In particular, azide 1 and 1 equiv. of triphenylphosphine were dissolved in CDCl3
(700 mL) and the ensuing reaction was monitored by 1H NMR spectroscopy at rt
1
over three days (Fig. 2 and Table 2). The H NMR spectrum after 18 h revealed two
new resonances at d 3.20 and 1.84 ppm (Fig. 2, blue), when compared to that of 2
(Fig. 2, purple, top) and 1 (Fig. 2, red, bottom). These new resonances are attributed
to the iminophosphorane intermediate (3, see Scheme 1), a known intermediate in
the Staudinger reduction.[9–11] Partial consumption of starting material 2 was

4
P. K. CAPON ET AL.
Figure 2. 1H NMR spectra following the reduction reaction of 4-azidobutanenitrile (2) with triphenyl-
phosphine in CDCl3. From top to bottom: 2 (purple), 18 h at rt after triphenylphosphine addition
(blue), 22 h after D2O addition (green), 22 h after heating at 40 ꢀC (yellow), and pure 4-aminobutane-
nitrile (1) (red). Signals in solid boxes correspond to the C(4)H2 signal for 2 (purple), and 1 (red). The
C(4)H2 signal for the iminophosphorane intermediate (3) and C(3)H2 signal for all compounds are
marked by black dashed boxes. Changes to the C(2)H2 signal are marked by colored arrows, where
the arrow for 2 is purple, intermediate 3 is black, and 1 is red.
Table 2. Summary of the reduction of 4-azidobutanenitrile (2) to 4-aminobutanenitrile (1) followed
1
by H NMR spectroscopy in CDCl3 at key intervals.
Conditions
Result
Azide 2 (1 equiv.), triphenylphosphine (1 equiv.), and
CDCl3 (700 mL), rt, 18 h
Iminophosphorane intermediate 3 observed by 1H NMR
D2O (2% v/v) added, rt, 22 h
1 and 3 observed in a 2:5 ratio by 1H NMR
1 and 3 observed in a 4:1 ratio by 1H NMR
Reaction increased to 40 ꢀC, 22 h
observed by the lower integration of its assigned C(4)H2 and C(2)H2 resonances at d
3.50 and 1.90 ppm, respectively, compared to the integration of the new resonances
assigned to 3 (d 3.20 and 1.84 ppm). A minor resonance was also observed at d
2.85 ppm (Fig. 2, blue), consistent with the production of a small quantity of 1.
D2O (2% v/v) was next added to the NMR tube to hydrolyze 3 to the desired product
1
1, and the reaction mixture stood at rt for a further 22 h. The H NMR spectrum was
recorded to reveal resonances occurring again at d 3.20 and 1.84 ppm due to C(4)H2
and C(2)H2 of 3, respectively (Fig. 2, green). Two new resonances were observed at d
2.85 and 1.80 ppm and were assigned to C(4)H2 and C(2)H2 of product 1, respectively.
The product 1 and intermediate 3 were present in a ratio of 2:5 based on integration of
the C(4)H2 resonances of 1 and 3.
Finally, the NMR tube reaction was heated at 40 ꢀC for 22 h in an attempt to com-
plete hydrolysis of 3 to 1 (Fig. 2, yellow). This gave rise to further 1, with 1 and 3 now
present in a ratio of 4:1. However, it should be noted that some of azide 2 remained

