One-pot microwave-promoted synthesis of nitriles from aldehydes via tert-butanesulfinyl imines

Article abstract of DOI:10.1055/s-2007-990805

A facile, one-pot method for the synthesis of nitriles from aldehydes via a microwave-promoted, concerted elimination of tert-butanesulfenic acid from tert-butanesulfinyl-protected imines, is described. The mild reaction conditions exhibit broad functional group compatibility and generate products in good isolated yield (69-87%). This method provides a rapid and mild procedure for the synthesis of various functionalized nitriles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990805

PAPER
3385
One-Pot Microwave-Promoted Synthesis of Nitriles from Aldehydes via
tert-Butanesulfinyl Imines
M
icrowa
v
e
e-Promoted
s
Synthesi
s
s
of
N
itril
i
e
s
ca Tanuwidjaja, Hillary M. Peltier, Jared C. Lewis, Laurie B. Schenkel, Jonathan A. Ellman*
Department of Chemistry, University of California, Berkeley, CA 94720, USA
Fax +1(510)6428369; E-mail: jellman@berkeley.edu
Received 11 April 2007
atures so that the condensation would go to completion
before the reaction mixture was subjected to the higher
temperature required for the elimination step. Using 1.8
equivalents of sulfinamide 1 and employing aldehyde 2a,
Abstract: A facile, one-pot method for the synthesis of nitriles
from aldehydes via a microwave-promoted, concerted elimination
of tert-butanesulfenic acid from tert-butanesulfinyl-protected
imines, is described. The mild reaction conditions exhibit broad
functional group compatibility and generate products in good isolat- it was determined that heating the reaction mixture for 10
ed yield (69–87%). This method provides a rapid and mild proce-
dure for the synthesis of various functionalized nitriles.
minutes at 100 °C was sufficient to drive the condensation
step to completion. Subsequent irradiation of the reaction
Key words: microwave, nitriles, aldehydes, tert-butanesulfin-
amide, tert-butanesulfinyl imine
mixture for 15 minutes at 200 °C promoted complete
elimination of sulfenic acid, giving a 74% isolated yield of
nitrile 4a (entry 6). When these conditions were applied to
the aliphatic hydrocinnamaldehyde 2b, nitrile 4b was pro-
The microwave-promoted conversion of an N-tert-bu- duced in 85% yield (entry 7).
tanesulfinyl imine to a nitrile was initially observed as a
This one-pot, sulfinamide condensation/imine elimination
side reaction in the asymmetric synthesis of a-branched
amines,1 and has since been used in the syntheses of bio-
logically important amine compounds2 (Scheme 1). As il-
lustrated by these syntheses, the tert-butanesulfinyl imine
can be selectively converted to a nitrile in the presence of
a sulfinyl-protected amine and other protected functional-
ities. Herein, we report a general and functional group
compatible, one-pot method for the conversion of alde-
hydes to nitriles using tert-butanesulfinamide. This meth-
od complements previously reported one-pot methods for
the synthesis of nitriles from aldehydes, which employ ei-
ther oxidizing3 or strongly dehydrating4 reaction condi-
tions.
sequence was then carried out on a variety of aldehydes
(2) using either Ti(Oi-Pr)4 or Ti(OEt)4 (Table 2). This se-
a)
O
microwave
15 min
150 °C
H
S
N
CN
H
N
S
N
S
O
MeCN, 78%
O
concd HCl
75 °C
H2N
CO2H
19 h, 100%
trans-2-aminocyclopentanecarboxylic acid
We began our investigation of the sulfinyl condensation/
elimination sequence between tert-butanesulfinamide (1)5
and naphthaldehyde (2a), using Ti(OEt)4 as a Lewis acid
and desiccant (Table 1). Neither the condensation nor the
elimination step went to completion when one equivalent
of sulfinamide 1 was used at 150 °C; 2a, 3a and 4a were
b)
O
O
O
O
1
all observed in the crude H NMR spectrum (entry 1).
microwave
15 min
While moderate increases in either the reaction time or the
temperature did not provide complete conversion to the
product (entries 2 and 3), increasing the temperature to
200 °C for 15 minutes was found to drive both steps to
completion and provided a 57% isolated yield of product
4a (entry 4). Increasing the amount of sulfinamide 1 to 1.8
equivalents, increased the yield of nitrile 4a to 71% (entry
5).
150 °C
O
S
O
S
O
S
CN
O
MeCN
84%
N
N
H
N
O
H
O
O
MeO
O
NH2
In an attempt to further increase the yield of the nitrile
product, the two steps were performed at different temper-
Cl
NH
H
N
SYNTHESIS 2007, No. 21, pp 3385–3389
x
x.
x
x
.
