A chemoselective, one-pot transformation of aldehydes to nitriles

Article abstract of DOI:10.1021/jo301133y

This paper describes a procedure for direct conversion of aldehydes to nitriles using O-(diphenylphosphinyl)hydroxylamine (DPPH). Aldehydes are smoothly transformed to their corresponding nitriles by heating with DPPH in toluene. The reaction can be accomplished in the presence of alcohol, ketone, ester, or amine functionality.

Full text of DOI:10.1021/jo301133y

Note
pubs.acs.org/joc
A Chemoselective, One-Pot Transformation of Aldehydes to Nitriles
Sebastien Laulhe, Sadakatali S. Gori, and Michael H. Nantz*
́
́
Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States
S
* Supporting Information
ABSTRACT: This paper describes a procedure for direct conversion of aldehydes to
nitriles using O-(diphenylphosphinyl)hydroxylamine (DPPH). Aldehydes are smoothly
transformed to their corresponding nitriles by heating with DPPH in toluene. The
reaction can be accomplished in the presence of alcohol, ketone, ester, or amine
functionality.
he preparation of nitriles by transformation of carbon-
equivalent functional groups is an important synthetic
route to these versatile intermediates and valued target
pharmacophores.1 Among the most popular approaches is the
oxidation-state neutral conversion of carboxylic acids to nitriles
via dehydration of intermediate primary amides (Figure 1) either
activated oxime ester as an intermediate (e.g., 1, Scheme 1), we
reasoned that it should be possible to thermally induce an
T
Scheme 1
Figure 1. Common functional group interconversions to prepare
nitriles.
electrocyclic rearrangement resulting in the elimination of
diphenylphosphinic acid. A similar mechanism involving
elimination of methanesulfonic acid has been proposed for
formation of nitriles from intermediate sulfonylated aldoximes.7
Although DPPH is well appreciated as an electrophilic reagent
for the amination of a variety of nucleophiles,8 including
Grignard reagents,9 enols,10 or for amination of tertiary amines
in syntheses of aziridines from α,β-unsaturated carbonyl
substrates,11 its use as a nucleophilic counterpart, especially in
chemoselective “click” transformations, has received limited
attention.12 To test the action of DPPH as a suitable reagent for
oxime ester formation as well as the subsequent elimination to
the nitrile, we examined the reaction between DPPH and α-
naphthaldehyde (Scheme 1).
While presently not commercially available, DPPH can be
readily prepared in good yield in one step from commercially
available diphenylphosphinic chloride and hydroxylamine hydro-
chloride.13 Reaction of DPPH with naphthaldehyde in THF gave
oxime ester 1 in 79% yield. Subsequent heating in toluene
revealed that the elimination of diphenylphosphinic acid from 1
required warming to above 80 °C to achieve a significant rate of
formation of naphthonitrile (2). Of particular note is that no
using traditional dehydrating reagents2 or recently developed
metal-mediated procedures.3 An efficient complement to amide
dehydration is the oxidative transformation of aldehydes to
nitriles. Isolation of aldoxime intermediates (Figure 1) generally
is followed by activation of the oxime hydroxyl group (e.g., as a
sulfonate ester derivative) and then its elimination to afford the
nitrile.4 The appeal of this approach has led to several one-pot
methods for direct synthesis of nitriles from aldehydes using
either hydroxylamine or ammonia in combination with a variety
of activating reagents.5
Unfortunately, the accompanying reagents for these one-pot
approaches, such as CuCl2/NaOMe/O2,5a Pb(OAc)4,5b Ox-
one,5e H2O2,5h I2,5i NBS,5j IBX,5k and NaICl2,5l often are not
tolerant of other functional groups or require somewhat harsh
conditions to effect the transformation. Ideally, an aldehyde-
selective reagent that would facilitate the conversion to the nitrile
under neutral conditions would greatly expand the utility of this
direct approach. We report here the use of O-
(diphenylphosphinyl)hydroxylamine (DPPH) as such a reagent.