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unreacted, as shown by the presence of the C(2)H2, C(3)H2, and C(4)H2 resonances for
2 in all spectra through the course of the NMR reaction study.
Based on the results of the NMR spectroscopy study, in a separate reaction, azide 2
was first stirred in anhydrous THF with triphenylphosphine (1 equiv.) for 3 h, then 2%
v/v H2O added and the reaction mixture heated at 40 ꢀC for 18 h. This was done in
order to separate the iminophosphorane formation and hydrolysis steps, as was done in
the NMR study. NMR analysis on this reaction mixture, prior to work up, revealed the
presence of 1 in a 2:5 ratio to 2. Further water, up to a final concentration of 8% v/v
was added and the reaction heated at 40 ꢀC over 72 h in an attempt to complete
hydrolysis of 3 to 1. The reaction mixture was cooled to rt and worked up by the litera-
ture procedure described earlier,[2] to give 1 in 13% yield.
Next, the Staudinger reduction was repeated, using anhydrous pyridine instead of
anhydrous THF, based on the authors’ prior experience with Staudinger reductions per-
formed on similar substrates. Azide 2 was stirred with triphenylphosphine (1.15 equiv.)
in anhydrous pyridine for 3 h, then water was added at 17% v/v and the reaction mix-
ture stirred at rt overnight (Scheme 1, bottom route). In this instance, the reaction mix-
ture was worked up by dilution with water, then
1 separated from the
triphenylphosphine oxide by-product by washing the aqueous mixture with ethyl acet-
ate. Water was removed under reduced pressure to give 1 in a 69% yield. This compares
to a yield of 5% using the reported literature Staudinger conditions.[2] The new workup
removes the need for the aqueous extraction, basification, and organic extraction
required in the literature workup.[2]
This new Staudinger reduction of 2 was next carried out on a larger 26 mmol scale,
given the importance of 1 as a precursor to pyrroline and pyrrolidine. The 14-fold
increased reaction scale required only a 3.3-fold increase in ethyl acetate for work up,
with 1 isolated in 71% yield. A purity of 94% was calculated by qHNMR using the
“100% method” as described by Pauli et al.[12] (see Supplementary Information Fig. S3),
without the need for chromatographic purification.
Stability of 1
A sample of thus prepared 1 (an oil) was stored on the bench for one week at rt, then
1
the H NMR spectrum was collected to reveal multiple new resonances, with those at d
3.51, 2.34, and 1.89 ppm consistent with 2-aminopyrroline (Fig. 3, red arrows).[13] We
propose that 1 cyclizes to give 2-aminopyrroline as has been previously reported for 1
(and the related compound 1,4-butanediamine) under nickel catalyzed hydrogen-
ation,[3,4,14] however, to the best of our knowledge, this is the first report of its occur-
1
rence at rt. The original sample of 1, still dissolved in CDCl3, was re-analyzed by H
NMR after one week and the resultant spectrum was unchanged relative to the first
spectrum obtained (Fig. 3). This sample had thus not cyclized, likely due to the forma-
tion of the hydrochloride salt of 1 due to residual HCl in the CDCl3 (Scheme 2).
The hydrochloride salt of amine 1 (1ꢁHCl) was prepared by bubbling HCl gas
through a solution of 1 (obtained by the new Staudinger reduction conditions) in
chloroform, to give a white precipitate (see Supplementary Information). A gravimetric
titration of 1ꢁHCl with AgNO3 revealed it to be the mono-hydrochloride salt, rather

6
P. K. CAPON ET AL.
Figure 3. Top; Production of 2-aminopyrroline from 4-aminobutanenitrile (1). Bottom; NMR in CDCl3
of 1 freshly synthesized (blue), after a week in CDCl3 solution (green), and after a week on the lab
bench at ambient conditions (red). Peaks corresponding to 2-aminopyrroline[13] are marked by
red arrows.
Scheme 2. Proposed cyclization of 4-aminobutanenitrile (1) to 2-aminopyrroline, and synthesis of the
corresponding hydrochloride salt (1ꢁHCl).
than the di-hydrochloride salt (see Supplementary Information). 1ꢁHCl was also charac-
1
terized by H NMR (Fig. 4, blue), where a broad singlet was observed at d 8.2 ppm and
assigned to the þNH3 group. The methylenes at the C2, C3, and C4 positions were
observed to have shifted downfield relative those of 1. The C(4)H2 resonance for 1ꢁHCl
(2.85 ppm) was also more complex compared to that of 1 (2.55 ppm, see Fig. 4 purple
and blue).
Finally, the stability of 1ꢁHCl was investigated by leaving a sample (solid) exposed to
1
air over 7 days at rt. The sample was analyzed by H NMR, with no changes observed
(Fig. 4, green). The 1ꢁHCl thus has improved stability compared to the free amine and
is as such the preferred method of storage (Scheme 2). The free amine 1 is liberated on
treatment with a base such as triethylamine.