2
0
0
7
SC-53116
Advanced online publication: 21.09.2007
DOI: 10.1055/s-2007-990805; Art ID: M02307SS
Scheme 1 Syntheses of biologically important amine compounds
© Georg Thieme Verlag Stuttgart · New York

3386
J. Tanuwidjaja et al.
PAPER
Table 1 Optimization of Microwave-Promoted Sulfinyl Condensation/Elimination
O
S
S
NH2
OH
1
S
H
Ti(OEt)4, MeCN
O
N
O
N
R
R
H
R
microwave
2a,b
4a,b
3a,b
Entry
1
Aldehyde
R
Temp (°C)
150
Time (min)
15
Equiv of 1
Yield (%)a
b
2a
1.0
–
b
b
2
3
4
5
6
2a
2a
2a
2a
2a
150
30
15
15
15
1.0
1.0
1.0
1.8
1.8
–
–
180
200
57
71
74
200
100 °C (10 min) then 200 °C (15 min)
7
2b
100 °C (10 min) then 200 °C (15 min)
1.8
85
a Yields of analytically pure material after chromatography.
b Isolated yields were not obtained because of the difficulty in separating starting material 2a from nitrile product 4a.
quence was found to be general for aryl, as well as also compatible with molecules containing pyridines, as
branched and unbranched alkyl aldehydes and provided 4d was produced in 59–69% yield (entry 4). This method
rapid access to the desired nitriles (entries 1–3). In gener- can also be employed with aldehydes that contain a-ste-
al, Ti(Oi-Pr)4 provided higher yields for electrophilic aro- reocenters (entry 8). For this chiral aldehyde, the reaction
matic aldehydes (entry 4), while the more Lewis acidic was performed with both enantiomers of tert-butane-
Ti(OEt)4 was more effective for electron-rich aromatic al- sulfinamide, which demonstrated that the enantiomers
dehydes (entry 5). A range of functional groups were also gave comparable yields. No epimerization of the a-stereo-
found to be compatible with this method. Notably, the pri- center was observed in either case under the reaction
mary amide present in aldehyde 2f did not dehydrate dur- conditions.
ing the microwave-assisted elimination (entry 6).
Aldehyde 2g, which contains an ester functionality, pro-
vided nitrile 4g in 71% yield (entry 7). This procedure was
Table 2 Preparation of Nitriles 4 from Aldehydes 2
O
S
S
NH2
OH
1
S
H
O
Ti(OEt)4, MeCN
N
O
N
R
R
H
R
microwave
2a–h
4a–h
3a–h
Entry
1
Aldehyde
R
Nitrile
Yield (%)a of 4 using Ti(Oi-Pr)4 Yield (%)a of 4 using Ti(OEt)4
2a
2b
4a
4b
82
82
74
85
2
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Microwave-Promoted Synthesis of Nitriles
3387
Table 2 Preparation of Nitriles 4 from Aldehydes 2 (continued)
O
S
S
NH2
OH
1
S
O
Ti(OEt)4, MeCN
N
O
N
R
R
H
R
H
microwave
2a–h
4a–h
3a–h
Entry
3
Aldehyde
R
Nitrile
Yield (%)a of 4 using Ti(Oi-Pr)4 Yield (%)a of 4 using Ti(OEt)4
2c
2d
2e
4c
4d
4e
73
69
60
78
59
87
4
5
N
O
6
2f
4f
77
–
H2N
O
O
7
8
2g
2h
4g
4h
71
–
O
OBn
60b
72–76b,c
a Yields of analytically pure material after chromatography.
b The product formed in >99% ee, as determined by HPLC analysis.
c The (R)- and (S)-enantiomers of tert-butanesulfinamide provided the desired product in 72% and 76% yields, respectively.
mixtures were performed on a Daicel CHIRALCEL OJ (4.6 by 250
In summary, reaction conditions have been developed for
the efficient conversion of aldehydes to nitriles. Stepwise
heating for 10 minutes at 100 °C, followed by 15 minutes
at 200 °C, enabled both the condensation and elimination
steps to go to completion. Notably, this method can be ap-
plied to substrates containing moieties such as ethers,
amides, esters and heterocycles. a-Stereocenters do not
racemize under the reaction conditions. Considering the
usefulness of the nitrile functionality, as well as the facile
nature of this procedure, this method should find wide use
in a variety of syntheses.
mm) column with UV detection at 210 and 254 nm. Microwave re-
actions were conducted in either 2 mL or 5 mL microwave vials
(Biotage No. 352016 or 351521) and heated in a Biotage Initiator
microwave reactor. Elemental analyses were performed by the Uni-
versity of California at Berkeley Micro-Mass Facility.