Our interest in aminooxy chemistry6 led us to consider the use
of DPPH (Ph2P(O)ONH2) as a possible chemoselective
alternative to hydroxylamine or ammonia for introduction of
nitrogen onto the carbonyl carbon of aldehydes. Since the
reaction of this reagent with an aldehyde would directly form an
Received: June 6, 2012
Published: August 28, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
a
Table 1. Conversion of Aldehydes to Nitriles Using Ph2P(O)ONH2
a
All reactions were performed in toluene at 85 °C for 4−6 h on ≥0.5 mmol scale using 1.15 equiv of reagent (method A), 2.0 equiv of reagent at 95
b
°C for 12 h (method B), or 1.15 equiv of reagent and 1.1 equiv of trifluoroacetic acid at 95 °C for 12 h (method C). Chromatographed (SiO2)
yield. Boc = tert-butyloxycarbonyl; TBS = tert-butyldimethylsilyl.
Lewis acid or base was required to effect the elimination, rather
simple warming under catalyst- and oxidant-free conditions was
sufficient to afford 2 in 88% yield.
We next examined the possibility of transforming aldehydes
directly into nitriles without isolation of the oxime ester adducts.
Despite the partial solubility of DPPH in toluene, we were
pleased to find that its reactions with a diverse panel of aldehydes
in toluene gave good yields of the corresponding nitriles on
heating at 85 °C (Table 1). The conversions to the nitriles
proceeded smoothly for aromatic as well as aliphatic aldehydes
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Note
room temperature was added DPPH (0.366 g, 1.57 mmol) in one
portion. The resulting suspension was stirred at room temperature for 3
h and then gradually warmed over 45 min to 95 °C. After heating at 95
°C for 12 h, the reaction was allowed to cool to room temperature and
then diluted by addition of EtOAc (20 mL) and saturated aq NaHCO3
to dissolve the precipitated diphenylphosphinic acid. The layers were
separated, and the organic layer was washed successively with saturated
aq NaHCO3 and brine (2 × 10 mL). The aqueous layer was extracted
with EtOAc (2×). The combined organic layer was dried (Na2SO4). The
solvents were removed by rotary evaporation, and the crude residue was
purified by column chromatography (SiO2), eluting with hexane/ethyl
acetate (2:1, v/v; Rf = 0.33) to afford 4-hydroxybenzonitrile (72 mg, 78%
yield) as a yellow solid: mp 111−113 °C, having spectral characteristics
in agreement with published data;16 1H NMR (CDCl3, 700 MHz) δ 7.55
(d, J = 8.4 Hz, 2 H), 6.91 (d, J = 8.4 Hz, 2 H), 5.78 (s, 1 H); 13C NMR
(CDCl3, 100 MHz) δ 159.9, 134.3, 119.2, 116.4, 103.3.
Preparation of 3-Pyridinecarbonitrile (Entry 11, Method C).
To 3-pyridinecarboxaldehyde (0.10 g, 0.93 mmol) in toluene (5 mL) at
room temperature was added trifluoroacetic acid (72 μL, 1 mmol). After
the mixture was stirred for 5 min, DPPH (0.250 g, 1.07 mmol) was
added in one portion. The resulting suspension was stirred at room
temperature for 3 h and then gradually warmed over 45 min to 95 °C.
After heating at 95 °C for 12 h, the reaction was allowed to cool to room
temperature and then diluted by addition of EtOAc (15 mL) and
saturated aq NaHCO3 to dissolve the precipitated diphenylphosphinic
acid. The layers were separated, and the organic layer was washed
successively with saturated aq NaHCO3 and brine (2 × 10 mL). The
aqueous layer was extracted with EtOAc (2×) and DCM (2×). The
combined organic layer was dried (Na2SO4). The solvents were
removed by rotary evaporation, and the crude residue was purified by
column chromatography (SiO2), eluting with CH2Cl2/hexane/ethyl
acetate (7:2:1, v/v; Rf = 0.34) to afford 3-pyridinecarbonitrile (60 mg,
64% yield) as a white solid, mp 49.1−50.2 °C, having spectral
characteristics in agreement with published data:17 1H NMR (CDCl3,
400 MHz) δ 8.90 (s, 1 H), 8.83 (d, J = 4.8 Hz, 1 H), 7.98 (d, J = 8 Hz, 1
H), 7.45 (dd, J = 4.8, 8.0 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ
153.2, 152.7, 139.4, 123.7, 116.7, 110.3.