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Figure 4. 1H NMR spectra in DMSO-d6 for 4-aminobutanenitrile (1) as synthesized (purple), with
changes in chemical shift on hydrochloride salt formation highlighted (1ꢁHCl, blue). 1ꢁHCl remains sta-
ble for one week on the lab bench under ambient conditions (green). A –þNH3 resonance was
observed for freshly synthesized 1ꢁHCl (blue) and after one week (green) at 8.1–8.3 ppm, shifted from
2.8 ppm for the –NH2 resonance in 1 (purple). There is a break in the x-axis between 3.9 and
7.9 ppm, with no resonances observed in this range.
Experimental
Synthesis of 4-aminobutanenitrile (1)
Compound 2 (200 mg, 1.82 mmol, 1 equiv.) was dissolved in anhydrous pyridine
(3.64 mL) under a nitrogen atmosphere. Triphenylphosphine (548 mg, 2.09 mmol, 1.15
equiv.) was added and the reaction stirred at rt for 3 h. Water (0.58 mL) was added and
the reaction mixture stirred for a further 16 h at rt. The reaction mixture was diluted
with water (15 mL) and the aqueous mixture was washed with ethyl acetate (3 ꢃ 10 mL).
The solvent was removed under reduced pressure to yield 1 as a colorless oil (106 mg,
1
1
69%). H NMR in CDCl3 was consistent with literature[2]: H NMR (500 MHz, CDCl3)
1
d 2.86 (t, J ¼ 6.7 Hz, 2H), 2.45 (t, J ¼ 7.1 Hz, 2H), 1.87 ꢂ 1.74 (m, 2H) ppm. H NMR
(600 MHz, DMSO-d6) d 2.61 (t, J ¼ 6.7 Hz, 2H), 2.52 (t, J ¼ 7.2 Hz, 2H), 1.61 (p,
J ¼ 6.9 Hz, 2H) ppm. 13C NMR (151 MHz, DMSO-d6) d 120.81, 40.00, 28.34, and
13.64 ppm. FTIR (ATR mode): 3370 (N–H), 3297 (N–H), 3183 (N–H), 2939 (C–H),
2870 (C–H), 2245 (CN), 1599 (N–H) cmꢂ1. HRMS (ESIþ) expected [M þ H]þ 84.0690
for C4H8N2, found 84.0687.
Conclusion
In conclusion, we report an improved synthesis of 4-aminobutanenitrile (1), from
4-azidobutanenitrile (2). The reaction involves treating 2 with triphenylphosphine in
pyridine rather than THF, with the reaction stirred for 3 h to allow for the formation of
the iminophosphorane intermediate (3) prior to the addition of water (17% v/v). The
optimum workup involves dilution with water and washing with ethyl acetate to give a
69% yield of 1. This compares to a yield of 5% using the reported literature Staudinger
conditions.[2] We show that this new procedure is amenable to scale up to 26 mmol of
2, to give 1 in 71% yield at 94% purity without chromatographic purification (qHNMR,

8
P. K. CAPON ET AL.
100% method). Finally, we have also shown that 1 cyclizes to 2-aminopyrroline at rt
over a period of several days. The corresponding hydrochloride salt 1ꢁHCl, prepared by
bubbling HCl(g) through a solution of 1 is however stable and is the preferred form
for storage.
Acknowledgments
The authors acknowledge support from the Australian Research Council Centre of Excellence for
Nanoscale Biophotonics (CE140100003). PKC would like to acknowledge PhD scholarship sup-
port from the MF and MH Joyner Scholarship in Science, and the Norman and Patricia Polglase
Supplementary Scholarship. The authors would like to thank Philip Clements for assistance with
NMR collection and analysis. This work was performed in part at the Optofab node of the
Australian National Fabrication Facility utilizing Commonwealth and SA State
Government funding.
ORCID
Patrick K. Capon
Thomas D. Avery
Malcolm S. Purdey
Andrew D. Abell
http://orcid.org/0000-0002-7396-5757
http://orcid.org/0000-0001-6882-5461
http://orcid.org/0000-0002-5063-8972
http://orcid.org/0000-0002-0604-2629
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