General Procedure
tert-Butanesulfinamide (1.8 equiv) and aldehyde (1.0 equiv, if sol-
id) were added to a microwave vial, which was then crimped closed.
The reaction vessel was flushed with N2. Lewis acid (2.0 equiv),
aldehyde (1.0 equiv, if liquid) and MeCN (made up to 0.4 M, with
respect to sulfinamide) were added under a N2 atmosphere. The re-
action mixture was stirred for 10 min. After a 30 s pre-stirring peri-
od inside the instrument, the sample was exposed to microwave
irradiation for 10 min at 100 °C, immediately followed by a 15 min
irradiation at 200 °C, using the fixed hold time option. The pressure
in the vial was released before opening by puncturing the cap with
a needle. The crude reaction mixture was filtered through a suitably
sized SPE cartridge, rinsing with a total of 40 mL EtOAc. The fil-
trate was concentrated and the product was purified by silica gel
chromatography (n-pentane–CH2Cl2).
MeCN was distilled from CaH2 prior to use. Aldehydes were ob-
tained from commercial suppliers and were purified prior to use.
Chromatography was carried out either with Merck 60 Å, 230–400
mesh silica gel or via normal-phase HPFC purification on a Biotage
SP1 instrument (Charlottesville, VA) equipped with a Biotage Si
flash column. Reactions were carried out in flame- or oven-dried
glassware under a N2 atmosphere. IR spectra were recorded on a
Nicolet Avatar 360 FTIR spectrometer equipped with an attenuated
total reflectance accessory; only partial data are listed. 1H NMR and
13C NMR spectra were obtained at r.t. in CDCl3 unless otherwise in-
dicated. Chemical shifts (d) are expressed in ppm relative to solvent.
Coupling constants are reported in Hz. HPLC analyses of racemic
2-Cyanonaphthalene (4a)
2-Naphthaldehyde was recrystallized from MeOH prior to use. The
general procedure was followed with a 0.4 M solution of (R)-1 (145
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3388
J. Tanuwidjaja et al.
PAPER
mg, 1.20 mmol, 1.8 equiv), Ti(Oi-Pr)4 (0.405 mL, 1.33 mmol, 2.0
equiv) and 2-naphthaldehyde (104 mg, 0.667 mmol, 1.0 equiv).
Column chromatography (n-pentane–CH2Cl2, 70:30), afforded 4a
as a light-brown solid (83.4 mg, 82%).
chromatography (n-pentane–CH2Cl2, 70:30) afforded 4e as a brown
crystalline solid (53.2 mg, 60%).
When Ti(Oi-Pr)4 was replaced by Ti(OEt)4 (0.322 mL, 1.33 mmol,
2.0 equiv), the general procedure describe above afforded 4e as a
brown crystalline solid (77.0 mg, 87%).
Mp 58–59 °C (Lit.4b 59 °C).
1H NMR (500 MHz): d = 3.86 (s, 3 H), 6.95 (d, J = 7.0 Hz, 2 H),
7.59 (d, J = 8.0 Hz, 2 H).
All analytical data were in agreement with literature data.4b
When Ti(Oi-Pr)4 was replaced by Ti(OEt)4 (0.322 mL, 1.33 mmol,
2.0 equiv), the general procedure describe above afforded 4a as a
light-brown solid (74.2 mg, 74%).
Mp 63–65 °C (Lit.6 64–66 °C).
1H NMR (400 MHz): d = 7.60–7.67 (m, 3 H), 7.89–7.94 (m, 3 H),
8.25 (s, 1 H).
All analytical data were in agreement with literature data.6
4-Cyanobenzamide (4f)
4-Formylbenzamide was prepared as previously reported12 and pu-
rified by chromatography on basic alumina (MeOH–EtOAc,
5:95→20:80) prior to use. The general procedure was followed
with a 0.4 M solution of (R)-1 (164 mg, 1.35 mmol, 1.8 equiv),
Ti(Oi-Pr)4 (0.470 mL, 1.50 mmol, 2.0 equiv) and 4-formylbenz-
amide (112 mg, 0.752 mmol, 1.0 equiv). Column chromatography
(MeOH–EtOAc, 5%) afforded 4f as a brown solid (84.7 mg, 77%).
Hydrocinnamonitrile (4b)
Hydrocinnamaldehyde was distilled from anhydrous CaSO4 prior to
use. The general procedure was followed with a 0.4 M solution of
(R)-1 (145 mg, 1.20 mmol, 1.8 equiv), Ti(Oi-Pr)4 (0.405 mL, 1.33
mmol, 2.0 equiv) and hydrocinnamaldehyde (0.0980 mL, 0.741
mmol, 1.0 equiv). Column chromatography (n-pentane–CH2Cl2,
70:30) afforded 4b as a brown oil (79.6 mg, 82%).