Polar Solvent Procedure: Preparation of 3-Phenylpropioni-
trile. To 3-phenylpropionaldehyde (0.70 g, 0.52 mmol) in water (8 mL)
at room temperature was added DPPH (0.14 g, 0.60 mmol) in one
portion. The resulting suspension was stirred at room temperature for 3
h and then gradually warmed over 45 min to 95 °C. After heating at 95
°C for 12 h, the reaction was cooled to room temperature and extracted
with EtOAc (2 × 10 mL) and Et2O (10 mL). The combined organic
layer was washed with brine (10 mL) and then dried (Na2SO4). The
solvents were removed by rotary evaporation, and the crude residue was
purified by column chromatography (SiO2), eluting with hexane/ethyl
acetate (2:1, v/v; Rf = 0.55) to afford 3-phenylpropionitrile (50 mg, 73%
yield) as a yellow oil, having spectral characteristics in agreement with
published data:18 1H NMR (400 MHz) δ 7.34 (t, J = 7.2 Hz, 2 H), 7.27
(t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.2 Hz, 3 H), 2.96 (t, J = 7.6 Hz, 2 H), 2.61
(t, J = 7.6 Hz, 2 H); 13C NMR (100 MHz) δ 138.2, 129.0, 128.5, 127.4,
119.3, 31.7, 19.5.
Ethyl 2-(3-cyano-1H-indol-1-yl)acetate (entry 14): light yellow
solid; mp 96.5−98 °C; 1H NMR (CDCl3, 400 MHz) δ 7.78 (d, J = 7.6
Hz, 1 H), 7.62 (s, 1 H), 7.34−7.30 (m, 3 H), 4.87 (s, 1 H), 4.25 (q, J = 7.2
Hz, 2 H), 4.25 (q, J = 7.2 Hz, 3 H); 13C NMR (CDCl3, 100 MHz) δ
167.2, 135.9, 135.6, 127.8, 124.5, 122.7, 120.3, 115.6, 110.2, 87.5, 62.5,
48.3, 14.2; IR (cm−1) 2223, 1740; FT-ICR-MS (ESI+, m/z) calcd for
C13H12N2O2, [M + Na]+ 251.0791, found 251.0791.
and accommodated α,β-unsaturation. Importantly, the aminooxy
group of DPPH afforded a measure of chemoselectivity that
enabled the selective, one-pot transformation of aldehydes to
nitriles in the presence of other carbonyl groups, such as ketone,
ester (including acetate), and carbamate carbonyls. While in
some cases the transformation of electron-rich aldehydes
required an additional equivalent of reagent for better overall
conversion (entries 3 and 5), the vinylogous formamide carbonyl
of entry 14 was only sluggishly transformed into the
corresponding nitrile even when using excess reagent. Given
that diphenylphosphinic acid (pKa 2.32)14 is produced during
the course of the reaction, we examined the aldehyde to nitrile
conversion in the presence of acid-sensitive N-Boc and silyl ether
protection groups. Whereas the Boc group was not affected
(entries 12 and 13), the TBS ether was cleaved during the
reaction (entry 15). In the entry 15 example, the initially formed
desilylated product, 4-hydroxybutyronitrile (isolated in 13%
yield), partially cyclized under the reaction conditions to
generate γ-butyrolactone (ca. 10% yield) after workup. Attempts
to buffer the reaction by addition of non-nucleophilic bases (e.g.,
Na2CO3) did not prevent loss of the silyl group. Since DPPH
readily reacts with amines,8b−d,11 we noted that an acidification
strategy, as in the case of 3-pyridinecarboxaldehyde (entry 11),
improved the overall conversion to the nitrile, presumably by in
situ pyridinium formation preventing electrophilic amination of
the pyridine nitrogen. Finally, as a probe to see whether the
process could be adapted to polar protic, more green solvents, we
examined the reaction of 3-phenylpropionaldehyde with DPPH
in water and found that heating at 95 °C for 12 h afforded the
corresponding nitrile in 73% yield. In addition, heating 3-
pyridinecarboxaldehyde and DPPH in acetic acid as solvent
under similar conditions gave 3-pyridinecarbonitrile in 60%
yield.