Mp 218–221 °C (Lit.13 224–226 °C).
When Ti(Oi-Pr)4 was replaced by Ti(OEt)4 (0.322 mL, 1.33 mmol,
2.0 equiv), the general procedure describe above afforded 4b as a
brown oil (82.5 mg, 85%).
1H NMR (400 MHz, DMSO-d6): d = 7.68 (br s, 1 H), 7.95 (d, J = 8.4
Hz, 2 H), 8.01 (d, J = 8.4 Hz, 2 H), 8.22 (br s, 1 H).
1H NMR (400 MHz): d = 2.63 (t, J = 7.2 Hz, 2 H), 2.97 (t, J = 7.2
4-(Isopropyloxycarbonyl)benzonitrile (4g)
4-(Isopropyloxycarbonyl)benzaldehyde was prepared as previously
reported.14
Hz, 2 H), 7.23–7.36 (m, 5 H).
All analytical data were in agreement with literature data.7
Mp 47–48 °C.
Adamantane-1-carbonitrile (4c)
IR (thin film): 1709, 1722, 2939, 2981 cm–1.
1-Adamantanecarbaldehyde was prepared as previously reported
and purified by chromatography on basic alumina (hexanes) prior to
use. The general procedure was followed with a 0.4 M solution of
(R)-1 (145 mg, 1.20 mmol, 1.8 equiv), Ti(Oi-Pr)4 (0.405 mL, 1.33
mmol, 2.0 equiv) and 1-adamantanecarbaldehyde (109 mg, 0.666
mmol, 1.0 equiv). Column chromatography (n-pentane–CH2Cl2,
70:30) afforded 4c as a colorless solid (78.4 mg, 73%).
1H NMR (400 MHz): d = 1.40 (d, J = 6.4 Hz, 6 H), 5.29 (sept,
J = 6.4 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 2 H), 8.19 (d, J = 8.0 Hz, 2 H),
10.10 (s, 1 H).
13C NMR (100 MHz): d = 22.1, 69.4, 129.7, 130.3, 136.1, 139.2,
165.3, 192.0.
Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.80; H,
6.44.
When Ti(Oi-Pr)4 was replaced by Ti(OEt)4 (0.322 mL, 1.33 mmol,
2.0 equiv), the general procedure describe above afforded 4c as a
colorless oil (83.7 mg, 78%).
Mp 184–187 °C (Lit.9 185–187 °C).
1H NMR (400 MHz): d = 1.70–1.77 (m, 6 H), 2.00–2.08 (m, 9 H).
All analytical data were in agreement with literature data.10
The general procedure was followed with a 0.4 M solution of (R)-1
(195 mg, 1.61 mmol, 1.8 equiv), Ti(Oi-Pr)4 (0.544 mL, 1.79 mmol,
2.0 equiv) and 4-(isopropyloxycarbonyl)benzaldehyde (172 mg,
0.895 mmol, 1.0 equiv). Column chromatography (n-pentane–
CH2Cl2, 55:45) afforded 4g as a brown solid (120 mg, 71%).
Mp 49–51 °C.
IR (thin film): 1710, 2228 cm–1.
4-Pyridinecarbonitrile (4d)
4-Pyridinecarboxaldehyde was passed through a plug of basic alu-
mina (activity I) prior to use. The general procedure was followed
with a 0.4 M solution of (R)-1 (263 mg, 2.16 mmol, 1.8 equiv),
Ti(Oi-Pr)4 (0.710 mL, 2.40 mmol, 2.0 equiv) and 4-pyridinecarbox-
aldehyde (0.120 mL, 1.20 mmol, 1.0 equiv). Column chromatogra-
phy (EtOAc–hexanes, 6→50%) afforded 4d (90.0 mg, 69%) as a
brown solid.
1H NMR (500 MHz): d = 1.39 (d, J = 6.0 Hz, 6 H), 5.28 (sept,
J = 6.5 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 2 H), 8.13 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz): d = 22.1, 69.7, 116.3, 118.3, 130.2, 132.3,
134.9, 164.6.
Anal. Calcd for C11H11NO2: C, 69.83; H, 5.86; N, 7.40. Found: C,
69.49; H, 6.00; N, 7.14.
When Ti(Oi-Pr)4 was replaced by Ti(OEt)4 (0.500 mL, 2.40 mmol,
2.0 equiv), the general procedure describe above afforded 4d as a
brown solid (77.4 mg, 59%).
Mp 75–77 °C (Lit.11 78–79 °C).
1H NMR (400 MHz): d = 7.54 (d, J = 5.8 Hz, 2 H), 8.83 (d, J = 5.8
Hz, 2 H).
2-Benzyloxypropionitrile (4h)
(–)-(S)-2-(Benzyloxy)propanal was prepared following a literature
procedure.15 The general procedure was followed with a 0.4 M so-
lution of (R)-1 (65.4 mg, 0.540 mmol, 1.8 equiv), Ti(Oi-Pr)4 (0.180
mL, 0.600 mmol, 2.0 equiv) and (–)-(S)-2-(benzyloxy)propanal
(50.1 mg, 0.300 mmol, 1.0 equiv). Column chromatography
(CH2Cl2–hexanes, 90:10) afforded 4h as a colorless oil (29.0 mg,
60%).
All analytical data were in agreement with literature data.11
4-Methoxybenzonitrile (4e)
When Ti(Oi-Pr)4 was replaced by Ti(OEt)4 (0.150 mL, 0.600 mmol,
2.0 equiv), the general procedure describe above afforded 4h as a
colorless oil (38.4 mg, 72%).
p-Anisaldehyde was distilled from CaSO4 prior to use. The general
procedure was followed with a 0.4 M solution of (R)-1 (145 mg,
1.20 mmol, 1.8 equiv), Ti(Oi-Pr)4 (0.405 mL, 1.33 mmol, 2.0 equiv)
and p-anisaldehyde (0.0809 mL, 0.667 mmol, 1.0 equiv). Column
Synthesis 2007, No. 21, 3385–3389 © Thieme Stuttgart · New York

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Microwave-Promoted Synthesis of Nitriles
3389
HPLC analysis (Diacel Chiralpak OJ column; hexanes–IPA, 99:1;
1.0 mL/min) indicated >99% ee; t1 = 16.3 min (major), t2 = 22.7
min (minor).
1H NMR (400 MHz, CCl4, TMS): d = 1.54 (d, J = 6.8 Hz, 3 H), 4.12
(q, J = 6.8 Hz, 1 H), 4.48 (d, J = 12 Hz, 1 H), 4.81 (d, J = 12 Hz,
1 H), 7.29 (m, 5 H).
(5) (a) For a review on tert-butanesulfinamide-based methods,
see: Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 984. (b) For a general review on sulfinyl imine
chemistry, see: Morton, D.; Stockman, R. A. Tetrahedron
2006, 62, 8869. (c) For a review on the synthesis and
applications of sulfinamides, see: Senanayake, C. H.;
Krishnamurthy, D.; Lu, Z.-H.; Zhengxu, H.; Gallou, I.
Aldrichimica Acta 2005, 38, 93. (d) For a general review on
additions to arenesulfinyl imines, see: Zhou, P.; Chen, B.-C.;
Davis, F. A. Tetrahedron 2004, 60, 8003.
(6) Hughes, T. V.; Cava, M. P. J. Org. Chem. 1999, 64, 313.
(7) Blay, G.; Cardona, L.; Garcia, B.; Lahoz, L.; Pedro, J. R.
Tetrahedron 1996, 52, 8611.
(8) Takeuchi, K.; Kitagawa, I.; Akiyama, F.; Shibata, T.; Kato,
M.; Okamoto, K. Synthesis 1987, 612.
All analytical data were in agreement with literature data.16
Acknowledgment
This work was supported by the National Science Foundation
(CHE-0446173). J.T. thanks the Department of Chemistry at the
University of California at Berkeley for an Undergraduate Summer
Research Award, and H.M.P. thanks Eli Lilly for a graduate student
fellowship.
(9) Olah, G. A.; Farooq, O.; Prakash, G. K. S. Synthesis 1985,
1140.
(10) Mlinaric-Majerski, K.; Margeta, R.; Veljkovic, J. Synlett
2005, 2089.
(11) Lee, K.; Han, S.-B.; Yoo, E.-M.; Chung, S.-R.; Oh, H.;
Hong, S. Synth. Commun. 2004, 34, 1775.
(12) Meisenbach, M.; Allmendinger, T.; Mak, C.-P. Org. Process
Res. Dev. 2003, 7, 553.
(13) Ohashi, M.; Miyake, K.; Tsujimoto, K. Bull. Chem. Soc. Jpn.
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McCoull, W.; McNulty, A. M.; Neubauer, B. L.; Pritchard,
G. J. J. Med. Chem. 2001, 44, 1491.
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Synthesis 2007, No. 21, 3385–3389 © Thieme Stuttgart · New York