In conclusion, the present method is applicable for the one-pot
conversion of aldehydes to nitriles in the presence of water,
alcohols, and other carbonyl functionalities. DPPH is sufficiently
selective in its reactions with aldehyde carbonyl groups that
chemoselection is achieved on simple mixing at room temper-
ature followed by warming to effect the transformation to the
nitrile. Ease of reaction, good yields, and the absence of base or
oxidant are other features of this method.
EXPERIMENTAL SECTION
■
Typical Procedures for One-Pot Aldehyde to Nitrile Trans-
formation: Preparation of trans-Cinnamonitrile (Entry 8,
Method A). To trans-cinnamaldehyde (0.13 g, 1.0 mmol) in toluene
(5 mL) at room temperature was added DPPH (0.267 g, 1.15 mmol) in
one portion. The resulting suspension was stirred at room temperature
for 3 h and then gradually warmed over 45 min to 85 °C. The reaction
mixture became clear as the temperature reached 80 °C. After being
heated at 85 °C for 5 h, the reaction was allowed to cool to room
temperature and then diluted by addition of Et2O (20 mL) and satd aq
NaHCO3 to dissolve precipitated diphenylphosphinic acid. The layers
were separated, and the organic layer was washed successively with
saturated aq NaHCO3 and brine (2 × 10 mL). The aqueous layer was
extracted with EtOAc (2×). All of the organic layers were combined and
then dried (Na2SO4). The solvents were removed by rotary evaporation,
and the crude residue was purified by column chromatography (SiO2,
hexane/ethyl acetate, 2:1 v/v, Rf = 0.62) to afford trans-cinnamonitrile
(105 mg, 81%) as a light yellow oil with spectroscopic data in agreement
with published15 values: 1H NMR (400 MHz, CDCl3) δ 7.46−7.38 (m,
6 H), 5.90 (d, J = 16.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 150.5,
133.5, 131.2, 129.1, 127.33, 118.11, 96.3.
1-Naphthaldehyde O-diphenylphosphoryl oxime (1): gum; 1H
NMR (CDCl3, 400 MHz) δ 9.04 (s, 1 H), 8.34 (d, J = 8.8 Hz, 1 H),
8.00−7.95 (m, 4 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.84 (d, J = 7.6 Hz, 1 H),
7.71 (d, J = 7.2 Hz, 1 H), 7.59−7.43 (m, 9H); 13C NMR (CDCl3, 100
MHz) δ 158.1, 158.0, 133.8, 132.6, 132.4, 132.3, 131.1, 130.6, 129.9,
129.8, 128.8, 128.7, 228.6, 127.8, 126.5, 126.3, 125.2, 125.0; 31P NMR
(CDCl3, 162 MHz) δ 35.60; FT-ICR-MS (ESI+, m/z) calcd for
C23H18NO2P, [M + Na]+ 394.0967, found 394.0976.
Preparation of 4-Hydroxybenzonitrile (Entry 3, Method B).
To 4-hydroxybenzaldehyde (0.09 g, 0.78 mmol) in toluene (5 mL) at
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Note
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all nitrile products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: michael.nantz@louisville.edu.
Notes
■
́
(13) Laulhe, S.; Nantz, M. H. Org. Prep. Proc. Int. 2011, 43, 475−476.
(14) Miyatake, K.; Hay, A. S. J. Polym. Sci., Part A: Polym. Chem. 2001,
39, 1854−1859.
The authors declare no competing financial interest.
(15) Li, Y.-T.; Liao, B.-S.; Chen, H.-P.; Liu, S.-T. Synthesis 2011, 16,
2639−2643.
ACKNOWLEDGMENTS
■
(16) Molander, G. A.; Cavalcanti, L. N. J. Org. Chem. 2011, 76, 623−
This work was partially supported by a grant from the Kentucky
Science and Engineering Foundation (KSEF-148-502-10-270).
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